In-vitro activity of newly-developed β-lactamase inhibitors avibactam, relebactam and vaborbactam in combination with anti-pseudomonal β-lactam antibiotics against AmpC-overproducing clinical Pseudomonas aeruginosa isolates.

Purpose: Overproduction of the intrinsic chromosomally-encoded AmpC β-lactamase is one of the main mechanisms responsible for broad-spectrum β-lactam resistance in Pseudomonas aeruginosa. Our study aimed to evaluate the in-vitro activity of anti-pseudomonal β-lactam molecules associated with the recently-developed and commercially-available β-lactamase inhibitors, namely avibactam, relebactam and vaborbactam, against P. aeruginosa isolates overproducing their AmpC.

Methods: MIC values of ceftazidime, cefepime, meropenem, imipenem and ceftolozane with or without β-lactam inhibitor were determined for 50 AmpC-overproducing P. aeruginosa clinical isolates. MIC breakpoints for resistance were retained at 8 mg/L for β-lactams and β-lactam/β-lactamase inhibitor combinations containing ceftazidime, cefepime and meropenem, while 4 mg/L was used for those containing imipenem and ceftolozane. The concentration of all β-lactamases inhibitors was fixed at 4 mg/L, except for vaborbactam (8 mg/L).

Results: The rates of isolates not being resistant to ceftazidime, cefepime, meropenem, imipenem and ceftolozane were found at 12%, 22%, 34%, 8% and 74%, respectively. When combined with avibactam, those rates increased to 60%, 62%, 60%, 46%, and 80%, respectively. The highest rates were found with relebactam-based combinations, being 76%, 64%, 66%, 76% and 84%, respectively. By contrast, associations with vaborbactam did not lead to significantly increased "non-resistance" rates.

Conclusion: Our results showed that all combinations including relebactam led to higher "non-resistance" rates against AmpC-overproducing P. aeruginosa clinical isolates. The best activity was achieved by combining ceftolozane and relebactam, that might therefore be considered as an excellent clinical alternative against AmpC overproducers.