Implications of the EUCAST Trailing Phenomenon in Candida tropicalis for the In Vivo Susceptibility in Invertebrate and Murine Models.

Details

Serval ID
serval:BIB_2BAD0EA1E2E6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Implications of the EUCAST Trailing Phenomenon in Candida tropicalis for the In Vivo Susceptibility in Invertebrate and Murine Models.
Journal
Antimicrobial agents and chemotherapy
Author(s)
Astvad KMT, Sanglard D., Delarze E., Hare R.K., Arendrup M.C.
ISSN
1098-6596 (Electronic)
ISSN-L
0066-4804
Publication state
Published
Issued date
12/2018
Peer-reviewed
Oui
Volume
62
Number
12
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Candida tropicalis isolates often display reduced but persistent growth (trailing) over a broad fluconazole concentration range during EUCAST susceptibility testing. Whereas weak trailing (<25% of the positive growth control) is common and found not to impair fluconazole efficacy, we investigated if more pronounced trailing impacted treatment efficacy. Fluconazole efficacy against two weakly (≤25% growth), two moderately (26% to 50% growth), and one heavily (>70% growth) trailing resistant isolate and one resistant (100% growth) isolate were investigated in vitro and in vivo (in a Galleria mellonella survival model and two nonlethal murine models). CDR1 expression levels and ERG11 sequences were characterized. The survival in fluconazole-treated G. mellonella was inversely correlated with the degree of trailing (71% to 9% survival in treatment groups). In mice, resistant and heavily trailing isolates responded poorly to fluconazole treatment. CDR1 expression was significantly higher in trailing and resistant isolates than in wild-type isolates (1.4-fold to 10-fold higher). All isolates exhibited ERG11 wild-type alleles. Heavily trailing isolates were less responsive to fluconazole in all in vivo models, indicating an impact on fluconazole efficacy. CDR1 upregulation may have contributed to the observed differences. Moderately trailing isolates responded less well to fluconazole in larvae only. This confirms clinical data suggesting fluconazole is effective against infections with such isolates in less severely ill patients and supports the current 50% growth endpoint for susceptibility testing. However, it is still unclear if the gradual loss of efficacy observed for moderately trailing isolates in the larva model may be a reason for concern in selected vulnerable patient populations.
Keywords
Animals, Antifungal Agents/administration & dosage, Antifungal Agents/pharmacology, Candida tropicalis/drug effects, Candida tropicalis/growth & development, Candida tropicalis/isolation & purification, Candida tropicalis/pathogenicity, Candidiasis/drug therapy, Candidiasis/microbiology, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Resistance, Fungal/drug effects, Fluconazole/administration & dosage, Fluconazole/pharmacology, Gene Expression Regulation, Fungal/drug effects, Humans, Mice, Inbred Strains, Microbial Sensitivity Tests/methods, Moths, EUCAST, Galleria mellonella , azoles, fluconazole, in vivo , trailing
Pubmed
Web of science
Create date
17/12/2018 9:01
Last modification date
14/10/2019 5:09
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