Impact of Fluoroquinolone Resistance on Bactericidal and Sterilizing Activity of a Moxifloxacin-Containing Regimen in Murine Tuberculosis

Abstract

It has been shown previously that fluoroquinolone resistance (defined by resistance to at least 2 mg/liter ofloxacin) has a different impact on moxifloxacin monotherapy depending on the mutation in the sole fluoroquinolone target in Mycobacterium tuberculosis, i.e., DNA gyrase. Since tuberculosis treatment relies on multidrug therapy, we wished to determine the impact of fluoroquinolone resistance on the bactericidal and sterilizing activity of a second-line antituberculous regimen containing moxifloxacin. A total of 280 mice were inoculated with the wild-type Mycobacterium tuberculosis H37Rv strain or one of 3 isogenic fluoroquinolone-resistant mutant strains with increasing moxifloxacin resistance (the GyrB D500N, GyrA A90V, and GyrA D94G strains) and then treated for 6 months with a second-line regimen containing moxifloxacin, pyrazinamide, and ethionamide supplemented with amikacin during the first 2 months. Mice were sacrificed during treatment for measurement of bactericidal activity and 3 months after treatment completion for measurement of relapse rates (sterilizing activity). The CFU counts decreased faster in mice inoculated with the wild type than in mice inoculated with the mutant strains. The relapse rate after treatment completion was different among mice inoculated with mutant strains in relation to the drug resistance level: wild type, 0%; GyrB D500N strain, 33%; GyrA A90V strain, 50%; and GyrA D94G strain, 86%. The relapse rate observed with the GyrB D500N strain was the only one not statistically different from that observed with the wild-type strain. We demonstrated that the impact on sterilizing activity of the most active second-line drug regimen containing moxifloxacin depends on the MIC of moxifloxacin. We suggest that the precise level of moxifloxacin resistance be determined for all strains resistant to 2 mg/liter ofloxacin.

A Comparison of the Sensititre MycoTB Plate, the Bactec MGIT 960, and a Microarray-Based Molecular Assay for the Detection of Drug Resistance in Clinical Mycobacterium tuberculosis Isolates in Moscow, Russia

“…In this model, the sterilizing activity of MFX against the low-level resistant strain with GyrB D500N was nearly the same as the sterilizing activity against the wild-type strain; however, relapse was observed in 30% of the cases [40]. In our set of isolates, the gyrB substitutions D500H and N538K led to moderately increased MICs for both OFX and MFX, confirming previous findings [41].…”

Risk Factors for Acquisition of Drug Resistance during Multidrug-Resistant Tuberculosis Treatment, Arkhangelsk Oblast, Russia, 2005–2010

“…The treatment and patient management characteristics that were associated with acquired ofloxacin resistance may be an artifact of clinical management practices when treatment regimens fail and probably reflect confounding. The treatment for severe disease or a failing regimen will often be switched to a newer generation fluoroquinolone because these are thought to be more effective and because cross-resistance within the class is not complete ( 32 , 33 ). Therefore, the only significant risk factor for acquired ofloxacin resistance in this population was being underweight, which is a risk factor for incident TB and an indicator of disease severity, regardless of drug susceptibility ( 34 ).…”

Moxifloxacin resistance in the F15/LAM4/KZN extensively drug-resistant strain of Mycobacterium tuberculosis

“…As per the WHO definition, these are classified as MXF-resistant, and this implies that MXF should not be recommended for treatment of cases harboring such isolates. However, there are reports of MXF efficacy in isolates with MXF MICs <2 mg/L 3,4,6,10,19…”

“…Mice infected with strains with MXF MICs of 0.5 mg/L and 4 mg/L recorded relapse rates of 50% and 86%, respectively, compared to the wild type. 10 …”

“…Additionally, double mutations in the gyrA or concomitant gyrA and gyrB mutations have been reported 6,8. The level of fluoroquinolone resistance is dependent on the mutation in the resistance-conferring gene and the fluoroquinolone tested 10. Studies have demonstrated that MIC levels of resistant isolates are higher for older-generation fluoroquinolones than for MXF 6–9…”