title: Correlation between GyrA substitutions and ofloxacin, levofloxacin, and moxifloxacin cross-resistance in Mycobacterium tuberculosis.
abstract: The newer fluoroquinolones moxifloxacin (MXF) and levofloxacin (LVX) are becoming more common components of tuberculosis (TB) treatment regimens. However, the critical concentrations for testing susceptibility of Mycobacterium tuberculosis to MXF and LVX are not yet well established. Additionally, the degree of cross-resistance between ofloxacin (OFX) and these newer fluoroquinolones has not been thoroughly investigated. In this study, the MICs for MXF and LVX and susceptibility to the critical concentration of OFX were determined using the agar proportion method for 133 isolates of M. tuberculosis. Most isolates resistant to OFX had LVX MICs of >1 μg/ml and MXF MICs of >0.5 μg/ml. The presence of mutations within the gyrA quinolone resistance-determining regions (QRDR) correlated well with increased MICs, and the level of LVX and MXF resistance was dependent on the specific gyrA mutation present. Substitutions Ala90Val, Asp94Ala, and Asp94Tyr resulted in low-level MXF resistance (MICs were >0.5 but ≤2 μg/ml), while other mutations led to MXF MICs of >2 μg/ml. Based on these results, a critical concentration of 1 μg/ml is suggested for LVX and 0.5 μg/ml for MXF drug susceptibility testing by agar proportion with reflex testing for MXF at 2 μg/ml.
authors.affiliation: Laboratory Branch, Division of TB Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Melisa
authors.initials: M
authors.lastname: Willby
authors.affiliation: Laboratory Branch, Division of TB Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: R David
authors.initials: RD
authors.lastname: Sikes
authors.affiliation: Laboratory Branch, Division of TB Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Seidu
authors.initials: S
authors.lastname: Malik
authors.affiliation: Laboratory Branch, Division of TB Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Beverly
authors.initials: B
authors.lastname: Metchock
authors.affiliation: Laboratory Branch, Division of TB Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA jposey@cdc.gov.
authors.forename: James E
authors.initials: JE
authors.lastname: Posey
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000494:pharmacology*; D064704:Levofloxacin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D064704:Levofloxacin; D027081:DNA Gyrase; D000077266:Moxifloxacin