title: The combined effects of extracorporeal membrane oxygenation and renal replacement therapy on meropenem pharmacokinetics: a matched cohort study.
abstract: BACKGROUND
  The scope of extracorporeal membrane oxygenation (ECMO) is expanding; however, optimal drug prescription during ECMO remains a developing science. Currently, there are no clear guidelines for antibiotic dosing during ECMO. This open-label, descriptive, matched-cohort pharmacokinetics (PK) study aimed to compare the PK of meropenem in ECMO patients to critically ill patients with sepsis not receiving ECMO (controls).
  
  
  METHODS
  Eleven adult patients on ECMO (venovenous (VV) ECMO, n = 6; venoarterial (VA) ECMO, n = 5) receiving intravenous (IV) meropenem were included. Meropenem plasma concentrations were determined using validated chromatography. Population PK analysis was performed using non-linear mixed effects modelling. This data was compared with previously published meropenem PK data from 10 critically ill adult patients not on ECMO (preserved renal function (n = 5) or receiving renal replacement therapy (RRT) (n = 5). Using these data, we then performed Monte Carlo simulations (n = 1,000) to describe the effect of creatinine clearance on meropenem plasma concentrations.
  
  
  RESULTS
  In total, five (two VV, three VA) out of eleven ECMO patients received RRT. The other six patients (four VV, two VA) had no significant impairment in renal function. A two-compartment model adequately described the data. ECMO patients had numerically higher volume of distribution (0.45 ± 0.17 versus 0.41 ± 0.13 L/kg, P = 0.21) and lower clearance compared to controls (7.9 ± 5.9 versus 11.7 ± 6.5 L/h, P = 0.18). Variability in meropenem clearance was correlated with creatinine clearance or the presence of RRT. The observed median trough concentrations in the controls were 4.2 (0.0 to 5.7) mg/L. In ECMO patients, while trough meropenem concentrations >2 mg/L were achieved in all patients, a more aggressive target of >8 mg/L for less susceptible microorganisms was observed in only eight out of eleven patients, with five of them being on RRT.
  
  
  CONCLUSIONS
  ECMO patients exhibit high PK variability. Decreased meropenem CL on ECMO appears to compensate for ECMO and critical illness-related increases in volume of distribution. Routine target concentrations >2 mg/L are maintained with standard dosing (1 g IV 8-hourly). However, an increase in dose may be necessary when targeting higher concentrations or in patients with elevated creatinine clearance.
authors: Critical Care Research Group, Adult Intensive Care Services, The Prince Charles Hospital and The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. kiran.shekar@health.qld.gov.au.
authors: Kiran
authors: K
authors: Shekar
authors: Critical Care Research Group, Adult Intensive Care Services, The Prince Charles Hospital and The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. john.fraser@uq.edu.au.
authors: John F
authors: JF
authors: Fraser
authors: Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, 808, Route de Lennik, 1070, Brussels, Belgium. ftaccone@ulb.ac.be.
authors: Fabio Silvio
authors: FS
authors: Taccone
authors: Intensive Care Services, St Vincent's Hospital, 683 George Street, Sydney, NSW 2000, Australia. swelch@stvincents.com.au.
authors: Susan
authors: S
authors: Welch
authors: Burns Trauma and Critical Care Research Centre, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. s.wallis@uq.edu.au.
authors: Steven C
authors: SC
authors: Wallis
authors: Critical Care Research Group, Adult Intensive Care Services, The Prince Charles Hospital and The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. dan.mullany@health.qld.gov.au.
authors: Daniel V
authors: DV
authors: Mullany
authors: Burns Trauma and Critical Care Research Centre, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. j.lipman@uq.edu.au.
authors: Jeffrey
authors: J
authors: Lipman
authors: Burns Trauma and Critical Care Research Centre, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. j.roberts2@uq.edu.au.
authors: Jason A
authors: JA
authors: Roberts
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015331:Cohort Studies; D016638:Critical Illness; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D009010:Monte Carlo Method; D017582:Renal Replacement Therapy; D018805:Sepsis / Q000378:metabolism; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem
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