Activity of Ceftolozane/tazobactam (C/T) and Ceftazidime/avibactam (CZA) against Extended-spectrum Β-lactamase (ESBL)-producing Enterobacteriaceae and Multidrug-resistant (MDR) Pseudomonas aeruginosa Isolates

Background Antibiotic resistance among Gram-negative bacterial pathogens is a serious public health threat underscored by a diminishing antibiotic development pipeline. This study evaluated the in vitro activity of two new β-lactam/β-lactamase inhibitors, C/T and CZA, against the problematic pathogens ESBL-producing Enterobacteriaceae and MDR P. aeruginosa. Methods A convenience sample of 74 ESBL-producing Enterobacteriaceae and 32 MDR P. aeruginosa clinical isolates (1 per patient episode), collected between 2012 and 2017 from 2 academic medical centers in Boston and Philadelphia, was used. MDR was defined as non-susceptibility to ≥1 agent in at least 3 antibiotic classes. Phenotypic confirmation of ESBL isolates was conducted via double disk testing. MICs were determined by broth microdilution in at least duplicate, on separate days, as recommended by CLSI. Klebsiella pneumoniae ATCC 700603 was used as a quality control strain with each experiment. Interpretive criteria for C/T per CLSI were: ≤2 (susceptible) / 4 (intermediate) / ≥8 (resistant) mg/L (Enterobacteriaceae) and ≤4 (susceptible) / 8 (intermediate) / ≥16 (resistant) mg/L (P. aeruginosa). Interpretive criteria for CZA per FDA were: ≤8 (susceptible) / ≥16 mg/L (resistant) (all organisms). Results Culture sites for the total isolate collection consisted of urine (n = 62), sputum (n = 30), wounds (n = 9), blood (n = 3), and bone (n = 2). ESBL-producing Enterobacteriaceae included Escherichia coli (n = 60), Klebsiella spp. (n = 12), Enterobacter cloacae (n = 1), and Citrobacter freundii (n = 1). ESBL Enterobacteriaceae isolates were 97.3% and 100% susceptible to C/T and CZA, respectively. The corresponding MIC50/90 values were 0.5/2 mg/L for C/T and 0.25/0.5 mg/L for CZA. MDR P. aeruginosa isolates were 90.6% and 96.9% susceptible to C/T and CZA, respectively. The corresponding MIC50/90 values were 1/4 mg/L for C/T and 2/8 mg/L for CZA. Conclusion C/T and CZA, two recently approved β-lactam/β-lactamase inhibitor combinations, maintained reliable activity against a collection of 106 MDR isolates from 2 geographically diverse medical centers. Disclosures E. B. Hirsch, Merck: Grant Investigator, Research grant The Medicines Company: Speaker’s Bureau, Speaker honorarium; T. Bias, Merck: Grant Investigator, Research grant The Medicines Company: Speaker’s Bureau, Speaker honorarium