Monte Carlo simulation evaluation of tigecycline dosing for bacteria with raised minimum inhibitory concentrations in non-critically ill adults

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 (AUC_{total, 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 AUC_{total, 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 AUC_{total, 0-24h}/MIC target, may require treatment with alternate antibiotics due to target attainment failure.

Keywords: Monte Carlo simulation; Non-critically ill patients; Pharmacodynamic(s); Pharmacokinetic(s); Resistant gram-negative bacteria; Tigecycline.