Differential In Vivo Activities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata Isolates with and without FKS Resistance Mutations

Arendrup, Maiken Cavling; Perlin, David S.; Jensen, Rasmus Hare; Howard, Susan Julie; Goodwin, Joanne; Hope, William

doi:10.1128/aac.06369-11

Cited by 117Antifungal resistance and susceptibilityFungal Plant Pathogen ControlAntibiotics Pharmacokinetics and Efficacy

Differential In Vivo Activities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata Isolates with and without FKS Resistance Mutations

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Arendrup, Maiken Cavling, Perlin, David S., Jensen, Rasmus Hare, Howard, Susan Julie, Goodwin, Joanne, Hope, William·2012·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.06369-11PMC PMC3346593

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Abstract

We recently observed that the micafungin MICs for some Candida glabrata fks hot spot mutant isolates are less elevated than those for the other echinocandins, suggesting that the efficacy of micafungin may be differentially dependent on such mutations. Three clinical C. glabrata isolates with or without (S3) fks hot spot mutations R83 (Fks2p-S663F) and RR24 (Fks1p-S629P) and low, medium, and high echinocandin MICs, respectively, were evaluated to assess the in vivo efficacy in an immunocompetent mouse model using three doses of each echinocandin. Drug concentrations were determined in plasma and kidneys by high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic mathematical model was used to define the area under the concentration-time curve (AUC) that produced half- and near-maximal activity. Micafungin was equally efficacious against the S3 and R83 isolates. The estimates for the AUCs of each echinocandin that induced half-maximal effect (E(50)s) were 194.2 and 53.99 mg · h/liter, respectively. In contrast, the maximum effect (E(max)) for caspofungin was higher against S3 than R83, but the estimates for E(50) were similar (187.1 and 203.5 mg · h/liter, respectively). Anidulafungin failed to induce a ≥1-log reduction for any of the isolates (AUC range, 139 to 557 mg · h/liter). None of the echinocandins were efficacious in mice challenged with the RR24 isolate despite lower virulence (reduced maximal growth, prolonged lag phase, and lower kidney burden). The AUC associated with half-maximal effect was higher than the average human exposure for all drug-dose-bug combinations except micafungin and the R83 isolate. In conclusion, differences in micafungin MICs are associated with differential antifungal activities in the animal model. This study may have implications for clinical practice and echinocandin breakpoint determination, and further studies are warranted.

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Echinocandin resistance is associated with a dismal outcome.
“It is most commonly detected after 3–4 weeks of treatment and is associated with a dismal outcome.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [25]
The F659-DEL in C. glabrata confers resistance to all three echinocandins.
“For example, the F659-DEL in C. glabrata confers resistance to all three echinocandins, whereas the F659S substitution at the same codon gives rise to anidulafungin and caspofungin resistance, whereas the micafungin MIC and in vivo efficacy in a murine animal model remains unchanged (23;25;27–30).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [25]
The outcome for patients with increased echinocandin MICs is significantly poorer.
“However, there is solid documentation that the outcome for patients with increased MICs is significantly poorer.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [25]
The F659-DEL in C. glabrata confers resistance to all three echinocandins.
“For example, the F659-DEL in C. glabrata confers resistance to all three echinocandins, whereas the F659S substitution at the same codon gives rise to anidulafungin and caspofungin resistance, whereas the micafungin MIC and in vivo efficacy in a murine animal model remains unchanged (23;25;27–30).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [27]
In two recent studies, 80% and 78.5% of candidaemia patients with an echinocandin-resistant C. glabrata isolate failed therapy, respectively.
“Not only has an unsuccessful outcome been reported in most case reports, but it was also documented in two recent studies that 80% and 78.5% candidaemia patients with an echinocandin resistant C. glabrata isolate fail therapy, respectively (23;25).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [25]

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Authors: Arendrup, M. C., Perlin, D. S., Jensen, R. H., Howard, S. J., Goodwin, J., & Hope, W.
Affiliations: Statens Serum Institut (DK)
Rutgers New Jersey Medical School (US)
Unit of Mycology and Parasitology, Statens Serum Institut, Copenhagen, Denmark
Manchester Academic Health Science Centre (GB)
ORCID: Arendrup, Maiken Cavling
Perlin, David S.
Hope, William
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2012-05
Volume: 56
Issue: 5
Pages: 2435-2442
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.06369-11
PMC: PMC3346593
OpenAlex: W2146599281
Cited by: 117
References: 43
Citations by year: 2026: 1 · 2025: 1 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 11 · 2017: 16 · 2016: 10 · 2015: 9 · 2014: 18 · 2013: 12 · 2012: 3
FWCI: 9.32
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)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Pfizer
Gilead Sciences
Astellas Pharma
National Institutes of Health
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords: Candida glabrata, echinocandins, micafungin, caspofungin, anidulafungin, antifungal susceptibility, pharmacokinetic-pharmacodynamic modeling, immunocompetent mouse model
MeSH terms: Caspofungin, Micafungin, Anidulafungin, Animals, Antifungal Agents, Biological Availability, Candidiasis, Chromatography, High Pressure Liquid, Disease Models, Animal, Genes, Fungal, Glucosyltransferases, Humans, Kidney, Microbial Sensitivity Tests, Mutation, Area Under Curve, Drug Resistance, Fungal, Candida glabrata, Mice, Echinocandins, Lipopeptides

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Differential In Vivo Activities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata Isolates with and without FKS Resistance Mutations

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