Moxifloxacin replacement in contemporary tuberculosis drug regimens is ineffective against persistent Mycobacterium tuberculosis : in the Cornell mouse model
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Tuberculosis (TB), which is caused by Mycobacterium tuberculosis, remains a leading killer worldwide, and disease control is hampered by the ineffective control of persistent infections. Substitution of moxifloxacin for isoniazid or ethambutol in standard anti-TB regimens reduces the treatment duration and relapse rates in animal studies, and 4-month regimens were not noninferior in clinical trials. Resuscitation-promoting factor (RPF)-dependent bacilli have recently been implicated in M. tuberculosis persistence. We aimed to investigate the therapeutic effects of the substitution of moxifloxacin for a drug used in the standard drug regimen in eradicating CFU count-positive and RPF-dependent persistent M. tuberculosis using the Cornell murine model. M. tuberculosis-infected mice were treated with regimens in which either isoniazid or ethambutol was replaced by moxifloxacin in the standard regimen. The efficacy of the regimens for bacterial CFU count elimination and removal of persistent tubercle bacilli, evaluated using culture filtrate (CF) derived from M. tuberculosis strain H37Rv, was compared to that of the standard regimen. We also measured disease relapse rates. The regimen in which moxifloxacin replaced isoniazid achieved total organ CFU count clearance at 11 weeks posttreatment, which was faster than that by the standard regimen (14 weeks), and showed a 34% lower relapse rate. The regimen in which moxifloxacin replaced ethambutol was similar to standard regimens in these regards. Importantly, neither the regimen in which moxifloxacin replaced isoniazid or ethambutol nor the standard regimen could remove CF-dependent persistent bacilli. The finding of CF-dependent persistent M. tuberculosis in TB treatment requires confirmation in human studies and has implications for future drug design, testing, and clinical applications.
Liu , Y , Pertinez , H , Davies , G R , Gillespie , S H , Coates , A R & Hu , Y 2018 , ' Moxifloxacin replacement in contemporary tuberculosis drug regimens is ineffective against persistent Mycobacterium tuberculosis : in the Cornell mouse model ' , Antimicrobial Agents and Chemotherapy , vol. 62 , no. 7 , e00190-18 . https://doi.org/10.1128/AAC.00190-18
Antimicrobial Agents and Chemotherapy
© 2018, American Society for Microbiology. This work has been made available online in accordance with the publisher’s policies. This is the final published version of the work, which was originally published at https://doi.org/10.1128/AAC.00190-18
DescriptionThis work was supported by the Innovative Medicines Initiative Joint Undertaking resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution (grant number 115337). The financial support of MRC (MR/P011144/1) is gratefully acknowledged.
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