Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study

Abstract

Background Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO. Methods Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints. Results The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem. Conclusions ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.

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

“…Therefore, our results are not surprising, as meropenem is a hydrophilic drug (log P −0.6) [ 40 ] and shows low plasma protein binding (2%) [ 26 ]. In contrast, a recent unmatched cohort study found ECMO treatment to be associated with lower serum concentrations of meropenem [ 19 ]. They reported that sequestration of meropenem in the ECMO circuit is a possible reason for this.…”

“…In a matched cohort study examining the effects of ECMO and renal replacement therapy, CrCL CG and renal replacement therapy were correlated with meropenem clearance [ 41 ]. In the previously mentioned unmatched cohort study of Kuhn et al, PK/PD targets were attained in >90% of all TDM measurements for meropenem [ 19 ]. This stands in great contrast to all previous studies.…”

“…A recent review recommended beta-lactam dosing in ECMO patients to align with dosing strategies used for critically ill patients not supported by ECMO [ 18 ]. In contrast, the largest therapeutic drug monitoring (TDM) study performed in ECMO patients until now, published last year, reported significantly lower meropenem plasma concentrations in ECMO patients [ 19 ]. As a result, it is still unclear whether meropenem PK is significantly affected by ECMO, and whether meropenem dosing should be adjusted in these patients.…”

Meropenem use and therapeutic drug monitoring in clinical practice: a literature review

“…Such fact seems to have no significant effect on the pharmacokinetic parameters of meropenem 27 . Kühn et al (2020) 51 found a statistically significant lower serum concentration of meropenem in patients receiving ECMO treatment when compared to non‐ECMO patients (15.0 mg/L vs. 17.8 mg/L, respectively). In this sense, more studies are needed to define a good dosage strategy for these patients and TDM can help in such definition.…”

“…Kühn et al (2020) 51 found a statistically significant lower serum concentration of meropenem in patients receiving ECMO treatment when compared to non-ECMO patients (15.0 mg/L vs. 17.8 mg/L, respectively). In this sense, more studies are needed to define a good dosage strategy for these patients and TDM can help in such definition.Dulhunty et al (2013)42 conducted a multicentre, double-blind, randomized controlled trial with 60 patients, also comparing continuous versus intermittent infusion.…”