Activity of Ceftazidime-Avibactam Alone and in Combination with Ertapenem, Fosfomycin, and Tigecycline Against Carbapenemase-Producing Klebsiella pneumoniae.

The aim of this study was to investigate the synergy between ceftazidime-avibactam, ertapenem, fosfomycin, and tigecycline against carbapenemase-producing Klebsiella pneumoniae using the E test MIC:MIC (minimum inhibitory concentration) ratio synergy method. The results were interpreted using fractional inhibitory concentration index (FICI) to describe the effects of antimicrobial combinations in vitro. To assess the clinical significance of each antibiotic combination, the susceptible breakpoint index (SBPI) was calculated for each combination, and within each strain. The FICI method revealed that the most synergistic combinations against carbapenemase-producing K. pneumoniae were ceftazidime-avibactam with ertapenem and ceftazidime-avibactam with fosfomycin. This effect was demonstrated in 47% (9/19) of all tested clinical K. pneumoniae isolates. Considering the effects of all drug combinations in K. pneumoniae harboring blaKPC, blaNDM, and blaOXA-48 genes, we observed that the combination of ceftazidime-avibactam with fosfomycin was the most synergistic in New Delhi metallo-β-lactamase (NDM)-producing K. pneumoniae, and the combination of ceftazidime-avibactam with ertapenem was the most synergistic in K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae. In addition, all tested combinations were synergistic against oxacillinase (OXA)-48-producing K. pneumoniae, except the combination of ceftazidime-avibactam with tigecycline. The SBPI index showed that ceftazidime-avibactam in combination with fosfomycin reduced the MIC to less than the susceptibility breakpoint among all tested carbapenemase-producing K. pneumoniae. Moreover, the combinations of ceftazidime-avibactam with ertapenem, and ceftazidime-avibactam with tigecycline were able to reduce the MIC to less than the susceptibility breakpoint in all KPC- and OXA-48-producing K. pneumoniae.