In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis

Background: Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis. Objectives: Our objective was to evaluate the synergy of biapenem/rifampicin against both low-and high-level rifampicin-resistant strains of M. tuberculosis, in vitro and in the mouse model. Methods: Biapenem/rifampicin activity was evaluated using three strains of M. tuberculosis: strain 115R (low-level rifampicin resistance); strain 124R (high-level rifampicin resistance); and the drug-susceptible H37Rv parent strain. Biapenem/rifampicin synergy was evaluated in vitro by chequerboard titration. In vivo, we first conducted a dose-ranging experiment with biapenem against H37Rv in the mouse model. We then evaluated biapenem/rifampicin activity in mice infected with each M. tuberculosis strain. Results: In vitro, synergy was observed between biapenem and rifampicin against H37Rv and strain 115R. In vivo, biapenem exhibited clear dose-dependent activity against H37Rv, with all biapenem doses as active or more active than rifampicin alone. Biapenem and rifampicin had synergistic bactericidal activity against H37Rv in the mouse model; no synergy was observed in mice infected with either of the rifampicin-resistant strains. Biapenem alone was active against all three strains. Conclusions: Our preclinical experiments indicate that biapenem has potential for use as an anti-TB drug, including for use against rifampicin-resistant TB. Thus, biapenem has promise for repurposing as a 'new' -and desperately needed -drug for the treatment of drug-resistant TB.