title: Resistance Mechanisms and Clinical Features of Fluconazole-Nonsusceptible Candida tropicalis Isolates Compared with Fluconazole-Less-Susceptible Isolates.
abstract: We investigated the azole resistance mechanisms and clinical features of fluconazole-nonsusceptible (FNS) isolates of Candida tropicalis recovered from Korean surveillance cultures in comparison with fluconazole-less-susceptible (FLS) isolates. Thirty-five clinical isolates of C. tropicalis, comprising 9 FNS (fluconazole MIC, 4 to 64 μg/ml), 12 FLS (MIC, 1 to 2 μg/ml), and 14 control (MIC, 0.125 to 0.5 μg/ml) isolates, were assessed. CDR1, MDR1, and ERG11 expression was quantified, and the ERG11 and UPC2 genes were sequenced. Clinical features of 16 patients with FNS or FLS bloodstream isolates were analyzed. Both FNS and FLS isolates had >10-fold higher mean expression levels of CDR1, MDR1, and ERG11 genes than control isolates (P values of <0.02 for all). When FNS and FLS isolates were compared, FNS isolates had 3.4-fold higher mean ERG11 expression levels than FLS isolates (P = 0.004), but there were no differences in those of CDR1 or MDR1 Of all 35 isolates, 4 (2 FNS and 2 FLS) and 28 (8 FNS, 11 FLS, and 9 control) isolates exhibited amino acid substitutions in Erg11p and Upc2p, respectively. Both FNS and FLS bloodstream isolates were associated with azole therapeutic failure (3/4 versus 4/7) or uncleared fungemia (4/6 versus 4/10), but FNS isolates were identified more frequently from patients with previous azole exposure (6/6 versus 3/10; P = 0.011) and immunosuppression (6/6 versus 3/10; P = 0.011). These results reveal that the majority of FNS C. tropicalis isolates show overexpression of CDR1, MDR1, and ERG11 genes, and fungemia develops after azole exposure in patients with immunosuppression.
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Choi
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Won
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea shinjh@chonnam.ac.kr.
authors.forename: Jong Hee
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Wee-Gyo
authors.initials: WG
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Mi-Na
authors.initials: MN
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyungwon
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Myung Geun
authors.initials: MG
authors.lastname: Shin
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Soon Pal
authors.initials: SP
authors.lastname: Suh
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Ryang
authors.affiliation: College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Im
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000935:Antifungal Agents / Q000494:pharmacology; D041022:Candida tropicalis / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000382:microbiology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics*; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D016469:Fungemia / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000382:microbiology*; D015870:Gene Expression; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D062486:Public Health Surveillance; D056910:Republic of Korea; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D005656:Fungal Proteins; D007166:Immunosuppressive Agents; D015534:Trans-Activators; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System