The blind spot in high-dose tigecycline pharmacokinetics in critically ill patients: membrane adsorption during continuous extracorporeal treatment

Honoré, Patrick M.; Jacobs, Rita; Waele, Elisabeth De; Gorp, Viola Van; Spapen, Herbert D.

doi:10.1186/s13054-015-0744-9

Cited by 8 publications

(5 citation statements)

References 6 publications

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“…According to the manufacturer’s SPC (SPC Tygacil 50 mg powder for solution for infusion, Pfizer Limited, Sandwich, UK), the in-vitro plasma protein binding of tigecycline ranges from 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mg/L), corresponding to an unbound fraction ( f u) of only 11–29%. These protein binding data have been suggested as an explanation for the poor elimination of tigecycline by intermittent hemodialysis [19]. However, the mean saturation coefficient of 0.79 for CVVHD or 0.90 for CVVHDF as found in the present study indicates good transfer of tigecycline through the dialysis membrane, and is a strong argument against a high plasma protein binding of tigecycline.…”

Section: Discussionsupporting

confidence: 42%

“…Protein binding of tigecycline is affected by divalent cations such as calcium [8]; hence, citrate anticoagulation within the extracorporeal circulation might theoretically affect its transfer through the dialysis membrane. Moreover, tigecycline can adsorb to plastic labware [8] and apparently also to dialysis membranes [19]. In one patient, we observed a time delay in the effluent concentrations which may have been caused by adsorption losses, e.g., after changing the filter, and which would have resulted in an underestimated dialysis clearance.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 42%

Section: Discussionmentioning

confidence: 97%

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

et al. 2018

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“…On the other hand, no relationship between CL and body weight was reported in a study of obese patients by Pai ( 22 ). Honore et al ( 23 ) suggested the influence of CRRT on tigecycline PK; however, the group of patients who did not receive CRRT in this study was too small to assess the impact of CRRT on individual PK parameters.…”

Section: Discussionmentioning

confidence: 68%

Population Pharmacokinetics of High-Dose Tigecycline in Patients with Sepsis or Septic Shock

Moor

Rypulak

Potręć

et al. 2018

Antimicrob Agents Chemother

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Tigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in intensive care unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high-dose tigecycline in patients with sepsis or septic shock and evaluate the relationship between individual PK parameters and patient covariates. The study population consisted of 37 adult ICU patients receiving a 200-mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8, and 12 h after dose administration. A two-compartment model with interindividual (IIV) and interoccasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline. The estimated values of mean population PK parameters were 22.1 liters/h and 69.4 liters/h for elimination and intercompartmental clearance, respectively, and 162 liters and 87.9 liters for volume of the central and peripheral compartment, respectively. The IIV and IOV in clearance were less than 20%. The estimated values of distribution volumes were different from previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient covariates was found. The developed model does not show evidence that individual tigecycline dosing adjustment based on patient covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility, and PK targets.

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“…Tigecycline is a lipophilic antibiotic with a small molecule and a large volume of distribution, particularly in critically ill patients. Recently published papers suggest that the doses should be increased to improve treatment efficacy in comparison to the currently recommended dose [23][24][25]. A relatively high degree of protein binding (71-78%) and a large volume of distribution (V ss > 900 L) theoretically decreases the elimination of this antibiotic through CRRT [26].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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The aim of this study was to assess the adsorption of selected antibiotics: vancomycin, gentamicin, ciprofloxacine and tigecycline in an experimental continuous veno-venous hemofiltration circuit with the use of both polyethyleneimine-treated polyacrylonitrile (PAN) and the polysulfone (PS) filter membranes. The crystalloid fluid dosed with one of antibiotic was pumped from a reservoir through a hemofiltration circuit (with PAN or PS membrane) and back to reservoir. All ultrafiltrate was also returned to the reservoir. During the procedures samples were collected from the post-hemofilter port at 5, 15, 30, 45, 60, 90, and 120 min. To determine spontaneous degradation of the antimicrobials, an additional bag with each study drug was prepared, which was not attached to the hemofiltration circuit. The samples from these bags were used as controls. In the case of vancomycin, gentamycin and tigecycline there was a statistically significant decrease in the drug concentration in the hemofiltration circuit in comparison to the control for PAN membrane (P < 0.05, P < 0.001, P < 0.001, respectively). In the case of ciprofloxacine adsorption was reversible and the drug concentrations increase to achieve the initial level for both membranes. Our studies indicated that a large portion of the administered dose of antibiotics may be adsorbed on a PAN membrane. In the case of gentamicin and tigecycline this amount is sufficiently big (over 90% of the administered dose) to be of clinical importance. In turn, adsorption on PS membranes is clearly lower (up to 10%) and may be clinically unimportant.

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The blind spot in high-dose tigecycline pharmacokinetics in critically ill patients: membrane adsorption during continuous extracorporeal treatment

Cited by 8 publications

References 6 publications

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

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

Population Pharmacokinetics of High-Dose Tigecycline in Patients with Sepsis or Septic Shock

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

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