Assessment of the additional value of verapamil to a moxifloxacin and linezolid combination regimen in a murine tuberculosis model. [PublishAheadOfPrint]

Favorable treatment outcome of multidrug resistant tuberculosis (MDR-TB) is only 54% and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the additional value of the efflux-pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug sensitive Mycobacterium tuberculosis and were treated with human-equivalent doses of moxifloxacin (200 mg/kg) and linezolid (100 mg/kg) with or without verapamil (12.5 mg/kg) for 12 weeks. Pharmacokinetic parameters were collected during treatment at steady state. After 12 weeks of treatment, a statistically significant decline in mycobacterial load in the lungs was observed with the moxifloxacin-linezolid regimen with and without verapamil (5.9 and 5.0 Log colony forming units, respectively), but sterilization was not achieved yet. The spleens of all mice were culture-negative after 12 weeks of treatment with both treatment modalities and the addition of verapamil caused a significant reduction in relapse (14/14 positive spleens without versus 9/15 with verapamil, p=0.017).

Concluding, treatment with a combination regimen of moxifloxacin and linezolid showed a strong decline in mycobacterial load in the mice. The addition of verapamil to this backbone had a modest additional effect in terms of reducing mycobacterial load in the lung as well as reducing spleen relapse rate. These results warrant further studies on the role of efflux pump inhibition in improving the efficacy of MDR-TB backbone regimens.

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