Tigecycline in critically ill patients on continuous renal replacement therapy: a population pharmacokinetic study

Abstract

Background: Tigecycline is a vital antibiotic treatment option for infections caused by multiresistant bacteria in the intensive care unit (ICU). Acute kidney injury (AKI) is a common complication in the ICU requiring continuous renal replacement therapy (CRRT), but pharmacokinetic data for tigecycline in patients receiving CRRT are lacking.

Methods: Eleven patients mainly with intra-abdominal infections receiving either continuous veno-venous hemodialysis (CVVHD, n = 8) or hemodiafiltration (CVVHDF, n = 3) were enrolled, and plasma as well as effluent samples were collected according to a rich sampling schedule. Total and free tigecycline was determined by ultrafiltration and high-performance liquid chromatography (HPLC)-UV. Population pharmacokinetic modeling using NONMEM® 7.4 was used to determine the pharmacokinetic parameters as well as the clearance of CVVHD and CVVHDF. Pharmacokinetic/pharmacodynamic target attainment analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT.

Results: A two-compartment population pharmacokinetic (PK) model was suitable to simultaneously describe the plasma PK and effluent measurements of tigecycline. Tigecycline dialysability was high, as indicated by the high mean saturation coefficients of 0.79 and 0.90 for CVVHD and CVVHDF, respectively, and in range of the concentration-dependent unbound fraction of tigecycline (45-94%). However, the contribution of CRRT to tigecycline clearance (CL) was only moderate (CL_CVVHD: 1.69 L/h, CL_CVVHDF: 2.71 L/h) in comparison with CL_body (physiological part of the total clearance) of 18.3 L/h. Bilirubin was identified as a covariate on CL_body in our collective, reducing the observed interindividual variability on CL_body from 58.6% to 43.6%. The probability of target attainment under CRRT for abdominal infections was ≥ 0.88 for minimal inhibitory concentration (MIC) values ≤ 0.5 mg/L and similar to patients without AKI.

Conclusions: Despite high dialysability, dialysis clearance displayed only a minor contribution to tigecycline elimination, being in the range of renal elimination in patients without AKI. No dose adjustment of tigecycline seems necessary in CRRT.

Trial registration: EudraCT, 2012-005617-39 . Registered on 7 August 2013.

Keywords: CVVHD; CVVHDF; Dosing; NONMEM; Population pharmacokinetics; Renal replacement therapy; Tigecycline.

Fig. 1

Visual predictive checks for the developed population PK model. Plasma concentrations (left) and effluent concentrations (right). Observed (solid lines) and predicted median (dashed-dotted lines) with 10th to 90th observed (dashed) and predicted (dotted) percentiles. Shaded areas: 95% confidence interval

Fig. 2

Probability of PK/PD target attainment analysis. Complicated intra-abdominal infections (AUC_24h/MIC of 6.96) for dialysis patients of the present study compared with patients with cSSSI/cIAI (simulated from [15]) and healthy volunteers (simulated from [14]). Horizontal dashed line indicates PTA ≥ 0.9 considered as reliable target attainment. cSSSI complicated skin and skin structure infections, MIC minimal inhibitory concentration