Aim:The objective of this study was to assess if avibactam, a new β-lactamase inhibitor, can restore the potency of carbapenems, a sub-class of β-lactams, against Mycobacterium abscessus clinical isolates. Materials & methods: 28 M. abscessus clinical isolates that are resistant to multiple drugs currently used to treat its infection were included. MIC of carbapenems alone and in combination with avibactam against these strains were determined. Results: Tebipenem, an oral carbapenem, and ertapenem and panipenem exhibited the greatest shift in MIC when supplemented with avibactam. Conclusion: Avibactam restores MICs of tebipenem, ertapenem and panipenem against M. abscessus to therapeutically achievable concentrations and raises the possibility of usefulness of these carbapenems to treat drug-resistant M. abscessus infections. Mycobacterium abscessus is a rapidly growing nontuberculous mycobacterium found widely in soil and water and can cause a spectrum of infections [1]. Prevalence of M. abscessus infections in the lungs of people with chronic conditions, such as cystic fibrosis is significant and can often lead to serious morbidity [2]. A survey revealed that M. abscessus is present in the sputum of approximately 13% of cystic fibrosis patients in the USA [3]. Among nontuberculous mycobacterium lung infections, M. abscessus is one of the prevalent species and often leads to a chronic and incurable disease [4][5][6]. Drug resistance in M. abscessus is steadily rising globally, making it increasingly difficult to manage infections with these strains [7]. Therefore, new drugs and novel regimens are acutely needed to treat infections with M. abscessus. An ideal new drug would inhibit a novel target so that it can be effective against M. abscessus strains that are resistant to currently used drugs.The peptidoglycan is an Achilles' heel of bacteria as agents that inhibit its biosynthesis, namely β-lactams and glycopeptides, comprise some of the most widely used class of antibacterials in modern medicine. β-lactams derive their activity by preventing formation of linkage between peptide side chains by inhibiting the transpeptidases that catalyze this reaction [8]. Recently it was demon strated that majority of the linkages in the peptidoglycan layer of M. abscessus are generated by LD-transpeptidases [9] and that this class of enzyme is selectively more susceptible to the carbapenem class of β-lactams [10][11][12]. Imipenem, a carbapenem, has superior activity compared with For reprint orders, please contact: reprints@futuremedicine.com

Patients with cystic fibrosis (CF) are at risk for recurrent pulmonary infections due to increased viscosity of airway secretions, leading to persistent colonization with pathogenic bacteria, including nontuberculous mycobacteria (NTM). Extensive antibiotic use for treatment of infections has led to increasing antimicrobial resistance, which is a significant barrier to the treatment of NTMs. We examined the in vitro activity of several antibiotics against a selection of the most drug-resistant clinical isolates of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium avium complex recovered from CF patients at our institution, as well as paired combinations of antibiotics against a subset of M. abscessus strains, to determine whether they exhibit synergy in inhibiting bacterial growth. Most isolates displayed resistance to at least six of the nine antibiotics tested for which phenotypic interpretation is available, and elevated minimum inhibitory concentrations (MICs) were observed for many of the other drugs. The major exception was clofazimine, which had relatively low MICs for most isolates across all species. When synergy testing was performed by using paired combinations of drugs, clofazamine and clarithromycin exhibited 100% synergy for all combinations tested, as did amikacin, with the exception of one isolate. These results suggest that synergistic antibiotic combinations are capable of overcoming drug resistance in vitro, and laboratories might consider implementation of synergy testing in multidrug-resistant (MDR)-NTM organisms to guide treatment decisions in the setting of extensive antimicrobial resistance.

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