In Vitro Antibacterial Activity of Ceftolozane/Tazobactam (C/T) Alone and in Combination with other Antimicrobial Agents against Multidrug-Resistant (MDR) Pseudomonas aeruginosa (PSA)

Abstract

Abstract Background Broad-spectrum antimicrobial resistance in MDR PSA isolates significantly limits our therapeutic options. C/T has been shown to be highly active against MDR PSA isolates. To assist the clinical decision-making process regarding the selection of agents and dosages for this pathogen, we performed time-kill studies assessing various C/T concentrations alone and in combination with other anti-pseudomonal agents. Methods Four clinical MDR P. aeruginosa isolates were selected. MICs were determined via broth microdilution methods according to CLSI. Time-kill analyses were performed in duplicate using C/T free concentrations reflective of the peak and trough of a 3g q8h dose (120/25.2 µg/mL,7.5/1.6 µg/mL) and the peak of a 1.5g q8h dose (60/12.6 µg/mL) in humans. The activity of C/T 120, 60, and 7.5 alone and C/T 7.5 in combination with free peak concentrations of FEP, CIP, CST, ATM, MEM, TZP, FOF, or AMK was tested for all isolates. Colony counts were determined at 0, 3, 6, and 24h by serial dilution plating. Synergy was defined at ≥ 2 log10 CFU reduction from the most active agent. Results MICs of the 4 MDR P. Aeruginosa isolates are in Table 1. As the C/T concentrations increased, bacterial reduction improved, achieving a mean (±SD) log10CFU change from 0 h of 0.03 (±0.67), −1.19 (±1.03), −2.59 (±0.86) with C/T 7.5, 60, 120, respectively. C/T 7.5 was synergistic with CST (PSA C8-21, PSA C45-10) and FOF (PSA C28-5, PSA C14-22) in two of four isolates. No synergy was observed with double β-lactam therapy or CIP. AMK alone achieved maximal bacterial kill; therefore, synergy could not be assessed. Conclusion C/T 3g and 1.5g q8h peak concentrations demonstrate killing against the MDR PSA. CST and FOF were synergistic with C/T in vitro. Our findings aide in identification of novel treatment options and dosing regimens for the treatment of MDR P. Aeruginosa. Disclosures D. P. Nicolau, Merck: Investigator and Speaker’s Bureau, Research support.