Characterizing the role of porin mutations in susceptibility of beta lactamase producing Klebsiella pneumoniae isolates to ceftaroline and ceftaroline-avibactam

Objectives: Evaluate the role of porins in the susceptibility of Klebsiella pneumoniae to ceftaroline and ceftaroline-avibactam. Methods: Susceptibility to ceftaroline and ceftaroline-avibactam was tested by broth microdilution method in Klebsiella pneumoniae isolates (n = 65), including isogenic mutants (n = 30) and clinical isolates (n = 35), with different outer membrane porin defects in the presence or absence of beta lactamases. Results: Ceftaroline exhibited excellent activity against all the isogenic porin mutants with a MIC range of 0.125-0.25 mu g/ml. Ceftaroline showed limited activity in the presence of extended spectrum beta-lactamase enzymes in isogenic mutant constructs as expected but regained effectiveness in combination with avibactam against these isolates except those carrying metallo-carbapenemase (IMP-4) with an MIC range of 0.25->32 mu g/ml. Ceftaroline-avibactam was able to inhibit 86% of the clinical isolates (n = 35) of Klebsiella pneumoniae carrying porin defects and multiple beta lactamases with only four isolates showing raised MICs against the combination (MIC range 0.125-4 mu g/ml). One clinical isolate with IMP-4 carbapenemase had an MIC value of >32 mu g/ml. Conclusion: Outer membrane porins play a key role in the transport of ceftaroline in Klebsiella pneumoniae but it remains effective in isolates with altered permeability due to common porin mutations. The addition of avibactam substantially enhances the potency of ceftaroline providing an effective remedy to the problem of omnipresent beta lactamases in these bacteria. (C) 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.