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Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia

Author

Listed:
  • Alexander Rosenberg

    (Tel Aviv University)

  • Iuliana V. Ene

    (Brown University)

  • Maayan Bibi

    (Tel Aviv University)

  • Shiri Zakin

    (Tel Aviv University)

  • Ella Shtifman Segal

    (Tel Aviv University)

  • Naomi Ziv

    (University of California)

  • Alon M. Dahan

    (Tel Aviv University)

  • Arnaldo Lopes Colombo

    (Federal University of São Paulo)

  • Richard J. Bennett

    (Brown University)

  • Judith Berman

    (Tel Aviv University)

Abstract

Tolerance to antifungal drug concentrations above the minimal inhibitory concentration (MIC) is rarely quantified, and current clinical recommendations suggest it should be ignored. Here, we quantify antifungal tolerance in Candida albicans isolates as the fraction of growth above the MIC, and find that it is distinct from susceptibility/resistance. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with intracellular drug accumulation. Many adjuvant drugs used in combination with fluconazole, a widely used fungistatic drug, reduce tolerance without affecting resistance. Accordingly, in an invertebrate infection model, adjuvant combination therapy is more effective than fluconazole in treating infections with highly tolerant isolates and does not affect infections with low tolerance isolates. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia display higher tolerance than isolates readily cleared by fluconazole. Thus, tolerance correlates with, and may help predict, patient responses to fluconazole therapy.

Suggested Citation

  • Alexander Rosenberg & Iuliana V. Ene & Maayan Bibi & Shiri Zakin & Ella Shtifman Segal & Naomi Ziv & Alon M. Dahan & Arnaldo Lopes Colombo & Richard J. Bennett & Judith Berman, 2018. "Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04926-x
    DOI: 10.1038/s41467-018-04926-x
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    Cited by:

    1. Amir Arastehfar & Farnaz Daneshnia & Nathaly Cabrera & Suyapa Penalva-Lopez & Jansy Sarathy & Matthew Zimmerman & Erika Shor & David S. Perlin, 2023. "Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Neil A. R. Gow & Carolyn Johnson & Judith Berman & Alix T. Coste & Christina A. Cuomo & David S. Perlin & Tihana Bicanic & Thomas S. Harrison & Nathan Wiederhold & Mike Bromley & Tom Chiller & Keegan , 2022. "The importance of antimicrobial resistance in medical mycology," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Liqing Hu & Cancan Sun & Justin M. Kidd & Jizhong Han & Xianjun Fang & Hongtao Li & Qingdai Liu & Aaron E. May & Qianbin Li & Lei Zhou & Qinglian Liu, 2023. "A first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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