Comparison of the inoculum effect of in vitro antibacterial activity of IMR and CZA against ESBL-, KPC- and AmpC-producing Escherichia coli and Klebsiella pneumoniae

Abstract Objective To evaluate effect of inoculum size of extended-spectrum β-Lactamase (ESBL)-producing-, AmpC-producing-, and KPC-producing Escherichia coli and Klebsiella pneumoniae on the in vitro antibacterial effects of imipenem/relebactam (IMR) and ceftazidime/avibactam (CZA). Methods We compared the impact of inoculum size on IMR and CZA of eight clinical isolates and two standard isolates through antimicrobial susceptibility tests, time-kill assays and in vitro PK/PD studies. Result When inoculum size increased from 10 5 to 10 7 CFU/mL, an inoculum effect was observed for 25% (3/12) and 66.7% (8/12) of IMR and CZA, respectively; time-kill assays revealed that the concentration of CZA increased from ≥ 4×MIC to 16×MIC to reach 99.9% killing rate against K. pneumoniae ATCC-BAA 1705(KPC-2-producing) and 60700(SHV-27-producing and DHA-1-producing). While for IMR, a concentration from 1×MIC to 4×MIC killed 99.9% of the four strains. When the inoculum size increased to 10 9 CFU/mL, neither IMR nor CZA showed a detectable antibacterial effect, even at a high concentration. An in vitro PK/PD study revealed a clear bactericidal effect when IMR administered as 1.25g q6h when inoculum size increased. Conclusion An inoculum effect on CZA was observed more frequent than that on IMR. Among the β-lactamase-producing strains, the inoculum effect was most common for SHV-producing and KPC-producing strains.