ORCID Profile
0000-0002-5965-9876
Current Organisation
Royal Brisbane and Women's Hospital
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Publisher: Elsevier BV
Date: 04-2009
Publisher: American Society for Microbiology
Date: 09-2010
DOI: 10.1128/AAC.00222-10
Abstract: The objective of the present prospective pharmacokinetic study was to describe the variability of plasma gentamicin concentrations in critically ill patients with acute kidney injury (AKI) necessitating extended daily diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently perform Monte Carlo dosing simulations to determine which dose regimen achieves the pharmacodynamic targets the most consistently. We collected data from 28 gentamicin doses in 14 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma s les were collected. A population pharmacokinetic model was used to describe the pharmacokinetics of gentamicin and perform Monte Carlo simulations with doses of between 3 mg/kg of body weight and 7 mg/kg and at various time points before commencement of EDD-f to evaluate the optimal dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic model adequately described the gentamicin clearance while patients were on and off EDD-f. The plasma half-life of gentamicin during EDD-f was 13.8 h, whereas it was 153.4 h without EDD-f. Monte Carlo simulations suggest that dosing with 6 mg/kg every 48 h either 30 min or 1 h before the commencement of EDD-f results in 100% attainment of the target maximum concentration drug in plasma ( mg/liter) and sufficient attainment of the target area under the concentration-time curve from 0 to 24 h (AUC 0-24 70 to 120 mg·h/liter). None of the simulated dosing regimens satisfactorily achieved the targets of the minimum concentrations of drug in plasma ( .0 mg/liter) at 24 h. In conclusion, dosing of gentamicin 30 min to 1 h before the commencement of an EDD-f treatment enables attainment of target peak concentrations for maximal therapeutic effect while enhancing drug clearance to minimize toxicity. Redosing in many patients should occur after 48 h, and we recommend the use of therapeutic drug monitoring to guide dosing to optimize achievement of the AUC 0-24 targets.
Publisher: American Society for Microbiology
Date: 02-2016
DOI: 10.1128/AAC.02461-15
Abstract: The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) was significantly higher than the median ISF AUC 0–24 (340.4 versus 141.1 mg · h/liter P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78 P = 0.106). Both minimum and the maximum concentrations of drug in serum ( C max and C min ) showed a significant correlation with the fluconazole plasma exposure ( C max , R 2 = 0.86, P 0.0001 C min , R 2 = 0.75, P 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.IJANTIMICAG.2006.08.031
Abstract: Sepsis and nosocomial infections continue to be a significant problem in intensive care, contributing heavily to mortality and prolonged hospital stay. Early and appropriate antibiotic therapy is critical for optimising outcomes. However, the emergence of highly resistant bacteria, coupled with reduced development of novel antibiotics, means that there is a real threat of development of untreatable nosocomial infections. Cefepime and ceftazidime are broad-spectrum cephalosporins that are widely used to treat Gram-negative nosocomial infections in critically ill patients. Available data suggest that cefepime may have advantages over ceftazidime owing to a broader spectrum of activity and reduced potential for development of bacterial resistance. However, whether either of these agents is superior can only be determined by a head-to-head study evaluating clinical and bacteriological outcomes. Such a study to determine whether apparent differences translate into clinically relevant differences in outcome is indicated.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2017
Publisher: American Chemical Society (ACS)
Date: 24-03-2022
Publisher: Wiley
Date: 09-2009
DOI: 10.1002/J.2055-2335.2009.TB00457.X
Abstract: In vitro studies suggest that administering beta‐lactam antibiotics by continuous infusion may maximise efficacy. Several pharmacokinetic studies have compared the distribution of beta‐lactam antibiotics administered by continuous and bolus dosing in plasma and tissues. Knowledge of pharmacokinetic exposure to tissues is essential, as tissue sites are most commonly the ‘target site’ for antibiotic therapy. To identify published studies that measure the serum and tissue concentrations of beta‐lactam antibiotics administered by continuous and bolus dosing. Data sources: A number of studies in animals, healthy volunteers and hospitalised patients were identified. More prospective clinical trials are required to validate that the continuous infusion of beta‐lactam antibiotics attain better tissue distribution at the target site. Beta‐lactam antibiotics administered by continuous infusion maintain higher concentrations in serum and tissue. There is also compelling evidence that tissue distribution of antibiotics is impaired with increased sickness severity, therefore, larger doses of beta‐lactam antibiotics may be required in severely sick patients to optimise antibiotic exposure at the target site.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC10262
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2010
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.IJANTIMICAG.2007.02.002
Abstract: Continuous infusion of beta-lactam antibiotics has been widely promoted to optimise their time-dependent activity. Increasing evidence is emerging suggesting potential benefits in patient populations with altered pathophysiology, such as seriously ill patients. From a pharmacokinetic viewpoint, much information supports higher trough concentrations of beta-lactam antibiotics when administered by continuous infusion. This advantage of continuous infusion translates into a superior ability to achieve pharmacodynamic targets, particularly when the minimum inhibitory concentration (MIC) of the pathogen is >or=4 mg/L. One drawback of continuous infusion may be limited physicochemical stability. This issue exists particularly for carbapenem antibiotics whereby prolonged infusions (i.e. >3h) can be used to improve the time above the MIC compared with conventional bolus dosing. Few studies have examined clinical outcomes of bolus and continuous dosing of beta-lactam antibiotics in seriously ill patients. No statistically significant differences have been shown for: mortality time to normalisation of leukocytosis or pyrexia or duration of mechanical ventilation, intensive care unit stay or hospital stay. Some evidence suggests improved clinical cure and resolution of illness with continuous infusion in seriously ill patients. Pharmacoeconomic advantages of continuous infusion of beta-lactam antibiotics are well characterised. Available data suggest that seriously ill patients with severe infections requiring significant antibiotic courses (>or=4 days) may be the subgroup that will achieve better outcomes with continuous infusion.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2011
Abstract: Surgical site infections are common, so effective antibiotic concentrations at the sites of infection are required. Surgery can lead to physiological changes influencing the pharmacokinetics of antibiotics. The aim of the study is to evaluate contemporary peri-operative prophylactic dosing of cefazolin by determining plasma and subcutaneous interstitial fluid concentrations in patients undergoing elective of semi-elective abdominal aortic aneurysm (AAA) open repair surgery. This is an observational pharmacokinetic study of patients undergoing AAA open repair surgery at the Royal Brisbane and Women's Hospital. All patients will be administered 2-g cefazolin by intravenous injection within 30-minutes of the procedure. Participants will have s les from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration by cefazolin. Participants will be administered indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes occurring during surgery. Analysis of s les will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine in idual and population pharmacokinetic parameters and the effect of peri-operative physiological changes on cefazolin disposition. The study will describe cefazolin levels in plasma and the interstitial fluid of tissues during AAA open repair surgery. The effect of physiological changes to the patient mediated by surgery will also be determined. The results of this study will guide clinicians and pharmacists to effectively dose cefazolin in order to maximize the concentration of antibiotics in the tissues which are the most common site of surgical site infections.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1991
DOI: 10.1097/00003246-199109000-00012
Abstract: To compare six disease severity scoring systems as predictors of mortality in septic shock when used in the first 24 hrs of diagnosis. The six scoring systems tested were: Multiorgan Failure the Acute Organ System Failure the Acute Physiology and Chronic Health Evaluation (APACHE II) the Multisystem Organ Failure scoring system the Mortality Prediction Model and the grading of sepsis. Retrospective, case series, consecutive s le. Adult ICUs of three teaching hospitals. Seventy-one patients from 12 to 84 yrs, fulfilling specific criteria for the diagnosis of septic shock, who were admitted to the ICU during 15 consecutive months. The Multiorgan Failure scoring system, Acute Physiology and Chronic Health Evaluation (APACHE II), and Acute Organ System Failure scoring system were found, with our modifications, to be statistically significant predictors of mortality. Predictive data for these three scoring systems were as follows: Multiorgan Failure scoring system p = .008, mean number of points of survivors 5.2 +/- 1.5 (SD), mean number of points of nonsurvivors 6.3 +/- 1.5 APACHE II p = .013, mean number of points of survivors 21.1 +/- 5.9, mean number of points of nonsurvivors 24.6 +/- 6.0 and Acute Organ System Failure scoring system p = .011. None of the other three scoring systems showed significant predictive ability: Multisystem Organ Failure scoring system p = .072, Mortality Prediction Model p = 0.091, and the grading of sepsis p = .27. There was a significant (p = .004) difference in the survival rate of the three hospitals. The Multiorgan Failure scoring system, APACHE II, and the Acute Organ System Failure scoring system, with minor modifications, were found to be useful prognostic tools for patients with septic shock and allowed us to compare the performance and treatment programs of different ICUs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2012
DOI: 10.2215/CJN.12211211
Abstract: Peritonitis is a major infectious complication in peritoneal dialysis patients, and intraperitoneal antibiotic administration is preferred to ensure maximal antibiotic concentrations at the site of infection. This study aimed to describe the plasma and infection site pharmacokinetics of intraperitoneal gentamicin in patients with peritonitis. This prospective pharmacokinetic study of intraperitoneal gentamicin was conducted in peritoneal dialysis patients presenting to hospital with clinically defined signs and symptoms of peritonitis. Twenty-four patients were administered a 0.6-mg/kg dose of intraperitoneal gentamicin, which was allowed to dwell for 6 hours. Serial blood and dialysate s les were collected for 24 hours after the first dose. Gentamicin concentrations in plasma and dialysate were measured using a validated assay. The median percentage of the dose absorbed into the systemic circulation was 76% (interquartile range=69%–82%) and significantly different between patients with low average, high average, and high peritoneal membrane transporter status ( P =0.03). The calculated pharmacokinetic parameters were plasma terminal elimination half-life of 24.7 (20.4–29.9) hours, terminal volume of distribution of 0.30 (0.20–0.36) L/kg, observed peak plasma concentration of 3.1 (2.4–3.4) mg/L, and observed trough plasma concentration of 1.9 (1.4–2.2) mg/L. The peak gentamicin concentration in dialysate was at least eight times the minimum inhibitory concentration of the likely pathogens. The high systemic absorption of gentamicin in patients with peritonitis and prolonged plasma elimination half-life may lead to drug accumulation in the systemic circulation, increasing the risk of toxicity.
Publisher: IOP Publishing
Date: 20-04-2012
Publisher: Wiley
Date: 02-1994
DOI: 10.1111/J.1365-2044.1994.TB03371.X
Abstract: We describe three critically ill patients receiving pressure-controlled ventilation who suffered acute hypotensive episodes associated with the development of tension pneumothoraces. In four documented episodes of tension pneumothorax a major decrease in cardiac index was the most consistently detected abnormality. The expected increases in central venous pressure and heart rate did not occur in three of the episodes in two of the patients, both of whom were receiving inotropic therapy. Any increases in airway pressure could not be assessed on pressure-controlled ventilation. The physiology of tension pneumothorax in the ventilated patient is described and the importance of decreased cardiac index as a haemodynamic indicator of tension pneumothorax is discussed.
Publisher: Oxford University Press (OUP)
Date: 27-04-2009
DOI: 10.1093/JAC/DKP139
Abstract: To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units. We randomized 10 patients with sepsis to receive meropenem by intermittent bolus administration (n = 5 1 g 8 hourly) or an equal dose administered by continuous infusion (n = 5). Serial subcutaneous tissue concentrations were determined using microdialysis and compared with plasma data for first-dose and steady-state pharmacokinetics. Population pharmacokinetic modelling of plasma data and Monte Carlo simulations were then undertaken with NONMEM. It was found that continuous infusion maintains higher median trough concentrations, in both plasma (intermittent bolus 0 versus infusion 7 mg/L) and subcutaneous tissue (0 versus 4 mg/L). All simulated intermittent bolus, extended and continuous infusion dosing achieved 100% of pharmacodynamic targets against most Gram-negative pathogens. Superior obtainment of pharmacodynamic targets was achieved using administration by extended or continuous infusion against less susceptible Pseudomonas aeruginosa and Acinetobacter species. This is the first study to compare the relative concentration-time data of bolus and continuous administration of meropenem at the subcutaneous tissue and plasma levels. We found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing. Administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction.
Publisher: Bentham Science Publishers Ltd.
Date: 05-2012
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.IJANTIMICAG.2010.02.013
Abstract: The substantial underlying disease burden, in combination with the therapeutic interventions provided, can result in significantly altered end-organ function in the critically ill. These changes can in turn affect key pharmacokinetic (PK) indices for many antibiotics, including drug clearance, promoting potentially subtherapeutic concentrations for lengthy periods of the dosing interval, therapeutic failure or the selection of resistant organisms. This paper presents three instructional cases from our tertiary-level Intensive Care Unit, where established antibiotic dosing regimens failed to achieve predefined PK targets for optimal bacterial killing. Using therapeutic drug monitoring (TDM), significant dose modification was subsequently undertaken. We propose augmented renal clearance as a possible mechanism underlying this phenomenon, particularly in young post-operative, burns or head-injured patients with normal serum creatinine concentrations. TDM, or at least a measured creatinine clearance, should be considered early in this setting to allow the optimisation of antibiotic exposure.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.IJANTIMICAG.2013.07.012
Abstract: The purpose of this paper was to review the potential utility of icillin/sulbactam (SAM) as a therapy for serious infections in critically ill patients. Data for this review were identified by searches of PubMed and of the reference lists of the included articles. We found that SAM appears to have a number of characteristics that support its use in the treatment of serious infections in critically ill patients. SAM demonstrates extensive penetration into many infection sites, supporting its use in a wide range of infection types. Microbiologically, sulbactam has strong intrinsic antibiotic activity against multidrug-resistant (MDR) bacteria, including Acinetobacter baumannii, which supports its use for the treatment of infections mediated by this pathogen. Of some concern, there have been reports showing a decline in susceptibility of some bacteria to SAM. As such, use of lower doses (4/2g/day), particularly for MDR A. baumannii, has been linked with a 30% reduced success rate in critically ill patients. The therapeutic challenges for ensuring achievement of optimal dosing of SAM result partly from bacterial susceptibility but also from the pharmacokinetic (PK) alterations common to β-lactam agents in critical illness. These PK changes are likely to reduce the ability of standard dosing to achieve the concentrations observed in non-critically ill patients. Optimisation of therapy may be more likely with the use of higher doses, administration by 4h infusion or by combination therapy, particularly for the treatment of infections caused by MDR pathogens.
Publisher: American Society for Microbiology
Date: 08-2016
DOI: 10.1128/AAC.00531-16
Abstract: Severe pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index (BMI) groups: nonobese (18.5 to 29.9 kg/m 2 ), obese (30.0 to 39.9 kg/m 2 ), and morbidly obese (≥40 kg/m 2 ). Serial plasma s les were taken, and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Nineteen critically ill patients with different BMI categories were enrolled. The patients' mean ± standard deviation (SD) age, weight, and BMI were 49 ± 15.9 years, 95 ± 22.0 kg, and 33 ± 7.0 kg/m 2 , respectively. A two-compartment model described the data adequately. The mean ± SD parameter estimates for the final covariate model were as follows: clearance (CL), 15.5 ± 6.0 liters/h volume of distribution in the central compartment ( V 1 ), 11.7 ± 5.8 liters intercompartmental clearance from the central compartment to the peripheral compartment, 25.6 ± 35.1 liters h −1 and intercompartmental clearance from the peripheral compartment to the central compartment, 8.32 ± 12.24 liters h −1 . Higher creatinine clearance (CL CR ) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increased V 1 , dose adjustment based on CL CR appears to be more important than patient BMI.
Publisher: Oxford University Press (OUP)
Date: 27-05-2014
DOI: 10.1093/CID/CIU403
Publisher: Oxford University Press (OUP)
Date: 04-2013
DOI: 10.1093/CID/CIT201
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC10274
Publisher: Wiley
Date: 02-2011
DOI: 10.1111/J.1553-2712.2010.00976.X
Abstract: The objective was to determine whether prior statin use is associated with lower mortality in emergency patients admitted with infection. A prospective observational study was conducted at the emergency department (ED) of a tertiary adult hospital with an annual census of over 73,000 patients. Patients presenting to the ED who were subsequently hospitalized with a primary diagnosis of infection were identified within 24 hours of presentation. Data were abstracted from patients' charts and from hospital electronic databases. Patients were stratified according to reported regular statin use on presentation. The outcome measure was in-hospital mortality truncated at 30 days. An association between statin use and mortality was sought using logistic regression analysis. Data were collected over a 60-week period from 2,642 admissions. Patients taking a statin on admission had a higher unadjusted mortality risk (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.32 to 3.46) compared to those not on a statin. However, this result became nonsignificant (OR = 0.96, 95% CI = 0.55 to 1.69) after adjusting for age, severity of disease, comorbid status, and propensity score. These data do not support an independent association between current preadmission statin use and lower 30-day in-hospital mortality in emergency patients admitted with infection. This result is contrary to most previously published studies.
Publisher: Public Library of Science (PLoS)
Date: 17-12-2015
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.JCHROMB.2010.05.027
Abstract: A simple and economical high performance liquid chromatography method was developed and validated for routine analysis of 12 Penicillin, Cephalosporin and Carbapenem antibiotics in 200 microL of human plasma. Antibiotics determined were Ceftazidime, Meropenem, Ceftriaxone, Ampicillin, Cefazolin, Ertapenem, Cephalothin, Benzylpenicillin, Flucloxacillin, Dicloxacillin, Piperacillin and Ticarcillin. There was a common s le preparation approach involving precipitation of proteins with acetonitrile and removal of lipid-soluble components by a chloroform wash. Separations were performed on a Waters X-bridge C18 column with, depending on analytes, one of three acetonitrile-phosphate buffer mobile phases. Detection was by UV at 210, 260 and 304 nm. Validation has demonstrated the method to be linear, accurate and precise. The method has been used in a pathology laboratory for therapeutic drug monitoring (TDM) of beta-lactams in critically ill patients.
Publisher: S. Karger AG
Date: 2008
DOI: 10.1159/000148400
Abstract: i Background/Aims: /i The optimal dose of renal replacement therapy (RRT) in acute renal failure (ARF) is uncertain. i Methods: /i The Randomized Evaluation of Normal versus Augmented Level Replacement Therapy Trial tests the hypothesis that higher dose continuous veno-venous hemodiafiltration (CVVHDF) at an effluent rate of 40 ml/kg/h will increase survival compared to CVVHDF at 25 ml/kg/h of effluent dose. i Results: /i This trial is currently randomizing critically ill patients in 35 intensive care units in Australia and New Zealand with a planned s le size of 1,500 patients. This trial will be the largest trial ever conducted on acute blood purification in critically ill patients. i Conclusion: /i A trial of this magnitude and with demanding technical requirements poses design difficulties and challenges in the logistics, conduct, data collection, data analysis and monitoring. Our report will assist in the development of future trials of blood purification in intensive care. This study was registered with ClinicalTrials.gov (NCT00221013).
Publisher: Springer Science and Business Media LLC
Date: 15-09-2009
DOI: 10.1007/S00134-009-1619-9
Abstract: To assess the generalisability of published clinical risk predictive models for invasive candidiasis in ICU patients. The performance characteristics of published clinical risk factor-only and Candida colonisation-only predictive models for invasive candidiasis were assessed in a multicentre cohort of Australian ICU patients. Clinical risk factors and Candida colonisation parameters were collected prospectively from patients. The two clinical risk factor-only predictive models applied to an Australian patient cohort (n = 615) performed less well than in published studies involving derivation populations. Model performance characteristics improved when Candida colonisation parameters were added post-hoc. Risk predictive models should factor in both clinical risk factors and Candida colonisation parameters. Integrating these models into therapeutic algorithms first requires external validation in different patient populations and settings.
Publisher: American Society for Microbiology
Date: 06-2011
DOI: 10.1128/AAC.01708-10
Abstract: Despite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m 2 would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.
Publisher: American Society for Microbiology
Date: 08-2016
DOI: 10.1128/AAC.00828-16
Abstract: The objective of this study was to describe amikacin pharmacokinetics (PK) in critically ill patients receiving equal doses (30 ml/kg of body weight/h) of continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF). Patients receiving amikacin and undergoing CVVH or CVVHDF were eligible. Population pharmacokinetic analysis and Monte Carlo simulation were undertaken using the Pmetrics software package for R. Sixteen patients (9 undergoing CVVH, 11 undergoing CVVHDF) and 20 s ling intervals were analyzed. A two-compartment linear model best described the data. Patient weight was the only covariate that was associated with drug clearance. The mean ± standard deviation parameter estimates were 25.2 ± 17.3 liters for the central volume, 0.89 ± 1.17 h −1 for the rate constant for the drug distribution from the central to the peripheral compartment, 2.38 ± 6.60 h −1 for the rate constant for the drug distribution from the peripheral to the central compartment, 4.45 ± 2.35 liters/h for hemodiafiltration clearance, and 4.69 ± 2.42 liters/h for hemofiltration clearance. Dosing simulations for amikacin supported the use of high dosing regimens (≥25 mg/kg) and extended intervals (36 to 48 h) for most patients when considering PK harmacodynamic (PD) targets of a maximum concentration in plasma ( C max )/MIC ratio of ≥8 and a minimal concentration of ≤2.5 mg/liter at the end of the dosing interval. The mean clearance of amikacin was 1.8 ± 1.3 liters/h by CVVHDF and 1.3 ± 1 liters/h by CVVH. On the basis of simulations, a strategy of an extended-interval high loading dose of amikacin (25 mg/kg every 48 h) associated with therapeutic drug monitoring (TDM) should be the preferred approach for aminoglycoside treatment in critically ill patients receiving continuous renal replacement therapy (CRRT). (This study is a substudy of a trial registered at ClinicalTrials.gov under number NCT01403220.)
Publisher: Springer Science and Business Media LLC
Date: 26-11-2018
Publisher: Springer Science and Business Media LLC
Date: 12-12-2010
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.JPBA.2015.07.013
Abstract: Quantification of fosfomycin in the plasma s les of patients is the basis of clinical pharmacokinetic studies from which evidence based dosing regimens can be devised to maximise antibiotic effectiveness against a pathogen. We have developed and validated a LC-MS/MS method to quantify fosfomycin using dried plasma spot s ling. Following HILIC chromatography, fosfomycin and ethylphosphonic acid, used as internal standard, were measured using negative-ion multiple reaction monitoring. The method was linear over the calibration range of 5-2000mg/L of fosfomycin. Intra-day assay results for dried plasma spot quality control s les at 15.6, 79.9 and 1581mg/L of fosfomycin had precision of ±4.2, 8.2, and 2.0%, respectively, and accuracy of +3.9, -0.1, and -1.2%, respectively. Recovery of fosfomycin from dried plasma spots was calculated as 83.6% and the dried plasma spot s les were found to be stable stored at room temperature for three months and when stored for four hours at 50°C. A Bland-Altman plot comparing DPS to plasma s ling found a negative bias of 16.6%, with all but one s le within the mean limits of agreement (-2.6 to 30.6%). Dried plasma spot s ling provides a useful tool for pharmacokinetic research of fosfomycin.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.IJANTIMICAG.2015.04.013
Abstract: Vancomycin is a glycopeptide antibiotic widely used in the management of meticillin-resistant Staphylococcus aureus (MRSA). Guidelines currently recommend vancomycin be administered by intermittent infusion, despite recent research suggesting that continuous infusion (CI) may be associated with lower rates of vancomycin-associated nephrotoxicity. In 2012, Cataldo et al. presented a meta-analysis supporting the use of CI. Here we present an updated meta-analysis, inclusive of a recently published large-scale retrospective study. PubMed, EMBASE and Cochrane Reviews databases were searched using the keywords 'vancomycin' and 'continuous' or 'intermittent' or 'infusion' or 'discontinuous' or 'administration'. Seven studies were included in the final analysis. Using a random-effects model, a non-significant trend of reduced nephrotoxicity in those who received vancomycin by CI (risk ratio=0.799, 95% confidence interval 0.523-1.220 P=0.299) was identified. A large, randomised controlled trial is necessary to confirm these results.
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.IJANTIMICAG.2007.09.013
Abstract: Plasma exchange (PE) is a treatment modality frequently used for many autoimmune diseases and may cause extracorporeal elimination of antibiotics. No data currently exist on antibiotic concentrations in extracellular fluid during PE. The aim of this study is to describe the effect of PE on the serum and subcutaneous tissue pharmacokinetics of piperacillin administered as a continuous infusion in a critically ill 17-year-old patient with Guillain-Barré syndrome and ventilator-associated pneumonia on Days 1 and 4 of antibiotic therapy. The effect of PE on piperacillin concentrations appears to be small. On Day 1, an estimated 7% of total piperacillin eliminated during PE was attributable to PE. On Day 4 this was estimated to be 11%. Using the in vivo s ling technique microdialysis, we have been able to show that a small redistribution of piperacillin from tissue to serum occurs in response to the reducing serum concentrations caused by PE. In critically ill patients, we believe that administration of a beta-lactam antibiotic by continuous infusion should be considered to maintain serum and tissue concentrations of these time-dependent antibiotics.
Publisher: Springer Science and Business Media LLC
Date: 26-01-2011
Publisher: Springer Science and Business Media LLC
Date: 28-03-2015
Publisher: Oxford University Press (OUP)
Date: 16-01-2014
DOI: 10.1093/JAC/DKT523
Abstract: Emerging evidence supports the use of therapeutic drug monitoring (TDM) of β-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for β-lactam TDM in ICUs. A questionnaire survey was developed to describe various aspects relating to the conduct of β-lactam TDM in an ICU setting. Data sought included: β-lactams chosen for TDM, inclusion criteria for selecting patients, blood s ling strategy, analytical methods, pharmacokinetic (PK) harmacodynamic (PD) targets and dose adjustment strategies. Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the β-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of β-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT>MIC up to 100% fT>4×MIC) and dose adjustment strategies used by each of the sites. Large variations were found in the type of β-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing β-lactam dosing with TDM.
Publisher: Springer Berlin Heidelberg
Date: 09-09-2012
Publisher: American Chemical Society (ACS)
Date: 25-01-2023
Publisher: Informa UK Limited
Date: 03-05-2016
DOI: 10.1080/17425255.2016.1178238
Abstract: Clinical pharmacokinetic studies of antibiotics can establish evidence-based dosing regimens that improve the likelihood of eradicating the pathogen at the site of infection, reduce the potential for selection of resistant pathogens, and minimize harm to the patient. Innovations in small volume s ling (< 50 μL) or 'micros ling' may result in less-invasive s le collection, self-s ling and dried storage. Micros ling may open up opportunities in patient groups where s ling is challenging. The challenges for implementation of micros ling to assure suitability of the results, include: acceptable study design, regulatory agency acceptance, and meeting bioanalytical validation requirements. This manuscript covers various micros ling methods, including dried blood lasma spots, volumetric absorptive micros ling, capillary micros ling, plasma preparation technologies and solid-phase microextraction. The available analytical technology is being underutilized due to a lack of bridging studies and validated bioanalytical methods. These deficiencies represent major impediments to the application of micros ling to antibiotic pharmacokinetic studies. A conceptual framework for the assessment of the suitability of micros ling in clinical pharmacokinetic studies of antibiotics is provided. This model establishes a 'contingency approach' with consideration of the antibiotic and the type and location of the patient, as well as the more prescriptive bioanalytical validation protocols.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.IJANTIMICAG.2014.09.009
Abstract: The objective of this study was to describe the pharmacokinetics of meropenem, administered by continuous infusion (CI) or intermittent bolus (IB), in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and to evaluate the frequency of pharmacokinetic harmacodynamic target attainment with each dosing strategy. This was a prospective, randomised controlled trial in critically ill patients receiving CVVH and administered meropenem by CI or IB. Serial meropenem concentrations in plasma and ultrafiltrate were measured after administration of a standard total daily dose (4 g/day on Day 1, followed by 3g/day thereafter) on two occasions during antibiotic therapy. Meropenem pharmacokinetic parameters were calculated using a non-compartmental approach. Sixteen critically ill patients receiving CVVH concurrently treated with meropenem were randomised to CI (n = 8) or IB dosing (n = 8). IB administration resulted in higher maximum concentrations (C(max)) [64.7 (58.9-80.3) and 64.8 (48.5-81.8) mg/L, respectively] on both s ling occasions compared with CI (P < 0.01 and P = 0.04, respectively). CI resulted in a higher meropenem steady-state concentration (Css) on occasion 1 [26.0 (24.5-41.6) mg/L] compared with the minimum concentration (C(min)) observed for IB patients [17.0 (15.7-19.8)mg/L P 4× the targeted susceptibility breakpoint (2mg/L) for 100% of the dosing interval, for both groups, on both occasions. CI could be an alternative to IB for meropenem administration in critically ill patients receiving CVVH.
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Elsevier BV
Date: 05-2011
Abstract: Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS significantly alters the patient's physiology, but the effects of these variations on pharmacokinetics have not been reviewed concisely. Therefore, the aims of this article are to summarize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main findings of this review are that the two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, "front-loaded" doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, maintenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction.
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 02-0007
Abstract: This report illustrates the difficulty in managing CNS infection in neurosurgical patients, the altered drug pharmacokinetics associated with critical illness, and the role that therapeutic drug monitoring (TDM) of CSF can play in assisting clinical decision making. The authors present a case of external ventricular drain–related ventriculitis in a critically ill patient who initially presented with a subarachnoid hemorrhage. They discuss the physiological changes found in such patients, in particular augmented renal clearance (demonstrated in this patient by a measured creatinine clearance of 375 ml/min/1.73 m 2 ), noting the effect this had on drug pharmacokinetics and leading to dosing requirements 2–3 times those recommended in standard regimens. The authors consider the bacterial “kill” characteristics of 2 different antibacterial agents (meropenem and vancomycin) and describe the unique approach of using plasma and CSF TDM to achieve optimal drug exposure at the site of infection while limiting toxic side effects. The authors demonstrate that simply using plasma TDM as a surrogate marker for drug concentration in the CNS may lead to underdosing, exemplified in this patient by CSF vancomycin concentrations as little as 13% of that in plasma. Finally, by measuring CSF and plasma ratios, the authors illustrate the disparity in pharmacokinetic properties between drugs, reminding the clinician of the importance of CNS penetration when selecting antibacterial agents in such cases. This work raises an important hypothesis in the accurate prescription of antibacterial agents in neurosurgical critical care, namely underdosing in the context of augmented elimination and impaired target site penetration. However, prior to any recommendations regarding empirical dose modification, more data are clearly needed, particularly with respect to the safety and efficacy of such an approach. In this respect, the authors would advocate further research using TDM in the management of CNS infection in this setting, in addition to work defining plasma and CSF concentrations associated with antibacterial efficacy and toxicity.
Publisher: Springer Science and Business Media LLC
Date: 10-2016
DOI: 10.1007/S00134-016-4577-Z
Abstract: Sepsis is a major growing global burden and a major challenge to intensive care clinicians, researchers, guideline committee members and policy makers, because of its high and increasing incidence and great pathophysiological, molecular, genetic and clinical complexity. In spite of recent progress, short-term mortality remains high and there is growing evidence of long-term morbidity and increased long-term mortality in survivors of sepsis both in developed and developing countries. Further improvement in the care of patients with sepsis will impact upon global health. In this narrative review, invited experts describe the expected challenges and progress to be made in the near future. We focus on diagnosis, resuscitation (fluids, vasopressors, inotropes, blood transfusion and hemodynamic targets) and infection (antibiotics and infection biomarkers), as these areas are key, if initial management and subsequent outcomes are to be improved in patients with sepsis.
Publisher: Cambridge University Press (CUP)
Date: 07-2015
DOI: 10.1016/J.EURPSY.2015.01.006
Abstract: To review the psychometric properties of the questionnaires commonly filled in by children and adolescents to measure circadian preference. We examined the Morningness-Eveningness Questionnaire for Children and Adolescents (MEQ-CA), the Morningness-Eveningness Scale for Children (MESC) and the Composite Scale of Morningness (CSM). We critically analyzed the reliability, in term of internal consistency (through the Cronbach's alpha) and test-retest reliability (through the correlation coefficient), and the type of validation against external criteria (objective assessment of the sleep/wake cycle, body temperature, hormones and other questionnaires). Fifty studies that reported these data were included in the review: 7 studies used the MEQ-CA, 28 used the MESC and 15 used the CSM. The percentage of studies reporting at least acceptable levels of internal consistency was high and similar between the three questionnaires. Evidence for test-retest reliability was scant, since only 3 studies were available it was at least acceptable for the MESC (two studies with a time interval of 1 month), not acceptable for the MEQ-CA (one study with a time interval of 6 months), while no information was available for the CSM. As regards the validation evidence, the MEQ-CA has been validated by the highest number of external criteria (actigraphy, oral body temperature and other questionnaires), followed by the CSM (cortisol s ling and other questionnaires). The MESC has been validated only against self-report measures. The present state of the art would suggest the use of the MEQ-CA to assess circadian preference in children and adolescents.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2012
Abstract: The pharmacokinetics of beta-lactam antibiotics in intensive care patients may be profoundly altered due to the dynamic, unpredictable pathophysiological changes that occur in critical illness. For many drugs, significant increases in the volume of distribution and/or variability in drug clearance are common. When “standard” beta-lactam doses are used, such pharmacokinetic changes can result in subtherapeutic plasma concentrations, treatment failure, and the development of antibiotic resistance. Emerging data support the use of beta-lactam therapeutic drug monitoring (TDM) and in idualized dosing to ensure the achievement of pharmacodynamic targets associated with rapid bacterial killing and optimal clinical outcomes. The purpose of this work was to describe the pharmacokinetic variability of beta-lactams in the critically ill and to discuss the potential utility of TDM to optimize antibiotic therapy through a structured literature review of all relevant publications between 1946 and October 2011. Only a few studies have reported the utility of TDM as a tool to improve beta-lactam dosing in critically ill patients. Moreover, there is little agreement between studies on the pharmacodynamic targets required to optimize antibiotic therapy. The impact of TDM on important clinical outcomes also remains to be established. Whereas TDM may be theoretically rational, clinical studies to assess utility in the clinical setting are urgently required.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2012
Abstract: There is controversy over whether traditional intermittent bolus dosing or continuous infusion of beta-lactam antibiotics is preferable in critically ill patients. No significant difference between these two dosing strategies in terms of patient outcomes has been shown yet. This is despite compelling in vitro and in vivo pharmacokinetic harmacodynamic (PK/PD) data. A lack of significance in clinical outcome studies may be due to several methodological flaws potentially masking the benefits of continuous infusion observed in preclinical studies. In this review, we explore the methodological shortcomings of the published clinical studies and describe the criteria that should be considered for performing a definitive clinical trial. We found that most trials utilized inconsistent antibiotic doses and recruited only small numbers of heterogeneous patient groups. The results of these trials suggest that continuous infusion of beta-lactam antibiotics may have variable efficacy in different patient groups. Patients who may benefit from continuous infusion are critically ill patients with a high level of illness severity. Thus, future trials should test the potential clinical advantages of continuous infusion in this patient population. To further ascertain whether benefits of continuous infusion in critically ill patients do exist, a large-scale, prospective, multinational trial with a robust design is required.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1989
DOI: 10.1097/00003246-198910000-00023
Abstract: Raltegravir is a recently, Food and Drug Administration-approved, small-molecule drug that inhibits retroviral integrase, thereby preventing HIV DNA from inserting itself into the human genome. We report here that the activity profile of raltegravir on the replication of murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role. While NZW and BALB/c mice, which do not succumb to autoimmune disease, are not affected by raltegravir, lupus-prone (NZBxNZW) F(1) mice die of glomerulonephritis more than a month earlier than untreated mice. Raltegravir-treated NZB mice, which share the H-2 haplotype with BALB/c mice, but which are predisposed to autoimmune hemolytic anemia, develop auto-antibodies to their red blood cells >3 months earlier than untreated mice of the same strain. Because nonautoimmune mice are not affected by raltegravir, we consider off-target effects unlikely and attribute the exacerbation of autoimmunity to the inhibition of retroviral integrase.
Publisher: Bentham Science Publishers Ltd.
Date: 12-2011
DOI: 10.2174/138920111798808248
Abstract: Intensive care medicine deals with the critically ill these patients usually have multiple organ failure, and complex medical conditions. The mortality in Australia and New Zealand among this population is approximately 16.1%, with approximately 24.2% having existing co-morbidities, and 23.4% of these patients experiencing sepsis or septic shock. Sepsis is a clinical syndrome that traditionally was regarded as a physiological maladaptive response to a foreign pathogen and ranges in disease severity from simple sepsis to septic shock, a life threatening condition, associated with multiple organ failure. Sepsis has profound effects on all systems of the body, and most notably the cardiovascular, renal and hepatic systems. There has been much research into the septic critically ill patient and recent developments in basic pharmacology and physiology has yielded results applicable to clinical practice. Sepsis may induce a state of increased cardiac output, which has significant effects on drug pharmacokinetics and pharmacodynamics. This increased cardiac output increases both renal and hepatic blood flow, and alters rates of antibiotic metabolism, and excretion. There are also alterations in the fluid compartments of the septic critically ill, that results in an altered volume of distribution, and ultimately decreased antibiotic concentrations at their site of action. This article will examine and review in detail the septic critically ill patient, and the effects that sepsis has on physiology and the resulting altered antibiotic pharmacokinetics and pharmacodynamics. Current knowledge suggests that the medical prescriber should be weary of antibiotic dosing in the septic critically ill, and consider alternative dosing regimes that are in idualized to the patient in order to maximize efficacy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1984
DOI: 10.1097/00003246-198403000-00002
Abstract: Long-term (greater than 48 h) sodium nitroprusside (SNP) infusion significantly reduced cobalamin (vitamin B12) levels in 23 patients treated in a CCU after myocardial infarction. There was no evidence of vitamin B12 deficiency or SNP toxicity. Low vitamin B12 levels should not limit the use of SNP, because prolonged infusion of SNP at maximum doses of 2.5 micrograms/kg X min did not adversely affect hemodynamic stability.
Publisher: Wiley
Date: 11-1992
DOI: 10.1111/J.1365-2044.1992.TB03199.X
Abstract: We report on a Jehovah's Witness who had severe blood loss following major trauma. The problems of her management without blood transfusion, and with the use of recombinant human erythropoietin therapy for severe anaemia, are described.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2017
Publisher: Informa UK Limited
Date: 14-06-2018
DOI: 10.1080/17425255.2018.1484452
Abstract: Some special patient populations (e.g. critically ill, burns, hematological malignancy, post-major surgery, post-major trauma) have characteristics that lead to higher rates of failure and mortality associated with infection. Choice of effective antibiotics and optimized doses are challenging in these patients that are commonly infected by multidrug-resistant pathogens. Areas covered: A review of the importance of diagnosis and the place of newer microbiological methods (e.g. whole-genome sequencing) to ensure rapid transition from empiric to directed antibiotic therapy is provided. The effects of pathophysiological changes on antibiotic pharmacokinetics are also provided. Expert opinion: Product information dosing regimens do not address the pharmacokinetic alterations that can occur in special patient populations and increase the likelihood of therapeutic failure and the emergence of bacterial resistance. Altered dosing approaches, supplemented with the use of dosing software and therapeutic drug monitoring, may be needed to ensure optimal antibiotic exposure and better therapeutic outcomes in these patients with severe infection. Dose optimization needs to be coupled with advanced microbiological techniques that enable rapid microbiological identification and characterization of resistance mechanism to ensure that maximally effective directed therapy can be chosen.
Publisher: BMJ
Date: 07-2017
Publisher: Wiley
Date: 24-04-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1987
Publisher: MDPI AG
Date: 30-01-2020
DOI: 10.3390/MICROORGANISMS8020191
Abstract: Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.IJANTIMICAG.2014.08.013
Abstract: Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60-80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood s les were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration-time curve (AUC0-24) were 2.1L/h and 152 mg·h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6h) compared with previous reports of 33-38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0-24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was 200mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f.
Publisher: Oxford University Press (OUP)
Date: 06-07-2010
DOI: 10.1093/JAC/DKQ267
Publisher: MDPI AG
Date: 20-12-2021
DOI: 10.3390/ANTIBIOTICS10121559
Abstract: Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC 11.9 and Cmax/MIC 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p 0.05). Mean bioavailability for ICU patients was -times higher than outpatients (p 0.0001). Clearance and volume of distribution were 93% (p 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.
Publisher: Wiley
Date: 08-1997
DOI: 10.1111/J.1365-2044.1997.173-AZ0307.X
Abstract: We prospectively investigated the effect of conventional resuscitation on gastric intramucosal pH and lactate over 5 days in a group of patients with newly diagnosed severe sepsis. Lactate and gastric intramucosal pH were measured on entry into the study, as soon as resuscitation end points were met, eight hourly for 48 h and daily for 5 days. Sixteen of 18 patients had a low gastric intramucosal pH (mean (SD) 7.17 (0.12)) at the time of diagnosis of severe sepsis. At no time did gastric intramucosal pH or lactate distinguish between shocked and nonshocked patients. Lactate distinguished survivors from nonsurvivors over time (p = 0.02). Gastric intramucosal pH did not distinguish survivors from nonsurvivors over time (p = 0.72). At 48 h lactate was lower in survivors (p < 0.01) and gastric intramucosal pH higher in survivors (p < 0.05). Receiver operating characteristic curves at this time indicate that lactate is a better predictor of survival. It is likely, based on the inability of gastric intramucosal pH to distinguish survivors from nonsurvivors until 48 h, that it is not possible to use this measurement to guide resuscitation in patients who are severely ill and who have gastric intramucosal acidosis.
Publisher: Springer Science and Business Media LLC
Date: 05-03-2020
Publisher: American Society for Microbiology
Date: 05-2017
DOI: 10.1128/AAC.02642-16
Abstract: Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MIC meropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼10 7.5 CFU/ml 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log 10 ). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h regrowth then occurred with 0.5- and 1-g regimens with normal renal function ( fT ×MIC = 56 and 69%, fC min /MIC 2) the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function ( fT ×MIC ≥ 82%, fC min /MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.CCA.2017.01.012
Abstract: Pyroglutamic acid (PGA) is challenging to quantify in plasma and is a rare cause of metabolic acidosis that is associated with inherited disorders or acquired after exposure to drugs. We developed a hydrophilic interaction liquid chromatography tandem mass spectrometry method with a short analysis time. We established a reference interval and then measured PGA in acutely ill patients to investigate associations with clinical, pharmaceutical and laboratory parameters. The assay limit of the blank was 0.14μmol/L and was linear to 5000μmol/L with good precision. In-source formation of PGA from glutamate and glutamine was avoided by chromatographic separation. The PGA in controls had a reference interval of 22.6 to 47.8μmol/L. The median PGA concentration in acutely ill patients was similar (P=0.21), but 18 in iduals were above the reference interval with concentrations up to 250μmol/L. We detected an association between PGA concentration and antibiotic and acetaminophen administration as well as renal impairment and severity of illness. Elevations of PGA in this unselected cohort were small compared to those reported in patients with pyroglutamic acidosis. The method is suitable for routine clinical use. We confirmed several expected associations with PGA in an acutely ill population.
Publisher: SAGE Publications
Date: 07-2016
Abstract: Patients with peritoneal dialysis (PD)-associated peritonitis may be advised to store PD-bags with pre-mixed antibiotics at home, although there is a paucity of antibiotic stability studies in the commonly used icodextrin solutions. The purpose of this study was to assess the stability of various antibiotics in PD-bags when stored at different temperatures over a 14-day period. 7.5% icodextrin PD-bags were dosed with gentamicin 20 mg/L ( n = 9), vancomycin 1,000 mg/L ( n = 9), cefazolin 500 mg/L ( n = 9) and ceftazidime 500 mg/L ( n = 9) as for intermittent dosing. Combinations of gentamicin/vancomycin ( n = 9), cefazolin/ceftazidime ( n = 9), and cefazolin/gentamicin ( n = 9) were also tested. Nine drug-free bags were used as controls. Bags were stored in triplicate at 37°C, room-temperature (25°C), and refrigeration (4°C). Antibiotic concentrations were quantified at various time intervals using validated chromatography. Storage duration was considered unstable if the concentration of the antibiotic dropped ≤ 90% of the initial value. Gentamicin was stable for 14 days at all temperatures. Vancomycin was stable for 4 days at 37°C and for 14 days at both 25°C and 4°C. The gentamicin and vancomycin combination was stable for 4 days at 37°C and for 14 days at 25°C and 4°C. Cefazolin alone was stable for 24 hours at 37°C, 7 days at 25°C, and 14 days at 4°C. Ceftazidime alone was stable for only 6 hours at 37°C, 2 days at 25°C, and 14 days at 4°C. The cefazolin and ceftazidime combination was stable for 24 hours at 37°C, 2 days at 25°C, and 14 days at 4°C. The cefazolin and gentamicin combination was stable for 1 day at 37°C, 4 days at 25°C, and 14 days at 4°C. Antibiotics premixed in icodextrin PD-bags have varying stabilities with stability generally least at 37°C and best at 4 o C, permitting storage for 14 days when refrigerated and pre-warming to body temperature prior to administration. Further research confirming the sterility of these antibiotic-containing bags is recommended.
Publisher: American Society for Microbiology
Date: 11-2005
Publisher: MDPI AG
Date: 24-03-2023
DOI: 10.3390/ANTIBIOTICS12040643
Abstract: Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 s les from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.51893/2021.3.OA4
Abstract: BACKGROUND: The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 randomised controlled trial comparing continuous infusion with intermittent infusion of β-lactam antibiotics in 7000 critically ill patients with sepsis. OBJECTIVE: To describe a statistical analysis plan for the BLING III study. METHODS: The statistical analysis plan was designed by the trial statistician and chief investigators and approved by the BLING III management committee before the completion of data collection. Statistical analyses for primary, secondary and tertiary outcomes and planned subgroup analyses are described in detail. Interim analysis by the Data Safety and Monitoring Committee (DSMC) has been conducted in accordance with a pre-specified DSMC charter. RESULTS AND CONCLUSIONS: The statistical analysis plan for the BLING III study is published before completion of data collection and unblinding to minimise analysis bias and facilitate public access and transparent analysis and reporting of study findings. TRIAL REGISTRATION: ClinicalTrials.gov Registry NCT03212990.
Publisher: Springer Science and Business Media LLC
Date: 02-2011
DOI: 10.2165/11539220-000000000-00000
Abstract: Low serum albumin levels are very common in critically ill patients, with reported incidences as high as 40-50%. This condition appears to be associated with alterations in the degree of protein binding of many highly protein-bound antibacterials, which lead to altered pharmacokinetics and pharmacodynamics, although this topic is infrequently considered in daily clinical practice. The effects of hypoalbuminaemia on pharmacokinetics are driven by the decrease in the extent of antibacterial bound to albumin, which increases the unbound fraction of the drug. Unlike the fraction bound to plasma proteins, the unbound fraction is the only fraction available for distribution and clearance from the plasma (central compartment). Hence, hypoalbuminaemia is likely to increase the apparent total volume of distribution (V(d)) and clearance (CL) of a drug, which would translate to lower antibacterial exposures that might compromise the attainment of pharmacodynamic targets, especially for time-dependent antibacterials. The effect of hypoalbuminaemia on unbound concentrations is also likely to have an important impact on pharmacodynamics, but there is very little information available on this area. The objectives of this review were to identify the original research papers that report variations in the highly protein-bound antibacterial pharmacokinetics (mainly V(d) and CL) in critically ill patients with hypoalbuminaemia and without renal failure, and subsequently to interpret the consequences for antibacterial dosing. All relevant articles that described the pharmacokinetics and/or pharmacodynamics of highly protein-bound antibacterials in critically ill patients with hypoalbuminaemia and conserved renal function were reviewed. We found that decreases in the protein binding of antibacterials in the presence of hypoalbuminaemia are frequently observed in critically ill patients. For ex le, the V(d) and CL of ceftriaxone (85-95% protein binding) in hypoalbuminaemic critically ill patients were increased 2-fold. A similar phenomenon was reported with ertapenem (85-95% protein binding), which led to failure to attain pharmacodynamic targets (40% time for which the concentration of unbound [free] antibacterial was maintained above the minimal inhibitory concentration [fT>MIC] of the bacteria throughout the dosing interval). The V(d) and CL of other highly protein-bound antibacterials such as teicoplanin, aztreonam, fusidic acid or daptomycin among others were significantly increased in critically ill patients with hypoalbuminaemia compared with healthy subjects. Increased antibacterial V(d) appeared to be the most significant pharmacokinetic effect of decreased albumin binding, together with increased CL. These pharmacokinetic changes may result in decreased achievement of pharmacodynamic targets especially for time-dependent antibacterials, resulting in sub-optimal treatment. The effects on concentration-dependent antibacterial pharmacodynamics are more controversial due to the lack of data on this topic. In conclusion, altered antibacterial-albumin binding in the presence of hypoalbuminaemia is likely to produce significant variations in the pharmacokinetics of many highly protein-bound antibacterials. Dose adjustments of these antibacterials in critically ill patients with hypoalbuminaemia should be regarded as another step for antibacterial dosing optimization. Moreover, some of the new antibacterials in development exhibit a high level of protein binding although hypoalbuminaemia is rarely considered in clinical trials in critically ill patients. Further research that defines dosing regimens that account for such altered pharmacokinetics is recommended.
Publisher: Cold Spring Harbor Laboratory
Date: 14-08-2020
DOI: 10.1101/2020.08.10.20166652
Abstract: Infections caused by carbapenem-resistant Acinetobacter baumannii (CR-Ab) have become increasingly prevalent in clinical settings and often result in significant morbidity and mortality due to their multidrug resistance (MDR). Here we present an integrated whole genome sequencing (WGS) response to a polymicrobial outbreak in a Brisbane hospital between 2016-2018. 28 CR-Ab (and 21 other MDR Gram negative bacilli) were collected from Intensive Care Unit and Burns Unit patients and sent for WGS with a 7-day turn-around-time in clinical reporting. All CR-Ab were sequence type (ST)1050 and within 10 single nucleotide polymorphisms (SNPs) apart, indicative of an ongoing outbreak, and distinct from historical CR-Ab isolates from the same hospital. Possible transmission routes between patients were identified on the basis of CR-Ab and K. pneumoniae SNP profiles. Continued WGS surveillance between 2016 to 2018 enabled suspected outbreak cases to be refuted, but a resurgence of the outbreak CR-Ab mid-2018 in the Burns Unit prompted additional screening. Environmental metagenomic sequencing identified the hospital plumbing as a potential source. Replacement of the plumbing and routine drain maintenance resulted in rapid resolution of the secondary outbreak and significant risk reduction with no discernable transmission in the Burns Unit since. Here we demonstrate implementation of a comprehensive WGS and metagenomics investigation that resolved a persistent CR-Ab outbreak in a critical care setting.
Publisher: Informa Healthcare
Date: 02-09-2011
DOI: 10.1517/17425255.2011.615309
Abstract: Invasive candidiasis has emerged over the last few decades as an increasingly important nosocomial problem for the critically ill, affecting around 2% of intensive care unit patients. Although poor outcomes associated with invasive candidiasis among critically ill patients may relate to severe underlying disease processes and delayed institution of antifungal therapy, inadequate dosing of antifungal agents may also contribute. This drug evaluation provides a critical appraisal of the published literature pertaining to the pharmacokinetics of fluconazole in critically ill, obese or severely burned patients, including those receiving acute renal replacement therapy. The pharmacodynamics of fluconazole is also covered, as well as the likely clinical implications for optimal dosing and the toxicity of fluconazole. Last, variations in fluconazole susceptibility patterns of Candida spp. are also discussed. Recently, there has been an increased but geographically variable prevalence of non-albicans Candida spp., causing invasive candidiasis and an overall trend towards reduced fluconazole susceptibility. The pathophysiological changes of critical illness, coupled with a lack of dose finding studies, support the use of local susceptibility patterns to guide fluconazole dosing until such time as pharmacokinetic-pharmacodynamic information to guide optimal fluconazole dosing strategies and pharmacodynamic targets becomes available.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.CLINTHERA.2016.07.093
Abstract: With a decreasing supply of antibiotics that are effective against the pathogens that cause sepsis, it is critical that we learn to use currently available antibiotics optimally. Pharmacokinetic studies provide an evidence base from which we can optimize antibiotic dosing. However, these studies are challenging in critically ill neonate and pediatric patients due to the small blood volumes and associated risks and burden to the patient from taking blood. We investigate whether micros ling, that is, obtaining a biologic s le of low volume (<50 μL), can improve opportunities to conduct pharmacokinetic studies. We performed a literature search to find relevant articles using the following search terms: sepsis, critically ill, severe infection, intensive care AND antibiotic, pharmacokinetic, p(a)ediatric, neonate. For micros ling, we performed a search using antibiotics AND dried blood spots OR dried plasma spots OR volumetric absorptive micros ling OR solid-phase microextraction OR capillary micros ling OR micros ling. Databases searched include Web of Knowledge, PubMed, and EMbase. Of the 32 antibiotic pharmacokinetic studies performed on critically ill neonate or pediatric patients in this review, most of the authors identified changes to the pharmacokinetic properties in their patient group and recommended either further investigations into this patient population or therapeutic drug monitoring to ensure antibiotic doses are suitable. There remain considerable gaps in knowledge regarding the pharmacokinetic properties of antibiotics in critically ill pediatric patients. Implementing micros ling in an antibiotic pharmacokinetic study is contingent on the properties of the antibiotic, the pathophysiology of the patient (and how this can affect the micros le), and the location of the patient. A validation of the s ling technique is required before implementation. Current antibiotic regimens for critically ill neonate and pediatric patients are frequently suboptimal due to a poor understanding of altered pharmacokinetic properties. An assessment of the suitability of micros ling for pharmacokinetic studies in neonate and pediatric patients is recommended before wider use. The method of s ling, as well as the method of bioanalysis, also requires validation to ensure the data obtained reflect the true result.
Publisher: Springer Science and Business Media LLC
Date: 23-01-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2002
DOI: 10.1097/00003246-200203000-00011
Abstract: The reliability of intermittent transcranial Doppler has not been accepted widely because of problems with interobserver variability and lack of accuracy. The limitations of intermittent transcranial Doppler are thought to be overcome by continuous measurement systems. However, little published data exist on their accuracy, feasibility, and moment-to-moment variability. In this study we aimed to determine the time-related variability of continuous transcranial Doppler signal from volunteers and patients with subarachnoid hemorrhage and to examine the feasibility, ease of use, and quality of data generated from continuous transcranial Doppler for the detection of vasospasm. Prospective observational study. Intensive care unit in a tertiary referral center. Ten volunteers and eight patients with aneurysmal subarachnoid hemorrhage. None. The middle cerebral artery blood flow velocities were recorded continuously from both patients and volunteers. The moment-to-moment variability of continuously recorded data was calculated. There was a wide range of velocity measurements in both volunteers and patients. There was a significant moment-to-moment variability in both volunteers (-31% to 58%) and in patients (-38% to 78%). There was a greater number of observations exceeding 10% moment-to-moment variability in the patient group with regard to systolic and diastolic velocities compared with volunteers (8% vs. 2%, p < .001). There was a trend toward a longer duration of good quality data in volunteers compared with patients (98 +/- 0.5% vs. 96 +/- 9%). Continuous measurement of cerebral blood flow velocities revealed a significant moment-to-moment variability in both patients and in volunteers, the magnitude of which was greater in the patients. The clinical implications of these findings are discussed.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Springer Science and Business Media LLC
Date: 10-02-2011
DOI: 10.1007/S00134-010-2117-9
Abstract: The intravenous fluid 6% hydroxyethyl starch (130/0.4) (6% HES 130/0.4) is used widely for resuscitation but there is limited information on its efficacy and safety. A large-scale multi-centre randomised controlled trial (CHEST) in critically ill patients is currently underway comparing fluid resuscitation with 6% HES 130/0.4 to 0.9% sodium chloride on 90-day mortality and other clinically relevant outcomes including renal injury. This report describes the study protocol. CHEST will recruit 7,000 patients to concealed, random, parallel assignment of either 6% HES 130/0.4 or 0.9% sodium chloride for all fluid resuscitation needs whilst in the intensive care unit (ICU). The primary outcome will be all-cause mortality at 90 days post-randomisation. Secondary outcomes will include incident renal injury, other organ failures, ICU and hospital mortality, length of ICU stay, quality of life at 6 months, health economic analyses and in patients with traumatic brain injury, functional outcome. Subgroup analyses will be conducted in four predefined subgroups. All analyses will be conducted on an intention-to-treat basis. The study run-in phase has been completed and the main trial commenced in April 2010. CHEST should generate results that will inform and influence prescribing of this commonly used resuscitation fluid.
Publisher: Oxford University Press (OUP)
Date: 21-10-2014
DOI: 10.1093/JAC/DKU413
Abstract: To describe the interstitial fluid (ISF) and plasma pharmacokinetics of meropenem in patients on continuous venovenous haemodiafiltration (CVVHDF). This was a prospective observational pharmacokinetic study. Meropenem (500 mg) was administered every 8 h. CVVHDF was targeted as a 2-3 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2 and a blood flow rate of 200 mL/min. Serial blood (pre- and post-filter), filtrate/dialysate and ISF concentrations were measured on 2 days of treatment (Profiles A and B). Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 384 s les were collected. During Profile A, the comparative median (IQR) ISF and plasma peak concentrations were 13.6 (12.0-16.8) and 40.7 (36.6-45.6) mg/L and the trough concentrations were 2.6 (2.4-3.4) and 4.9 (3.5-5.0) mg/L, respectively. During Profile B, the ISF trough concentrations increased by ∼40%. Meropenem ISF penetration was estimated at 63% (60%-69%) and 69% (65%-74%) for Profiles A and B, respectively, using comparative plasma and ISF AUCs. For Profile A, the plasma elimination t1/2 was 3.7 (3.3-4.0) h, the volume of distribution was 0.35 (0.25-0.46) L/kg, the total clearance was 4.1 (4.1-4.8) L/h and the CVVHDF clearance was 2.9 (2.7-3.1) L/h. This is the first known report of concurrent plasma and ISF concentrations of a meropenem antibiotic during CVVHDF. We observed that the ISF concentrations of meropenem were significantly lower than the plasma concentrations, although the present dose was appropriate for infections caused by intermediately susceptible pathogens (MIC≤4 mg/L).
Publisher: Springer Science and Business Media LLC
Date: 11-2007
DOI: 10.1038/NATURE06341
Publisher: AME Publishing Company
Date: 08-2016
Publisher: American Thoracic Society
Date: 15-09-2016
Publisher: Wiley
Date: 29-05-2012
DOI: 10.1111/J.1440-1681.2012.05715.X
Abstract: 1. Infections and related sepsis are two of the most prevalent issues in the care of critically ill patients, with mortality as high as 70%. Appropriate antibiotic selection, as well as adequate dosing, is important to improve the clinical outcome for these patients. 2. β-Lactams are the most common antibiotic class used in critically ill sepsis patients because of their broad spectrum of activity and high tolerability. β-Lactams exhibit time-dependent antibacterial activity. Therefore, concentrations need to be maintained above the minimum inhibitory concentration (MIC) of pathogenic bacteria. β-Lactams are hydrophilic antibiotics with small distribution volumes similar to extracellular water and are predominantly excreted through the renal system. 3. Critically ill patients experience a myriad of physiological changes that result in changes in the pharmacokinetics (PK) of hydrophilic drugs such as β-lactams. A different approach to dosing with β-lactams may increase the likelihood of positive outcomes considering the pharmacodynamics (PD) of β-lactams, as well as the changes in PK in critically ill patients. 4. The present review describes the strategies for dose optimization of β-lactams in critically ill patients in line with the PK and PD of these drugs.
Publisher: Oxford University Press (OUP)
Date: 08-1997
DOI: 10.1093/JAC/40.2.269
Abstract: Ceftazidime is frequently used in critically ill patients, particularly for the treatment of Pseudomonas aeruginosa infections. The recommended dosing regimen is based on pharmacokinetic data obtained in healthy volunteers and may not be appropriate in the critically ill. We administered ceftazidime in the maximum recommended dose (2 g i.v. every 8 h) to ten critically ill patients with normal plasma creatinine. Eighteen arterial blood s les were taken from each patient over the first 8 h for measurement of ceftazidime concentrations and subsequent compartmental pharmacokinetic analysis. An additional trough s le was taken from each patient on day 3. Although mean pharmacokinetic variables did not differ from previously reported data in normal volunteers there was wide variability in plasma drug concentrations. Three of our patients had plasma ceftazidime concentrations less than the MIC for P. aeruginosa (8 mg/L) and nine had concentrations less than 5 x MIC, which has been recommended to ensure efficacy. On day 3 trough ceftazidime concentrations were less than the MIC in four out of the seven patients in whom measurements were made and less than 5 x MIC in the remaining three. There was no clinical predictor of which patients would have low plasma concentrations. Our results show that plasma concentrations of ceftazidime are very variable when the recommended intermittent bolus dosing regimen is used and may result in inadequate plasma concentrations of drug in critical infections. This may result in treatment failure and the emergence of antibiotic resistance. A loading dose followed by continuous infusion should overcome these problems but this awaits in-vivo evaluation.
Publisher: American Society for Microbiology
Date: 07-2010
DOI: 10.1128/AAC.01582-09
Abstract: Use of high ultrafiltrate flow rates with continuous venovenous hemofiltration (CVVHF) in critically ill patients is an emerging setting, for which there are few data to guide drug dosing. The objectives of this study were, firstly, to investigate the pharmacokinetics of meropenem in critically ill patients with severe sepsis who are receiving high-volume CVVHF with high-volume exchanges (≥4 liters/h) secondly, to determine whether standard dosing regimens (1,000 mg intravenously [i.v.] every 8 h) are sufficient for treatment of less susceptible organisms such as Burkholderia pseudomallei (MIC, 4 mg/liter) and, finally, to compare the clearances observed in this study with data from previous studies using lower-volume exchanges (1 to 2 liters/h). We recruited 10 eligible patients and collected serial pre- and postfilter blood s les and ultrafiltrate and urine s les. A noncompartmental method was used to determine meropenem pharmacokinetics. The cohort had a median age of 56.6 years, a median weight of 70 kg, and a median APACHE II (acute physiology and chronic health evaluation) score of 25. The median (interquartile range) values for meropenem were as follows: terminal elimination half-life, 4.3 h (2.9 to 6.0) terminal volume of distribution, 0.2 liters/kg (0.2 to 0.3) trough concentration, 7.7 mg/liter (6.2 to 12.9) total clearance, 6.0 liters/h (5.2 to 6.2) hemofiltration clearance, 3.5 liters/h (3.4 to 3.9). In comparing the meropenem clearance here with those in previous studies, ultrafiltration flow rate was found to be the parameter that accounted for the differences in clearance of meropenem ( R 2 = 0.89). In conclusion, high-volume CVVHF causes significant clearance of meropenem, necessitating steady-state doses of 1,000 mg every 8 h to maintain sufficient concentrations to treat less susceptible organisms such as B. pseudomallei .
Publisher: Springer Science and Business Media LLC
Date: 03-2015
Publisher: American Society for Microbiology
Date: 2017
DOI: 10.1128/AAC.01763-16
Abstract: There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the in idual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 10 8 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid lification of resistant P. aeruginosa strains (about 10 8 to 10 9 CFU/ml within 24 to 48 h). For K. pneumoniae , amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae . In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.
Publisher: American Society for Microbiology
Date: 11-2017
DOI: 10.1128/AAC.00311-17
Abstract: Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two-compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 ± 12 years [means ± standard deviations] and weight of 77 ± 16 kg). Parameter estimates were CL of 18.0 ± 4.8 liters/h, volume of distribution of the central compartment of 14.3 ± 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 ± 1.35 h −1 , and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 ± 7.81 h −1 . High creatinine clearance (CL CR ) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of % for an unbound concentration of piperacillin remaining above the MIC ( fT MIC ) of 50%. Only continuous regimens achieved % PTA for 100% fT MIC when CL CR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal ( %) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT MIC . FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL CR or with known resumed infections from high-MIC bacteria.
Publisher: Informa UK Limited
Date: 2005
Publisher: Springer Science and Business Media LLC
Date: 29-12-2016
DOI: 10.1007/S40262-016-0495-Z
Abstract: Sepsis and continuous renal replacement therapy (CRRT) can both significantly affect antifungal pharmacokinetics. This study aimed to describe the pharmacokinetics of caspofungin in critically ill patients during different CRRT modes. Patients receiving caspofungin and undergoing continuous veno-venous haemofiltration (CVVH) or haemodiafiltration (CVVHDF) were eligible to take part in the study. Blood s les were collected at seven s ling times during a dosing interval. Demographics and clinical data were recorded. Population pharmacokinetic analysis and Monte-Carlo simulation were undertaken using Pmetrics. Twelve pharmacokinetic profiles from nine patients were analysed. The caspofungin CRRT clearance (CL) was 0.048 ± 0.12 L/h for CVVH and 0.042 ± 0.042 L/h for CVVHDF. A two-compartment linear model best described the data. Patient weight was the only covariate affecting drug CL and central volume. The mean (standard deviation) parameter estimates were 0.64 ± 0.12 L/h for CL, 9.35 ± 3.56 L for central volume, 0.25 ± 0.19 per h for the rate constant for drug distribution from central to peripheral compartments and 0.19 ± 0.10 per h from peripheral to central compartments. Based on simulation results, a caspofungin 100 mg loading dose followed by a 50 mg maintenance dose for patients with a total body weight of ≤80 kg best achieved the pharmacokinetic/PD targets whilst a 70 mg maintenance dose was required for patients with a weight of >80 kg. No caspofungin dosing adjustment is necessary for patients undergoing either form of CRRT. However, higher than recommended loading doses of caspofungin are required to achieve pharmacokinetic harmacodynamic targets in critically ill patients. Registration: ClinicalTrials.gov Identifier NCT01403220.
Publisher: Springer Science and Business Media LLC
Date: 31-03-2016
Publisher: Cambridge University Press (CUP)
Date: 13-05-2016
DOI: 10.1017/ICE.2016.107
Abstract: Healthcare workers (HCWs) lack familiarity with evidence-based guidelines for the prevention of healthcare-associated infections (HAIs). There is good evidence that effective educational interventions help to facilitate guideline implementation, so we investigated whether e-learning could enhance HCW knowledge of HAI prevention guidelines. We developed an electronic course (e-course) and tested its usability and content validity. An international s le of voluntary learners submitted to a pretest (T0) that determined their baseline knowledge of guidelines, and they subsequently studied the e-course. Immediately after studying the course, posttest 1 (T1) assessed the immediate learning effect. After 3 months, during which participants had no access to the course, a second posttest (T2) evaluated the residual learning effect. A total of 3,587 HCWs representing 79 nationalities enrolled: 2,590 HCWs (72%) completed T0 1,410 HCWs (39%) completed T1 and 1,011 HCWs (28%) completed T2. The median study time was 193 minutes (interquartile range [IQR], 96–306 minutes) The median scores were 52% (IQR, 44%–62%) for T0, 80% (IQR, 68%–88%) for T1, and 74% (IQR, 64%–84%) for T2. The immediate learning effect (T0 vs T1) was +24% (IQR, 12%–34% P .001), and a residual effect (T0 vs T2) of +18% (IQR 8–28) remained ( P .001). A 200-minute study time was associated with a maximum immediate learning effect (28%). A study time minutes yielded the greatest residual effect (24%). Moderate time invested in e-learning yielded significant immediate and residual learning effects. Decision makers could consider promoting e-learning as a supporting tool in HAI prevention. Infect Control Hosp Epidemiol 2016 :1052–1059
Publisher: Oxford University Press (OUP)
Date: 06-09-2016
DOI: 10.1093/CID/CIW610
Abstract: Delayed antifungal therapy for invasive candidiasis (IC) contributes to poor outcomes. Predictive risk models may allow targeted antifungal prophylaxis to those at greatest risk. A prospective cohort study of 6685 consecutive nonneutropenic patients admitted to 7 Australian intensive care units (ICUs) for ≥72 hours was performed. Clinical risk factors for IC occurring prior to and following ICU admission, colonization with Candida species on surveillance cultures from 3 sites assessed twice weekly, and the occurrence of IC ≥72 hours following ICU admission or ≤72 hours following ICU discharge were measured. From these parameters, a risk-predictive model for the development of ICU-acquired IC was then derived. Ninety-six patients (1.43%) developed ICU-acquired IC. A simple summation risk-predictive model using the 10 independently significant variables associated with IC demonstrated overall moderate accuracy (area under the receiver operating characteristic curve = 0.82). No single threshold score could categorize patients into clinically useful high- and low-risk groups. However, using 2 threshold scores, 3 patient cohorts could be identified: those at high risk (score ≥6, 4.8% of total cohort, positive predictive value [PPV] 11.7%), those at low risk (score ≤2, 43.1% of total cohort, PPV 0.24%), and those at intermediate risk (score 3-5, 52.1% of total cohort, PPV 1.46%). Dichotomization of ICU patients into high- and low-risk groups for IC risk is problematic. Categorizing patients into high-, intermediate-, and low-risk groups may more efficiently target early antifungal strategies and utilization of newer diagnostic tests.
Publisher: Springer Science and Business Media LLC
Date: 06-2004
Publisher: Elsevier BV
Date: 10-2016
Publisher: SAGE Publications
Date: 08-04-2015
DOI: 10.5301/IJAO.5000422
Abstract: To determine the adsorption and elimination characteristics of meropenem and piperacillin during simulated continuous renal replacement therapy (CRRT), and to compare the observed data from this ex vivo study with previous data from clinical studies. This was an experimental study utilizing a modified CRRT circuit and polysulfone membrane (1.2 m 2 ), circulated with a blood-crystalloid mixture. Adsorption onto the CRRT circuit was tested over a 4-h period, and clearance was assessed separately using variable continuous hemofiltration settings. A rapid 9% reduction in circulating meropenem and piperacillin concentrations was observed at approximately 0.5 and 1.0 h for each antibiotic, respectively. The post-dilution setting was associated with a significantly higher sieving coefficient (Sc) and filter clearance (CL filter ) (mean ± SD) (Sc 1.14 ± 0.10 versus 1.06 ± 0.04 CL filter 19.05 ± 1.63 versus 17.59 ± 0.62 ml/min, P values .05) for meropenem. No significant differences were observed for piperacillin pharmacokinetics. Clinically comparable Sc data were observed between data obtained from the ex vivo study and data from previous clinical studies, for both antibiotics. Meropenem and piperacillin appear to be rapidly adsorbed into the CRRT circuit, and the delivery site of fluid replacement significantly influences meropenem pharmacokinetics. However, these findings are likely to be clinically insignificant and not affect dosing requirements. This ex vivo method could be a surrogate for future clinical pharmacokinetic studies of CRRT. Further research is required to explore the applicability of the ex vivo method to further characterize antibiotic pharmacokinetics during CRRT.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JCRC.2016.06.022
Abstract: The purpose was to determine the efficacy of prophylactic inhaled heparin for the prevention and treatment of pneumonia in patients receiving mechanical ventilation (MV). A phase 2, double-blind, randomized controlled trial stratified for study center and patient type (nonoperative, postoperative) was conducted in 3 university-affiliated intensive care units. Patients aged at least 18 years and requiring invasive MV for more than 48 hours were randomized to usual care, nebulization of unfractionated sodium heparin (5000 U in 2 mL), or nebulization with 0.9% sodium chloride (2 mL) 4 times daily with the main outcome measures, the development of ventilator-associated pneumonia (VAP), ventilator-associated complication, and Sequential Organ Failure Assessment scores in patients with admission pneumonia or developing VAP. ACTRN12612000038897. A total of 214 patients were enrolled (72 usual care, 71 inhaled sodium heparin, 71 inhaled sodium chloride). There were no differences between treatment groups in terms of the development of VAP using either Klompas criteria (6%-7%, P=1.00) or clinical diagnosis (24%-26%, P=.85). Low-dose nebulized heparin cannot be recommended for prophylaxis against VAP or to hasten recovery from pneumonia in patients receiving MV.
Publisher: MDPI AG
Date: 13-01-2022
DOI: 10.3390/ANTIBIOTICS11010101
Abstract: We evaluated piperacillin-tazobactam and tobramycin regimens against Pseudomonas aeruginosa isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MICpiperacillin 4 mg/L, MICtobramycin 0.5 mg/L) and CR380 (MICpiperacillin 32 mg/L, MICtobramycin 1 mg/L), simulating the pharmacokinetics of: (A) tobramycin 7 mg/kg q24 h (0.5 h-infusions, t1/2 = 3.1 h) (B) piperacillin 4 g q4 h (0.5 h-infusions, t1/2 = 1.5 h) (C) piperacillin 24 g/day, continuous infusion A + B A + C. Total and less-susceptible bacteria were determined. SCTK demonstrated synergy of the combination for all isolates. In the IVM, regimens A and B provided initial killing, followed by extensive regrowth by 72 h for both isolates. C provided log10 CFU/mL killing, followed by regrowth close to initial inoculum by 96 h for Pa1281, and suppressed growth to log10 CFU/mL for CR380. A and A + B initially suppressed counts of both isolates to log10 CFU/mL, before regrowth to control or starting inoculum and resistance emergence by 72 h. Overall, the combination including intermittent piperacillin-tazobactam did not provide a benefit over tobramycin monotherapy. A + C, the combination regimen with continuous infusion of piperacillin-tazobactam, provided synergistic killing (counts log10 CFU/mL) of Pa1281 and CR380, and suppressed regrowth to and log10 CFU/mL, respectively, and resistance emergence over 120 h. The shape of the concentration–time curve was important for synergy of the combination.
Publisher: American Society for Microbiology
Date: 03-2015
DOI: 10.1128/AAC.04001-14
Abstract: Population pharmacokinetic analyses can be applied to predict optimized dosages for in idual patients. The aim of this study was to compare the prediction performance of the published population pharmacokinetic models for meropenem in critically ill patients. We coded the published population pharmacokinetic models with covariate relationships into dosing software to predict unbound meropenem concentrations measured in a separate cohort of critically ill patients. The agreements between the observed and predicted concentrations were evaluated with Bland-Altman plots. The absolute and relative bias and precision of the models were determined. The clinical implications of the results were evaluated according to whether dose adjustments were required from the predictions to achieve a meropenem concentration of mg/liter throughout the dosing interval. A total of 157 free meropenem concentrations from 56 patients were analyzed. Eight published population pharmacokinetic models were compared. The models showed an absolute bias in predicting the unbound meropenem concentrations from a mean percent difference (95% confidence interval [CI]) of −108.5% (−119.9% to −97.3%) to 19.9% (7.3% to 32.7%), while absolute precision ranged from −249.1% (−263.4% to −234.8%) to 31.9% (17.6% to 46.2%) and −178.9% (−196.9% to −160.9%) to 175.0% (157.0% to 193.0%). A dose change was required in 44% to 64% of the concentration results. Seven of the eight equations evaluated underpredicted free meropenem concentrations. In conclusion, the overall accuracy of these models supports their inclusion in dosing software and application for in idualizing meropenem doses in critically ill patients to increase the likelihood of achievement of optimal antibiotic exposures.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2017
DOI: 10.1097/CCM.0000000000002210
Abstract: Drugs are key weapons that clinicians have to battle against the profound pathologies encountered in critically ill patients. Antibiotics in particular are commonly used and can improve patient outcomes dramatically. Despite this, there are strong opportunities for further reducing the persisting poor outcomes for infected critically ill patients. However, taking these next steps for improving patient care requires a new approach to antibiotic therapy. Giving the right dose is highly likely to increase the probability of clinical cure from infection and suppress the emergence of resistant pathogens. Furthermore, in some patients with higher levels of sickness severity, reduced mortality from an optimized approach to antibiotic use could also occur. To enable optimized dosing, the use of customized dosing regimens through either evidence-based dosing nomograms or preferably through the use of dosing software supplemented by therapeutic drug monitoring data should be embedded into daily practice. These customized dosing regimens should also be given as soon as practicable as reduced time to initiation of therapy has been shown to improve patient survival, particularly in the presence of septic shock. However, robust data supporting these logical approaches to therapy, which may deliver the next step change improvement for treatment of infections in critically ill patients, are lacking. Large prospective studies of patient survival and health system costs are now required to determine the value of customized antibiotic dosing, that is, giving the right dose at the right time.
Publisher: Bentham Science Publishers Ltd.
Date: 12-2011
DOI: 10.2174/138920111798808446
Abstract: In-hospital and intensive care unit mortality rates for sepsis remain un-acceptably high, and have prompted the publication of international guidelines on best practice. Crucial to this is the application of early appropriate antibacterial therapy, in the correct dose. However, antibacterial regimes in this setting have largely been extrapolated from those in healthy volunteers, and fail to consider the unique pathophysiology and treatment provided to this population. As such, augmented renal clearance (ARC) - the enhanced renal elimination of circulating solute - is likely to be one of the more common physiological changes encountered in this setting, although to date remains largely under-appreciated. Significantly this may alter the pharmacokinetics of many routinely prescribed agents in this setting, pre-disposing to subtherapeutic levels or treatment failure. This review paper examines this phenomenon in detail, providing a summary of the likely underlying mechanisms, those patients at greatest risk, and the implications for antibacterial dosing in the critically ill.
Publisher: American Chemical Society (ACS)
Date: 25-01-2023
Publisher: Oxford University Press (OUP)
Date: 25-08-2009
DOI: 10.1093/JAC/DKP302
Abstract: Drug dosing for septic patients with acute renal failure receiving continuous renal replacement therapy (CRRT) is complicated, and failure to correctly dose may result in either drug toxicity or treatment failure and development of antibiotic resistance. The aim of this study was to establish an ideal dataset that needs to be reported when presenting pharmacokinetic data for these patients and review current literature for completeness of this dataset. An ideal dataset was established of the parameters that should be reported when calculating a drug dosing regimen from first principles. A Medline search was performed of relevant literature producing 64 citations from which completeness of the specified criteria was examined. None of the studies analysed presented the full dataset that we established as necessary. Of concern, basic pharmacokinetic parameters such as volume of distribution (V(d)) and clearance (CL) were specified in only 79% and 81% of studies, respectively. A large proportion of current studies do not report key information necessary to devise a rational dosing regimen for patients with acute renal failure receiving CRRT, and we hope this dataset will be a useful guide when reporting future pharmacokinetic data.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2012
Publisher: IEEE
Date: 03-2011
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.ADDR.2014.07.006
Abstract: Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for in idual fine-tuning of antimicrobial therapy seems the way forward.
Publisher: Springer Science and Business Media LLC
Date: 29-11-1999
Publisher: Wiley
Date: 20-06-2011
DOI: 10.1111/J.1399-6576.2011.02477.X
Abstract: The practical and ethical issues in determining authorship in multicenter trials raise significant and unique challenges. This systematic review examines methods of assigning authorship in multicenter clinical trials. A literature search (October 2009) was conducted to identify articles with the terms 'authorship' and 'clinical trial,' 'multicenter' or 'multicentre.' Abstracts were reviewed for potential relevance and the complete manuscript was obtained where indicated. Additional articles were identified by a review of the reference list from sourced articles. Methods for determining authorship were reviewed in terms of practicality, fairness and the time course for decision-making. Eight methods for determining authorship were identified: four used a scoring system, two articles contained guidelines with reference to scoring systems and two articles outlined general guidelines. All methods attempted to provide a fair and practical approach and appeared to achieve this to varying degrees. No one method was applicable across all multicenter trials. The authors propose a guide for determining authorship based on the methods identified and the number of collaborators and anticipated publications. For smaller collaborative groups (e.g. <10 persons), byline inclusion of all authors based on relative contributions is recommended. For larger collaborations (e.g. ≥ 10 persons), authorship guidelines should be explicit from the outset of the trial with consideration of relevant scoring systems.
Publisher: Informa Healthcare
Date: 07-04-2016
DOI: 10.1517/14740338.2016.1164690
Abstract: The altered pathophysiology in critically ill patients presents a unique challenge in both the diagnosis of infection and the appropriate prescription of antibiotics. In this context, the importance of effective and timely treatment needs to be weighed against the in idual and community harms associated with antibiotic collateral damage and antibiotic resistance. We evaluate the principles of antibiotic use in critically ill patients, including dose optimisation, use of combination antibiotic therapy, therapeutic drug monitoring, appropriate antibiotic therapy duration, de-escalation, and utilisation of sepsis biomarkers. We also describe the potential risks associated with antibiotic therapy including antibiotic resistance, delayed treatment, treatment failure, and collateral damage. Prescribing teams must be aware of the impact of critical illness on their patients and tailor antibiotic therapy appropriately to prevent the significant harms associated with suboptimal antibiotic administration.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.IJANTIMICAG.2013.02.023
Abstract: Meropenem and piperacillin are two commonly prescribed antibiotics in critically ill surgical patients. To date, the pharmacokinetics of these antibiotics in the presence of indwelling abdominal surgical drains is poorly defined. This was a prospective pharmacokinetic study of meropenem and piperacillin. Serial plasma, urine and surgical drain fluid s les were collected over one dosing interval of antibiotic treatment in ten patients (meropenem, n = 5 piperacillin n = 5). Drug concentrations were measured using a validated high-performance liquid chromatography assay. Median (interquartile range) pharmacokinetic parameter estimates for meropenem were as follows: area under concentration-time curve (AUC), 128.7 mgh/L (95.3-176.7 mgh/L) clearance (CL), 5.7 L/h (5.1-10.5 L/h) volume of distribution (Vd), 0.41 L/kg (0.35-0.56 L/kg) AUC ratio (drain:plasma), 0.2 (0.1-0.2) and calculated antibiotic clearance via surgical drain, 3.8% (2.8-5.4%). For piperacillin, unbound pharmacokinetic results were as follows AUC, 344.3 mgh/L (341.1-348.4 mgh/L) CL, 13.1 L/h (12.9-13.2 L/h) Vd, 0.63 L/kg (0.38-1.28 L/kg) AUC ratio (drain:plasma), 0.2 (0.2-0.3) and calculated antibiotic clearance via surgical drain 8.2% (3.3-14.0%). A linear correlation was present between the percentage of antibiotic cleared through the drain and the volume of surgical drain fluid output for meropenem (r(2) = 0.89 P = 0.05) and piperacillin (r(2) = 0.63 P = 0.20). Meropenem and piperacillin have altered pharmacokinetics in critically ill patients with indwelling surgical drains. We propose that only when very high drain fluid output is present (>1000 mL/day) would an additional dose of antibiotic be necessary.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.CCC.2010.09.006
Abstract: Antimicrobial pharmacokinetics (PK) and pharmacodynamics (PD) are important considerations, particularly in critically ill patients with severe sepsis and septic shock. The pathophysiologic changes that occur in these conditions can have a major effect on pharmacokinetic parameters, which in turn could result in failure to achieve pharmacodynamic targets for antimicrobials thus adversely affecting clinical outcome. This paper discusses the pathophysiologic changes that occur during severe sepsis and septic shock and the consequent effects on antimicrobial PK and PD. The effect of PK/PD on specific antimicrobial classes is discussed and a rational framework for antimicrobial dosing is provided. Knowledge of PK/PD properties of antimicrobials can be used to personalize dosing regimens not only to maximize antimicrobial activity but also to minimize toxicity and reduce the development of antimicrobial resistance.
Publisher: American Society for Microbiology
Date: 10-2015
DOI: 10.1128/AAC.01321-15
Abstract: This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood s les were taken over several dosing intervals of intravenous fosfomycin treatment. Blood s les were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood s les were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CL CR ) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment ( V c ) described the data adequately. Calculated CL CR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, V c of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient s le, which may be explained somewhat by the observed variations in renal function.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2008
Publisher: Oxford University Press (OUP)
Date: 09-06-2022
DOI: 10.1093/JAC/DKAC168
Abstract: To describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary micros ling to facilitate data-rich blood s ling. Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma s les collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve pharmacokinetic harmacodynamic (PK/PD) targets, including 100% ƒT& MIC with an MIC breakpoint of 1 mg/L. Thirty-six patients (0.2–12 years) provided 160 conventional s les for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L/h and 39.4 L, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg q6h was only able to achieve the PK/PD target of 100% ƒT& MIC in patients & kg and with impaired renal function or patients of 40 kg with normal renal function. Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary micros ling demonstrated skin-prick s ling can facilitate data-rich pharmacokinetic studies.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.IJANTIMICAG.2005.04.005
Abstract: This study aimed to investigate whether fluid shifts alter ciprofloxacin pharmacokinetics in critically ill patients over time. Patients > or = 18 years, with normal renal function, requiring intensive care treatment and parenteral antibiotics were enrolled. Group A (22 patients) included patients with documented intra-abdominal infections. Group B (18 patients) included patients with severe sepsis from other causes. All patients received intravenous ciprofloxacin 400 mg every 8 h infused over 60 min. Eight timed blood specimens were taken on days 0, 2 and 7. Ciprofloxacin plasma concentrations were determined using high performance liquid chromatography. There were no significant differences between the pharmacokinetics of the two groups or over time. Ciprofloxacin pharmacokinetics in critically ill patients do not change over time, and intra-abdominal sepsis does not alter ciprofloxacin pharmacokinetic parameters to a greater degree than sepsis from other causes in critically ill patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2007
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.DIAGMICROBIO.2014.01.015
Abstract: Optimal dosing of antimicrobial therapy is pivotal to increase the likelihood of survival in critically ill patients with sepsis. Drug exposure that maximizes bacterial killing, minimizes the development of antimicrobial resistance, and avoids concentration-related toxicities should be considered the target of therapy. However, antimicrobial dosing is problematic as pathophysiological factors inherent to sepsis that alter may result in reduced concentrations. Alternatively, sepsis may evolve to multiple-organ dysfunction including acute kidney injury (AKI). In this case, decreased clearance of renally cleared drugs is possible, which may lead to increased concentrations that may cause drug toxicities. Consequently, when dosing antibiotics in septic patients with AKI, one should consider factors that may lead to underdosing and overdosing. Drug-specific pharmacokinetic and pharmacodynamic data may be helpful to guide dosing in these circumstances. Yet, because of the high interpatient variability in pharmacokinetics of antibiotics during sepsis, this issue remains a significant challenge.
Publisher: Elsevier BV
Date: 06-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2017
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.IJANTIMICAG.2011.05.013
Abstract: Controversy continues regarding whether the presence of meticillin resistance increases mortality risk in Staphylococcus aureus infections. In this study, we assessed the role of meticillin resistance in survival of patients with S. aureus infection included in the EPIC II point-prevalence study of infection in critically ill patients performed on 8 May 2007. Demographic, physiological, bacteriological and therapeutic data were collected for 13796 adult patients in 1265 participating Intensive Care Units (ICUs) from 75 countries on the study day. ICU and hospital outcomes were recorded. Characteristics of patients with meticillin-sensitive S. aureus (MSSA) and meticillin-resistant S. aureus (MRSA) infections were compared. Co-morbidities, age, Simplified Acute Physiology Score (SAPS) II, site of infection, geographical region and MRSA/MSSA were entered into a multivariate model, and adjusted odds ratios (ORs) [95% confidence interval (CI)] for ICU and hospital mortality rates were calculated. On the study day, 7087 (51%) of the 13796 patients were classified as infected. There were 494 patients with MRSA infections and 505 patients with MSSA infections. There were no significant differences between the two groups in use of mechanical ventilation or haemofiltration/haemodialysis. Cancer and chronic renal failure were more prevalent in MRSA than in MSSA patients. ICU mortality rates were 29.1% and 20.5%, respectively (P<0.01) and corresponding hospital mortality rates were 36.4% and 27.0% (P<0.01). Multivariate analysis of hospital mortality for MRSA infection showed an adjusted OR of 1.46 (95% CI 1.03-2.06) (P=0.03). In ICU patients, MRSA infection is therefore independently associated with an almost 50% higher likelihood of hospital death compared with MSSA infection.
Publisher: Oxford University Press (OUP)
Date: 07-03-2016
DOI: 10.1093/JAC/DKW043
Abstract: Whilst commonly performed in ICUs, renal replacement therapies (RRTs) differ in their solute clearances. There is a paucity of data on ciprofloxacin clearances in different RRT techniques. The aim of this study was to compare the population pharmacokinetics of ciprofloxacin during equal doses of continuous venovenous haemofiltration (CVVHF) and continuous venovenous haemodiafiltration (CVVHDF) in septic patients. Patients receiving 400 mg of ciprofloxacin intravenously 8 or 12 hourly and undergoing either CVVHF or CVVHDF were eligible. Up to 10 blood s les were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo simulation was undertaken using Pmetrics. Eighteen s ling intervals were included (8 CVVHDF and 10 CVVHF) from 11 patients (6 patients having s ling during both RRT modes). A two-compartment linear model best described the data. Increasing patient weight was the only covariate associated with increasing drug clearance. The mean (SD) parameter estimates were: clearance, 10.7 (5.3) L/h volume of distribution of the central compartment, 21.3 (11.3) L rate constant for drug distribution from the central compartment to the peripheral compartment, 10.9 (4.3) L/h and rate constant for drug distribution from the peripheral compartment to the central compartment, 2.3 (1.8) L/h. After accounting for patient weight, the mean ciprofloxacin clearance was not statistically different between CVVHF and CVVHDF [11.8 (9.9) and 10.3 (7.4) L/h, respectively, P = 0.43]. The present study indicates a high pharmacokinetic variability of ciprofloxacin during CVVHF and CVVHDF with no significant differences in clearance apparent. Based on patient weight, higher ciprofloxacin dosing regimens should be used in critically ill patients when difficult-to-treat pathogens are suspected.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2008
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.IJANTIMICAG.2016.12.022
Abstract: Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CL
Publisher: Bentham Science Publishers Ltd.
Date: 11-2010
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.IJANTIMICAG.2014.03.009
Abstract: This study aimed to describe the population pharmacokinetics of vancomycin in critically ill patients with refractory septic shock undergoing continuous venovenous high-volume haemofiltration (HVHF) and to define appropriate dosing for these patients. This was a prospective pharmacokinetic study in the ICU of a university hospital. Eight blood s les were taken over one vancomycin dosing interval. S les were analysed by a validated liquid chromatography-tandem mass spectrometry assay. Non-linear mixed-effects modelling was used to describe the population pharmacokinetics. Dosing simulations were used to define therapeutic vancomycin doses for different HVHF settings. Nine patients were included (five male). The mean weight and SOFA score were 70 kg and 11, respectively. Mean HVHF settings were: blood flow rate, 240 mL/min and haemofiltration exchange rate, 100 mL/kg/h. A linear two-compartment model with zero-order input adequately described the data. Mean parameter estimates were: clearance, 2.9 L/h volume of distribution of central compartment (V(1)), 11.8L volume of distribution of peripheral compartment (V(2)), 18.0 L and intercompartmental clearance, 9.3 L/h. HVHF intensity was strongly associated with vancomycin clearance (P < 0.05) and was a covariate in the final model. Simulations indicate that after a loading dose, vancomycin doses required for different HVHF intensities would be 750 mg every 12h (q12h) for 69 mL/kg/h, 1000 mg q12h for 100 mL/kg/h and 1500 mg q12h for 123 mL/kg/h. Continuous infusion would also be a valuable administration strategy. In conclusion, variable and much higher than standard vancomycin doses are required to achieve therapeutic concentrations during different HVHF settings.
Publisher: Elsevier BV
Date: 07-1990
Abstract: Acute preload effects (as reflected by the pulmonary capillary wedge pressure [PCWP]) of an intravenous furosemide bolus were studied in 33 patients. In those patients receiving no vasoactive drug and in those receiving predominantly preload reducing agents, there was an initial rise in PCWP up until 15 minutes followed by a diuresis-induced fall in PCWP below baseline levels at 1 h. Patients who were receiving preload and significant afterload reduction showed an immediate drop in PCWP which was sustained. This trend is independent of underlying pathology or dose of furosemide used. It is postulated that furosemide causes an early deleterious release of endogenous vasoconstrictors which may be blocked by combined preload and afterload reduction.
Publisher: Oxford University Press (OUP)
Date: 23-12-2015
DOI: 10.1093/CID/CIV1199
Abstract: Antimicrobial de-escalation (ADE) is a strategy to reduce the spectrum of antimicrobials and aims to prevent the emergence of bacterial resistance. We present a systematic review describing the definitions, determinants and outcomes associated with ADE. We included 2 randomized controlled trials and 12 cohort studies. There was considerable variability in the definition of ADE. It was more frequently performed in patients with broad-spectrum and/or appropriate antimicrobial therapy (P= .05 to .002), when more agents were used (P= .002), and in the absence of multidrug-resistant pathogens (P< .05). Where investigated, lower or improving severity scores were consistently associated with ADE (P= .04 to <.001). The pooled effect of ADE on mortality is protective (relative risk, 0.68 95% confidence interval, .52-.88). Because the determinants of ADE are markers of clinical improvement and/or of lower risk of treatment failure this effect on mortality cannot be retained as evidence. None of the studies were designed to investigate the effect of ADE on antimicrobial resistance.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1093/BJA/AEL286
Abstract: The central venous catheter (CVC) is associated with numerous complications more so during the process of insertion. We report for the first time how an indwelling catheter was entrapped by a replacement catheter on the same side, after being speared by the introducer needle and guidewire. The diagnosis was made when there was difficulty in removing the old catheter. Subsequently, interventional radiology services were used to define the problem and help in removal of the entrapped catheter. The mechanism of entrapment and the actual procedure used for removal of the catheter is described. The dangers of insertion of a CVC on the same side as a pre-existing one are highlighted.
Publisher: Oxford University Press (OUP)
Date: 29-08-2022
DOI: 10.1093/JAC/DKAC273
Abstract: To compare the bacterial killing and emergence of resistance of intermittent versus prolonged (extended and continuous infusions) infusion dosing regimens of piperacillin/tazobactam against two Escherichia coli clinical isolates in a dynamic hollow-fibre infection model (HFIM). Three piperacillin/tazobactam dosing regimens (4/0.5 g 8 hourly as 0.5 and 4 h infusions and 12/1.5 g/24 h continuous infusion) against a ceftriaxone-susceptible, non-ESBL-producing E. coli 44 (Ec44, MIC 2 mg/L) and six piperacillin/tazobactam dosing regimens (4/0.5 g 8 hourly as 0.5 and 4 h infusions and 12/1.5 g/24 h continuous infusion 4/0.5 g 6 hourly as 0.5 and 3 h infusions and 16/2 g/24 h continuous infusion) were simulated against a ceftriaxone-resistant, AmpC- and ESBL-producing E. coli 50 (Ec50, MIC 8 mg/L) in a HFIM over 7 days (initial inoculum ∼107 cfu/mL). Total and less-susceptible subpopulations and MICs were determined. All simulated dosing regimens against Ec44 exhibited 4 log10 of bacterial killing over 8 h without regrowth and resistance emergence throughout the experiment. For Ec50, there was the initial bacterial killing of 4 log10 followed by regrowth to 1011 cfu/mL within 24 h against all simulated dosing regimens, and the MICs for resistant subpopulations exceeded 256 mg/L at 72 h. Our study suggests that, for critically ill patients, conventional intermittent infusion, or prolonged infusions of piperacillin/tazobactam may suppress resistant subpopulations of non-ESBL-producing E. coli clinical isolates. However, intermittent, or prolonged infusions may not suppress the resistant subpopulations of AmpC- and ESBL-producing E. coli clinical isolates. More studies are required to confirm these findings.
Publisher: American Society for Microbiology
Date: 2009
DOI: 10.1128/AAC.00718-08
Abstract: Burn tissue sites are a potential source of bacteremia during debridement surgery. Burn injury is likely to affect the distribution of antibiotics to tissues, but direct evidence of this is lacking. The aim of this study was to directly evaluate the influence of burn trauma on the distribution of cephalothin to peripheral tissues. We used subcutaneous microdialysis techniques to monitor interstitial fluid concentrations of cephalothin in the burnt and nonburnt tissues of adult patients with severe burns following parenteral administration of 1 g cephalothin for surgical prophylaxis. Analogous simultaneous studies conducted with healthy adult volunteers provided reference tissue concentration data. Equivalent tissue exposures were seen for burn and nonburn sites, giving overall median interstitial cephalothin concentrations (from 0 to 240 min) of 2.84 mg/liter and 3.06 mg/liter, respectively. A lower overall median interstitial cephalothin concentration of 0.54 mg/liter was observed for healthy in iduals, and the patient nonburnt tissue and volunteer control tissue cephalothin concentrations exhibited significantly different data distributions ( P 0.001 Kolmogorov-Smirnov nonparametric test). The duration of tissue residence for cephalothin was longer for burn patients than for healthy volunteers. The results demonstrate the potential fallibility of using healthy population models to extrapolate tissue pharmacodynamic predictions from plasma data for burn patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2015
Publisher: Oxford University Press (OUP)
Date: 16-10-2012
DOI: 10.1093/CID/CIS856
Abstract: Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival. Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43% P = .037), but ICU-free days (19.5 vs 17 days P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.
Publisher: Informa UK Limited
Date: 22-03-2014
DOI: 10.1586/14787210.2014.902308
Abstract: Stewardship of all antimicrobials, including β-lactam antibiotics, has gained in prominence over the last decade. Appropriate use of these agents has become vitally important especially in the treatment and management of the critically ill. Opportunities therefore exist to develop innovations to optimise the use of antimicrobials in places like the intensive care unit. The next few years represent an important window in which routine antimicrobial stewardship principles such as surveillance of local ecology, minimising overlap of spectrum of activity and prompt de-escalation upon review of cultures can be integrated with new technologies including improved diagnostic techniques, in idualised dosing strategies and computerised decision support. It is important though, that these measures to improve stewardship in the intensive care unit continue to be critically evaluated in the literature.
Publisher: American Society for Microbiology
Date: 15-11-2022
DOI: 10.1128/AAC.00321-22
Abstract: Critically ill patients are characterized by substantial pathophysiological changes that alter the pharmacokinetics (PK) of hydrophilic antibiotics, including carbapenems. Meropenem is a key antibiotic for multidrug-resistant Gram-negative bacilli, and such pathophysiological alterations can worsen treatment outcomes.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-0818-8
Abstract: Continuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. In a nested cohort within a large randomized controlled trial, we assessed the effect of higher (40 mL/kg per hour) and lower (25 mL/kg per hour) intensity CRRT on antibiotic pharmacokinetics. We collected serial blood s les to measure ciprofloxacin, meropenem, piperacillin-tazobactam, and vancomycin levels. We calculated extracorporeal clearance (CL), systemic CL, and volume of distribution (Vd) by non-linear mixed-effects modelling. We assessed the influence of CRRT intensity and other patient factors on antibiotic pharmacokinetics. We studied 24 patients who provided 179 pairs of s les. Extracorporeal CL increased with higher-intensity CRRT but the increase was significant for vancomycin only (mean 28 versus 22 mL/minute P = 0.0003). At any given prescribed CRRT effluent rate, extracorporeal CL of in idual antibiotics varied widely, and the effluent-to-plasma concentration ratio decreased with increasing effluent flow. Overall, systemic CL varied to a greater extent than Vd, particularly for meropenem, piperacillin, and tazobactam, and large intra-in idual differences were also observed. CRRT dose did not influence overall (systemic) CL, Vd, or half-life. The proportion of systemic CL due to CRRT varied widely and was high in some cases. In patients receiving CRRT, there is great variability in antibiotic pharmacokinetics, which complicates an empiric approach to dosing and suggests the need for therapeutic drug monitoring. More research is required to investigate the apparent relative decrease in clearance at higher CRRT effluent rates. ClinicalTrials.gov NCT00221013 . Registered 14 September 2005.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.BURNS.2011.12.018
Abstract: The principal aim of this study was to describe infection related characteristics of blood stream infections (BSI) in patients with burns. We sought to determine the organisms that caused BSI and factors that could predict the outcome of BSI. Data was collected on admitted patients with burns from January 1998 to December 2008. Selected information from databases was analysed using SPSS version 17 (SPSS Inc., Chicago). Descriptive, univariate and multivariate analysis was undertaken to determine factors predictive of clinical outcome. The factors analysed by univariate analysis were selected on clinical plausibility. Multivariate analysis used a crosstabs procedure initially to estimate maximum likelihood. Factors that were associated with a p value <0.15 were entered into a binary logistic regression to detect which factors were independent predictors of mortality in BSI and outcome according to specific organisms. Ninety-nine out of 2364 (4%) patients developed 212-documented BSI. The median time from burn to BSI was 7 (interquartile range 3-16) days. Gram-positive organisms, in particular Methicillin resistant Staphylococcus aureus and Coagulase negative Staphylococci, were the most common bacteria associated with BSI in the first week of hospital admission. The mortality rate for all admissions over the data collection period was 3%. Of the 99 patients with BSI, 13 died giving a mortality rate, in the presence of BSI, of 13%. Univariate analysis found that the factors predictive of P. aeruginosa mortality were inhalational injury, higher total body surface area burns, total days of antibiotic treatment and elevated Acute Physiological and Chronic Health Evaluation (APACHE) II scores. Multivariate analysis identified inhalational injury to be the only factor associated with BSI-related mortality. Whilst the overall mortality in our cohort was low, the presence of BSI increased this four-fold. Whilst infections caused by Gram-positive pathogens occurred earlier in the patient stay than Gram-negative organisms, the highest mortality was associated with P. aeruginosa infections. This study highlights the negative effects of BSI on clinical outcomes in burn patients.
Publisher: Oxford University Press (OUP)
Date: 15-11-2000
DOI: 10.1086/317462
Abstract: Nosocomial meningitis due to gram-negative organisms is a difficult clinical problem to manage because of both antibiotic resistance and poor penetration of many antimicrobials across the blood-brain barrier. Ciprofloxacin has potential in treating this condition when used in high doses. We investigated the plasma and cerebrospinal fluid (CSF) levels of ciprofloxacin in a patient with Pseudomonas aeruginosa meningitis who was treated with 400 mg of intravenous ciprofloxacin every 8 hours. Ciprofloxacin levels in plasma peaked at 10.29 mg/L without resulting in accumulation (8-hour trough levels, <1 mg/L), whereas the CSF level increased to 0.9 mg/L. This CSF level was confirmed to be similar 1 week later. After 1 week of therapy, during which there were no side effects attributable to ciprofloxacin, the organism was eradicated, and there was some clinical improvement. We recommend that 400 mg of intravenous ciprofloxacin every 8 hours be considered for treatment of difficult-to-treat gram-negative bacillary meningitis.
Publisher: Wiley
Date: 10-07-2017
DOI: 10.1002/BMC.4030
Abstract: Through blocking the cardiac persistent sodium current, riluzole has the potential to prevent myocardial damage post cardiac bypass surgery. A sensitive UHPLC-MS/MS method was developed and validated for quantitation of riluzole and 5-methoxypsoralen in human plasma and myocardial tissue homogenate using a liquid-liquid extraction with dichloromethane. The chromatographic separation was achieved using Shimadzu Shim-pack XR-ODS III, 2.0 × 50 mm, 1.6 μm column with a gradient mobile phase comprising methanol and ammonium acetate buffer pH 3.6 in purified water. The analyte and internal standard were separated within 3.5 min. Riluzole quantitation was achieved using the mass transitions of 235-138 for riluzole and 217-156 for 5-methoxypsoralen. The method was linear for riluzole plasma concentrations from 0.2 to 500 ng/mL and myocardial tissue homogenate concentrations from 0.2 to 100 ng/mL. The method developed was successfully applied to a clinical study for patients receiving riluzole while undergoing cardiac bypass surgery.
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.HRTLNG.2006.10.008
Abstract: To investigate the effect of 90 degrees lateral positioning on oxygenation, respiratory mechanics, and hemodynamics in ventilated intensive care patients. Thirty-four subjects (mean age = 46.1 +/- 17.3 years) with no, unilateral, or bilateral pulmonary infiltrates on chest radiograph participated. Arterial blood gas, respiratory mechanic, and hemodynamic data were analyzed at the supine starting position (T0), then 30 minutes and 2 hours into the lateral turn (T30 and T120, respectively) and 30 minutes post return to the supine position (T150). No difference was found in PaO(2)/FiO(2) due to positioning patients from supine to lateral (P = .15) regardless of the underlying lung pathology. Dynamic compliance decreased during lateral positioning, particularly in the subjects with no lung pathology (T0 = 56 +/- 18.6 > (T30 = 49.9 +/- 18 T120 = 49.2 +/- 17) L/cmH(2)0, P (T30 = 36.6 +/- 8.8 T120 = 37.3 +/- 9.5) L/cmH(2)0, P < .01). Blood pressure and heart rate were unaffected, but cardiac index significantly increased at T30 (T0 = 3.7 +/- 1.2, T30 = 4.8 +/- 1.3 L/min/m(2), P < .01). While the incidence of adverse events was high (21%), they were primarily minor and transient. In this heterogeneous population, lateral positioning had no beneficial effect on gas exchange. However, in ventilated patients who were hemodynamically stable, it was well tolerated and not associated with significant serious adverse events.
Publisher: Springer Science and Business Media LLC
Date: 02-2001
Abstract: To measure plasma levels and pharmacokinetics of cefpirome in critically ill septic patients with normal renal function. To use the pharmacokinetic model to simulate alternate dosing regimens and identify those that predict sustained levels. A prospective, open-label, descriptive study in a 22-bed, multidisciplinary, adult ICU in a university-affiliated, tertiary referral hospital. Twelve adults with normal renal function on enrollment and with suspected or documented sepsis in whom cefpirome was judged to be the appropriate therapy by the managing clinician. Cefpirome 2 g was infused intravenously over 3 min every 12 h. Timed blood s les were taken prior to and during two dosing intervals. Urine was collected for creatinine clearance determination. Two patients were non-evaluable due to renal dysfunction post-enrollment. The median cefpirome trough level was 1.1 mg/l (range 0.5-8.1 mg/l) after the initial dose and 1.4 mg/l (range < 0.5-15.9 mg/l) at 'steady state'. The volumes of distribution and elimination half-lives were greater and more variable than in healthy volunteers. Pharmacokinetic simulation predicted that more frequent bolus dosing, increased doses and continuous infusions would result in concentrations greater than 4 mg/l for over 60% of the dosing interval for all patients. Cefpirome 2 g twice daily produced low plasma troughs in a number of patients. Our data suggest that this drug regimen may be inadequate for successful treatment of difficult-to-treat infections in critically ill patients with normal renal function.
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.IJANTIMICAG.2016.12.014
Abstract: In highly invasive procedures such as open heart surgery, the risk of post-operative infection is particularly high due to exposure of the surgical field to multiple foreign devices. Adequate antibiotic prophylaxis is an essential intervention to minimise post-operative morbidity and mortality. However, there is a lack of clear understanding on the adequacy of traditional prophylactic dosing regimens, which are rarely supported by data. The aim of this structured review is to describe the relevant pharmacokinetic harmacodynamic (PK/PD) considerations for optimal antibiotic prophylaxis for major cardiac surgery including cardiopulmonary bypass (CPB). A structured review of the relevant published literature was performed and 45 relevant studies describing antibiotic pharmacokinetics in patients receiving extracorporeal CPB as part of major cardiac surgery were identified. Some of the studies suggested marked PK alterations in the peri-operative period with increases in volume of distribution (V
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-0750-Y
Abstract: The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic harmacodynamic (PK/PD) target attainment (time above MIC ( f T MIC )) in critically ill patients with sepsis receiving intermittent dosing. To be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood s les were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CL CR ). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% f T MIC was calculated for varying MIC and CL CR values. In total, 48 patients provided data. Increasing CL CR values were associated with lower trough plasma piperacillin concentrations ( P 0.01), such that with an MIC of 16 mg/L, 100% f T MIC would be achieved in only one-third ( n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CL CR ( r = 0.58, P 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% f T MIC , was noted with increasing CL CR measures. Standard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CL CR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JPBA.2017.10.023
Abstract: Piperacillin-tazobactam is a beta-lactam/beta-lactamase combination antibiotic used in patients with moderate to severe infection. Dosing of piperacillin-tazobactam requires an understanding of this patient group to maximise the effectiveness of this antibiotic and limit a further emergence of resistant pathogens. This is the first method that measures piperacillin and tazobactam simultaneously, across this range of clinically-relevant biological matrices. The calibration line was linear across the concentration range of 0.5-500μg/mL for piperacillin and 0.625-62.5μg/mL for tazobactam. All validation testing for matrix effects, precision and accuracy, specificity and stability were within 15%. A calibration equivalence study was performed to investigate the suitability of applying calibration curves prepared in an alternative matrix, with a mean bias of -10.8% identified for the application of a calibration line prepared for tazobactam in plasma only. Bias for all other calibration lines prepared in alternate matrices was within the 5% acceptance criteria. The method was successfully applied to a pharmacokinetic study of a critically ill patient receiving renal replacement therapy, with the results included.
Publisher: Springer Science and Business Media LLC
Date: 15-01-2002
DOI: 10.1007/S00134-002-1212-Y
Abstract: To determine the pharmacokinetic profile of ciprofloxacin 20 mg/kg per day (10 mg/kg administered intravenously 12 hourly) in paediatric patients with severe sepsis. Open and prospective. Tertiary referral multi-disciplinary ICU. Twenty patients (two groups - group A: 3 months-1 year group B 1-5 years). Timed blood s les were taken for pharmacokinetics after the first dose (D(0)), as well as day 2 (D(2)) and then between days 6-8. Ciprofloxacin serum levels were measured by high performance liquid chromatography. Demographic and clinical data and all adverse events were noted. Standard pharmacokinetic variables were calculated by non-compartmental methods. Peak concentrations (C(max)) for group A were D(0) 6.1+/-1.2 mg/l, D(2) 9.0+/-1.8 mg/l and D(7) 5.8+/-1.3 mg/l and, for group B, 7.4+/-1.3 mg/l, 7.8+/-1.6 mg/l and 6.4+/-1.3 mg/l, respectively, for the study periods. Concentration 12 h after the start of infusion (C(min)) for all periods were 0.2 mg/l or less. Areas under the curve (AUC, 12 h) were group A: 15.6+/-1.3, 19.2+/-1.63 and 14.1+/-1.4 mg/h per l, and group B: 15.9+/-1.3, 18.0+/-1.7 and 13.2+/-1.26 mg/h per l. One patient presenting with seizures, initially controlled, had another convulsion and a further patient developed seizures whilst on ciprofloxacin. C(max) in these patients were higher than the average C(max). The convulsions of both patients were easily controlled. No other drug-related serious adverse events occurred. No arthropathy was noted. Three patients died of their underlying disease. There was no accumulation of drug even after 7 days of administration. Our C(max) and AUC were lower than that achieved in a similar adult pharmacokinetic study. To achieve end points of area under the inhibitory curve (AUIC) of 100-150 mg/h per l, 10 mg/kg ciprofloxacin eight hourly would be required for some resistant ICU organisms.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.CHEST.2016.10.057
Abstract: A proposed revision of sepsis definitions has abandoned the systemic inflammatory response syndrome (SIRS), defined organ dysfunction as an increase in total Sequential Organ Function Assessment (SOFA) score of ≥ 2, and conceived "qSOFA" (quick SOFA) as a bedside indicator of organ dysfunction. We aimed to (1) determine the prognostic impact of SIRS, (2) compare the diagnostic accuracy of SIRS and qSOFA for organ dysfunction, and (3) compare standard (Sepsis-2) and revised (Sepsis-3) definitions for organ dysfunction in ED patients with infection. Consecutive ED patients admitted with presumed infection were prospectively enrolled over 3 years. Sufficient observational data were collected to calculate SIRS, qSOFA, SOFA, comorbidity, and mortality. We enrolled 8,871 patients, with SIRS present in 4,176 (47.1%). SIRS was associated with increased risk of organ dysfunction (relative risk [RR] 3.5) and mortality in patients without organ dysfunction (OR 3.2). SIRS and qSOFA showed similar discrimination for organ dysfunction (area under the receiver operating characteristic curve, 0.72 vs 0.73). qSOFA was specific but poorly sensitive for organ dysfunction (96.1% and 29.7%, respectively). Mortality for patients with organ dysfunction was similar for Sepsis-2 and Sepsis-3 (12.5% and 11.4%, respectively), although 29% of patients with Sepsis-3 organ dysfunction did not meet Sepsis-2 criteria. Increasing numbers of Sepsis-2 organ system dysfunctions were associated with greater mortality. SIRS was associated with organ dysfunction and mortality, and abandoning the concept appears premature. A qSOFA score ≥ 2 showed high specificity, but poor sensitivity may limit utility as a bedside screening method. Although mortality for organ dysfunction was comparable between Sepsis-2 and Sepsis-3, more prognostic and clinical information is conveyed using Sepsis-2 regarding number and type of organ dysfunctions. The SOFA score may require recalibration.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.BURNS.2008.01.011
Abstract: Excessive fluid resuscitation of large burn injuries has been associated with adverse outcomes. We reviewed our experience in patients with major-burn injury to assess the relationship between fluid, clinical outcome and cause of variance from expected resuscitation volumes as defined by the Parkland formula. Eighty patients with new burns > or =15% total body surface area (TBSA) admitted to the intensive care unit within 48 h of injury were included. Mean fluid volume was 6.0+/-2.3 mL/kg/% TBSA at 24h. Bolus fluids for hypotension and oliguria explained 39% of excess variance from Parkland estimates and inaccurate burn size and weight assessment explained 9% of variance. Higher fluid volume was associated with pneumonia (adjusted odds ratio [AOR]=2.0 95% confidence interval [CI] 1.2-3.4) and extremity compartment syndrome (AOR=7.9 95% CI 2.4-26). Colloid use during the first 24h reduced the risk of extremity compartment syndrome (AOR=0.06 95% CI 0.007-0.49) and renal failure (AOR=0.11 95% CI 0.014-0.82). In-hospital mortality was low (10%) and not associated with >125% Parkland resuscitation (P=0.39). Although fluid resuscitation in excess of the Parkland formula was associated with several adverse events, mortality was low. A multi-centre trial is needed to more specifically define the indications and volumes needed for burns fluid resuscitation and revise traditional formulae emphasising patient outcome. Improved training in burn size assessment is needed.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.IJANTIMICAG.2015.02.017
Abstract: Acute kidney injury is a common complication in critically ill patients, and hybrid techniques including sustained low-efficiency dialysis/diafiltration (SLED-f) are being increasingly utilised in intensive care units. Most fungal infections occur in the interstitial fluid (ISF) of tissues and successful treatment of a fungal infection relies on the ability of an antifungal agent to achieve adequate concentrations at the site of infection. Tissue distribution of antimicrobials is impaired in critically ill patients owing to a variety of disease-related physiological changes, e.g. sepsis. Fluconazole is a widely used antifungal agent used to treat Candida spp. infections in critically ill patients. The implications for ISF concentrations of enhanced elimination during renal replacement therapy have not yet been reported for fluconazole. The aim of this single-patient case report was to describe the influence of SLED-f on subcutaneous (SC) ISF concentrations of fluconazole and the implications for achieving pharmacokinetic harmacodynamic targets. Serial blood and ISF s les were collected at pre- and post-filter ports within the SLED-f circuit and subcutaneously inserted microdialysis probe, respectively. Fluconazole concentrations were measured using a validated chromatography method. The SC ISF-to-plasma partition coefficient of fluconazole in this patient was 0.91, indicating rapid equilibrium. SC ISF fluconazole concentrations consistently decreased after initiating SLED-f. The majority of the fluconazole was eliminated from the SC ISF as a result of redistribution. Considering the extensive tissue re-distribution of fluconazole and observed elimination from tissue compartments, higher doses may be required to treat deep-seated fungal infections.
Publisher: Springer Science and Business Media LLC
Date: 29-12-2017
DOI: 10.1007/S00134-017-5036-1
Abstract: Antimicrobial resistance (AMR) is a clear and present danger to patients in any intensive care unit (ICU) around the world. Whereas AMR may affect any patient in the hospital, patients in the ICU are particularly at risk of acquiring AMR infections due to the intensity of the treatment, use of invasive devices, increased risk of transmission and exposure to antibiotics. AMR is present in every ICU, although prevalence is geographically different and AMR pathogens encountered are variable. Intensive care and infectious disease specialists from the European Society of Intensive Care Medicine, European Society of Microbiology and Infectious Diseases and World Alliance Against Antimicrobial Resistance, united in the ANTARCTICA (Antimicrobial Resistance in Critical Care) coalition, call for increased awareness and action among health care professionals to reduce AMR development in critically ill patients, to improve treatment of AMR infections and to coordinate scientific research in this high-risk patient population. Close collaboration with other specialties, and combining these and other interventions in antibiotic stewardship programmes should be a priority in every ICU. Considerate antibiotic use and adopting strict infection control practices to halt AMR remains a responsibility shared by all healthcare workers, from physicians to maintenance personnel, from nurses to physiotherapists, from consultants to medical students. Together, we can reduce AMR in our ICUs and continue to treat our patients effectively.
Publisher: Mary Ann Liebert Inc
Date: 10-02-2017
Abstract: Furosemide, a loop diuretic, is used to increase urine output in patients with acute kidney injury (AKI). It remains uncertain whether the benefits of furosemide in AKI outweigh its potential harms. We investigated if furosemide influenced oxidative stress in 30 critically ill patients with AKI by measuring changes in F
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.IJANTIMICAG.2015.02.014
Abstract: Here we describe the pharmacokinetics of piperacillin administered by continuous infusion (CI) versus intermittent bolus (IB) dosing in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and compare the frequency of pharmacodynamic harmacokinetic (PK/PD) target attainment with each dosing strategy. This was a prospective pharmacokinetic trial in 16 critically ill patients with severe sepsis or septic shock undergoing CVVH and randomised to receive either CI or IB administration of a standard daily dose of piperacillin/tazobactam (11.25g/day on Day 1 followed by 9g/day). Serial blood s les were measured on two occasions. Piperacillin pharmacokinetics were calculated using a non-compartmental approach. Blood concentrations were compared with established PK/PD targets. On occasion 1 (Days 1-3 of therapy), IB administration resulted in significantly higher piperacillin peak concentrations (169 vs. 89mg/L P=0.002), whereas significantly higher steady-state concentrations were observed in CI patients (83 vs. 57mg/L P=0.04). Total clearance and clearance not mediated by CVVH were significantly higher with CI administration [median (interquartile range), 1.0 (0.7-1.1) and 0.8 (0.6-1.0)mL/kg/min P=0.001 and 0.001, respectively]. The estimated unbound piperacillin concentrations were four times above the target susceptibility breakpoint (16mg/L) for the entire dosing interval (100%fT>4xMIC) in 87.5% of patients receiving CI administration (s ling occasion 1), compared with 62.5% of IB patients achieving the desired target (50%fT>4xMIC). Compared with IB dosing, and despite similar CVVH settings, CI administration of piperacillin results in a pharmacokinetic profile that may optimise outcomes for less susceptible pathogens.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2009
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.IJANTIMICAG.2022.106591
Abstract: To describe epidemiology and age-related mortality in critically ill older adults with intra-abdominal infection. A secondary analysis was undertaken of a prospective, multi-national, observational study (Abdominal Sepsis Study, ClinicalTrials.gov #NCT03270345) including patients with intra-abdominal infection from 309 intensive care units (ICUs) in 42 countries between January and December 2016. Mortality was considered as ICU mortality, with a minimum of 28 days of observation when patients were discharged earlier. Relationships with mortality were assessed by logistic regression analysis. The cohort included 2337 patients. Four age groups were defined: middle-aged patients [reference category 40-59 years n=659 (28.2%)], young-old patients [60-69 years n=622 (26.6%)], middle-old patients [70-79 years n=667 (28.5%)] and very old patients [≥80 years n=389 (16.6%)]. Secondary peritonitis was the predominant infection (68.7%) and was equally prevalent across age groups. Mortality increased with age: 20.9% in middle-aged patients, 30.5% in young-old patients, 31.2% in middle-old patients, and 44.7% in very old patients (P 60 years was associated with mortality patients aged ≥80 years had the worst prognosis. Comorbidities and overall disease severity further compromised survival. As all of these factors are non-modifiable, it remains unclear how to improve outcomes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2015
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.IJANTIMICAG.2013.01.018
Abstract: Treatment of resistant bacteria such as meticillin-resistant Staphylococcus aureus (MRSA) relies on achieving adequate antibiotic concentrations at the site of infection. Strategies to attain such targets in septic critically ill patients receiving renal replacement therapy (RRT) are uncommon but could be useful for increasing the likelihood of therapeutic dosing. The aim of this study was to conduct a population pharmacokinetic (PK) analysis in septic patients undergoing continuous RRT and to determine which parameters were associated with inadequate vancomycin concentrations. In total, 81 patients with 199 blood s les were included in the study. All patients received vancomycin dosing according to the local protocol, which included a weight-based loading dose followed by continuous infusion. The vancomycin concentration-time points were adequately described with a one-compartment model with zero order input. The median population PK estimate for vancomycin clearance (CL) was 2.9 L/h [interquartile range (IQR) 2.4-3.4 L/h] and for volume of distribution (Vd) was 0.8 L/kg (IQR 0.6-1.1 L/kg). The goodness-of-fit plots for the model were adequate. When covariates were tested, none were found to adequately explain changing vancomycin CL or Vd in the population PK model. In particular, the lack of correlation between CL and RRT settings was likely due to the multiple confounders known to influence antibiotic prescription in this setting. These data provide a cautionary tale of the challenges of describing pharmacokinetics in critically ill patients receiving RRT and highlights the need for a detailed, prospective, multicentre study to better inform dosing practice.
Publisher: Public Library of Science (PLoS)
Date: 25-06-2012
Publisher: S. Karger AG
Date: 2010
DOI: 10.1159/000321488
Abstract: i Background: /i Appropriate antibacterial therapy is important to maximize patient survival in sepsis. Acute renal failure complicates optimal antibiotic administration. i Methods: /i MEDLINE search from 1986 to 2010 using the terms ‘acute renal failure’, ‘pharmacokinetics’, ‘clearance’, ‘dosage’, ‘h(a)emofiltration’, ‘h(a)emodialysis’, ‘h(a)emodiafiltration’, ‘continuous renal replacement therapy’, ‘antibiotics’, ‘intensive care’ and ‘critically ill’. i Results: /i Maximal bacterial killing and minimization of side effects depend on achieving pharmacokinetic targets appropriate to the selected antibacterial agent. Volume of distribution and clearance may be altered by critical illness and/or acute kidney injury. Clearance is determined by nonrenal clearance, residual renal clearance and continuous renal replacement therapy dose. Sieving and saturation coefficients are membrane specific, but may be altered by changes in protein binding induced by critical illness. A significant proportion of studies failed to report the essential dataset required for adequate antibacterial dosage calculation. i Conclusions: /i In idualized dosing based on first principles may be the most appropriate method of dosing, particularly when enhanced by therapeutic drug monitoring.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JCRC.2014.08.004
Abstract: Life-sustaining treatment (LST) limitation for elderly patients is highly controversial. In that context, it is useful to evaluate the attitudes to LST in the elderly among experienced intensive care unit (ICU) physicians with different backgrounds and cultures. A panel of 22 international ICU physicians from 13 countries responded to a questionnaire related to withholding (WH) and withdrawing (WD) LST in elderly patients using a semi-Likert scale. Most experts disagree or strongly disagree (77%) that age should be used as the sole criterion for WH or WD LST, and almost all disagree (91%) that there should be a specific age for such decision making. However, the vast majority (91%) acknowledge that age should be an important consideration in conjunction with other factors. Disagreement for consideration of prioritizing the young over the old in normal ICU operations was reported in 68%, whereas in an emergency triage situation, disagreement dropped to 18%. There is a consensus among ICU physicians that age cannot be the sole criterion on which health care decisions should be made. In that perspective, it is important to provide data showing that outcome differences between elderly and nonelderly patients are partly related to decisions to forgo LSTs.
Publisher: MDPI AG
Date: 27-03-2022
DOI: 10.3390/ANTIBIOTICS11040452
Abstract: Multidrug resistant organisms (MDRO) are commonly isolated in respiratory specimens taken from mechanically ventilated patients. The purpose of this narrative review is to discuss the approach to antimicrobial prescription in ventilated patients who have grown a new MDRO isolate in their respiratory specimen. A MEDLINE and PubMed literature search using keywords “multidrug resistant organisms”, “ventilator-associated pneumonia” and “decision making”, “treatment” or “strategy” was used to identify 329 references as background for this review. Lack of universally accepted diagnostic criteria for ventilator-associated pneumonia, or ventilator-associated tracheobronchitis complicates treatment decisions. Consideration of the clinical context including signs of respiratory infection or deterioration in respiratory or other organ function is essential. The higher the quality of respiratory specimens or the presence of bacteremia would suggest the MDRO is a true pathogen, rather than colonization, and warrants antimicrobial therapy. A patient with higher severity of illness has lower safety margins and may require initiation of antimicrobial therapy until an alternative diagnosis is established. A structured approach to the decision to treat with antimicrobial therapy is proposed.
Publisher: American Society for Microbiology
Date: 12-2011
DOI: 10.1128/AAC.00424-11
Abstract: Fluconazole is a widely used antifungal agent that is extensively reabsorbed in patients with normal renal function. However, its reabsorption can be compromised in patients with acute kidney injury, thereby leading to altered fluconazole clearance and total systemic exposure. Here, we explore the pharmacokinetics of fluconazole in 10 critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF). We performed Monte Carlo simulations to optimize dosing to appropriate pharmacodynamic endpoints for this population. Pharmacokinetic profiles of initial and steady-state doses of 200 mg intravenous fluconazole twice daily were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis and to perform Monte Carlo simulations. For each dosing regimen, the free drug area under the concentration-time curve (fAUC)/MIC ratio was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values. A two-compartment model adequately described the disposition of fluconazole in plasma. The estimate for total fluconazole clearance was 2.67 liters/h and was notably 2.3 times faster than previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CL CVVHDF ) represented 62% of its total systemic clearance. Furthermore, the predicted efficiency of CL CVVHDF decreased to 36.8% when filters were in use h. Monte Carlo simulations demonstrated that a dose of 400 mg twice daily maximizes empirical treatment against fungal organisms with MIC up to 16 mg/liter. This is the first study we are aware of that uses Monte Carlo simulations to inform dosing requirements in patients where tubular reabsorption of fluconazole is probably nonexistent.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.CMI.2016.10.023
Abstract: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2010
Publisher: MDPI AG
Date: 08-03-2022
DOI: 10.3390/ANTIBIOTICS11030362
Abstract: Bloodstream infections (BSIs) in critically ill patients are associated with significant mortality. For patients with septic shock, antibiotics should be administered within the hour. Probabilistic treatment should be targeted to the most likely pathogens, considering the source and risk factors for bacterial resistance including local epidemiology. Source control is a critical component of the management. Sending blood cultures (BCs) and other specimens before antibiotic administration, without delaying them, is key to microbiological diagnosis and subsequent opportunities for antimicrobial stewardship. Molecular rapid diagnostic testing may provide faster identification of pathogens and specific resistance patterns from the initial positive BC. Results allow for antibiotic optimisation, targeting the causative pathogen with escalation or de-escalation as required. Through this clinically oriented narrative review, we provide expert commentary for empirical and targeted antibiotic choice, including a review of the evidence and recommendations for the treatments of extended-spectrum β-lactamase-producing, AmpC-hyperproducing and carbapenem-resistant Enterobacterales carbapenem-resistant Acinetobacter baumannii and Staphylococcus aureus. In order to improve clinical outcomes, dosing recommendations and pharmacokinetics harmacodynamics specific to ICU patients must be followed, alongside therapeutic drug monitoring.
Publisher: Oxford University Press (OUP)
Date: 1991
DOI: 10.1093/JAC/28.5.753
Abstract: Three hundred and forty eight critically-ill patients with a documented Gram-negative infection were randomized to receive amikacin once- (od) or twice-daily (bd). The amikacin was given by slow intravenous injection in a daily dose of 20 mg/kg in patients under the age of one year (paediatric group) and 15 mg/kg in patients over the age of one year (adult group). Paediatric and adult patients on the od regimen received a loading dose of 25 and 20 mg/kg respectively. The dosages were subsequently adjusted to achieve desirable blood levels. Patients received other antibiotics as clinically indicated. Forty-eight patients were withdrawn from the study due to death or azotaemia occurring in the first 72 h. One hundred and fifty five patients (76 paediatric) received an od dose and 145 (65 paediatric) received a bd dose. The clinical cure rate was 83% in the od group compared to 66% in the bd group (P = 0.001). The bacteriological cure rate was 81% in the od group compared to 58% in the bd group (P = 0.005). In the paediatric sub-group the cure rate was higher with the od regimen (P = 0.002) but this difference was not statistically significant in the adult patients (P = 0.1). The serum creatinine rose in 35% of patients in the bd group compared to 21% in the od group (P = 0.05). Although audiometry was not performed there was no clinical evidence of ototoxicity in any of the patients. In conclusion od amikacin dosing resulted in a higher cure and less nephrotoxicity than conventional bd dosing.
Publisher: Springer Singapore
Date: 2018
Publisher: Elsevier BV
Date: 06-2018
Publisher: Wiley
Date: 11-1996
DOI: 10.1111/J.1365-2044.1996.TB15002.X
Abstract: We report the case of a 48-year-old woman, referred to the Intensive Care Unit with community-acquired pneumonia, who was noted to have stridor of acute onset. Subsequent indirect laryngoscopy revealed bilateral abductor vocal cord paralysis, secondary to unsuspected carcinoma of the oesophagus, requiring immediate tracheostomy. We highlight the importance of visualisation of the vocal cords in cases of stridor of uncertain aetiology.
Publisher: Wiley
Date: 20-01-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: Springer Science and Business Media LLC
Date: 06-04-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2009
Publisher: Oxford University Press (OUP)
Date: 15-03-2018
DOI: 10.1093/CID/CIS311
Publisher: BMJ
Date: 14-11-2011
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1093/BJA/AEX026
Abstract: Perioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative re-dosing of cefazolin is commonly given between 2 and 5 h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. Patients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h -1 ) of cefazolin until skin closure. Blood s les were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics ® software. Calculations of PTA and FTA were performed for common pathogens. Ten patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44-80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean ( sd ) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h -1 . Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. Our study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens. NCT02058979.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2006
Publisher: American Society for Microbiology
Date: 04-2015
DOI: 10.1128/JCM.03239-14
Abstract: Colonization with Candida species is an independent risk factor for invasive candidiasis (IC), but the minimum and most practicable parameters for prediction of IC have not been optimized. We evaluated Candida colonization in a prospective cohort of 6,015 nonneutropenic, critically ill patients. Throat, perineum, and urine were s led 72 h post-intensive care unit (ICU) admission and twice weekly until discharge or death. Specimens were cultured onto chromogenic agar, and a subset underwent molecular characterization. Sixty-three (86%) patients who developed IC were colonized prior to infection 61 (97%) tested positive within the first two time points. The median time from colonization to IC was 7 days (range, 0 to 35). Colonization at any site was predictive of IC, with the risk of infection highest for urine colonization (relative risk [RR] = 2.25) but with the sensitivity highest (98%) for throat and/or perineum colonization. Colonization of ≥2 sites and heavy colonization of ≥1 site were significant independent risk factors for IC (RR = 2.25 and RR = 3.7, respectively), increasing specificity to 71% to 74% but decreasing sensitivity to 48% to 58%. Molecular testing would have prompted a resistance-driven decision to switch from fluconazole treatment in only 11% of patients infected with C. glabrata , based upon species-level identification alone. Positive predictive values (PPVs) were low (2% to 4%) and negative predictive values (NPVs) high (99% to 100%) regardless of which parameters were applied. In the Australian ICU setting, culture of throat and perineum within the first two time points after ICU admission captures 84% (61/73 patients) of subsequent IC cases. These optimized parameters, in combination with clinical risk factors, should strengthen development of a setting-specific risk-predictive model for IC.
Publisher: Mary Ann Liebert Inc
Date: 2017
Abstract: Augmented renal clearance (ARC) is being increasingly described in neurocritical care practice. The mechanisms driving this phenomenon are largely unknown. The aim of this project was therefore to explore changes in renal function, cardiac output (CO), and atrial natriuretic peptide (ANP) concentrations in patients with isolated traumatic brain injury (TBI). This prospective observational cohort study was conducted in a tertiary-level, university-affiliated intensive care unit (ICU). Patients with normal plasma creatinine concentrations (<120 μmol/L) at admission and no history of chronic kidney disease, admitted with isolated TBI, were eligible for enrollment. Continuous CO measures were obtained using arterial pulse waveform analysis. Eight-hour urinary creatinine clearances (CL
Publisher: Springer Science and Business Media LLC
Date: 21-12-2021
DOI: 10.1007/S40262-021-01062-6
Abstract: The aim of this study was to report the pharmacokinetics (PK) of caspofungin in plasma and peritoneal fluid and to identify optimal dosing strategies in septic patients with intra-abdominal infections. Eleven patients with secondary peritonitis with septic shock received the standard dosing regimen of caspofungin. Total caspofungin plasma and peritoneal concentrations were subject to a population PK analysis using Pmetrics Fat-free mass (FFM) was retained in the final model of caspofungin, reporting a total clearance (standard deviation) of 0.78 (0.17) L/h and a central volume of distribution of 9.36 (2.61) L. The peritoneal fluid lasma ratio of caspofungin was 33% on the first day of therapy (AUC There is moderate penetration of caspofungin into the peritoneal cavity (33%). For empirical treatment, a dose escalation of 100 mg loading dose on the first day is suggested for higher FFM to ensure adequate concentrations into the abdominal cavity for the most susceptible candida species.
Publisher: Wiley
Date: 07-2017
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/CC12544
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.IJANTIMICAG.2011.11.002
Abstract: Optimising antimicrobial dosing for critically ill patients is highly challenging and when it is not achieved can lead to worse patient outcomes. To this end, use of dosing regimens recommended in package inserts from drug manufacturers is frequently insufficient to guide dosing in these patients appropriately. Whilst the effect of critical illness pathophysiology on the pharmacokinetic (PK) behaviour of antimicrobials can be profound, the variability of these changes between patients is still being quantified. The PK effects of hypoproteinaemia, organ dysfunction and the presence of augmented renal clearance may lead to plasma antimicrobial concentrations that are difficult to predict at the bedside, which may result in excess toxicity or suboptimal bacterial killing. This paper outlines the factors that affect pharmacokinetics in critically ill patients and how knowledge of these factors can increase the likelihood of achieving optimal antimicrobial plasma concentrations. In selected settings, we advocate in idualised dosing of renally cleared antimicrobials using physiological data such as measured creatinine clearance and published non-renal clearance data. Where such data do not exist, therapeutic drug monitoring may be a useful alternative and has been associated with significant clinical benefits, although it is not currently widely available.
Publisher: Springer Science and Business Media LLC
Date: 2014
DOI: 10.1186/CC13874
Publisher: SAGE Publications
Date: 20-06-2014
Abstract: Objective: To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections. Case Summary: We present a case of a 36-year-old man who was admitted to the intensive care unit with diffuse central nervous system and peripheral methicillin-sensitive Staphylococcus aureus infection (minimum inhibitory concentration MIC, 1 µg/mL). Owing to the complicated nature of the infection, sequential concentrations of free flucloxacillin were measured in plasma and cerebrospinal fluid (CSF) and used to direct antibiotic dosing. Unsurprisingly, the trough plasma concentrations of flucloxacillin were below the MIC (0.2-0.4 µg/mL), and the corresponding CSF concentrations were undetectable ( .1 µg/mL) with standard intermittent bolus dosing of 2 g every 4 hours. By administering flucloxacillin by continuous infusion (CI) and increasing the dose to 20 g daily, the plasma (2.2-5.7 µg/mL) and CSF (0.1 µg/mL) levels were increased, albeit lower than the predefined targets (plasma, 40 µg/mL CSF, 4 µg/mL). Discussion: The presence of physiological changes associated with critical illness—namely, hypoalbuminemia and augmented renal clearance—may significantly alter antibiotic pharmacokinetics, and this phenomenon may lead to suboptimal antibiotic exposure if they are not accounted for. This case also highlights the value of applying CI in such patient groups and demonstrates the significance of monitoring plasma and CSF drug concentrations in optimizing antibiotic delivery. Conclusions: Future research should aim to evaluate the utility of such drug monitoring with regard to patient outcomes and cost-effectiveness.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
Publisher: Bentham Science Publishers Ltd.
Date: 11-2010
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.IJANTIMICAG.2014.01.009
Abstract: This prospective pharmacokinetic study aimed to describe plasma and interstitial fluid (ISF) pharmacokinetics of piperacillin and tazobactam in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF). Piperacillin/tazobactam (4g/0.5g) was administered every 8h and CVVHDF was performed as a 3-3.5L/h exchange using a polyacrylonitrile filter with a surface area of 1.05m(2). Serial blood (pre- and post-filter), filtrate/dialysate, urine and ISF concentrations were measured. Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 407 s les were collected. Median peak plasma concentrations were 210.5 (interquartile range=161.5-229.0) and 29.4 (27.9-32.0) mg/L and median trough plasma concentrations were 64.3 (49.0-68.9) and 12.3 (7.7-13.7) mg/L for piperacillin and tazobactam, respectively. The plasma elimination half-life was 6.4 (4.6-8.7) and 7.3 (4.6-11.8) h, volume of distribution 0.42 (0.29-0.49) and 0.32 (0.24-0.36) L/kg, total clearance 5.1 (4.2-6.2) and 3.8 (3.3-4.2) L/h and CVVHDF clearance 2.5 (2.3-3.1) and 2.5 (2.3-3.2) L/h for piperacillin and tazobactam, respectively. The tissue penetration ratio or ratio of area under the concentration-time curve of the unbound drug in ISF to plasma (unbound AUCISF/AUCplasma) was ca. 1 for both piperacillin and tazobactam. This is the first report of concurrent plasma and ISF concentrations of piperacillin and tazobactam during CVVHDF. For the CVVHDF settings used in this study, a dose of 4.5g piperacillin/tazobactam administered evry 8h resulted in piperacillin concentrations in plasma and ISF >32mg/L throughout most of the dosing interval.
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.51893/2021.1.OA5
Abstract: Background: Nosocomial pneumonia in the critical care setting is associated with increased morbidity, significant crude mortality rates and high health care costs. Ventilator-associated pneumonia represents about 80% of nosocomial pneumonia cases in intensive care units (ICUs). Wide variance in incidence of nosocomial pneumonia and diagnostic techniques used has been reported, while successful treatment remains complex and a matter of debate. Objective: To describe the epidemiology, diagnostic strategies and treatment modalities for nosocomial pneumonia in contemporary ICU settings across multiple countries around the world. Design, setting and patients: PneumoINSPIRE is a large, multinational, prospective cohort study of adult ICU patients diagnosed with nosocomial pneumonia. Participating ICUs from at least 20 countries will collect data on 10 or more consecutive ICU patients with nosocomial pneumonia. Site-specific information, including hospital policies on antibiotic therapy, will be recorded along with patient-specific data. Variables that will be explored include: aetiology and antimicrobial resistance patterns, treatment-related parameters (including time to initiation of antibiotic therapy, and empirical antibiotic choice, dose and escalation or de-escalation), pneumonia resolution, ICU and hospital mortality, and risk factors for unfavourable outcomes. The concordance of ventilator-associated pneumonia diagnosis with accepted definitions will also be assessed. Results and conclusions: PneumoINSPIRE will provide valuable information on current diagnostic and management practices relating to ICU nosocomial pneumonia, and identify research priorities in the field. Trial registration: ClinicalTrials.gov identifier NCT02793141.
Publisher: Elsevier BV
Date: 2011
Publisher: Oxford University Press (OUP)
Date: 30-11-2010
DOI: 10.1093/JAC/DKQ449
Abstract: Infections in critically ill patients continue to result in unacceptably high morbidity and mortality. Although few data exist for correlating antibiotic exposure with outcome, antibiotic dosing is likely to be highly important for maximizing resolution of infection in many patients. The practical and financial difficulties of performing pharmacokinetic (PK) studies in critically ill patients mean that analyses to maximize data such as Monte Carlo simulation (MCS) are highly valuable. MCS uses computer software to perform virtual clinical trials. The building blocks for MCS are: firstly, a robust population PK model from the patient population of interest secondly, descriptors of the effect of covariates that influence the PK parameters thirdly, description of the susceptibility of bacteria to the antibiotic and finally a PK harmacodynamic (PD) target associated with antibiotic efficacy. Probability of target attainment (PTA) outputs can then be generated that describe the proportion of patients that will achieve a pre-specified PD target for an MIC distribution. Such analyses can then inform dosing requirements, which can be used to have a high likelihood of achieving PK/PD targets for organisms with different MICs. In this issue of JAC, Zelenitsky et al. provide a very useful ex le of MCS for interpreting the optimal methods for dosing meropenem, piperacillin/tazobactam, cefepime and ceftobiprole in critically ill patients.
Publisher: Elsevier BV
Date: 06-2014
Publisher: Springer Science and Business Media LLC
Date: 08-01-2015
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.DIAGMICROBIO.2015.01.013
Abstract: Determining appropriate antibiotic dosing for critically ill patients receiving renal replacement therapy (RRT) is complex. Worldwide unstandardized and heterogeneous prescribing of RRT as well as altered patient physiology and pathogen susceptibility all cause drug disposition to be much different to that seen in non-critically ill patients. Significant changes to pharmacokinetic parameters, including volume of distribution and clearance, could be expected, in particular, for antibiotics that are hydrophilic with low plasma protein binding and that are usually primarily eliminated by the renal system. Antibiotic clearance is likely to be significantly increased when higher RRT intensities are used. The combined effect of these factors that alter antibiotic disposition is that non-standard dosing strategies should be considered to achieve therapeutic exposure. In particular, an aggressive early approach to dosing should be considered and this may include administration of a 'loading dose', to rapidly achieve therapeutic concentrations and maximally reduce the inoculum of the pathogen. This approach is particularly important given the pharmacokinetic changes in the critically ill as well as the increased likelihood of less susceptible pathogens. Dose in idualization that applies knowledge of the RRT and patient factors causing altered pharmacokinetics remains the key approach for ensuring effective antibiotic therapy for these patients. Where possible, therapeutic drug monitoring should also be used to ensure more accurate therapy. A lack of pharmacokinetic data for antibiotics during the prolonged intermittent RRT and intermittent hemodialysis currently limits evidence-based antibiotic dose recommendations for these patients.
Publisher: Springer Science and Business Media LLC
Date: 2014
DOI: 10.1186/CC13767
Publisher: Springer Science and Business Media LLC
Date: 18-04-2016
Publisher: Bentham Science Publishers Ltd.
Date: 11-2010
Publisher: Informa UK Limited
Date: 31-12-2015
DOI: 10.3109/23744235.2015.1021831
Abstract: A 35-year-old patient in intensive care with severe burn injury developed episodes of sepsis. Blood culture yielded a multidrug-resistant Pseudomonas aeruginosa and treatment was commenced with amikacin (minimum inhibitory concentration (MIC) 2-4 mg/L, dose 20 mg/kg adjusted body weight 24-hourly) and meropenem (MIC 8 mg/L, dose 2 g IV 8-hourly and later 6-hourly). Despite the use of extended infusions with β-lactam therapeutic drug monitoring and doses that were more than 2.5 times higher than standard meropenem doses, resistance emerged. This case report describes the application of therapeutic drug monitoring to optimize β-lactam therapy in a difficult-to-treat critically ill patient.
Publisher: Springer Science and Business Media LLC
Date: 04-2004
DOI: 10.1007/S00134-004-2157-0
Abstract: To determine the population incidence and outcome of severe sepsis occurring in adult patients treated in Australian and New Zealand intensive care units (ICUs), and compare with recent retrospective estimates from the USA and UK. Inception cohort study. Twenty-three closed multi-disciplinary ICUs of 21 hospitals (16 tertiary and 5 university affiliated) in Australia and New Zealand. A total of 5878 consecutive ICU admission episodes. Main outcome measures were population-based incidence of severe sepsis, mortality at ICU discharge, mortality at 28 days after onset of severe sepsis, and mortality at hospital discharge. A total of 691 patients, 11.8 (95% confidence intervals 10.9-12.6) per 100 ICU admissions, were diagnosed with 752 episodes of severe sepsis. Site of infection was pulmonary in 50.3% of episodes and abdominal in 19.3% of episodes. The calculated incidence of severe sepsis in adults treated in Australian and New Zealand ICUs is 0.77 (0.76-0.79) per 1000 of population. 26.5% of patients with severe sepsis died in ICU, 32.4% died within 28 days of the diagnosis of severe sepsis and 37.5% died in hospital. In this prospective study, 11.8 patients per 100 ICU admissions were diagnosed with severe sepsis and the calculated annual incidence of severe sepsis in adult patients treated in Australian and New Zealand ICUs is 0.77 per 1000 of population. This figure for the population incidence falls in the lower range of recent estimates from retrospective studies in the U.S. and the U.K.
Publisher: Wiley
Date: 11-1994
DOI: 10.1111/J.1365-2044.1994.TB04316.X
Abstract: We compared three arterial line insertion techniques and two types of arterial catheters in 69 critically ill patients. Use of the direct-puncture technique (method A) was associated with a significantly higher failure rate (23%) than use of a catheter with a separate guide wire (method B, 'classical' Seldinger technique, p < 0.001) or a catheter with an integral guide wire (method C, 'modified' Seldinger technique, p < 0.02). Operators randomly allocated to using method A took significantly longer to perform the procedure than those using method C (p < 0.01), used significantly more catheters (p < 0.0001) and made significantly more punctures in achieving a successful insertion than those using either methods B (p < 0.001) or C (p < 0.001). Both catheter types B and C (polyurethane) were significantly less likely to block, thus requiring less likely to block, thus requiring re-insertion, than catheter type A (Teflon) (p < 0.02, p < 0.01 respectively). We recommend the use of a 'classical' Seldinger technique (method B) for arterial line insertion in critically ill patients and the use of a polyurethane catheter, in preference to Teflon, to maximise catheter life after insertion.
Publisher: American Society for Microbiology
Date: 12-2009
DOI: 10.1128/AAC.01600-08
Abstract: Cephalothin (cefalotin) pharmacokinetics were evaluated for nine severely burned patients (42% ± 9% mean burn areas) and five healthy volunteers by using non-plasma-protein-bound concentration-time profiles. Burn patients gave increased mean residence times (36%) and reduced total clearances (25%). Mean residence times and distribution volumes increased between 1 and 4 days posttrauma, suggesting that burn patient pharmacokinetics change during the initial fluid resuscitation phase of treatment.
Publisher: Wiley
Date: 10-06-2008
DOI: 10.1111/J.1365-2044.2008.05477.X
Abstract: The effect of charcoal haemoperfusion on the pharmacokinetics of diltiazem is described in a patient with severe clinical toxicity following acute overdose. The patient presented within 3 h following acute ingestion of multiple medications including sustained-release diltiazem. Routine resuscitation and supportive care were administered, but hypotension did not resolve despite intravenous fluids and infusions of calcium, adrenaline, noradrenaline and vasopressin. Multiple-doses of activated charcoal, haemodialysis and charcoal haemoperfusion were prescribed to expedite the elimination of diltiazem. The maximum diltiazem concentration (577 microg.l(-1)) was recorded 7 h post ingestion which was followed by an erratic and prolonged elimination phase. The maximum clearance of diltiazem due to haemoperfusion was calculated to be 19.4 and 15.1 ml.min(-1) at different times, equating to removal of approximately 1.5 mg diltiazem during 4 h of haemoperfusion. Haemoperfusion did not appear to remove sufficient diltiazem to recommend its routine use in the treatment of patients with acute diltiazem overdose.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2013
Publisher: Springer Science and Business Media LLC
Date: 11-01-2011
DOI: 10.1007/S10096-010-1146-1
Abstract: Surveillance cultures may detect colonisation with drug-resistant Gram-negative bacteria and can be hypothesised to guide appropriate initial antibiotic treatment for intensive care unit (ICU) patients. We investigated the microbiological data of 228 episodes of nosocomial bloodstream infection (BSI) due to Gram-negative bacteria in an ICU in which piperacillin/tazobactam or meropenem was used empirically for serious infections, to evaluate the contribution of surveillance cultures to an appropriate choice of initial antibiotic therapy. Surveillance cultures were taken in advance of BSI in 218 (95.6%) of 228 episodes. Concordant organisms with identical identification and susceptibilities were found in prior surveillance cultures and subsequent blood cultures in 65 (29.8%) of 218 episodes. Surveillance cultures predicted resistance in 52.9% and 51.4% of BSIs caused by resistant pathogens to piperacillin/tazobactam and meropenem, respectively. The negative predictive value of surveillance cultures negative for a resistant organism also exceeded 90% for piperacillin/tazobactam and meropenem. Given that the overall resistant rates of BSI pathogens of our study were 11.3% to piperacillin/tazobactam and 16.4% to meropenem, surveillance cultures in our setting may provide important information on the probability of drug resistance of the causative pathogens and some utility in aiding empiric antibiotic therapy for ICU patients who subsequently develop BSI.
Publisher: Springer Science and Business Media LLC
Date: 11-11-2014
DOI: 10.1007/S40262-014-0209-3
Abstract: Optimal antibacterial dosing is imperative for maximising clinical outcome. Many factors can contribute to changes in the pharmacokinetics of antibacterials to the extent where dose adjustment may be needed. In acute illness, substantial changes in important pharmacokinetic parameters such as volume of distribution and clearance can occur for certain antibacterials. The possibility of interethnic pharmacokinetic differences can further complicate attempts to design an appropriate dosing regimen. Factors of ethnicity, such as genetics, body size and fat distribution, contribute to differences in absorption, distribution, metabolism and elimination of drugs. Despite extensive previous work on the altered pharmacokinetics of antibacterials in some patient groups such as the critically ill, knowledge of interethnic pharmacokinetic differences for antibacterials is limited. This systematic review aims to describe any pharmacokinetic differences in antibacterials between different ethnic groups, and discuss their probable mechanisms as well as any clinical implications. We performed a structured literature review to identify and describe available data of the interethnic differences in the pharmacokinetics of antibacterials. We found 50 articles that met our inclusion criteria and only six of these compared antibacterial pharmacokinetics between different ethnicities within the same study. Overall, there was limited evidence available. We found that interethnic pharmacokinetic differences are negligible for carbapenems, most β-lactams, aminoglycosides, glycopeptides, most fluoroquinolones, linezolid and daptomycin, whereas significant difference is likely for ciprofloxacin, macrolides, clindamycin, tinidazole and some cephalosporins. In general, subjects of Asian ethnicity achieve drug exposures up to two to threefold greater than Caucasian counterparts for these antibacterials. This difference is caused by a comparatively lower volume of distribution and/or drug clearance. Interethnic pharmacokinetic differences of antibacterials are likely however, the clinical relevance of these differences is unknown and warrants further research.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2013
Publisher: Elsevier BV
Date: 02-2018
Publisher: Elsevier BV
Date: 07-2012
Abstract: β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets. Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR). Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis. Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.IJANTIMICAG.2009.10.008
Abstract: The objectives of this study were (i) to compare the plasma concentration-time profiles for first-dose and steady-state piperacillin administered by intermittent or continuous dosing to critically ill patients with sepsis and (ii) to use population pharmacokinetics to perform Monte Carlo dosing simulations in order to assess the probability of target attainment (PTA) by minimum inhibitory concentration (MIC) for different piperacillin dosing regimens against bacterial pathogens commonly encountered in critical care units. Plasma s les were collected on Days 1 and 2 of therapy in 16 critically ill patients, with 8 patients receiving intermittent bolus dosing and 8 patients receiving continuous infusion of piperacillin (administered with tazobactam). A population pharmacokinetic model was developed using NONMEM, which found that a two-compartment population pharmacokinetic model best described the data. Total body weight was found to be correlated with drug clearance and was included in the final model. In addition, 2000 critically ill patients were simulated for pharmacodynamic evaluation of PTA by MIC [free (unbound) concentration maintained above the MIC for 50% of the dosing interval (50% f(T>MIC))] and it was found that continuous infusion maintained superior free piperacillin concentrations compared with bolus administration across the dosing interval. Dosing simulations showed that administration of 16g/day by continuous infusion vs. bolus dosing (4g every 6h) provided superior achievement of the pharmacodynamic endpoint (PTA by MIC) at 93% and 53%, respectively. These data suggest that administration of piperacillin by continuous infusion, with a loading dose, both for first dose and for subsequent dosing achieves superior pharmacodynamic targets compared with conventional bolus dosing.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1093/BJA/AEM080
Publisher: Springer Science and Business Media LLC
Date: 09-06-2020
Publisher: Public Library of Science (PLoS)
Date: 08-12-2015
Publisher: Oxford University Press (OUP)
Date: 02-1999
DOI: 10.1093/JAC/43.2.309
Abstract: We randomized 18 critically ill patients to receive ceftazidime 6 g/day by continuous infusion or bolus dosing (2 g 8 hourly), each with a loading dose of 12 mg/kg ceftazidime. During the first 8 h, plasma ceftazidime concentration fell below 40 mg/L in only one patient (trough 38 mg/L) from the infusion group, compared with eight from the bolus group (2-33 mg/L) for periods ranging from 73 to 369 min. Thereafter all infusion patients remained above 40 mg/L for 40 h of study versus 20-30% of bolus patients. The pharmacokinetic and pharmacodynamic characteristics of ceftazidime suggest that continuous infusions should be clinically investigated in outcome studies.
Publisher: Wiley
Date: 06-09-2007
DOI: 10.1111/J.1365-2044.2007.05217.X
Abstract: Severe tetanus is seen infrequently in the developed world, but often requires intensive care support. Mechanical ventilation with neuromuscular blockade and heavy sedation, good wound care and prompt administration of antitoxin are important. The management of autonomic dysfunction remains challenging. We measured serum catecholamine levels in a patient with severe tetanus in whom autonomic crises were a major and persistent feature, and investigated the impact of sedatives plus alpha(2)-agonists on these levels. Serum adrenaline levels were elevated up to 100-fold with clinically observed crises, although noradrenaline levels were much more difficult to interpret. There was no appreciable difference in catecholamine levels following administration of alpha(2)-agonists in the doses we used, although clonidine did allow easier control of crises with other agents. This case highlights some important lessons in the management of severe tetanus.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.IJANTIMICAG.2011.07.013
Abstract: The prevalence of invasive fungal infections (IFIs) caused by Candida spp. is increasing in critically ill patients. Recent development of new antifungal agents has significantly contributed to the successful treatment of IFIs. However, the pharmacokinetics of antifungal agents can be altered in a number of disease states, including critical illness. Therefore, doses established in healthy volunteers and other patient groups may not be appropriate for the critically ill. Moreover, inadequate dosing may contribute to treatment failure and the emergence of resistance. This systematic review provides a critical analysis of the pharmacokinetics of antifungal agents in the critically ill and their relevance to dosing requirements in clinical practice. Based on the limited data available, dosing of some antifungal agents may have to be adjusted in critically ill patients with conserved renal function as well as in those requiring renal replacement therapy. Further research to confirm the appropriateness of current dosing strategies to attain the appropriate pharmacodynamic targets is recommended.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.IJANTIMICAG.2016.02.017
Abstract: Although there is a biological precedent for administration of β-lactam antibiotics by continuous or extended infusion, there is no definitive evidence of a survival benefit compared with intermittent administration. The aim of this study was to explore clinician uncertainty with regard to the administration of β-lactam antibiotics by continuous infusion. Doctors and pharmacists in Australian and New Zealand intensive care units (ICUs) were surveyed to investigate current β-lactam antibiotic administration practices as well as the degree of uncertainty regarding the benefit of continuous infusion of two commonly used broad-spectrum β-lactams, namely meropenem and piperacillin/tazobactam (TZP). There were 111 respondents to the survey. Intermittent infusion was reported as standard practice for meropenem (73.9%) and TZP (82.0%). A greater proportion of pharmacists compared with doctors believed continuous infusion to be more effective than intermittent administration (85.4% vs. 34.3%, respectively P <0.001). Both groups reported uncertainty as to whether administration by continuous infusion resulted in better patient outcomes (65.9% and 74.6%, respectively P = 0.85). Overall, 91.0% of respondents were prepared to enrol eligible patients into a definitive randomised controlled trial on β-lactam antibiotic administration. In conclusion, there is equipoise among clinicians working in Australian and New Zealand ICUs as to whether administration by continuous infusion offers a survival benefit in critically ill patients.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.IJANTIMICAG.2016.09.021
Abstract: In the absence of specific data to guide optimal dosing, this study aimed to describe the pharmacokinetics of ceftriaxone in severely septic Australian Indigenous patients and to assess achievement of the pharmacodynamic target of the regimens prescribed. A pharmacokinetic study was conducted in a remote hospital intensive care unit in patients receiving ceftriaxone dosing of 1 g every 12 h (q12h). Serial blood and urine s les were collected over one dosing interval on two consecutive days. S les were assayed using a validated chromatography method for total and unbound concentrations. Concentration-time data collected were analysed with a non-compartmental approach. A total of 100 plasma s les were collected from five subjects. Ceftriaxone clearance, volume of distribution at steady-state, elimination half-life and elimination rate constant estimates were 0.9 (0.6-1.5) L/h, 11.2 (7.6-13.4) L, 9.5 (3.2-10.2) h and 0.07 (0.07-0.21) h
Publisher: Springer Science and Business Media LLC
Date: 1982
DOI: 10.1007/BF01686855
Abstract: Proteins are marginally stable molecules that fluctuate between folded and unfolded states. Here, we provide a high-resolution description of unfolded states under refolding conditions for the N-terminal domain of the L9 protein (NTL9). We use a combination of time-resolved Förster resonance energy transfer (FRET) based on multiple pairs of minimally perturbing labels, time-resolved small-angle X-ray scattering (SAXS), all-atom simulations, and polymer theory. Upon dilution from high denaturant, the unfolded state undergoes rapid contraction. Although this contraction occurs before the folding transition, the unfolded state remains considerably more expanded than the folded state and accommodates a range of local and nonlocal contacts, including secondary structures and native and nonnative interactions. Paradoxically, despite discernible sequence-specific conformational preferences, the ensemble-averaged properties of unfolded states are consistent with those of canonical random coils, namely polymers in indifferent (theta) solvents. These findings are concordant with theoretical predictions based on coarse-grained models and inferences drawn from single-molecule experiments regarding the sequence-specific scaling behavior of unfolded proteins under folding conditions.
Publisher: American Medical Association (AMA)
Date: 02-12-2009
Abstract: Infection is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. However, relatively little information is available about the global epidemiology of such infections. To provide an up-to-date, international picture of the extent and patterns of infection in ICUs. The Extended Prevalence of Infection in Intensive Care (EPIC II) study, a 1-day, prospective, point prevalence study with follow-up conducted on May 8, 2007. Demographic, physiological, bacteriological, therapeutic, and outcome data were collected for 14,414 patients in 1265 participating ICUs from 75 countries on the study day. Analyses focused on the data from the 13,796 adult (>18 years) patients. On the day of the study, 7087 of 13,796 patients (51%) were considered infected 9084 (71%) were receiving antibiotics. The infection was of respiratory origin in 4503 (64%), and microbiological culture results were positive in 4947 (70%) of the infected patients 62% of the positive isolates were gram-negative organisms, 47% were gram-positive, and 19% were fungi. Patients who had longer ICU stays prior to the study day had higher rates of infection, especially infections due to resistant staphylococci, Acinetobacter, Pseudomonas species, and Candida species. The ICU mortality rate of infected patients was more than twice that of noninfected patients (25% [1688/6659] vs 11% [ 682/6352], respectively P < .001), as was the hospital mortality rate (33% [2201/6659] vs 15% [ 942/6352], respectively P < .001) (adjusted odds ratio for risk of hospital mortality, 1.51 95% confidence interval, 1.36-1.68 P < .001). Infections are common in patients in contemporary ICUs, and risk of infection increases with duration of ICU stay. In this large cohort, infection was independently associated with an increased risk of hospital death.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2013
Publisher: Elsevier BV
Date: 06-2012
Publisher: MDPI AG
Date: 14-10-2021
DOI: 10.3390/ANTIBIOTICS10101246
Abstract: Ventriculitis, or infection of the cerebrospinal fluid, in the presence of external ventricular drains (EVD), is an important complication and associated with substantial mortality, morbidity, and healthcare costs. Further, the conditions that require the insertion of an EVD, such as neurotrauma and subarachnoid hemorrhage, are themselves associated with inflammation of the cerebrospinal fluid. Phenotypically, patients with inflammation of the cerebrospinal fluid can present with very similar symptoms, signs, and laboratory findings to those with infection. This review examines various controversies relating to the definitions, diagnosis, challenges of differentiating infection from inflammation, prevention, and treatment of ventriculitis in patients with EVDs.
Publisher: Springer Science and Business Media LLC
Date: 05-2000
Abstract: The cutaneous and splanchnic circulations undergo early vasoconstriction in shock. Methodological problems and insufficient information on subcutaneous carbon dioxide partial pressures limit the usefulness of previous studies on splanchnic and subcutaneous gas tensions in shock. Little comparative data exist on the responses of these tissues to shock and resuscitation. We therefore compared continuous subcutaneous PO2 (PO2sc) and PCO2 (PCO2sc) with simultaneous continuous gut luminal PCO2 (PCO2gi) in an animal model of haemorrhagic shock and resuscitation. Prospective observational study. Intensive care laboratory in a teaching hospital. Five anaesthetised rats. Electrochemical-fiberoptic gas sensors inserted into Silastic tubing placed in the subcutaneous tissue and in the ileal lumen measured PCO2sc, PO2sc and PCO2gi continuously in five anaesthetised rats. After steady state conditions, hypotension [mean arterial blood pressure (MAP) 40 mmHg] was induced by controlled haemorrhage. The rats were allowed to remain hypotensive for 15 min and then resuscitated with shed blood and crystalloids. Arterial plasma lactate concentrations were measured at defined periods during the study. Hypovolaemia resulted in a significant decrease in PO2sc (P < 0.01) and a significant increase in PCO2gi and PCO2sc (P < 0.05). These values returned to baseline with resuscitation. PO2sc appeared to respond to haemorrhage earlier than PCO2gi and PCO2sc (P = 0.02). PO2sc was inversely correlated with PCO2gi (r2 0.7, P < 0.001). There were no significant changes in arterial plasma lactate concentrations. In our rat model, subcutaneous oxygen tension provided similar information to ileal luminal PCO2 and was more rapidly responsive than subcutaneous carbon dioxide tensions and arterial lactate during evolving haemorrhagic shock and resuscitation.
Publisher: MDPI AG
Date: 24-03-2022
DOI: 10.3390/ANTIBIOTICS11040434
Abstract: Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma s les were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients.
Publisher: American Society for Microbiology
Date: 12-2016
DOI: 10.1128/AAC.01657-16
Abstract: There are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis. A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit. Plasma s les were collected over two dosing intervals and assayed by validated chromatography. Population pharmacokinetic modeling was conducted using Pmetrics. Nine patients were recruited, and a two-compartment model adequately described the data. The piperacillin clearance (CL), volume of distribution of the central compartment ( V c ), and distribution rate constants from the central to the peripheral compartment and from the peripheral to the central compartment were 5.6 ± 3.2 liters/h, 14.5 ± 6.6 liters, 1.5 ± 0.4 h −1 , and 1.8 ± 0.9 h −1 , respectively, where CL and V c were found to be described by creatinine clearance (CL CR ) and total body weight, respectively. In this patient population, piperacillin demonstrated high interin idual pharmacokinetic variability. CL CR was found to be the most important determinant of piperacillin pharmacokinetics.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2016
Publisher: Cambridge University Press (CUP)
Date: 08-2004
DOI: 10.1086/502456
Abstract: To determine the effect of routine intravenous (IV) administration set changes on central venous catheter (CVC) colonization and catheter-related bacteremia. Prospective, randomized, controlled trial. Eighteen-bed intensive care unit (ICU) in a large metropolitan hospital. Two hundred fifty-one patients with 404 chlorhexidine gluconate and silver sulfadiazine–coated multilumen CVCs. CVCs inserted in the ICU and in situ on day 4 were randomized to have their IV administration sets changed on day 4 (n = 203) or not at all (n = 201). Use of fluid containers and blood product administration sets was limited to 24 hours. CVCs were removed when not required, infection was suspected, or in place on day 7. Catheter cultures were performed on removal by blinded laboratory staff. Catheter-related bacteremia was diagnosed by a blinded intensivist using strict definitions. Data were collected regarding catheter duration, site, Acute Physiology and Chronic Health Evaluation (APACHE) II score, patient age, diagnosis, hyperglycemia, hypoalbuminemia, immune status, number of fluid containers and IV injections, and administration of propofol, blood, total parenteral nutrition, or lipid infusion. There were 10 colonized CVCs in the group receiving a set change and 19 in the group not receiving one. This difference was not statistically significant on Kaplan–Meier survival analysis. There were 3 cases of catheter-related bacteremia per group. Logistic regression found that burns diagnosis and increased ICU stay significantly predicted colonization. IV administration sets can be used for 7 days in patients with short-term, antiseptic-coated CVCs.
Publisher: Springer Science and Business Media LLC
Date: 06-2015
DOI: 10.1007/S00134-015-3757-6
Abstract: To compare the effect of intensive versus conventional blood glucose control in patients with traumatic brain injury. In a large international randomized trial patients were randomly assigned to a target blood glucose (BG) range of either 4.5-6.0 mmol/L (intensive control) or <10 mmol/L (conventional control). Patients with traumatic brain injury (TBI) were identified at randomization and data were collected to examine the extended Glasgow outcome score (includes mortality) at 24 months. Of the 6104 randomized patients, 391 satisfied diagnostic criteria for TBI 203 (51.9%) were assigned to intensive and 188 (48.1%) to conventional control the primary outcome was available for 166 (81.8%) and 149 (79.3%) patients, respectively. The two groups had similar baseline characteristics. At 2 years 98 (58.7%) patients in the intensive group and 79 (53.0%) in the conventional group had a favorable neurological outcome (odds ratio [OR] 1.26, 95% CI 0.81-1.97 P = 0.3) 35 patients (20.9%) in the intensive group and 34 (22.8%) in the conventional group had died (OR 0.90, 95% CI 0.53-1.53 P = 0.7) moderate hypoglycemia (BG 2.3-3.9 mmol/L 41-70 mg/dL) occurred in 160/202 (79.2%) and 17/188 (9.0%), respectively (OR 38.3, 95% CI 21.0-70.1 P < 0.0001) severe hypoglycemia (BG ≤ 2.2 mmol/L ≤40 mg/dL) in 10 (4.9%) and 0 (0.0%), respectively (OR 20.5 95% CI 1.2-351.6, P = 0.003). Although patients with traumatic brain injury randomly assigned to intensive compared to conventional glucose control experienced moderate and severe hypoglycemia more frequently, we found no significant difference in clinically important outcomes.
Publisher: American Society for Microbiology
Date: 11-2011
DOI: 10.1128/AAC.05033-11
Abstract: Surgical site infections are common, so effective antibiotic concentrations at the sites of infection, i.e., in the interstitial fluid (ISF), are required. The aim of this study was to evaluate contemporary perioperative prophylactic dosing of cefazolin by determining plasma and subcutaneous ISF concentrations in patients undergoing elective/semielective abdominal aortic aneurysm (AAA) open repair surgery. This was a prospective pharmacokinetic study in a tertiary referral hospital. Cefazolin (2 g) was administered as a 3-min slow bolus 30 min prior to incision in 12 enrolled patients undergoing elective/semielective AAA open repair surgery. Serial blood, urine, and ISF (via microdialysis) s les were collected and analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Cardiac output was determined using pulse waveform contours with Vigileo. The recruited patients had a median (interquartile range) age of 70 (66 to 76) years and weight of 88 (81 to 95) kg. The median (interquartile range) terminal volume of distribution was 0.14 (0.11 to 0.15) liter/kg, total clearance was 0.05 (0.03 to 0.06) liter/h, and minimum observed unbound concentration was 5.7 (5.4 to 8.1) mg/liter. The penetration of unbound drug from plasma to ISF was 85% (78% to 106%). We found correlations present, albeit weak, between cefazolin clearance and cardiac output ( r 2 = 0.11) and urinary creatinine clearance ( r 2 = 0.12). In conclusion, we found that a single 2-g dose of cefazolin administered 30 min before incision provides plasma and ISF concentrations in excess of the likely MICs for susceptible pathogens in patients undergoing AAA open repair surgery.
Publisher: Oxford University Press (OUP)
Date: 11-1994
Abstract: We describe the haemodynamic and oxygen transport response in a patient undergoing exchange transfusion for severe falciparum malaria. We found that exchange transfusion produced a significant increase in left ventricular stroke work index, systemic oxygen delivery and oxygen consumption. This potentially beneficial effect of exchange transfusion has not been reported previously.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.DIAGMICROBIO.2017.12.019
Abstract: We described bacterial killing and resistance emergence at various fixed concentrations of meropenem and piperacillin/tazobactam against Pseudomonas aeruginosa and Escherichia coli. Time-kill studies were conducted utilizing nine isolates and a large range of concentrations. Within each strain and antibiotic, initial killing was similar, with concentrations ≥2×MIC. At many (strain-specific) concentrations causing substantial initial killing, regrowth occurred at 24-48h. For remaining concentrations, growth typically remained suppressed (<5-log
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.JCRC.2016.04.005
Abstract: To determine whether prophylactic inhaled heparin is effective for the prevention and treatment of pneumonia patients receiving mechanical ventilation (MV) in the intensive care unit. A phase 2, double blind randomized controlled trial stratified for study center and patient type (non-operative, post-operative) was conducted in three university-affiliated intensive care units. Patients aged ≥18years and requiring invasive MV for more than 48hours were randomized to usual care, nebulization of unfractionated sodium heparin (5000 units in 2mL) or placebo nebulization with 0.9% sodium chloride (2mL) four times daily with the main outcome measures of the development of ventilator associated pneumonia (VAP), ventilator associated complication (VAC) and sequential organ failure assessment scores in patients with pneumonia on admission or who developed VAP. Australian and New Zealand Clinical Trials Registry ACTRN12612000038897. Two hundred and fourteen patients were enrolled (72 usual care, 71 inhaled sodium heparin, 71 inhaled sodium chloride). There were no differences between treatment groups in terms of the development of VAP, using either Klompas criteria (6-7%, P=1.00) or clinical diagnosis (24-26%, P=0.85). There was no difference in the clinical consistency (P=0.70), number (P=0.28) or the total volume of secretions per day (P=.54). The presence of blood in secretions was significantly less in the usual care group (P=0.005). Nebulized heparin cannot be recommended for prophylaxis against VAP or to hasten recovery from pneumonia in patients receiving MV.
Publisher: Wiley
Date: 02-2002
DOI: 10.1046/J.1365-2648.2002.02099.X
Abstract: The ideal duration of intravascular administration set use is unknown. Studies have compared the infective implications of 1--7 days of use. The Centers for Disease Control recommend at least 3 days usage. No previous study has evaluated the accuracy of volume delivery or integrity of administration sets after prolonged use. To evaluate the accuracy and condition of intravascular administration sets used continuously for 7 days. Prospective, randomized, experimental study in the laboratory setting. Four administration sets were randomly assigned to deliver 2 mL/hour (IMEDreg syringe set 2280--0000), 20, 50 or 100 mL/hour (IMEDreg infusion sets 2210--0500) of crystalloid solution continuously for 7 days through an IMEDreg Geminireg four channel infusion pump (PC4). At study commencement and daily for 7 days, a 4-hour volume measurement and an inspection for leaks/erosion of administration sets occurred for each administration set (total measurements = 32). Mean volume outputs over 4 hours were 7.84 mL (2 mL/hour), 80.66 mL (20 mL/hour), 205.35 (50 mL/hour) and 406.37 (100 mL/hour). These differed significantly from the programmed volumes (P=0.00--0.01). Usage duration did not influence performance (F=0.866, P=0.55). Accuracy of volume delivery differed significantly with pump speed (F=106.933, P < 0.001) exhibiting increased volume to 50 mL/hour then a reduction at 100 mL/hour. Differences were within manufacturer specifications (+/-5%) and were clinically acceptable. All administration sets remained in appropriate condition displaying no leakage or erosion. There were small inaccuracies found between programmed and delivered volumes, however, there was no deterioration in performance over time. This suggests that inaccuracies were because of normal pump performance rather than the administration sets. Administration sets retain acceptable accuracy and condition after 7 days continuous use. Further research should assess the infective and other impacts of prolonged usage.
Publisher: Wiley
Date: 17-01-2012
DOI: 10.1111/J.1742-6723.2011.01516.X
Abstract: The use of appropriate resuscitation targets or end-points may facilitate early detection and appropriate management of shock. There is a fine balance between oxygen delivery and consumption, and when this is perturbed, an oxygen debt is generated. In this narrative review, we explore the value of global haemodynamic resuscitation end-points, including pulse rate, blood pressure, central venous pressure and mixed/central venous oxygen saturations. The evidence supporting the reliability of these parameters as end-points for guiding resuscitation and their potential limitations are evaluated.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2016
Publisher: Oxford University Press (OUP)
Date: 30-05-2014
DOI: 10.1093/JAC/DKU177
Abstract: Doripenem is a newer carbapenem with little data available to guide effective dosing during renal replacement therapy in critically ill patients. The objective of this study was to determine the population pharmacokinetics of doripenem in critically ill patients undergoing continuous venovenous haemodiafiltration (CVVHDF) for acute kidney injury (AKI). This was an observational pharmacokinetic study in 12 infected critically ill adult patients with AKI undergoing CVVHDF and receiving 500 mg of doripenem intravenously every 8 h as a 60 min infusion. Serial blood s les were taken on 2 days of treatment and used for population pharmacokinetic analysis with S-ADAPT. The median (IQR) age was 62 (53-71) years, the median (IQR) weight was 77 (67-96) kg and the median (IQR) APACHE II score was 29 (19-32). The median blood, dialysate and replacement fluid rates were 200, 1000 and 1000 mL/h, respectively. A two-compartment linear model with doripenem clearance described by CVVHDF, renal or non-renal mechanisms was most appropriate. The mean value for total doripenem clearance was 4.46 L/h and volume of distribution was 38.0 L. Doripenem clearance by CVVHDF was significantly correlated with the replacement fluid flow rate and accounted for ∼30%-37% of total clearance. A dose of 500 mg intravenously every 8 h achieved favourable pharmacokinetic harmacodynamics for all patients up to an MIC of 4 mg/L. This is the first paper describing the pharmacokinetics harmacodynamics of doripenem in critically ill patients with AKI receiving CVVHDF. A dose of 500 mg intravenously every 8 h was appropriate for our CVVHDF settings for infections caused by susceptible bacteria.
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2021
DOI: 10.1101/2021.03.27.21254449
Abstract: Gentamicin is recommended as first-line treatment of neonatal sepsis. The use of gentamicin is associated with toxicity which complicates neonatal dosing and necessitates therapeutic drug monitoring (TDM). In a proof-of-concept investigation, we sought to compare (1) gentamicin concentrations obtained using volumetric absorptive micros ling (VAMS) to standard TDM plasma s les, and (2) the time taken to report results obtained using VAMS compared to standard TDM by the local hospital chemical pathology service. The difference between gentamicin concentrations obtained from plasma collected for routine clinical care and calculated plasma concentrations, based on s les collected in whole blood using VAMS, was −18.0% and −0.4% for two patients. The research laboratory reported results within the time taken for the routine chemical pathology laboratory to report results. This proof-of-concept study demonstrates that the use of micros ling for TDM by pathology services can fulfil the requirements of providing an accurate gentamicin concentration in a timely manner.
Publisher: American Society for Microbiology
Date: 08-2016
DOI: 10.1128/AAC.00330-16
Abstract: Despite the development of new agents with activity against Gram-positive bacteria, vancomycin remains one of the primary antibiotics for critically ill septic patients. Because sepsis can alter antimicrobial pharmacokinetics, the development of an appropriate dosing strategy to provide adequate concentrations is crucial. The aim of this study was to prospectively validate a new dosing regimen of vancomycin given by continuous infusion (CI) to septic patients. We included all adult septic patients admitted to a mixed intensive care unit (ICU) between January 2012 and May 2013, who were treated with a new vancomycin CI regimen consisting of a loading dose of 35 mg/kg of body weight given as a 4-h infusion, followed by a daily CI dose adapted to creatinine clearance (CrCL), as estimated by the Cockcroft-Gault formula (median dose, 2,112 [1,500 to 2,838] mg). Vancomycin concentrations were measured at the end of the loading dose (T1), at 12 h (T2), at 24 h (T3), and the day after the start of therapy (T4). Vancomycin concentrations of 20 to 30 mg/liter at T2, T3, and T4 were considered adequate. A total of 107 patients (72% male) were included. Median age, weight, and CrCL were 59 (interquartile range [IQR], 48 to 71) years, 75 (IQR, 65 to 85) kg, and 94 (IQR, 56 to 140) ml/min, respectively. Vancomycin concentrations were 44 (IQR, 37 to 49), 25 (IQR, 21 to 32), 22 (IQR, 19 to 28), and 26 (IQR, 22 to 29) mg/liter at T1, T2, T3, and T4, respectively. Concentrations were adequate in 56% (60/107) of patients at T2, in 54% (57/105) at T3, and in 73% (41/56) at T4. This vancomycin regimen permitted rapid attainment of target concentrations in serum for most patients. Concentrations were insufficient in only 16% of patients at 12 h of treatment.
Publisher: American Thoracic Society
Date: 12-2015
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.IJANTIMICAG.2017.03.018
Abstract: This prospective pharmacokinetic study aimed to compare the clearance of piperacillin-tazobactam administered as a 24-h continuous infusion between continuous venovenous haemodiafiltration (CVVHDF) and continuous venovenous haemofiltration (CVVH) applied at equal dose in critically ill patients. A loading dose of 4.5 g of piperacillin-tazobactam followed by a continuous infusion (500 mg/h) was administered to patients randomized to receive CVVHDF or CVVH. Serial pre- and postfilter blood s les were drawn during an 8-h s ling interval. Piperacillin plasma concentrations were measured using a validated chromatography method. Piperacillin pharmacokinetics were calculated using a non-compartmental approach. In total, 212 piperacillin plasma concentrations were determined. Median [interquartile range (IQR)] total piperacillin clearance was 7.5 (5.9-11.2) L/h in the CVVHDF group and 4.7 (4.5-9.6) L/h in the CVVH group (P = 0.21). Median (IQR) piperacillin clearance related to continuous renal replacement therapy (CRRT) was 3.0 (2.7-3.2) L/h in the CVVHDF group and 2.6 (1.9-3.0) L/h in the CVVH group (P = 0.29). Mean (standard deviation) steady state concentrations were 68.4 (25.8) mg/L in the CVVHDF group and 89.1 (35.6) mg/L in the CVVH group (P = 0.16). The estimated unbound concentrations resulting from piperacillin continuous infusion were above the target susceptibility breakpoint (16 mg/L) for the entire dosing interval (100% fT
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2007
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.IJANTIMICAG.2016.01.009
Abstract: The increased prevalence of obesity presents challenges for clinicians aiming to provide optimised antimicrobial dosing in the intensive care unit. Obesity is likely to exacerbate the alterations to antimicrobial pharmacokinetics when the chronic diseases associated with obesity exist with the acute pathophysiological changes associated with critical illness. The purpose of this paper is to review the potential pharmacokinetic (PK) changes of antimicrobials in obese critically ill patients and the implications for appropriate dosing. We found that hydrophilic antimicrobials (e.g. β-lactams, vancomycin, daptomycin) were more likely to manifest altered pharmacokinetics in critically ill patients who are obese. In particular for β-lactam antibiotics, obesity is associated with a larger volume of distribution (V(d)). In obese critically ill patients, piperacillin is also associated with a lower drug clearance (CL). For doripenem, these PK changes have been associated with reduced achievement of pharmacodynamic (PD) targets when standard drug doses are used. For vancomycin, increases in Vd are associated with increasing total body weight (TBW), meaning that the loading dose should be based on TBW even in obese patients. For daptomycin, an increased Vd is not considered to be clinically relevant. For antifungals, little data exist in obese critically ill patients during fluconazole therapy, an obese patient had a lower V(d) and higher CL than non-obese comparators. Overall, most studies suggested that standard dosage regimens of most commonly used antimicrobials are sufficient to achieve PD targets. However, it is likely that larger doses would be required for pathogens with higher minimum inhibitory concentrations.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.IJANTIMICAG.2012.10.002
Abstract: β-Lactams are routinely prescribed in the treatment of serious infections. Empirical dosing schedules are typically derived from studies in healthy volunteers and largely fail to consider the significant changes in antibacterial pharmacokinetics often encountered in the critically ill. These changes are primarily driven by the underlying pathophysiology and the interventions provided, leading to altered protein binding, poor tissue penetration, and fluctuations in the volume of distribution and drug clearance. Each separately, and in combination, is likely to complicate successful β-lactam administration in this setting. Although antibacterial therapeutic drug monitoring (TDM) has traditionally been employed to minimise drug toxicity, the challenges to achieving 'optimal' drug concentrations in the critically ill suggest β-lactam TDM as an attractive means to optimise drug exposure. Whilst there is currently little evidence to support routine widespread application of such a service, β-lactam TDM may still have a role in select patients where difficulty in establishing therapeutic concentrations can be illustrated. This series utilises three representative cases from a β-lactam TDM service that highlight the utility of this intervention in optimising antibacterial dosing. These preliminary data support an expanding role for β-lactam TDM in select critically ill patients and provide insight into the subpopulations most at risk of suboptimal drug exposure. Future studies investigating the clinical outcome benefits of β-lactam TDM in these patient groups are now warranted.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2011
Publisher: Oxford University Press (OUP)
Date: 13-11-2006
DOI: 10.1093/JAC/DKL478
Abstract: To compare the clinical and bacteriological outcome of critically ill patients with sepsis treated by ceftriaxone administered as a once-a-day intermittent bolus dose or by 24 h continuous infusion. We conducted an open-label, randomized controlled pilot study in 57 patients clinically diagnosed with sepsis (suspected roven infection and systemic inflammatory response syndrome) in a tertiary level intensive care unit. Patients were randomized to receive 2 g of ceftriaxone administered by once-daily intermittent bolus dosing or by 24 h continuous infusion. Clinical and bacteriological outcomes were assessed by blinded clinicians. Fifty-seven patients were enrolled in the study, 50 of whom fulfilled the a priori definition of treatment for 4 or more days. The infusion (n = 29) and bolus groups (n = 28) were similar in terms of demographics, although the median age of those receiving the infusion was younger. Intention-to-treat analysis found no statistically significant differences in the primary outcomes for clinical response (P = 0.17), clinical cure [infusion n = 13/29 versus bolus n = 5/28 adjusted odds ratio (AOR) = 3.74 95% confidence interval (95% CI) = 1.11-12.57 P = 0.06], bacteriological response (P = 0.41) and bacteriological cure (infusion n = 18/29 versus bolus 14/28 AOR = 1.64 95% CI = 0.57-4.70 P = 0.52). However, logistic regression in patients that complied with the a priori definitions who received ceftriaxone by continuous infusion (AOR = 22.8 95% CI = 2.24-232.3 P = 0.008) or patients with a low Acute Physiology and Chronic Health Evaluation (APACHE) II score (AOR = 0.70 95% CI = 0.54-0.91 P = 0.008) were associated with an improved clinical outcome when age and Sepsis Organ Failure Assessment (SOFA) score at time of study entry were controlled for. This pilot study suggests clinical and bacteriological advantages of continuous infusion of ceftriaxone over bolus administration in critically ill patients in patients requiring 4 or more days of treatment. This sets the scene for a large multicentre double-blind randomized controlled trial to confirm these findings.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
Publisher: Informa UK Limited
Date: 03-09-2013
DOI: 10.3109/07420528.2013.817415
Abstract: The accurate measurement of circadian typology (CT) is critical because the construct has implications for a number of health disorders. In this review, we focus on the evidence to support the reliability and validity of the more commonly used CT scales: the Morningness-Eveningness Questionnaire (MEQ), reduced Morningness-Eveningness Questionnaire (rMEQ), the Composite Scale of Morningness (CSM), and the Preferences Scale (PS). In addition, we also consider the Munich ChronoType Questionnaire (MCTQ). In terms of reliability, the MEQ, CSM, and PS consistently report high levels of reliability (>0.80), whereas the reliability of the rMEQ is satisfactory. The stability of these scales is sound at follow-up periods up to 13 mos. The MCTQ is not a scale therefore, its reliability cannot be assessed. Although it is possible to determine the stability of the MCTQ, these data are yet to be reported. Validity must be given equal weight in assessing the measurement properties of CT instruments. Most commonly reported is convergent and construct validity. The MEQ, rMEQ, and CSM are highly correlated and this is to be expected, given that these scales share common items. The level of agreement between the MCTQ and the MEQ is satisfactory, but the correlation between these two constructs decreases in line with the number of "corrections" applied to the MCTQ. The interesting question is whether CT is best represented by a psychological preference for behavior or by using a biomarker such as sleep midpoint. Good-quality subjective and objective data suggest adequate construct validity for each of the CT instruments, but a major limitation of this literature is studies that assess the predictive validity of these instruments. We make a number of recommendations with the aim of advancing science. Future studies need to (1) focus on collecting data from representative s les that consider a number of environmental factors (2) employ longitudinal designs to allow the predictive validity of CT measures to be assessed and preferably make use of objective data (3) employ contemporary statistical approaches, including structural equation modeling and item-response models and (4) provide better information concerning s le selection and a rationale for choosing cutoff points.
Publisher: Springer Science and Business Media LLC
Date: 26-09-2012
DOI: 10.1007/S00134-012-2695-9
Abstract: The recent increase in drug-resistant micro-organisms complicates the management of hospital-acquired bloodstream infections (HA-BSIs). We investigated the epidemiology of HA-BSI and evaluated the impact of drug resistance on outcomes of critically ill patients, controlling for patient characteristics and infection management. A prospective, multicentre non-representative cohort study was conducted in 162 intensive care units (ICUs) in 24 countries. We included 1,156 patients [mean ± standard deviation (SD) age, 59.5 ± 17.7 years 65 % males mean ± SD Simplified Acute Physiology Score (SAPS) II score, 50 ± 17] with HA-BSIs, of which 76 % were ICU-acquired. Median time to diagnosis was 14 [interquartile range (IQR), 7-26] days after hospital admission. Polymicrobial infections accounted for 12 % of cases. Among monomicrobial infections, 58.3 % were gram-negative, 32.8 % gram-positive, 7.8 % fungal and 1.2 % due to strict anaerobes. Overall, 629 (47.8 %) isolates were multidrug-resistant (MDR), including 270 (20.5 %) extensively resistant (XDR), and 5 (0.4 %) pan-drug-resistant (PDR). Micro-organism distribution and MDR occurrence varied significantly (p < 0.001) by country. The 28-day all-cause fatality rate was 36 %. In the multivariable model including micro-organism, patient and centre variables, independent predictors of 28-day mortality included MDR isolate [odds ratio (OR), 1.49 95 % confidence interval (95 %CI), 1.07-2.06], uncontrolled infection source (OR, 5.86 95 %CI, 2.5-13.9) and timing to adequate treatment (before day 6 since blood culture collection versus never, OR, 0.38 95 %CI, 0.23-0.63 since day 6 versus never, OR, 0.20 95 %CI, 0.08-0.47). MDR and XDR bacteria (especially gram-negative) are common in HA-BSIs in critically ill patients and are associated with increased 28-day mortality. Intensified efforts to prevent HA-BSIs and to optimize their management through adequate source control and antibiotic therapy are needed to improve outcomes.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2017
Publisher: Informa UK Limited
Date: 24-09-2012
DOI: 10.3109/07420528.2012.719971
Abstract: The interest in the systematic study of the circadian typology (CT) is relatively recent and has developed rapidly in the two last decades. All the existing data suggest that this in idual difference affects our biological and psychological functioning, not only in health, but also in disease. In the present study, we review the current literature concerning the psychometric properties and validity of CT measures as well as in idual, environmental and genetic factors that influence the CT. We present a brief overview of the biological markers that are used to define differences between CT groups (sleep-wake cycle, body temperature, cortisol and melatonin), and we assess the implications for CT and adjustment to shiftwork and jet lag. We also review the differences between CT in terms of cognitive abilities, personality traits and the incidence of psychiatric disorders. When necessary, we have emphasized the methodological limitations that exist today and suggested some future avenues of work in order to overcome these. This is a new field of interest to professionals in many different areas (research, labor, academic and clinical), and this review provides a state of the art discussion to allow professionals to integrate chronobiological aspects of human behavior into their daily practice.
Publisher: American Society for Microbiology
Date: 06-2014
DOI: 10.1128/AAC.02340-14
Abstract: This study assessed the pharmacokinetics and dosing adequacy of piperacillin in febrile neutropenic patients after the first dose. Pharmacokinetic analysis was performed using noncompartmental methods. We observed an elevated volume of distribution (29.7 ± 8.0 liters [mean ± standard deviation]) and clearance (20.2 ± 7.5 liters/h) compared to data from other patient populations. Antibiotic exposure did not consistently result in therapeutic targets. We conclude that alternative dosing strategies guided by therapeutic drug monitoring may be required to optimize exposure.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2010
Publisher: S. Karger AG
Date: 2009
DOI: 10.1159/000195091
Abstract: i Background and Objectives: /i Aspects of trial design, screening and study efficiency can affect recruitment and the findings of the trial itself. A clear understanding of the screening and study inclusion process will assist clinicians in interpreting trial results. i Design: /i Prospective observational data collection on all patients screened for possible inclusion in a randomized controlled trial of normal vs. augmented renal replacement therapy in critically ill patients (the RENAL Trial). i Setting: /i 35 hospitals in Australia and New Zealand. i Participants: /i All patients screened for the RENAL Trial. i Results: /i We screened 4,551 patients. Of these patients, 767 were ineligible because of lack of inclusion criteria and 2,085 because of exclusion criteria. Of the remaining 1,699, 1,508 (88.7%) were enrolled. The three most common exclusion criteria which prevented recruitment of potentially eligible patients were that the patient had end-stage kidney failure and was already on chronic dialysis (484 23.2%), the patient’s body weight was either or kg (456 21.8%), and the fact that the patient had already received renal replacement therapy during the index admission. Important modifiable impediments to recruitment were inability to obtain consent in 191 cases, unavailability of research staff in 124 cases, physician objection in 89 cases, and inability to deliver the trial protocol in 78 cases. i Conclusion: /i The RENAL Trial’s enrolment efficiency was high and compared favourably with previous large intensive care units trials and with that of trials in patients with acute renal failure. The high rate of enrolment suggests that the results can be applied with confidence to most patients with de novo acute renal failure. The loss of close to 1.5% of patients due to consent issues highlights a common problem in critical care trials. The low rate of physician objection suggests clinical equipoise.
Publisher: Elsevier BV
Date: 02-1999
DOI: 10.1093/BJA/82.2.213
Abstract: The zero deadspace tracheal tube (ZEDS-TT) is a double-lumen endobronchial tube with a truncated bronchial limb. Functionally it is unrelated to the familiar endobronchial tube used in lung isolation surgery. It is placed in the same position as a regular tracheal tube and, by means of special connectors, one limb is used for inspiration and the other for expiration, thereby greatly reducing anatomical and apparatus deadspace. In this study, we have compared respiratory and ventilatory effects of reduction of tidal volume (VT) via a single-lumen tracheal tube and the ZEDS-TT during controlled ventilation with a Siemens Elema 900C Servo ventilator. Eleven consenting adult patients (ASA I and II) undergoing elective peripheral surgery were studied. Starting at a VT value of 10 ml kg-1, data were recorded for each tube type. VT was reduced by 2.5 ml kg-1 every 10 min and stabilized data recorded. Minute volume was kept constant by increasing ventilatory frequency at each reduction in VT. We found that the ZEDS-TT produced a significant reduction in PaCO2 and airway pressure for any VT used, while maintaining oxygenation.
Publisher: Elsevier BV
Date: 04-0004
DOI: 10.1016/J.IJANTIMICAG.2016.08.015
Abstract: Currently there are no pharmacokinetic (PK) data to guide antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis. This study aimed to determine whether the population pharmacokinetics of meropenem were different between critically ill Australian Indigenous and critically ill Caucasian patients. Serial plasma and urine s les as well as clinical and demographic data were collected over two dosing intervals from critically ill Australian Indigenous patients. Plasma meropenem concentrations were assayed by validated chromatography. Concentration-time data were analysed with data from a previous PK study in critically ill Caucasian patients using Pmetrics. The population PK model was subsequently used for Monte Carlo dosing simulations to describe optimal doses for these patients. Six Indigenous and five Caucasian subjects were included. A two-compartment model described the data adequately, with meropenem clearance and volume of distribution of the central compartment described by creatinine clearance (CL
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.JHIN.2010.01.005
Abstract: Intravascular devices (IVDs) are essential in the management of critically ill patients however, IVD-related sepsis remains a major complication. Arterial catheters (ACs) are one of the most manipulated IVDs in critically ill patients. When bloodstream infection (BSI) is suspected in a patient with an IVD in situ, clinicians have focused their attention on the central venous catheter (CVC) while largely ignoring the AC. Although it would be routine for the CVC to be cultured and replaced if necessary for suspected IVD or catheter-related sepsis, the AC may not be treated in the same manner. The reasons for this may in part relate to the patient groups studied. In lower acuity patients with short dwell times, AC sepsis rates are indeed low. In the higher acuity patient, earlier studies suggested that ACs had an infective potential at least equal to short term CVCs, a finding that has translated poorly into clinical practice. It has been estimated that there may be up to 48,000 BSIs per year arising from ACs in the USA alone, suggesting a significant clinical problem. Recent evidence now shows that the infective potential of the AC is comparable with that in short term CVCs regarding both colonisation (which precedes BSI) and BSI, consolidating earlier studies. In critically ill patients suspected of catheter-related bloodsteam infection it is suggested that both the AC and CVC must now be assessed together.
Publisher: South African Medical Association NPC
Date: 27-05-2015
DOI: 10.7196/SAMJ.9665
Publisher: Oxford University Press (OUP)
Date: 07-1994
Abstract: Brainstem gliomas are rare primary brain tumours which most commonly occur in the midbrain and pons. Malignant gliomas and tumours at the cervico-medullary junction are particularly unusual. The diagnosis of tumours at this site is particularly difficult using computed tomographic (CT) scanning owing to artifacts around the base of the skull. Intrinsic tumours of the cervico-medullary junction may lead to a dissociated motor deficit and the onset of symptoms can be rapid. We describe a patient in whom an isolated ascending motor deficit in association with a raised cerebrospinal fluid protein and a normal CT scan led to an erroneous diagnosis of Guillain-Barré syndrome. The patient was treated on the intensive care unit for an 8-week period before further investigation demonstrated a malignant glioma of the cervico-medullary junction. We recommend confirmation of the diagnosis of polyradiculopathy by nerve conduction studies wherever possible.
Publisher: Elsevier BV
Date: 04-1997
DOI: 10.1016/S0749-0704(05)70308-0
Abstract: The medical fraternity in Africa needs to ration resource allocation and aptly apply distributive justice. At present, pockets of Intensive Care Units are held together largely by in iduals. Unless the correct assistance and support is provided to develop its vast potential, African Intensive Care will degenerate into primary health care.
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.IJANTIMICAG.2010.06.008
Abstract: The extreme pharmacokinetic behaviour of drugs sometimes observed in critically ill patients poses a significant threat to the achievement of optimal antibiotic treatment outcomes. Scant information on beta-lactam antibiotic therapeutic drug monitoring (TDM) is available. The objective of this prospective study was to evaluate the practicality and utility of a beta-lactam TDM programme in critically ill patients. TDM was performed twice weekly on all eligible patients at a 30-bed tertiary referral critical care unit. Blood concentrations were determined by fast-throughput high-performance liquid chromatography (HPLC) assays and were available within 12h of s ling. Dose adjustment was instituted if the trough or steady-state blood concentration was below 4-5x the minimum inhibitory concentration (MIC) or above 10x MIC. A total of 236 patients were subject to TDM over an 11-month period. The mean+/-standard deviation age was 53.5+/-18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM. For outcome of therapy, 206 (87.3%) courses resulted in a positive treatment outcome and there were 30 (12.7%) treatment failures observed including 14 deaths and 15 courses requiring escalation to broader-spectrum agents 1 course was ceased due to an adverse drug reaction. Using binomial logistic regression, only an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score (P<0.01) and elevated plasma creatinine concentration (P=0.05) were found to be predictive of mortality. In conclusion, further research is required to determine definitively whether achievement of optimal beta-lactam pharmacodynamic targets improves clinical outcomes.
Publisher: Oxford University Press (OUP)
Date: 03-10-2015
DOI: 10.1093/JAC/DKV288
Abstract: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic harmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT>MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic harmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30) P = 0.012]. Additionally, in patients with a SOFA score of ≥9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20) P = 0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20) P = 0.025]. Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections.
Publisher: Oxford University Press (OUP)
Date: 13-07-2015
DOI: 10.1093/JAC/DKV165
Abstract: There is little evidence and few guidelines to inform the most appropriate dosing and monitoring for antimicrobials in the ICU. We aimed to survey current practices around the world. An online structured questionnaire was developed and sent by e-mail to obtain information on local antimicrobial prescribing practices for glycopeptides, piperacillin/tazobactam, carbapenems, aminoglycosides and colistin. A total of 402 professionals from 328 hospitals in 53 countries responded, of whom 78% were specialists in intensive care medicine (41% intensive care, 30% anaesthesiology, 14% internal medicine) and 12% were pharmacists. Vancomycin was used as a continuous infusion in 31% of units at a median (IQR) daily dose of 25 (25-30) mg/kg. Piperacillin/tazobactam was used as an extended infusion by 22% and as a continuous infusion by 7%. An extended infusion of carbapenem (meropenem or imipenem) was used by 27% and a continuous infusion by 5%. Colistin was used at a daily dose of 7.5 (3.9-9) million IU (MIU)/day, predominantly as a short infusion. The most commonly used aminoglycosides were gentamicin (55%) followed by amikacin (40%), with administration as a single daily dose reported in 94% of the cases. Gentamicin was used at a daily dose of 5 (5-6) mg/day and amikacin at a daily dose of 15 (15-20) mg/day. Therapeutic drug monitoring of vancomycin, piperacillin/tazobactam and meropenem was used by 74%, 1% and 2% of the respondents, respectively. Peak aminoglycoside concentrations were s led daily by 28% and trough concentrations in all patients by 61% of the respondents. We found wide variability in reported practices for antibiotic dosing and monitoring. Research is required to develop evidence-based guidelines to standardize practices.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2014
DOI: 10.1007/S00134-014-3403-8
Abstract: Risk factors for β-lactam antibiotic underdosing in critically ill patients have not been described in large-scale studies. The objective of this study was to describe pharmacokinetic harmacodynamic (PK/PD) target non-attainment envisioning empirical dosing in critically ill patients and considering a worst-case scenario as well as to identify patient characteristics that are associated with target non-attainment. This analysis uses data from the DALI study, a prospective, multi-centre pharmacokinetic point-prevalence study. For this analysis, we assumed that these were the concentrations that would be reached during empirical dosing, and calculated target attainment using a hypothetical target minimum inhibitory concentration (MIC), namely the susceptibility breakpoint of the least susceptible organism for which that antibiotic is commonly used. PK/PD targets were free drug concentration maintained above the MIC of the suspected pathogen for at least 50 % and 100 % of the dosing interval respectively (50 % and 100 % f T (>MIC)). Multivariable analysis was performed to identify factors associated with inadequate antibiotic exposure. A total of 343 critically ill patients receiving eight different β-lactam antibiotics were included. The median (interquartile range) age was 60 (47-73) years, APACHE II score was 18 (13-24). In the hypothetical situation of empirical dosing, antibiotic concentrations remained below the MIC during 50 % and 100 % of the dosing interval in 66 (19.2 %) and 142 (41.4 %) patients respectively. The use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets creatinine clearance was independently associated with not reaching the 100 % f T( >MIC) target. This study found that-in empirical dosing and considering a worst--case scenario--19 % and 41 % of the patients would not achieve antibiotic concentrations above the MIC during 50 % and 100 % of the dosing interval. The use of intermittent infusion (compared to extended and continuous infusion) was the main determinant of non-attainment for both targets increasing creatinine clearance was also associated with not attaining concentrations above the MIC for the whole dosing interval. In the light of this study from 68 ICUs across ten countries, we believe current empiric dosing recommendations for ICU patients are inadequate to effectively cover a broad range of susceptible organisms and need to be reconsidered.
Publisher: Oxford University Press (OUP)
Date: 10-06-2014
DOI: 10.1093/JAC/DKU195
Abstract: To investigate the population pharmacokinetics of cefuroxime in critically ill patients. In this observational pharmacokinetic study, multiple blood s les were taken over one dosing interval of intravenous cefuroxime. Blood s les were analysed using a validated ultra HPLC tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling. One hundred and sixty blood s les were collected from 20 patients. CL(CR) ranged between 10 and 304 mL/min. A two-compartment model with between-subject variability on CL, V of the central compartment and V of the peripheral compartment described the data adequately. Twenty-four hour urinary CL(CR) was supported as a descriptor of drug CL. The population model for CL was CL = θ(1) × CL(CR)/100, where θ(1) is the typical cefuroxime CL in the population, which is 9.0 L/h. The mean V was 22.5 L. Dosing simulations showed failure to achieve the pharmacokinetic harmacodynamic target of 65% fT(>MIC) for an MIC of 8 mg/L with standard dosing regimens for patients with CL(CR) ≥50 mL/min. Administration of standard doses by intermittent bolus is likely to result in underdosing for many critically ill patients. Continuous infusion of higher than normal doses after a loading dose is more likely to achieve pharmacokinetic harmacodynamic targets. However, even continuous infusion of high doses (up to 9 g per day) does not guarantee adequate levels for all patients with a CL(CR) of ≥300 mL/min if the MIC is 8 mg/L.
Publisher: American Society for Microbiology
Date: 08-2015
DOI: 10.1128/AAC.00409-15
Abstract: De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum β-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. We performed a simulation study using published population pharmacokinetic (PK) studies in critically ill patients for a number of broad-spectrum β-lactam antibiotics and narrower-spectrum antibiotics. Simulations were undertaken using a data set obtained from critically ill patients with sepsis without absolute renal failure ( n = 49). The probability of target attainment of antibiotic therapy for different microorganisms for which de-escalation was applied was analyzed. EUCAST MIC distribution data were used to calculate fractional target attainment. The probability that therapeutic exposure will be achieved was lower for the narrower-spectrum antibiotics with conventional dosing than for the broad-spectrum alternatives and could drastically be improved with higher dosages and different modes of administrations. For a selection of microorganisms, the probability that therapeutic exposure will be achieved was overall lower for the narrower-spectrum antibiotics using conventional dosing than for the broad-spectrum antibiotics.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.IJANTIMICAG.2011.08.017
Abstract: Vancomycin is currently recommended as first-line therapy for many meticillin-resistant Staphylococcus aureus (MRSA) infections. Recent guidelines have advocated loading doses (25-30 mg/kg) in critically ill patients in order to achieve therapeutic concentrations rapidly. However, weight-based loading doses are still not widely practised. A drug use evaluation was performed to improve the appropriateness of vancomycin initial doses in a population of critically ill adults. An educational intervention incorporating a vancomycin dosing protocol was carried out. Data were collected pre and post intervention. Vancomycin exposure [area under the concentration-time curve (AUC)] in the first 24h was determined using serum concentrations and the Bayesian software TCIWorks. Initial vancomycin doses and exposures were compared between the pre- and post-intervention groups using χ(2) and Mann-Whitney tests. A total of 111 vancomycin courses were analysed in the pre-intervention (n=80) and post-intervention (n=31) groups. Patients in the post-intervention group had significantly higher median weight-based initial doses (20.0mg/kg vs. 12.5mg/kg P<0.001) compared with the pre-intervention group. This corresponded to significantly higher median vancomycin exposures (366.0 mg h/L vs. 262.5 mg h/L P<0.01) in the post-intervention group. Despite higher weight-based initial doses, only 32.3% of patients in the post-intervention group had achieved optimal vancomycin exposures (AUC/minimum inhibitory concentration ratio ≥400) in the first 24h of therapy. A vancomycin dosing protocol improved the initial dosing of vancomycin and the proportion of patients who rapidly achieved optimal vancomycin exposures. However, subtherapeutic exposures were still prevalent and may warrant more vigilant promotion of the dosing protocol to ensure that recommended vancomycin doses are used in this population.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2015
Publisher: American Society for Microbiology
Date: 2016
DOI: 10.1128/AAC.01543-15
Abstract: Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood s les were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL CR ), such that a 30-ml/min increase in the estimated CL CR would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL CR of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL CR of ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.
Publisher: Wiley
Date: 2008
Publisher: Georg Thieme Verlag KG
Date: 12-2007
Abstract: The escalation of serious infections in critically ill patients over the past 25 years has continued despite advances in contemporary medicine. Ongoing research to reduce the high morbidity and mortality rates is mandated. beta-lactam antibiotics are often used empirically in serious infections. The efficacy of these time-dependent antibiotics is correlated with the time that concentrations are maintained above the minimum inhibitory concentration of the infective pathogen. In critically ill patients, pathophysiological changes can reduce antibiotic concentrations and thus alternative modes of administration such as continuous infusion have been studied and shown to standardize beta-lactam pharmacokinetics and meet pharmacodynamic targets. Clinical data supporting the efficacy of continuous infusion are currently scarce, but data continue to grow. Likewise antibiotic resistance continues to grow. Recent data suggest that poor dosing strategies may be contributing to this problem, which is exacerbated by a lack of development of alternate antibiotics. Suffice to say clinicians must use antibiotic regimens that optimally treat the in idual patient and reduce the development of antibiotic resistance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1997
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.IJANTIMICAG.2015.06.016
Abstract: In some patient groups, including critically ill patients, the pharmacokinetics of β-lactam antibiotics may be profoundly disturbed due to pathophysiological changes in distribution and elimination. Therapeutic drug monitoring (TDM) is a strategy that may help to optimise dosing. The aim of this review was to identify and analyse the published literature on the methods used for β-lactam quantification in TDM programmes. Sixteen reports described methods for the simultaneous determination of three or more β-lactam antibiotics in plasma/serum. Measurement of these antibiotics, due to low frequency of usage relative to some other tests, is generally limited to in-house chromatographic methods coupled to ultraviolet or mass spectrometric detection. Although many published methods state they are fit for TDM, they are inconvenient because of intensive s le preparation and/or long run times. Ideally, methods used for routine TDM should have a short turnaround time (fast run-time and fast s le preparation), a low limit of quantification and a sufficiently high upper limit of quantification. The published assays included a median of 6 analytes [interquartile range (IQR) 4-10], with meropenem and piperacillin being the most frequently measured β-lactam antibiotics. The median run time was 8 min (IQR 5.9-21.3 min). There is also a growing number of methods measuring free concentrations. An assay that measures antibiotics without any s le preparation would be the next step towards real-time monitoring no such method is currently available.
Publisher: Wiley
Date: 13-03-2009
DOI: 10.1111/J.1365-2044.2008.05818.X
Abstract: We report the utility of an enzymatic point of care system for estimation of plasma creatinine concentration in critically ill patients with acute kidney injury. Multiple measurements were obtained from a heterogenous population admitted to a multi-disciplinary intensive care unit. The acute kidney injury network guidelines were used to identify and stratify patients based on the creatinine concentration. Central laboratory values were used as comparators to assess the precision and bias of the system. Overall, point of care measurements correlated well with central pathology results (R(2) = 0.991, p < 0.001), although there tended to be a small negative bias in patients with acute kidney injury (3 micromol x l(-1)). The accuracy of point of care measurement is within clinically acceptable limits and given the much shorter turn around time can be used to identify and monitor patients with acute kidney injury in the critical care environment.
Publisher: Oxford University Press (OUP)
Date: 07-07-2016
DOI: 10.1093/JAC/DKW247
Abstract: To use Monte Carlo simulation with an integrated pharmacokinetic-pharmacodynamic (PK-PD) model to evaluate guideline-recommended antimicrobial prophylaxis (AP) regimens with anaerobic coverage in abdominal surgery. AP regimens were tested in simulated subjects undergoing elective abdominal surgery using relevant PK models and pathogen distributions in surgical site infections (SSIs). Predicted cumulative target attainment was the percentage of simulated subjects with free (unbound) antimicrobial plasma concentrations above the MICs for potential SSI pathogens. Cefazolin plus metronidazole covered SSI aerobes in 70% and the Bacteroides fragilis group in 99% of subjects, whereas cefoxitin only covered aerobes and anaerobes in 63% and 27% of cases, respectively. The broad-spectrum ceftriaxone plus metronidazole covered aerobes in 82% and anaerobes in 99% of simulations, while ertapenem covered aerobes in 88% and anaerobes in 90% of cases. Clindamycin covered the B. fragilis group in only 11% of cases. For cefazolin, 2 g doses maintained target attainment in simulated subjects from 80 to 120 kg, whereas 1 g doses were associated with lower target attainment against potential Gram-negative pathogens even in those <80 kg. For gentamicin, 3 mg/kg doses were comparable to the suggested 5 mg/kg, but superior to the traditional 1.5 mg/kg. This study demonstrates the use of PK-PD to inform decisions regarding AP in abdominal surgery. In this case, the findings support avoiding cefoxitin, avoiding clindamycin for anaerobic coverage, selecting 2 g doses of cefazolin even in patients <80 kg and using 3 mg/kg doses of gentamicin.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2008
DOI: 10.1007/S00134-008-1160-2
Abstract: To compare the time course of organ dysfunction/failure, mortality and cause of death in patients with severe sepsis (SS) and patients with severe non-infectious systemic inflammatory response syndrome (SNISIRS). Secondary analysis of a multi-centre inception cohort study. Twenty-three multidisciplinary intensive care units (ICUs) in Australia and New Zealand. 3,543 ICU admissions > or = 48 h or <48 h if SIRS and organ dysfunction present. None. ICU prevalence of SS and SNISIRS was 20% (707/3,543) and 28% (980/3,543), respectively. ICU mortality was similar in patients with SNISIRS and with SS (25 vs. 27%, P = 0.40). Central nervous system (CNS) failure occurred more frequently in patients with SNISIRS (33 vs. 22%, P < 0.001) and resulted in death more commonly than in SS (relative risk = 1.6, 95% confidence interval 1.4-1.7, P < 0.001). The time to peak organ dysfunction (0.67 vs. 0.91 days, P = 0.004), overall episode length (3.6 vs. 5.6 days, P < 0.001) and ICU stay (geometric mean: 4.1 vs. 5.8 days, P < 0.001) were significantly shorter in patients with SNISIRS. Whilst SNISIRS and SS have similarities, including their crude mortality rate, important differences exist. SNISIRS is more common on admission to the ICU, and is more commonly coupled with CNS dysfunction and death from neurological failure. SIRS/sepsis: clinical studies.
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2005
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.IJANTIMICAG.2022.106537
Abstract: Ceftriaxone is a broad-spectrum cephalosporin that may be one option to treat methicillin-susceptible Staphylococcus aureus (MSSA). Although MSSA may be susceptible to ceftriaxone, the minimum inhibitory concentration (MIC) is generally two- to four-fold higher than other susceptible bacterial pathogens. This study aimed to explore the pharmacodynamics of ceftriaxone against MSSA and to determine the likely optimal dose. A hollow-fibre infection model was used with one clinical MSSA isolate (MIC = 4 mg/L) at an initial inoculum of 1 × 10
Publisher: Oxford University Press (OUP)
Date: 12-09-2017
DOI: 10.1093/JAC/DKX330
Abstract: To use a population pharmacokinetic approach to define maximally effective meropenem dosing recommendations for treatment of Acinetobacter baumannii and Pseudomonas aeruginosa infections in a large cohort of patients with septic shock. Adult patients with septic shock and conserved renal function, treated with meropenem, were eligible for inclusion. Seven blood s les were collected during a single dosing interval and meropenem concentrations were measured by a validated HPLC-MS/MS method. Monte Carlo simulations were employed to define optimum dosing regimens for treatment of empirical or targeted therapy of A. baumannii and P. aeruginosa. EudraCT-no. 2014-002555-26 and NCT02240277. Fifty patients were included, 26 male and 24 female, with a median age of 64 years with an all-cause 90 day mortality of 34%. A two-compartment linear model including creatinine clearance (CLCR) as a covariate best described meropenem pharmacokinetics. For empirical treatment of A. baumannii, 2000 mg/6 h was required by intermittent (30 min) or prolonged (3 h) infusion, whereas 6000 mg/day was required with continuous infusion. For P. aeruginosa, 2000 mg/8 h or 1000 mg/6 h was required for both empirical and targeted treatment. In patients with a CLCR of ≤ 100 mL/min, successful concentration targets could be reached with intermittent dosing of 1000 mg/8 h. In patients with septic shock and possible augmented renal clearance, doses should be increased and/or administration should be performed by prolonged or continuous infusion to increase the likelihood of achieving therapeutic drug concentrations. In patients with normal renal function, however, standard dosing seems to be sufficient.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.HRTLNG.2013.11.011
Abstract: To compare the effect of semi-recumbent and sitting positions on gas exchange, respiratory mechanics and hemodynamics in patients weaning from mechanical ventilation. Upright positions are encouraged during rehabilitation of the critically ill but there effects have not been well described. A prospective, randomized, cross-over trial was conducted. Subjects were passively mobilized from supine into a seated position (out of bed) and from supine to a semi-recumbent position (>45° backrest elevation in bed). Arterial blood gas (PaO2/FiO2, PaO2, SaO2, PaCO2 and A-a gradient), respiratory mechanics (VE,VT, RR, Cdyn, RR/VT) and hemodynamic measurements (HR, MABP) were collected in supine and at 5 min and 30 min after re-positioning. Thirty-four intubated and ventilated subjects were enrolled. The angle of backrest inclination in sitting (67 ± 5°) was greater than gained with semi-recumbent positioning (50 ± 5°, p < 0.001). There were no clinically important changes in arterial blood gas, respiratory mechanic or hemodynamic values due to either position. Neither position resulted in significant changes in respiratory and hemodynamic parameters. Both positions can be applied safely in patients being weaned from ventilation.
Publisher: Public Library of Science (PLoS)
Date: 11-02-2014
Publisher: Oxford University Press (OUP)
Date: 02-2013
Abstract: Field crickets (family Gryllidae) frequently are used in studies of behavioral genetics, sexual selection, and sexual conflict, but there have been no studies of transcriptomic differences among different tissue types. We evaluated transcriptome variation among testis, accessory gland, and the remaining whole-body preparations from males of the field cricket, Teleogryllus oceanicus. Non-normalized cDNA libraries from each tissue were sequenced on the Roche 454 platform, and a master assembly was constructed using testis, accessory gland, and whole-body preparations. A total of 940,200 reads were assembled into 41,962 contigs, to which 36,856 singletons (reads not assembled into a contig) were added to provide a total of 78,818 sequences used in annotation analysis. A total of 59,072 sequences (75%) were unique to one of the three tissues. Testis tissue had the greatest proportion of tissue-specific sequences (62.6%), followed by general body (56.43%) and accessory gland tissue (44.16%). We tested the hypothesis that tissues expressing gene products expected to evolve rapidly as a result of sexual selection—testis and accessory gland—would yield a smaller proportion of BLASTx matches to homologous genes in the model organism Drosophila melanogaster compared with whole-body tissue. Uniquely expressed sequences in both testis and accessory gland showed a significantly lower rate of matching to annotated D. melanogaster genes compared with those from general body tissue. These results correspond with empirical evidence that genes expressed in testis and accessory gland tissue are rapidly evolving targets of selection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2016
DOI: 10.1097/CCM.0000000000001823
Abstract: This study assessed the determinants of urinary output response to furosemide in acute kidney injury specifically, whether the response is related to altered pharmacokinetics or pharmacodynamics. Prospective cohort. Tertiary ICU. Thirty critically ill patients with acute kidney injury without preexisting renal impairment or recent diuretic exposure. A single dose of IV furosemide. Baseline markers of intravascular volume status were obtained prior to administering furosemide. Six-hour creatinine clearance, hourly plasma/urinary furosemide concentrations, and hourly urinary output were used to assess furosemide pharmacokinetics harmacodynamics parameters. Of 30 patients enrolled, 11 had stage-1 (37%), nine had stage-2 (30%), and 10 had stage-3 (33%) Acute Kidney Injury Network acute kidney injury. Seventy-three percent were septic, 47% required norepinephrine, and 53% were mechanically ventilated. Urinary output doubled in 20 patients (67%) following IV furosemide. Measured creatinine clearance was strongly associated with the amount of urinary furosemide excreted and was the only reliable predictor of the urinary output after furosemide (area under the receiver-operating-characteristic curve, 0.75 95% CI, 0.57–0.93). In addition to an altered pharmacokinetics ( p 0.01), a reduced pharmacodynamics response to furosemide also became important when creatinine clearance was reduced to less than 40 mL/min/1.73 m 2 ( p = 0.01). Acute kidney injury staging and markers of intravascular volume, including central venous pressure, brain-natriuretic-peptide concentration, and fractional urinary sodium excretion were not predictive of urinary output response to furosemide. The severity of acute kidney injury, as reflected by the measured creatinine clearance, alters both pharmacokinetics and pharmacodynamics of furosemide in acute kidney injury, and was the only reliable predictor of the urinary output response to furosemide in acute kidney injury.
Publisher: Future Science Ltd
Date: 10-2015
DOI: 10.4155/BIO.15.173
Abstract: Background: Fosfomycin is an antibiotic of considerable interest for the treatment of infection by multidrug-resistant bacteria. Translating micros ling techniques into clinical PK studies may provide effective dosing information to improve patient outcomes and minimize the potential development of resistance. Results: Accuracy and precision results were within ±15% the method was validated across the range of 5–2000 µg/ml of fosfomycin using volumetric absorptive micros ling (VAMS) devices. Conclusion: The VAMS techniques provide acceptable validation data as assessed for lower limit of quantification, linearity, intra- and interday precision and accuracy, selectivity and matrix effects. Results from the recovery and stability studies suggest challenges remain for the analysis of fosfomycin in whole blood using VAMS.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2017
Publisher: Mary Ann Liebert Inc
Date: 08-2014
DOI: 10.1089/SUR.2012.228
Abstract: Infectious complications are frequent in severe acute pancreatitis (SAP) but multinational epidemiologic data are lacking. The aim of the study was to analyze the characteristics of the infectious complications and antimicrobial use in this setting. One-day point prevalence study of infection in critically ill patients (Extended Prevalence of Infection in the ICU-II study), performed in 1,265 ICUs in 75 countries. Of the 13,796 patients in the study, 159 were admitted with SAP. One-hundred sixteen (73%) had infections: 31% intra-abdominal, 16% extra-abdominal, and 26% both. Gram-negative bacteria were more prevalent than gram-positive organisms, anaerobes, or fungi. Therapeutically, penicillins and other beta-lactams were used most frequently. Prophylactic antibiotics were administered to 24% of the patients with SAP. Infections are frequent in patients admitted with SAP most are intra-abdominal infections. Microbiology is erse with gram-negative micro-organisms most frequently isolated. Most patients admitted to the ICU for SAP receive antibiotics at some point.
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/CC12705
Publisher: Elsevier BV
Date: 08-1995
Abstract: We report an 18-year-old patient with severe mitral stenosis complicated by right lower lobe pneumonia, sepsis, and shock. Intractable low cardiac output led to an emergency percutaneous balloon mitral valvotomy in a patient, resulting in immediately improved hemodynamic parameters. We are unaware of another report of percutaneous balloon mitral valvotomy performed in a patient with sepsis and shock. This case supports previous isolated reports of the benefit from emergency percutaneous balloon mitral valvotomy in critical situations where thoracotomy is not possible due to coexisting medical problems.
Publisher: Oxford University Press (OUP)
Date: 26-05-2016
DOI: 10.1093/JAC/DKW153
Abstract: Pathophysiological changes in critically ill patients can cause severely altered pharmacokinetics and widely varying antibiotic exposures. The impact of altered pharmacokinetics on bacterial killing and resistance has not been characterized in the dynamic hollow-fibre in vitro infection model (HFIM). A clinical Pseudomonas aeruginosa isolate (piperacillin MIC 4 mg/L) was studied in the HFIM (inoculum ∼10(7) cfu/mL). Pharmacokinetic profiles of three piperacillin dosing regimens (4 g 8-, 6- and 4-hourly, 30 min intravenous infusion) as observed in critically ill patients with augmented renal clearance (ARC), normal renal function or impaired renal function (creatinine clearances of 250, 110 or 30 mL/min, respectively) were simulated over 7 days. The time courses of total and less-susceptible populations and MICs were determined. Mechanism-based modelling was performed in S-ADAPT. For all regimens with ARC and regimens with 8- or 6-hourly dosing with normal renal function, initial killing of ≤∼2 log10 was followed by regrowth to 10(8)-10(9) cfu/mL at 48 h. For 8- and 6-hourly dosing at normal renal function, the proportion of less-susceptible colonies increased ∼10-100-fold above those in ARC and control arms. Regimens achieving an fCmin of ≥5× MIC resulted in bacterial killing of 3-4 log10 without regrowth and suppressed less-susceptible populations to ≤∼2 log10. The mechanism-based model successfully quantified the time course of bacterial growth, killing and regrowth. Only high piperacillin concentrations prevented regrowth of P. aeruginosa. In idualized dosing regimens that account for altered pharmacokinetics and aim for higher-than-standard antibiotic exposures to achieve an fCmin of ≥5× MIC were required to maximize bacterial killing and suppress emergence of resistance.
Publisher: Future Science Ltd
Date: 09-2015
DOI: 10.4155/BIO.15.143
Abstract: Background: With few new antibiotics available and an increased prevalence of multidrug-resistant bacteria, optimizing the effectiveness of currently available antibiotics and minimizing the potential for emerging resistance, through PK characterization, is of paramount importance. Results: Inter- and intra-assay results for icillin were within 5% for accuracy and 7% for precision, and for sulbactam within 7% for accuracy and 7% for precision, for both plasma and urine. The plasma Cmax was 38.4 µg/ml for icillin and 19.0 µg/ml for sulbactam. The urine concentrations were 668 µg/ml for icillin and 438 µg/ml for sulbactam. Conclusion: An UHPLC–MS/MS method to simultaneously measure co-formulated icillin and sulbactam in plasma and urine, for use in a patient PK study, has been developed and validated.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.IJANTIMICAG.2015.01.007
Abstract: Prolonged infusion (PI) of β-lactam antibiotics is increasingly used in order to optimise antibiotic exposure in critically ill patients. Physicians are often not aware of a number of subtleties that may jeopardise the treatment. In this clinically based paper, we stress pragmatic issues, such as the importance of a loading dose before PI, and discuss a number of important practicalities that are mandatory to benefit from the pharmacokinetic advantages of prolonged β-lactam antibiotic administration.
Publisher: Oxford University Press (OUP)
Date: 15-05-2007
DOI: 10.1093/JAC/DKM128
Abstract: To determine how long single-dose prophylactic antibiotic regimens for burns surgery maintained plasma concentrations above the MICs for target organisms during surgery. We monitored antibiotic plasma concentrations in 12 patients (mean +/- SD 43 +/- 12% total burn surface area) throughout debridement surgery after administration of the standard prophylactic antibiotic dosing regimens of either 1 g of intravenous cefalotin or 4.5 g of intravenous piperacillin/tazobactam. The eschar debridement and grafting procedures ranged in duration from 2.25 to over 8.5 h. The duration of total plasma cefalotin concentration above an MIC of 0.2 mg/L for Staphylococcus aureus was 6.49 +/- 2.85 h, whereas the mean duration of total plasma piperacillin concentration above an MIC of 64 mg/L for Pseudomonas aeruginosa was only 1.15 +/- 0.59 h. None of the patients dosed with piperacillin/tazobactam was adequately protected for the duration of their surgery and adequate prophylaxis was only evident in four of the nine patients administered cefalotin. These results suggest a need to review antibiotic prophylaxis dosage regimens for burns surgery and the adoption of regimens that will minimize the risk of infection in this high-risk patient group. It is suggested that the antibiotic prophylaxis guideline for burn debridement surgery be modified to include re-dosing or a continuous infusion of beta-lactam antibiotics.
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.IJANTIMICAG.2015.01.015
Abstract: The impact of decreased serum albumin concentrations on free antibiotic concentrations in non-critically ill patients is poorly described. This study aimed to describe the pharmacokinetics of a high-dose regimen of teicoplanin, a highly protein-bound antibiotic, in non-critically ill patients with hypoalbuminaemia. Ten patients with chronic bone sepsis and decreased serum albumin concentrations (<35 g/L) receiving teicoplanin 12 mg/kg 12-hourly intravenously for 48 h followed by 12 mg/kg once daily were enrolled. Surgical debridement was performed on Day 3. S les of venous blood were collected pre-infusion and post-infusion during the first 4 days of therapy. Total and free teicoplanin concentrations were assayed using validated chromatographic methods. The median serum albumin concentration for the cohort was 18 (IQR 15-24) g/L. After 48 h, the median (IQR) free trough (fC(min)) and total trough (tC(min)) concentrations were 2.90 (2.67-3.47) mg/L and 15.54 (10.28-19.12) mg/L, respectively, although trough concentrations declined thereafter. Clearance of the free concentrations was significantly high relative to the total fraction at 38.6 (IQR 29.9-47.8) L/h and 7.0 (IQR 6.8-9.8) L/h, respectively (P<0.001). Multiple linear regression analysis demonstrated that whereas total teicoplanin concentration did not impact on free concentrations (P=0.174), albumin concentration did (P<0.001). This study confirms the significant impact of hypoalbuminaemia on free concentrations of teicoplanin in non-critically ill patients, similar to that in critically ill patients. Furthermore, the poor correlation with total teicoplanin concentration suggests that therapeutic drug monitoring of free concentrations should be used in these patients.
Publisher: Future Science Ltd
Date: 11-2016
Abstract: The reliability of extraction recovery of an analyte in bioanalysis is fundamentally important for downstream analytical testing. For dried format micros les, if the recovery changes with time the concentration in clinical s les, derived from calibration standards and alongside quality control s les prepared following different drying protocols, may not reflect the true result. The purpose of this paper was therefore to evaluate changes to extraction recovery across time for one analyte, the glycopeptide antibiotic vancomycin, in plasma using two dried micros ling formats, dried plasma spots and volumetric absorptive micros ling.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.MEDIN.2015.07.009
Abstract: The judicious use of existing antibiotics is essential for preserving their activity against infections. In the era of multi-drug resistance, this is of particular importance in clinical areas characterized by high antibiotic use, such as the ICU. Antibiotic dose optimization in critically ill patients requires sound knowledge not only of the altered physiology in serious infections - including severe sepsis, septic shock and ventilator-associated pneumonia - but also of the pathogen-drug exposure relationship (i.e. pharmacokinetic harmacodynamic index). An important consideration is the fact that extreme shifts in organ function, such as those seen in hyperdynamic patients or those with multiple organ dysfunction syndrome, can have an impact upon drug exposure, and constant vigilance is required when reviewing antibiotic dosing regimens in the critically ill. The use of continuous renal replacement therapy and extracorporeal membrane oxygenation remain important interventions in these patients however, both of these treatments can have a profound effect on antibiotic exposure. We suggest placing emphasis on the use of therapeutic drug monitoring and dose in idualization when optimizing therapy in these settings.
Publisher: American Society for Microbiology
Date: 12-2013
DOI: 10.1128/AAC.00951-13
Abstract: The use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there are limited data describing the potential impact of altered protein binding on achievement of target concentrations. The aim of this study was to compare the measured unbound concentration to the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood s les obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 220 plasma s les at the midpoint of the dosing interval and trough, respectively, for ceftriaxone, cefazolin, meropenem, piperacillin, icillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentrations were marked for all antibiotics, with significant differences being present between measured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval ( P 0.05). The predictive performance for calculating unbound concentrations using published protein binding values was poor, with bias for overprediction of unbound concentrations for ceftriaxone (83.3%), flucloxacillin (56.8%), and benzylpenicillin (25%) and underprediction for meropenem (12.1%). Linear correlations between the measured total and unbound concentrations were observed for all beta-lactams ( R 2 = 0.81 to 1.00 P 0.05) except ceftriaxone and flucloxacillin. The percent protein binding of flucloxacillin and the plasma albumin concentration were also found to be linearly correlated ( R 2 = 0.776 P 0.01). In conclusion, significant differences between measured and predicted unbound drug concentrations were found only for the highly protein-bound beta-lactams ceftriaxone and flucloxacillin. However, direct measurement of unbound drug in research and clinical practice is suggested for selected beta-lactams.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.COPH.2015.07.003
Abstract: Critical illness, acute renal failure and continuous renal replacement therapy (CRRT) are associated with changes in pharmacokinetics. Initial antibiotic dose should be based on published volume of distribution and generally be at least the standard dose, as volume of distribution is usually unchanged or increased. Subsequent doses should be based on total clearance. Total clearance varies with the CRRT clearance which mainly depends on effluent flow rate, sieving coefficient/saturation coefficient. As antibiotic clearance by healthy kidneys is usually higher than clearance by CRRT, except for colistin, subsequent doses should generally be lower than given to patients without renal dysfunction. In the future therapeutic drug monitoring, together with sophisticated pharmacokinetic models taking into account the pharmacokinetic variability, may enable more appropriate in idualized dosing.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Future Science Ltd
Date: 06-2017
Abstract: Aim: Critical illness and medical interventions, such as renal replacement therapy, can cause changes to vancomycin pharmacokinetics and lead to suboptimal dosing. To comprehensively characterize vancomycin pharmacokinetic a method must measure vancomycin in a range of clinical matrices. Results: A LC–MS/MS method was developed using hydrophilic interaction liquid chromatography and micros le volumes, where possible. For all matrices, the linear concentration range was 1–100 μg/ml, interassay accuracy and precision was within 15%, and recovery above 80%. No matrix effects were observed. Calibration equivalence may be applied for some matrix combinations. Conclusion: A method for the analysis of vancomycin in plasma (total, unbound), urine and renal replacement therapy effluent, suitable for use in any patient pharmacokinetic study, has been developed and validated.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.IJANTIMICAG.2008.10.035
Abstract: This multicentre study (i) evaluated geographic and temporal changes in candidaemia ecology in the critically ill, (ii) identified risk factors associated with non-albicans candidaemia and (iii) examined the association of Candida ecology with mortality. A retrospective cohort study of patients who developed candidaemia in four general Intensive Care Units located in Australia, Greece, Belgium and Brazil was performed. Two hundred Candida organisms were identified by positive blood culture in 189 patients, including 112 Candida albicans (56.0%), 38 Candidaglabrata (19.0%), 21 Candidaparapsilosis (10.5%), 18 Candidatropicalis (9.0%), 6 Candidakrusei (3.0%), 1 Candidafamata (0.5%), 1 Candidazeylanoides (0.5%) and 3 non-differentiated Candida spp. (1.5%). No trend towards increased non-albicans species over the study period (P=0.68) or by geographic area (P=0.35) was demonstrated. Independent risk factors for non-albicans candidaemia included: female gender [odds ratio (OR) 2.09, 95% confidence interval (CI) 1.13-3.86] and increased central venous catheter days (OR 1.16 per 5-day interval, 95% CI 1.05-1.28). Mortality in the non-albicans group was non-significantly higher than in the albicans group (65% vs. 53% P=0.10). This study is unique in that a large number of intensive care candidaemias in four geographically erse units have been studied.
Publisher: Springer Berlin Heidelberg
Date: 2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1016/S1036-7314(06)80025-1
Abstract: To investigate the process of providing patient positioning in intensive care units (ICUs), a self-reported survey was distributed to a senior physiotherapist and a nurse in each of the 38 Level 3 Australian ICUs. The survey explored the rationales, aims, type, frequency and duration of directed patient positioning used, and perceived risks that may impede the implementation of an effective positioning regime. The response rate was 93%. Fifty nine respondents (83%) agreed that there is an accepted standard of care for the duration of a position change with ventilated patients. Of these respondents, 51 (86%) agreed that the standard is to turn patients every 2 hours, but this was only achievable "more than 50% of the time" in 47% (n=34) of ICUs. Educational and environmental issues were found to impact on positioning practices. Semi-recumbent and full side-lie positions were recommended in the management of a range of patient conditions. However, full side-lie was less commonly used than supine positioning. The prone and head down tilt positions were the least frequently utilised. Levels of agreement for precautions and contraindications to positioning patients into full side-lie and sitting were high. We conclude that, in Australia, experienced ICU physiotherapy and nursing staff are aware of evidence-based positioning practices and agree on indications and potential risk factors associated with positioning. However, educational and environmental resources are needed to improve the frequency and type of positioning used. Results from this survey can now be incorporated into educational tools to facilitate the safe use of positioning.
Publisher: Wiley
Date: 12-1993
DOI: 10.1111/J.1365-2044.1993.TB07528.X
Abstract: The use of continuous veno-venous haemofiltration after failure of conventional treatment in a patient with severe peripartum cardiomyopathy is described. Treatment with inotropes and diuretics failed to produce a diuresis despite the presence of severe fluid overload. Haemofiltration over a 9-day period allowed removal of 171 of fluid with a concomitant improvement in haemodynamic function and a spontaneous diuresis.
Publisher: Springer Science and Business Media LLC
Date: 03-1990
DOI: 10.1007/BF01724807
Publisher: BMJ
Date: 08-2013
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.HRTLNG.2005.12.002
Abstract: To measure hemodynamics and plasma catecholamines during manual hyperinflation (MHI) in ventilated patients. MHI was performed with a Mapleson "C" circuit, 2l-reservoir bag peak inspiratory pressure was standardized to 35 mL water and positive expiratory-end pressure of 5 mL water was administered to seven mechanically ventilated patients with septic (6) and cardiogenic (1) shock (67.2 +/- 5.2 years, Acute Physiology Assessment and Chronic Health Evaluation II score 22.1 +/- 3.1). Diastolic (DAP) and mean arterial pressure (MAP), continuous cardiac index, pulmonary artery occlusion pressure, dynamic compliance, plasma norepinephrine and epinephrine, and arterial blood gases were recorded, and systemic vascular resistance index (SVRI) and oxygenation ratio were calculated. There were no significant changes in pulmonary artery occlusion pressure, mean arterial pressure, or PaO2/FiO2. There were significant increases in SVRI (P < .001), DAP (P < .001), dynamic compliance (P < .01), and plasma norepinephrine (P < .001) and a decrease in cardiac index (P < .05) after MHI. The increases in DAP, SVRI, and plasma norepinephrine suggest a sympathetic vasoconstrictive response during the application of MHI.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2015
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.JCRC.2014.10.011
Abstract: When terminal illness exists, it is common clinical practice worldwide to withhold (WH) or withdraw (WD) life-sustaining treatments. Systematic documentation of professional opinion and perceived practice similarities and differences may allow recommendations to be developed. Speakers from invited faculty of the World Federation of Societies of Intensive and Critical Care Medicine Congress that took place in Durban (2013), with an interest in ethics, were approached to participate in an ethics round table. Key domains of health care professional end-of-life decision making were defined, explored by discussion, and then questions related to current practice and opinion developed and subsequently answered by round-table participants to establish the presence or absence of agreement. Agreement was established for the desirability for early goal-of-care discussions and discussions between health care professionals to establish health care provider consensus and confirmation of the grounds for WH/WD, before holding formal WH/WD discussions with patients/surrogates. Nurse and other health care professional involvement were common in most but not all countries/regions. Principles and practical triggers for initiating discussions on WH/WD, such as multiorgan failure, predicted short-term survival, and predicted poor neurologic outcome, were identified. There was majority agreement for many but not all statements describing health care professional end-of-life decision making.
Publisher: American Society for Microbiology
Date: 08-2017
DOI: 10.1128/AAC.00345-17
Abstract: We sought to describe the population pharmacokinetics of tigecycline in critically ill patients and to determine optimized dosing regimens of tigecycline for different bacterial infections. This prospective study included 10 critically ill patients given a standard dose of tigecycline. Blood s les were collected during one dosing interval and were analyzed using validated chromatography. Population pharmacokinetics and Monte Carlo dosing simulations were undertaken using Pmetrics. Three target exposures, expressed as ratios of the 24-h area under the curve to MICs (AUC 0–24 /MIC), were evaluated (≥17.9 for skin infections, ≥6.96 for intra-abdominal infections, ≥4.5 for hospital-acquired pneumonia). The median age, total body weight, and body mass index (BMI) were 67 years, 69.1 kg, and 24.7 kg/m 2 , respectively. A two-compartment linear model best described the time course of tigecycline concentrations. The parameter estimates (expressed as means ± standard deviations [SD]) from the final model were as follows: clearance (CL), 7.50 ± 1.11 liters/h volume in the central compartment, 72.50 ± 21.18 liters rate constant for tigecycline distribution from the central to the peripheral compartment, 0.31 ± 0.16 h −1 and rate constant for tigecycline distribution from the peripheral to the central compartment, 0.29 ± 0.30 h −1 . A larger BMI was associated with increased CL of tigecycline. Licensed doses were found to be sufficient for Enterobacter cloacae , Escherichia coli , Klebsiella pneumoniae , and methicillin-resistant Staphylococcus aureus for an AUC 0–24 /MIC target of 4.5 or 6.96. For a therapeutic target of 17.9, an increased tigecycline dose is required, especially for patients with higher BMI. The dosing requirements of tigecycline differ with the indication, with pathogen susceptibility, and potentially with patient BMI.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2015
Publisher: Springer Science and Business Media LLC
Date: 25-07-2020
Publisher: Springer Berlin Heidelberg
Date: 2007
Publisher: Springer Berlin Heidelberg
Date: 2007
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.IJANTIMICAG.2014.12.020
Abstract: Successful application of antibacterial therapy in the critically ill requires an appreciation of the complex interaction between the host, the causative pathogen and the chosen pharmaceutical. A pathophysiological change in the intensive care unit (ICU) patient challenging the 'one dose fits all' concept includes augmented renal clearance (ARC), defined as a creatinine clearance (CL(Cr)) of ≥130 mL/min. Ideally, CL(Cr) values should be obtained by a timed measured collection of urine, with plasma and urine creatinine levels. Increased renal clearance of antibiotics also occurs in the ICU patient and therefore β-lactam antibiotic exposure in the critically ill could easily lead to trough drug concentrations below therapeutic ranges. One way to document and alter drug levels is via therapeutic drug monitoring (TDM). The interactions of ARC and β-lactam TDM are further explored in this article in specific reference to a concomitant article in this issue of the journal.
Publisher: Wiley
Date: 04-06-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2013
Publisher: Springer Science and Business Media LLC
Date: 06-2004
DOI: 10.1007/S00134-004-2203-Y
Abstract: To compare the efficacy of two forms of eye care (hypromellose and Lacri-Lube combination vs polyethylene/Cling wrap covers) for intensive care patients. Randomised-controlled trial. University affiliated, tertiary referral hospital. One hundred ten patients with a reduced or absent blink reflex were followed through until they regained consciousness, were discharged from the facility during study enrolment, died or developed a positive corneal ulcer or eye infection. All patients received standard eye cleansing every 2 h. In addition to this, group one ( n=60) received a treatment combining hypromellose drops and Lacri-Lube (HL) to each eye every 2 h. Group two ( n=50) had polyethylene covers only placed over the eye to create a moisture chamber. Corneal ulceration was determined using corneal fluorescein stains and mobile slit l evaluation, performed daily. No patients had corneal ulceration in the polyethylene cover group, but 4 patients had corneal ulceration in the HL group. Polyethylene covers are as effective as HL in reducing the incidence of corneal damage in intensive care patients.
Publisher: Oxford University Press (OUP)
Date: 08-06-2010
DOI: 10.1093/JAC/DKQ184
Abstract: To describe the total and unbound plasma concentration-time profiles for highly protein-bound flucloxacillin (95%-97% protein binding) in critically ill patients with hypoalbuminaemia and without severe renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the probability of target attainment against an MIC distribution. Ten patients with hypoalbuminaemia and receiving flucloxacillin as part of therapy were enrolled. Sixty-seven total, 67 unbound plasma and 10 urine s les were collected and analysed. Population pharmacokinetic modelling of unbound plasma data and Monte Carlo simulations were then undertaken with NONMEM. Non-compartmental pharmacokinetic analysis was performed for total plasma concentrations. Total flucloxacillin V was increased in critically ill patients with hypoalbuminaemia 2-fold compared with healthy volunteer data. Unbound flucloxacillin concentrations after 2 g bolus fell below 1 mg/L 4 h after the end of the infusion, providing evidence that standard dosing would be insufficient for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) (MIC = 2 mg/L). Monte Carlo simulations suggest that continuous infusion of 8 g/24 h flucloxacillin would enable 100% successful attainment of the pharmacodynamic target, 50% fT( > MIC). For more aggressive targets (4-5x MIC for 100% fT( > MIC)), continuous infusion of higher doses (i.e. 12 g/24 h) would be required. Administration of standard doses by intermittent bolus is likely to result in underdosing, and continuous infusion of higher doses is more likely to achieve pharmacokinetic-pharmacodynamic targets for the treatment of infections caused by the most common wild type of MSSA. Our data emphasize the importance of using unbound concentrations for determining dosage regimens for highly bound antibiotics.
Publisher: MDPI AG
Date: 10-11-2020
DOI: 10.3390/ANTIBIOTICS9110793
Abstract: The present study assessed the proportion of intensive care unit (ICU) patients who had a vancomycin serum concentration between 20 and 25 mg/L after 24–48 h of intravenous vancomycin administration. From 2016 to 2018, adult ICU patients with vancomycin continuous infusion (CI) for any indication were included. The primary outcome was the proportion of patients with a first-available vancomycin serum concentration between 20–25 mg/L at 24 h (D2) or 48 h (D3). Of 3894 admitted ICU patients, 179 were included. A median loading dose of 15.6 (interquartile range (IQR) = (12.5–20.8) mg/kg) was given in 151/179 patients (84%). The median daily doses of vancomycin infusion for D1 and D2 were 2000 [(IQR (1600–2000)) and 2000 (IQR (2000–2500)) mg/d], respectively. The median duration of treatment was 4 (2–7) days. At D2 or D3, the median value of first serum vancomycin concentration was 19.8 (IQR (16.0–25.1)) with serum vancomycin concentration between 20–25 mg/L reported in 43 patients (24%). Time spent in the ICU before vancomycin initiation was the only risk factor of non-therapeutic concentration at D2 or D3. Acute kidney injury occurred significantly more when vancomycin concentration was supra therapeutic at D2 or D3. At D28, 44 (26%) patients had died. These results emphasize the need of appropriate loading dose and regular monitoring to improve vancomycin efficacy and avoid renal toxicity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2013
Publisher: Springer Science and Business Media LLC
Date: 25-07-2008
DOI: 10.1007/S00134-008-1219-0
Abstract: To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients. Prospective, double-blind, randomised-controlled trial. Four Australian university-affiliated multidisciplinary ICUs. Patients who required vasopressors for any cause at randomisation. Patients with septic shock and acute circulatory failure were analysed separately. Blinded infusions of epinephrine or norepinephrine to achieve a MAP >or=70 mmHg for the duration of ICU admission. Primary outcome was achievement of MAP goal >24 h without vasopressors. Secondary outcomes were 28 and 90-day mortality. Two hundred and eighty patients were randomised to receive either epinephrine or norepinephrine. Median time to achieve the MAP goal was 35.1 h (interquartile range (IQR) 13.8-70.4 h) with epinephrine compared to 40.0 h (IQR 14.5-120 h) with norepinephrine (relative risk (RR) 0.88 95% confidence interval (CI) 0.69-1.12 P = 0.26). There was no difference in the time to achieve MAP goals in the subgroups of patients with severe sepsis (n = 158 RR 0.81 95% CI 0.59-1.12 P = 0.18) or those with acute circulatory failure (n = 192 RR 0.89 95% CI 0.62-1.27 P = 0.49) between epinephrine and norepinephrine. Epinephrine was associated with the development of significant but transient metabolic effects that prompted the withdrawal of 18/139 (12.9%) patients from the study by attending clinicians. There was no difference in 28 and 90-day mortality. Despite the development of potential drug-related effects with epinephrine, there was no difference in the achievement of a MAP goal between epinephrine and norepinephrine in a heterogenous population of ICU patients.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.IJANTIMICAG.2013.05.018
Abstract: As treatment options for critically ill patients with multidrug-resistant bacteria diminish, older antibiotics such as fosfomycin are being investigated for use as last-resort drugs. Fosfomycin is a broad-spectrum antibiotic with activity both against Gram-positive and Gram-negative bacteria. The aim of this review was to examine the effectiveness of current fosfomycin dosing strategies in critically ill patients. These patients can be subject to pathophysiology that can impact antibiotic pharmacokinetic (PK) profiles and potentially the effectiveness of their treatment. As a hydrophilic drug with negligible protein binding, fosfomycin is eliminated almost entirely by glomerular filtration and is subject to patient renal function. If altered as seen in augmented renal clearance, renal function in a critically ill patient may lead to low blood concentrations and predispose patients to the risk of treatment failure. If altered as seen in acute kidney injury, toxic blood concentrations may develop. Fosfomycin has a volume of distribution comparable with β-lactams and aminoglycosides and may therefore increase in critically ill patients. Altered dosing strategies may be required to optimise dosing given these PK changes, although the current paucity of data on fosfomycin in critically ill patients prevents accurate dosing guidance being recommended at this time.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2014
Publisher: Oxford University Press (OUP)
Date: 08-2021
DOI: 10.1093/OFID/OFAB387
Abstract: Carbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative. We enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days. Seventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI}, –12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC β-lactamase genes identified were blaCMY-2, blaDHA-17, blaCMH-3, and blaACT-17. No ESBL, OXA, or other carbapenemase genes were identified. Among patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen. NCT02437045.
Publisher: Wiley
Date: 28-10-2015
DOI: 10.1002/BMC.3622
Abstract: An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the analysis of cefazolin and cefalothin in human plasma (total and unbound), urine and peritoneal dialysate has been developed and validated. Total plasma concentrations are measured following protein precipitation and are suitable for the concentration range of 1-500 µg/mL. Unbound concentrations are measured from ultra-filtered plasma acquired using Centrifree(®) devices and are suitable for the concentration range of 0.1-500 µg/mL for cefazolin and 1-500 µg/mL for cefalothin. The urine method is suitable for a concentration range of 0.1-20 mg/mL for cefazolin and 0.2-20 mg/mL for cefalothin. Peritoneal dialysate concentrations are measured using direct injection, and are suitable for the concentration range of 0.2-100 µg/mL for both cefazolin and cefalothin. The cefazolin and cefalothin plasma (total and unbound), urine and peritoneal dialysate results are reported for recovery, inter-assay precision and accuracy, and the lower limit of quantification, linearity, stability and matrix effects, with all results meeting acceptance criteria. The method was used successfully in a pilot pharmacokinetic study with patients with peritoneal dialysis-associated peritonitis, receiving either intraperitoneal cefazolin or cefalothin. Copyright © 2015 John Wiley & Sons, Ltd.
Publisher: Georg Thieme Verlag KG
Date: 04-2021
Abstract: Oligo(p-phenylene)s with a donor phenol group and an acceptor pyridinium moiety separated by one and two p-phenylene units were synthesized by the linear iterative Suzuki–Miyaura coupling method using aryl nonaflates as effective coupling reagents. Zwitterionic forms of these push–pull molecules were generated upon deprotonation of the phenol leading to large redshifts in absorbance maxima. UV-vis absorbance studies also revealed strong dependence of the band position on solvent polarity: a smooth bathochromic shift can be observed with the decrease of the solvent polarity. The molecule with one p-phenylene bridging unit showed the strongest solvatochromic characteristics in the series, spanning the range of 167 nm while moving from polar water to less polar N,N-dimethylformamide. The magnitude of this shift was close to Reichardt's dye — one of the most solvatochromic organic dyes known.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Wiley
Date: 09-1994
DOI: 10.1111/J.1365-2044.1994.TB04454.X
Abstract: A 32-year-old man presented with symptoms of severe organophosphate poisoning and required an atropine infusion for 5 weeks. We believe the development of a paralytic ileus occurred as a rare feature of atropine toxicity when other signs were masked by the underlying condition. The onset of a paralytic ileus coincided with a spontaneous increase in red cell cholinesterase levels and may be an early sign of recovery from organophosphate poisoning.
Publisher: Springer Science and Business Media LLC
Date: 12-2009
Publisher: Oxford University Press (OUP)
Date: 25-06-2013
DOI: 10.1093/JAC/DKT240
Abstract: The objective of this study was to investigate the population pharmacokinetics and pharmacodynamics of amoxicillin and clavulanic acid in critically ill patients. In this observational pharmacokinetic study, multiple blood s les were taken over one dosing interval of intravenous amoxicillin/clavulanic acid (1000/200 mg). Blood s les were analysed using a validated ultra HPLC-tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling. One-hundred-and-four blood s les were collected from 13 patients. For both amoxicillin and clavulanic acid, a two-compartment model with between-subject variability for both the clearance and the volume of distribution of the central compartment described the data adequately. For both compounds, 24 h urinary creatinine clearance was supported as a descriptor of drug clearance. The mean clearance of amoxicillin was 10.0 L/h and the mean volume of distribution was 27.4 L. For clavulanic acid, the mean clearance was 6.8 L/h and the mean volume of distribution was 19.2 L. Dosing simulations for amoxicillin supported the use of standard dosing regimens (30 min infusion of 1 g four-times daily or 2 g three-times daily) for most patients when using a target MIC of 8 mg/L and a pharmacodynamic target of 50% fT>MIC, except for those with a creatinine clearance >190 mL/min. Dosing simulations for clavulanic acid showed little accumulation when high doses were administered to patients with high creatinine clearance. Although vast pharmacokinetic variability exists for both amoxicillin and clavulanic acid in intensive care unit patients, current dosing regiments are appropriate for most patients, except those with very high creatinine clearance.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2014
Publisher: MDPI AG
Date: 08-06-2023
DOI: 10.3390/TROPICALMED8060312
Abstract: Background: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rif in, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. Methods: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. Results: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rif in, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. Conclusions: ICU patients had a lower clearance and volume of distribution for rif in, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.
Publisher: Informa Healthcare
Date: 19-07-2010
DOI: 10.1517/17425255.2010.506187
Abstract: Piperacillin-tazobactam is a frequently prescribed intravenous antibiotic for moderate to severe infections used in hospital settings because of its broad activity against many pathogenic bacteria including Pseudomonas aeruginosa. However, its pharmacokinetics (PK) can be significantly altered in a variety of states. This article provides a comprehensive and critical review of the PK of piperacillin-tazobactam in different patient populations. The pharmacodynamics (PD) of piperacillin-tazobactam is also discussed. The importance of appropriate antibiotic dosing in the context of the global tendency for reduced susceptibility of bacteria, including P. aeruginosa is emphasized. The interrelationship between PK and PD is discussed to provide an understanding of methods for procuring dosing regimens that increase the likelihood of clinical success for in idual patients. Alternative dosing regimens, which may include administration by extended or continuous infusion of piperacillin-tazobactam as a mechanism to increase the likelihood of pharmacodynamic target attainment, are described. Where piperacillin-tazobactam is required for treatment, applying knowledge of PK and PD characteristics can facilitate optimal outcomes.
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.IJANTIMICAG.2004.06.005
Abstract: We studied an in vitro model of continuous venous-venous haemofiltration (CVVH), into which levofloxacin 100 mg was infused, to determine levofloxacin adsorption and to determine the effect of filter material and point of dilution (pre- or post-filter) on sieving coefficient. Mean (standard deviation S.D.) adsorption was 18.7 (5.3) mg for the polyamide filter and 40.2 (2.0) mg for the polyacrylonitrile (PAN) filter (P < 0.001). Post-dilution resulted in a minor, but statistically significant, decrease in sieving coefficient (pre-dilution 0.96 (S.D. 0.10), post-dilution 0.88 (S.D. 0.11) with the PAN filter. These data indicate that the variability in published values for levofloxacin sieving coefficient are not due to variation in point of dilution or membrane type (PAN or polyamide). Significant adsorption of levofloxacin onto PAN filters occurs.
Publisher: Springer Science and Business Media LLC
Date: 1999
Abstract: Published data on the observer variability with the transcranial doppler (TCD) ultrasound are limited by the use of the product moment correlation coefficient. This study was designed to quantify the intra and inter observer variability with the TCD in terms of the intra class correlation coefficient (ICC) and to assess the impact of lack of practice on the observer variability and the accuracy of data generated. The study was performed in two phases. In phase I, three observers insonated the middle cerebral artery in 10 healthy volunteers and measured peak systolic and end diastolic cerebral blood flow velocities. In phase II, the same observers repeated the experiment on five healthy volunteers after an eight week break during which none of the observers were allowed to use the TCD system. The observers were blinded to the measurements obtained. The ICC for peak velocity measurement was 0.9 (0.81-0.99) in phase I and 0.85 (0.66-1.00) in phase II (p < 0.05). The ICCs for end diastolic velocity measurements for phase I and II were 0.8 (0.64-0.96) and 0.67 (0.33-1.00) respectively (p < 0.01). A high level of observer agreement is possible with the TCD for measurement of cerebral blood flow velocities. Lack of regular practice with the system reduces the accuracy of measurements and impacts on both measured and calculated indices.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.IJANTIMICAG.2017.01.009
Abstract: The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of β-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). β-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered β-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10× the minimum inhibitory concentration (MIC). A total of 111 TDM s les from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of β-lactam antibiotics in 39 (35%) instances in 27 (24%) s les, TDM values resulted in decreasing the prescribed dose of β-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. β-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive β-lactam concentrations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
Publisher: Wiley
Date: 25-07-2014
DOI: 10.1111/NEP.12276
Abstract: To describe renal replacement therapy (RRT) prescribing practices in Malaysian intensive care units (ICU), and compare this with previously published data from other regions. A survey was sent to physicians responsible for prescribing RRT in major ICU throughout Malaysia. The questionnaire sought information on the physicians' background, and detailed information regarding RRT settings. Nineteen physicians from 24 sites throughout Malaysia responded to the survey (response rate 79.2%). Sixteen respondents were intensivists (84%), 2 were anaesthetists (11%) and one was a nephrologist (5%). The majority (58%) used continuous venovenous haemofiltration (CVVH) as the treatment of choice for acute kidney injury (AKI) in critically ill patients. RRT prescription was predominantly practitioner-dependent (63%), while 37% reported use of a dedicated protocol. The mean blood flow rate and effluent flow rate used for continuous RRT (CRRT) were 188.9 ± 28.9 mL/min and 30.6 ± 4.7 mL/kg/h respectively. Replacement fluid solutions containing both lactate and bicarbonate were commonly used during CRRT, applied both pre- and post-dilution. CRRT was the first-choice modality used to treat AKI in critically ill patients. CVVH was the most common CRRT technique used, while other RRT modalities were used less frequently. Overall, RRT practices were similar to those observed in other regions, although the modality and settings used were slightly different, likely due to local availability.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JCRC.2014.06.022
Abstract: Withholding life-sustaining treatments (WHLST) and withdrawing life-sustaining treatments (WDLST) occur in most intensive care units (ICUs) around the world to varying degrees. Speakers from invited faculty of the World Federation of Societies of Intensive and Critical Care Medicine Congress in 2013 with an interest in ethics were approached to participate in an ethics round table. Participants were asked if they agreed with the statement "There is no moral difference between withholding and withdrawing a mechanical ventilator." Differences between WHLST and WDLST were discussed. Official statements relating to WHLST and WDLST from intensive care societies, professional bodies, and government statements were sourced, documented, and compared. Sixteen respondents stated that there was no moral difference between withholding or withdrawing a mechanical ventilator, 2 were neutral, and 4 stated that there was a difference. Most ethicists and medical organizations state that there is no moral difference between WHLST and WDLST. A review of guidelines noted that all but 1 of 29 considered WHLST and WDLST as ethically or legally equivalent. Most respondents, practicing intensivists, stated that there is no difference between WHLST and WDLST, supporting most ethicists and professional organizations. A minority of physicians still do not accept their equivalency.
Publisher: Oxford University Press (OUP)
Date: 24-03-2010
DOI: 10.1093/JAC/DKQ088
Abstract: The lack of prospective, randomized, controlled trial data to guide optimal antibiotic use in bacteraemic critically ill patients has led to a wide variety of strategies and major issues with drug resistance. We therefore prospectively investigated the epidemiology of bacteraemia and fungaemia in intensive care units (ICUs) and the impact of timing, type and appropriateness of antibiotic intervention. We conducted a multinational, multicentre, prospective observational study in 132 ICUs from 26 countries with no interventions. 1702 patients [European (69.6%), Australasian (12.2%), South American (8.3%) and Asian (9.9%)] developed 1942 bacteraemic episodes over the study period. Mortality rates were similar for those receiving empirical (40.5%), semi-targeted (37.6%) or fully targeted (33.3%) antibiotic therapy (P=0.40), and in those initially receiving broad- (39.3%) or restricted-spectrum (39.1%) therapy (P=0.94). First-line therapy was effective in terms of the antibiogram (where available) in 70.4% of cases. This in vitro susceptibility ranged from 76.3% for broad-spectrum antibiotics to 46.3% for restricted-spectrum antibiotics (P<0.0001). However, no antibiotic policy-associated variable, including in vitro susceptibility (odds ratio 0.89, 95% confidence interval 0.61-1.30), was a statistically significant predictor of mortality. We could not show an impact of antibiotics on mortality in critically ill patients, despite in vitro activity and early commencement. Randomized, multicentre trials are urgently needed to establish the appropriate duration, timing and combinations of antibiotics that will both optimally treat infection and minimize development of resistance and other complications.
Publisher: Oxford University Press (OUP)
Date: 24-12-2015
DOI: 10.1093/JAC/DKV412
Abstract: The objectives of this study were to determine the effects of obesity on unbound trough concentrations and on the achievement of pharmacokinetic (PK) harmacodynamic (PD) targets of piperacillin and meropenem in critically ill patients. This study retrospectively analysed therapeutic-drug-monitoring data from ICU databases in Australia, Germany and Spain, as well as from a large PK study. The presence of obesity was defined as a BMI ≥30 kg/m(2), and patients were also categorized based on level of renal function. The presence of obesity was compared with unbound piperacillin and meropenem trough concentrations. We also used logistic regression to describe factors associated with the achievement of the PK/PD targets, an unbound concentration maintained above the MIC breakpoint (100% fT>MIC and 100% fT>4×MIC) of Pseudomonas aeruginosa. In all, 1400 patients were eligible for inclusion in the study. The median age and weight were 67 years (IQR 52-76 years) and 79 kg (69-90 kg), respectively, and 65% of participants were male. Significantly lower median piperacillin trough concentrations [29.4 mg/L (IQR 17.0-58.0 mg/L)] were found in obese patients compared with non-obese patients [42.0 mg/L (21.5-73.5 mg/L)] (P = 0.001). There was no difference for meropenem trough concentrations [obese 10.3 mg/L (IQR 4.8-16.0 mg/L) versus non-obese 11.0 mg/L (4.3-18.5 mg/L) P = 0.296]. Using logistic regression, we found that the presence of obesity was not associated with achievement of 100% fT>MIC, but the use of prolonged infusion, a creatinine clearance ≤100 mL/min, increasing age and female gender were for various PK/PD targets for both piperacillin and meropenem (P < 0.05). This large dataset has shown that the presence of obesity in critically ill patients may affect piperacillin, but not meropenem, unbound trough concentrations.
Publisher: Oxford University Press (OUP)
Date: 20-01-2015
DOI: 10.1093/JAC/DKU564
Abstract: The objective of this study was to describe the population pharmacokinetics of cefazolin in plasma and the interstitial fluid of subcutaneous tissue of post-trauma critically ill patients and provide clinically relevant dosing recommendations that result in optimal concentrations at the target site. This was a pharmacokinetic study in a tertiary referral ICU. We recruited 30 post-trauma critically ill adult patients and collected serial total and unbound plasma cefazolin concentrations. Interstitial fluid concentrations were determined using in vivo microdialysis. Population pharmacokinetic analysis and Monte Carlo simulations were undertaken with Pmetrics®. Fractional target attainment against an MIC distribution for Staphylococcus aureus isolates was calculated. The mean (SD) age, weight, APACHE II score and CLCR were 37.0 (14.1) years, 86.8 (22.7) kg, 16.9 (5.3) and 163 (44) mL/min, respectively. A three-compartment linear population pharmacokinetic model was most appropriate. Covariates included in the model were CLCR on drug clearance and serum albumin concentration and body weight on the volume of the central compartment. The fractional target attainment for a 1 g intravenous 8-hourly dose for a CLCR of 50 mL/min was 88%, whereas for a patient with a CLCR of 215 mL/min, a dose of 2 g 6-hourly achieved 84% fractional target attainment. Clinicians should be mindful of the effects of elevated CLCR and serum albumin concentrations on dosing requirements for post-trauma critically ill patients.
Publisher: SAGE Publications
Date: 07-2016
Abstract: The standard treatment of peritoneal dialysis (PD)-associated peritonitis (PD-peritonitis) is intraperitoneal (IP) administration of antibiotics. Only limited data on the pharmacokinetics and appropriateness of contemporary dose recommendations of IP cefalothin and cefazolin exist. The aim of this study was to describe the pharmacokinetics of IP cefalothin and cefazolin in patients treated for PD-peritonitis. As per international guidelines, IP cefalothin or cefazolin 15 mg/kg once daily was dosed with gentamicin in a 6-hour dwell to patients with PD-peritonitis during routine care. Serial plasma and PD effluent s les were collected over the first 24 hours of therapy. Antibiotic concentrations were quantified using a validated chromatographic method with pharmacokinetic analysis performed using a non-compartmental approach. Nineteen patients were included (cefalothin n = 8, cefazolin n = 11). The median bioavailability for both antibiotics exceeded 92%, but other pharmacokinetic parameters varied markedly between antibiotics. Both antibiotics achieved high PD effluent concentrations throughout the antibiotic dwell. Cefazolin had a smaller volume of distribution compared with cefalothin (14 vs 40 L, p = 0.003). The median trough total plasma antibiotic concentration for cefazolin and cefalothin during the dwell differed (plasma 56 vs 13 mg/L, p 0.0001) despite a similar concentration in PD effluent (37 vs 38 mg/L, p = 0.58). Lower antibiotic concentrations were noted during PD dwells not containing antibiotic, particularly cefalothin, which was frequently undetectable in plasma and PD effluent. The median duration that the unbound antibiotic concentration was above the minimum inhibitory concentration (MIC) was approximately 13% (plasma) and 25% (IP) for cefalothin, and 100% (plasma and IP) for cefazolin, of the dosing interval. When IP cefalothin or cefazolin is allowed to dwell for 6 hours, sufficient PD effluent concentrations are present for common pathogens during this time. However, with once-daily IP dosing, in contrast to cefazolin, there is a risk of subtherapeutic plasma and PD effluent cefalothin concentrations, so more frequent dosing may be required.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2009
Publisher: Cold Spring Harbor Laboratory
Date: 13-03-2022
DOI: 10.1101/2022.03.11.22272285
Abstract: This study aimed to describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary micros ling to facilitate data-rich blood s ling. Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma s les collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve PK/PD targets, including 100% ƒT MIC with an MIC breakpoint of 1 mg/L. 36 patients (0.2 – 12 y) provided 160 conventional s les for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L and 39.4 L/h, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg Q6h was only able to achieve the PK/PD target of 100% ƒT MIC in patients 10 kg and with impaired renal function or patients of 40 kg with normal renal function. Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary micros ling demonstrated skin-prick s ling can facilitate data-rich pharmacokinetic studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2008
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.IJANTIMICAG.2014.07.001
Abstract: Linezolid is a valuable treatment option for central nervous system (CNS) infections caused by multidrug-resistant Gram-positive micro-organisms. Data regarding its penetration into the CNS have shown wide variability. The aim of this study was to describe the population pharmacokinetics of linezolid in plasma and cerebrospinal fluid (CSF) in critically ill patients with external CSF drainage and proven or suspected CNS infections. This was an observational pharmacokinetic (PK) study in 11 critically ill patients with proven or suspected CNS infection receiving linezolid. Serial blood and CSF s les were taken and were subject to population PK analysis. The median (interquartile range) of AUC(0-12h) was 47.6 (17.9-58.6) mgh/L in plasma and 21.1 (18.8-30.4) mgh/L in CSF, with a median CSF lasma ratio of 0.77. At pre-dose at steady state, a strong positive correlation was observed between linezolid concentrations in CSF and plasma (Spearman's rho=0.758 P=0.011). For a minimum inhibitory concentration (MIC) of 2 mg/L, the median AUC(0-24h)/MIC values in plasma and CSF were <80 in all patients. A three-compartment linear model was found to be most appropriate. The mean value for linezolid clearance was 16.6L/h and mean volume of distribution was 101.3 L. No covariate relationships could be supported on any of the parameters. Linezolid demonstrated good penetration into the CNS but high interin idual PK variability. Administration of higher than standard doses of linezolid and therapeutic drug monitoring should therefore be considered as options to optimise linezolid dosing in critically ill patients with CNS infections.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2016
DOI: 10.1007/S00134-015-4188-0
Abstract: This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic harmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis. This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation. A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p MIC than the IB arm on day 1 (97 versus 70 %, p < 0.001) and day 3 (97 versus 68 %, p < 0.001) post-randomisation. There was no difference in 14-day or 30-day survival between the treatment arms. In critically ill patients with severe sepsis not receiving RRT, CI demonstrated higher clinical cure rates and had better PK/PD target attainment compared to IB dosing of beta-lactam antibiotics. Continuous beta-lactam infusion may be mostly advantageous for critically ill patients with high levels of illness severity and not receiving RRT. Malaysian National Medical Research Register ID: NMRR-12-1013-14017.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2015
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-0758-3
Abstract: The objective of the study was to describe the pharmacokinetics (PK) of fluconazole, anidulafungin, and caspofungin in critically ill patients and to compare with previously published data. We also sought to determine whether contemporary fluconazole doses achieved PK harmacodynamic (PD PK/PD) targets in this cohort of intensive care unit patients. The Defining Antibiotic Levels in Intensive care unit patients (DALI) study was a prospective, multicenter point-prevalence PK study. Sixty-eight intensive care units across Europe participated. Inclusion criteria were met by critically ill patients administered fluconazole ( n = 15), anidulafungin ( n = 9), and caspofungin ( n = 7). Three blood s les (peak, mid-dose, and trough) were collected for PK/PD analysis. PK analysis was performed by using a noncompartmental approach. The mean age, weight, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores of the included patients were 58 years, 84 kg, and 22, respectively. Fluconazole, caspofungin, and anidulafungin showed large interin idual variability in this study. In patients receiving fluconazole, 33% did not attain the PK/PD target, ratio of free drug area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration ( f AUC 0–24 /MIC) ≥100. The fluconazole dose, described in milligrams per kilogram, was found to be significantly associated with achievement of f AUC 0–24 /MIC ≥100 ( P = 0.0003). Considerable interin idual variability was observed for fluconazole, anidulafungin, and caspofungin. A large proportion of the patients (33%) receiving fluconazole did not attain the PK/PD target, which might be related to inadequate dosing. For anidulafungin and caspofungin, dose optimization also appears necessary to minimize variability.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2016
Publisher: Springer Science and Business Media LLC
Date: 04-1998
Abstract: 1) To establish a protocol within international and local ethical guidelines to obtain informed consent for critical care research, overcoming constraints previously described and 2) To evaluate eventual recruitment using this protocol. Prospective descriptive study. Multidisciplinary ICU in a community-based university teaching hospital. Following approval by the University Ethics Committee and Hospital Review Board, patients admitted between January and May 1996 were assessed on weekdays for potential enrollment into existing clinical trials. Discussion with potential candidates and/or next-of-kin occurred at the earliest opportunity and informed consent was obtained preemptively. Next-of-kin was notified if enrollment subsequently occurred. We evaluated the number of patients screened, the number of potential study candidates, the number for whom consent was obtained or refused and the number subsequently enrolled. None Of 249 patients screened, 149 (60%) did not meet the inclusion criteria. Of 100 potential study candidates (40% of all patients screened), we failed to make contact with the next-of-kin in 29 cases (12% of all patients screened). Thus 71 patients or next-of-kin were counselled (28% of all patients screened). In all, 30 patients (12% of all patients screened) were subsequently enrolled into a study. A policy of pre-emptive informed consent enabled us to overcome some of the problems previously experienced in our unit with regards to patient enrollment in critical care research. Although overall recruitment remained low, predictions for future enrollment can be made from this study.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2013
DOI: 10.1007/S00134-013-3088-4
Abstract: Successful antibiotic therapy in the critically ill requires sufficient drug concentrations at the site of infection that kill or suppress bacterial growth. The relationship between antibiotic exposure and achieving the above effects is referred to as pharmacokinetics harmacodynamics (PK/PD). The associated indices therefore provide logical targets for optimal antibiotic therapy. While dosing regimens to achieve such targets have largely been established from studies in animals and non-critically ill patients, they are often poorly validated in the ICU. Endothelial dysfunction, capillary leak, altered major organ blood flow, deranged plasma protein concentrations, extremes of body habitus, the application of extracorporeal support modalities, and a higher prevalence of intermediate susceptibility, independently, and in combination, significantly confound successful antibiotic treatment in this setting. As such, the prescription of standard doses are likely to result in sub-therapeutic concentrations, which in turn may promote treatment failure or the selection of resistant pathogens. This review article considers these issues in detail, summarizing the key changes in antibiotic PK/PD in the critically ill, and suggesting alternative dosing strategies that may improve antibiotic therapy in these challenging patients.
Publisher: Elsevier BV
Date: 12-2023
Publisher: Oxford University Press (OUP)
Date: 07-2010
Publisher: Oxford University Press (OUP)
Date: 17-07-2015
DOI: 10.1093/JAC/DKV201
Abstract: Traditional antibiotic dosing was not designed for today's escalating antibiotic resistance, lack of novel antibiotics and growing complexity in patient populations. Dosing that ensures optimal antibiotic exposures should be considered essential to increase the likelihood of effective patient treatment. Given the variability in these exposures across different patients, a 'one-dose-fits-all' approach is increasingly problematic. Therapeutic drug monitoring (TDM) of the β-lactams, the most widely used antibiotic class, is underutilized in certain populations. Clinical experience with β-lactam TDM remains relatively scarce. Patients most likely to benefit from such an intervention include the critically ill, the obese, the elderly and those with cystic fibrosis. Most centres actively performing β-lactam TDM target a minimum 100% of the time during the dosing interval that the free (unbound) concentration of antibiotic exceeds the MIC of the pathogen (100% fT>MIC), which is higher than a traditional target supported by in vitro data. Ideally, isolated pathogens should undergo MIC testing along with TDM on a regular basis, allowing clinicians to address the triad of bug, drug and patient ('mug') in equal measure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2014
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.JCHROMB.2012.09.016
Abstract: With the clinical imperative to further research in the area of optimising antibiotic dosing in the intensive care setting, a simple high performance liquid chromatography method was developed and validated for routinely determining the free (unbound) concentration of ten beta-lactam antibiotics in 200 μL of human plasma. Antibiotics determined include three cephalosporins (ceftriaxone, cephazolin and cephalotin) two carbapenems (meropenem and ertapenem) and five penicillins ( icillin, piperacillin, benzylpenicillin, flucloxacillin and dicloxacillin). There was a single common s le preparation method involving ultracentrifugation and stabilisation. Chromatography was performed on a Waters XBridge C18 column with, depending on analytes, one of four acetonitrile-phosphate buffered mobile phases. Peaks of interest were detected via ultraviolet absorbance at 210, 260 and 304 nm. The method has been validated and used in a pathology laboratory for therapeutic drug monitoring in critically ill patients. The significant variability in the level of protein binding that is common with antibiotics traditionally considered to have high protein binding (e.g. ceftriaxone, cephazolin, ertapenem, flucloxacillin and dicloxacillin) suggests that this assay should be preferred for measuring the pharmacologically active concentration of beta-lactam antibiotics in a therapeutic drug monitoring programme.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2017
Publisher: Wiley
Date: 17-01-2012
DOI: 10.1111/J.1742-6723.2011.01515.X
Abstract: Haemodynamic targets, such as cardiac output, mean arterial blood pressure and central venous oxygen saturations, remain crude predictors of tissue perfusion and oxygen supply at a cellular level. Shocked patients may appear adequately resuscitated based on normalization of global vital signs, yet they are still experiencing occult hypoperfusion. If targeted resuscitation is employed, appropriate use of end-points is critical. In this review, we consider the value of directing resuscitation at the microcirculation or cellular level. Current technologies available include sublingual capnometry, video microscopy of the microcirculation and near-infrared spectroscopy providing a measure of tissue oxygenation, whereas base deficit and lactate potentially provide a surrogate measure of the adequacy of global perfusion. The methodology and evidence for these technologies guiding resuscitation are considered in this narrative review.
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.IJANTIMICAG.2010.08.013
Abstract: Pneumonia is a form of lung infection that may be caused by various micro-organisms. The predominant site of infection in pneumonia is debatable. Advances in the fields of diagnostic and therapeutic medicine have had a less than optimal effect on the outcome of pneumonia and one of the many causes is likely to be inadequate antimicrobial concentrations at the site of infection in lung tissue. Traditional antimicrobial therapy guidelines are based on indirect modelling from blood antimicrobial levels. However, studies both in humans and animals have shown the fallacy of this concept in various tissues. Many different methods have been employed to study lung tissue antimicrobial levels with limited success, and each has limitations that diminish their utility. An emerging technique being used to study the pharmacokinetics of antimicrobial agents in lung tissue is microdialysis. Development of microdialysis catheters, along with improvement in analytical techniques, has improved the accuracy of the data. Unfortunately, very few studies have reported the use of microdialysis in lung tissue, and even fewer antimicrobial classes have been studied. These studies generally suggest that this technique is a safe and effective way of assessing the pharmacokinetics of antimicrobial agents in lung tissue. Further descriptive studies need to be conducted to study the pharmacokinetics and pharmacodynamics of different antimicrobial classes in lung tissue. Data emanating from these studies could inform decisions for appropriate dosing schedules of antimicrobial agents in pneumonia.
Publisher: Oxford University Press (OUP)
Date: 25-06-2013
DOI: 10.1093/JAC/DKT261
Abstract: Continuous infusion (CI) of high-dose vancomycin is often used to treat life-threatening infections caused by less-susceptible Gram-positive bacteria. However, this approach has not been well studied in patients on continuous renal replacement therapy (CRRT). The aim of this study was to evaluate the adequacy of a new CI vancomycin regimen in septic patients undergoing CRRT. In this prospective study we measured vancomycin concentrations obtained with a new CI regimen for CRRT, which included a loading dose of 35 mg/kg given over a 4 h period followed by a daily dose of 14 mg/kg. Vancomycin concentrations were measured: at the end of the loading dose (T1) 12 h after the onset of therapy (T2) and 24 h after the onset of therapy (T3). Drug concentrations (at T2 and T3) were considered adequate if between 20 and 30 mg/L. CRRT intensity was calculated as: dialysate rate (mL/kg/h) + ultrafiltration rate (mL/kg/h). Vancomycin population pharmacokinetics were calculated using non-linear mixed-effects modelling. We studied 32 patients who received median (IQR) loading and daily vancomycin doses of 2750 mg (2250-3150) and 1100 mg (975-1270), respectively. Drug concentrations were: T1, 44 mg/L (38-58) T2, 27 mg/L (24-31) and T3, 23 mg/L (19-31). Vancomycin concentrations were adequate in 22/32 patients (69%) at T2 and in 20/32 (63%) at T3. The two relevant covariates that significantly affected drug concentrations were body weight and CRRT intensity. This new vancomycin regimen allowed the rapid achievement of target drug concentrations in the majority of patients. CRRT intensity had an influence on vancomycin clearance.
Publisher: Springer Science and Business Media LLC
Date: 08-1988
DOI: 10.1007/BF00263521
Abstract: SNAP25 regulates membrane fusion events at the plasma membrane and in the endosomal system, and a functional pool of the protein is delivered to recycling endosomes (REs) and the trans Golgi network (TGN) through an ARF6-dependent cycling pathway. SNAP25 is a peripheral membrane protein, and palmitoylation of a cluster of four cysteine residues mediates its stable association with the membrane. Here, we report that palmitoylation also determines the precise intracellular distribution of SNAP25, and that mutating single palmitoylation sites enhances the amount of SNAP25 at the RE and TGN. The farnesylated CAAX motif from Hras was ligated onto a SNAP25 mutant truncated immediately distal to the cysteine-rich domain. This construct displayed the same intracellular distribution as full-length SNAP25, and decreasing the number of cysteine residues in this construct increased its association with the RE and TGN, confirming the dominant role of the cysteine-rich domain in directing the intracellular distribution of SNAP25. Marked differences in the localisations of SNAP25-CAAX and Hras constructs, each with two palmitoylation sites, were observed, showing that subtle differences in palmitoylated sequences can have a major impact upon intracellular targeting. We propose that the cysteine-rich domain of SNAP25 is designed to facilitate the dual function of this SNARE protein at the plasma membrane and endosomes, and that dynamic palmitoylation acts as a mechanism to regulate the precise intracellular patterning of SNAP25.
Publisher: Springer Science and Business Media LLC
Date: 03-2016
Publisher: American Society for Microbiology
Date: 11-2016
DOI: 10.1128/AAC.01088-16
Abstract: Our objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m 2 ), obese (30.0 to 39.9 kg/m 2 ), and morbidly obese (≥40 kg/m 2 ). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese ( n = 6) and morbidly obese ( n = 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m 2 , respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment ( V c ) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of kg/m 2 . A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2017
DOI: 10.1007/S40262-017-0588-3
Abstract: Ventriculostomy-associated infections, or ventriculitis, in critically ill patients are associated with considerable morbidity. Efficacious antibiotic dosing for the treatment of these infections may be complicated by altered antibiotic concentrations in the cerebrospinal fluid due to variable meningeal inflammation and antibiotic properties. Therefore, doses used to treat infections with a higher degree of meningeal inflammation (such as meningitis) may often fail to achieve equivalent exposures in patients with ventriculostomy-associated infections such as ventriculitis. This paper aims to review the disease burden, infection rates, and common pathogens associated with ventriculostomy-associated infections. This review also seeks to describe the disease- and drug-related factors that influence antibiotic distribution into cerebrospinal fluid and provide a critical appraisal of current dosing of antibiotics commonly used to treat these types of infections. A Medline search of relevant articles was conducted and used to support a review of cerebrospinal fluid penetration of vancomycin, including critical appraisal of the recent paper by Beach et al. recently published in this journal. We found that in the intensive care unit, ventriculostomy-associated infections are the most common and serious complication of external ventricular drain insertion and often result in prolonged patient stay and increased healthcare costs. Reported infection rates are extremely variable (between 0 and 45%), hindered by the inherent diagnostic difficulty. Both Gram-positive and Gram-negative organisms are associated with such infections and the rise of multi-drug-resistant pathogens means that effective treatment is an ongoing challenge. Disease factors that may need to be considered are reduced meningeal inflammation and the presence of critical illness drug factors include physiochemical properties, degree of plasma-protein binding, and affinity to active transporter proteins present in the blood-cerebrospinal fluid barrier. The relationship between cerebrospinal fluid antibiotic exposures in the setting of ventriculostomy-associated infection and clinical response has not been fully elucidated for many of the antibiotics commonly used in its treatment. More thorough and clinically relevant investigations are needed to better define blood pharmacokinetic harmacodynamics targets and optimal therapeutic exposures for treatment of ventriculostomy-associated infections. It is hoped that this future research will be able to provide clearer recommendations for clinicians frequently faced with dosing-related dilemmas when treating patients with these challenging infections.
Publisher: Springer Science and Business Media LLC
Date: 05-2010
DOI: 10.2165/10898550-000000000-00000
Abstract: Invasive candidiasis (IC) is an important infection in the intensive care unit (ICU) setting given its association with poor clinical outcomes. The epidemiology of IC is complex and, although incompletely elucidated, is characterized by considerable regional and temporal variability. Overall, there appears to be an increase in the incidence of IC and a change in distribution of the causative Candida spp. Of particular concern is an increase in the proportion of episodes caused by Candida glabrata, which is associated with reduced susceptibility to azole antifungal agents. The management of IC has been aided by the availability of several new antifungal agents. In particular, given their broad spectrum of activity and low toxicity, the use of echinocandins as first-line therapy is increasing, especially in settings where fluconazole-resistant Candida spp. are prevalent. Fluconazole remains a reliable agent where an azole-susceptible pathogen is confirmed or in settings where resistance is uncommon. Lipid formulations of hotericin B are now generally reserved as second-line or salvage therapy. Voriconazole and posaconazole currently enjoy limited use for IC in the ICU setting. Although the poor outcomes associated with IC are, in part, related to the severity of underlying host factors, it is clear that optimization of treatment-related factors is also important. In particular, the speed of initiation of antifungal therapy and the achievement of pharmacodynamic parameters both influence outcomes. The most difficult challenge is early initiation of an effective antifungal drug, given the slow turnaround time and lack of sensitivity of conventional culture-based diagnostic techniques. New approaches, such as non-culture-based assays and/or clinical risk-predictive models are required to better target prophylactic, pre-emptive and empirical antifungal strategies.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2009
Abstract: Qualitative pathogen resistance in both dicotyledenous and monocotyledonous plants has been attributed to the action of resistance (R) genes, including those encoding nucleotide binding site – leucine rich repeat (NBS-LRR) proteins and receptor-like kinase enzymes. This study describes the large-scale isolation and characterisation of candidate R genes from perennial ryegrass. The analysis was based on the availability of an expressed sequence tag (EST) resource and a functionally-integrated bioinformatics database. Amplification of R gene sequences was performed using template EST data and information from orthologous candidate using a degenerate consensus PCR approach. A total of 102 unique partial R genes were cloned, sequenced and functionally annotated. Analysis of motif structure and R gene phylogeny demonstrated that Lolium R genes cluster with putative ortholoci, and evolved from common ancestral origins. Single nucleotide polymorphisms (SNPs) predicted through resequencing of licons from the parental genotypes of a genetic mapping family were validated, and 26 distinct R gene loci were assigned to multiple genetic maps. Clusters of largely non-related NBS-LRR genes were located at multiple distinct genomic locations and were commonly found in close proximity to previously mapped defence response (DR) genes. A comparative genomics analysis revealed the co-location of several candidate R genes with disease resistance quantitative trait loci (QTLs). This study is the most comprehensive analysis to date of qualitative disease resistance candidate genes in perennial ryegrass. SNPs identified within candidate genes provide a valuable resource for mapping in various ryegrass pair cross-derived populations and further germplasm analysis using association genetics. In parallel with the use of specific pathogen virulence races, such resources provide the means to identify gene-for-gene mechanisms for multiple host pathogen-interactions and ultimately to obtain durable field-based resistance.
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.IJANTIMICAG.2006.03.025
Abstract: We studied an in vitro model of continuous venovenous haemofiltration to determine levofloxacin adsorption by polyacrylonitrile (PAN) filters. Four doses of levofloxacin (5, 25, 50 and 100 mg) were used, resulting in circulating concentrations of levofloxacin at 120 min of 3.56+/-0.14, 15.84+/-2.08, 31.42+/-1.95 and 58.23+/-1.10 mg/L, respectively. Adsorption at 2 h was 0.65+/-0.17, 5.99+/-2.49, 12.30+/-2.34 and 30.13+/-1.32 mg, respectively (P<0.001). From 2h to 4h, increasing the blood pump rate and the ultrafiltration rate had no effect on adsorption. When the concentration was decreased from 3.55+/-0.13 mg/L at 4h to 2.16+/-0.11 mg/L at 5 h by addition of lactated Ringer's solution, adsorption decreased from 0.67+/-0.16 mg to 0.21+/-0.25 mg (P<0.05). These data show that adsorption of levofloxacin by PAN haemofilters is concentration dependent and reversible in vitro and suggest that adsorption by haemofilters is unlikely to affect levofloxacin pharmacokinetics significantly in vivo.
Publisher: SAGE Publications
Date: 13-09-2017
Abstract: The hospital-based care of pregnant women who are obese is complex. Current guidelines recommend early epidural analgesia, but there is disagreement about the guidelines and their implementation by anesthesiologists. In this study, we conducted semistructured interviews with 42 specialist anesthesiologists about their experiences implementing the “early epidural” recommendation. We examined the impact of intergroup identity and system factors on the language used by anesthesiologists to express their experiences, framing the work by social identity and communication accommodation theory. Leximancer text mining was used to elicit the dominant theme “epidural” in the interviews, and discourse analysis aided in exploring selected extracts. Findings indicated that anesthesiologists expressed their role primarily as technical experts, along with the core value of accommodating patients’ wishes. Furthermore, the extent to which they were prepared to accommodate the perspective of other health professionals was a key indicator of the intergroup climate.
Publisher: Oxford University Press (OUP)
Date: 11-2006
Publisher: Mary Ann Liebert Inc
Date: 02-2012
DOI: 10.1089/SUR.2011.046
Abstract: The objective of this structured review was to analyze critically the findings of pharmacokinetic studies of beta-lactam antibiotics in patients with intra-abdominal disease that is, intra-abdominal infection (IAI) or previous abdominal surgery and determine the requirements for dosage modification in this population. Data were identified by structured review of PUBMED from February 1983 to February 2011. All 14 articles reviewed described the pharmacokinetics of beta-lactam antibiotics in patients with intra-abdominal disease. Antibiotic classes included carbapenems, penicillins, cephalosporins, and monobactams. Possible physiological changes in these patients include development of abscesses, perforation, or ischemia of the bowel as well as intra-abdominal hypertension. These disorders may cause changes in antibiotic pharmacokinetics, including increased volume of distribution and faster drug clearance, both resulting in lower antibiotic concentrations. High inter-in idual pharmacokinetic variability was common to each of the studies. Most of the available data demonstrate that drug volume of distribution can be increased significantly in the presence of intra-abdominal disease. Drug clearance is likely to vary in line with renal or hepatic function. Thus, dose optimization is important to prevent development of antibiotic resistance or therapeutic failure. However, further research is necessary to determine the clinical outcome of in idualized dosing on the basis of pharmacokinetic harmacodynamic studies.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2011
Abstract: Critically ill patients can display markedly abnormal physiological parameters compared with those in ward-based or ambulatory settings. As a function of both the underlying inflammatory state and the interventions provided, these patients manifest substantial changes in their cardiovascular and renal function that are not always immediately discernable using standard diagnostic tests. Impaired renal function is well documented among such in iduals however, even patients with normal serum creatinine concentrations might display elevated glomerular filtration rates, a phenomenon we have termed augmented renal clearance (ARC). This finding has important ramifications for the accurate dosing of renally eliminated drugs, given that most pharmaceutical dosing regimens were validated outside the critical care environment. Empirical approaches to dosing are unlikely to achieve therapeutic drug concentrations in patients with ARC, placing them at risk of suboptimal drug exposure and potential treatment failure. With an increasing appreciation of this phenomenon, alternative dosing strategies will need to be investigated.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2016
Publisher: Springer Science and Business Media LLC
Date: 13-11-2012
DOI: 10.1007/S40262-012-0018-5
Abstract: Controversy reigns as to how protein binding changes alter the time course of unbound drug concentrations in patients. Given that the unbound concentration is responsible for drug efficacy and potential drug toxicity, this area is of significant interest to clinicians and academics worldwide. The present uncertainty means that many questions relating to this area exist, including "How important is protein binding?", "Is protein binding always constant?", "Do pH and temperature changes alter binding?" and "How do protein binding changes affect dosing requirements?". In this paper, we seek to address these questions and consider the data associated with altered pharmacokinetics in the presence of changes in protein binding and the clinical consequences that these may have on therapy, using ex les from the critical care area. The published literature consistently indicates that a change in the protein binding and unbound concentrations of some drugs are common in certain specific patient groups such as the critically ill. Changes in pharmacokinetic parameters, including clearance and apparent volume of distribution (V(d)), may be dramatic. Drugs with high protein binding, high intrinsic clearance (e.g. clearance by glomerular filtration) and where dosing is not titrated to effect are most likely to be affected in a clinical context. Drugs such as highly protein bound antibacterials with multiple half-lives within a dosing interval and that have some level of renal clearance, such as ertapenem, teicoplanin, ceftriaxone and flucloxacillin, are commonly affected. In response to these challenges, clinicians need to adapt dosing regimens rationally based on the pharmacokinetic harmacodynamic characteristics of the drug. We propose that further pharmacokinetic modelling-based research is required to enable the design of robust dosing regimens for drugs affected by altered protein binding.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2014
Publisher: Cambridge University Press (CUP)
Date: 04-2010
DOI: 10.1086/651312
Abstract: In the midst of an outbreak, carbapenem-resistant Acinetobacter baumannii was grown from s les of multiple environmental sites in an intensive care unit. A commercial oxidizing disinfectant (potassium peroxomonosulphate 50%, sodium alkyl benzene sulphonate 15%, and sulphamic acid 5%) was introduced throughout the intensive care unit, and its use coincided with cessation of the outbreak.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1996
DOI: 10.1097/00003246-199609000-00013
Abstract: The use of the Pediatric Risk of Mortality (PRISM) score or other scoring systems in the intensive care unit (ICU) is of great importance for evaluating the efficacy and efficiency of a particular ICU. However, the PRISM score was developed and validated in the United States and subsequently validated in Europe, but has not been evaluated in a less affluent society. In general, scoring systems should be used only in populations similar to the reference population in which the prediction model was developed. We set out to determine the applicability of the PRISM score at Baragwanath Hospital, South Africa. Prospective, descriptive study. Twenty-four-bed multidisciplinary ICU. We analyzed 1,528 consecutive pediatric admissions from January 1989 to June 1994. None. PRISM scores, Therapeutic Intervention Scoring System scores, demographic, and clinical data collected prospectively were entered and stored by means of a commercial software package at the time of admission of each patient. The prediction of actual mortality by PRISM scoring was evaluated by the Hosmer and Lemeshow goodness-of-fit test (chi2[8 degrees of freedom]). Receiver operating characteristic curves were constructed and compared with those curves from pediatric ICU populations in the United States and Europe. In idual receiver operating characteristic curves were constructed for surgical and nonsurgical patients, age categories, and diagnostic categories. Compared with European and American ICU populations, our patients were younger, were mostly nonsurgical emergency admissions, stayed longer in the ICU, and were more severely ill with a higher admission PRISM score and overall mortality rate. Respiratory and septic diagnoses predominated, with very few surgical cases admitted. The Hosmer and Lemeshow goodness-of-fit test showed a significant failure of the PRISM scoring system to accurately predict mortality over a wide range of expected mortality rates (chi2[8 degrees of freedom] = 465, p = 0). Similarly, receiver operating characteristic analysis indicated a poor predictive power (Az = 0.73 +/- 0.01 [SEM]), with an area under the curve significantly less than that for the PRISM reference population (p = 0). PRISM showed equally poor discriminatory function at all age groups and diagnostic categories. The PRISM score needs to be recalibrated or recalculated for our patient population in view of the high discrepancy and poor discriminatory function shown. Part of the inaccuracy may derive from different demographic characteristics of our ICU population and a different pattern of diseases. It appears that PRISM is not population independent.
Publisher: Wiley
Date: 09-2009
DOI: 10.1002/J.2055-2335.2009.TB00452.X
Abstract: To compare the clearance of midazolam and its metabolites in critically ill paediatric and adult patients. A prospective study conducted in paediatric and adult intensive care units. Patients over 2 years of age receiving midazolam for therapeutic sedation were eligible for enrolment. Midazolam and its metabolite concentrations were determined in plasma and urine. The median (interquartile range) steady‐state concentrations observed in the paediatric and adult groups were 90 mg/L (48–135) and 253 mg/L (148–404), respectively (p = 0.90). The median daily doses were 1.8 mg/kg (0.6–2.2) and 1.9 mg/kg (0.6–2.7), respectively (p = 0.84). Midazolam clearance in paediatric and adult patients was 1.1 mL/kg/min (0.9–3.8) and 2.9 mL/kg/min (0.9–3.8), respectively. Analysis of clearances by age identified two peaks in midazolam and its metabolites occurring around 12 years of age and at 45 years of age. Neither midazolam nor its metabolites appeared to accumulate in blood after long courses of treatment ( 3 days). A conclusion that could be drawn from this study is that some of midazolam's pharmacokinetic variability may be explained by age‐related changes in metabolism. These findings require validation in a larger study.
Publisher: Oxford University Press (OUP)
Date: 03-11-2015
DOI: 10.1093/JAC/DKV349
Abstract: Few data are available to guide linezolid dosing during renal replacement therapy. The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL/kg/h) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h). Patients requiring linezolid 600 mg iv every 12 h and CVVHF or CVVHDF were eligible for this prospective study. Seven blood s les were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics. Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an AUC from 0-24 h to MIC (AUC0-24/MIC) of 80. Nine CVVHDF and eight CVVHF treatments were performed in 13 patients. Regimens of CVVHDF and CVVHF were similar. A two-compartment linear model best described the data. CVVHDF was associated with a 20.5% higher mean linezolid clearance than CVVHF, without statistical significance (P = 0.39). Increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were: clearance (CL), 3.8 (2.2) L/h volume of the central compartment, 26.5 (10.3) L intercompartmental clearance constants from central to peripheral, 8.1 (12.1) L/h and peripheral to central compartments, 3.6 (4.0) L/h. Achievement of pharmacodynamic targets was poor for an MIC of 2 mg/L with the studied dose. During CVVHF and CVVHDF, there is profound pharmacokinetic variability of linezolid. Suboptimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg iv every 12 h.
Publisher: Informa UK Limited
Date: 27-03-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2008
Publisher: Bentham Science Publishers Ltd.
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 23-03-2001
Abstract: To investigate the pharmacokinetics of intravenous ciprofloxacin 200 mg every 8 h in critically ill patients on continuous veno-venous haemodiafiltration (CVVHDF), one form of continuous renal replacement therapy (CRRT). Open, prospective clinical study in a multidisciplinary, intensive care unit in a university-affiliated tertiary referral hospital. Six critically ill patients with acute renal failure on CVVHDF. Timed blood and ultrafiltrate s les were collected to allow pharmacokinetics and clearances to be calculated of initial and subsequent doses of 200 mg intravenous ciprofloxacin. CVVHD was performed with 1 l/h of dialysate and 2 l/h of predilution filtration solution, producing 3 l/h of dialysis effluent. The blood was pumped at 200 ml/min using a Gambro BMM-10 blood pump through a Hospal AN69HF haemofilter. Ten pharmacokinetic profiles were measured. The CVVHDF displayed a urea clearance of 42 +/- 3 ml/min, and removed ciprofloxacin with a clearance of 37 +/- 7 ml/min. This rate was 2-2.5 greater than previously published for ciprofloxacin in other forms of CRRT. On average the CVVHDF was responsible for clearing a fifth of all ciprofloxacin eliminated (21 +/- 10%). The total body clearance of ciprofloxacin was 12.2 +/- 4.3 l/h. The trough concentration following the initial dose was 0.7 +/- 0.3 mg/l. The area under the plasma concentration time curves over a 24-h period ranged from 21 to 55 mg.h l-1. Intravenous ciprofloxacin 600 mg/day in critically ill patients using this form of CRRT produced adequate plasma levels for many resistant microbes found in intensive care units.
Publisher: SAGE Publications
Date: 11-2002
Abstract: The authors investigated the effect of manual hyperinflation (MHI) with set parameters applied to patients on mechanical ventilation on hemodynamics, respiratory mechanics, and gas exchange. Sixteen critically ill patients post-septic shock, with acute lung injury, were studied. Heart rate, arterial pressure, and mean pulmonary artery pressure were recorded every minute. Pulmonary artery occlusion pressure, cardiac output, arterial blood gases, and dynamic compliance (C dyn ) were recorded pre- and post-MHI. From this, systemic vascular resistance index (SVRI), cardiac index, oxygen delivery, and partial pressure of oxygen: fraction of inspired oxygen (PaO 2 :FiO 2 ) ratio were calculated. There were significant increases in SVRI ( P 0.05) post-MHI and diastolic arterial pressure ( P 0.01) during MHI. C dyn increased post-MHI ( P 0.01) and was sustained at 20 minutes post-MHI ( P 0.01). Subjects with an intrapulmonary cause of lung disease had a significant decrease ( P = 0.02) in PaO 2 :FiO 2 , and those with extrapulmonary causes of lung disease had a significant increase ( P 0.001) in PaO 2 :FiO 2 post-MHI. In critically ill patients, MHI resulted in an improvement in lung mechanics and an improvement in gas exchange in patients with lung disease due to extrapulmonary events and did not result in impairment of the cardiovascular system.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2014
Publisher: Wiley
Date: 07-2011
DOI: 10.1111/J.1445-5994.2009.02160.X
Abstract: Accurate knowledge of the glomerular filtration rate (GFR) is imperative in the intensive care unit (ICU) as renal status is important for medical decisions, including drug dosing. Recently, an estimation of GFR (eGFR) was suggested as a method of estimating GFR. How well this formula predicts GFR in unwell patients with normal initial serum creatinine concentrations has not been examined. The accuracy of the eGFR (before and after adjustment for actual body surface area (BSA)) was compared with measured and with estimated creatinine clearance using the Cockcroft Gault (CG) formula adjusted for total and lean body weight. A total of 237 observations was recorded in 47 subjects. These were initially analysed independently, and then using the first observation only. Overall the mean difference between measured creatinine clearance and eGFR was -12 mL/min (95% confidence interval (CI) -20 to -3), between measured creatinine clearance and CG +17 mL/min (95% CI 9-24), between measured creatinine clearance and CG adjusted for ideal body weight +12 mL/min (95% CI 4-21) and between measured creatinine clearance and eGFR 'unadjusted' for BSA 5 mL/min (95% CI -2-13). Using either eGFR or CG formulae to estimate renal function in ICU subjects with normal serum creatinine concentrations is inaccurate. Although correcting for BSA improves the eGFR, this requirement to measure height and weight removes a major attraction for its use. We suggest that eGFR should not be automatically calculated in the ICU setting.
Publisher: Massachusetts Medical Society
Date: 15-11-2012
Publisher: American Society for Microbiology
Date: 03-2017
DOI: 10.1128/AAC.01276-16
Abstract: The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma s les were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m 2 , respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h −1 , and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h −1 . A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.ADDR.2017.09.019
Abstract: Patients suffering major burn injury represent a unique population of critically ill patients. Widespread skin and tissue damage causes release of systemic inflammatory mediators that promote endothelial leak, extravascular fluid shifts, and cardiovascular derangement. This phase is characterized by relative intra-vascular hypovolaemia and poor peripheral perfusion. Large volume intravenous fluid resuscitation is generally required. The patients' clinical course is then typically complicated by ongoing inflammation, protein catabolism, and marked haemodynamic perturbation. At all times, drug distribution, metabolism, and elimination are grossly distorted. For hydrophilic agents, changes in volume of distribution and clearance are marked, resulting in potentially sub-optimal drug exposure. In the case of antibiotics, this may then promote treatment failure, or the development of bacterial drug resistance. As such, empirical dose selection and pharmaceutical development must consider these features, with the application of strategies that attempt to counter the unique pharmacokinetic changes encountered in this setting.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.JPBA.2014.11.042
Abstract: A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, using hydrophilic interaction liquid chromatography (HILIC) chromatography for the analysis of fosfomycin in human plasma and urine, has been developed and validated. The plasma method uses a simple protein precipitation using a low volume s le (10 μL) and is suitable for the concentration range of 1 to 2000 μg/mL. The urine method involves a simple dilution of 10 μL of s le and is suitable for a concentration range of 0.1 to 10 mg/mL. The plasma and urine results, reported, respectively, are for recovery (68, 72%), inter-assay precision (≤9.1%, ≤8.1%) and accuracy (range -7.2 to 3.3%, -1.9 to 1.6%), LLOQ precision (4.7%, 3.1%) and accuracy (1.7% and 1.2%), and includes investigations into the linearity, stability and matrix effects. The method was used in a pilot pharmacokinetic study of a critically ill patient receiving i.v. fosfomycin, which measured a maximum and minimum plasma concentration of 222 μg/mL and 172 μg/mL, respectively, after the initial dose, and a maximum and minimum plasma concentration of 868 μg/mL and 591μg/mL, respectively, after the fifth dose. The urine concentration was 2.03 mg/mL after the initial dose and 0.29 mg/mL after the fifth dose.
Publisher: Wiley
Date: 24-04-2007
DOI: 10.1111/J.1558-5646.2007.00104.X
Abstract: Few studies have examined genotype by environment (GxE) effects on premating reproductive isolation and associated behaviors, even though such effects may be common when speciation is driven by adaptation to different environments. In this study, mating success and courtship song differences among erging populations of Drosophila mojavensis were investigated in a two-environment quantitative trait locus (QTL) analysis. Baja California and mainland Mexico populations of D. mojavensis feed and breed on different host cacti, so these host plants were used to culture F2 males to examine host-specific QTL effects and GxE interactions influencing mating success and courtship songs. Linear selection gradient analysis showed that mainland females mated with males that produced songs with significantly shorter L(long)-IPIs, burst durations, and interburst intervals. Twenty-one microsatellite loci distributed across all five major chromosomes were used to localize effects of mating success, time to copulation, and courtship song components. Male courtship success was influenced by a single detected QTL, the main effect of cactus, and four GxE interactions, whereas time to copulation was influenced by three different QTLs on the fourth chromosome. Multiple-locus restricted maximum likelihood (REML) analysis of courtship song revealed consistent effects linked with the same fourth chromosome markers that influenced time to copulation, a number of GxE interactions, and few possible cases of epistasis. GxE interactions for mate choice and song can maintain genetic variation in populations, but alter outcomes of sexual selection and isolation, so signal evolution and reproductive isolation may be slowed in erging populations. Understanding the genetics of incipient speciation in D. mojavensis clearly depends on cactus-specific expression of traits associated with courtship behavior and sexual isolation.
Publisher: Informa UK Limited
Date: 15-04-2016
DOI: 10.1586/17512433.2016.1172209
Abstract: Initial adequate anti-infective therapy is associated with significantly improved clinical outcomes for patients with severe infections. However, in critically ill patients, several pathophysiological and/or iatrogenic factors may affect the pharmacokinetics of anti-infective agents leading to suboptimal drug exposure, in particular during the early phase of therapy. Therapeutic drug monitoring (TDM) may assist to overcome this problem. We discuss the available evidence on the use of TDM in critically ill patient populations for a number of anti-infective agents, including aminoglycosides, β-lactams, glycopeptides, antifungals and antivirals. Also, we present the available evidence on the practices of anti-infective TDM and describe the potential utility of TDM to improve treatment outcome in critically ill patients with severe infections. For aminoglycosides, glycopeptides and voriconazole, beneficial effects of TDM have been established on both drug effectiveness and potential side effects. However, for other drugs, therapeutic ranges need to be further defined to optimize treatment prescription in this setting.
Publisher: Georg Thieme Verlag KG
Date: 02-02-2015
Abstract: The recent surge in multidrug-resistant pathogens combined with the diminishing antibiotic pipeline has created a growing need to optimize the use of our existing antibiotic armamentarium, particularly in the management of intensive care unit (ICU) patients. Optimal and timely pharmacokinetic harmacodynamic (PK/PD) target attainment has been associated with an increased likelihood of clinical and microbiological success in critically ill patients. Emerging data, mostly from in vitro and in vivo studies, suggest that optimization of antibiotic therapy should not only aim to maximize clinical outcomes but also to include the suppression of resistance. The development of antibiotic dosing regimens that adheres to the PK/PD principles may prolong the clinical lifespan of our existing antibiotics by minimizing the emergence of resistance. This article summarizes the relevance of PK/PD characteristics of different antibiotic classes on the development of antibiotic resistance. On the basis of the available data, we propose dosing recommendations that can be adopted in the clinical setting, to maximize therapeutic success and limit the emergence of resistance in the ICU.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2009
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JCRC.2014.05.022
Abstract: The purpose of this study is to determine the approaches used in withdrawing mechanical ventilator support. Speakers from the invited faculty of the World Federation of Societies of Intensive and Critical Care Medicine Congress in 2013 with an interest in ethics were asked to provide a detailed description of in idual approaches to the process of withdrawal of mechanical ventilation. Twenty-one participants originating from 13 countries, responded to the questionnaire. Four respondents indicated that they do not practice withdrawal of mechanical ventilation, and another 4 indicated that their approach is highly variable depending on the clinical scenario. Immediate withdrawal of ventilation was practiced by a large number of the respondents (7/16 44%). A terminal wean was practiced by just more than a third of the respondents (6/16 38%). Extubation was practiced in more than 70% of instances among most of the respondents (9/17 53%). Two of the respondents (2/17 12%) indicated that they would extubate all patients, whereas 14 respondents indicated that they would not extubate all their patients. The emphasis was on tailoring the approach used to suit in idual case scenarios. Withdrawing of ventilator support is not universal. However, even when withdrawing mechanical ventilation is acceptable, the approach to achieve this end point is highly variable and in idualized.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2014
Publisher: Springer Science and Business Media LLC
Date: 06-06-2016
No related grants have been discovered for Jeffrey Lipman.