1317. Pharmacokinetics (PK) of Ampicillin-Sulbactam (SAM) during Orthotopic Liver Transplantation (OLT)

Abstract

BackgroundSAM is used as surgical prophylaxis during OLT due to its broad spectrum activity against Gram-positive,-negative and anaerobic pathogens. SAM resistance among Gram-negatives is rising, making dosage selection paramount to preventing surgical site infections. Current guidelines recommend a 3g dose, consisting of 2g ampicillin (AMP) and 1g sulbactam (SUL), every 2h. There are no data; however, describing SAM PK during OLT to support an optimized dosing regimen.MethodsThis was a single-center PK study of OLT patients receiving SAM for surgical prophylaxis at a dose selected by the anesthesiologist. Patients were excluded if they were undergoing simultaneous liver and kidney transplantation and had a CrCL < 30 mL/min at start of surgery. Up to 24 blood samples, along with times of pertinent events, were collected throughout the OLT. AMP and SUL plasma concentrations were determined. Population PK analyses were conducted in Pmetrics using R. Akaike information criterion (AIC) and visual inspection determined best model fit. Individual PK parameters were simulated to describe free AMP time above the MIC90 (fT >MIC90) of 32 mg/L.ResultsFive patients were enrolled. Participants had a mean ± SD age of 64 ± 7 years, body weight 82 ± 8 kg, CrCL of 75 ± 35 mL/min, and received various SAM doses (1.5-3g q2-3h). A 2 compartment model fitted the data better than a 1 compartment model for both AMP (AIC: 396 vs. 423) and SUL (AIC: 334 vs. 347). Final models included fractional clearance (CLf) terms on typical total body clearance (CLθ) to account for the placement of the portal vein clamp. AMP PK parameters (AIC: 372) were: CLθ, 9.7 ± 2.6 L/h; CLf, 0.73 ± 0.49; volume of central compartment (Vc), 7.2 ± 1.4 L; intercompartment constants (k12 and k21), 4.08 ± 3.28 and 2.63 ± 2.9 h-1, respectively. Final SUL PK parameters (AIC: 314) were: CLθ, 8.3 ± 2.5 L/h; CLf, 0.92 ± 0.55; Vc, 7.3 ± 1.6 L; k12, 4.60 ± 4.41 h-1, and k21, 4.07 ± 3.31 h-1. Exposures ranged from 58-96% with only 3g q2h providing nearly 100% fT >MIC90.ConclusionThis is the first study to describe intra-operative SAM PK in OLT recipients and the effect of portal vein clamp on AMP and SUL clearance. These data will help guide optimized SAM dosing regimens for OLT surgery based on local MIC distributions for targeted pathogens.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))