Impact of timing of aggressive joint PK/PD target attainment of continuous infusion piperacillin-tazobactam on early clinical response of febrile neutropenia to antimicrobial treatment: insights from a prospective, monocentric, observational study in pediatric hematopoietic stem cell recipients

Objective: To evaluate the impact of timing of aggressive joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin-tazobactam on early clinical response in pediatric hematopoietic stem cell (HSCT) recipients with febrile neutropenia (FN). Methods: This prospective, monocentric, observational study included pediatric HSCT recipients receiving at least 72 hours of TDM-guided CI piperacillin-tazobactam monotherapy for treating FN episodes. Plasma C-reactive protein, procalcitonin, and interleukin-6 levels were assessed at the onset of febrile neutropenia episodes and at day +1 and +3 after starting antibiotic therapy, together with steady-state piperacillin-tazobactam concentrations (Css). Aggressive piperacillin-tazobactam joint PK/PD target attainment was calculated at each timepoint. Multivariate logistic regression analyses were performed for identifying at each timepoint independent predictors significantly associated with the attainment of aggressive PK/PD target. Results: Overall, 42 patients who received CI piperacillin-tazobactam for 49 documented FN episodes were enrolled. The proportion of aggressive joint PK/PD target attainment was 46.7% at day +1 and increased to 67.3% at day +3 (p=0.04). Clinical response at day +3 was reported in 35 FN episodes (71.4%). Aggressive PK/PD target attainment occurred more frequently in cases having lower baseline creatinine clearance values at day +1 (OR 1.01; 95%CI 1.00-1.02; p=0.018), and was an independent predictor of >50% reduction of baseline plasma interleukin-6 levels at day +3 (OR 4.62; 95%CI 1.22-17.45; p=0.024). Conclusions: Attaining aggressive piperacillin-tazobactam joint PK/PD target in pediatric HSCT recipients with FN was significantly associated with reduction >50% in interleukin-6 levels at day +3, although no significant impact on early clinical response was found.