title: Are interstitial fluid concentrations of meropenem equivalent to plasma concentrations in critically ill patients receiving continuous renal replacement therapy?
abstract: OBJECTIVE
  To describe the interstitial fluid (ISF) and plasma pharmacokinetics of meropenem in patients on continuous venovenous haemodiafiltration (CVVHDF).
  
  
  METHODS
  This was a prospective observational pharmacokinetic study. Meropenem (500 mg) was administered every 8 h. CVVHDF was targeted as a 2-3 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2 and a blood flow rate of 200 mL/min. Serial blood (pre- and post-filter), filtrate/dialysate and ISF concentrations were measured on 2 days of treatment (Profiles A and B). Subcutaneous tissue ISF concentrations were determined using microdialysis.
  
  
  RESULTS
  A total of 384 samples were collected. During Profile A, the comparative median (IQR) ISF and plasma peak concentrations were 13.6 (12.0-16.8) and 40.7 (36.6-45.6) mg/L and the trough concentrations were 2.6 (2.4-3.4) and 4.9 (3.5-5.0) mg/L, respectively. During Profile B, the ISF trough concentrations increased by ∼40%. Meropenem ISF penetration was estimated at 63% (60%-69%) and 69% (65%-74%) for Profiles A and B, respectively, using comparative plasma and ISF AUCs. For Profile A, the plasma elimination t1/2 was 3.7 (3.3-4.0) h, the volume of distribution was 0.35 (0.25-0.46) L/kg, the total clearance was 4.1 (4.1-4.8) L/h and the CVVHDF clearance was 2.9 (2.7-3.1) L/h.
  
  
  CONCLUSIONS
  This is the first known report of concurrent plasma and ISF concentrations of a meropenem antibiotic during CVVHDF. We observed that the ISF concentrations of meropenem were significantly lower than the plasma concentrations, although the present dose was appropriate for infections caused by intermediately susceptible pathogens (MIC≤4 mg/L).
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6 Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Varghese
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Level 3, Ned Hanlon Building, Brisbane, Queensland 4029, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Jarrett
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6 Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6 Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Level 3, Ned Hanlon Building, Brisbane, Queensland 4029, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Boots
authors.affiliation: Centre for Medicine Use and Safety, Monash University, 381 Royal Parade, Melbourne, Victoria 3052, Australia.
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6 Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Level 3, Ned Hanlon Building, Brisbane, Queensland 4029, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6 Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Level 3, Ned Hanlon Building, Brisbane, Queensland 4029, Australia Pharmacy Department, Royal Brisbane and Women's Hospital, Level 1, Ned Hanlon Building, Brisbane, Queensland 4029, Australia j.roberts2@uq.edu.au.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016638:Critical Illness / Q000628:therapy*; D045604:Extracellular Fluid; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D010949:Plasma; D011446:Prospective Studies; D017582:Renal Replacement Therapy; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem
keywords: microdialysis; pharmacodynamics; pharmacokinetics; target sites; β-lactams