Activity of faropenem with and without rifampicin against Mycobacterium tuberculosis: evaluation in a whole-blood bactericidal activity trial

Abstract

Background: Faropenem has in vitro activity against Mycobacterium tuberculosis (Mtb) and shows synergy with rifampicin.We tested this in a whole-blood bactericidal activity (WBA) trial. Methods: We randomized healthy volunteers to receive a single oral dose of faropenem (600 mg) with amoxicillin/ clavulanic acid (500/125 mg) (n=8), rifampicin (10 mg/kg) (n=14) or the combination rifampicin+ faropenem+amoxicillin/clavulanic acid (n=14). Blood was drawn at intervals to 8 h post-dose. Drug levels were measured using LC-tandem MS. WBA was measured by inoculating blood samples with Mtb and estimating the change in bacterial cfu after 72 h. Trial registration: ClinicalTrials.gov (NCT02393586). Results: There was no activity in the faropenem+amoxicillin/clavulanic acid group (cumulative WBA 0.02 Δlog cfu; P=0.99 versus zero change). There was a suggestion of a trend favouring the rifampicin+faropenem+amoxicillin/clavulanic acid group at 8 h (cumulative WBA -0.19±0.03 and -0.26±0.03 Δlog cfu in the rifampicin and rifampicin+faropenem+amoxicillin/clavulanic acid groups, respectively; P=0.180), which was significant in the first hour post-dose (P=0.032). Faropenem Cmax and AUC were 5.4 mg/L and 16.2mg·h/L, respectively, and MIC for Mtb H37Rv was 5-10 mg/L. Conclusions: Faropenem is not active when used alone, possibly due to inadequate plasma levels relative to MIC. However, there was a suggestion of modest synergy with rifampicin that may merit further testing in clinical trials.