Meropenem Pharmacokinetics and Target Attainment in Critically Ill Patients Are Not Affected by Extracorporeal Membrane Oxygenation: A Matched Cohort Analysis

Abstract

Existing evidence is inconclusive whether meropenem dosing should be adjusted in patients receiving extracorporeal membrane oxygenation (ECMO). Therefore, the aim of this observational matched cohort study was to evaluate the effect of ECMO on pharmacokinetic (PK) variability and target attainment (TA) of meropenem. Patients admitted to the intensive care unit (ICU) simultaneously treated with meropenem and ECMO were eligible. Patients were matched 1:1, based on renal function and body weight, with non-ECMO ICU patients. Meropenem blood sampling was performed over one or two dosing intervals. Population PK modelling was performed using NONMEM7.5. TA was defined as free meropenem concentrations >2 or 8 mg/L (i.e., 1 or 4× minimal inhibitory concentration, respectively) throughout the whole dosing interval. In total, 25 patients were included, contributing 27 dosing intervals. The overall TA was 56% and 26% for the 2 mg/L and 8 mg/L target, respectively. Population PK modelling identified estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology equation and body weight, but not ECMO, as significant predictors. In conclusion, TA of meropenem was confirmed to be poor under standard dosing in critically ill patients but was not found to be influenced by ECMO. Future studies should focus on applying dose optimisation strategies for meropenem based on renal function, regardless of ECMO.

Prediction of Insufficient Beta-Lactam Concentrations in Extracorporeal Membranous Oxygenation Patients

“…In another study, optimal TZP daily regimen was 4.5 q6h, although half of patients were on renal replacement therapy and, therefore, had reduced drug clearance [19]. Additionally, 44% of MEM concentrations were found below desired targets in a small cohort of ECMO patients [20]; insufficient MEM levels were more frequently observed in patients with elevated CrCL [21]. Importantly, the discrepancy observed among these studies, including our findings, could be explained by the different definition of insufficient drug levels.…”

“…Most ECMO equipment were implanted percutaneously or surgically with peripheral (mainly femoro-femoral if VA and femoro-jugular if VV ECMO) cannulation (20)(21)(22) Fr arterial cannula and 22-24 Fr venous cannula, Edwards Lifesciences, Irvine, CA, USA), as described elsewhere [12]. A centrifugal blood pump (Revolution blood pump, Sorin, Milano, Italy) was initially set at a blood flow of 3-4 L/min (based on patient body surface area).…”

“…As such, 110 patients for a total of 222 TDMs (CEF, n = 41; TZP, n = 85; MEM, n = 96) were included in the final analysis. Characteristics of the study population are shown in Table 2; APACHE II score on admission was 24 [17][18][19][20][21][22][23][24][25][26][27][28][29] and VA ECMO was used in 33 (30%) patients. Respiratory infections were the most frequent; Pseudomonas aeruginosa was identified in 24 (21%) patients.…”

“…Respiratory infections were the most frequent; Pseudomonas aeruginosa was identified in 24 (21%) patients. ICU length of stay was 19 [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] days and ICU mortality was reported in 61 (55%) patients.…”

Image1.TIFF

“…There have been still few population PK studies on ECMOrelated PK alterations of meropenem (Shekar et al, 2014;Hanberg et al, 2018;Gijsen et al, 2021). Meropenem, one of the antimicrobials typically used in ECMO patients, is a parenteral carbapenem antimicrobial agent and has a broad spectrum of antibacterial activity against Gram-positive, Gram-negative, and anaerobic pathogens.…”