ORCID Profile
0000-0001-7352-3097
Current Organisation
University of Florida
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Medical Bacteriology | Pharmacology and Pharmaceutical Sciences | Pharmaceutical Sciences | Pharmacology and Pharmaceutical Sciences not elsewhere classified |
Human Pharmaceutical Treatments (e.g. Antibiotics) | Infectious Diseases
Publisher: American Society for Microbiology
Date: 07-2016
DOI: 10.1128/AAC.02927-15
Abstract: Infections caused by multidrug-resistant Acinetobacter baumannii are a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinical A. baumannii strains in a dynamic one-compartment in vitro model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused ≥4 log 10 killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log 10 CFU/ml) lification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the lification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.
Publisher: Informa UK Limited
Date: 06-2009
Publisher: American Society for Microbiology
Date: 06-2012
DOI: 10.1128/AAC.06380-11
Abstract: The in vitro pharmacodynamics of colistin against Pseudomonas aeruginosa PAO1 wild-type and isogenic knockout strains of phoP and pmrA were evaluated. Colistin killing at subinhibitory concentrations was greater against the phoP and pmrA mutants than the wild type within the first 8 h: the concentration that results in 50% of maximal effect (EC 50 ) of the pmrA mutant (0.413 mg/liter) was less than that of the wild type (0.718 mg/liter) ( P 0.05). An in vitro pharmacodynamic model simulating human colistin regimens displayed initial killing followed by regrowth in the phoP mutant and gradual regrowth in the pmrA mutant and wild type.
Publisher: Wiley
Date: 13-02-2018
DOI: 10.1002/CPT.1012
Publisher: American Society for Microbiology
Date: 02-2012
DOI: 10.1128/AAC.05664-11
Abstract: For methicillin-resistant Staphylococcus aureus (MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is ≥400. While the AUC/MIC ratio is the accepted pharmacokinetic harmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in an in vitro hollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 μg/ml) using an inoculum of ∼10 6 CFU/ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of ≥400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of μg/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the lification of nonsusceptible subpopulations. No colonies were found on agar plates with 3× MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena.
Publisher: Oxford University Press (OUP)
Date: 06-11-2015
DOI: 10.1093/JAC/DKU437
Abstract: For fluoroquinolones, the area under the free plasma concentration-time curve ided by the MIC (fAUC/MIC) best predicts bacterial killing in mice and outcomes in patients. However, it is unknown whether the shape of the antibiotic concentration profile affects resistance emergence. Our objective was to compare killing and resistance between ciprofloxacin concentration profiles with different shapes at the same fAUC/MIC and identify the durations of ciprofloxacin exposure that minimize resistance emergence. Static time-kill studies over 24 h using Pseudomonas aeruginosa ATCC 27853 assessed fAUC/MIC of 44 and 132 of ciprofloxacin (MICCIP = 0.25 mg/L) and fAUC/MIC of 22, 44 and 132 of ciprofloxacin plus an efflux pump inhibitor (MICCIP+EPI = 0.031 mg/L) at initial inocula of 10(4), 10(5) and 10(6) cfu/mL. Ciprofloxacin was added at 0 h and rapidly removed at 1, 4, 10, 16 or 24 h. Mutant frequencies and MICs were determined at 24 h. High ciprofloxacin concentrations over 1-10 h yielded more rapid and extensive initial killing compared with 16 and 24 h exposures at the same fAUC/MIC. No resistance emerged for 1-10 h exposures, although regrowth of susceptible bacteria was extensive. Ciprofloxacin exposure over 24 h yielded less regrowth, but ciprofloxacin-resistant bacteria at 5× MIC lified by over 5 log10 and almost completely replaced the susceptible bacteria by 24 h MICs increased 4- to 8-fold. Resistance also emerged on 3× MIC, but not 5× MIC, plates when efflux was inhibited. Pre-existing resistant subpopulations lified extensively with 24 and 16 h exposures, but not with shorter durations. The shape of the ciprofloxacin concentration profile was critical to minimize resistance emergence.
Publisher: American Society for Microbiology
Date: 10-2015
DOI: 10.1128/AAC.00259-15
Abstract: Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m 2 ). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, min). The area under the curve (AUC) in subcutaneous tissue ided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were % after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.)
Publisher: American Society for Microbiology
Date: 07-2019
DOI: 10.1128/AAC.00425-19
Abstract: There is a great need for efficacious therapies against Gram-negative bacteria. Double β-lactam combination(s) (DBL) are relatively safe, and preclinical data are promising however, their clinical role has not been well defined.
Publisher: Wiley
Date: 21-01-2010
Publisher: American Society for Microbiology
Date: 08-2013
DOI: 10.1128/AAC.00703-13
Abstract: Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii . This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rif in combinations against MDR A. baumannii . Studies were conducted over 72 h in an in vitro pharmacokinetic (PK) harmacodynamic (PD) model at inocula of ∼10 6 and ∼10 8 CFU/ml using two MDR clinical isolates of A. baumannii , FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rif in maximum concentration [ C max ] of 5 mg/liter every 24 hours half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 10 6 -CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 10 8 -CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log 10 CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rif in combinations against colistin-susceptible and -resistant MDR A. baumannii .
Publisher: American Society for Microbiology
Date: 17-08-2021
DOI: 10.1128/AAC.00692-21
Abstract: Antibiotic combinations, including ceftazidime/avibactam (CAZ/AVI), are frequently employed to combat KPC-producing Klebsiella pneumoniae (KPC-Kp), though such combinations have not been rationally optimized. Clinical KPC-Kp isolates with common genes encoding aminoglycoside-modifying enzymes (AMEs), aac(6′)-Ib′ or aac(6′)-Ib , were used in static time-kill assays ( n = 4 isolates) and the hollow-fiber infection model (HFIM n = 2 isolates) to evaluate the activity of gentamicin, amikacin, and CAZ/AVI alone and in combinations.
Publisher: Springer Science and Business Media LLC
Date: 03-1999
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.2165/00003088-200948020-00002
Abstract: Antibacterials play a key role in the treatment of bone infections and appropriate surgical prophylaxis. The rate and extent of penetration of antimicrobials into bone has been assessed and shown to be important for successful treatment in numerous studies. However, no recent review or critical evaluation of the analytical techniques is available. This review compares established and new s le preparation and analytical methods to measure bone concentrations. We performed a systematic literature search in MEDLINE, EMBASE, conference abstracts and references from published articles on bone penetration of antibacterials. This article focuses on the standardization of drug analysis in bone, the extent and rate of bone penetration of antibacterials, and the design, evaluation and reporting techniques of pharmacokinetic studies of bone penetration. The focus is on studies conducted between 1998 and 2007, since a previous review was published in 1999. WinNonlin Professional version 5.0.1 software was used for statistics. Very different methods for s le preparation, drug analysis, data handling and reporting have been employed in bone penetration studies. There is substantial variability in the reported mean bone penetration between drugs and between different studies of the same drug. Quinolones, macrolides and linezolid have mean bone : serum concentration ratios that are commonly between 0.3 and 1.2, and higher ratios have been found for azithromycin (bone concentration in mg/kg of total bone). The ratios are usually between 0.15 and 0.3 for cephalosporins and glycopeptides, and between 0.1 and 0.3 for penicillins. Cephalosporins and penicillins have shown significantly lower (p < 0.05) concentration ratios than linezolid. For 20 of 25 different drugs, the ratios were higher for cancellous bone than for cortical bone. The available data show a larger extent of bone penetration for quinolones, macrolides and linezolid than for beta-lactams. The bone penetration of penicillins and cephalosporins was significantly lower than that of linezolid. Guidelines on s le preparation, drug analysis, study design and pharmacokinetic evaluation of bone penetration studies are vitally needed.
Publisher: American Society for Microbiology
Date: 09-2018
DOI: 10.1128/AAC.00967-18
Abstract: Zika virus (ZIKV) infection is associated with serious, long-term neurological manifestations. There are currently no approved therapies for the treatment or prevention of ZIKV infection.
Publisher: Oxford University Press (OUP)
Date: 11-08-2016
DOI: 10.1093/JAC/DKW297
Publisher: American Society for Microbiology
Date: 09-2007
DOI: 10.1128/AAC.01410-06
Abstract: Flucloxacillin is often used for the treatment of serious infections due to sensitive staphylococci. The pharmacokinetic (PK)-pharmacodynamic (PD) breakpoint of flucloxacillin has not been determined by the use of population PK. Targets based on the duration of non-protein-bound concentrations above the MIC ( fT MIC ) best correlate with clinical cure rates for beta-lactams. We compared the breakpoints for flucloxacillin between several dosage regimens. In a randomized, two-way crossover study, 10 healthy volunteers received 500 mg and 1,000 mg flucloxacillin as 5-min intravenous infusions. Drug concentrations were determined by high-pressure liquid chromatography. We used the programs WinNonlin for noncompartmental analysis and statistics and NONMEM for population PK and Monte Carlo simulation. We compared the probability of target attainment (PTA) for intermittent- and continuous-dosage regimens based on the targets of fT MIC s of ≥50% and ≥30% of the dosing interval. The clearance and the volume of distribution were very similar after the administration of 500 mg and 1,000 mg flucloxacillin. We estimated renal and nonrenal clearances of 5.37 liters/h (coefficient of variation, 19%) and 2.73 liters/h (33%). For near maximal killing (target, fT MIC of ≥50%) flucloxacillin showed a robust (≥90%) PTA up to MICs of 0.75 to 1 mg/liter (PTA of 86% at 1 mg/liter) for a continuous or a prolonged infusion of 6 g/day. Short-term infusions of 6 g/day had a lower breakpoint of 0.25 to 0.375 mg/liter. The flucloxacillin PK was linear for doses of 500 mg and 1,000 mg. Prolonged and continuous infusion at a 66% lower daily dose achieved the same PK-PD breakpoints as short-term infusions. Prolonged infusion and continuous infusion are appealing options for the treatment of serious infections caused by sensitive staphylococci.
Publisher: Elsevier BV
Date: 2017
Publisher: Oxford University Press (OUP)
Date: 03-08-2016
DOI: 10.1093/JAC/DKW293
Publisher: American Society for Microbiology
Date: 02-2011
DOI: 10.1128/AAC.00076-10
Abstract: Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind phase 2 study evaluated three levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis, and 5.9% had wound infections. S. aureus , the most common pathogen, was isolated in 90.3% of patients (139/154) with a baseline pathogen 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2% at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters (35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase 3 trials.
Publisher: Public Library of Science (PLoS)
Date: 18-07-2019
Publisher: MDPI AG
Date: 24-02-2022
DOI: 10.3390/MOLECULES27051518
Abstract: Infections due to Gram-negative bacteria are increasingly dangerous due to the spread of multi-drug resistant strains, emphasizing the urgent need for new antibiotics with alternative modes of action. We have previously identified a novel class of antibacterial agents, thioacetamide-triazoles, using an antifolate targeted screen and determined their mode of action which is dependent on activation by cysteine synthase A. Herein, we report a detailed examination of the anti-E. coli structure–activity relationship of the thioacetamide-triazoles. Analogs of the initial hit compounds were synthesized to study the contribution of the aryl, thioacetamide, and triazole sections. A clear structure–activity relationship was observed generating compounds with excellent inhibition values. Substitutions to the aryl ring were generally best tolerated, including the introduction of thiazole and pyridine heteroaryl systems. Substitutions to the central thioacetamide linker section were more nuanced the introduction of a methyl branch to the thioacetamide linker substantially decreased antibacterial activity, but the isomeric propionamide and N-benzamide systems retained activity. Changes to the triazole portion of the molecule dramatically decreased the antibacterial activity, further indicating that 1,2,3-triazole is critical for potency. From these studies, we have identified new lead compounds with desirable in-vitro ADME properties and in-vivo pharmacokinetic properties.
Publisher: MDPI AG
Date: 18-06-2019
DOI: 10.3390/PHARMACEUTICS11060286
Abstract: The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.
Publisher: American Society for Microbiology
Date: 2018
DOI: 10.1128/AAC.01983-17
Abstract: Zika virus (ZIKV) is a major public health concern due to its overwhelming spread into the Americas. Currently, there are neither licensed vaccines nor antiviral therapies available for the treatment of ZIKV. We aimed to identify and rationally optimize effective therapeutic regimens for ZIKV by evaluating the antiviral potentials of the approved broad-spectrum antiviral agents favipiravir (FAV), interferon alpha (IFN), and ribavirin (RBV) as single agents and in combinations. For these studies, Vero cells were infected with ZIKV in the presence of increasing concentrations of FAV, IFN, or/and RBV for 4 days. Supernatants were harvested daily, and the viral burden was quantified by a plaque assay on Vero cells. The time course of the viral burden during treatment in vitro was characterized by a novel translational, mechanism-based model, which was subsequently used to rationally optimize combination dosage regimens. The combination regimen of FAV plus IFN provided the greatest extent of viral inhibition without cytotoxicity, reducing the viral burden by 4.4 log 10 PFU/ml at concentrations of 250 μM FAV and 100 IU/ml IFN. Importantly, these concentrations are achievable in humans. The translational, mechanism-based model yielded unbiased and reasonably precise curve fits. Simulations with the model predicted that clinically relevant regimens of FAV plus IFN would markedly reduce viral burdens in humans, resulting in at least a 10,000-fold reduction in the amount of the virus during the first 4 days of treatment. These findings highlight the substantial promise of rationally optimized combination dosage regimens of FAV plus IFN, which should be further investigated to combat ZIKV.
Publisher: Elsevier BV
Date: 12-2016
Publisher: Public Library of Science (PLoS)
Date: 11-03-2016
Publisher: American Society for Microbiology
Date: 04-2017
DOI: 10.1128/AAC.00096-16
Abstract: The impact of quorum sensing on polymyxin and azithromycin pharmacodynamics was assessed in Pseudomonas aeruginosa PAO1 and an isogenic rhlR / lasR double knockout. For polymyxin B, greater killing against the rhlR / lasR knockout than against PAO1 was observed at 10 8 CFU/ml (polymyxin B half-maximal effective concentration [EC 50 ], 5.61 versus 12.5 mg/liter, respectively P 0.005). Polymyxin B combined with azithromycin (256 mg/liter) was synergistic against each strain, significantly reducing the respective polymyxin B EC 50 compared to those with monotherapy ( P 0.005), and is a promising strategy by which to combat P. aeruginosa .
Publisher: American Society for Microbiology
Date: 11-2018
DOI: 10.1128/AAC.01150-18
Abstract: Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF) these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa .
Publisher: American Society for Microbiology
Date: 16-12-2020
DOI: 10.1128/AAC.01983-20
Abstract: The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled “Advancing Animal Models for Antibacterial Drug Development” on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii . The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.
Publisher: American Society for Microbiology
Date: 03-2010
DOI: 10.1128/AAC.00936-09
Abstract: Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia , there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK harmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF patients (total body weight [WT] [average ± standard deviation] = 42.9 ± 18.4 kg) and seven healthy volunteers (WT = 66.2 ± 4.9 kg) received 2 g ceftazidime as a 5-min intravenous infusion. High-performance liquid chromatography (HPLC) was used for drug analysis, and NONMEM (results reported), S-ADAPT, and NPAG were used for parametric and nonparametric population PK modeling. We considered linear and allometric body size models to scale clearance and volume of distribution. Monte Carlo simulations were based on a target time of non-protein-bound plasma concentration of ceftazidime above MIC of ≥65%, which represents near-maximal killing. Unscaled total clearance was 19% lower in CF patients, and volume of distribution was 36% lower. Total clearance was 7.82 liters/h for CF patients and 6.68 liters/h for healthy volunteers with 53 kg fat-free mass. Allometric scaling by fat-free mass reduced the between-subject variability by 32% for clearance and by 18 to 26% for volume of both peripheral compartments compared to linear scaling by WT. A 30-min ceftazidime infusion of 2 g/70 kg WT every 8 h (q8h) achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤1 mg/liter in CF patients and ≤3 mg/liter in healthy volunteers. Alternative modes of administration achieved robust PTAs up to markedly higher MICs of ≤8 to 12 mg/liter in CF patients for 5-h infusions of 2 g/70 kg WT q8h and ≤12 mg/liter for continuous infusion of 6 g/70 kg WT daily.
Publisher: Informa UK Limited
Date: 10-2010
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.EJPS.2017.06.008
Abstract: Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-course of the antihypertensive activity of fimasartan via a new population pharmacokinetic harmacodynamic model and to define its optimal dose range. We simultaneously modelled all fimasartan plasma concentrations and 24-h ambulatory blood pressure monitoring (ABPM) data from 39 patients with essential hypertension and 56 healthy volunteers. Patients received placebo, 20, 60, or 180mg fimasartan every 24h for 28days and healthy volunteers received placebo or 20 to 480mg as a single oral dose or as seven doses every 24h. External validation was performed using data on 560 patients from four phase II or III studies. One turnover model each was used to describe diastolic and systolic blood pressure. The input rates into these compartments followed a circadian rhythm and were inhibited by fimasartan. The average predicted (observed) diastolic blood pressure over 24-h in patients decreased by 10.1±7.5 (12.6±9.2 mean±SD)mmHg for 20mg, 14.2±7.0 (15.1±9.3) mmHg for 60mg, and 15.9±6.8 (11.5±9.9)mmHg for 180mg daily relative to placebo. The model explained the saturation of antihypertensive activity by counter-regulation at high fimasartan concentrations. Drug effect was maximal at approximately 23ng/mL fimasartan for diastolic and 12ng/mL for systolic blood pressure. The proposed mechanism-based population model characterized the circadian rhythm of ABPM data and the antihypertensive effect of fimasartan. After internal and external model validation, 30 to 60mg oral fimasartan given once daily was predicted as optimal dose range.
Publisher: American Society for Microbiology
Date: 05-2010
DOI: 10.1128/AAC.00881-09
Abstract: Colistin is increasingly being utilized against Gram-negative pathogens, including Pseudomonas aeruginosa , resistant to all other antibiotics. Since limited data exist regarding killing by colistin at different initial inocula (CFUo), we evaluated killing of Pseudomonas aeruginosa by colistin at several CFUo and developed a mechanism-based mathematical model accommodating a range of CFUo. In vitro time-kill experiments were performed using ≥8 concentrations up to 64 × the MIC of colistin against P. aeruginosa PAO1 and two clinical P. aeruginosa isolates at CFUo of 10 6 , 10 8 , and 10 9 CFU/ml. Serial s les up to 24 h were simultaneously modeled in the NONMEM VI (results shown) and S-ADAPT software programs. The mathematical model was prospectively “validated” by additional time-kill studies assessing the effect of Ca 2+ and Mg 2+ on killing of PAO1 by colistin. Against PAO1, killing of the susceptible population was 23-fold slower at the 10 9 CFUo and 6-fold slower at the 10 8 CFUo than at the 10 6 CFUo. The model comprised three populations with different second-order killing rate constants (5.72, 0.369, and 0.00210 liters/h/mg). Bacteria were assumed to release signal molecules stimulating a phenotypic change that inhibits killing. The proposed mechanism-based model had a good predictive performance, could describe killing by colistin for all three studied strains and for two literature studies, and performed well in a prospective validation with various concentrations of Ca 2+ and Mg 2+ . The extent and rate of killing of P. aeruginosa by colistin were markedly decreased at high CFUo compared to those at low CFUo. This was well described by a mechanism-based mathematical model, which should be further validated using dynamic in vitro models.
Publisher: American Society for Microbiology
Date: 17-08-2023
DOI: 10.1128/AAC.00414-23
Abstract: Pseudomonas aeruginosa remains a challenge in chronic respiratory infections in cystic fibrosis (CF). Ceftolozane-tazobactam has not yet been evaluated against multidrug-resistant hypermutable P. aeruginosa isolates in the hollow-fiber infection model (HFIM). Isolates CW41, CW35, and CW44 (ceftolozane-tazobactam MICs of 4, 4, and 2 mg/L, respectively) from adults with CF were exposed to simulated representative epithelial lining fluid pharmacokinetics of ceftolozane-tazobactam in the HFIM.
Publisher: American Society for Microbiology
Date: 20-09-2022
DOI: 10.1128/AAC.00527-22
Abstract: Metallo-β-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam.
Publisher: American Society for Microbiology
Date: 03-2014
DOI: 10.1128/AAC.00327-13
Abstract: Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10 8 CFU/ml) of Pseudomonas aeruginosa . The pharmacokinetics were simulated for patients with hepatic (half-life [ t 1/2 ] of 3.2 h) or renal ( t 1/2 of 14.8 h) disease. Front-loaded regimens ( n = 5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve ( f AUC) compared to those with traditional dosing regimens ( n = 14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures ( f AUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens ( f AUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log 10 within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa . The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.
Publisher: Informa UK Limited
Date: 11-2009
DOI: 10.1080/15287390903212774
Abstract: This study was conducted to characterize the disposition, oral bioavailability, and tissue distribution of zearalenone in rats. The pharmacokinetics and tissue distribution of zearalenone were studied after intravenous (i.v.) or oral (p.o.) administration at doses ranging from 1 to 8 mg/kg in intact and bile duct-cannulated rats. Serum, bile, and urine concentrations were determined by liquid chromatography and mass spectroscopy (LC/MS/MS) and tissue concentrations by high-performance liquid chromatography (HPLC)/fluorescence detection assays. Noncompartmental methods were used for pharmacokinetic analysis. Average Cl(s) (range 5.0-6.6 L/h/kg) and V(dss) (range 2-4.7 L/kg) remained unaltered over an i.v. dose range from 1 to 8 mg/kg, and area under the concentration-time curve (AUC) and initial peak concentrations increased linearly with dose. Minimal quantities of zearalenone were excreted unchanged in urine (f(e,urine) 0.5 +/- 0.2%) and bile (f(e,bile) 0.91 +/- 0.64%). After p.o. administration of 8 mg/kg, zearalenone was rapidly absorbed and serum concentration-time profiles showed a distinct second peak. The absolute oral bioavailability was low (2.7%). Comparing bile duct-cannulated to intact rats at a dose of 8 mg/kg, the impact of biliary excretion on overall pharmacokinetics was more pronounced after p.o. than after i.v. administration. Upon i.v. infusion to steady state, the highest zearalenone concentration was found in small intestine, followed by kidneys, liver, adipose tissue, and lung. Zearalenone concentrations in stomach, heart, brain, spleen, muscle, and testes were lower than those found in serum. The pharmacokinetics and tissue distribution data from this study may be useful to develop physiologically based pharmacokinetic (PBPK) models for zearalenone and subsequently to predict the pharmacokinetics and toxicity in humans.
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: 10-2018
DOI: 10.1016/J.EJPS.2018.07.054
Abstract: Understanding the pharmacokinetics in patients with cystic fibrosis (CF) is important for dosing. For antibiotics with extensive metabolism, however, a comparison of metabolite formation and elimination between patients with CF and healthy volunteers has never been performed via population modeling. We aimed to compare the population pharmacokinetics of fleroxacin and its N‑oxide and demethyl metabolites between patients with CF and healthy volunteers. Our analysis included eleven adult patients with CF and twelve healthy volunteers who received 800 mg fleroxacin as a single oral dose followed by five doses every 24 h from a previously published study. All plasma concentrations and amounts in urine for fleroxacin and its metabolites were simultaneously modelled. The estimates below accounted for differences in body size and body composition via allometric scaling by lean body mass. Oral absorption was slower in patients with CF than in healthy volunteers. For fleroxacin, the population mean in patients with CF ided by that in healthy volunteers was 1.12 for renal clearance, 1.01 for linear nonrenal clearance, 0.83 for saturable exsorption clearance into intestine, and 0.81 for volume of distribution. The formation clearances of N‑oxide fleroxacin and N‑demethylfleroxacin were 0.520 L/h and 0.496 L/h in patients with CF these formation clearances were 0.378 L/h and 0.353 L/h in healthy volunteers. Renal clearance in patients with CF ided by that in healthy volunteers was 1.53 for N‑oxide fleroxacin and 1.70 for N‑demethyl fleroxacin. Allometric scaling by lean body mass best explained the variability. While fleroxacin pharmacokinetics was comparable, both formation and elimination clearances of its two metabolites were substantially larger in patients with CF compared to those in healthy volunteers.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2011
Publisher: American Society for Microbiology
Date: 06-09-2017
Abstract: The rapid increase of carbapenem resistance in Gram-negative bacteria has resurrected the importance of the polymyxin antibiotics. The recent discovery of plasmid-mediated polymyxin resistance ( mcr - 1 ) in carbapenem-resistant Enterobacteriaceae serves as an important indicator that the golden era of antibiotics is under serious threat. We assessed the bacterial killing of 15 different FDA-approved antibiotics alone and in combination with polymyxin B in time-killing experiments against Escherichia coli MCR1_NJ, the first reported isolate in the United States to coharbor mcr-1 and a New Delhi metallo-β-lactamase gene ( bla NDM-5 ). The most promising regimens were advanced to the hollow-fiber infection model (HFIM), where human pharmacokinetics for polymyxin B, aztreonam, and amikacin were simulated over 240 h. Exposure to polymyxin B monotherapy was accompanied by MCR1_NJ regrowth but not resistance lification (polymyxin B MIC from 0 to 240 h [MIC 0h to MIC 240h ] of 4 mg/liter), whereas amikacin monotherapy caused regrowth and simultaneous resistance lification (amikacin MIC 0h of 4 mg/liter versus MIC 240h of mg/liter). No MCR1_NJ colonies were observed for any of the aztreonam-containing regimens after 72 h. However, HFIM cartridges for both aztreonam monotherapy and the polymyxin B-plus-aztreonam regimen were remarkably turbid, and the presence of long, filamentous MCR1_NJ cells was evident in scanning electron microscopy, suggestive of a nonreplicating persister (NRP) phenotype. In contrast, the 3-drug combination of polymyxin B, aztreonam, and amikacin provided complete eradication ( -log 10 CFU/ml reduction) with suppression of resistance and prevention of NRP formation. This is the first comprehensive pharmacokinetic harmacodynamic study to evaluate triple-drug combinations for polymyxin- and carbapenem-resistant E. coli coproducing MCR-1 and NDM-5 and will aid in the preparation for a so-called “postantibiotic” era. IMPORTANCE A global health crisis may be on the horizon, as the golden era of antibiotics is under serious threat. We recently reported the first case in the United States of a highly resistant, Escherichia coli so-called “superbug” (MCR1_NJ), coharboring two of the most worrying antibiotic resistance genes, encoding mobile colistin resistance ( mcr - 1 ) and a New Delhi metallo-β-lactamase ( bla NDM-5 ). Worryingly, the medical community is vulnerable to this emerging bacterial threat because optimal treatment strategies are undefined. Here, we report the activity of an optimized combination using simulated human doses of commercially available antibiotics against MCR1_NJ. A unique triple combination involving a cocktail of polymyxin B, aztreonam, and amikacin eradicated the MCR-1- and NDM-5-producing E. coli . Each antimicrobial agent administered as monotherapy or in double combinations failed to eradicate MCR1_NJ at a high inoculum. To our knowledge, this is the first study to propose 3-drug therapeutic solutions against superbugs coharboring mcr-1 and bla NDM , seeking to prepare clinicians for future occurrences of these pathogens.
Publisher: Springer International Publishing
Date: 2016
Publisher: Oxford University Press (OUP)
Date: 15-09-2017
DOI: 10.1093/JAC/DKW355
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: Springer Science and Business Media LLC
Date: 08-02-2008
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.EJPS.2015.07.017
Abstract: Disintegration of finished dosage forms (FDF) and drug dissolution are fundamentally important processes that affect bioavailability. Established theories do not account for disintegration and usually assume sink conditions for drug dissolution that often do not apply. We present the theory to describe the disintegration of FDF with subsequent dissolution of liberated particles containing the active pharmaceutical ingredient (API) and its application using population data analysis. Population modeling, using dissolution profiles of 400mg cefditoren pivoxil tablets manufactured under various tableting pressures, characterized the intrinsic lifetime distribution of the particles and identified the presence of crystalline API in the formulation that was proven by X-ray diffraction. Modeling further estimated the disintegration time of FDF, the solubility of the amorphous API and its chemical instability in the medium that were in agreement with the experimentally determined values. This novel approach provides a quantitative understanding of the manufacturing process of FDF and can substantially contribute to the targeted development of finished dosage forms.
Publisher: Wiley
Date: 07-2009
DOI: 10.1002/PST.393
Abstract: This review aims to introduce the concepts and principles underpinning the time course of drug effects. Models describing the time course of drug concentrations (pharmacokinetic models) and the ensuing concentration-effect (pharmacodynamics models) as well as the linked time-effect (pharmacokinetic-pharmacodynamic models) are introduced. Different types of drug time-effects models are discussed with ex les which aim to explain the time course of onset, duration, and maximal effect that occurs from any given dosing schedule. These drug effects are also described in relation to disease progression models.
Publisher: American Society for Microbiology
Date: 04-2019
DOI: 10.1128/AAC.02538-18
Abstract: Hypermutable Pseudomonas aeruginosa isolates (hypermutators) have been identified in patients with cystic fibrosis (CF) and are associated with reduced lung function. Hypermutators display a greatly increased mutation rate and an enhanced ability to become resistant to antibiotics during treatment.
Publisher: Wiley
Date: 14-07-2010
Publisher: American Society for Microbiology
Date: 06-2011
DOI: 10.1128/AAC.01484-10
Abstract: Cystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] = 45.7 kg) and 12 healthy volunteers (LBM = 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC ≥ 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher ( P ≤ 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust ( %) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs ≤ 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs ≤ 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs ≤ 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.
Publisher: American Society for Microbiology
Date: 07-2009
DOI: 10.1128/AAC.01193-08
Abstract: Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14( R )-hydroxy-clarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The pharmacokinetics of clarithromycin and its 14( R )-hydroxyl metabolite were adequately described by a one-compartment model each for clarithromycin and its metabolite as well as an inhibition compartment that reflects the autoinhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.
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: American Society for Microbiology
Date: 12-2011
DOI: 10.1128/AAC.05298-11
Abstract: Combination therapy may be required for multidrug-resistant (MDR) Pseudomonas aeruginosa . The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against MDR P. aeruginosa . Studies were conducted in a one-compartment in vitro pharmacokinetic harmacodynamic model for 96 h at two inocula (∼10 6 and ∼10 8 CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum. Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 s le points) at the 10 6 - and 10 8 -CFU/ml inocula, respectively the corresponding values for 19147 n/m were 16 and 9. Combinations containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of detection at ∼50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations.
Publisher: American Society for Microbiology
Date: 2013
DOI: 10.1128/AAC.01354-12
Abstract: The objectives of this analysis were to develop a population pharmacokinetic (PK) model to describe the absorption and disposition of fusidic acid after single and multiple doses and to determine the effect of food on the rate and extent of bioavailability. Plasma PK data from three phase 1 studies ( n = 75 n = 14 with and without food) in which healthy subjects received sodium fusidate (500 to 2,200 mg) as single or multiple oral doses every 8 h (q8h) or q12h for up to 7 days were modeled using S-ADAPT (MCPEM algorithm). Accumulation of fusidic acid after multiple doses was more than that predicted based on single-dose data. The PK of fusidic acid was best described using a time-dependent mixed-order absorption process, two disposition compartments, and a turnover process to describe the autoinhibition of clearance. The mean total clearance (% coefficient of variation) was 1.28 liters/h (33%) and the maximum extent of autoinhibition was 71.0%, with a 50% inhibitory concentration (IC 50 ) of 46.3 mg/liter (36%). Food decreased the extent of bioavailability by 18%. As a result of the autoinhibition of clearance, steady state can be achieved earlier with dosing regimens that contain higher doses (after 8 days for 750 mg q12h and 1 day for 1,500 mg q12h on day 1 followed by 600 mg q12h versus 3 weeks for 500 mg q12h). Given that large initial doses autoinhibit the clearance of fusidic acid, this characteristic provides a basis for the administration of front-loaded dosing regimens of sodium fusidate which would allow for effective concentrations to be achieved early in therapy.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000328027
Abstract: i Background: /i This study assessed the population pharmacokinetics and metabolic conversion of a novel histone deacetylase (HDAC) inhibitor, SD-2007, into its active metabolite, apicidin, in rats. i Methods: /i SD-2007 was given to rats by intravenous injection (4 mg/kg) and oral administration (40 mg/kg). Serum concentrations of SD-2007 and apicidin were determined by LC-MS/MS. All concentrations were analyzed using a population pharmacokinetic model with 9 compartments in S-ADAPT. i Results: /i The area under the curve for apicidin was 96 ± 16 mg·h/ml after 4 mg/kg administered intravenously and 2,455 ± 1,211 mg·h/ml after 40 mg/kg given orally. The population pharmacokinetic model described all profiles well. After oral administration of SD-2007, the median absolute bioavailability of SD-2007 was 6.67% (range 3.83–9.89) and the median apparent bioavailability was 22.3% (range 15.7–35.8) for apicidin, whereas only a median of 8.85% (range 7.57–9.34) of an intravenous SD-2007 dose was converted to apicidin. i Conclusions: /i Oral SD-2007 displayed a substantial presystemic metabolism to active apicidin. The high serum concentrations of apicidin after oral administration of SD-2007 may cause significant HDAC inhibition.
Publisher: American Chemical Society (ACS)
Date: 18-02-2015
DOI: 10.1021/MP5006189
Abstract: The lymphatic system plays a major role in the metastatic dissemination of cancer and has an integral role in immunity. PEGylation enhances drainage and lymphatic uptake following subcutaneous (sc) administration of proteins and protein-like polymers, but the impact of PEGylation of very large proteins (such as antibodies) on subcutaneous and lymphatic pharmacokinetics is unknown. This study therefore aimed to evaluate the impact of PEGylation on the sc absorption and lymphatic disposition of the anti-HER2 antibody trastuzumab in rats. PEG-trastuzumab was generated via the conjugation of a single 40 kDa PEG-NHS ester to trastuzumab. PEG-trastuzumab showed a 5-fold reduction in HER2 binding affinity, however the in vitro growth inhibitory effects were preserved as a result of changes in cellular trafficking when compared to native trastuzumab. The lymphatic pharmacokinetics of PEG-trastuzumab was evaluated in thoracic lymph duct cannulated rats after iv and sc administration and compared to the pharmacokinetics of native trastuzumab. The iv pharmacokinetics and lymphatic exposure of PEG-trastuzumab was similar when compared to trastuzumab. After sc administration, initial plasma pharmacokinetics and lymphatic exposure were also similar between PEG-trastuzumab and trastuzumab, but the absolute bioavailability of PEG-trastuzumab was 100% when compared to 86.1% bioavailability for trastuzumab. In contrast to trastuzumab, PEG-trastuzumab showed accelerated plasma clearance beginning approximately 7 days after sc, but not iv, administration, presumably as a result of the generation of anti-PEG IgM. This work suggests that PEGylation does not significantly alter the lymphatic disposition of very large proteins, and further suggests that it is unlikely to benefit therapy with monoclonal antibodies.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.DIAGMICROBIO.2009.06.018
Abstract: Our objectives were to compare the pharmacokinetics (PK) of carumonam, a monobactam, between cystic fibrosis (CF) patients and healthy volunteers and assess its pharmacodynamic profile. We studied 10 adult CF patients and 18 healthy volunteers of similar body size (dose: 2.166 g of carumonam as 15-min intravenous infusion). High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used for drug analysis and NONMEM (ICON, Ellicot City, MD) for population PK and Monte Carlo simulation with targets between > or =20% and 100% free time above MIC (fT > MIC). Unscaled renal clearance was 24% higher in CF patients. Lean body mass and creatinine clearance explained the difference in average clearance and volume of distribution between both subject groups. For a daily dose of 6 g per 70 kg of total body weight, 15-min infusions q8h achieved robust (>90%) probabilities of target attainment (PTAs) (target, 60% fT > MIC) for MICs < or =3 mg/L in CF patients and < or =6 mg/L in healthy volunteers. At the same dose, 4-h infusions q8h achieved robust PTAs up to markedly higher MICs < or =8 to 12 mg/L in CF patients and < or =16 mg/L in healthy volunteers.
Publisher: Oxford University Press (OUP)
Date: 23-02-2015
DOI: 10.1093/JAC/DKU567
Abstract: Colistin is an ‘old’ drug, which is being increasingly utilized due to limited therapeutic options. However, resistance emergence during monotherapy is concerning. Here, our objective was to optimize colistin combinations against Pseudomonas aeruginosa by profiling the time course of synergistic killing and prevention of resistance. Hollow-fibre infection models over 10 days simulated clinically relevant dosage regimens of colistin and doripenem against two heteroresistant P. aeruginosa strains (MIC 1 mg/L) and one resistant (MIC 128 mg/L) strain (inoculum 109.3 cfu/mL). New mathematical mechanism-based models (MBMs) were developed using S-ADAPT. Against heteroresistant P. aeruginosa strains, colistin monotherapy resulted in initial killing (up to 2.64 log10 cfu/mL) within 24 h followed by regrowth. High-intensity combinations involving free steady-state colistin concentrations of 5 mg/L achieved complete eradication (& .3 log10 killing) within 48 h. These combinations achieved synergy with up to 9.38 log10 greater killing compared with the most active monotherapy. Against the colistin-resistant strain, the combination yielded marked initial synergy with up to 6.11 log10 cfu/mL bacterial reductions within 72 h followed by regrowth. The MBMs quantified total and resistant subpopulations and the proposed synergy between colistin and doripenem. Our findings provide insight into optimal antibiotic treatment and may serve as a framework for new drug combinations and combination modelling.
Publisher: American Society for Microbiology
Date: 04-2011
DOI: 10.1128/AAC.01629-10
Abstract: Intravenous zanamivir is recommended for the treatment of hospitalized patients with complicated oseltamivir-resistant influenza virus infections. In a companion paper, we show that the time above the 50% effective concentration (time EC 50 ) is the pharmacodynamic (PD) index predicting the inhibition of viral replication by intravenous zanamivir. However, for other neuraminidase inhibitors, the ratio of the area under the concentration-time curve to the EC 50 (AUC/EC 50 ) is the most predictive index. Our objectives are (i) to explain the dynamically linked variable of intravenous zanamivir by using different half-lives and (ii) to develop a new, mechanism-based population pharmacokinetic (PK)/PD model for the time course of viral load. We conducted dose fractionation studies in the hollow-fiber infection model (HFIM) system with zanamivir against an oseltamivir-resistant influenza virus. A clinical 2.5-h half-life and an artificially prolonged 8-h half-life were simulated for zanamivir. The values for the AUC from 0 to 24 h (AUC 0-24 ) of zanamivir were equivalent for the two half-lives. Viral loads and zanamivir pharmacokinetics were comodeled using data from the present study and a previous dose range experiment via population PK/PD modeling in S-ADAPT. Dosing every 8 h (Q8h) suppressed the viral load better than dosing Q12h or Q24h at the 2.5-h half-life, whereas all regimens suppressed viral growth similarly at the 8-h half-life. The model provided unbiased and precise in idual (Bayesian) ( r 2 , .96) and population (pre-Bayesian) ( r 2 , .87) fits for log 10 viral load. Zanamivir inhibited viral release (50% inhibitory concentration [IC 50 ], 0.0168 mg/liter maximum extent of inhibition, 0.990). We identified AUC/EC 50 as the pharmacodynamic index for zanamivir at the 8-h half-life, whereas time EC 50 best predicted viral suppression at the 2.5-h half-life, since the trough concentrations approached the IC 50 for the 2.5-h but not for the 8-h half-life. The model explained data at both half-lives and holds promise for optimizing clinical zanamivir dosage regimens.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2008
DOI: 10.1007/S00280-008-0827-2
Abstract: Our objectives were (1) to compare the disposition and in vivo release of paclitaxel between a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol) in human subjects, and (2) to develop a mechanistic model for unbound and total paclitaxel pharmacokinetics. A total of 35 patients (average +/- SD age: 59 +/-13 years) with advanced non-hematological malignancies were studied in a randomized two-way crossover trial. Patients received 175 mg/m(2) paclitaxel as 15 min (Tocosol Paclitaxel) or 3 h (Taxol) intravenous infusion in each study period. Paclitaxel concentrations were determined by LC-MS/MS in plasma ultrafiltrate and whole blood. NONMEM VI was used for population pharmacokinetics. A linear disposition model with three compartments for unbound paclitaxel and a one-compartment model for Cremophor were applied. Total clearance of unbound paclitaxel was 845 L/h (variability: 25% CV). The prolonged release with Tocosol Paclitaxel was explained by the limited solubility of unbound paclitaxel of 405 ng/mL (estimated) in plasma. The 15 min Tocosol Paclitaxel infusion yielded a mean time to 90% cumulative input of 1.14 +/- 0.16 h. Tocosol Paclitaxel was estimated to release 9.8% of the dose directly into the deep peripheral compartment. The model accounted for the presence of drug-containing nanodroplets in blood. Population pharmacokinetic analysis indicated linear disposition and a potentially higher bioavailability of unbound paclitaxel following Tocosol Paclitaxel administration due to direct release at the target site. The prolonged release of Tocosol Paclitaxel supports 15 min paclitaxel infusions. This mechanistic model may be important for development of prolonged release formulations that distribute in and from the systemic circulation.
Publisher: American Society for Microbiology
Date: 09-2007
DOI: 10.1128/AAC.01318-06
Abstract: Beta-lactams are regularly administered in intermittent short-term infusions. The percentage of the dosing interval during which free drug concentrations exceed the MIC ( fT MIC ) is the measure of drug exposure that best correlates with clinical outcome for beta-lactams. Therefore, administration by continuous infusion has gained increasing interest recently. We studied 20 critically ill patients with nosocomial pneumonia and investigated whether continuous infusion with a reduced total dose, compared to the standard regimen of intermittent short-term infusion, results in a superior probability of target attainment as assessed by the fT MIC value of imipenem. In this prospective, randomized, controlled clinical study, patients received either a loading dose of 1 g/1 g imipenem and cilastatin (as a short-term infusion) at time zero, followed by 2 g/2 g imipenem-cilastatin per 24 h as a continuous infusion for 3 days ( n = 10), or 1 g/1 g imipenem-cilastatin three times per day as a short-term infusion for 3 days (total daily dose, 3 g/3 g n = 10). Imipenem concentrations in plasma were determined by using a validated liquid chromatography-tandem mass spectrometry assay. A two-compartment open model was employed for population pharmacokinetic modeling. We simulated 10,000 intensive-care-unit patients via Monte Carlo simulations for pharmacodynamic evaluation using the target 40% fT MIC . The probability of target attainment by MIC for intermittent infusion was robust ( %) up to MICs of 1 to 2 mg/liter. The corresponding value for continuous infusion was 2 to 4 mg/liter. Although all 20 patients had an fT MIC of 100%, 3 patients died. Patient survival was best described by employing a sepsis-related organ failure assessment score as a covariate in a logistic regression analysis. Larger clinical trials are warranted for evaluation of continuous infusions at a reduced dose of imipenem for critically ill patients.
Publisher: American Society for Microbiology
Date: 2017
DOI: 10.1128/AAC.00952-16
Abstract: Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in the plasma, subcutaneous tissue, and peritoneal fluid of morbidly obese patients. Six female patients (body mass index, 43.7 to 55.9 kg/m 2 ) received 1,000 mg ertapenem as 15-min infusions at 0 and 26 h. On day 2, the unbound ertapenem concentrations in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis total plasma concentrations were additionally quantified. The probability of attaining a target of an unbound ertapenem concentration above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3 liters/h (coefficient of variation, 21.6% for between-patient variability) and the volume of distribution at steady state was 57.8 liters in patients with a 53-kg fat-free mass. The area under the concentration-time curve (AUC) for ertapenem was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid than the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life, min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust ( %) target attainment probabilities for MICs of up to 1 mg/liter in plasma, 0.25 to 0.5 mg/liter in subcutaneous tissue, and 0.5 mg/liter in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery. (This study has been registered at ClinicalTrials.gov under identifier NCT01407965.)
Publisher: Wiley
Date: 13-11-2014
DOI: 10.1111/JVP.12091
Publisher: Wiley
Date: 2004
Publisher: Elsevier BV
Date: 09-2016
Publisher: Informa UK Limited
Date: 12-2013
DOI: 10.1586/14787210.2013.845523
Abstract: The emergence of resistant to carbapenems Gram-negative bacteria (CR GNB) has severely challenged antimicrobial therapy. Many CR GNB isolates are only susceptible to polymyxins however, therapy with polymyxins and other potentially active antibiotics presents some drawbacks, which have discouraged their use in monotherapy. In this context, along with strong pre-clinical evidence of benefit in combining antimicrobials against CR GNB, the clinical use of combination therapy has been raised as an interesting strategy to overcome these potential limitations of a single agent. Polymyxins, tigecycline and even carbapenems are usually the cornerstone agents in combination schemes. Optimization of the probability to attain the pharmacokinetic harmacodynamic targets by both cornerstone drug and adjuvant drug is of paramount importance to achieve better clinical and microbiological outcomes. Clinical evidence of the major drugs utilized in combination schemes and how they should be prescribed considering pharmacokinetic harmacodynamic characteristics against CR GNB will be reviewed in this article.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2011
Publisher: Elsevier BV
Date: 03-2011
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1007/S10856-015-5444-0
Abstract: Mesoporous silica nanoparticles (MSNs) have been explored as controlled drug delivery systems since the early 2000s, but many fundamental questions remain for this important application. We sought to design a pH controlled delivery system of gentamicin, an aminoglycoside antibiotic, based on MSNs. Under optimal conditions, MSN was able to load 219 µg gentamicin per mg MSNs. Polymeric networks encompassing gentamicin loaded MSNs were then established to tune the release kinetics. Embedding of drug pre-loaded MSNs was performed by an efficient layer-by-layer (LbL) self-assemble strategy using polystyrene sulfonate (PSS) and poly (allylamine hydrochloride) (PAH). We characterised the release kinetics by nonlinear mixed-effects modelling in the S-ADAPT software. The mean release time from uncoated MSNs was 3.6 days at pH 7.4 and 0.4 days at pH 1.4. A further slower release was achieved by diffusion through one or two PSS/PAH bilayer(s) which had a mean transit time of 6.0 days at pH 7.4 and 3.5 days at pH 1.4. The number of bilayers affected the shape of the release profile. The developed nano-drug carriers combined with the self-assembled polyelectrolyte coating allowed us to tune the release kinetics by pH and the number of bilayers.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Publisher: American Society for Microbiology
Date: 06-2009
DOI: 10.1128/AAC.01119-08
Abstract: Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone s les were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for ≥50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Informa UK Limited
Date: 11-2010
DOI: 10.1080/15287394.2010.511584
Abstract: The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 μg/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2018
DOI: 10.1007/S13346-018-0482-Z
Abstract: The current prophylactic treatment to prevent rheumatic heart disease requires four-weekly intramuscular injection of a suspension of the poorly soluble benzathine salt form of penicillin G (BPG) often for more than 10 years. In seeking to reduce the frequency of administration to improve adherence, biodegradable polymer matrices have been investigated. Poly(lactide-co-glycolide) (PLGA)-based in situ forming precursor systems containing N-methyl-2-pyrrolidone as solvent and PLGA-based monolithic implants for surgical implantation containing BPG were developed. Long-term release studies indicated low and plateaued release of penicillin G, but continual favourable release profiles for the benzathine counterion, indicating degradation of the polymer and generation of acidic microenvironment being detrimental to penicillin stability. In order to avoid the issue of the acidic product, poly(caprolactone)(PCL) implants were also investigated, with favourable penicillin G release behaviour being achieved, and slow release over 180 days. However, when taking into account the mass of polymer, and the total dose of drug calculated from literature pharmacokinetic parameters for penicillin G, we concluded that an implant size of over 7 g would still be required. This may preclude clinical deployment of a polymer matrix type delivery system for this indication in children and adolescents. Therefore, we have learned that biodegradable PLGA-type systems are not suitable for development of sustained release BPG treatments and that although the PCL system provides favourable release behaviour, the total size of the implant may still present a hurdle for future development.
Publisher: Wiley
Date: 12-2010
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000329520
Abstract: i Background: /i Our objectives were to assess the pharmacokinetic interaction and body fluid penetration of ciprofloxacin and levofloxacin. i Methods: /i This study was a single-dose open randomized three-way crossover in 15 healthy volunteers receiving 500 mg oral levofloxacin, 500 mg oral ciprofloxacin, or 250 mg levofloxacin and 250 mg ciprofloxacin co-administered. Serum, urine, and body fluid concentrations were determined by high-performance liquid chromatography and analyzed via population pharmacokinetic modeling. i Results: /i Modeling indicated that ciprofloxacin inhibited the renal reabsorption of levofloxacin. Ciprofloxacin increased the net renal clearance of levofloxacin by 13%, as its estimated affinity for a putative tubular reabsorption transporter was 12-fold higher (Km: 568 µ i M /i ) compared to levofloxacin (Km: 6,830 µ i M /i ). Levofloxacin increased the bioavailability of ciprofloxacin by 12% and achieved significantly (p 0.05) higher concentrations at 3 h in ejaculate, prostatic, seminal, and vaginal fluid compared to ciprofloxacin. i Conclusion: /i Modeling suggested that ciprofloxacin inhibited the tubular reabsorption of levofloxacin due to a 12-fold higher affinity for a putative tubular reabsorption transporter compared to levofloxacin. This pharmacokinetic interaction was not clinically relevant.
Publisher: MDPI AG
Date: 10-07-2019
DOI: 10.3390/PHARMACEUTICS11070323
Abstract: Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 ± 6.9 kg, average ± SD) and ten healthy volunteers (FFM: 51.7 ± 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF ided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2016
DOI: 10.1038/SREP26233
Abstract: Polymyxins are often last-line therapeutic agents used to treat infections caused by multidrug-resistant A. baumannii . Recent reports of polymyxin-resistant A. baumannii highlight the urgent need for research into mechanisms of polymyxin resistance. This study employed genomic and transcriptomic analyses to investigate the mechanisms of polymyxin resistance in A. baumannii AB307-0294 using an in vitro dynamic model to mimic four different clinically relevant dosage regimens of polymyxin B and colistin over 96 h. Polymyxin B dosage regimens that achieved peak concentrations above 1 mg/L within 1 h caused significant bacterial killing (~5 log 10 CFU/mL), while the gradual accumulation of colistin resulted in no bacterial killing. Polymyxin resistance was observed across all dosage regimens partial reversion to susceptibility was observed in 6 of 8 bacterial s les during drug-free passaging. Stable polymyxin-resistant s les contained a mutation in pmrB . The transcriptomes of stable and non-stable polymyxin-resistant s les were not substantially different and featured altered expression of genes associated with outer membrane structure and biogenesis. These findings were further supported via integrated analysis of previously published transcriptomics data from strain ATCC19606. Our results provide a foundation for understanding the mechanisms of polymyxin resistance following exposure to polymyxins and the need to explore effective combination therapies.
Publisher: American Society for Microbiology
Date: 12-2017
DOI: 10.1128/AAC.01268-17
Abstract: We previously optimized imipenem and tobramycin combination regimens against a double-resistant clinical Pseudomonas aeruginosa isolate by using in vitro infection models, mechanism-based pharmacokinetic harmacodynamic modeling (MBM), and Monte Carlo simulations. The current study aimed to evaluate these regimens in a neutropenic murine thigh infection model and to characterize the time course of bacterial killing and regrowth via MBM. We studied monotherapies and combinations of imipenem with tobramycin in vivo against the double-resistant clinical P. aeruginosa isolate by using humanized dosing schemes. Viable count profiles of total and resistant populations were quantified over 24 h. Tobramycin monotherapy (7 mg/kg every 24 h [q24h] as a 0.5-h infusion) was ineffective. Imipenem monotherapies (continuous infusion of 4 or 5 g/day with a 1-g loading dose) yielded 2.47 or 2.57 log 10 CFU/thigh killing at 6 h. At 24 h, imipenem at 4 g/day led to regrowth up to the initial inoculum (4.79 ± 0.26 log 10 CFU/thigh), whereas imipenem at 5 g/day displayed 1.75 log 10 killing versus the initial inoculum. The combinations (i.e., imipenem at 4 or 5 g/day plus tobramycin) provided a clear benefit, with bacterial killing of ≥2.51 or ≥1.50 log 10 CFU/thigh compared to the respective most active monotherapy at 24 h. No colonies were detected on 3×MIC agar plates for combinations, whereas increased resistance (at 3×MIC) emerged for monotherapies (except imipenem at 5 g/day). MBM suggested that tobramycin considerably enhanced the imipenem target site concentration up to 2.6-fold. The combination regimens, rationally optimized via a translational modeling approach, demonstrated substantially enhanced bacterial killing and suppression of regrowth in vivo against a double-resistant isolate and are therefore promising for future clinical evaluation.
Publisher: American Society for Microbiology
Date: 03-2017
DOI: 10.1128/AAC.01268-16
Abstract: Acinetobacter baumannii is emerging with resistance to polymyxins. In 24-h time-kill experiments, high-dose icillin-sulbactam in combination with meropenem and polymyxin B achieved additivity or synergy against 10 8 CFU/ml of two clinical A. baumannii isolates resistant to all three drugs (maximum reductions, 1.6 and 3.1 logs). In a 14-day hollow-fiber infection model, high-dose icillin-sulbactam (8/4 g every 8 h, respectively) in combination with meropenem (2 g every 8 h) and polymyxin B (1.43 mg/kg of body weight every 12 h with loading dose) resulted in rapid (96 h) eradication of A. baumannii .
Publisher: Informa UK Limited
Date: 17-04-2017
DOI: 10.1080/14787210.2017.1316193
Abstract: The emergence of carbapenem-resistant Enterobacteriaceae (CRE) has brought aminoglycosides to the frontline since an aminoglycoside may be the only antimicrobial to which CRE isolates show in vitro susceptibility. The appropriateness of aminoglycoside-based therapies for severe infections by CRE is discussed considering the current breakpoints and recent pharmacokinetic (PK) studies in critically ill patients. Areas covered: Many aminoglycoside-susceptible CRE isolates present minimal inhibitory concentrations (MICs) at or slightly below the breakpoint of amikacin or gentamicin. However, recent PK studies with these aminoglycosides in critically ill have invariably shown that the PK harmacodynamic (PD) target is very unlikely attained even when high doses are administered, if the MICs are near the breakpoint. Expert commentary: While new antimicrobials are not widely available, the authors forecast an increasing use of aminoglycosides as backbone antibiotics against CRE isolates. However, the altered PK of aminoglycosides in critically ill patients severely impairs their predicted efficacy in these patients. Aminoglycoside breakpoints may hide 'aminoglycoside-susceptible' CRE isolates for that aminoglycosides will unlikely be effective if used in monotherapy. Therefore, these breakpoints may need to be revised due to the increasing use of aminoglycosides as backbone antibiotics to treat severe infections by CRE isolates in critically ill patients.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2018
DOI: 10.1007/S13346-018-0511-Y
Abstract: Jürgen B. Bulitta's name was misspelled in the original version of the article. It is correct as reflected here. The original article has been revised.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2017
DOI: 10.1007/S00134-017-4780-6
Abstract: Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic harmacodynamic models to guide the design of more effective antimicrobial dosing regimens. In idualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the in idual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.
Publisher: American Society for Microbiology
Date: 10-2004
DOI: 10.1128/AAC.48.10.3765-3772.2004
Abstract: The pharmacokinetics of ertapenem and ceftriaxone were investigated in an open, randomized, two-period crossover study after single- and multiple-dose administration in 10 healthy volunteers (five women and five men). Both antibiotics were administered intravenously once daily for 7 days at dosages of 1 g (ertapenem) and 2 g (ceftriaxone). The concentrations of the antibiotics in serum and urine were quantified by the agar well diffusion method bioassay and, in addition, for ertapenem only, by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). For ertapenem the maximum concentration of the drug in plasma ( C max ) was 256 mg/liter, the half-life was 20.7 h, and the area under the plasma concentration-time curve (AUC) was 830 mg · h/liter. The concentrations in fecal s les were (mean value) 37.2 and 32.7 mg/kg on day 4 and day 8, respectively. Ceftriaxone exhibited a mean C max of 315 mg/liter, a half-life of 7.6 h, and an AUC of 1,556 mg · h/liter. The mean concentrations in fecal s les were 153 and 258 mg/kg on day 4 and day 8, respectively. No accumulation of ertapenem or ceftriaxone was detected at steady state. A slightly but significantly decreased AUC for ertapenem was detected for the female volunteers. No serious adverse event was observed. Both antibiotics induced a marked decrease in the anaerobic microflora (4-log-unit decreases in lactobacilli, bifidobacteria, clostridia, and bacteroides) and Escherichia coli , whereas the number of enterococci increased (4 log units). A slight overgrowth of yeasts was observed with both regimens. In all cases the microflora returned to normal levels on days 21 to 35.
Publisher: American Society for Microbiology
Date: 15-06-2023
DOI: 10.1128/AAC.01603-22
Abstract: The β-lactam antibiotics have been successfully used for decades to combat susceptible Pseudomonas aeruginosa , which has a notoriously difficult to penetrate outer membrane (OM). However, there is a dearth of data on target site penetration and covalent binding of penicillin-binding proteins (PBP) for β-lactams and β-lactamase inhibitors in intact bacteria.
Publisher: American Society for Microbiology
Date: 12-2017
DOI: 10.1128/AAC.00722-17
Abstract: This study aimed to systematically identify the aminoglycoside concentrations required for synergy with a carbapenem and characterize the permeabilizing effect of aminoglycosides on the outer membrane of Pseudomonas aeruginosa . Monotherapies and combinations of four aminoglycosides and three carbapenems were studied for activity against P. aeruginosa strain AH298-GFP in 48-h static-concentration time-kill studies (SCTK) (inoculum: 10 7.6 CFU/ml). The outer membrane-permeabilizing effect of tobramycin alone and in combination with imipenem was characterized via electron microscopy, confocal imaging, and the nitrocefin assay. A mechanism-based model (MBM) was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by imipenem combined with each of the four aminoglycosides. Notably, 0.25 mg/liter of tobramycin, which was inactive in monotherapy, achieved synergy (i.e., ≥2-log 10 more killing than the most active monotherapy at 24 h) combined with imipenem. Electron micrographs, confocal image analyses, and the nitrocefin uptake data showed distinct outer membrane damage by tobramycin, which was more extensive for the combination with imipenem. The MBM indicated that aminoglycosides enhanced the imipenem target site concentration up to 4.27-fold. Tobramycin was the most potent aminoglycoside to permeabilize the outer membrane tobramycin (0.216 mg/liter), gentamicin (0.739 mg/liter), amikacin (1.70 mg/liter), or streptomycin (5.19 mg/liter) was required for half-maximal permeabilization. In summary, our SCTK, mechanistic studies and MBM indicated that tobramycin was highly synergistic and displayed the maximum outer membrane disruption potential among the tested aminoglycosides. These findings support the optimization of highly promising antibiotic combination dosage regimens for critically ill patients.
Publisher: American Society for Microbiology
Date: 04-2018
DOI: 10.1128/AAC.02053-17
Abstract: We aimed to prospectively validate an optimized combination dosage regimen against a clinical carbapenem-resistant Acinetobacter baumannii (CRAB) isolate (imipenem MIC, 32 mg/liter tobramycin MIC, 2 mg/liter). Imipenem at constant concentrations (7.6, 13.4, and 23.3 mg/liter, reflecting a range of clearances) was simulated in a 7-day hollow-fiber infection model (inoculum, ∼10 7.2 CFU/ml) with and without tobramycin (7 mg/kg q24h, 0.5-h infusions). While monotherapies achieved no killing or failed by 24 h, this rationally optimized combination achieved log 10 bacterial killing and suppressed resistance.
Publisher: American Society for Microbiology
Date: 20-12-2022
Abstract: In this study, we showed that early intervention with molnupiravir resulted in a greater antiviral effect, and we explained the mechanism behind this phenomenon. Our results predicted and explained the failure of molnupiravir in hospitalized patients and highlighted the utility of preclinical pharmacodynamic studies to design optimal antiviral regimens for the treatment of viral diseases.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2012
DOI: 10.1007/S11095-012-0799-0
Abstract: The purpose was to calculate distributions of powder strength of a cohesive bed to explain the de-agglomeration of lactose. De-agglomeration profiles of Lactohale 300(®) (L300) and micronized lactose (ML) were constructed by particle sizing aerosolised plumes dispersed at air flow rates of 30-180 l/min. The work of cohesion distribution was determined by inverse gas chromatography. The primary particle size and tapped density distributions were determined. Powder strength distributions were calculated by Monte Carlo simulations from distributions of particle size, work of cohesion and tapped density measurements. The powder strength distribution of L300 was broader than that of ML. Up to 85th percentile, powder strength of L300 was lower than ML which was consistent with the better de-agglomeration of L300 at low flow rates. However, ~15% of L300 particles had higher powder strength than ML which likely to cause lower de-agglomeration for L300 at high air flow rates. Cohesive lactose powders formed matrices of non-homogenous powder strength. De-agglomeration of cohesive powders has been shown to be related to powder strength. This study provided new insights into powder de-agglomeration by a new approach for calculating powder strength distributions to better understand complex de-agglomeration behaviour.
Publisher: Oxford University Press (OUP)
Date: 08-06-2012
DOI: 10.1093/JAC/DKS201
Abstract: Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen in medical centres worldwide. This study evaluated the impact of front-loading of linezolid on bacterial killing and suppression of resistance against VRE strains with defined genetic mutations. Time-killing experiments over 48 h assessed the concentration effect relationship of linezolid against eight strains of vancomycin-resistant Enterococcus faecalis. A hollow fibre infection model (HFIM) simulated traditional and front-loaded human therapeutic linezolid regimens against VRE strains at 10(6) cfu/mL over 240 h. Translational modelling was performed using S-ADAPT and NONMEM. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity with >2 log(10) cfu/mL killing for all strains with an MIC of 4 and minimal activity against VRE with MICs of 16 and 64 mg/L. Against one strain with no resistant alleles (MIC 4 mg/L), 600 mg of linezolid every 12 h achieved maximal reductions of 0.96 log(10) cfu/mL over 240 h in the HFIM, whereas front-loaded 1200 mg of linezolid every 12 h ×10 doses or 2400 mg of linezolid every 12 h ×10 doses followed by 600 mg of linezolid every 12 h provided significantly improved killing with maximal reductions of 3.02 and 3.46 log(10) cfu/mL. Front-loaded regimens suppressed lification of resistant subpopulations against VRE strains with no resistant alleles (MIC 4 mg/L) and postponed regrowth of resistant subpopulations against a VRE with 3.2 resistant alleles (MIC 4 mg/L). Modelling yielded excellent population fits (r = 0.934) and identified the number of sensitive alleles as a critical covariate. Early, high-dose regimens of linezolid provided promising killing against selected susceptible strains and may be clinically beneficial if early bactericidal activity is necessary.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2008
DOI: 10.1007/S00280-008-0828-1
Abstract: Our objective was to build a mechanism-based pharmacodynamic model for the time course of neutropenia in cancer patients following paclitaxel treatment with a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol). A randomized two-way crossover trial was performed with 35 adult patients who received 175 mg/m(2) paclitaxel as either 15 min (Tocosol Paclitaxel) or 3 h (Taxol) intravenous infusions. Paclitaxel concentrations were measured by LC-MS/MS. NONMEM VI was used for population pharmacodynamics. The cytotoxic effect on neutrophils was described by four mechanism-based models predicated on known properties of paclitaxel that used unbound concentrations in the central, deep peripheral or an intracellular compartment as forcing functions. Tocosol Paclitaxel was estimated to release 9.8% of the dose directly into the deep peripheral compartment (DPC). All models provided reasonable fitting of neutropenic effects. The model with the best predictive performance assumed that this dose fraction was released into 22.5% of the DPC which included the site of toxicity. The second-order cytotoxic rate constant was 0.00211 mL/ng per hour (variability: 52% CV). The relative exposure at the site of toxicity was 2.21 +/- 0.41 times (average +/- SD) larger for Tocosol Paclitaxel compared to Taxol. Lifespan was 11.0 days for progenitor cells, 1.95 days for maturating cells, and 4.38 days for neutrophils. Total drug exposure in blood explained half of the variance in nadir to baseline neutrophil count ratio. The relative exposure of unbound paclitaxel at the site of toxicity was twice as large for Tocosol Paclitaxel compared to Taxol. The proposed mechanism-based models explained the extent and time course of neutropenia jointly for both formulations.
Publisher: American Society for Microbiology
Date: 09-2009
DOI: 10.1128/AAC.01200-08
Abstract: Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid ided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated K m and V max for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an ∼200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.
Publisher: Oxford University Press (OUP)
Date: 27-04-2016
DOI: 10.1093/JAC/DKW127
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 18-03-2014
Abstract: Apicidin, a potential oral chemotherapeutic agent, possesses potent anti-histone-deacetylase activity. After oral administration, the total bioavailability of apicidin is known to be low (14.2%-19.3%). In the present study, we evaluated the factors contributing to the low bioavailability of apicidin by means of quantitative determination of absorption fraction and first-pass metabolism after oral administration. Apicidin was given to rats by five different routes: into the femoral vein, duodenum, superior mesenteric artery, portal vein, and carotid artery. Especially, the fraction absorbed (FX) and the fraction that is not metabolized in the gut wall (FG) were separated by injection of apicidin via superior mesenteric artery, which enables bypassing the permeability barrier. The FX was 45.9% ± 9.7%, the FG was 70.9% ± 8.1% and the hepatic bioavailability (FH) was 70.6% ± 12.3%, while the pulmonary first-pass metabolism was minimal (FL = 102.8% ± 7.4%), indicating that intestinal absorption was the rate-determining step for oral absorption of apicidin. The low FX was further examined in terms of passive diffusion and transporter-mediated efflux by in vitro immobilized artificial membrane (IAM) chromatographic assay and in situ single-pass perfusion method, respectively. Although the passive diffusion potential of apicidin was high (98.01%) by the IAM assay, the in situ permeability was significantly enhanced by the presence of the P-glycoprotein (P-gp) inhibitor elacrider. These data suggest that the low bioavailability of apicidin was mainly attributed to the P-gp efflux consistent with the limited FX measured in vivo experiment.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2016
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1002/JPS.23597
Publisher: Springer Science and Business Media LLC
Date: 24-10-2016
DOI: 10.1007/S00063-016-0185-5
Abstract: Optimized dosage regimens of antibiotics have remained obscure since their introduction. During the last two decades pharmacokinetic(PK)-pharmacodynamic(PD) relationships, originally established in animal experiments, have been increasingly used in patients. The action of betalactams is believed to be governed by the time the plasma concentration is above the minimum inhibitory concentration (MIC). Aminoglycosides act as planned when the peak concentration is a multiple of the MIC and vancomycin seems to work best when the area under the plasma vs. time curve (AUC) to MIC has a certain ratio. Clinicians should be aware that these relationships can only be an indication in which direction dosing should go. Larger studies with sufficiently high numbers of patients and particularly severely sick patients are needed to prove the concepts. In times where all antibiotics can be measured with new technologies, the introduction of therapeutic drug monitoring (TDM) is suggested for ICUs (Intensive Care Unit). The idea of a central lab for TDM of antibiotics such as PEAK (Paul Ehrlich Antibiotika Konzentrationsmessung) is supported.
Publisher: American Society for Microbiology
Date: 16-12-2020
DOI: 10.1128/AAC.01956-20
Abstract: Mycobacterium abscessus causes serious infections that often require over 18 months of antibiotic combination therapy. There is no standard regimen for the treatment of M. abscessus infections, and the multitude of combinations that have been used clinically have had low success rates and high rates of toxicities. With β-lactam antibiotics being safe, double β-lactam and β-lactam/β-lactamase inhibitor combinations are of interest for improving the treatment of M. abscessus infections and minimizing toxicity.
Publisher: American Society for Microbiology
Date: 11-2012
DOI: 10.1128/AAC.00937-12
Abstract: Piperacillin in combination with tazobactam is one of the most commonly used intravenous antibiotics. There is evidence for a possible saturable elimination of piperacillin. Therefore, the saturable elimination and its impact on the choice of optimal dosage regimens were quantified. In a randomized crossover study, 10 healthy volunteers received 1,500 mg and 3,000 mg of piperacillin as 5-min intravenous infusion. Population pharmacokinetics based on plasma and urine data were determined utilizing NONMEM and S-ADAPT. Probabilities of target attainment (PTAs) were compared for different models and dosage regimens, based on the target time of the non-protein-bound concentration above the MIC of at least 50% of the dosing interval. Total clearance of piperacillin was 18% (geometric mean ratio, 90% confidence interval, 11 to 24%) lower ( P 0.01), and renal clearance was 24% (9 to 37%) lower ( P = 0.02) at the high compared to the low dose. The final model included first-order nonrenal elimination and parallel first-order and mixed-order renal elimination. Nonrenal clearance was 5.44 liter/h (coefficient of variation, 18%), first-order renal clearance was 4.42 liter/h (47%), and the maximum elimination rate of mixed-order renal elimination was 219 mg/h (84%), with a Michaelis-Menten constant of 36.1 mg/liter (112%). Compared to models with saturable elimination, a linear model predicted up to 10% lower population PTAs for high-dose short-term infusions (6 g every 8 h) and up to 4% higher population PTAs for low-dose continuous infusions (6 g/day). While renal elimination of piperacillin was saturable at therapeutic concentrations, the extent of saturation of nonrenal clearance was small. The influence of saturable elimination on PTAs for clinically relevant dosage regimens was relatively small.
Publisher: Elsevier BV
Date: 04-2014
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: American Society for Microbiology
Date: 05-2013
DOI: 10.1128/AAC.00092-13
Abstract: Quantitative modeling of combination therapy can describe the effects of each antibiotic against multiple bacterial populations. Our aim was to develop an efficient experimental and modeling strategy that evaluates different synergy mechanisms using a rapidly killing peptide antibiotic (nisin) combined with amikacin or linezolid as probe drugs. Serial viable counts over 48 h were obtained in time-kill experiments with all three antibiotics in monotherapy against a methicillin-resistant Staphylococcus aureus USA300 strain (inoculum, 10 8 CFU/ml). A sequential design (initial dosing of 8 or 32 mg/liter nisin, switched to amikacin or linezolid at 1.5 h) assessed the rate of killing by amikacin and linezolid against nisin-intermediate and nisin-resistant populations. Simultaneous combinations were additionally studied and all viable count profiles comodeled in S-ADAPT and NONMEM. A mechanism-based model with six populations (three for nisin times two for amikacin) yielded unbiased and precise ( r = 0.99, slope = 1.00 S-ADAPT) in idual fits. The second-order killing rate constants for nisin against the three populations were 5.67, 0.0664, and 0.00691 liter/(mg · h). For amikacin, the maximum killing rate constants were 10.1 h −1 against its susceptible and 0.771 h −1 against its less-susceptible populations, with 14.7 mg/liter amikacin causing half-maximal killing. After incorporating the effects of nisin and amikacin against each population, no additional synergy function was needed. Linezolid inhibited successful bacterial replication but did not efficiently kill populations less susceptible to nisin. Nisin plus amikacin achieved subpopulation synergy. The proposed sequential and simultaneous dosing design offers an efficient approach to quantitatively characterize antibiotic synergy over time and prospectively evaluate antibiotic combination dosing strategies.
Publisher: Wiley
Date: 28-10-2008
Publisher: American Society for Microbiology
Date: 05-2005
DOI: 10.1128/AAC.49.5.1881-1889.2005
Abstract: Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following doses: 500 mg as an intravenous infusion over 30 min three times a day (t.i.d.) versus a 250-mg loading dose followed by a 1,500 mg continuous infusion over 24 h for group A and 1,000 mg as an intravenous infusion over 30 min t.i.d. versus a 500-mg loading dose followed by a 3,000-mg continuous infusion over 24 h for group B. Meropenem concentrations in plasma and urine were determined by liquid chromatography-mass spectrometry/mass spectrometry and high-performance liquid chromatography with UV detection, respectively. Pharmacokinetic calculations were done by use of a two-compartment open model, and the data were extrapolated by Monte Carlo simulations for 10,000 simulated subjects for pharmacodynamic evaluation. There were no significant differences in total clearance and renal clearance between group A and group B or between the intermittent treatment and the continuous infusion. The analyses of the probability of target attainment by MIC for the high- and low-dose continuous infusions were robust up to MICs of 4 mg/liter and 2 mg/liter, respectively. The corresponding values for intermittent infusions were only 0.5 mg/liter and 0.25 mg/liter. When these observations were correlated with MICs obtained from the MYSTIC database, intermittent infusion results in adequate activity against two of the most common nosocomially acquired pathogens, Klebsiella pneumoniae and Enterobacter cloacae . However, against Pseudomonas aeruginosa , the evaluation shows a clear advantage of high-dose therapy administered as a continuous infusion. We believe that in the empirical therapy situation, the continuous-infusion mode of administration is most worth the extra efforts. We conclude that clinical trials for evaluation of the continuous infusions of meropenem in critically ill patients are warranted.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2018
DOI: 10.1007/S40262-018-0678-X
Abstract: The pharmacokinetics (PK) of β-lactam antibiotics in cystic fibrosis (CF) patients has been compared with that in healthy volunteers for over four decades however, no quantitative models exist that explain the PK differences between CF patients and healthy volunteers in older and newer studies. Our aims were to critically evaluate these studies and explain the PK differences between CF patients and healthy volunteers. We reviewed all 16 studies that compared the PK of β-lactams between CF patients and healthy volunteers within the same study. Analysis of covariance (ANCOVA) models were developed. In four early studies that compared adolescent, lean CF patients with adult healthy volunteers, clearance (CL) in CF ided by that in healthy volunteers was 1.72 ± 0.90 (average ± standard deviation) in four additional studies comparing age-matched (primarily adult) CF patients with healthy volunteers, this ratio was 1.46 ± 0.16. The CL ratio was 1.15 ± 0.11 in all eight studies that compared CF patients and healthy volunteers who were matched in age, body size and body composition, or that employed allometric scaling by lean body mass (LBM). Volume of distribution was similar between subject groups after scaling by body size. For highly protein-bound β-lactams, the unbound fraction was up to 2.07-fold higher in older studies that compared presumably sicker CF patients with healthy volunteers. These protein-binding differences explained over half of the variance for the CL ratio (p < 0.0001, ANCOVA). Body size, body composition and lower protein binding in presumably sicker CF patients explained the PK alterations in this population. Dosing CF patients according to LBM seems suitable to achieve antibiotic target exposures.
Publisher: American Chemical Society (ACS)
Date: 12-12-2016
DOI: 10.1021/ACS.MOLPHARMACEUT.6B00677
Abstract: Establishing a level A in vitro-in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on population pharmacokinetic (POP-PK) modeling that incorporated physiologically relevant absorption kinetics. To prepare three extended release (ER) tablets of loxoprofen, three types of hydroxypropyl methylcellulose (HPMC 100, 4000, and 15000 cps) were used as drug release modifiers, while lactose and magnesium stearate were used as the diluent and lubricant, respectively. An in vitro dissolution test in various pH conditions showed that loxoprofen dissolution was faster at higher pH. The in vivo pharmacokinetics of loxoprofen was assessed following oral administration of the different loxoprofen formulations to Beagle dogs (n = 22 in total). Secondary peaks or shoulders were observed in many of the in idual plasma concentration vs time profiles after ER tablet administration, which may result from secondary absorption in the intestine due to a dissolution rate increase under intestinal pH compared to that observed at stomach pH. In addition, in vivo oral bioavailability was found to decrease with prolonged drug dissolution, indicating site-specific absorption. Based on the in vitro dissolution and in vivo absorption data, a POP-PK IVIVC model was developed using S-ADAPT software. pH-dependent biphasic dissolution kinetics, described using modified Michaelis-Menten kinetics with varying V
Publisher: American Society for Microbiology
Date: 05-2016
DOI: 10.1128/AAC.02377-15
Abstract: Development of spontaneous mutations in Pseudomonas aeruginosa has been associated with antibiotic failure, leading to high rates of morbidity and mortality. Our objective was to evaluate the pharmacodynamics of polymyxin B combinations against rapidly evolving P. aeruginosa mutator strains and to characterize the time course of bacterial killing and resistance via mechanism-based mathematical models. Polymyxin B or doripenem alone and in combination were evaluated against six P. aeruginosa strains: wild-type PAO1, mismatch repair (MMR)-deficient ( mutS and mutL ) strains, and 7,8-dihydro-8-oxo-deoxyguanosine system (GO) base excision repair (BER)-deficient ( mutM , mutT , and mutY ) strains over 48 h. Pharmacodynamic modeling was performed using S-ADAPT and facilitated by SADAPT-TRAN. Mutator strains displayed higher mutation frequencies than the wild type ( -fold). Exposure to monotherapy was followed by regrowth, even at high polymyxin B concentrations of up to 16 mg/liter. Polymyxin B and doripenem combinations displayed enhanced killing activity against all strains where complete eradication was achieved for polymyxin B concentrations of mg/liter and doripenem concentrations of 8 mg/liter. Modeling suggested that the proportion of preexisting polymyxin B-resistant subpopulations influenced the pharmacodynamic profiles for each strain uniquely (fraction of resistance values are −8.81 log 10 for the wild type, −4.71 for the mutS mutant, and −7.40 log 10 for the mutM mutant). Our findings provide insight into the optimization of polymyxin B and doripenem combinations against P. aeruginosa mutator strains.
Publisher: Public Library of Science (PLoS)
Date: 10-06-2016
Publisher: American Society for Microbiology
Date: 2017
DOI: 10.1128/AAC.01011-16
Abstract: Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa . This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 10 7.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MIC imipenem ] of 16 mg/liter and MIC tobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5× MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded ≥2-log 10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by ≥0.88× MIC imipenem in combination with a median of 0.75× MIC tobramycin (range, 0.032× to 2.0× MIC tobramycin ) or 0.50× MIC amikacin (range, 0.25× to 0.50× MIC amikacin ). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve .0-log 10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, .0 log 10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.
Publisher: Cold Spring Harbor Laboratory
Date: 12-02-2018
Abstract: Pasteurella multocida is a Gram-negative bacterium responsible for many important animal diseases. While a number of P. multocida virulence factors have been identified, very little is known about how gene expression and protein production is regulated in this organism. Small RNA (sRNA) molecules are critical regulators that act by binding to specific mRNA targets, often in association with the RNA chaperone protein Hfq. In this study, transcriptomic analysis of the P. multocida strain VP161 revealed a putative sRNA with high identity to GcvB from Escherichia coli and Salmonella enterica serovar Typhimurium. High-throughput quantitative liquid proteomics was used to compare the proteomes of the P. multocida VP161 wild-type strain, a gcvB mutant, and a GcvB overexpression strain. These analyses identified 46 proteins that displayed significant differential production after inactivation of gcvB , 36 of which showed increased production. Of the 36 proteins that were repressed by GcvB, 27 were predicted to be involved in amino acid biosynthesis or transport. Bioinformatic analyses of putative P. multocida GcvB target mRNAs identified a strongly conserved 10 nucleotide consensus sequence, 5′-AACACAACAT-3′, with the central eight nucleotides identical to the seed binding region present within GcvB mRNA targets in E. coli and S. Typhimurium. Using a defined set of seed region mutants, together with a two-plasmid reporter system that allowed for quantification of sRNA–mRNA interactions, this sequence was confirmed to be critical for the binding of the P. multocida GcvB to the target mRNA, gltA .
Publisher: American Society for Microbiology
Date: 17-05-2023
DOI: 10.1128/AAC.00197-23
Abstract: Polymyxin B is a “last-line-of-defense” antibiotic approved in the 1960s. However, the population pharmacokinetics (PK) of its four main components has not been reported in infected mice. We aimed to determine the PK of polymyxin B1, B1-Ile, B2, and B3 in a murine bloodstream and lung infection model of Acinetobacter baumannii and develop humanized dosage regimens.
Publisher: American Society for Microbiology
Date: 09-2010
DOI: 10.1128/AAC.00903-09
Abstract: Colistin plays a key role in treatment of serious infections by Pseudomonas aeruginosa . The aims of this study were to (i) identify the pharmacokinetic harmacodynamic (PK/PD) index (i.e., the area under the unbound concentration-time curve to MIC ratio [ƒAUC/MIC], the unbound maximal concentration to MIC ratio [ƒ C max /MIC], or the cumulative percentage of a 24-h period that unbound concentrations exceed the MIC [ƒ T MIC ]) that best predicts colistin efficacy and (ii) determine the values for the predictive PK/PD index required to achieve various magnitudes of killing effect. Studies were conducted in a one-compartment in vitro PK/PD model for 24 h using P. aeruginosa ATCC 27853, PAO1, and the multidrug-resistant mucoid clinical isolate 19056 muc. Six intermittent dosing intervals, with a range of ƒ C max colistin concentrations, and two continuous infusion regimens were examined. PK/PD indices varied from 0.06 to 18 for targeted ƒ C max /MIC, 0.36 to 312 for ƒAUC/MIC, and 0 to 100% for ƒ T MIC . A Hill-type model was fit to killing effect data, which were expressed as the log 10 ratio of the area under the CFU/ml curve for treated regimens versus control. With ƒ C max values equal to or above the MIC, rapid killing was observed following the first dose substantial regrowth occurred by 24 h with most regimens. The overall killing effect was best correlated with ƒAUC/MIC ( R 2 = 0.931) compared to ƒ C max /MIC ( R 2 = 0.868) and ƒ T MIC ( R 2 = 0.785). The magnitudes of ƒAUC/MIC required for 1- and 2-log 10 reductions in the area under the CFU/ml curve relative to growth control were 22.6 and 30.4, 27.1 and 35.7, and 5.04 and 6.81 for ATCC 27853, PAO1, and 19056 muc, respectively. The PK/PD targets identified will assist in designing optimal dosing strategies for colistin.
Publisher: American Society for Microbiology
Date: 05-2009
DOI: 10.1128/AAC.01056-08
Abstract: Moxifloxacin is a fluoroquinolone with a broad spectrum of activity and good penetration into many tissues, including bone. Penetration of moxifloxacin into bone has not yet been studied using compartmental modeling techniques. Therefore, we determined the rate and extent of bone penetration by moxifloxacin and evaluated its pharmacodynamic profile in bone via Monte Carlo simulation. Twenty-four patients (10 males, 14 females) undergoing total hip replacement received 400 mg moxifloxacin orally 2 to 7 h prior to surgery. Blood and bone specimens were collected. Bone s les were pulverized under liquid nitrogen by a cryogenic mill, including an internal standard. Drug concentrations were analyzed by high-performance liquid chromatography. We used ADAPT II (results reported), NONMEM, and WinBUGS for pharmacokinetic analysis. Monte Carlo simulation was performed to reverse engineer the necessary area under the free concentration-time curve f AUC SERUM /MIC in serum and total AUC BONE /MIC in bone for a successful clinical or microbiological outcome. The median (10% to 90% percentile for between-subject variability) of the AUC in bone ided by the AUC in serum (AUC BONE /AUC SERUM ) was 80% (51 to 126%) for cortical bone and 78% (42 to 144%) for cancellous bone. Equilibration between serum and bone was rapid. Moxifloxacin achieved robust (≥90%) probabilities of target attainment (PTAs) in serum, cortical bone, and cancellous bone up to MICs of ≤0.375 mg/liter based on the targets f AUC SERUM /MIC ≥ 40 and AUC BONE /MIC ≥ 33. Moxifloxacin showed high bone concentrations and a rapid equilibrium between bone and serum. The favorable PTAs compared to the 90%-inhibitory MIC of Staphylococcus aureus warrant future clinical trials on the effectiveness of moxifloxacin in the treatment of bone infections.
Publisher: Springer Science and Business Media LLC
Date: 20-05-2015
Publisher: Springer Science and Business Media LLC
Date: 05-09-2017
DOI: 10.1208/S12248-017-0138-9
Abstract: Cyclooxygenase-2 (COX-2) isoform has a critical role in the development of pain. Inhibition of COX-2 in vitro serves as a biomarker for nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAID concentrations yielding 80% COX-2 inhibition (IC
Publisher: American Society for Microbiology
Date: 15-03-2022
DOI: 10.1128/AAC.02203-21
Abstract: Acute exacerbations of chronic respiratory infections in patients with cystic fibrosis are highly challenging due to hypermutable Pseudomonas aeruginosa biofilm formation and resistance emergence. We aimed to systematically evaluate the effects of intravenous versus inhaled tobramycin (TOB) with and without intravenous ceftazidime (CAZ).
Publisher: Informa UK Limited
Date: 30-04-2014
DOI: 10.3109/00498254.2014.915359
Abstract: 1. The objectives of this study were to evaluate the pharmacokinetics and metabolism of fimasartan in rats. 2. Unlabeled fimasartan or radiolabeled [(14)C]fimasartan was dosed by intravenous injection or oral administration to rats. Concentrations of unlabeled fimasartan in the biological s les were determined by a validated LC/MS/MS assay. Total radioactivity was quantified by liquid scintillation counting and the radioactivity associated with the metabolites was analyzed by using the radiochemical detector. Metabolite identification was conducted by product ion scanning using LC/MS/MS. 3. After oral administration of [(14)C]fimasartan, total radioactivity was found primarily in feces. In bile duct cannulated rats, 58.8 ± 14.4% of the radioactive dose was excreted via bile after oral dosing. Major metabolites of fimasartan including the active metabolite, desulfo-fimasartan, were identified, yet none represented more than 7.2% of the exposure of the parent drug. Fimasartan was rapidly and extensively absorbed and had an oral bioavailability of 32.7-49.6% in rats. Fimasartan plasma concentrations showed a multi-exponential decline after oral administration. Double peaks and extended terminal half-life were observed, which was likely caused by enterohepatic recirculation. 4. These results provide better understanding on the pharmacokinetics of fimasartan and may aid further development of fimasartan analogs.
Publisher: American Society for Microbiology
Date: 04-2015
DOI: 10.1128/AAC.04379-14
Abstract: Acinetobacter baumannii is among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize β-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistant A. baumannii . We studied combinations of 10 β-lactams and three aminoglycosides against four A. baumannii strains, including two imipenem-intermediate (MIC, 4 mg/liter) and one imipenem-resistant (MIC, 32 mg/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance of A. baumannii using Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (≤2.3 log 10 ) of A. baumannii ATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other β-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg/liter combined with an aminoglycoside yielded synergistic killing ( log 10 ) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant A. baumannii (MIC, 32 mg/liter), optimized combination regimens (imipenem at 4 g/day as a continuous infusion plus tobramycin at 7 mg/kg of body weight every 24 h) were predicted to achieve log 10 killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000333377
Abstract: i Background: /i There are only limited data on tissue kinetics of ertapenem in colorectal tissue more than 3 h after administration of the drug. The purpose of this study was to assess the pharmacokinetics (PK) of ertapenem in colorectal tissue via population PK modeling. i Patients and Methods: /i Patients ≧18 years requiring surgical intervention at the colon and/or rectum were eligible (ClinicalTrials.gov identifier: NCT 00535652). Tissue and blood s les were taken during surgery after a single dose of 1 g ertapenem. Ertapenem concentration was determined by high-performance liquid chromatography/mass spectrometry. Population PK modeling was performed in S-ADAPT. i Results: /i Twenty-three patients were enrolled. The highest tissue concentration was 6.4 ± 2.3 mg/kg, the highest total plasma concentration 51.34 ± 9.4 mg/l, the highest unbound plasma concentration 7.05 ± 1.1 mg/l, and the unbound fraction in plasma was 14–15% for total ertapenem concentrations below approximately 22 mg/l, 19% at 100 mg/l, and 25% at 250 mg/l. The estimated geometric mean terminal half-life was 2.5 h for plasma and tissue. In the Monte Carlo simulation, a single dose of 1,000 mg ertapenem achieved robust (≧90%) probabilities of target attainment up to a minimum inhibitory concentration (MIC) of approximately 2 mg/l for the bacteriostasis target (free time above MIC, i f /i T sub /sub sub MIC /sub = 20%) and up to 0.25–0.5 mg/l for the near-maximal killing target (40% i f /i T sub /sub sub MIC /sub ). i Conclusion: /i Our data indicate an adequate penetration of ertapenem into uninfected colorectal tissue up to 8.5 h (35% of the dosing interval) after administration of 1 g intravenously.
Publisher: Wiley
Date: 2015
DOI: 10.1002/PHAR.1537
Publisher: American Society for Microbiology
Date: 08-2009
DOI: 10.1128/AAC.00054-09
Abstract: Cefuroxime axetil is widely used to treat respiratory tract infections. We are not aware of a population pharmacokinetic (PK) model for cefuroxime axetil. Our objectives were to develop a semiphysiological population PK model and evaluate the pharmacodynamic profile for cefuroxime axetil. Twenty-four healthy volunteers received 250 mg oral cefuroxime as a suspension after a standardized breakfast. Liquid chromatography-tandem mass spectrometry was used for drug analysis, NONMEM and S-ADAPT (results reported) were used for parametric population PK modeling, and NPAG was used for nonparametric population PK modeling. Monte Carlo simulations were used to predict the duration for which the non-protein-bound-plasma concentration was above the MIC ( f T MIC ). A model with one disposition compartment, a saturable and time-dependent drug release from the stomach, and fast drug absorption from the intestine yielded precise ( r 0.992) and unbiased curve fits and an excellent predictive performance. The apparent clearance was 21.7 liters/h (19.8% coefficient of variation [CV]) and the volume of distribution 38.7 liters (18.3% CV). Robust (≥90%) probabilities of target attainment (PTAs) were achieved by 250 mg cefuroxime given every 12 h (q12h) or q8h for MICs of ≤0.375 mg/liter or ≤0.5 mg/liter, respectively, for the bacteriostasis target f T MIC of ≥40% and for MICs of ≤0.094 mg/liter or ≤0.375 mg/liter, respectively, for the near-maximal-killing target f T MIC of ≥65%. For the ≥40% f T MIC target, the PTAs for 250 mg cefuroxime q12h were ≥97.8% for S treptococcus pyogenes and penicillin-susceptible S treptococcus pneumoniae . Cefuroxime at 250 mg q12h or q8h achieved PTAs below 73% or 92%, respectively, for H aemophilus influenzae , M oraxella catarrhalis , and penicillin-intermediate S. pneumoniae for susceptibility data from various countries. Depending on the MIC distribution, 250 mg oral cefuroxime q8h instead of q12h should be considered, especially for more-severe infections that require near-maximal killing by cefuroxime.
Publisher: American Society for Microbiology
Date: 07-2007
DOI: 10.1128/AAC.01477-06
Abstract: Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa , but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 ± 7.8 kg) and 26 healthy volunteers (WT, 71.1 ± 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (≥90%) probability-of-target attainment (PTA) for MICs of ≤12 mg/liter in CF patients and ≤16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of ≤16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.
Publisher: Oxford University Press (OUP)
Date: 28-02-2017
DOI: 10.1093/JAC/DKX002
Publisher: American Society for Microbiology
Date: 11-2011
DOI: 10.1128/AAC.05028-11
Abstract: The use of combination antibiotic therapy may be beneficial against rapidly emerging resistance in Pseudomonas aeruginosa . The aim of this study was to systematically investigate in vitro bacterial killing and resistance emergence with colistin alone and in combination with imipenem against multidrug-resistant (MDR) P. aeruginosa . Time-kill studies were conducted over 48 h using 5 clinical isolates and ATCC 27853 at two inocula (∼10 6 and ∼10 8 CFU/ml) MDR, non-MDR, and colistin-heteroresistant and -resistant strains were included. Nine colistin-imipenem combinations were investigated. Microbiological response was examined by log changes at 6, 24, and 48 h. Colistin combined with imipenem at clinically relevant concentrations increased the levels of killing of MDR and colistin-heteroresistant isolates at both inocula. Substantial improvements in activity with combinations were observed across 48 h with all colistin concentrations at the low inoculum and with colistin at 4× and 16× MIC (or 4 and 32 mg/liter) at the high inoculum. Combinations were additive or synergistic against imipenem-resistant isolates (MICs, 16 and 32 mg/liter) at the 10 6 -CFU inoculum in 9, 11, and 12 of 18 cases (i.e., 9 combinations across 2 isolates) at 6, 24, and 48 h, respectively, and against the same isolates at the 10 8 -CFU inoculum in 11, 7, and 8 cases, respectively. Against a colistin-resistant strain (MIC, 128 mg/liter), combinations were additive or synergistic in 9 and 8 of 9 cases at 24 h at the 10 6 - and 10 8 -CFU inocula, respectively, and in 5 and 7 cases at 48 h. This systematic study provides important information for optimization of colistin-imipenem combinations targeting both colistin-susceptible and colistin-resistant subpopulations.
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: 15-05-2017
DOI: 10.1093/JAC/DKX121
Publisher: American Society for Microbiology
Date: 04-2014
DOI: 10.1128/AAC.01885-13
Abstract: Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of ×10 9 /liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose in idualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.
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: American Society for Microbiology
Date: 2015
DOI: 10.1128/AAC.04182-14
Abstract: In vitro static concentration time-kill (SCTK) studies are a cornerstone for antibiotic development and designing dosage regimens. However, mathematical approaches to efficiently model SCTK curves are scarce. The currently used model-free, descriptive metrics include the log 10 change in CFU from 0 h to a defined time and the area under the viable count versus time curve. These metrics have significant limitations, as they do not characterize the rates of bacterial killing and regrowth and lack sensitivity. Our aims were to develop a novel rate-area-shape modeling approach and to compare, against model-free metrics, its relative ability to characterize the rate, extent, and timing of bacterial killing and regrowth from SCTK studies. The rate-area-shape model and the model-free metrics were applied to data for colistin and doripenem against six Acinetobacter baumannii strains. Both approaches identified exposure-response relationships from 0.5- to 64-fold the MIC. The model-based approach estimated an at least 10-fold faster killing by colistin than by doripenem at all multiples of the MIC. However, bacterial regrowth was more extensive (by 2 log 10 ) and occurred approximately 3 h earlier for colistin than for doripenem. The model-free metrics could not consistently differentiate the rate and extent of killing between colistin and doripenem. The time to 2 log 10 killing was substantially faster for colistin. The rate-area-shape model was successfully implemented in Excel. This new model provides an improved framework to distinguish between antibiotics with different rates of bacterial killing and regrowth and will enable researchers to better characterize SCTK experiments and design subsequent dynamic studies.
Publisher: American Society for Microbiology
Date: 25-02-2020
Abstract: Antimicrobial resistance is causing a global human health crisis and is affecting all antibiotic classes. While β-lactams have been commonly used against susceptible isolates of Klebsiella pneumoniae and Enterobacter cloacae , carbapenem-resistant isolates are spreading worldwide and pose substantial clinical challenges. Rapid penetration of β-lactams leads to high drug concentrations at their periplasmic target sites, allowing β-lactams to more completely inactivate their target receptors. Despite this, there are limited tangible data on the permeability of β-lactams through the outer membranes of many Gram-negative pathogens. This study presents a novel, cassette assay, which can simultaneously characterize the permeability of five β-lactams in multidrug-resistant clinical isolates. We show that carbapenems, and especially imipenem, penetrate the outer membrane of K. pneumoniae and E. cloacae substantially faster than noncarbapenem β-lactams. The ability to efficiently characterize the outer membrane permeability is critical to optimize the use of β-lactams and combat carbapenem-resistant isolates.
Publisher: Springer Science and Business Media LLC
Date: 2002
Abstract: Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N -desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N -desmethylsildenafil. In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N -desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography-tandem mass spectrometry (limit of quantification, 1 ng/ml). Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethyl sildenafil AUC(0-infinity) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (C(max)) of sildenafil and N -desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach C(max) during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0-0.63 hour). Interin idual variability was pronounced in both periods. Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.
Publisher: MDPI AG
Date: 12-09-2019
DOI: 10.3390/PHARMACEUTICS11090470
Abstract: Hypermutable Pseudomonas aeruginosa strains have a greatly increased mutation rate and are prevalent in chronic respiratory infections. Initially, we systematically evaluated the time-course of total and resistant populations of hypermutable (PAO∆mutS) and non-hypermutable (PAO1) P. aeruginosa strains in 48-h static concentration time-kill studies with two inocula. Both strains were exposed to clinically relevant concentrations of important antibiotics (aztreonam, ceftazidime, imipenem, meropenem, tobramycin, and ciprofloxacin) in monotherapy. The combination of tobramycin and ciprofloxacin was subsequently assessed in 48-h static concentration time-kill studies against PAO1, PAO∆mutS, and two hypermutable clinical P. aeruginosa strains. Mechanism-based mathematical modelling was conducted to describe the time-course of total and resistant bacteria for all four strains exposed to the combination. With all monotherapies, bacterial regrowth and resistant populations were overall more pronounced for PAO∆mutS compared to PAO1. The combination of tobramycin and ciprofloxacin was synergistic, with up to 106.1 colony forming units (CFU)/mL more bacterial killing than the most active monotherapy for all strains, and largely suppressed less-susceptible populations. This work indicates that monotherapies against hypermutable P. aeruginosa strains are not a viable option. Tobramycin with ciprofloxacin was identified as a promising and tangible option to combat hypermutable P. aeruginosa strains.
Publisher: American Society for Microbiology
Date: 06-2018
DOI: 10.1128/AAC.00282-18
Abstract: Penicillin-binding proteins (PBPs) are the high-affinity target sites of all β-lactam antibiotics in bacteria. It is well known that each β-lactam covalently binds to and thereby inactivates different PBPs with various affinities. Despite β-lactams serving as the cornerstone of our therapeutic armamentarium against Klebsiella pneumoniae , PBP binding data are missing for this pathogen. We aimed to generate the first PBP binding data on 13 chemically erse and clinically relevant β-lactams and β-lactamase inhibitors in K. pneumoniae . PBP binding was determined using isolated membrane fractions from K. pneumoniae strains ATCC 43816 and ATCC 13883. Binding reactions were conducted using β-lactam concentrations from 0.0075 to 256 mg/liter (or 128 mg/liter). After β-lactam exposure, unbound PBPs were labeled by Bocillin FL. Binding affinities (50% inhibitory concentrations [IC 50 ]) were reported as the β-lactam concentrations that half-maximally inhibited Bocillin FL binding. PBP occupancy patterns by β-lactams were consistent across both strains. Carbapenems bound to all PBPs, with PBP2 and PBP4 as the highest-affinity targets (IC 50 , .0075 mg/liter). Preferential PBP2 binding was observed by mecillinam (amdinocillin IC 50 , .0075 mg/liter) and avibactam (IC 50 , 2 mg/liter). Aztreonam showed high affinity for PBP3 (IC 50 , 0.06 to 0.12 mg/liter). Ceftazidime bound PBP3 at low concentrations (IC 50 , 0.06 to 0.25 mg/liter) and PBP1a/b at higher concentrations (4 mg/liter), whereas cefepime bound PBPs 1 to 4 at more even concentrations (IC 50 , 0.015 to 2 mg/liter). These PBP binding data on a comprehensive set of 13 clinically relevant β-lactams and β-lactamase inhibitors in K. pneumoniae enable, for the first time, the rational design and optimization of double β-lactam and β-lactam–β-lactamase inhibitor combinations.
Publisher: Springer Science and Business Media LLC
Date: 03-03-2011
Publisher: American Society for Microbiology
Date: 05-2019
DOI: 10.1128/AAC.02307-18
Abstract: In June 2017, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens.” The aims were to discuss details of various PK/PD models and identify sound practices for deriving and utilizing PK/PD relationships to design optimal dosage regimens for patients. Workshop participants encompassed in iduals from academia, industry, and government, including the United States Food and Drug Administration.
Publisher: Elsevier BV
Date: 10-2013
Publisher: American Society for Microbiology
Date: 2013
DOI: 10.1128/AAC.01463-12
Abstract: Murine models are used to study erythrocytic stages of malaria infection, because parasite morphology and development are comparable to those in human malaria infections. Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models for antimalarials are scarce, despite their potential to optimize antimalarial combination therapy. The aim of this study was to develop a mechanism-based growth model (MBGM) for Plasmodium berghei and then characterize the parasiticidal effect of dihydroartemisinin (DHA) in murine malaria (MBGM-PK-PD). Stage-specific (ring, early trophozoite, late trophozoite, and schizont) parasite density data from Swiss mice inoculated with Plasmodium berghei were used for model development in S-ADAPT. A single dose of intraperitoneal DHA (10 to 100 mg/kg) or vehicle was administered 56 h postinoculation. The MBGM explicitly reflected all four erythrocytic stages of the 24-hour P. berghei life cycle. Merozoite invasion of erythrocytes was described by a first-order process that declined with increasing parasitemia. An efflux pathway with subsequent return was additionally required to describe the schizont data, thus representing parasite sequestration or trapping in the microvasculature, with a return to circulation. A 1-compartment model with zero-order absorption described the PK of DHA, with an estimated clearance and distribution volume of 1.95 liters h −1 and 0.851 liter, respectively. Parasite killing was described by a turnover model, with DHA inhibiting the production of physiological intermediates (IC 50 , 1.46 ng/ml). Overall, the MBGM-PK-PD described the rise in parasitemia, the nadir following DHA dosing, and subsequent parasite resurgence. This novel model is a promising tool for studying malaria infections, identifying the stage specificity of antimalarials, and providing insight into antimalarial treatment strategies.
Publisher: American Society for Microbiology
Date: 04-2018
DOI: 10.1128/AAC.02055-17
Abstract: Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔ mutS strain (MIC meropenem of 1.0 mg/liter and MIC tobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼10 8.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔ mutS strain in the HFIM, all monotherapies resulted in rapid regrowth to 8.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused -log 10 bacterial killing followed by regrowth to log 10 CFU/ml by day 5 and high-level resistance (MIC meropenem , 32 mg/liter MIC tobramycin , 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved -log 10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to log 10 over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.
Publisher: Springer Berlin Heidelberg
Date: 2009
Publisher: American Society for Microbiology
Date: 06-2008
DOI: 10.1128/AAC.00736-06
Abstract: Cefditoren is a broad-spectrum, oral cephalosporin that is highly active against clinically relevant respiratory tract pathogens, including multidrug-resistant Streptococcus pneumoniae . This study described its pharmacodynamic profile in plasma and epithelial lining fluid (ELF). Plasma and ELF pharmacokinetic data were obtained from 24 patients under fasting conditions. Cefditoren and urea concentrations were determined in plasma and bronchoalveolar lavage fluid by liquid chromatography-tandem mass spectrometry. Concentration-time profiles in plasma and ELF were modeled using a model with three disposition compartments and first-order absorption, elimination, and transfer. Pharmacokinetic parameters were identified in a population pharmacokinetic analysis (big nonparametric adaptive grid with adaptive γ). Monte Carlo simulation (9,999 subjects) was performed with the ADAPT II program to estimate the probability of target attainment at which the free-cefditoren plasma concentrations (88%) protein binding and total ELF concentrations exceeded the MIC for 33% of the dosing interval for 400 mg cefditoren given orally every 12 h. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. In the plasma probability of target attainment analysis, the probability of achieving a time for which free, or unbound, plasma concentration exceeds the MIC of the organism for 33% of the dosing interval was % for a MIC of .06 mg/liter. Similar to plasma, the probability of achieving a time above the MIC of 33% was % for MIC of .06 mg/liter in ELF. Cefditoren was found to have a low probability of achieving a bacteriostatic effect against MICs of .06 mg/liter, which includes most S. pneumoniae isolates with intermediate susceptibility to penicillin, when given in the fasting state in both plasma and ELF.
Publisher: Informa UK Limited
Date: 11-2009
DOI: 10.1080/15287390903212741
Abstract: The objectives of this study were to (1) develop physiologically based pharmacokinetic (PBPK) models for zearalenone following intravenous (i.v.) and oral (p.o.) dosing in rats and (2) predict concentrations in humans via interspecies scaling. The model for i.v. dosing consisted of vein, artery, lung, liver, spleen, kidneys, heart, testes, brain, muscle, adipose tissue, stomach, and small intestine. To describe the secondary peak phenomenon observed after p.o. administration, the absorption model was constructed to reflect glucuronidation, biliary excretion, enterohepatic recirculation, and fast and slow absorption processes from the lumenal compartment. The developed models adequately described observed concentration-time data in rats after i.v. or p.o. administration. Upon model validation in rats, steady-state zearalenone concentrations in blood and tissues were simulated for rats after once daily p.o. exposures (0.1 mg/kg/d). The average steady-state blood zearalenone concentration predicted in rat was 0.014 ng/ml. Subsequently, a daily human p.o. dose needed to achieve the same steady-state blood concentration found in rats (0.014 ng/ml) was determined to be 0.0312 mg/kg/d or 2.18 mg/70 kg/d. The steady-state zearalenone concentration-time profiles in blood and tissues were also simulated for human after multiple p.o. administrations (dose 0.0312 mg/kg/d). The developed PBPK models adequately described the pharmacokinetics in rats and may be useful in predicting human blood and tissue concentrations for zearalenone under different p,o, exposure conditions.
Publisher: American Society for Microbiology
Date: 2012
DOI: 10.1128/AAC.05252-11
Abstract: The panoply of resistance mechanisms in Pseudomonas aeruginosa makes resistance suppression difficult. Defining optimal regimens is critical. Cefepime is a cephalosporin whose 3′ side chain provides some stability against AmpC β-lactamases. We examined the activity of cefepime against P. aeruginosa wild-type strain PAO1 and its isogenic AmpC stably derepressed mutant in our hollow-fiber infection model. Dose-ranging studies demonstrated complete failure with resistance emergence (both isolates). Inoculum range studies demonstrated ultimate failure for all inocula. Lower inocula failed last (10 days to 2 weeks). Addition of a β-lactamase inhibitor suppressed resistance even with the stably derepressed isolate. Tobramycin combination studies demonstrated resistance suppression in both the wild-type and the stably derepressed isolates. Quantitating the RNA message by quantitative PCR demonstrated that tobramycin decreased the message relative to that in cefepime-alone experiments. Western blotting with AmpC-specific antibody for P. aeruginosa demonstrated decreased expression. We concluded that suppression of β-lactamase expression by tobramycin (a protein synthesis inhibitor) was at least part of the mechanism behind resistance suppression. Monte Carlo simulation demonstrated that a regimen of 2 g of cefepime every 8 h plus 7 mg/kg of body weight of tobramycin daily would provide robust resistance suppression for Pseudomonas isolates with cefepime MIC values up to 8 mg/liter and tobramycin MIC values up to 1 mg/liter. For P. aeruginosa resistance suppression, combination therapy is critical.
Publisher: Wiley
Date: 09-2006
Publisher: American Society for Microbiology
Date: 07-2015
DOI: 10.1128/AAC.04629-14
Abstract: The interplay between polymyxin B pharmacodynamics and pathogenicity was examined in Pseudomonas aeruginosa PAO1 and isogenic DNA repair-deficient mutators ( mutM and mutS strains). Against mutS mutators, polymyxin B initial killing was concentration dependent, with .9% bacterial reduction at 2 h followed by regrowth and resistance. The pre- versus postexposed strains were inoculated real time into Galleria mellonella waxworms, resulting in increased median survival times from 20 h to 23 h ( P 0.001). Emergence of resistance in mutS P. aeruginosa resulted in attenuation of virulence.
Publisher: American Society for Microbiology
Date: 09-2009
DOI: 10.1128/AAC.01585-08
Abstract: Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) in pneumonia since the extent of vancomycin penetration into epithelial lining fluid (ELF) has not been definitively established. We evaluated the impact of the extent of ELF penetration on bacterial killing and resistance by simulating a range of vancomycin exposures (24-h free drug area under the concentration-time curve [ƒAUC 24 ]/MIC) using an in vitro pharmacodynamic model and population-based mathematical modeling. A high-dose, 1.5-g-every-12-h vancomycin regimen according to American Thoracic Society/Infectious Diseases Society of America guidelines (trough concentration, 15 mg/liter) with simulated ELF lasma penetration of 0, 20, 40, 60, 80, or 100% (ƒAUC 24 /MIC of 0, 70, 140, 210, 280, or 350) was evaluated against two agr -functional, group II MRSA clinical isolates obtained from patients with a bloodstream infection (MIC = 1.0 mg/liter) at a high inoculum of 10 8 CFU/ml. Despite high vancomycin exposures and 100% penetration, all regimens up to a ƒAUC 24 /MIC of 350 did not achieve bactericidal activity. At regimens of ≤60% penetration (ƒAUC 24 /MIC ≤ 210), stasis and regrowth occurred, lifying the development of intermediately resistant subpopulations. Regimens simulating ≥80% penetration (ƒAUC 24 /MIC ≥ 280) suppressed development of resistance. Resistant mutants lified by suboptimal vancomycin exposure displayed reduced rates of autolysis (Triton X-100) at 72 h. Bacterial growth and death were well characterized by a Hill-type model ( r 2 ≥ 0.984) and a population pharmacodynamic model with a resistant and susceptible subpopulation ( r 2 ≥ 0.965). Due to the emergence of vancomycin-intermediate resistance at a ƒAUC 24 /MIC of ≤210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.
Publisher: Oxford University Press (OUP)
Date: 06-2011
DOI: 10.1093/CID/CIR166
Abstract: Perhaps the most crucial step in the clinical development of an antimicrobial agent is the selection of a dosing regimen. Such decisions impact not only the success of a program but also the well being of in idual patients, the emergence of resistance, and society as a whole. For fusidic acid, the selection of a dosing regimen for the treatment of patients with acute bacterial skin and skin-structure infection (ABSSSI) was based on the integration of knowledge gained from human population pharmacokinetic, in vitro infection, and mathematical models. The overarching goal of these studies was to identify a dosing regimen that would maximize the probabilities of positive clinical outcomes and limit the emergence of bacterial resistance during therapy. Novel dosing regimens identified included 1500 mg twice daily on day 1 followed by 600 mg twice daily for 10-14 days, a regimen that was subsequently found to be effective in a phase 2 clinical study of patients with ABSSSI. Herein, we review the data supporting the use of this novel fusidic acid dosing regimen, which will undergo further clinical evaluation in phase 3 clinical trials.
Publisher: American Society for Microbiology
Date: 07-2012
DOI: 10.1128/AAC.05453-11
Abstract: Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr ) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 10 6 CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of log 10 CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of −6.15 and −6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a .27× increase in the fractional decreases in platelets for all front-loaded regimens versus the 600 mg q12h regimen, except for the highest-dose front-loaded regimen. Front-loading strategies for linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary.
Publisher: American Chemical Society (ACS)
Date: 29-02-2016
DOI: 10.1021/ACS.MOLPHARMACEUT.5B00749
Abstract: The lymphatic system is a major conduit by which many diseases spread and proliferate. There is therefore increasing interest in promoting better lymphatic drug targeting. Further, antibody fragments such as Fabs have several advantages over full length monoclonal antibodies but are subject to rapid plasma clearance, which can limit the lymphatic exposure and activity of Fabs against lymph-resident diseases. This study therefore explored ideal PEGylation strategies to maximize biological activity and lymphatic exposure using trastuzumab Fab' as a model. Specifically, the Fab' was conjugated with single linear 10 or 40 kDa PEG chains at the hinge region. PEGylation led to a 3-4-fold reduction in binding affinity to HER2, but antiproliferative activity against HER2-expressing BT474 cells was preserved. Lymphatic pharmacokinetics were then examined in thoracic lymph duct cannulated rats after intravenous and subcutaneous dosing at 2 mg/kg, and the data were evaluated via population pharmacokinetic modeling. The Fab' displayed limited lymphatic exposure, but conjugation of 10 kDa PEG improved exposure by approximately 11- and 5-fold after intravenous (15% dose collected in thoracic lymph over 30 h) and subcutaneous (9%) administration, respectively. Increasing the molecular weight of the PEG to 40 kDa, however, had no significant impact on lymphatic exposure after intravenous (14%) administration and only doubled lymphatic exposure after subcutaneous administration (18%) when compared to 10 kDa PEG-Fab'. The data therefore suggests that minimal PEGylation has the potential to enhance the exposure and activity of Fab's against lymph-resident diseases, while no significant benefit is achieved with very large PEGs.
Publisher: American Society for Microbiology
Date: 10-2012
DOI: 10.1128/AAC.01064-12
Abstract: Multidrug-resistant (MDR) Klebsiella pneumoniae may require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDR K. pneumoniae and emergence of colistin resistance. A one-compartment in vitro pharmacokinetic harmacodynamic model was employed over a 72-h period with two inocula (∼10 6 and ∼10 8 CFU/ml) a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological responses were examined by determining log changes and population analysis profiles (for emergence of colistin resistance) over 72 h. Against colistin-susceptible and -heteroresistant isolates, combinations of colistin (constant concentration regimens of 0.5 or 2 mg/liter) plus doripenem (steady-state peak concentration [ C max ] of 2.5 or 25 mg/liter over 8 h half-life, 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032, and FADDI-KP033 in 9, 9, and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 10 6 -CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 10 8 -CFU/ml inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of colistin-resistant subpopulations in colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the colistin-resistant isolate, colistin at 2 mg/liter plus doripenem ( C max , 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations.
Publisher: American Society for Microbiology
Date: 07-2016
DOI: 10.1128/AAC.02831-15
Abstract: Administering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains of Acinetobacter baumannii in the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B ( t 1/2 = 8 h): non-loading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against both A. baumannii isolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of −1.25, −1.43, −2.84, −2.84, and −3.40 log 10 CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic harmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was an f AUC 0–24 (area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in lification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-density A. baumannii infections.
Publisher: American Society for Microbiology
Date: 18-05-2021
DOI: 10.1128/AAC.00124-21
Abstract: Ceftazidime (CAZ)-avibactam (AVI) is a β-lactam/β-lactamase inhibitor combination with activity against type A and type C β-lactamases. Resistance emergence has been seen, with multiple mechanisms accounting for the resistance. We performed four experiments in the dynamic hollow-fiber infection model, delineating the linkage between drug exposure and both the rate of bacterial kill and resistance emergence by all mechanisms.
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: 2009
DOI: 10.1128/AAC.00489-08
Abstract: Evidence is mounting in support of the inoculum effect (i.e., slow killing at large initial inocula [CFUo]) for numerous antimicrobials against a variety of pathogens. Our objectives were to (i) determine the impact of the CFUo of Pseudomonas aeruginosa on ceftazidime activity and (ii) to develop and validate a pharmacokinetic harmacodynamic (PKPD) mathematical model accommodating a range of CFUo. Time-kill experiments using ceftazidime at seven concentrations up to 128 mg/liter (MIC, 2 mg/liter) were performed in duplicate against P. aeruginosa PAO1 at five CFUo from 10 5 to 10 9 CFU/ml. S les were collected over 24 h and fit by candidate models in NONMEM VI and S-ADAPT 1.55 (all data were comodeled). External model qualification integrated data from eight previously published studies. Ceftazidime displayed approximately 3 to 4 log 10 CFU/ml net killing at 10 6.2 CFUo and concentrations of 4 mg/liter (or higher), less than 1.6 log 10 CFU/ml killing at 10 7.3 CFUo, and no killing at 10 8.0 CFUo for concentrations up to 128 mg/liter. The proposed mechanism-based model successfully described the inoculum effect and the concentration-independent lag time of killing. The mean generation time was 28.3 min. The effect of an autolysin was assumed to inhibit successful replication. Ceftazidime concentrations of 0.294 mg/liter stimulated the autolysin effect by 50%. The model was predictive in the internal cross-validation and had excellent in silico predictive performance for published studies of P. aeruginosa ATCC 27853 for various CFUo. The proposed PKPD model successfully described and predicted the pronounced inoculum effect of ceftazidime in vitro and integrated data from eight literature studies to support translation from time-kill experiments to in vitro infection models.
Publisher: American Society for Microbiology
Date: 03-0003
DOI: 10.1128/AAC.47.3.1129-1131.2003
Abstract: We assessed the pharmacokinetics and interaction of ABT-773 in 12 volunteers receiving ABT-773 alone or concomitantly with ranitidine or sucralfate. Data for 150 mg of ABT-773 were as follows: the maximum concentration of the drug in plasma ( C max ) was 318 ng/ml, its half-life was 5.66 h, and its area under the plasma concentration-time curve from 0 h to ∞ (AUC 0-∞ ) was 1,662 ng · h/ml. Coadministration of ranitidine, reduced the C max (−25.7%) and AUC 0-∞ (−15.8%) significantly. Sucralfate had no impact on the bioavailability of ABT-773.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.DIAGMICROBIO.2011.03.001
Abstract: The pharmacokinetics-pharmacodynamics (PK-PD) of fusidic acid were investigated against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pyogenes using in vitro infection models. Front-loaded and non-front-loaded fusidic acid dosing regimens were evaluated over 48 h using a 1-compartment infection model and over 240 h using a hollow fiber infection model (HFIM). All dosing regimens demonstrated initial decreases in bacterial density against both isolates in both in vitro models. A mechanism-based PK-PD model was developed to describe the effect of the concentration-time course of fusidic acid on the time course of MRSA in the in vitro infection model. With the use of this model and Monte Carlo simulation to evaluate the effect of different dosing regimens against MRSA, front-loaded [≥ 1200 mg every 12 h (Q12) × 2 doses followed by ≥ 600 mg Q12 h] compared to non-front-loaded (600 mg Q12 h) dosing regimens demonstrated better activity. HFIM data confirmed the effect of the front-loaded dosing regimens over 48 h and also demonstrated the suppression of growth of the total population and resistant subpopulations for MRSA over 96 and 120 h, respectively, associated with these dosing regimens.
Publisher: MDPI AG
Date: 02-02-2021
DOI: 10.3390/MICROORGANISMS9020307
Abstract: Chikungunya virus (CHIKV) is an alphavirus associated with a broad tissue tropism for which no antivirals or vaccines are approved. This study evaluated the antiviral potential of favipiravir (FAV), interferon-alpha (IFN), and ribavirin (RBV) against CHIKV as mono- and combination-therapy in cell lines that are clinically relevant to human infection. Cells derived from human connective tissue (HT-1080), neurons (SK-N-MC), and skin (HFF-1) were infected with CHIKV and treated with different concentrations of FAV, IFN, or RBV. Viral supernatant was s led daily and the burden was quantified by plaque assay on Vero cells. FAV and IFN were the most effective against CHIKV on various cell lines, suppressing the viral burden at clinically achievable concentrations although the degree of antiviral activity was heavily influenced by cell type. RBV was not effective and demonstrated substantial toxicity, indicating that it is not a feasible candidate for CHIKV. The combination of FAV and IFN was then assessed on all cell lines. Combination therapy enhanced antiviral activity in HT-1080 and SK-N-MC cells, but not in HFF-1 cells. We developed a pharmacokinetic harmacodynamic model that described the viral burden and inhibitory antiviral effect. Simulations from this model predicted clinically relevant concentrations of FAV plus IFN completely suppressed CHIKV replication in HT-1080 cells, and considerably slowed down the rate of viral replication in SK-N-MC cells. The model predicted substantial inhibition of viral replication by clinical IFN regimens in HFF-1 cells. Our results highlight the antiviral potential of FAV and IFN combination regimens against CHIKV in clinically relevant cell types.
Publisher: American Society for Microbiology
Date: 04-2015
DOI: 10.1128/AAC.04099-14
Abstract: Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-negative bacteria remains poorly characterized. Here, we developed a novel quantitative model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three Pseudomonas aeruginosa strains. At low-intermediate tobramycin concentrations ( mg/liter), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concentrations (≥8 mg/liter). The extent of killing was comparable across all inocula however, the rate of bacterial killing and growth was substantially lower at the 10 8.9 CFU/ml inoculum than that at the lower inocula. At 1 to 4 mg/liter tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quantitative model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens.
Publisher: Springer Science and Business Media LLC
Date: 11-11-2010
DOI: 10.1007/S00280-010-1502-Y
Abstract: The objectives of this study were to develop physiologically based models for the pharmacokinetics (PK) and organ distribution of apicidin in rats and mice and to predict human PK in blood and organs. The PK of apicidin was characterized in rats and mice after i.v. bolus injection, and distribution to various tissues was determined in rats following i.v. infusions at steady state. The developed models were prospectively validated within rat and within mouse and by scaling from rat to mouse using data after multiple i.v. injections. Human PK was predicted by the physiologically based modeling using intrinsic clearance data for humans from in vitro experiments. The Cl(s) predicted for human (9.8 ml/min/kg) was lower than those found in mice (116.9 ml/min/kg) and rats (61.6 ml/min/kg), and the V(ss) predicted for human (1.9 l/kg) was less than in mice (2.0 l/kg) and rats (2.5 l/kg). Consequently, the predicted t (1/2) was longer in human (2.3 h) than in mice and rats (0.4 and 0.9 h, respectively). The highest concentrations of apicidin were predicted in liver followed by adipose tissue, kidney, lung, spleen, heart, arterial blood, venous blood, small intestine, stomach, muscle, testis, and brain. The developed models adequately described the PK of apicidin in rats and mice and were applied to predict human PK. These models may be useful in predicting human blood and tissue concentrations of apicidin under different exposure conditions.
Location: United States of America
Location: Germany
Start Date: 2008
End Date: 2012
Funder: National Institute of Allergy and Infectious Diseases
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: U.S. Food and Drug Administration
View Funded ActivityStart Date: 2013
End Date: 2017
Funder: U.S. Food and Drug Administration
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: U.S. Food and Drug Administration
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: Florida Department of Health
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: U.S. Food and Drug Administration
View Funded ActivityStart Date: 2017
End Date: 2019
Funder: University of Florida
View Funded ActivityStart Date: 2014
End Date: 2019
Funder: National Institute of Allergy and Infectious Diseases
View Funded ActivityStart Date: 2017
End Date: 2017
Funder: College of Pharmacy
View Funded ActivityStart Date: 2014
End Date: 2014
Funder: National Research Foundation of Korea
View Funded ActivityStart Date: 2017
End Date: 2022
Funder: National Institute of Allergy and Infectious Diseases
View Funded ActivityStart Date: 2018
End Date: 2023
Funder: National Institute of Allergy and Infectious Diseases
View Funded ActivityStart Date: 2014
End Date: 2017
Funder: Australian Research Council
View Funded ActivityStart Date: 2012
End Date: 2014
Funder: Australian Research Council
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: Australian Research Council
View Funded ActivityStart Date: 2015
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 01-2012
End Date: 07-2015
Amount: $375,000.00
Funder: Australian Research Council
View Funded Activity