Comparison of the sterilising activities of the nitroimidazopyran PA-824 and moxifloxacin against persisting Mycobacterium tuberculosis.
OBJECTIVE
To measure the bactericidal activity of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis, strain H37Rv, in the three Hu/Coates models of bacterial persistence, in comparison with the activity of moxifloxacin (MXF), a drug shown to be likely to shorten treatment in current clinical trials.


METHODS
The bactericidal activity of a wide range of PA-824 and MXF concentrations was tested against a 100-day static, starved, anaerobically-adapted culture in Model 1. In Models 2 and 3, rifampicin (RMP) 100 mg/ml was added to the 100-day culture for 5-7 days and bactericidal activities against surviving tolerant bacilli were tested by addition of the test drugs after removal of RMP in Model 2, and during exposure to RMP in Model 3.


CONCLUSIONS
PA-824 exhibited little bactericidal activity at low concentrations up to 1.25 microg/ml in each of these models, but high concentrations of >or=10 microg/ml showed considerable bactericidal activity, sufficient to kill all bacilli in Model 3, and appreciably greater than with MXF. However, as PA-824 is 94% plasma bound, concentrations of free drug sufficient to reach the zone of high bactericidal activity may not be obtained in cavities of pulmonary tuberculosis.
Hu
Y
Y
Medical Microbiology, Department of Cellular & Molecular Medicine, St George's Hospital, University of London, London, United Kingdom.
Coates
A R M
AR
Mitchison
D A
DA
D000995:Antitubercular Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D024841:Fluoroquinolones; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D009593:Nitroimidazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D013997:Time Factors
D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D009593:Nitroimidazoles; D011804:Quinolines; C410767:pretomanid; D000077266:Moxifloxacin