Monte Carlo simulation evaluation of tigecycline dosing for bacteria with raised minimum inhibitory concentrations in no
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PHARMACOKINETICS AND DISPOSITION
Monte Carlo simulation evaluation of tigecycline dosing for bacteria with raised minimum inhibitory concentrations in non-critically ill adults Brianna Kispal 1,2 & Sandra A. N. Walker 1,3 Received: 17 July 2020 / Accepted: 14 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Tigecycline is one of few antibiotics active against multidrug-resistant bacteria; however, the assessment of dosing strategies to optimize its activity is needed. The purpose was to use Monte Carlo Simulation (MCS) to determine if safe tigecycline dosing options attaining breakpoints for pharmacokinetic/pharmacodynamic (PK-PD) targets in non-critically ill adults could be identified. Methods Publications that evaluated tigecycline dosing regimens and provided mean PK variables of interest (minimum 2 of: elimination rate constant or half-life and volume of distribution or clearance), with SDs, were included. Weighted mean (±SDs) for each PK parameter were determined. Food and Drug Administration minimum inhibitory concentration (MIC) tigecycline breakpoints for susceptible (MIC ≤ 2 μg/mL), intermediate (MIC 4 μg/mL), and resistant (MIC ≥ 8 μg/mL) Enterobacteriaceae were used. MCS probability distributions for PK-PD target attainment of AUC for total tigecycline plasma concentration from 0 to 24 h following an intravenous dose (AUCtotal, 0-24h) to MIC ratios of ≥ 18, 7, and 4.5 were generated, with success defined as ≥ 80% probability of target attainment at a given MIC. Results Ten studies (n = 442) were eligible. Tigecycline 150 mg IV q12h for ward patients with resistant bacteria up to a MIC of 0.48, 1, and 2 μg/mL for an AUCtotal, 0-24h/MIC target attainment of 18, 7, and 4.5, respectively, may be appropriate. Conclusion Bacterial infections with tigecycline MICs ≥ 0.48–2 μg/mL, depending on AUCtotal, 0-24h/MIC target, may require treatment with alternate antibiotics due to target attainment failure. Keywords Tigecycline . Monte Carlo simulation . Resistant gram-negative bacteria . Non-critically ill patients . Pharmacokinetic(s) . Pharmacodynamic(s)
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-02998-7) contains supplementary material, which is available to authorized users. * Sandra A. N. Walker [email protected] Brianna Kispal [email protected] 1
Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, Ontario M5S 3M2, Canada
2
Present address: Department of Pharmacy, Kingston General Hospital, 76 Stuart St, Kingston, Ontario K7L 2V7, Canada
3
Department of Pharmacy Bayview Campus, Sunnybrook Health Sciences Center (SHSC), 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada
Worldwide, over 700,000 patients die annually from infections caused by multidrug resistant (MDR) pathogens (resistance to 3 or more potentially useful antibiotics), with millions more suffering from serious complications [1]. By 2050, an estimated 10 million patie
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