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.

doi:10.1093/jac/dkr142

Cited by 23Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

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

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Abstract

BACKGROUND: Echinocandin resistance in Aspergillus species is rare. We examined if mutations in FKS1 would result in a complete loss of echinocandin activity in vivo in an experimental model of aspergillosis. METHODS: Neutropenic mice were infected with either an echinocandin-susceptible Aspergillus fumigatus (AF 293) or an echinocandin-resistant A. fumigatus laboratory strain harbouring 'hot-spot' substitution in Fks1p (AF Ser678Pro). Mice then received daily treatment with either anidulafungin or caspofungin at varying dosages (0.25-16 mg/kg/day) for 5 days and Aspergillus lung fungal burden was assessed by quantitative real-time PCR. RESULTS: Both strains produced histological evidence of progressive invasive pulmonary aspergillosis, but AF Ser678Pro was less virulent than AF 293, as evidenced by lower lung fungal burden and longer median survival time. At > 0.5 mg/kg/day, both anidulafungin and caspofungin reduced the lung fungal burden in neutropenic animals infected with AF 293, but had mixed efficacy against the resistant AF Ser678Pro strain. For caspofungin, the fungal burden was reduced only at doses <1 mg/kg/day. Anidulafungin also modestly reduced AF Ser678Pro lung fungal burden, but only at > 4 mg/kg/day. CONCLUSIONS: Despite a lack of appreciable antifungal activity in vitro, both anidulafungin and caspofungin were still modestly effective in vivo against a laboratory-generated A. fumigatus mutant harbouring the Ser678Pro mutation in Fks1p. This persistent activity, combined with impaired fitness of the isolate in vivo, could partially explain why microbiologically documented echinocandin-resistance in Aspergillus species remains a rare clinical occurrence.

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Echinocandins retained some activity against the A. fumigatus FKS1 mutant strain in vivo, albeit a lack of appreciable activity in vitro.
“Notably, echinocandins retained some activity against the A. fumigatus FKS1 mutant strain in vivo, albeit a lack of appreciable activity in vitro, which may further contribute to the rare clinical occurrence of echinocandin resistance in this species44.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [44]
In a mouse model of invasive pulmonary aspergillosis, infection with an echinocandin-resistant strain of A. fumigatus was less lethal than with the echinocandin-susceptible strain, with reduced lung fungal burden and significantly longer survival time.
“In a mouse model of invasive pulmonary aspergillosis, infection with an echinocandin-resistant strain of A. fumigatus was less lethal when compared with the echinocandin-susceptible strain, as demonstrated by reduced lung fungal burden and significantly longer survival time44.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [44]
For A. fumigatus, echinocandin resistance in clinical settings is extremely rare, likely due to the fitness cost of FKS1 mutations in vivo.
“For A. fumigatus, echinocandin resistance in clinical settings is extremely rare, likely due to the fitness cost of FKS1 mutations in vivo44.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [44]

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Authors: Lewis, R. E., Liao, G., Hou, J., Prince, R. A., & Kontoyiannis, D. P.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
University of Houston (US)
Corresponding author: Lewis, R. E.
ORCID: Lewis, R. E.
Venue: Journal of Antimicrobial Chemotherapy
Publisher: Oxford University Press (OUP)
Published: 2011-04-11
Volume: 66
Issue: 6
Pages: 1324-1331
ISSN: 0305-7453 (ISSN-L)
1460-2091
DOI: 10.1093/jac/dkr142
OpenAlex: W2164337152
Cited by: 23
References: 39
Citations by year: 2026: 4 · 2025: 1 · 2024: 1 · 2023: 1 · 2020: 1 · 2019: 2 · 2017: 2 · 2015: 1 · 2014: 3 · 2013: 4 · 2012: 2
FWCI: 2.16
Type: journal article
Language: en
Open access: closed
Locations: Journal of Antimicrobial Chemotherapy (publishedVersion)
PubMed (publishedVersion)
Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
HighWire Press Open Archive (submittedVersion)
Funders: Pfizer
Merck
Gilead Sciences
Astellas Pharma
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: echinocandin resistance, Aspergillus fumigatus, caspofungin, anidulafungin, FKS1 mutations, invasive pulmonary aspergillosis, neutropenic mice, antifungal susceptibility
MeSH terms: Caspofungin, Anidulafungin, Animals, Antifungal Agents, Aspergillosis, Aspergillus fumigatus, Disease Models, Animal, Mice, Inbred BALB C, Treatment Outcome, Drug Resistance, Fungal, Mice, Echinocandins, Lipopeptides

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Comparative in vivo dose-dependent activity of caspofungin and anidulafungin against echinocandin-susceptible and -resistant Aspergillus fumigatus

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