A pre-post quasi-experimental study of the impact of TDM-guided aggressive pharmacokinetic/pharmacodynamic target attainment of continuous infusion ceftolozane/tazobactam monotherapy in treating severe Pseudomonas aeruginosa infections: a strategy useful for raising the bar?

Abstract

Objectives: To assess the clinical usefulness of a therapeutic drug monitoring (TDM)-guided strategy for attaining an aggressive pharmacokinetic/pharmacodynamic (PK/PD) target of continuous infusion (CI) ceftolozane/tazobactam monotherapy in patients having Pseudomonas aeruginosa infections.

Methods: We performed a pre-post quasi-experimental study including adult patients with documented P. aeruginosa bacteraemia and/or pneumonia who were treated with CI ceftolozane/tazobactam monotherapy tailored by means of a TDM-guided strategy in the period 1 November 2023 to 31 July 2024 (post-intervention phase) compared with patients receiving standard management with CI ceftolozane/tazobactam monotherapy in the period 1 April 2022 to 31 October 2023 (pre-intervention phase). Clinical outcomes were compared between pre- and post-intervention phase. Univariate and multivariate analyses were performed for identifying variables associated with microbiological failure.

Results: Eighty-five patients (48 in pre- and 37 in post-intervention phase) were included. Demographics and clinical features were similar in both groups. No significant difference emerged between groups in terms of microbiological eradication (P = 0.10), 30 day resistance to ceftolozane/tazobactam (P = 0.37), clinical cure (P = 0.26) and 30 day mortality rate (P = 0.79). All patients in the post-intervention phase attained an optimal PK/PD target, allowing the use of a lower ceftolozane/tazobactam CI daily dosing regimen compared with the pre-intervention phase (3.0 g/1.5 g versus 6.0 g/3.0 g; P = 0.06). The only independent predictors of microbiological failure were difficult-to-treat resistant P. aeruginosa isolates in the pre-intervention group (OR 6.99; 95% CI 1.34-36.55), and a ratio of partial pressure of arterial oxygen to fraction of oxygen in the inhaled air (Pao2/Fio2 ratio) <200 in the post-intervention group (OR 18.00; 95% CI 1.86-174.22).

Conclusions: Our TDM-guided strategy of CI ceftolozane/tazobactam was cost-effective in attaining an aggressive PK/PD target of ceftolozane against susceptible P. aeruginosa strains with lower than standard daily doses without compromising efficacy.