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



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).



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 C max and AUC were 5.4 mg/L and 16.2 mg·h/L, respectively, and MIC for Mtb H37Rv was 5-10 mg/L.



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.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Meera
M
Gurumurthy
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Rupangi
R
Verma
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Claire M
CM
Naftalin
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Kim Hor
KH
Hee
Singapore Clinical Research Institute, Singapore.
Qingshu
Q
Lu
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Kin Hup
KH
Tan
Dean's Office (BSL3 Core Facility), Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Simi
S
Issac
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Wenwei
W
Lin
Investigational Medicine Unit, National University Health System, Singapore.
Angelia
A
Tan
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Kok-Yong
KY
Seng
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Lawrence Soon-U
LS
Lee
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Nicholas I
NI
Paton
D000328:Adult; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D015610:Serum Bactericidal Test; D055815:Young Adult; D047090:beta-Lactams / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D047090:beta-Lactams; D019980:Amoxicillin-Potassium Clavulanate Combination; C107057:fropenem; D012293:Rifampin