Dual β-lactam therapy to improve treatment outcome in Mycobacterium abscessus disease

Abstract

BackgroundAntibiotic treatment of Mycobacterium abscessus disease is toxic and poorly effective and lacks a firm evidence base. Dual β-lactam and β-lactam/β-lactamase inhibitor combinations may be interesting leads to improve treatment outcomes. ObjectivesTo summarize the current preclinical studies on dual β-lactam and β-lactam/β-lactamase inhibitor combinations against M. abscessus. SourcesWe performed a literature search using the National Center for Biotechnology Information's PubMed interface with additional snowball sampling. ContentSelect combinations of β-lactam antibiotics, as well as β-lactam/β-lactamase inhibitor combinations show promising in vitro activity and synergy against M. abscessus. β-Lactam antibiotics differ in their ability to reach and interfere with their targets and their resistance to the M. abscessus β-lactamase. The synergy is typically observed for combinations of β-lactam antibiotics or a β-lactam antibiotic with a β-lactamase inhibitor. No additional killing capacity was demonstrated in three-drug combinations of synergistic β-lactam antibiotics and a β-lactamase inhibitor. The efficacy of select dual β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations is retained in intracellular infection assays and mouse models, but no combination has a complete preclinical portfolio. ImplicationsFuture clinical strategies should entail either dual β-lactam or β-lactam/β-lactamase inhibitor combinations. Imipenem-ceftaroline and an all-oral tebipenem-avibactam combination are promising leads but still require a complete preclinical portfolio, target product profiles as well as clinical trial confirmation.