Population Pharmacokinetics of Fluconazole in Critically Ill Patients Receiving Continuous Venovenous Hemodiafiltration: Using Monte Carlo Simulations To Predict Doses for Specified Pharmacodynamic Targets

Patel, Kashyap; Roberts, Jason A.; Lipman, Jeffrey; Tett, S. E.; DelDot, Megan E.; Kirkpatrick, Carl M.

doi:10.1128/aac.00424-11

Cited by 53 publications

(39 citation statements)

References 39 publications

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“…The results of the aforementioned study support the current study, which demonstrated that fluconazole at lower dosing failed to achieve the desired PK/PD in various scenarios. In a population PK study of fluconazole in critically ill patients receiving continuous veno-venous hemodiafiltration (CVVHDF), fluconazole clearance was higher than previously observed (32). Thus, this study recommended that higher fluconazole dosing is required in patients undergoing CVVHDF.…”

Section: Discussionmentioning

confidence: 83%

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Alobaid

Wallis

Jarrett

et al. 2016

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 83%

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Alobaid

Wallis

Jarrett

et al. 2016

Antimicrob Agents Chemother

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“…The possible exception to this conclusion is when ECMO is combined with hemofiltration or CVVHD. Studies in adults show that fluconazole CL increases in the presence of hemofiltration and CVVHD (26)(27)(28)(29). Only 5 children received hemofiltration, and two received CVVHD, limiting our ability to draw conclusions about their impact on CL.…”

Section: Discussionmentioning

confidence: 99%

Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

Watt

González

Benjamin

et al. 2015

Antimicrob Agents Chemother

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f Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance ( Extracorporeal membrane oxygenation (ECMO) is life-saving in children with refractory cardiorespiratory failure. ECMO is a cardiopulmonary bypass device that provides complete respiratory and cardiac support. Mechanically, blood is drained from the venous system, pumped through an artificial lung membrane in which oxygen is added and carbon dioxide is removed, and then returned to either venous or arterial circulation. ECMO has been used successfully to support children with multiple disease processes, including meconium aspiration syndrome, fulminant myocarditis, and sepsis (1). Despite these successes, children supported by ECMO are at high risk for ECMO-related complications, especially nosocomial infections (2).Invasive candidiasis is common and fatal in children on ECMO. In this population, Candida species are the most common infectious organism (2). The incidence of infection varies by center, and rates as high as 10% have been reported (2, 3). Candida infections cause substantial morbidity and mortality (3) and are difficult to eradicate due to the ability of the organism to adhere to indwelling catheters. For this reason, routine management of candidiasis consists not only of the use of antifungal agents but also the removal of catheters (4). Catheter removal for children on ECMO is often impossible, because the ECMO cannulas connect the child to the ECMO circuit. Therefore, therapy on ECMO relies on either the prevention of invasive candidiasis or optimal therapeutic dosing in children with infection.Optimal dosing for prevention or treatment of candidiasis in children on ECMO can differ greatly from that with other populations due to the pharmacokinetic (PK) changes induced by the ECMO circuit. PK changes attributed to ECMO support include increased volume of distribution (V) and decreased clearance (CL), but these vary by drug and are not consistently predicted using drug physicochemical properties (5-8). This study describes the population PK of fluconazole in children supported by ECMO and provides rational dosing recommendations for the prevention and treatment of invasive candidiasis in this vulnerable population. MATERIALS AND METHODSStudy design. Fluconazole samples were obtained from three prospective trials. Study 1 was a single-center open-label PK study of fluconazole in children on ECMO (n ϭ 20) (9), study 2 was a single-center PK study of a fluconazole loading dose in critically ill children (n...

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“…In some instances, critically ill patients requiring RRTs require higher doses of antibiotic than recommended for individuals receiving intermittent hemodialysis for end-stage renal disease (13,23,24). A pharmacokinetic study of ertapenem in critically ill subjects requiring extended daily dialysis (blood and dialysate flow rates of 160 ml/min, treatment duration of 480 min) suggested that a dose of 1 g every 24 h, substantially higher than the manufacturer's suggested dosing for patients with creatinine clearance of Ͻ30 ml/min/1.73 m 2 (500 mg q24h) or receiving maintenance hemodialysis (500 mg within 6 h prior to hemodialysis, supplementary 150 mg following the hemodialysis session), is more appropriate to achieve bactericidal targets (1,25).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Ertapenem in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis or Hemodiafiltration

Eyler

Vilay

Nader

et al. 2014

Antimicrob Agents Chemother

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jThis study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 g/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 g/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.)

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Population Pharmacokinetics of Fluconazole in Critically Ill Patients Receiving Continuous Venovenous Hemodiafiltration: Using Monte Carlo Simulations To Predict Doses for Specified Pharmacodynamic Targets

Cited by 53 publications

References 39 publications

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

Pharmacokinetics of Ertapenem in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis or Hemodiafiltration

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