Bactericidal and intracellular activity of β-lactams against Mycobacterium abscessus

Objectives: Cefoxitin and imipenem are the sole recommended beta-Lactams for the treatment of Mycobacterium abscessus puLmonary infections. Here, we investigated whether one of these drugs displays superiority in terms of kiLLing and intraceLLuLar activity. We have also evaluated whether the use of a beta-Lactamase inhibitor couLd improve their activity. Methods: The impact of the beta-Lactamase Bla(Mab) on the activity of beta-Lactams was assessed by comparing M. abscessus CIP104536 and its beta-Lactamase-deficient Delta bla(Mab) derivative, as well as by using the beta-Lactamase inhibitor avibactam. The activity of cefoxitin, imipenem, amoxiciLLin and ceftaroLine, alone and in various combinations incLuding amikacin, was compared based on determination of time-kill curves and of intraceLLuLar proliferation in human macrophages. Results: Imipenem was superior to cefoxitin in both the time-kill and macrophage assays. Production of Bla(Mab) Limited the activity of imipenem. The combination of imipenem and amikacin was bactericidal against the Ablamab mutant. Deletion of bla(Mab) extended the spectrum of beta-Lactams active against M. abscessus to incLude amoxiciLLin and ceftaroLine. In the absence of Bla(Mab), amoxiciLLin was as active as imipenem. These drugs were more active than ceftaroLine and cefoxitin was the Least active. Avibactam increased the intraceLLuLar activity of ceftaroLine, but inhibition of Bla(Mab) was only partial, as previously reported for amoxicillin. Conclusions: Evaluation of the kiLLing and intracellular activities of beta-Lactams indicates that imipenem is superior to cefoxitin at clinically achievable drug concentrations. Inhibition of Bla(Mab) couLd improve the efficacy of imipenem and extend the spectrum of drugs potentially useful to treat puLmonary infections.