β-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case–control study

https://doi.org/10.1016/j.ijantimicag.2014.11.005Get rights and content

Highlights

  • No significant differences in serum β-lactam concentrations between extracorporeal membrane oxygenation (ECMO) and non-ECMO patients were found in this study.

  • No significant differences in volume of distribution or drug elimination were observed in these two groups.

  • One-third of ECMO patients had insufficient drug concentrations to treat Pseudomonas aeruginosa.

  • Insufficient drug concentrations were more frequent with piperacillin/tazobactam than meropenem therapy.

Abstract

Most adult patients receiving extracorporeal membrane oxygenation (ECMO) require antibiotic therapy, however the pharmacokinetics of β-lactams have not been well studied in these conditions. In this study, data from all patients receiving ECMO support and meropenem (MEM) or piperacillin/tazobactam (TZP) were reviewed. Drug concentrations were measured 2 h after the start of a 30-min infusion and just before the subsequent dose. Therapeutic drug monitoring (TDM) results in ECMO patients were matched with those in non-ECMO patients for (i) drug regimen, (ii) renal function, (iii) total body weight, (iv) severity of organ dysfunction and (v) age. Drug concentrations were considered adequate if they remained 4–8× the clinical MIC breakpoint for Pseudomonas aeruginosa for 50% (TZP) or 40% (MEM) of the dosing interval. A total of 41 TDM results (27 MEM; 14 TZP) were obtained in 26 ECMO patients, with 41 matched controls. There were no significant differences in serum concentrations or pharmacokinetic parameters between ECMO and non-ECMO patients, including Vd [0.38 (0.27–0.68) vs. 0.46 (0.33–0.79) L/kg; P = 0.37], half-life [2.6 (1.8–4.4) vs. 2.9 (1.7–3.7) h; P = 0.96] and clearance [132 (66–200) vs. 141 (93–197) mL/min; P = 0.52]. The proportion of insufficient (13/41 vs. 12/41), adequate (15/41 vs. 19/41) and excessive (13/41 vs. 10/41) drug concentrations was similar in ECMO and non-ECMO patients. Achievement of target concentrations of these β-lactams was poor in ECMO and non-ECMO patients. The influence of ECMO on MEM and TZP pharmacokinetics does not appear to be significant.

Introduction

Extracorporeal membrane oxygenation (ECMO) has become an essential means of support for severe cardiorespiratory failure in critically ill patients [1]. Venovenous (VV) ECMO may play a key role in the advanced management of severe respiratory failure [2] with reported survival rates of up to 71% [3], and venoarterial (VA) ECMO has been associated with survival rates of >50% in adult patients with cardiogenic shock [4]. Some of these patients have serious infections that require effective antibiotic therapy. However, critical illness induces significant changes in antibiotic pharmacokinetics, in particular in the volume of distribution (Vd) and total drug clearance (CL), which may result in antibiotic concentrations that are insufficient to treat even more susceptible pathogens [5]. ECMO is thought to introduce additional confounding factors, including sequestration of antibiotics in the ECMO circuit, and the associated systemic inflammation can further increase the antibiotic Vd and reduce CL [6]. Nevertheless, despite the increasing use of ECMO support, few data are available related to how it may influence antibiotic pharmacokinetics.

This study investigated whether ECMO could alter the pharmacokinetics of meropenem (MEM) and piperacillin/tazobactam (TZP) in intensive care unit (ICU) patients. Using a case–control design, it was evaluated whether antibiotic concentrations achieved desirable pharmacodynamic (PD) targets to treat severe infections in patients treated with ECMO.

Section snippets

Patients and data collection

The medical charts of all adult patients who were treated with MEM or TZP during ECMO (VV, VA or both) over a 3-year period (January 2010–December 2012) at Erasme Hospital (Brussels, Belgium) were reviewed. Patients were identified using the patient data monitoring system (PDMS) (Picis Inc., Wakefield, MA). Pregnant patients and patients with burns or cystic fibrosis were excluded. The protocol was approved by the Ethics Committee of Erasme Hospital (Brussels, Belgium), which waived the need

Results

In total, 67 patients were studied, with a total of 41 pairs of TDM results (27 MEM and 14 TZP), comprising 26 patients treated with ECMO (n = 41 TDM results) and 41 well-matched controls (n = 41 TDM results); 9 TDM measurements were performed in patients on CRRT. Patient characteristics are shown in Table 1. In total, 9 patients were treated with VA ECMO for cardiogenic shock (4 after heart surgery, 4 due to decompensated ischaemic heart disease and 1 for drug intoxication) and 17 patients were

Discussion

In this study of MEM and TZP use during ECMO, PK parameters were not significantly altered in ECMO patients compared with control ICU patients. However, almost 30% of the overall TDM results were associated with insufficient antibiotic concentrations to optimally treat P. aeruginosa.

β-Lactams, including penicillins, cephalosporins and carbapenems, are widely prescribed in critically ill patients as first-line antibiotic therapy against Gram-negative pathogens. Their bactericidal properties are

Conclusions

In this case–control study, ECMO therapy did not significantly influence MEM or TZP pharmacokinetics compared with well-matched non-ECMO controls. However, the variability in PK parameters was high for both antibiotics, which resulted in a high proportion of all patients not achieving target concentrations.

Funding: JAR is funded in part by an Australian National Health and Medical Research Council Fellowship [APP1048652].

Competing interests: None declared.

Ethical approval: This study was

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