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

Abstract

BackgroundTigecycline 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.MethodsEleven 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.ResultsA 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 (CLCVVHD: 1.69 L/h, CLCVVHDF: 2.71 L/h) in comparison with CLbody (physiological part of the total clearance) of 18.3 L/h. Bilirubin was identified as a covariate on CLbody in our collective, reducing the observed interindividual variability on CLbody 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.ConclusionsDespite 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 registrationEudraCT, 2012–005617-39. Registered on 7 August 2013.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2278-4) contains supplementary material, which is available to authorized users.

Comparison of adsorption of selected antibiotics on the filters in continuous renal replacement therapy circuits: in vitro studies

“…To date there have been no studies on the adsorption of tigecycline on the filter membranes used for CRRT. Broeker et al [27] report that during the pharmacokinetic assessment of tigecycline during CRRT using PS filters in a group of 11 patients, one of the patients experienced a time delay in the effluent concentrations of tigecycline, which may have been caused by adsorption losses. In our study, a statistically significant, substantial adsorption was observed (more than 95%) for the AN69ST membrane.…”

Assessing parameter uncertainty in small-n pharmacometric analyses: value of the log-likelihood profiling-based sampling importance resampling (LLP-SIR) technique

“…All methods, SE, BS, LLP, BAY, SE-SIR, BS-SIR and LLP-SIR, were also applied to a clinical dataset example [5] and the 95% CI by the different methods were compared. The dataset originating from a hemodialysis study with 11 patients contained 180 blood and 109 dialysate samples thereby represented a typical example for a small-n study.…”

“…Nonlinear mixed-effects modelling has gained an important role in quantitative clinical pharmacology, drug development and therapeutic drug use [1,2]. In many applications when non-linear mixed effects modelling is employed, small datasets containing ten or even fewer subjects appear regularly [3][4][5], for example due to ethical concerns, high risks, high costs, low availability of patient (sub)groups of interest to the study or multiple factors. Conclusions drawn from such 'small-n' studies depend on the estimated parameters as well as parameter uncertainty.…”

No dose adjustment of tigecycline is necessary during continuous renal replacement therapy: we are not sure

“…Broeker et al conclude that tigecycline (TGC) losses during continuous renal replacement therapy (CRRT) are comparable to those of patients with normal renal function, indicating that no dose adjustment of TGC is necessary during CRRT [1]. We would like to make some comments.…”