ORCID Profile
0000-0002-2392-9854
Current Organisations
Wuxi University
,
University of Queensland
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Publisher: American Society for Microbiology
Date: 16-12-2202
DOI: 10.1128/AAC.01698-20
Abstract: The aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF s les were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.PUPT.2018.04.006
Abstract: Preservative-free tobramycin is commonly used as aerosolized therapy for ventilator associated pneumonia. The comparative delivery profile of the formulations of two different concentrations (100 mg/ml and 40 mg/ml) is unknown. This study aims to evaluate the aerosol characteristics of these tobramycin formulations in a simulated adult mechanical ventilation model. Simulated adult mechanical ventilation set up and optimal settings were used in the study. Inhaled mass study was performed using bacterial/viral filters at the tip of the tracheal tube and in the expiratory limb of circuit. Laser diffractometer was used for characterising particle size distribution. The physicochemical characteristics of the formulations were described and nebulization characteristics compared using two airways, an endotracheal tube (ET) and a tracheostomy tube (TT). For each type of tube, three internal tube diameters were studied, 7 mm, 8 mm and 9 mm. The lung dose was significantly higher for 100 mg/ml solution (mean 121.3 mg vs 41.3 mg). Viscosity was different (2.11cp vs 1.58cp) for 100 mg/ml vs 40 mg/ml respectively but surface tension was similar. For tobramycin 100 mg/ml vs 40 mg/ml, the volume median diameter (2.02 vs 1.9 μm) was comparable. The fine particle fraction (98.5 vs 85.4%) was higher and geometric standard deviation (1.36 vs 1.62 μm) was significantly lower for 100 mg/ml concentration. Nebulization duration was longer for 100 mg/ml solution (16.9 vs 10.1 min). The inhaled dose percent was similar (30%) but the exhaled dose was higher for 100 mg/ml solution (18.9 vs 10.4%). The differences in results were non-significant for type of tube or size except for a small but statistically significant reduction in inhaled mass with TT compared to ET (0.06%). Aerosolized tobramycin 100 mg/ml solution delivered higher lung dose compared to tobramycin 40 mg/ml solution. Tracheal tube type or size did not influence the aerosol characteristics and delivery parameters.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2012
Publisher: Springer Science and Business Media LLC
Date: 09-12-2019
DOI: 10.1007/S00228-019-02792-0
Abstract: We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration (SLED-HDF) to inform the dosing of these drugs in an acute setting. Six stable patients with end-stage kidney disease. An open-label pilot pharmacokinetic study of meropenem and piperacillin-tazobactam. SLED-HDF was undertaken for 4 h. Plasma drug concentrations were measured pre- and post-filter and in the effluent at multiple time points. The pharmacokinetic data was analysed using non-compartmental methods. The fraction of time that in idual plasma concentration profiles were predicted to remain above the MIC break-points for commonly isolated gram-negative pathogens during a prolonged SLED-HDF session was assessed using two targets fT > MIC (fraction of time above the MIC) and the more aggressive fT > 4 × MIC (fraction of time above 4 × MIC). Meropenem total and SLED-HDF clearance ranged from 141 to 180 mL/min and 126-205 mL/min, respectively. Piperacillin total and SLED-HDF clearance values ranged from 131 to 252 mL/min and 135-162 mL/min, respectively. Our results suggest that prolonged SLED-HDF (12 h) will only maintain a sufficient meropenem and piperacillin-tazobactam plasma concentration to achieve a target of fT > MIC for gram-negative pathogens (MIC 2 mg/L-meropenem, 8 mg/L-piperacillin-tazobactam) for less than 40% of the time. Plasma concentrations would be inadequate to achieve the more aggressive target of 100 % fT > 4xMIC target recommended for critically unwell patients. The pharmacokinetic data obtained from this pilot study demonstrate significant quantities of meropenem and piperacillin are removed during a SLED-HDF session. This may lead to subtherapeutic concentrations of piperacillin and meropenem over the duration of HDF session. Australasian Clinical Trials Registry Network (ACTRN12616000078459).
Publisher: Springer Science and Business Media LLC
Date: 06-06-2019
Publisher: American Society for Microbiology
Date: 20-12-2019
DOI: 10.1128/AAC.01655-19
Abstract: The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane-tazobactam and CVVHDF. Unbound drug concentrations were measured from serial prefilter blood, postfilter blood, and ultrafiltrate s les by a chromatographic assay.
Publisher: Royal Society of Chemistry (RSC)
Date: 1992
DOI: 10.1039/DT9920002971
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/CC11679
Publisher: Wiley
Date: 29-05-2020
Publisher: Springer Science and Business Media LLC
Date: 11-07-2018
Publisher: American Geophysical Union (AGU)
Date: 08-1996
DOI: 10.1021/JS960087F
Publisher: American Society for Microbiology
Date: 06-2018
DOI: 10.1128/AAC.00242-18
Abstract: To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma s les collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years) median weight, 68 kg (IQR, 65 to 82 kg) and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during s ling period ( C max ), 1,702 ng/ml (1,352 to 2,141 ng/ml) area under the concentration-time curve from zero to infinity (AUC 0–∞ ), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml) clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h) and volume of distribution ( V ), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC 0–∞ was 39% of the values reported for heathy volunteers. The AUC 0–∞ was only 52% of the steady-state AUC 0–24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in this cohort of critically ill patients compared to those in healthy volunteers and hematology patients.
Publisher: Wiley
Date: 12-03-2021
DOI: 10.1002/CPT.2191
Publisher: Frontiers Media SA
Date: 12-06-2020
Publisher: American Society for Microbiology
Date: 23-06-2020
DOI: 10.1128/AAC.02584-19
Abstract: Optimal concentrations of unbound antimicrobials are essential for a maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare the effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model. The study design was a prospective, three-phase intervention observational study.
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: BMJ
Date: 16-12-2019
Publisher: Elsevier BV
Date: 06-2021
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: Oxford University Press (OUP)
Date: 07-12-2022
DOI: 10.1093/JAC/DKAC402
Abstract: Pharmacodynamic profiling of oral ciprofloxacin dosing for urinary tract infections caused by ceftriaxone-resistant Escherichia coli isolates with ciprofloxacin MIC ≥ 0.25 mg/L. Urine-specific breakpoints for ciprofloxacin do not exist. However, high urinary concentrations may promote efficacy in isolates with low-level resistance. Ceftriaxone-resistant E. coli urinary isolates were screened for ciprofloxacin susceptibility. Fifteen representative strains were selected and tested using a dynamic bladder infection model. Oral ciprofloxacin dosing was simulated over 3 days (250 mg daily, 500 mg daily, 250 mg 12 hourly, 500 mg 12 hourly and 750 mg 12 hourly). The model was run for 96 h. Primary endpoint was change in bacterial density at 72 h. Secondary endpoints were follow-up change in bacterial density at 96 h and area-under-bacterial-kill-curve. Bacterial response was related to exposure (AUC0–24/MIC Cmax/MIC). PTA was determined using Monte-Carlo simulation. Ninety-three clinical isolates demonstrated a trimodal ciprofloxacin MIC distribution (modal MICs at 0.016, 0.25 and 32 mg/L). Fifteen selected clinical isolates (ciprofloxacin MIC 0.25–512 mg/L) had a broad range of quinolone-resistance genes. Following ciprofloxacin exposure, E. coli ATCC 25922 (MIC 0.008 mg/L) was killed in all dosing experiments. Six isolates (MIC ≥ 16 mg/L) regrew in all experiments. Remaining isolates (MIC 0.25–8 mg/L) regrew variably after an initial period of killing, depending on simulated ciprofloxacin dose. A & % PTA, using AUC0–24/MIC targets, supported 250 mg 12 hourly for susceptible isolates (MIC ≤ 0.25 mg/L). For isolates with MIC ≤ 1 mg/L, 750 mg 12 hourly promoted 3 log10 kill at the end of treatment (72 h), 1 log10 kill at follow-up (96 h) and 90% maximal activity (AUBKC0–96). Bladder infection modelling supports oral ciprofloxacin activity against E. coli with low-level resistance (ciprofloxacin MIC ≤ 1 mg/L) when using high dose therapy (750 mg 12 hourly).
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: 05-2019
DOI: 10.1016/J.JPBA.2019.03.018
Abstract: A bridging study is presented to investigate the applicability of measuring vancomycin concentrations obtained by finger-prick. A total of 25 paired plasma s les, collected from finger prick as capillary micros ling and arterial plasma s les collected from an indwelling cannula as conventional s ling, were obtained from critically ill patients receiving vancomycin. The maximum concentration (C
Publisher: American Society for Microbiology
Date: 10-2018
DOI: 10.1128/AAC.01306-18
Abstract: The combination product meropenem-vaborbactam, with activity against KPC-producing carbapenem-resistant Enterobacteriaceae , is likely to be used during renal replacement therapy. The aim of this work was to describe the extracorporeal removal (adsorption and clearance) of meropenem-vaborbactam during continuous venovenous hemofiltration (CVVH).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2020
DOI: 10.1213/ANE.0000000000004766
Abstract: Obesity is a risk factor for surgical site infection after cesarean delivery. There is inadequate pharmacokinetic data available regarding prophylactic cefazolin dosing in obese pregnant women. We aimed to describe the plasma and interstitial fluid (ISF) pharmacokinetics of cefazolin in obese women undergoing elective cesarean delivery and use dosing simulations to predict optimal dosing regimens. Eligible women were scheduled for elective cesarean delivery at term, with a body mass index (BMI) of kg·m −2 . Plasma and ISF s les were collected following 2 g of intravenous cefazolin. Concentrations were determined using liquid chromatography-mass spectrometry. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. Total and unbound cefazolin concentrations in plasma and ISF were compared with the minimum inhibitory concentration at which 90% of isolates are inhibited (MIC 90 ) of cefazolin for Staphylococcus aureus , 2 mg·L −1 . The fractional target attainment (FTA) of dosing regimens to achieve a pre-established target of 95% unbound ISF concentrations mg·L −1 throughout a 3-hour duration of the surgery was calculated. The 12 women recruited had a median (interquartile range [IQR]) BMI of 41.5 (39.7–46.6) kg·m −2 and a median (IQR) gestation of 38.7 weeks (37.9–39.0). For each timepoint up to 180 minutes, the median across subjects of total and unbound plasma concentration of cefazolin remained above 2 mg·L −1 . The minimum observed total plasma concentration was 31.7 mg·L −1 and plasma unbound concentration was 7.7 mg·L −1 (observed in the same participant). For each timepoint up to 150 minutes, the median across subjects of unbound ISF concentrations remained above 2 mg·L −1 . The minimum observed unbound ISF concentration was 0.7 mg·L −1 (observed in 1 participant). In 2 participants, the ISF concentration of cefazolin was not maintained above 2 mg·L −1 . The mean (± standard error [SE]) penetration of cefazolin (calculated as area under the concentration-time curve for the unbound fraction of drug [ f AUC] tissue / f AUC plasma ) into the ISF was 0.884 ± 1.11. Simulations demonstrated that FTA % was achieved in patients weighing 90–150 kg by an initial 2 g dose with redosing of 2 g at 2 hours. FTA was improved to % when an initial 3 g dose was repeated at 2 hours. To maintain adequate ISF antibiotic concentrations in obese pregnant women, our results suggest that redosing of cefazolin may be required. When wound closure has not occurred within 2 hours, redosing is suggested, following either a 2 or 3 g initial bolus. These preliminary results require validation in a larger population.
Publisher: Walter de Gruyter GmbH
Date: 25-11-2020
Abstract: Novel treatment options for some carbapenem-resistant Gram-negative pathogens have been identified by the World Health Organization as being of the highest priority. Ceftolozane–tazobactam is a novel cephalosporin–beta-lactamase inhibitor combination antibiotic with potent bactericidal activity against the most difficult-to-treat multi-drug resistant and extensively drug resistant Gram-negative pathogens. This study aimed to develop and validate a liquid chromatography – tandem mass spectrometry method for the simultaneous quantification of ceftolozane and tazobactam in plasma (total and unbound), renal replacement therapy effluent (RRTE), cerebrospinal fluid (CSF) and urine. Analytes were separated using mixed-mode chromatography with an intrinsically base-deactivated C18 column and a gradient mobile phase consisting of 0.1% formic acid, 10 mM ammonium formate and acetonitrile. The analytes and internal standards were detected using rapid ionisation switching between positive and negative modes with simultaneous selected reaction monitoring. A quadratic calibration was obtained for plasma (total and unbound), RRTE and CSF over the concentration range of 1–200 mg/L for ceftolozane and 0.5–100 mg/L for tazobactam, and for urine the concentration range of 10–2,000 mg/L for ceftolozane and 5–1,000 mg/L for tazobactam. For both ceftolozane and tazobactam, validation testing for matrix effects, precision and accuracy, specificity and stability were all within the acceptance criteria of ±15%. This methodology was successfully applied to one pilot pharmacokinetic study in infected critically ill patients, including patients receiving renal replacement therapy, and one case study of a patient with ventriculitis, where all patients received ceftolozane–tazobactam.
Publisher: Oxford University Press (OUP)
Date: 25-02-2022
DOI: 10.1093/JAC/DKAC045
Abstract: The use of oral fosfomycin for urinary tract infections (UTIs) caused by non-Escherichia coli uropathogens is uncertain, including Klebsiella pneumoniae, the second most common uropathogen. A multicompartment bladder infection in vitro model was used with standard media and synthetic human urine (SHU) to simulate urinary fosfomycin exposure after a single 3 g oral dose (fAUC0–72 16884 mg·h/L, t½ 5.5 h) against 15 K. pneumoniae isolates including ATCC 13883 (MIC 2 to & mg/L) with a constant media inflow (20 mL/h) and 4-hourly voiding of each bladder. The impact of the media (CAMHB + G6P versus SHU) on fosfomycin MIC measurements, drug-free growth kinetics and regrowth after fosfomycin administration was assessed. A low and high starting inoculum (5.5 versus 7.5 log10 cfu/mL) was assessed in the bladder infection model. Compared with CAMHB, isolates in SHU had a slower growth rate doubling time (37.7 versus 24.1 min) and reduced growth capacity (9.0 ± 0.3 versus 9.4 ± 0.3 log10 cfu/mL), which was further restricted with increased inflow rate (40 mL/h) and more frequent voids (2-hourly). Regrowth was commonly observed in both media with emergence of fosfomycin resistance promoted by a high starting inoculum in CAMHB (MIC rise to ≥1024 mg/L in 13/14 isolates). Resistance was rarely detected in SHU, even with a high starting inoculum (MIC rise to ≥1024 mg/L in 2/14 isolates). Simulated in an in vitro UTI model, the regrowth of K. pneumoniae urinary isolates was inadequately suppressed following oral fosfomycin therapy. Efficacy was further reduced by a high starting inoculum.
Publisher: SAGE Publications
Date: 07-2018
DOI: 10.1177/0310057X1804600405
Abstract: Vancomycin is a commonly used antibiotic due to the high burden of methicillin-resistant Staphylococcus aureus infections. This study aimed to describe the pharmacokinetics (PK) of vancomycin in Australian Indigenous patients with severe sepsis, and advise an optimal dosing strategy. A population PK study was conducted in a remote Australian intensive care unit (ICU). Serial plasma s les were collected over one to two dosing intervals and assayed by validated chromatography. Concentration–time data collected were analysed using Pmetrics® software. The final population PK model was then used for Monte Carlo dosing simulations to determine optimal loading and intermittent maintenance doses. Fifteen Indigenous subjects were included for analysis with a median (interquartile range, IQR) age, weight and creatinine clearance (CrCL) of 43 (34–46) years, 73 (66–104) kg and 99 (56–139) ml/minute respectively. A two-compartment model described the data adequately. Vancomycin clearance (CL) and volume of distribution of the central compartment (Vc) were described by CrCL and patient weight respectively. Median (IQR) CL, Vc, distribution rate constants from central to peripheral, and from peripheral to central compartments were 4.6 (3.8–5.6) litres per hour, 25.4 (16.1–31.3) litres, 0.46 (0.28–0.52)/hour and 0.25 (0.12–0.37)/hour respectively. No significant interethnic PK differences were observed in comparison to published data. Therapeutic loading doses were significantly dependent on both weight and CrCL, whereas maintenance doses were dependent on CrCL. In the absence of severe renal impairment, initiation of maintenance dose eight hours post–loading dose achieved higher probability of target attainment at 24 hours. This is the first report of vancomycin PK in this patient group.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2000
DOI: 10.1016/S0304-3959(99)00230-4
Abstract: Oxycodone and morphine are structurally related, strong opioid analgesics, commonly used to treat moderate to severe pain in humans. Although it is well-established that morphine is a mu-opioid agonist, this is not the case for oxycodone. Instead, our recent studies have shown that oxycodone appears to be a kappa-opioid agonist (Ross and Smith, 1997). In the current study, we now show that co-administration of sub-antinociceptive doses of oxycodone (putative kappa-opioid agonist) with morphine (mu-opioid agonist) to rats by both the intracerebroventricular and by systemic routes (intraperitoneal and subcutaneous), results in markedly increased (synergistic) levels of antinociception. Behaviourally, rats co-administered sub-antinociceptive doses of oxycodone and morphine were similar to control rats dosed with saline, whereas rats that received equi-potent doses of either opioid alone, were markedly sedated. These results suggest that co-administration of sub-analgesic doses of oxycodone and morphine to patients may provide excellent pain relief with a reduction in opioid-related CNS side-effects. Controlled clinical trials in appropriate patient populations are required to evaluate this possibility.(1)
Publisher: Future Science Ltd
Date: 06-2023
Abstract: Aim: To describe the stability of nafamostat in infusion solutions, during blood s le collection and in extracted plasma s les in the autos ler. Methods: Nafamostat infusion solutions were stored at room temperature in the light for 24 h. For s le collection stability, fresh blood spiked with nafamostat was subjected to combinations of anticoagulants, added esterase inhibitor and temperature. Nafamostat was monitored in the extracted plasma s les in the autos ler. Results: Nafamostat was stable in infusion solutions. Nafamostat in whole blood was stable for 3 h before centrifugation when collected in sodium fluoride otassium oxalate tubes (4°C). Nafamostat in extracted plasma s les degraded at 4.7 ± 0.7% per h. Conclusion: Viable s les can be obtained using blood collection tubes with sodium fluoride, chilling and processing promptly.
Publisher: Oxford University Press (OUP)
Date: 26-02-2019
DOI: 10.1093/JAC/DKZ069
Abstract: Patients with septic shock may undergo extensive physiological alterations that can alter antibiotic pharmacokinetics. To describe the population pharmacokinetics of ciprofloxacin in septic shock and to define recommendations for effective ciprofloxacin dosing in these patients. Adult patients with septic shock treated with ciprofloxacin were eligible for inclusion. Concentrations were measured by HPLC-MS/MS. Population pharmacokinetic modelling was performed with Monte Carlo simulations then used to define dosing regimens that optimize the PTA of an AUC/MIC ratio >125 for different MICs and fractional target attainment (FTA) of empirical and targeted therapy against Pseudomonas aeruginosa. We included 48 patients with median Simplified Acute Physiology Score (SAPS) II of 49 and 90 day mortality of 33%. Ciprofloxacin pharmacokinetics was best described by a two-compartment linear model including CLCR and body weight as covariates on CL and central volume respectively. With a dose of 400 mg q8h and CLCR of 80 mL/min, >95% PTA was achieved for bacteria with MICs ≤0.25 mg/L. For empirical treatment of P. aeruginosa, 600 mg q8h only reached a maximum of 68% FTA. For directed therapy against P. aeruginosa, a dose of 600 mg q8h was needed to achieve sufficient AUC/MIC ratios. In patients with septic shock, standard ciprofloxacin dosing achieved concentrations to successfully treat bacteria with MICs ≤0.25 mg/L and then only in patients with normal or reduced CLCR. To cover pathogens with higher MICs or in patients with augmented renal CL, doses may have to be increased.
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: Elsevier BV
Date: 04-1996
DOI: 10.1016/0162-0134(95)00082-8
Abstract: Reaction of the fluoroquinolone antimicrobial ciprofloxacin with copper(II) nitrate in the presence of 2,2'-bipyridine resulted in the isolation of the complex [Cu(cip)(bipy) (Cl)0.7(NO3)0.3] (NO3).2H2O. Reaction of an aqueous solution of ciprofloxacin.HCl and NaCl with CuCl2 at pH 5.0 resulted in the isolation of [Cu(cip)2]Cl2.11H2O. The complex [Cu(cip) (bipy)(Cl)0.7(NO3)0.3] (NO3).2H2O crystallizes in the monoclinic space group P2(1)/n, with a = 13.955(8), b = 14.280(8), c = 14.192(6) A, beta = 93.10(4) degrees, Z = 4 with R = 0.046. The selective broadening of resonances in the 13C NMR spectrum of ciprofloxacin by the addition of Cu2+(aq) was employed to probe metal ion binding sites in the ligand. The protonation constants of norfloxacin and ciprofloxacin, and the formation constants with copper(II), were determined by potentiometric titrations at 25 degrees C. The additions of ciprofloxacin to metal to form ML and ML2 complexes exhibit stepwise formation constants of log K1 6.2(1) and log K2 11.1(3), respectively.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2019
DOI: 10.1097/ALN.0000000000002752
Abstract: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis s les were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637 interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P & 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P & 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P & 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P & 0.001). Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.
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: 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: Elsevier BV
Date: 02-2022
Publisher: Elsevier BV
Date: 09-2020
Publisher: Oxford University Press (OUP)
Date: 25-06-2020
DOI: 10.1093/JAC/DKAA211
Abstract: To compare bacterial killing and the emergence of resistance to piperacillin/tazobactam, administered by intermittent versus prolonged infusion (i.e. extended or continuous), for ceftriaxone-resistant Klebsiella pneumoniae clinical isolates in an in vitro dynamic hollow-fibre infection model (HFIM). K. pneumoniae 68 (Kp68 MIC = 8 mg/L, producing SHV-106 and DHA-1) and K. pneumoniae 69 (Kp69 MIC = 1 mg/L, producing CTX-M-14) were studied in the HFIM over 7 days (initial inoculum ~107 cfu/mL). Six piperacillin/tazobactam dosing regimens for Kp68 (4/0.5 g 8 hourly as 0.5 and 4 h infusions, 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) and three piperacillin/tazobactam dosing regimens for Kp69 (4/0.5 g 8 hourly as 0.5 and 4 h infusions and 12/1.5 g/24 h continuous infusion) were simulated (piperacillin clearance = 14 L/h, creatinine clearance = 100 mL/min). Total and resistant populations and MICs were quantified/determined. For Kp68, all simulated dosing regimens exhibited approximately 4 log10 of bacterial killing at 8 h followed by regrowth to approximately 1011 cfu/mL within 24 h. The MICs for resistant subpopulations exceeded 256 mg/L at 72 h. Similarly, for Kp69, all simulated dosing regimens exhibited approximately 4 log10 of bacterial killing over 8 h however, only the continuous infusion prevented bacterial regrowth. Compared with intermittent infusion, prolonged infusion did not increase initial bacterial killing and suppression of regrowth of plasmid-mediated AmpC- and ESBL-producing K. pneumoniae. However, continuous infusion may suppress regrowth of some ESBL-producing susceptible K. pneumoniae, although more data are warranted to confirm this observation.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.IJANTIMICAG.2021.106431
Abstract: Extracorporeal membrane oxygenation (ECMO) can affect antimicrobial pharmacokinetics. This case report describes a 33-year-old male with newly diagnosed acquired immunodeficiency syndrome presenting in acute severe type 1 respiratory failure. On investigation, the patient had positive cultures for Candida albicans from respiratory specimens and high blood cytomegalovirus titres, and required venovenous ECMO therapy for refractory respiratory failure. Intravenous fluconazole (6 mg/kg, 24-h) and ganciclovir (5 mg/kg, 12-h) was commenced. Pre-oxygenator, post-oxygenator and arterial blood s les were collected after antibiotic administration, and were analysed for total fluconazole and ganciclovir concentrations. Although there was a 40% increase in the volume of distribution for fluconazole relative to healthy volunteers, the pharmacodynamic targets for prophylaxis were still met. The area under the curve exposure of ganciclovir (50.78 mg•h/L) achieved target thresholds. The ECMO circuit had no appreciable effect on achievement of therapeutic exposures of fluconazole and ganciclovir.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2020
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: 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: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/CC12705
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: Oxford University Press (OUP)
Date: 30-10-2012
DOI: 10.1093/JAC/DKS435
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.IJANTIMICAG.2019.06.027
Abstract: The aim of this study was to describe the population pharmacokinetics of ticarcillin during extended daily diafiltration (EDDf) in critically ill patients with acute kidney injury. Blood s les were collected from critically ill patients prescribed ticarcillin during one to two dosing intervals during which EDDf was performed. Plasma s les were measured using a validated ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Concentration-time data were analysed using a population pharmacokinetics approach with Pmetrics®. A total of 53 blood s les were collected from six critically ill patients (three male). The mean ± standard deviation patient age, weight and body mass index (BMI) was 43 ± 22 years, 88 ± 14 kg and 31 ± 5 kg/m
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: Elsevier BV
Date: 06-2018
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.IJANTIMICAG.2022.106623
Abstract: Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are a global public-health concern. We evaluated the pharmacodynamic activity of piperacillin/tazobactam (TZP) dosing regimens against ESBL-producing versus non-ESBL-producing E. coli. Five E. coli clinical isolates were obtained from Bangladesh. Broth microdilution and whole-genome sequencing (WGS) were performed on the five studied isolates. Three TZP-susceptible ESBL-producing and two non-ESBL-producing E. coli were exposed to TZP regimens of 4.5 g every 6 h (q6h) and every 8 h (q8h) as a 30-min infusion in a dynamic hollow-fibre infection model over 7 days. The extent of bacterial killing was ∼4-5 log
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: American Society for Microbiology
Date: 05-2018
DOI: 10.1128/AAC.00078-18
Abstract: Augmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa by use of the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (10 5.8 and 10 7.6 CFU/ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log 10 versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log 10 initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log 10 at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log 10 killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC.
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: Elsevier BV
Date: 09-2022
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: Springer Science and Business Media LLC
Date: 11-01-2021
DOI: 10.1007/S40262-020-00979-8
Abstract: Patients with severe trauma exhibit augmented renal clearance, which can alter the dosing requirement of renally eliminated drugs. This study aimed to develop a population pharmacokinetic model for levetiracetam in patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage, and use it to describe optimal dosing regimens. This was a prospective open-label observational study. Critically ill adult patients with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage without renal dysfunction and receiving levetiracetam were eligible. Serial levetiracetam plasma concentrations were analyzed to develop a population pharmacokinetic model and perform dosing simulations. A two-compartment model best described the concentration-time data from 30 patients. The mean ± standard deviation parameter estimates were bioavailability (F) of 0.8 ± 0.2, absorption rate constant of 2.4 ± 2 h Patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage with augmented renal clearance are at risk of not achieving target levetiracetam plasma concentrations. We suggest dose titration guided by measured creatinine clearance, and/or, therapeutic drug monitoring if available, to minimize the risk of seizures.
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: 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: Elsevier BV
Date: 12-2018
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: American Society for Microbiology
Date: 23-06-2020
DOI: 10.1128/AAC.00469-20
Abstract: Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation, and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOΔ mutS (MIC of ciprofloxacin [MIC ciprofloxacin ], 0.
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: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1007/S00216-019-02184-4
Abstract: A simple method for the simultaneous quantification of meropenem and the recently approved β-lactamase inhibitor, vaborbactam, in human plasma and renal replacement therapy effluent (RRTE) was developed and validated. This antibiotic combination protects a primary β-lactam, meropenem, with a new β-lactamase inhibitor, and expands the limited options for treatment of multidrug-resistant Gram-negative infections. Meropenem, vaborbactam, and the internal standards [
Publisher: BMJ
Date: 2013
Publisher: Oxford University Press (OUP)
Date: 19-01-2022
DOI: 10.1093/JAC/DKAB497
Abstract: Bacterial biofilm is a key component in the pathogenesis of prosthetic joint infection (PJI). Synovial fluid has been shown to have inhibitory activity against planktonic bacteria. However, the contribution of synovial fluid in prevention of Staphylococcus aureus (including MRSA) planktonic and biofilm forms is unknown. To test the antibacterial and antibiofilm activities of synovial fluid, including that containing cefazolin, against MSSA and MRSA. We determined the antiplanktonic and antibiofilm activities of synovial fluid collected from patients given preoperative cefazolin while undergoing elective arthroplasty surgery. MICs of cefazolin were determined for planktonic and biofilm cultures of biofilm-forming strains of MSSA and MRSA. Synovial fluid inhibited planktonic and biofilm cultures of MSSA and MRSA. Cefazolin-containing synovial fluid had greater antibacterial and antibiofilm activities than the same cefazolin concentration in glucose LB (GLB) broth. MSSA and MRSA MICs of cefazolin suspended in synovial fluid were 0.7 mg/L. The MICs of cefazolin diluted in GLB broth were higher, measuring 1.4 mg/L for MSSA and 23 mg/L for MRSA. Synovial fluid containing cefazolin inhibited biofilm- and planktonic-state MRSA cultures. This may explain the apparent effect of cefazolin in the prevention of MRSA PJI.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.IJANTIMICAG.2021.106466
Abstract: This study aimed to describe the population pharmacokinetics (PK) of cefepime during extracorporeal membrane oxygenation (ECMO) and through dosing simulations, identify a maximally effective and safe dosing strategy. Serial cefepime plasma concentrations were measured in patients on ECMO, and data were analysed using a population PK approach with Pmetrics®. Dosing simulations were used to identify the optimal dosing strategy that achieved target trough concentrations (C Based on simulations, patients with CrCL of 120 mL/min receiving 1 g 8-hourly dosing achieved a 40-44% probability of efficacy (C This study reported reduced cefepime clearance in patients receiving ECMO, resulting in an increased risk of cefepime toxicity. To avoid drug accumulation, modified dosing regimens should be used in critically ill patients on ECMO. Clinicians should adopt therapeutic drug monitoring when treating less susceptible organisms and in patients with reduced renal clearance on ECMO.
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: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.IJANTIMICAG.2019.03.018
Abstract: There are very limited data on ticarcillin-clavulanate elimination by haemofiltration. We measured in vitro ticarcillin-clavulanate adsorption to polyacrylonitrile (PAN) filters and the sieving coefficient using a well-described bench model of haemofiltration. The dose of ticarcillin-clavulanate was 60/2 mg or 180/3 mg, and 0 or 12 g albumin was added to the 1 L of circulating blood-crystalloid mixture to produce four different experimental conditions. The experiment was repeated four times under each condition. Median (interquartile range [IQR] ) ticarcillin adsorption varied from 28 (27-30) mg to 85 (78-90) mg. Adsorption was increased when the dose of ticarcillin was higher (P<0.001), but was not affected by the addition of albumin. Median (IQR) adsorption of clavulanate ranged from 0.67 (0.55-0.75) mg to 1.8 (0.33-3.5) mg and was neither dose dependent (P = 0.505) nor significantly affected by the addition of albumin. Median (IQR) ticarcillin sieving coefficient ranged from 0.73 (0.67-0.75) to 0.99 (0.97-1.03). It was significantly higher with a higher dose of ticarcillin (P = 0.021) and without addition of albumin (P = 0.015). Median (IQR) clavulanate sieving coefficient ranged from 1.03 (1.00-2.24) to 2.0 (1.98-2.47). Clavulanate sieving coefficient was not significantly affected by dose or the addition of albumin. These data indicate that significant adsorption of both ticarcillin and clavulanate occurs in vitro however, this requires confirmation by clinical pharmacokinetic studies. The sieving coefficient data may help guide appropriate dosing of critically ill patients receiving haemofiltration until more extensive clinical pharmacokinetic data are available.
Publisher: Elsevier BV
Date: 09-1995
Publisher: Future Science Ltd
Date: 03-2018
Abstract: Conventional s ling techniques for clinical pharmacokinetic studies often require the removal of large blood volumes from patients. This can result in a physiological or emotional burden, particularly for neonates or pediatric patients. Antibiotic pharmacokinetic studies are typically performed on healthy adults or general ward patients. These may not account for alterations to a patient’s pathophysiology and can lead to suboptimal treatment. Micros ling offers an important opportunity for clinical pharmacokinetic studies in vulnerable patient populations, where smaller s le volumes can be collected. This systematic review provides a description of currently available micros ling techniques and an overview of studies reporting the quantitation and validation of antibiotics using micros ling. A comparison of micros ling to conventional s ling in clinical studies is included.
Publisher: Walter de Gruyter GmbH
Date: 12-11-2020
Abstract: The aim of our work was to develop and validate a hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry (HILIC-ESI-MS/MS) methods for the quantification of tobramycin (TMC) and lincomycin (LMC)in plasma, microdialysis fluid and urine. Protein precipitation was used to extract TMC and LMC from plasma, while microdialysis fluid and urine s le were diluted prior to instrumental analysis. Mobile phase A consisted of 2 mM ammonium acetate in 10% acetonitrile with 0.2% formic acid (v/v) and mobile phase B consisted of 2 mM ammonium acetate in 90% acetonitrile with 0.2% formic acid (v/v). Gradient separation (80%–10% of mobile phase B) for TMC was done using a SeQuant zic-HILIC analytical guard column. While separation of LMC was performed using gradient elution (100%–40% of mobile phase B) on a SeQuant zic-HILIC analytical column equipped with a SeQuant zic-HILIC guard column. Vancomycin (VCM) was used as an internal standard. A quadratic calibration was obtained over the concentration range for plasma of 0.1–20 mg/L for TMC and 0.05–20 mg/L for LMC, for microdialysis fluid of 0.1–20 mg/L for both TMC and LMC, and 1–100 mg/L for urine for both TMC and LMC. For TMS and LMC, validation testing for matrix effects, precision and accuracy, specificity and stability were all within acceptance criteria of ±15%. The methods described here meet validation acceptance criteria and were suitable for application in a pilot pharmacokinetic research study performed in a sheep model.
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: Oxford University Press (OUP)
Date: 20-06-2022
DOI: 10.1093/JAC/DKAC186
Abstract: Urosepsis caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli is increasing worldwide. Carbapenems are commonly recommended for the treatment of ESBL infections however, to minimize the emergence of carbapenem resistance, interest in alternative treatments has heightened. This study compared pharmacodynamics of piperacillin/tazobactam versus meropenem against ESBL-producing and non-producing E. coli clinical isolates. E. coli isolates, obtained from national reference laboratory in Bangladesh, were characterized by phenotypic tests, WGS, susceptibility tests and mutant frequency analysis. Three ESBL-producing and two non-producing E. coli were exposed to piperacillin/tazobactam (4.5 g, every 6 h and every 8 h, 30 min infusion) and meropenem (1 g, every 8 h, 30 min infusion) in a hollow-fibre infection model over 7 days. Piperacillin/tazobactam regimens attained ∼4–5 log10 cfu/mL bacterial killing within 24 h and prevented resistance emergence over the experiment against ESBL-producing and non-producing E. coli. However, compared with 8 hourly meropenem, the 6 hourly piperacillin/tazobactam attained ∼1 log10 lower bacterial kill against one of three ESBL-producing E. coli (CTAP#173) but comparable killing for the other two ESBL-producing (CTAP#168 and CTAP#169) and two non-producing E. coli (CTAP#179 and CTAP#180). The 6 hourly piperacillin/tazobactam regimen attained ∼1 log10 greater bacterial kill compared with the 8 hourly regimen against CTAP#168 and CTAP#179 at 24 h. Our study suggests piperacillin/tazobactam may be a potential alternative to carbapenems to treat urosepsis caused by ESBL-producing E. coli, although clinical trials with robust design are needed to confirm non-inferiority of outcome.
Publisher: American Society for Microbiology
Date: 20-12-2019
DOI: 10.1128/AAC.01679-19
Abstract: Augmented renal clearance (ARC) is common in critically ill patients and is associated with subtherapeutic concentrations of renally eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance lification for meropenem and tobramycin regimens in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates were studied in static-concentration time-kill studies. One isolate was examined comprehensively in a 7-day hollow-fiber infection model (HFIM).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2019
DOI: 10.1213/ANE.0000000000003377
Abstract: Ketorolac tromethamine has been used for joint infiltration by the orthopedic surgeons as a part of postoperative multimodal analgesia. The objective of this study is to investigate the pharmacokinetic properties of S (−) and R (+) enantiomers of ketorolac in adult patients undergoing total hip (THA) and knee arthroplasty (TKA). Adult patients with normal preoperative renal function received a periarticular infiltration of 30 mg of ketorolac tromethamine along with 100 mL of 0.2% ropivacaine and 1 mg of epinephrine at the end of their THA or TKA surgery. Blood s les were taken from a venous cannula at various time points after infiltration. Pharmacokinetic modeling was performed using PMetrics 1.5.0. From 18 participants, 104 s les were analyzed. The peak plasma concentration for S (−) ketorolac was found to be lower than that of R (+) ketorolac, for both THA (0.19–1.22 mg/L vs 0.39–1.63 mg/L, respectively) and TKA (0.28–0.60 mg/L vs 0.48–0.88 mg/L, respectively). The clearance of the S (−) ketorolac enantiomer was higher than R (+) ketorolac (4.50 ± 2.27 vs 1.40 ± 0.694 L/h, respectively). Our study demonstrates that with periarticular infiltration, S (−) ketorolac was observed to have increased clearance rate and highly variable volume of distribution and lower peak plasma concentration compared to R (+) ketorolac.
Publisher: Elsevier BV
Date: 12-1995
DOI: 10.1016/0378-4347(95)00316-9
Abstract: A rapid and economical high-performance liquid chromatographic assay is described for norfloxacin in serum. S les (100 microliters) containing N-ethylnorfloxacin as the internal standard were extracted into 1 ml of chloroform. Chromatography was performed at 30 degrees C on a 40 x 3.2 mm I.D. C18 guard cartridge (3 microns spherical particles) using a mobile phase of 11% (v/v) acetonitrile in 0.01 M phosphate buffer (pH 2.5) containing 0.001 M triethylamine, and pumped at 1 ml/min. Detection was at 279 nm. The retention times of norfloxacin and internal standard were 1.9 and 2.9 min, respectively. Calibration curves were linear (r > 0.999) from 0.1 mg/l to at least 2.0 mg/l. Within-day and between-day precision (C.V.) were 8.6% or less, and accuracy was 5.3% or less. Absolute assay recovery of norfloxacin was over 70%.
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: Oxford University Press (OUP)
Date: 09-03-2020
DOI: 10.1093/CID/CIAA224
Abstract: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4–8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35–65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P & .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9–18.8), piperacillin was 78.6 mg/L (49.5–127.3), tazobactam was 9.5 mg/L (6.3–14.2), and vancomycin was 14.3 mg/L (11.6–21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.
Publisher: Oxford University Press (OUP)
Date: 27-06-2023
DOI: 10.1093/JAC/DKAD190
Abstract: To describe the total and unbound population pharmacokinetics of a 2 g three-times-weekly post-dialysis ceftriaxone regimen in Indigenous Australian patients requiring hemodialysis. A pharmacokinetic study was carried out in the dialysis unit of a remote Australian hospital. Adult Indigenous patients on intermittent hemodialysis (using a high-flux dialyzer) and treated with a 2 g three-times-weekly ceftriaxone regimen were recruited. Plasma s les were serially collected over two dosing intervals and assayed using validated methodology. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics in R. The probability of pharmacokinetic harmacodynamic target attainment (unbound trough concentrations ≥1 mg/L) and toxicity [trough concentrations (total) ≥100 mg/L] were simulated for various dosing strategies. Total and unbound concentrations were measured in 122 plasma s les collected from 16 patients (13 female) with median age 57 years. A two-compartment model including protein-binding adequately described the data, with serum bilirubin concentrations associated (inversely) with ceftriaxone clearance. The 2 g three-times-weekly regimen achieved 98% probability to maintain unbound ceftriaxone concentrations ≥1 mg/L for a serum bilirubin of 5 µmol/L. Incremental accumulation of ceftriaxone was observed in those with bilirubin concentrations & µmol/L. Three-times-weekly regimens were less probable to achieve toxic exposures compared with once-daily regimens. Ceftriaxone clearance was increased by & -fold during dialysis. A novel 2 g three-times-weekly post-dialysis ceftriaxone regimen can be recommended for a bacterial infection with an MIC ≤1 mg/L. A 1 g three-times-weekly post-dialysis regimen is recommended for those with serum bilirubin ≥10 µmol/L. Administration of ceftriaxone during dialysis is not recommended.
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000502474
Abstract: Extra-corporeal membrane oxygenation (ECMO) therapy could affect effective drug concentrations via adsorption onto the oxygenator or associated circuit. We describe a case of a 25-year-old female who required a veno-arterial ECMO therapy for refractory cardiac arrest due to massive pulmonary embolism. She had mild renal dysfunction as a result of the cardiac arrest. A total of 2 g of intravenous cefazolin 8-hourly was administered. Pre- and post-oxygenator blood s les were collected at 0, 1, 4, and 8 h post antibiotic administration. S les were analyzed for total and unbound cefazolin concentrations. Protein binding was ∼60%. Clearance was reduced due to impaired renal function. The pharmacokinetics of cefazolin appear to not be affected by ECMO therapy and dosing adjustment may not be required.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2021
DOI: 10.1097/FTD.0000000000000874
Abstract: In this study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous venovenous hemofiltration (CVVH, 30 mL·kg −1 ·h −1 ) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL·kg −1 ·h −1 + 15 mL·kg −1 ·h −1 ) and determine the optimal dosing regimen using the developed model. Patients with septic shock undergoing continuous renal replacement therapy and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from 8 CVVH sessions and 8 CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 hours to the minimum inhibitory concentration (MIC) (AUC 0-24 /MIC) in plasma. The median total body weight (min–max) was 94.8 (66–138) kg. Micafungin concentrations were best described by a 2-compartmental PK model. No covariates, including continuous renal replacement therapy modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (SD) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis . No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2003
Publisher: American Society for Microbiology
Date: 20-08-2020
DOI: 10.1128/AAC.00879-20
Abstract: Given that aminoglycosides, such as amikacin, may be used for multidrug-resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P. aeruginosa to inform ventilator-associated pneumonia (VAP) and sepsis treatment choices. A hollow-fiber infection model with two P. aeruginosa isolates (MICs of 2 and 8 mg/liter) with an initial inoculum of ∼10 8 CFU/ml was used to test different amikacin dosing regimens.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.IJANTIMICAG.2018.07.008
Abstract: This article reports a pharmacokinetic case study of intravenous posaconazole in a 49-year-old male patient with intra-abdominal sepsis and hypoalbuminaemia receiving continuous venovenous haemodiafiltration. Concentration-time data following 300 mg intravenous posaconazole was analysed using a population pharmacokinetics approach. The 300-mg intravenous dose appears to be adequate for the treatment of yeast infections however, for the treatment of invasive aspergillosis in isolated cases of critically ill patients with hypoalbuminaemia, the current dosing may not achieve desired exposure, although steady state exposure data are needed.
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: Wiley
Date: 02-06-2020
DOI: 10.1002/PHAR.2413
Publisher: American Society for Microbiology
Date: 10-2019
DOI: 10.1128/AAC.01265-19
Abstract: Evaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and to assess the adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane-tazobactam according to clinician recommendation.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2012
Publisher: American Society for Microbiology
Date: 17-06-2021
DOI: 10.1128/AAC.02307-20
Abstract: The objective of this study was to describe the pharmacokinetics (PK) of micafungin in plasma and peritoneal fluid in septic patients with intra-abdominal infections. Twelve patients with secondary peritonitis in septic shock receiving 100 mg micafungin once daily were included.
Publisher: Wiley
Date: 19-09-2023
DOI: 10.1002/JPER.23-0086
No related grants have been discovered for Steven Wallis.