Resistance mechanisms and clinical features of fluconazole-nonsusceptible Candida tropicalis isolates compared with fluconazole-less-susceptible isolates

Min Ji Choi, Eun Jeong Won, Jong Hee Shin, Soo Hyun Kim, Wee Gyo Lee, Mi Na Kim, Kyungwon Lee, Myung Geun Shin, Soon Pal Suh, Dong Wook Ryang, Young Jun Im

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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. Thirtyfive 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.

Original languageEnglish
Pages (from-to)3653-3661
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number6
DOIs
Publication statusPublished - 2016 Jun 1

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Candida tropicalis
Fluconazole
Azoles
Fungemia
Immunosuppression

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Choi, Min Ji ; Won, Eun Jeong ; Shin, Jong Hee ; Kim, Soo Hyun ; Lee, Wee Gyo ; Kim, Mi Na ; Lee, Kyungwon ; Shin, Myung Geun ; Suh, Soon Pal ; Ryang, Dong Wook ; Im, Young Jun. / Resistance mechanisms and clinical features of fluconazole-nonsusceptible Candida tropicalis isolates compared with fluconazole-less-susceptible isolates. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 6. pp. 3653-3661.
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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. Thirtyfive 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.",
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Resistance mechanisms and clinical features of fluconazole-nonsusceptible Candida tropicalis isolates compared with fluconazole-less-susceptible isolates. / Choi, Min Ji; Won, Eun Jeong; Shin, Jong Hee; Kim, Soo Hyun; Lee, Wee Gyo; Kim, Mi Na; Lee, Kyungwon; Shin, Myung Geun; Suh, Soon Pal; Ryang, Dong Wook; Im, Young Jun.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 6, 01.06.2016, p. 3653-3661.

Research output: Contribution to journalArticle

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T1 - Resistance mechanisms and clinical features of fluconazole-nonsusceptible Candida tropicalis isolates compared with fluconazole-less-susceptible isolates

AU - Choi, Min Ji

AU - Won, Eun Jeong

AU - Shin, Jong Hee

AU - Kim, Soo Hyun

AU - Lee, Wee Gyo

AU - Kim, Mi Na

AU - Lee, Kyungwon

AU - Shin, Myung Geun

AU - Suh, Soon Pal

AU - Ryang, Dong Wook

AU - Im, Young Jun

PY - 2016/6/1

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N2 - 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. Thirtyfive 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.

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