Paradoxical effect of caspofungin against Candida bloodstream isolates is mediated by multiple pathways but eliminated in human serum

Shields, Ryan K.; Nguyen, M. Hong; Du, Chen; Press, Ellen; Cheng, Shaoji; Clancy, Cornelius J.

doi:10.1128/aac.00999-10

Cited by 65Antifungal resistance and susceptibilityFungal Infections and StudiesFungal and yeast genetics research

Paradoxical effect of caspofungin against Candida bloodstream isolates is mediated by multiple pathways but eliminated in human serum

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Shields, Ryan K., Nguyen, M. Hong, Du, Chen, Press, Ellen, Cheng, Shaoji, Clancy, Cornelius J.·2011·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.00999-10PMC PMC3101391

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Abstract

Paradoxical growth of Candida in vitro at echinocandin concentrations exceeding the MIC is well described, but the clinical relevance is unknown. We assessed echinocandin paradoxical effects against Candida bloodstream isolates (BSI) in the presence or absence of human serum and investigated regulatory mechanisms. As determined by broth microdilution, a paradoxical effect was evident for 60% (18/30), 23% (7/30), and 13% (4/30) of Candida albicans BSI exposed to caspofungin, anidulafungin, and micafungin, respectively, at achievable human serum concentrations (≤8 μg/ml). A paradoxical effect was not evident among 34 C. glabrata BSI and was observed only for caspofungin against C. parapsilosis (4%, 1/23). As determined in time-kill studies, a caspofungin paradoxical effect was demonstrated by C. albicans (2/3), C. glabrata (1/3), and C. parapsilosis (1/3), including BSI that were determined to be negative by microdilution. In 50% human serum, a paradoxical effect was eliminated at caspofungin concentrations up to 64 μg/ml for 100% (8/8) of the C. albicans BSI. A caspofungin paradoxical effect was also eliminated by chitin synthase inhibitor nikkomycin Z and at achievable concentrations of calcineurin pathway inhibitors, tacrolimus and cyclosporine. Moreover, these agents were synergistic with caspofungin against 100, 100, and 88% (7/8) of C. albicans, respectively, and exerted their own paradoxical effects. Finally, paradoxical growth was eliminated in C. albicans irs4- and inp51-null mutants, which lack phosphatidylinositol-(4,5)-bisphosphate 5'-phosphatase. Our findings suggest that the paradoxical effect is unlikely to be important in vivo but remains an important tool to study cell wall stress responses. We implicate the Irs4-Inp51 phosphatidylinositol-(4,5)-bisphosphate 5'-phosphatase as a novel regulator of paradoxical growth.

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A paradoxical echinocandin effect has been observed in which increased Candida growth is detected at higher than MIC drug concentrations.
“A paradoxical (or eagle) echinocandin effect has been observed in which increased Candida growth is detected at higher than MIC drug concentrations.”
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Pappas, P. G., Kauffman, C. A., Andes, D., Benjamin, D. K., Calandra, T. F., Edwards, J. E., Filler, S. G., Fisher, J. F., Kullberg, B.-J., Zeichner, L. O., et al. (2009) · Clinical Infectious Diseases · doi:10.1086/596757 · Cited by 3,191 · see citing works
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Reference method for broth dilution antifungal susceptibility testing of yeasts : Approved standard
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Authors: Shields, R. K., Nguyen, M. H., Du, C., Press, E., Cheng, S., & Clancy, C. J.
Affiliations: University of Pittsburgh (US)
Corresponding author: Nguyen, M. Hong
ORCID: Shields, Ryan K.
Nguyen, M. Hong
Clancy, Cornelius J.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2011-06
Volume: 55
Issue: 6
Pages: 2641-2647
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.00999-10
PMC: PMC3101391
OpenAlex: W1987399194
Cited by: 65
References: 30
Citations by year: 2026: 1 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 7 · 2017: 7 · 2016: 7 · 2015: 3 · 2014: 7 · 2013: 10 · 2012: 7
FWCI: 5.39
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: University of Pittsburgh
National Institutes of Health (UL1TR000005, KL2TR000146)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: caspofungin, paradoxical effects, echinocandins, Candida albicans, Candida glabrata, Candida parapsilosis, bloodstream infection, human serum, chitin synthase inhibitors, nikkomycin Z, tacrolimus, cyclosporine, calcineurin pathway, IRS4, cell wall stress response
MeSH terms: Caspofungin, Antifungal Agents, Candida, Chitin, Fungal Proteins, Humans, Microbial Sensitivity Tests, Fungemia, Calcineurin, Mitogen-Activated Protein Kinase 3, Echinocandins, Lipopeptides

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Paradoxical effect of caspofungin against Candida bloodstream isolates is mediated by multiple pathways but eliminated in human serum

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