In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model

Andes, D.; Diekema, D. J.; Pfaller, M. A.; Prince, R. A.; Marchillo, K.; Ashbeck, J.; Hou, J.

doi:10.1128/aac.01061-07

Cited by 140Antifungal resistance and susceptibilityAntibiotics Pharmacokinetics and EfficacyFungal Infections and Studies

In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model

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Andes, D., Diekema, D. J., Pfaller, M. A., Prince, R. A., Marchillo, K., Ashbeck, J., Hou, J.·2008·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.01061-07PMC PMC2224754

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Abstract

Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans , Candida tropicalis , and Candida glabrata infection to characterize the time course of activity of the new echinocandin anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] to the MIC, and the ratio of the maximum serum drug concentration [ C max ] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C max /MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C max /MIC and AUC/MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans , C. tropicalis , and C. glabrata isolates with various anidulafungin susceptibilities (MICs of anidulafungin for these strains, 0.015 to 2.0 μg/ml) to determine if similar C max /MIC and AUC 0-24 /MIC ratios for these isolates were associated with efficacy. The anidulafungin exposures associated with efficacy were similar among Candida species.

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PK/PD studies with echinocandins demonstrate concentration-dependent activity with a prolonged PAFE similar to that observed with amphotericin B.
“PK/PD studies with the echinocandin class of antifungals demonstrate concentrationdependent activity with a prolonged PAFE similar to that observed with amphotericin B.”
From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [157]
The concentration-dependent indices Cmax/MIC and AUC/MIC are both closely linked to efficacy for echinocandins and support administration of large infrequent doses.
“The concentration-dependent indices, C max /MIC and AUC/MIC, are both closely linked to efficacy and support administration of large infrequent doses.”
From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [157]

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Lakota, E. A., Bader, J. C., Ong, V., Bartizal, K., Miesel, L., Andes, D. R., Bhavnani, S. M., Rubino, C. M., Ambrose, P. G., & Lepak, A. J. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00758-17 · Cited by 40 · see citing works
Self-citation
Dose optimization of voriconazole/anidulafungin combination against Aspergillus fumigatus using an in vitro pharmacokinetic/pharmacodynamic model and response surface analysis: clinical implications for azole-resistant aspergillosis
Siopi, M., Siafakas, N., Vourli, S., Mouton, J. W., Zerva, L., & Meletiadis, J. (2016) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkw276 · Cited by 23 · see citing works
Comparative in vivo dose-dependent activity of caspofungin and anidulafungin against echinocandin-susceptible and -resistant Aspergillus fumigatus
Lewis, R. E., Liao, G., Hou, J., Prince, R. A., & Kontoyiannis, D. P. (2011) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkr142 · Cited by 23 · see citing works
Self-citation

In vitro interactions of anidulafungin with azole antifungals, amphotericin B and 5-fluorocytosine against Candida species
Karlowsky, J. A., Hoban, D. J., Zhanel, G. G., & Goldstein, B. P. (2006) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2005.10.014 · Cited by 38 · see citing works
In vitro activity of anidulafungin in combination with amphotericin B or voriconazole against biofilms of five Candida species
Valentín, A., Cantón, R., Pemán, J., Fernández-Rivero, M. E., Tormo‐Más, M. Á., & Martínez, J. P. (2016) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkw316 · Cited by 17 · see citing works
In Vivo Comparison of the Pharmacodynamic Targets for Echinocandin Drugs against Candida Species
Andes, D., Diekema, D. J., Pfaller, M. A., Bohrmuller, J., Marchillo, K., & Lepak, A. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01584-09 · Cited by 226 · see citing works
Self-citation
[In vitro activity of a new semisynthetic echinocandin, micafungin, against clinical isolates of Candida species isolated in Tenri Hospital].
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Antifungal Activity of 14-Helical β-Peptides against Planktonic Cells and Biofilms of Candida Species
Raman, N., Lee, M., Lynn, D. M., & Palecek, S. P. (2015) · Pharmaceuticals · doi:10.3390/ph8030483 · Cited by 28 · see citing works

Authors: Andes, D., Diekema, D. J., Pfaller, M. A., Prince, R. A., Marchillo, K., Ashbeck, J., & Hou, J.
Affiliations: University of Wisconsin–Madison (US)
University of Iowa (US)
School of Pharmacy, University of Texas, Houston, Houston, Texas
Department of Medicine
ORCID: Andes, D.
Diekema, D. J.
Pfaller, M. A.
Hou, J.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2008-02
Volume: 52
Issue: 2
Pages: 539-550
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.01061-07
PMC: PMC2224754
OpenAlex: W2137119350
Cited by: 140
References: 53
Citations by year: 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 2 · 2018: 8 · 2017: 10 · 2016: 7 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 6
FWCI: 9.51
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
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)
Funders: Pfizer
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: anidulafungin, echinocandins, pharmacodynamics, pharmacokinetic-pharmacodynamic modeling, Candida albicans, Candida tropicalis, Candida glabrata, Cmax/MIC ratio, AUC/MIC ratio, dosing interval, antifungal susceptibility, mouse infection model
MeSH terms: Anidulafungin, Animals, Antifungal Agents, Candida, Candidiasis, Disease Models, Animal, Female, Humans, Mice, Inbred ICR, Microbial Sensitivity Tests, Neutropenia, Treatment Outcome, Area Under Curve, Mice, Echinocandins

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In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model

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