Dual β-lactams for the treatment of Mycobacterium abscessus: a review of the evidence and a call to act against an antibiotic nightmare

Abstract

Mycobacterium abscessus complex is a group of rapidly growing non-tuberculous mycobacteria (NTM), increasingly emerging as opportunistic pathogens. Current treatment options for these microorganisms are limited and associated with a high rate of treatment failure, toxicity and recurrence. In search of new therapeutic strategies, interest has grown in dual β-lactam (DBL) therapy, as research recently discovered that M. abscessus cell wall synthesis is mainly regulated by two types of enzymes (d,d-transpeptidases and l,d-transpeptidases) differently susceptible to inhibition by distinct β-lactams. In vitro studies testing several DBL combinations have shown synergy in extracellular broth cultures as well as in the intracellular setting: cefoxitin/imipenem, ceftaroline/imipenem, ceftazidime/ceftaroline and ceftazidime/imipenem. The addition of specific β-lactamase inhibitors (BLIs) targeting M. abscessus β-lactamase did not significantly enhance the activity of DBL combinations. However, in vivo data are lacking. We reviewed the literature on DBL/DBL-BLI-based therapies for M. abscessus infections to raise greater attention on this promising yet overlooked treatment option and to guide future preclinical and clinical studies.

Figure 1.

Interactions between M. abscessus cell wall transpeptidases (DDCs, LDTS and DDTs), Bla_Mab and β-lactams/BLIs. Lines indicate proven interaction between target enzymes and β-lactams/BLIs (continuous lines for more robust evidence; dotted lines for weaker evidence). Absence of a line indicates no demonstrated interaction. Within each β-lactam subclass, molecules with a greater abundance of reported data in the literature were highlighted as example. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.