title: Carbapenems and Rifampin Exhibit Synergy against Mycobacterium tuberculosis and Mycobacterium abscessus.
abstract: An effective regimen for treatment of tuberculosis (TB) is comprised of multiple drugs that inhibit a range of essential cellular activities in Mycobacterium tuberculosis. The effectiveness of a regimen is further enhanced if constituent drugs act with synergy. Here, we report that faropenem (a penem) or biapenem, doripenem, or meropenem (carbapenems), which belong to the β-lactam class of antibiotics, and rifampin, one of the drugs that forms the backbone of TB treatment, act with synergy when combined. One of the reasons (carba)penems are seldom used for treatment of TB is the high dosage levels required, often at the therapeutic limits. The synergistic combination of rifampin and these (carba)penems indicates that (carba)penems can be administered at dosages that are therapeutically relevant. The combination of faropenem and rifampin also limits the frequency of resistant mutants, as we were unable to obtain spontaneous mutants in the presence of these two drugs. The combinations of rifampin and (carba)penems were effective not only against drug-sensitive Mycobacterium tuberculosis but also against drug-resistant clinical isolates that are otherwise resistant to rifampin. A combination of doripenem or biapenem and rifampin also exhibited synergistic activity against Mycobacterium abscessus. Although the MICs of these three drugs alone against M. abscessus are too high to be of clinical relevance, their concentrations in combinations are therapeutically relevant; therefore, they warrant further evaluation for clinical utility to treat Mycobacterium abscessus infection, especially in cystic fibrosis patients.
authors.affiliation: Taskforce to Study Resistance Emergence & Antimicrobial Development Technology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Kaushik
authors.affiliation: Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Nayani
authors.initials: N
authors.lastname: Makkar
authors.affiliation: Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Pooja
authors.initials: P
authors.lastname: Pandey
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Parrish
authors.affiliation: Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Urvashi
authors.initials: U
authors.lastname: Singh
authors.affiliation: Taskforce to Study Resistance Emergence & Antimicrobial Development Technology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA lamichhane@jhu.edu.
authors.forename: Gyanu
authors.initials: G
authors.lastname: Lamichhane
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D000077726:Doripenem; D004357:Drug Synergism; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D015780:Carbapenems; D013845:Thienamycins; D047090:beta-Lactams; D000077726:Doripenem; C107057:fropenem; D000077731:Meropenem; D012293:Rifampin; C065257:biapenem