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Table 3 PK/PD studies of beta-lactams in patients with extracorporeal membrane oxygenation

From: Pharmacokinetics–pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients

Study Endpoints Antibiotic Design Results Conclusions
Donadello et al. [100] To investigate whether ECMO could alter the pharmacokinetics of meropenem and piperacillin/tazobactam in ICU patients Meropenem
Piperacilin/tazobactam
Retrospective, case-control study in 67 ICU patients
Antibiotics daily dosing was done according to renal dosing
Beta-lactam plasma concentrations were measured T2 and just before administration of the subsequent dose T0
TDM results in ECMO patients (VV or VA) were matched (1:1) to TDM results of non-ECMO patients (total 41 TDM matches) according to the following criteria: drug regimen; renal function (same ClCr or, if on CRRT, same CRRT intensity with an acceptable difference of 10%); total body weight; SOFA score at the time of treatment initiation; age
For both antibiotics, there were numerical differences but with no statistical significance in Vd, t1/2 and CL between ECMO patients and controls
The proportions of insufficient (13/41 vs12/41), adequate (15/41 vs 19/41), and excessive (13/41 vs 10/41) drug concentrations were similar in ECMO and control patients
PK parameters and TDM results were not significantly altered in ECMO patients compared with control ICU patients
Almost 30% of the overall TDM results were associated with insufficient antibiotic concentrations to optimally treat P. aeruginosa
Shekar et al. [101] To describe single-dose meropenem PK during ECMO using critically ill patients with sepsis and not receiving ECMO as controls Meropenem Open-label, descriptive, matched-cohort PK study
Adult ICU patients on ECMO (no RRT n = 6; on RRT n = 5) and controls (no renal dysfunction n = 5; on RRT n = 5)
Meropenem doses in ECMO: 1 g 8/8 h (n = 8); 1.5 g 8/8 h (n = 2) and 2 g bolus; and 1 g 8/8 h (n = 1) Controls: 1.5 g bolus and 1 g 8/8 h (no renal dysfunction); 1 g 8/8 h
Controls vs ECMO
Cmax: 65.4 (58.7–74.4) vs 55.3 (37.8–60.4) mg/L
Cmin: 4.2 (0.0–5.7) vs 7.2 (4.0–17.2) mg/L
Vd: 0.45 ± 0.17 vs 0.41 ± 0.13 L/kg, P = 0.21
Clearance: 7.9 ± 5.9 vs 11.7 ± 6.5 L/h, P = 0.18
ECMO patients, trough concentrations > 2 mg/L were achieved in all patients. Through concentrations > 8 mg/L (targeting less susceptible microorganisms) were achieved in only 8 out of 11 patients, 5 of them being on RRT
Standard meropenem dosing (1 g IV 8-hourly) as an intermittent bolus infusion in ECMO patients is likely to result in drug concentrations sufficient to treat highly susceptible Gram-negative pathogens
However, when treating less susceptible P. aeruginosa (MIC90 8 mg/L) and Acinetobacter
species (MIC90 16 mg/L) higher meropenem doses may have to be considered
Welsch et al. [102] To report the cases of two patients on VV ECMO for refractory ARDS following lung transplantation and treated empirically with imipenem Imipenem Case report
Imipenem 1 g every 6 h
Serum and mini-BAL samples (native and transplant lung) collected at steady state after 2 days of therapy immediately before the fifth drug dose
Enterobacter cloacae was isolated from the respiratory sample of patient 1 and Klebsiella pneumoniae was isolated from the respiratory sample of patient 2
MIC of the two isolated strains were 0.125 and 0.25 mg/L, respectively
BAL concentrations were undetectable (< 0.5 mg/L)
Serum T > MIC of both microorganisms was 100%
Considering more resistant microorganisms, such as P. aeruginosa with MIC > 2 mg/L, the probability of achieving a fractional time above MIC > 50% or 100% was also high
There was great variability in the residual serum
concentration of imipenem between the two patients
An elevated dosing regimen (4 g/24 h) is more likely to optimize drug exposure, and therapeutic drug monitoring is recommended
  1. ARDS acute respiratory distress syndrome, BAL bronchial-alveolar lavage, CL clearance, ClCr creatinine clearance, CRRT continuous renal replacement therapy, ECMO extracorporeal membrane oxygenation, ICU intensive care unit, MIC minimal inhibitory concentration, RRT renal replacement therapy, SOFA sequential organ failure assessment, T > MIC percentage of time above minimal inhibitory concentration, T0 0 h after the start of infusion, T2 2 h after the start of infusion, TDM therapeutic drug monitoring, Vd volume of distribution, venous-arterial, VV venous-venous