A pre-post quasi-experimental study of antimicrobial stewardship exploring the impact of a multidisciplinary approach aimed at attaining an aggressive joint pharmacokinetic/pharmacodynamic target with ceftazidime/avibactam on treatment outcome of KPC-producing Klebsiella pneumoniae infections and on ceftazidime/avibactam resistance development

Abstract

To assess the impact of a multidisciplinary approach aimed at attaining aggressive joint pharmacokinetic/pharmacodynamic (PK/PD) target with ceftazidime/avibactam on treatment outcome of KPC-Klebsiella pneumoniae (Kp) infections and prevention of ceftazidime/avibactam resistance development, a pre-post quasi-experimental study on adult patients with documented KPC-Kp who were treated with ceftazidime/avibactam according to a multidisciplinary approach in the period 1 March 2021-31 October 2024 and patients receiving standard management with ceftazidime/avibactam in the period 1 January 2018-28 February 2021 was performed. Multivariate analysis was performed to identify variables associated with microbiological failure and 90-day resistance development to ceftazidime/avibactam in both pre- and post-intervention phases. A total of 116 and 102 patients in pre- and post-intervention phases were included. A significantly lower microbiological eradication rate (53.0% vs. 81.0%; P < 0.001), a lower clinical cure rate (48.3% vs. 70.6%; P < 0.001), and a higher rate of 90-day resistance development (15.5% vs. 5.9%; P = 0.02) were found in the pre-intervention phase. Continuous renal replacement therapy (odds ratio [OR] 5.20; 95% confidence interval [CI] 1.21-22.34) and a ceftazidime/avibactam MIC value ≥ 4 mg/L (OR 3.08; 95% CI 1.10-8.64) emerged as independent predictors of microbiological failure in the pre-intervention phase. Conversely, attaining aggressive joint PK/PD target (OR 0.03; 95% CI 0.005-0.20) and bloodstream infections (OR 0.09; 95% CI 0.02-0.53) resulted in protection against microbiological failure in the post-intervention phase. Attaining aggressive joint PK/PD targets resulted in protection against 90-day resistance development in the post-intervention phase (OR 0.07; 95% CI 0.01-0.69). Implementing a multidisciplinary approach for maximizing the attainment of aggressive joint PK/PD targets of ceftazidime/avibactam could represent an effective strategy for preventing resistance development to ceftazidime/avibactam in KPC-Kp infections.

Keywords: KPC-producing Klebsiella pneumoniae; TDM-guided approach; aggressive joint PK/PD target; ceftazidime/avibactam; continuous infusion; microbiological failure; multidisciplinary approach; resistance development.

Fig 1

Flowchart of patients’ inclusion and exclusion criteria.