Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Gumbo
Tawanda
T
Emerging Infections and Host Defense Section, Ordway Research Institute, Albany, New York 12208, USA.
Louie
Arnold
A
Deziel
Mark R
MR
Parsons
Linda M
LM
Salfinger
Max
M
Drusano
George L
GL
D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001372:Aza Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin