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 paediatric hematopoietic stem cell recipients

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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 (C ss ). 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.

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