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.

OBJECTIVE

To evaluate the impact of timing of aggressive joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion piperacillin-tazobactam on early clinical response in paediatric hematopoietic stem cell (HSCT) recipients with febrile neutropenia (FN).

METHODS

This prospective, monocentric, observational study included paediatric HSCT recipients receiving at least 72 h of therapeutic drug monitoring-guided continuous infusion piperacillin-tazobactam monotherapy for treating FN episodes. Plasma CRP, procalcitonin, and IL-6 levels were assessed at the onset of FN 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 independent predictors significantly associated with the attainment of aggressive PK/PD target at each timepoint.

RESULTS

Overall, 42 patients who received continuous infusion 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.