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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Rosenberg, Alexander [1] ; Ene, V, Iuliana ; Bibi, Maayan [1] ; Zakin, Shiri [1] ; Segal, Ella Shtifman [1] ; Ziv, Naomi [2] ; Dahan, Alon M. [1] ; Colombo, Arnaldo Lopes [3] ; Bennett, Richard J. [4] ; Berman, Judith [1]
Total Authors: 10
Affiliation:
[1] Tel Aviv Univ, Sch Mol Cell Biol & Biotechnol, IL-6997801 Ramat Aviv - Israel
[2] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 - USA
[3] Univ Fed Sao Paulo, Dept Med, BR-04021001 Sao Paulo - Brazil
[4] Ene, Iuliana, V, Brown Univ, Dept Mol Microbiol & Immunol, Providence, RI 02912 - USA
Total Affiliations: 4
Document type: Journal article
Source: NATURE COMMUNICATIONS; v. 9, JUN 25 2018.
Web of Science Citations: 20
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. (AU)

FAPESP's process: 17/02203-7 - Multidisciplinary and international network to characterize microbiological aspects and natural history of invasive fungal infections due Candida spp
Grantee:Arnaldo Lopes Colombo
Support Opportunities: Research Projects - Thematic Grants