Pharmacodynamic Comparison of Ceftolozane/tazobactam and Ceftazidime/avibactam Against Carbapenem-resistant Pseudomonas aeruginosa Using the Hollow Fiber Infection Model

다국어 초록 (Multilingual Abstract)

Ceftolozane/tazobactam (CFT/TAZ) and ceftazidime/avibactam (CFZ/AVI) are relatively novel cephalosporin/beta-lactamase inhibitor combinations that are expected to be widely used as a reasonable option for treating against multi-drug resistant organisms due to their broader spectrum of activity. However, little is known regarding their comparative bactericidal activity against multidrug-resistant Pseudomonas aeruginosa, one of the most significant clinical pathogens. The objective of this study was to compare the pharmacodynamics of CFT/TAZ and CFZ/AVI against carbapenem-resistant Pseudomonas aeruginosa (CRPA) using different methods of administration in an in vitro translational hollow fiber infection model (HFIM). Bactericidal activities of each drug were assessed by HFIM experiments over 7 days against a clinically isolated CRPA strain. Concentration-time profiles of both medications administered by intermittent infusion (II) and continuous infusion (CI), were simulated in the HFIM. The PK parameters for HFIM simulations were obtained from prescribing information. No bactericidal activity, defined as a reduction of at least 3 log10 CFU/mL in bacterial burden, was observed with II for either drug. For CI, bacterial burden was reduced to the minimum of 6.2 log10 CFU/mL in the CFT/TAZ group at 8 h and 4.21 log10 CFU/mL in the CFZ/AVI arm at 24 h. The reduction in bacterial burden was significantly greater with CFZ/AVI compared to CFT/TAZ from 24 h to 120 h (P < 0.05). At 48 h after the start of CI, the difference in bacterial burden between the CFZ/AVI and CFT/TAZ arms was the largest at -2.93 log10 CFU/mL. with a difference of approximately 3 log10 CFU/mL between 24h and 72h. In conclusion, conventional intermittent infusion of ceftolozane/tazobactam and ceftazidime/avibactam is unsuitable for treating CRPA. Continuous infusion of ceftazidime/avibactam inhibits the growth of CRPA most effectively, suggesting the best option for treating infections caused by CRPA. Future clinical studies might be warranted to comparatively evaluate real-world treatment outcomes of CFZ/AVI and CFT/TAZ in patients with CRPA infections.

목차 (Table of Contents)

• 1. Introduction 1
• 2. Materials and Methods 2
• 1) Antimicrobial agents 2
• 2) Strains 2
• 3) Hollow fiber infection model 2
• 3. Results 5
• 1) Standard strain, ATCC27853 5
• 2) Carbapenem-resistant clinical isolate, intermittent infusion 10
• 3) Carbapenem-resistant clinical isolate, continuous infusion 15
• 4) Comparison by regimen 20
• 4. Discussion 23
• 5. Conclusion 31
• 6. References 32