Pharmacodynamic Comparison of Ceftolozane/Tazobactam and Ceftazidime/Avibactam, Administered by Intermittent or Continuous Infusion, Against a Clinical Isolate of Carbapenem-Resistant Pseudomonas aeruginosa Producing GES β-Lactamase in a Hollow Fiber Infection Model

Background/Objectives: Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA) are critical therapeutic options for multidrug-resistant Gram-negative infections; however, their comparative pharmacodynamics against carbapenem-resistant Pseudomonas aeruginosa (CRPA) remain incompletely defined. This study aimed to compare the bactericidal activity of C/T and CZA administered by intermittent infusion (II) or continuous infusion (CI) using a hollow fiber infection model (HFIM) against a clinical isolate of CRPA. Methods: Clinically relevant concentration–time profiles for C/T and CZA based on prescribing information were simulated in the HFIM. The standard P. aeruginosa strain ATCC 27853 and a GES-producing clinical CRPA isolate were utilized. The primary endpoint was bactericidal activity (≥3 log₁₀ CFU/mL reduction from baseline), while secondary endpoints included regrowth prevention and resistance development based on population analysis profiles (PAPs). Results: Against the standard strain, both agents achieved rapid killing without regrowth. However, for the GES-producing clinical isolate, C/T failed to achieve bactericidal activity. In contrast, CZA demonstrated sustained bacterial killing activity with the most pronounced early-phase bactericidal activity with CI of CZA (−4.25 log₁₀ CFU/mL at 24 h). The bactericidal activity was persistent over 7 days without bacterial regrowth after treatment discontinuation. Conversely, bacterial regrowth occurred with II of CZA after drug withdrawal. PAPs showed the lack of resistance development against CZA, whereas resistance to C/T developed within 48 h after initiating therapy. Conclusions: In this HFIM study, CI of CZA demonstrated the most sustained suppression of bacterial growth and prevented resistance emergence against the tested clinical isolate of CRPA producing GES β-lactamases. Future clinical studies are warranted to assess the effectiveness of the CI regimen.