Background: Mycobacterium abscessus is an emerging multi-drug resistant pathogen, harboring the β-lactamse BlaMAB. Avibactam is a non-β-lactam, β-lactamase inhibitor shown to inhibit BlaMAB and improve the efficacy of ampicillin for M. abscessus infections in in vitro and in vivo models. Whether the addition of avibactam to piperacillin enables use of the latter against M. abscessus is unknown
Methods: We used a recombinant, luminescent M. abscessus to measure the reduction of MIC to meropenem, ampicillin and piperacillin induced by avibactam. We then used our previously established G. mellonella infection model (fig 1) 1 to evaluate the effect of antimicrobial treatments in vivo.
Results: Addition of avibactam (4 µg/ml) consistently decreased MIC of ampicillin and piperacillin by 16 and 16-32 fold respectively, but as expected had no significant effect on meropenem MIC (fig 2). We inoculated 60 G. mellonella larvae with luminescent M. abscessus on day 0, and treated larvae with meropenem, piperacillin, avibactam alone, or piperacillin combined with avibactam on days 2 and 3. Using IVIS® imaging, we measured infection progression in live infected larvae on day 4. Larvae treated with meropenem and piperacillin-avibactam had significantly lower infection burden compared to untreated controls (p<0.0001 and p=0.004 respectively). Piperacillin and avibactam alone had no significant inhibitory effect (fig 3).
Conclusion: Our findings suggest that the piperacillin-avibactam combination is effective against M. abscessus infections. This novel combination may hold a great promise for patients with cystic fibrosis suffering from M. abscessus, Pseudomonas aeruginosa and/or Staphylococcus aureus co-infections. The G. mellonella infection model may be used in future studies to assess the efficacy of various antimicrobials and antimicrobial combinations on M. abscessus, P. aeruginosa and S. aureus co-infections.
1 Meir M et al. Antimicrob Agents Chemother. 2018