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Cited by 98Antifungal resistance and susceptibilityAntibiotics Pharmacokinetics and EfficacyFungal Infections and Studies

In vivo pharmacodynamics of a new triazole, ravuconazole, in a murine candidiasis model

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Andes, D., Marchillo, K., Stamstad, T., Conklin, R.·2003·Antimicrobial Agents and Chemotherapy
DOI 10.1128/aac.47.4.1193-1199.2003PMC PMC152484
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Abstract

In vivo studies have characterized the pharmacodynamic characteristics of the triazole fluconazole. These investigations demonstrated that the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (24-h AUC/MIC ratio) is the critical pharmacokinetic/pharmacodynamic (PK/PD) parameter associated with treatment efficacy. Further analysis demonstrated that a fluconazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole ravuconazole. The PK/PD parameters (percent time above the MIC, AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 24 and 72 h of therapy. Ravuconazole kinetics and protein binding were performed in neutropenic infected mice. Peak/dose and AUC/dose values ranged from 0.03 to 0.04 and 0.30 to 0.34, respectively. Serum elimination half-life ranged from 3.9 to 4.8 h. Protein binding was 95.8%. Single-dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum ravuconazole levels had fallen below the MIC. Treatment efficacies with the five dosing intervals studied were similar, supporting the argument for the AUC/MIC ratio as the PK/PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio, R 2 = 91%; peak/MIC ratio, R 2 = 85%; percent time above the MIC, R 2 = 47 to 65%). Similar studies were conducted with seven additional C. albicans isolates with various ravuconazole susceptibilities (MIC, 0.016 to 0.12 μg/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The ravuconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (10 to 36; mean ± SD = 20.3 ± 8.2; P = 0.43). These free-drug AUC/MIC ratios are similar to those observed for fluconazole in this model.

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  • In vivo animal studies against Candida strains with widely varying MICs show that the 24-hour AUC/MIC target associated with 50% maximal effect for triazoles is near 25 when free drug levels are considered.

    “In vivo animal studies against a large number of Candida strains with widely varying MICs (more than 2000-fold) show that the 24-hour AUC/MIC target associated with efficacy (50% maximal effect) for triazoles occurs at a value near 25 when free drug (non-protein bound) levels are considered.”

    From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [140]

  • In vivo studies have revealed prolonged periods of growth suppression after triazole concentrations decrease to less than the MIC (long PAFE).

    “In addition, in vivo studies have revealed prolonged periods of growth suppression after triazole concentrations decrease to less than the MIC (long PAFE).”

    From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [140]

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Research works printed but not linked: 3

  1. [4]Craig, W. A. 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 26:1-12. [DOI] [PubMed] [Google Scholar]
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Authors
Andes, D., Marchillo, K., Stamstad, T., & Conklin, R.
Affiliations
  • University of Wisconsin System (US)
  • William S. Middleton Memorial Veterans Hospital (US)
Corresponding author
Andes, D.
ORCID
Andes, D.
Venue
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Published
2003-04
Volume
47
Issue
4
Pages
1193-1199
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
DOI
10.1128/aac.47.4.1193-1199.2003
PMC
PMC152484
OpenAlex
W2166682252
Cited by
98
References
29
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 2 · 2016: 6 · 2015: 1 · 2014: 6 · 2013: 9 · 2012: 4
FWCI
5.47
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
ravuconazole, triazole antifungals, pharmacodynamics, pharmacokinetics, Candida albicans, candidiasis, PK/PD relationship, AUC/MIC ratio, neutropenic mice, free drug concentration, drug sensitivity, treatment efficacy prediction, fluconazole comparison, elimination half-life, protein binding, dosing interval
MeSH terms
Animals, Antifungal Agents, Candidiasis, Disease Models, Animal, Female, Humans, Mice, Inbred ICR, Microbial Sensitivity Tests, Thiazoles, Triazoles, Area Under Curve, Mice

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