Real-time TDM-based optimization of continuous-infusion meropenem for improving treatment outcome of febrile neutropenia in oncohaematological patients: results from a prospective, monocentric, interventional study

Objectives: To assess the role that real-time therapeutic drug monitoring (TDM)-guided optimization of continuous-infusion (CI) meropenem may have in maximizing empirical treatment and in preventing breakthrough infection and/or colonization with carbapenem-resistant Enterobacteriaceae (CRE) among oncohaematological patients with febrile neutropenia (FN). Methods: A monocentric, interventional, prospective study was conducted. The pharmacodynamic (PD) target was a steady-state meropenem concentration-to-MIC ratio (C-ss/MIC) of 4-8. The primary endpoint was 14day all-cause mortality. The secondary endpoint was the prevalence of CRE colonization in rectal swabs of patients rehospitalized within 3months. Results: Among the 75 patients enrolled, most (56%) had AML, almost half (37/75, 49.3%) underwent HSCT and one-third (32%) received meropenem as monotherapy. Meropenem dosages were adjusted in 30.1% of TDM reassessments. Gram-negative infections were microbiologically documented in 20.0% of patients. All of the 12 patients having infections caused by in vitro meropenem-susceptible pathogens attained the desired PD target and were cured. Three patients had infections caused by in vitro meropenem-resistant pathogens. Two of these achieved a C-ss/MIC target of 1 and were cured; the other one achieved a suboptimal PD target (0.59) and died. The 14day all-cause mortality (10.7%) was significantly associated, at multivariate regression, with HSCT (OR 0.086, 95% CI 0.008-0.936, P=0.044) and with augmented renal clearance (OR 10.846, 95% CI 1.534-76.672, P=0.017). None of the patients who had hospital readmissions in the 3month follow-up (63/75) had CRE colonization in rectal swabs. Conclusions: Real-time TDM-guided CI meropenem may be a useful approach for attaining adequate exposure and preventing CRE emergence in FN oncohaematological patients.