The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis

Implications for echinocandin therapy in neonates

William W. Hope, Diana Mickiene, Vidmantas Petraitis, Ruta Petraitiene, Amy M. Kelaher, Joanna E. Hughes, Margaret P. Cotton, John Bacher, James J. Keirns, Donald Buell, Gloria Heresi, Daniel K. Benjamin, Andreas H. Groll, George L. Drusano, Thomas J. Walsh

Research output: Contribution to journalArticle

Abstract

Background. Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME. Methods. We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation. Results. Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses > 2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of ∼8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg. Conclusions. These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

Original languageEnglish (US)
Pages (from-to)163-171
Number of pages9
JournalJournal of Infectious Diseases
Volume197
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

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Echinocandins
Meningoencephalitis
Candida
Pharmacokinetics
Newborn Infant
Central Nervous System
Rabbits
Therapeutics
Candidiasis
Cerebrospinal Fluid
micafungin
Clinical Trials
Pediatrics
Mortality
Brain
Pharmaceutical Preparations
Population

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis : Implications for echinocandin therapy in neonates. / Hope, William W.; Mickiene, Diana; Petraitis, Vidmantas; Petraitiene, Ruta; Kelaher, Amy M.; Hughes, Joanna E.; Cotton, Margaret P.; Bacher, John; Keirns, James J.; Buell, Donald; Heresi, Gloria; Benjamin, Daniel K.; Groll, Andreas H.; Drusano, George L.; Walsh, Thomas J.

In: Journal of Infectious Diseases, Vol. 197, No. 1, 01.01.2008, p. 163-171.

Research output: Contribution to journalArticle

Hope, WW, Mickiene, D, Petraitis, V, Petraitiene, R, Kelaher, AM, Hughes, JE, Cotton, MP, Bacher, J, Keirns, JJ, Buell, D, Heresi, G, Benjamin, DK, Groll, AH, Drusano, GL & Walsh, TJ 2008, 'The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis: Implications for echinocandin therapy in neonates', Journal of Infectious Diseases, vol. 197, no. 1, pp. 163-171. https://doi.org/10.1086/524063
Hope, William W. ; Mickiene, Diana ; Petraitis, Vidmantas ; Petraitiene, Ruta ; Kelaher, Amy M. ; Hughes, Joanna E. ; Cotton, Margaret P. ; Bacher, John ; Keirns, James J. ; Buell, Donald ; Heresi, Gloria ; Benjamin, Daniel K. ; Groll, Andreas H. ; Drusano, George L. ; Walsh, Thomas J. / The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis : Implications for echinocandin therapy in neonates. In: Journal of Infectious Diseases. 2008 ; Vol. 197, No. 1. pp. 163-171.
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abstract = "Background. Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME. Methods. We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation. Results. Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses > 2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of ∼8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg. Conclusions. These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.",
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AU - Petraitiene, Ruta

AU - Kelaher, Amy M.

AU - Hughes, Joanna E.

AU - Cotton, Margaret P.

AU - Bacher, John

AU - Keirns, James J.

AU - Buell, Donald

AU - Heresi, Gloria

AU - Benjamin, Daniel K.

AU - Groll, Andreas H.

AU - Drusano, George L.

AU - Walsh, Thomas J.

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N2 - Background. Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME. Methods. We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation. Results. Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses > 2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of ∼8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg. Conclusions. These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

AB - Background. Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME. Methods. We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation. Results. Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses > 2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of ∼8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg. Conclusions. These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

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