gyrA mutations and phenotypic susceptibility levels to ofloxacin and moxifloxacin in clinical isolates of Mycobacterium tuberculosis.

Abstract

OBJECTIVES:

To compare mutations in the quinolone resistance-determining region of the gyrA gene and flanking sequences with the MICs of ofloxacin and moxifloxacin for Mycobacterium tuberculosis.

METHODS:

The presence of mutations in 177 drug-resistant M. tuberculosis isolates was determined by DNA sequencing and the MICs quantified by MGIT 960.

RESULTS:

Single nucleotide polymorphisms were detected at codons 94 (n = 30), 90 (n = 12), 91 (n = 3), 89 (n = 1), 88 (n = 1) and 80 (n = 1). Four isolates with double mutations D94G plus A90V (n = 2) and D94G plus D94N (n = 2) reflect mixed populations. Agreement between genotypic and phenotypic susceptibility was high (≥97%) for both drugs. Mutant isolates had an MIC(50) of 8.0 mg/L and an MIC(90) of >10 mg/L for ofloxacin compared with an MIC(50) and MIC(90) of 2.0 mg/L for moxifloxacin. Codons 94 and 88 were linked to higher levels of fluoroquinolone resistance compared with codons 90, 91 and 89. The MIC distributions for the wild-type isolates ranged from ≤0.5 to 2.0 mg/L for ofloxacin and from ≤0.125 to 0.25 mg/L for moxifloxacin. However, 96% of the isolates with genetic alterations had MICs ≤2.0 mg/L for moxifloxacin, which is within its achievable serum levels.

CONCLUSIONS:

This study provides quantitative evidence that the addition of moxifloxacin to extensively drug-resistant tuberculosis (XDR-TB) regimens based on a clinical breakpoint of 2.0 mg/L has merit. The use of moxifloxacin in the treatment of multidrug-resistant tuberculosis may prevent the acquisition of additional mutations and development of XDR-TB.

• Authors: Frederick A Sirgel, Robin M Warren, Elizabeth M Streicher, Thomas C Victor, Paul D van Helden, Erik C Böttger
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 67 Issue 5 Pg. 1088-93 (May 2012) ISSN: 1460-2091 [Electronic] England
• PMID: 22357804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Aza Compounds
• Fluoroquinolones
• Quinolines
• Ofloxacin
• DNA Gyrase
• Moxifloxacin

Topics

• Antitubercular Agents (pharmacology)
• Aza Compounds (pharmacology)
• DNA Gyrase (genetics)
• Drug Resistance, Bacterial
• Fluoroquinolones
• Humans
• Microbial Sensitivity Tests
• Moxifloxacin
• Mutation, Missense
• Mycobacterium tuberculosis (drug effects, genetics)
• Ofloxacin (pharmacology)
• Polymorphism, Single Nucleotide
• Quinolines (pharmacology)