Ceftazidime-avibactam as monotherapy or in combination for targeted treatment of KPC-producing Klebsiella pneumoniae infections in ICUs: a comparative analysis through counterfactual framework and desirability of outcome ranking

PURPOSE: To evaluate the causal effect of ceftazidime/avibactam (C/A) combination therapy versus monotherapy on mortality and clinical success in patients with KPC-producing Klebsiella pneumoniae (KPC-Kp) infections in intensive care unit. METHODS: This multi-centre, retrospective observational study (2021-2023) included adults with KPC-Kp bloodstream infections or pneumonia treated with C/A-based regimens. We employed a counterfactual framework using inverse probability of treatment weighting (IPTW) to estimate the average treatment effect on 30-day mortality. Clinical success was further assessed using Desirability of Outcome Ranking (DOOR) analysis and partial credit scoring based on patient-perspective scenarios. RESULTS: Among 123 included patients, 77 (62.6%) received monotherapy and 46 (37.4%) received combination therapy. The combination group presented with significantly higher baseline severity, including higher APACHE II scores and rates of septic shock. In the IPTW-adjusted analysis, 30-day survival was 73.8% (95% CI: 56-92%) with combination therapy compared with 60.8% (95% CI: 46.8-77%) with monotherapy. The survival probability ratio was 1.21 (95% CI: 0.80-1.45), indicating no statistically significant survival benefit. The DOOR analysis showed a 54.7% (95% CI: 48.9%-60.4%) probability of a more favourable outcome with combination therapy, which was not statistically significant. Mean partial credit scores did not differ significantly across scenarios prioritizing survival or adverse event avoidance. CONCLUSIONS: In this cohort, C/A-based combination therapy did not provide a significant survival advantage or an improved clinical desirability ranking compared with monotherapy, after adjusting for confounding factors.