Ceftazidime-avibactam for multidrug-resistant gram-negative infections: outcomes and timing of initiation across 22 U.S. medical centers.

Ceftazidime-avibactam (CAZ-AVI) is a crucial treatment for multidrug-resistant (MDR) gram-negative infections; however, the impact of treatment timing and outcomes in real-world practice remains unclear. This study evaluated CAZ-AVI use across diverse U.S. centers, with emphasis on early initiation. We conducted a retrospective cohort study at 22 U.S. medical centers (2019-2025), including adults with MDR gram-negative infections who received CAZ-AVI ≥ 72 h. The primary outcome was composite clinical success, defined as 30-day survival, absence of microbiological recurrence, and resolution of fever and/or leukocytosis within 72 h of initiation. Early vs late initiation was assessed at 48 h. Classification and regression tree (CART) analysis was used to identify optimal thresholds. Among 613 patients (median age 60 years, 62.5% male, 57.1% admitted to the ICU within 24 h of index culture), the most common infection source was pneumonia (55.5%), and the most frequent pathogens were Pseudomonas aeruginosa (36.1%) and carbapenem-resistant Enterobacterales (34.7%). Composite clinical success occurred in 64.8%. CAZ-AVI initiation within 48 h was not significantly associated with improved outcomes (P = 0.064). Among patients who did not receive prior active antimicrobial therapy (n = 429), CART analysis identified a 42 h threshold. Initiation within 42 h was associated with higher clinical success (73.3% vs 63.4%, P = 0.046) and lower 30-day all-cause mortality (10.7% vs 19.1%, P = 0.030). In patients with pneumonia, the same threshold remained discriminatory, with improved clinical success and lower mortality. CAZ-AVI was effective for MDR gram-negative infections in real-world practice. Among patients without prior active therapy, initiation within 42 h was associated with improved outcomes, including in pneumonia.