Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis

Rijn, van Sander; Zuur, Marlanka A; Altena, Richard van; Akkerman, Onno W.; Proost, Johannes H.; Lange, D; Kerstjens, Huib A. M.; Touw, Daan; Werf, van der Tjipke; Kosterink, Jos G. W.; Alffenaar, Jan-Willem

doi:10.1128/aac.01783-16

Cited by 9 publications

(5 citation statements)

References 27 publications

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“…The pharmacokinetic model composed in this study was shown to adequately predict ertapenem exposure in MDR-TB patients. The Monte Carlo simulation, which had a time restriction of 0 to 6 h, showed that the best-performing limited sampling strategy was at 1 and 5 h after intravenous injection (60). In another pharmacokinetic model study using prospective data from 12 TB patients, it was observed that 2 g ertapenem once daily resulted in more than a dose-proportional increase in AUC compared to the results for 1 g ertapenem once daily.…”

Section: Meropenemmentioning

confidence: 99%

Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis

Rijn

Zuur

Anthony

et al. 2019

Antimicrob Agents Chemother

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Multi- and extensively drug-resistant tuberculosis (M/XDR-TB) has become an increasing threat not only in countries where the TB burden is high but also in affluent regions, due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of Mycobacterium tuberculosis. To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo, and clinical data on carbapenems in the treatment of M. tuberculosis and to detect knowledge gaps, in order to target future research. In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall, the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and laboratory strains of M. tuberculosis, are consistent. In vitro, the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore, it is impossible in practice to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, including one prospective, two observational, and seven retrospective clinical studies to assess the effectiveness, safety, and tolerability of three different carbapenems (imipenem, meropenem, and ertapenem). We found no clear evidence at the present time to select one particular carbapenem among the different candidate compounds to design an effective M/XDR-TB regimen. Therefore, more clinical evidence and dose optimization substantiated by hollow-fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.

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Section: Meropenemmentioning

confidence: 99%

Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis

Rijn

Zuur

Anthony

et al. 2019

Antimicrob Agents Chemother

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“…Aside from the work described herein, to our knowledge, only three other groups previously utilized nonlinear functions to characterize ertapenem protein binding when conducting ertapenem PK-PD target attainment analyses (30)(31)(32). Additional strengths of these analyses were the utilization of a population PK model which included formally selected covariates and the evaluation of effect-site exposures for patients with HABP/VABP (i.e., ELF AUC values), two considerations which appear to be absent in the available literature describing ertapenem PK-PD target attainment analyses (30)(31)(32)(33)(34)(35)(36)(37). The former consideration allowed for the evaluation of simulated exposures which accounted for the impact of body size and renal function on ertapenem PK.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

Bader

Lakota

Dale

et al. 2019

Antimicrob Agents Chemother

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Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa. A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%TϾMIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %TϾMIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 g/ml, respectively (MIC 90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/ VABP.

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“…Adapted TCI uses Bayesian forecasting to individualize dosing regimens based on TDM data. Approaches using more traditional PK modeling software have been described by others in the field of antibiotic [ 43 , 44 ], antifungal [ 45 , 46 ] and antiviral therapy [ 47 ]. Although aTCI and more traditional TDM software use a similar theoretical framework for dosage individualisation, aTCI has some advantages.…”

Section: Discussionmentioning

confidence: 99%

Target-Controlled Continuous Infusion for Antibiotic Dosing: Proof-of-Principle in an In-silico Vancomycin Trial in Intensive Care Unit Patients

2018

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ObjectivesIn this in-silico study, we investigate the clinical utility of target-controlled infusion for antibiotic dosing in an intensive care unit setting using vancomycin as a model compound. We compared target-controlled infusion and adaptive target-controlled infusion, which combines target-controlled infusion with data from therapeutic drug monitoring, with conventional (therapeutic drug monitoring-based) vancomycin dosing strategies.MethodsA clinical trial simulation was conducted. This simulation was based on a comprehensive database of clinical records of intensive care unit patients and a systematic review of currently available population-pharmacokinetic models for vancomycin in intensive care unit patients. Dosing strategies were compared in terms of the probability of achieving efficacious concentrations as well as the potential for inducing toxicity.ResultsAdaptive target-controlled infusion outperforms rule-based dosing guidelines for vancomycin. In the first 48 h of treatment, the probability of target attainment is significantly higher for adaptive target-controlled infusion than for the second-best method (Cristallini). Probability of target attainments of 54 and 72% and 47 and 59% for both methods after 24 and 48 h, respectively. Compared to the Cristallini method, which is characterized by a probability of attaining concentrations above 30 mg.L−1 > 65% in the first few hours of treatment, adaptive target-controlled infusion shows negligible time at risk and a probability of attaining concentrations above 30 mg.L−1 not exceeding 25%. Finally, in contrast to the other methods, the performance of target-controlled infusion is consistent across subgroups within the population.ConclusionsOur study shows that adaptive target-controlled infusion has the potential to become a practical tool for patient-tailored antibiotic dosing in the intensive care unit.Electronic supplementary materialThe online version of this article (10.1007/s40262-018-0643-8) contains supplementary material, which is available to authorized users.

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Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis

Cited by 9 publications

References 27 publications

Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis

Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

Target-Controlled Continuous Infusion for Antibiotic Dosing: Proof-of-Principle in an In-silico Vancomycin Trial in Intensive Care Unit Patients

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