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

Background Antibiotic treatment of Mycobacterium abscessus disease is toxic, 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. Objectives To summarize the current preclinical studies on dual β-lactam and β-lactam/β-lactamase inhibitor combinations against Mycobacterium abscessus. Sources We performed a literature search using the NCBI’s PubMed interface with additional snowball sampling. Content Select combinations of β-lactam antibiotics, as well as β-lactam/β-lactamase inhibitor combinations show promising in vitro activity and synergy against Mycobacterium 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. Implications Future 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.