• A Padullés Zamora, R Juvany Roig, E Leiva Badosa, J Sabater Riera, X L Pérez Fernández, P Cárdenas Campos, R Rigo Bonin, P Alía Ramos, F Tubau Quintano, E Sospedra Martinez, and H Colom Codina.
• Pharmacy Department, Bellvitge University Hospital, Barcelona, Spain.
• J. Antimicrob. Chemother. 2019 Oct 1; 74 (10): 2979-2983.

BackgroundThe pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris® high-adsorbent membrane.ObjectivesTo develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris® membrane, and to design an optimal dosing regimen assessed according to the PTA.MethodsA prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24 h after concomitant administration of CVVHDF and meropenem 1 g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT>MIC).ResultsThe PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78 L/h [relative standard error (RSE) 16.45 L/h] and central compartment V (Vc) was 24.9 L (RSE 13.73 L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC ≤2 mg/L) and attainment of 100%fT>MIC, 500 mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT>4×MIC, CI of 3000 mg q24h or 2000 mg q8h administered as EI or CI would be required.ConclusionsWe have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris® membrane. This tool will support physicians when calculating the optimal initial dose.© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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