Pharmacokinetics and Safety of Fluconazole in Young Infants Supported With Extracorporeal Membrane Oxygenation

Watt, Kevin M.; Benjamin, Daniel K.; Cheifetz, Ira M.; Moorthy, Ganesh; Wade, Kelly C.; Smith, P. Brian; Brouwer, Kim L. R.; Capparelli, Edmund V.; Cohen‐Wolkowiez, Michael

doi:10.1097/inf.0b013e31825d3091

Cited by 47 publications

(37 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings are consistent with previous literature reporting increased V due to the ECMO prime volume in infants on fluconazole, vancomycin and gentamicin. 10,18,20,29-32 …”

Section: Discussionmentioning

confidence: 99%

“…6-8 However, the optimal dosing of micafungin remains to be established in the setting of ECMO because ECMO support can alter drug pharmacokinetics (PK). 9,10 In infants on ECMO, the volume of distribution (V) of drugs typically increases due to the large volume of blood required to prime the ECMO circuit, disease state (e.g., inflammation, anasarca), and drug adsorption by the ECMO circuit itself. 9-13 Clearance (CL) of drugs can be affected by the organ dysfunction commonly observed in infants on ECMO, as well as non-specific drug extraction by the circuit itself.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

Autmizguine

Hornik

Benjamin

et al. 2016

Pediatric Infectious Disease Journal

Self Cite

View full text Add to dashboard Cite

Background Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK). Methods To characterize micafungin PK and safety in infants on ECMO, we conducted an open label PK trial. Infants on ECMO either received IV micafungin 4 mg/kg/day for invasive candidiasis prophylaxis, or 8 mg/kg/day when a fungal infection was suspected or confirmed. We collected plasma samples after single and multiple micafungin doses. We defined the therapeutic target as the adult exposure associated with efficacy in Phase III trials, and the prophylactic target as one-half of the therapeutic target. Results We enrolled 12 infants (124 samples) with a median age of 59 days. Using a 1-compartment model, median weight-normalized volume of distribution and clearance were 0.64 L/kg and 0.041 L/kg/h, respectively. Dose-exposure simulations revealed that doses of 2.5 and 5 mg/kg/day matched exposure targets for prophylaxis and treatment of invasive candidiasis, respectively. We did not observe any drug-related adverse events. Conclusions In infants on ECMO, micafungin volume of distribution was higher and clearance was in the upper range of previously published values for infants not on ECMO. Based on these data, we recommend dosing of 2.5 and 5 mg/kg/day for prophylaxis and treatment of invasive candidiasis, respectively, to match adult exposure proven effective against Candida spp.

show abstract

“…Our findings are consistent with previous literature reporting increased V due to the ECMO prime volume in infants on fluconazole, vancomycin and gentamicin. 10,18,20,29-32 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

Autmizguine

Hornik

Benjamin

et al. 2016

Pediatric Infectious Disease Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…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 ϭ 12) (10), and study 3 was a multicenter PK study of fluconazole in infants (n ϭ 8) (11). The study designs are described in detail elsewhere (9)(10)(11). In brief, study 1 included critically ill children Ͻ18 years of age supported by ECMO who received intravenous (i.v.)…”

Section: Methodsmentioning

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…voriconazole and fentanyl) are significantly sequestered in the circuit, hydrophilic drugs (e.g. β-lactam antibiotics, glycopeptides) are significantly affected by hemodilution and other pathophysiologic changes that occur during ECMO(3-5). However, it is unknown if, and unlikely that, the published data and PK models are generalizable between circuit systems and over the wide, complex range of patient pathologies and physiology given the influence of drug molecular weight, volume of distribution, lipid solubility, protein binding, drug-drug interactions, circuit-related factors and the degree of hepatic and renal injury.…”

Section: Influence Of Mods Upon Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Pediatric Multiple Organ Dysfunction Syndrome: Promising Therapies

Doctor

Zimmerman

Agus

et al. 2017

Pediatric Critical Care Medicine

View full text Add to dashboard Cite

Objective To describe the state of the science, identify knowledge gaps, and offer potential future research questions regarding promising therapies for children with multiple organ dysfunction syndrome (MODS) presented during the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop on Pediatric Multiple Organ Dysfunction Syndrome (March 26-27, 2015). Data Sources Literature review, research data, and expert opinion. Study Selection Not applicable. Data Extraction Moderated by an expert from the field, issues relevant to the association of MODS with a variety of conditions were presented, discussed and debated with a focus on identifying knowledge gaps and research priorities. Data Synthesis Summary of presentations and discussion supported and supplemented by relevant literature. Conclusions Among critically ill children, MODS is relatively common and associated with significant morbidity and mortality. For outcomes to improve, effective therapies aimed at preventing and treating this condition must be discovered and rigorously evaluated. In this manuscript, a number of potential opportunities to enhance current care are highlighted including the need for a better understanding of the pharmacokinetics and pharmacodynamics of medications, the effect of early and optimized nutrition, and the impact of effective glucose control in the setting of MODS. Additionally, a handful of the promising therapies either currently being implemented or developed are described. These include extracorporeal therapies, anti-cytokine therapies, anti-toxin treatments, anti-oxidant approaches and multiple forms of exogenous steroids. For the field to advance, these and other therapies must be assessed in rigorous manner and implemented accordingly.

show abstract

Pharmacokinetics and Safety of Fluconazole in Young Infants Supported With Extracorporeal Membrane Oxygenation

Cited by 47 publications

References 25 publications

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

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

Pediatric Multiple Organ Dysfunction Syndrome: Promising Therapies

Contact Info

Product

Resources

About