Activity of β-lactam plus β-lactam-enhancer combination cefepime/zidebactam against Klebsiella pneumoniae harbouring defective OmpK35/36 porins and carbapenemases.

Cefepime/zidebactam is a β-lactam/β-lactam-enhancer based novel antibiotic which is in clinical development for treating infections caused by multidrug-resistant Gram-negative bacteria. Here, in vitro activity of cefepime/zidebactam was determined against multicentre Klebsiella pneumoniae clinical isolates co-expressing serine and/or metallo-carbapenemases and defective OmpK35 and OmpK36 porins. The MICs were determined using the reference broth microdilution method. Outer membrane protein expression was assessed using SDS-PAGE and mutations in the genes encoding OmpK35 and OmpK36 were identified by DNA sequencing. Among 34 isolates studied, carbapenemase genes, blaKPC and blaOXA-48-like, were present in 18 and 11 isolates, respectively; 5 isolates harboured both blaOXA-48-like and blaNDM. Point mutations, insertions, and duplications in OmpK35 and OmpK36, which are known to impact the activity of carbapenems, were detected. Against these isolates, cefepime/zidebactam (1:1) showed a consistent activity (MICs ≤4 mg/L). In conclusion, cefepime/zidebactam overcomes enzymatic, and non-enzymatic carbapenem-impacting resistance mechanisms concurrently expressed in K. pneumoniae.