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Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy.

ABSTRACT: Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100?ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60?kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5?mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8?h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.).

SUBMITTER: Leuppi-Taegtmeyer AB

PROVIDER: S-EPMC6355613 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy.

Leuppi-Taegtmeyer Anne B AB Decosterd Laurent L Osthoff Michael M Mueller Nicolas J NJ Buclin Thierry T Corti Natascia N

Antimicrobial agents and chemotherapy 20190129 2

Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS ...[more]

PMID: 30478168

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Project description: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 (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. 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.

Project description:BackgroundRhabdomyolysis is a condition that is characterised by the breakdown of skeletal muscle tissue and leakage of intracellular myocyte contents into circulating blood. Rhabdomyolysis can lead to acute kidney injury (AKI) and is a potentially life-threatening condition. Studies have indicated that continuous renal replacement therapy (CRRT) may provide benefits for people with rhabdomyolysis by removing potentially damaging myoglobin and stabilising haemodynamic and metabolic status.ObjectivesWe aimed to: i) assess the efficacy of CRRT in removing myoglobin; ii) investigate the influence of CRRT on mortality and kidney-related outcomes; and iii) evaluate the safety of CRRT for the treatment of people with rhabdomyolysis.Search methodsWe searched the Cochrane Renal Group's Specialised Register to 6 January 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We also searched China National Knowledge Infrastructure (from 1 January 1979 to 16 April 2013) and the Chinese Clinical Trials Register (to 16 April 2013).Selection criteriaAll randomised controlled trials (RCTs) and quasi-RCTs that investigated clinical outcomes of CRRT for people with rhabdomyolysis were included.Data collection and analysisTwo authors independently assessed studies for inclusion and extracted data. We derived risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Methodological risk of bias was assessed using the Cochrane risk of bias tool.Main resultsOf the three included studies (101 participants), one evaluated continuous arteriovenous haemodialysis and two investigated continuous venovenous haemofiltration; all included conventional therapy as control.We found significant decreases in myoglobin in patients among whom CRRT therapy was initiated on days four, eight, and 10 (day 4: MD -11.00 (μg/L), 95% CI -20.65 to -1.35; Day 8: MD -23.00 (μg/L), 95% CI -30.92 to -15.08; day 10: MD -341.87 (μg/L), 95% CI -626.15 to -57.59) compared with those who underwent conventional therapy.Although CRRT was associated with improved serum creatinine, blood urea nitrogen, and potassium levels; reduced duration of the oliguria phase; and was associated with reduced time in hospital, no significant differences were found in mortality rates compared with conventional therapy (RR 0.17, 95% CI 0.02 to 1.37). The included studies did not report on long-term outcomes or prevention of AKI.Overall, we found that study quality was suboptimal: blinding and randomisation allocation were not reported by any of the included studies, leading to the possibility of selection, performance and detection bias.Authors' conclusionsAlthough CRRT may provide some benefits for people with rhabdomyolysis, the poor methodological quality of the included studies and lack of data relating to clinically important outcomes limited our findings about the effectiveness of CRRT for people with rhabdomyolysis.There was insufficient evidence to discern any likely benefits of CRRT over conventional therapy for people with rhabdomyolysis and prevention of rhabdomyolysis-induced AKI.

Dataset Information

Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy.

Publications

Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy.

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