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

Abstract

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 (Css/MIC) of 4–8. The primary endpoint was 14 day all-cause mortality. The secondary endpoint was the prevalence of CRE colonization in rectal swabs of patients rehospitalized within 3 months. 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 Css/MIC target of 1 and were cured; the other one achieved a suboptimal PD target (0.59) and died. The 14 day 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 3 month 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.

Key Challenges in Providing Effective Antibiotic Therapy for Critically Ill Patients with Bacterial Sepsis and Septic Shock

“…In addition, the regression analysis included patients having both empirical and definitive therapy with meropenem. 52 Overall, the five studies discussed above returned apparently conflicting results and all studies had limitations. Thus, there have been calls for specific, directed clinical investigations into the optimal administration and dosing of different antimicrobial agents in the context of ARC.…”

Evaluation of Meropenem‐Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance

“…drug monitoring to guide selection of a dosage regimen to safely achieve a desired target plasma exposure has been advocated, including for patients with ARC who may require daily doses higher than those in the product label. 5,7,16,[34][35][36][37][38] The additive and synergistic bacterial killing and the suppression of less-susceptible populations observed with the combination regimens in this study are probably the result of the differences in the mechanism of action and resistance of carbapenems and The blue highlight indicates additivity (1-to < 2-log 10 colony-forming unit (CFU)/mL greater reduction with the combination compared with the most active single agent in the combination). The green highlight indicates synergy (≥ 2-log 10 CFU/mL greater reduction with the combination compared to the most active single agent in the combination).…”

“…1,2 Treatment is rendered difficult by augmented renal clearance (ARC), a state of accelerated glomerular filtration (creatinine clearance > 130 mL/minute) leading to suboptimal exposures to renally eliminated antibiotics (e.g., meropenem and ciprofloxacin), which is commonly observed among patients in the ICU and some other groups. [3][4][5][6][7] Indeed, in patients undergoing treatment with meropenem, ARC was significantly associated with an increased risk of 14-day all-cause mortality. 7 In the dynamic hollow-fiber infection model (HFIM) simulating pharmacokinetic (PK) profiles typical of patients with ARC, approved doses of meropenem and piperacillin as monotherapy against a susceptible P. aeruginosa isolate failed to achieve sufficient bacterial killing and resistance suppression.…”

“…[3][4][5][6][7] Indeed, in patients undergoing treatment with meropenem, ARC was significantly associated with an increased risk of 14-day all-cause mortality. 7 In the dynamic hollow-fiber infection model (HFIM) simulating pharmacokinetic (PK) profiles typical of patients with ARC, approved doses of meropenem and piperacillin as monotherapy against a susceptible P. aeruginosa isolate failed to achieve sufficient bacterial killing and resistance suppression. 8,9 Beta-lactam and aminoglycoside combinations studied in the HFIM under ARC conditions demonstrated good bacterial killing and resistance suppression, 10,11 but this combination has the potential to cause aminoglycoside-associated nephrotoxicity.…”

“…Severe infections caused by Pseudomonas aeruginosa are increasingly encountered in intensive care units (ICUs) resulting in high morbidity and mortality 1,2 . Treatment is rendered difficult by augmented renal clearance (ARC), a state of accelerated glomerular filtration (creatinine clearance > 130 mL/minute) leading to suboptimal exposures to renally eliminated antibiotics (e.g., meropenem and ciprofloxacin), which is commonly observed among patients in the ICU and some other groups 3–7 . Indeed, in patients undergoing treatment with meropenem, ARC was significantly associated with an increased risk of 14‐day all‐cause mortality 7 …”