In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model

D R Andes; D J Diekema; M A Pfaller; K Marchillo; J Bohrmueller

doi:10.1128/AAC.00478-08

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In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model

Journal article

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Peer reviewed

In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model

D R Andes, D J Diekema, M A Pfaller, K Marchillo and J Bohrmueller

Antimicrobial agents and chemotherapy, Vol.52(10), pp.3497-3503

10/2008

DOI: 10.1128/AAC.00478-08

PMCID: PMC2565916

PMID: 18625768

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Abstract

Previous studies using in vivo candidiasis models have demonstrated that the concentration-associated pharmacodynamic indices, the maximum concentration of a drug in serum/MIC and 24-h area under the curve (AUC)/MIC, are associated with echinocandin treatment efficacy. The current investigations used a neutropenic murine model of disseminated Candida albicans and C. glabrata infection to identify the 24-h AUC/MIC index target associated with a stasis and killing endpoint for the echinocandin, micafungin. The kinetics after intraperitoneal micafungin dosing were determined in neutropenic infected mice. Peak levels and AUC values were linear over the 16-fold dose range studied. The serum drug elimination half-life ranged from 7.5 to 16 h. Treatment studies were conducted with 4 C. albicans and 10 C. glabrata isolates with micafungin MICs varying from 0.008 to 0.25 microg/ml to determine whether similar 24-h AUC/MIC ratios were associated with efficacy. The free drug AUC/MICs associated with stasis and killing (1-log) endpoints were near 10 and 20, respectively. The micafungin exposures associated with efficacy were similar for the two Candida species. Furthermore, the free drug micafungin exposures required to produce stasis and killing endpoints were similar to those recently reported for another echinocandin, anidulafungin, against the identical Candida isolates in this model.

Antifungal Agents - pharmacology

Lipopeptides - pharmacokinetics

Lipopeptides - pharmacology

Echinocandins - pharmacokinetics

Colony Count, Microbial

Candidiasis - microbiology

Candidiasis - complications

Mice, Inbred ICR

Echinocandins - administration & dosage

Neutropenia - complications

Candidiasis - blood

Animals

Candida albicans - drug effects

Candidiasis - drug therapy

Antifungal Agents - pharmacokinetics

Female

Mice

Lipopeptides - administration & dosage

Antifungal Agents - administration & dosage

Echinocandins - pharmacology

Candida glabrata - drug effects

Disease Models, Animal

Details

Title: Subtitle: In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model
Creators: D R Andes - Department of Medicine, University of Wisconsin, 600 Highland Ave., Madison, WI 53792, USA. dra@medicine.wisc.edu
D J Diekema
M A Pfaller
K Marchillo
J Bohrmueller
Resource Type: Journal article
Publication Details: Antimicrobial agents and chemotherapy, Vol.52(10), pp.3497-3503
DOI: 10.1128/AAC.00478-08
PMID: 18625768
PMCID: PMC2565916
NLM abbreviation: Antimicrob Agents Chemother
ISSN: 0066-4804
eISSN: 1098-6596
Publisher: United States
Language: English
Date published: 10/2008
Academic Unit: Infectious Diseases; Epidemiology; Pathology; Internal Medicine
Record Identifier: 9983986364302771

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