title: Should moxifloxacin be used for the treatment of extensively drug-resistant tuberculosis? An answer from a murine model.
abstract: The prevalence of extensively drug-resistant tuberculosis (XDR-TB), defined as TB that is resistant to isoniazid, rifampin, fluoroquinolones, and aminoglycosides, is rising worldwide. The extent of Mycobacterium tuberculosis resistance to fluoroquinolones depends on the mutation in the DNA gyrase, the only target of fluoroquinolones. The MIC of moxifloxacin, the most active fluoroquinolone against M. tuberculosis, may be lower than its peak serum level for some ofloxacin-resistant strains of Mycobacterium tuberculosis. Therefore, if the MIC of moxifloxacin is lower than its peak serum level, it may be effective against XDR-TB. Our objective was to determine the efficacy of moxifloxacin in treating ofloxacin-resistant TB. We selected isogenic fluoroquinolone-resistant mutants of M. tuberculosis H37Rv in vivo. We infected Swiss mice with either wild-type H37Rv or one of three mutant strains with different MICs that are commonly seen in clinical practice. The MICs of the mutant strains ranged from below to above the peak moxifloxacin level seen in humans (3 μg/ml). Each mouse was treated with one of four moxifloxacin doses for 1 month. Moxifloxacin was effective against mutant strain GyrB D500N, with the lowest MIC (0.5 μg/ml), when the standard dose was doubled. Moxifloxacin reduced mortality in mice infected with mutant strain GyrA A90V with an intermediate MIC (2 μg/ml). However, it had no impact on the mutant strain GyrA D94G with the highest MIC (4 μg/ml). Our study underscores current WHO recommendations to use moxifloxacin when there is resistance to early-generation fluoroquinolones such as ofloxacin, restricting this recommendation to strains with moxifloxacin MICs of less than or equal to 2 μg/ml.
authors.affiliation: Laboratoire de Bactériologie-Hygiène, Faculté de Médecine, Pierre et Marie Curie Université Paris, 91 Boulevard de l'hôpital, Paris Cedex 13, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Poissy
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aubry
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Lott
authors.forename: Aurelie
authors.initials: A
authors.lastname: Chauffour
authors.forename: Vincent
authors.initials: V
authors.lastname: Jarlier
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Nicolas
authors.initials: N
authors.lastname: Veziris
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001372:Aza Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D027081:DNA Gyrase / Q000235:genetics; D015365:Enoxacin / Q000627:therapeutic use; D024841:Fluoroquinolones / Q000627:therapeutic use; D000077734:Gatifloxacin; D051379:Mice; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D015242:Ofloxacin / Q000627:therapeutic use; D011804:Quinolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014376:Tuberculosis / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D015365:Enoxacin; D015242:Ofloxacin; D027081:DNA Gyrase; D000077734:Gatifloxacin; D000077266:Moxifloxacin
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