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Susceptibility

Antifungal Susceptibility Profiles and Drug Resistance Mechanisms of Clinical Lomentospora prolificans Isolates

Yongqin Wu, Nina Grossman, Marissa Totten, Warda Memon, Anna Fitzgerald, Chunmei Ying, Sean X. Zhang
Yongqin Wu
aDepartment of Clinical Laboratory, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
bDivision of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Nina Grossman
cDepartment of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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Marissa Totten
bDivision of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Warda Memon
dMicrobiology Laboratory, Johns Hopkins Hospital, Baltimore, Maryland, USA
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Anna Fitzgerald
dMicrobiology Laboratory, Johns Hopkins Hospital, Baltimore, Maryland, USA
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Chunmei Ying
aDepartment of Clinical Laboratory, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
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Sean X. Zhang
bDivision of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
dMicrobiology Laboratory, Johns Hopkins Hospital, Baltimore, Maryland, USA
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DOI: 10.1128/AAC.00318-20
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ABSTRACT

Lomentospora prolificans is an opportunistic fungal pathogen with low susceptibility to current antifungal drugs. Here, we tested the in vitro susceptibility of 8 drugs against 42 clinical L. prolificans isolates. All isolates showed high MICs to voriconazole (MIC90>16 μg/ml), itraconazole (MIC90>16 μg/ml), posaconazole (MIC90>16 μg/ml), isavuconazole (MIC90>16 μg/ml), amphotericin B (MIC90>16 μg/ml), and terbinafine (MIC90>64 μg/ml) and high minimum effective concentrations (MECs) to micafungin (MEC90>8 μg/ml), with the exception of miltefosine showing an MIC90 value of 4 μg/ml. We examined six different in vitro drug combinations and found that the combination of voriconazole and terbinafine achieved the most synergistic effort against L. prolificans. We then annotated the L. prolificans whole genome and located its Cyp51 and Fks1 genes. We completely sequenced the two genes to determine if any mutation would be related to azole and echinocandin resistance in L. prolificans. We found no amino acid changes in Cyp51 protein and no tandem repeats in the 5′ upstream region of the Cyp51 gene. However, we identified three intrinsic amino acid residues (G138S, M220I, and T289A) in the Cyp51 protein that were linked to azole resistance. Likewise, two intrinsic amino acid residues (F639Y, W695F) that have reported to confer echinocandin resistance were found in Fks1 hot spot regions. In addition, three new amino acid alterations (D440A, S634R, and H1245R) were found outside Fks1 hot spot regions, and their contributions to echinocandin resistance need future investigation. Overall, our findings support the notion that L. prolificans is intrinsically resistant to azoles and echinocandins.

FOOTNOTES

    • Received 19 February 2020.
    • Returned for modification 28 March 2020.
    • Accepted 10 August 2020.
    • Accepted manuscript posted online 17 August 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

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Antifungal Susceptibility Profiles and Drug Resistance Mechanisms of Clinical Lomentospora prolificans Isolates
Yongqin Wu, Nina Grossman, Marissa Totten, Warda Memon, Anna Fitzgerald, Chunmei Ying, Sean X. Zhang
Antimicrobial Agents and Chemotherapy Oct 2020, 64 (11) e00318-20; DOI: 10.1128/AAC.00318-20

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Antifungal Susceptibility Profiles and Drug Resistance Mechanisms of Clinical Lomentospora prolificans Isolates
Yongqin Wu, Nina Grossman, Marissa Totten, Warda Memon, Anna Fitzgerald, Chunmei Ying, Sean X. Zhang
Antimicrobial Agents and Chemotherapy Oct 2020, 64 (11) e00318-20; DOI: 10.1128/AAC.00318-20
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KEYWORDS

Lomentospora prolificans
antifungal susceptibility
synergy
resistance mechanisms
antifungal agents
antifungal resistance
antifungal susceptibility testing

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