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

Amit Kaushik, Nicole C. Ammerman, Rokeya Tasneen, Elizabeth Story-Roller, Kelly E. Dooley, Susan E. Dorman, Eric L. Nuermberger, Gyanu Lamichhane

Research output: Contribution to journalArticle

Abstract

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, biapenemhas promise for repurposing as a 'new' - and desperately needed - drug for the treatment of drug-resistant TB.

Original languageEnglish (US)
Article numberdkx152
Pages (from-to)2320-2325
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Volume72
Issue number8
DOIs
StatePublished - Aug 1 2017

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Rifampin
Mycobacterium tuberculosis
In Vitro Techniques
Carbapenems
Drug Therapy

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis. / Kaushik, Amit; Ammerman, Nicole C.; Tasneen, Rokeya; Story-Roller, Elizabeth; Dooley, Kelly E.; Dorman, Susan E.; Nuermberger, Eric L.; Lamichhane, Gyanu.

In: Journal of Antimicrobial Chemotherapy, Vol. 72, No. 8, dkx152, 01.08.2017, p. 2320-2325.

Research output: Contribution to journalArticle

Kaushik, Amit; Ammerman, Nicole C.; Tasneen, Rokeya; Story-Roller, Elizabeth; Dooley, Kelly E.; Dorman, Susan E.; Nuermberger, Eric L.; Lamichhane, Gyanu / In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis.

In: Journal of Antimicrobial Chemotherapy, Vol. 72, No. 8, dkx152, 01.08.2017, p. 2320-2325.

Research output: Contribution to journalArticle

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abstract = "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, biapenemhas promise for repurposing as a 'new' - and desperately needed - drug for the treatment of drug-resistant TB.",
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