Comparative effectiveness of ceftolozane/tazobactam relative to ceftazidime/avibactam for the treatment of adult, hospitalized patients with pneumonia due to multidrug-resistant Pseudomonas aeruginosa in U.S. Veterans Health Administration facilities.

Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (C/A) are frequently used for the treatment of multidrug-resistant Pseudomonas aeruginosa (MDR-PSA) pneumonia. However, comparative "real-world" effectiveness data are limited. We performed a retrospective cohort study within the U.S. Veterans Health Administration (VHA; 2015-2019, 2022-2024), including adults with microbiologically confirmed MDR-PSA pneumonia receiving C/T or C/A within ≤5 days of index culture. Inverse probability of treatment weighting (IPTW) was applied to balance baseline covariates. The primary outcome was 30-day all-cause mortality, and secondary outcomes were 60-day mortality, 90-day mortality, and 30-, 60-, and 90-day MDR-PSA recurrence and all-cause hospital readmission. A prespecified sensitivity analysis examined the effect of early treatment initiation ≤72 h. Among 260 patients (C/T, n = 132; C/A, n = 128), C/T recipients demonstrated more extensive prior antimicrobial exposure and substantially longer time-to-therapy (median, 56 versus 19 h; P < 0.001). After IPTW, balance improved across most prespecified covariates, although residual imbalance persisted for age and geographic region. No statistically significant between-group differences were observed in 30-day mortality (adjusted risk ratio [aRR], 1.02; 95% confidence interval [CI], 0.56-1.83; P = 0.944) or in other clinical outcomes. Among patients with early treatment within 72 h (n = 175), no significant differences in 30-day mortality (aRR, 1.18; 95% CI, 0.47-2.93; P = 0.724) or other mortality, recurrence, or readmission outcomes were observed between C/T and C/A. In this national VHA cohort, C/T and C/A demonstrated comparable clinical, microbiologic, and healthcare utilization outcomes. These findings support consideration of either C/T or C/A for MDR-PSA pneumonia when used at appropriate doses.