Selection of a Moxifloxacin Dose That Suppresses Drug Resistance in<i>Mycobacterium tuberculosis,</i>by Use of an In Vitro Pharmacodynamic Infection Model and Mathematical Modeling

TLDR

Moxifloxacin is a potent quinolone antibiotic effective against *Mycobacterium tuberculosis*. The study seeks to identify pharmacodynamic exposure targets that maximize microbial kill and fully suppress resistance to optimize moxifloxacin dosing. Using a human‑PK‑matched in vitro TB infection model, the authors mathematically modeled drug exposure to determine a suppression breakpoint and performed Monte Carlo simulations to estimate the probability of achieving this breakpoint across patients. Target attainment rates for 400, 600, and 800 mg/day were 59%, 86%, and 93% respectively, indicating that 800 mg/day is likely to achieve optimal kill and resistance suppression, though its tolerability remains uncertain.

Abstract

Moxifloxacin is a quinolone antimicrobial that has potent activity against Mycobacterium tuberculosis. To optimize moxifloxacin dose and dose regimen, pharmacodynamic antibiotic-exposure targets associated with maximal microbial kill and complete suppression of drug resistance in M. tuberculosis must be identified.We used a novel in vitro pharmacodynamic infection model of tuberculosis in which we exposed M. tuberculosis to moxifloxacin with a pharmacokinetic half-life of decline similar to that encountered in humans. Data obtained from this model were mathematically modeled, and the drug-exposure breakpoint associated with the suppression of drug resistance was determined. Monte-Carlo simulations were performed to determine the probability that 10,000 clinical patients taking different doses of moxifloxacin would achieve or exceed the drug-exposure breakpoint needed to suppress resistance to moxifloxacin in M. tuberculosis.The ratio of the moxifloxacin-free (non-protein-bound) area under the concentration-time curve from 0 to 24 h to the minimum inhibitory concentration associated with complete suppression of the drug-resistant mutant population was 53. For patients taking moxifloxacin doses of 400, 600, or 800 mg/day, the calculated target-attainment rates to suppress drug resistance were 59%, 86%, and 93%, respectively.A moxifloxacin dose of 800 mg/day is likely to achieve excellent M. tuberculosis microbial kill and to suppress drug resistance. However, tolerability of this higher dose is still unknown.