Supporting the ceftaroline fosamil/avibactam Enterobacteriaceae breakpoint determination using humanised in vivo exposures in a thigh model

• Enterobacteriaceae have developed more resistance due to enzyme mediated mechanisms.
• Ceftaroline/avibactam showed activity against these resistant Enterobacteriaceae.
• Enhanced activity was recognised in the presence of a functional immune system.

Previous in vivo studies using a human-simulated regimen of ceftaroline/avibactam 600/600 mg every 8 h (q8h) showed activity against extended-spectrum β-lactamase-, AmpC- and KPC-producing Enterobacteriaceae with minimum inhibitory concentrations (MICs) ≤1 μg/mL. Here we sought to determine the efficacy of this human-simulated regimen against organisms with MICs ≥1 μg/mL to help determine a breakpoint value that would reliability predict efficacy in humans. In total, 31 isolates (1 Escherichia coli, 9 Klebsiella pneumoniae, 9 Enterobacter cloacae, 1 Citrobacter koseri, 2 Serratia marcescens, 1 Klebsiella oxytoca and 8 Pseudomonas aeruginosa) with ceftaroline/avibactam MICs of 1 to 16 μg/mL were tested in a murine immunocompromised thigh infection model; 15 isolates were also tested in an immunocompetent model. Doses were given to simulate human free drug exposures of ceftaroline fosamil/avibactam 600/600 mg q8h over 24 h as a 1-h infusion by targeting the fT>MIC profile. Efficacy was evaluated as the change in log10 CFU compared with 0-h controls after 24 h. Reductions in bacterial CFU in the neutropenic model were seen against a majority of isolates tested with MICs ≤4 μg/mL, where fT>MIC was >55%. More variable efficacy was seen in isolates with MICs ≥8 μg/mL, where fT>MIC drops below 40%. Overall activity was enhanced in the immunocompetent model. The humanised regimen of ceftaroline fosamil/avibactam 600/600 mg q8h as a 1-h infusion showed predictable efficacy against isolates with various genotypic and phenotypic profiles and MICs ≤4 μg/mL. These data provide valuable information to help determine a ceftaroline/avibactam breakpoint for Enterobacteriaceae.