Background: Moxifloxacin, a later-generation quinolone, is currently undergoing evaluation in clinical trials for use as first-line antituberculous agent. Human and animal data suggest that there is cross resistance among various quinolones and that quinolone-resistance in Mycobacterium tuberculosis (MTB) isolates can affect the efficacy of the treatment. There are no published systematic analyses of the prevalence of resistance to moxifloxacin or other quinolones in MTB clinical isolates in the general population. Moreover, data suggest that mutations in the QRDR region of the gyrA gene account for only 42-85% of quinolone drug resistance in MTB isolates, suggesting that mutations outside the QRDR or in other genes play a role in quinolone resistance in MTB.
Specific Aims : 1) To analyze the prevalence of MTB strains with reduced susceptibility to moxifloxacin, levofloxacin and ofloxacin in MTB clinical isolates from Houston, Harris County over 24 months and 2) To identify mutations in the gyrA, gyrB and Rv2686c- Rv2687c-Rv2688c genes that are associated with reduced susceptibility to the studied quinolones. Methods: As part of the tuberculosis control efforts in the city, >95% of MTB clinical isolates from Houston, Harris County are sent to the Texas State Department of Health Services. We will prospectively test all MTB clinical isolates for resistance to isoniazid, rifampin, ethambutol, ofloxacin, levofloxacin and moxifloxacin over a 24-month period, using the agar proportion indirect susceptibility method. We will extract the DNA from MTB isolates with reduced susceptibility to quinolones and a matched number of quinolone susceptible isolates to compare the sequences of the gyrA, gyrB and Rv2686c-Rv2687c-Rv2688c genes; genes of putative or demonstrated role in susceptibility to quinolones. Results/data: The study results will be presented as data on the prevalence of MTB moxifloxacin resistance and its correlation with resistance to first-line anti-TB drugs and other quinolones. Mutations associated with quinolone resistance in MTB will be identified. The data will represent the first comprehensive analysis of the prevalence of quinolone drug resistance in MTB isolates and its genetic mechanisms in the general population. In October 2005, TB Alliance (Global Alliance for tuberculosis (TB) drug development) and Bayer Pharmaceuticals announced plans to study moxifloxacin in clinical trials aiming at shortening the length of TB treatment regimens, after decades of exceedingly slow TB drug development. Resistance to moxifloxacin in TB can potentially reduce the effectiveness of its inclusion in TB drug regimens, and the medical literature lacks systemic data on how prevalent moxifloxacin resistance in Mycobacterium tuberculosis (MTB) is. We propose to systematically study the prevalence of moxifloxacin drug resistance in MTB strains collected from patients in Houston, Harris County over a period of 24 months, thus providing data that can be used as a too to help design better treatment regimens and provide the basis for future monitoring and research on the topic of quinolone drug resistance in MTB. ? ? ?
| El Sahly, Hana M; Teeter, Larry D; Jost Jr, Kenneth C et al. (2011) Incidence of moxifloxacin resistance in clinical Mycobacterium tuberculosis isolates in Houston, Texas. J Clin Microbiol 49:2942-5 |
