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  1. Article ; Online: Antifungal Susceptibility of Yeasts and Filamentous Fungi by CLSI Broth Microdilution Testing.

    Wiederhold, Nathan P

    Methods in molecular biology (Clifton, N.J.)

    2023  Volume 2658, Page(s) 3–16

    Abstract: Antifungal susceptibility testing is performed against yeasts and filamentous fungi (molds) for various purposes. In clinical settings, the results of these in vitro assays may be used to help guide therapy for individual patients. Surveillance studies ... ...

    Abstract Antifungal susceptibility testing is performed against yeasts and filamentous fungi (molds) for various purposes. In clinical settings, the results of these in vitro assays may be used to help guide therapy for individual patients. Surveillance studies use susceptibility testing to monitor for the development of resistance to different agents. These assays are also frequently used in preclinical drug development to determine the spectrum of activity and assess the in vitro potency of investigational agents. Broth microdilution is a form of antifungal susceptibility testing that is frequently used for each of these purposes. The Clinical and Laboratory Standards Institute (CLSI) has developed standardized methods for broth microdilution antifungal susceptibility testing of both yeasts and molds. These methods are useful in the clinical diagnostics arena for determining if a particular fungal isolate may be resistant to clinically available antifungals, and they are also amendable for research purposes, as the microtiter trays can be prepared in different formats with different antifungal and investigational agent concentration ranges and with different growth media if necessary. This chapter describes the CLSI methods for antifungal susceptibility testing by broth microdilution for both yeasts and molds, how endpoints are read for different classes of antifungal agents, and how the results may be interpreted.
    MeSH term(s) Humans ; Antifungal Agents/pharmacology ; Antifungal Agents/therapeutic use ; Fungi ; Yeasts ; Reference Standards ; Culture Media ; Microbial Sensitivity Tests
    Chemical Substances Antifungal Agents ; Culture Media
    Language English
    Publishing date 2023-04-05
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-3155-3_1
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  2. Article ; Online: Pharmacodynamics, Mechanisms of Action and Resistance, and Spectrum of Activity of New Antifungal Agents.

    Wiederhold, Nathan P

    Journal of fungi (Basel, Switzerland)

    2022  Volume 8, Issue 8

    Abstract: Several new antifungals are currently in late-stage development, including those with novel pharmacodynamics/mechanisms of action that represent new antifungal classes (manogepix, olorofim, ATI-2307, GR-2397). Others include new agents within established ...

    Abstract Several new antifungals are currently in late-stage development, including those with novel pharmacodynamics/mechanisms of action that represent new antifungal classes (manogepix, olorofim, ATI-2307, GR-2397). Others include new agents within established classes or with mechanisms of action similar to clinically available antifungals (ibrexafungerp, rezafungin, oteseconazole, opelconazole, MAT2203) that have been modified in order to improve certain characteristics, including enhanced pharmacokinetics and greater specificity for fungal targets. Many of the antifungals under development also have activity against
    Language English
    Publishing date 2022-08-16
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2784229-0
    ISSN 2309-608X ; 2309-608X
    ISSN (online) 2309-608X
    ISSN 2309-608X
    DOI 10.3390/jof8080857
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  3. Article ; Online: Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential.

    Wiederhold, Nathan P

    Journal of fungi (Basel, Switzerland)

    2021  Volume 7, Issue 2

    Abstract: Invasive infections caused ... ...

    Abstract Invasive infections caused by
    Language English
    Publishing date 2021-02-11
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2784229-0
    ISSN 2309-608X ; 2309-608X
    ISSN (online) 2309-608X
    ISSN 2309-608X
    DOI 10.3390/jof7020130
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  4. Article: Antifungal Susceptibility Testing: A Primer for Clinicians.

    Wiederhold, Nathan P

    Open forum infectious diseases

    2021  Volume 8, Issue 11, Page(s) ofab444

    Abstract: Clinicians treating patients with fungal infections may turn to susceptibility testing to obtain information regarding the activity of different antifungals against a specific fungus that has been cultured. These results may then be used to make ... ...

    Abstract Clinicians treating patients with fungal infections may turn to susceptibility testing to obtain information regarding the activity of different antifungals against a specific fungus that has been cultured. These results may then be used to make decisions regarding a patient's therapy. However, for many fungal species that are capable of causing invasive infections, clinical breakpoints have not been established. Thus, interpretations of susceptible or resistant cannot be provided by clinical laboratories, and this is especially true for many molds capable of causing severe mycoses. The purpose of this review is to provide an overview of susceptibility testing for clinicians, including the methods used to perform these assays, their limitations, how clinical breakpoints are established, and how the results may be put into context in the absence of interpretive criteria. Examples of when susceptibility testing is not warranted are also provided.
    Language English
    Publishing date 2021-09-09
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2757767-3
    ISSN 2328-8957
    ISSN 2328-8957
    DOI 10.1093/ofid/ofab444
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  5. Article ; Online: Emerging Fungal Infections: New Species, New Names, and Antifungal Resistance.

    Wiederhold, Nathan P

    Clinical chemistry

    2021  Volume 68, Issue 1, Page(s) 83–90

    Abstract: Background: Infections caused by fungi can be important causes of morbidity and mortality in certain patient populations, including those who are highly immunocompromised or critically ill. Invasive mycoses can be caused by well-known species, as well ... ...

    Abstract Background: Infections caused by fungi can be important causes of morbidity and mortality in certain patient populations, including those who are highly immunocompromised or critically ill. Invasive mycoses can be caused by well-known species, as well as emerging pathogens, including those that are resistant to clinically available antifungals.
    Content: This review highlights emerging fungal infections, including newly described species, such as Candida auris, and those that having undergone taxonomic classification and were previously known by other names, including Blastomyces and Emergomyces species, members of the Rasamsonia argillacea species complex, Sporothrix brasiliensis, and Trichophyton indotinae. Antifungal resistance also is highlighted in several of these emerging species, as well as in the well-known opportunistic pathogen Aspergillus fumigatus. Finally, the increased recognition and importance of fungal co-infections with respiratory pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is discussed.
    Summary: Both clinicians and clinical microbiology laboratories should remain vigilant regarding emerging fungal infections. These may be difficult both to diagnose and treat due to the lack of experience of clinicians and laboratory personnel with these organisms and the infections they may cause. Many of these fungal infections have been associated with poor clinical outcomes, either due to inappropriate therapy or the development of antifungal resistance.
    MeSH term(s) Antifungal Agents/pharmacology ; COVID-19 ; Communicable Diseases, Emerging/epidemiology ; Communicable Diseases, Emerging/microbiology ; Drug Resistance, Fungal ; Fungi/drug effects ; Fungi/pathogenicity ; Humans ; Mycoses/drug therapy ; Mycoses/epidemiology
    Chemical Substances Antifungal Agents
    Language English
    Publishing date 2021-12-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80102-1
    ISSN 1530-8561 ; 0009-9147
    ISSN (online) 1530-8561
    ISSN 0009-9147
    DOI 10.1093/clinchem/hvab217
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  6. Article ; Online: Review of the Novel Investigational Antifungal Olorofim.

    Wiederhold, Nathan P

    Journal of fungi (Basel, Switzerland)

    2020  Volume 6, Issue 3

    Abstract: The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance ... ...

    Abstract The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among
    Language English
    Publishing date 2020-07-30
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2784229-0
    ISSN 2309-608X ; 2309-608X
    ISSN (online) 2309-608X
    ISSN 2309-608X
    DOI 10.3390/jof6030122
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  7. Article ; Online: Pharmacodynamics, Mechanisms of Action and Resistance, and Spectrum of Activity of New Antifungal Agents

    Nathan P. Wiederhold

    Journal of Fungi, Vol 8, Iss 8, p

    2022  Volume 857

    Abstract: Several new antifungals are currently in late-stage development, including those with novel pharmacodynamics/mechanisms of action that represent new antifungal classes (manogepix, olorofim, ATI-2307, GR-2397). Others include new agents within established ...

    Abstract Several new antifungals are currently in late-stage development, including those with novel pharmacodynamics/mechanisms of action that represent new antifungal classes (manogepix, olorofim, ATI-2307, GR-2397). Others include new agents within established classes or with mechanisms of action similar to clinically available antifungals (ibrexafungerp, rezafungin, oteseconazole, opelconazole, MAT2203) that have been modified in order to improve certain characteristics, including enhanced pharmacokinetics and greater specificity for fungal targets. Many of the antifungals under development also have activity against Candida and Aspergillus strains that have reduced susceptibility or acquired resistance to azoles and echinocandins, whereas others demonstrate activity against species that are intrinsically resistant to most clinically available antifungals. The tolerability and drug–drug interaction profiles of these new agents also appear to be promising, although the number of human subjects that have been exposed to many of these agents remains relatively small. Overall, these agents have the potential for expanding our antifungal armamentarium and improving clinical outcomes in patients with invasive mycoses.
    Keywords pharmacodynamics ; antifungals ; mechanism of action ; resistance ; olorofim ; manogepix ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article: Kneiffiella palmae:

    Ituarte, Bianca E / Cañete-Gibas, Connie / Wiederhold, Nathan P / Olarte, Liset

    Medical mycology case reports

    2023  Volume 41, Page(s) 36–40

    Abstract: We report the first known human case ... ...

    Abstract We report the first known human case of
    Language English
    Publishing date 2023-08-03
    Publishing country Netherlands
    Document type Case Reports
    ZDB-ID 2670415-8
    ISSN 2211-7539
    ISSN 2211-7539
    DOI 10.1016/j.mmcr.2023.08.001
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  9. Article ; Online: Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential

    Nathan P. Wiederhold

    Journal of Fungi, Vol 7, Iss 2, p

    2021  Volume 130

    Abstract: Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non- albicans Candida species have been documented in multiple countries on several ... ...

    Abstract Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non- albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the last several years by Candida auris , as isolates of this emerging pathogen that are often resistant to multiple antifungals. T-2307 is an aromatic diamidine currently in development for the treatment of invasive fungal infections. This agent has been shown to selectively cause the collapse of the mitochondrial membrane potential in yeasts when compared to mammalian cells. In vitro activity has been demonstrated against Candida species, including C. albicans , C. glabrata , and C. auris strains, which are resistant to azole and echinocandin antifungals. Activity has also been reported against Cryptococcus species, and this has translated into in vivo efficacy in experimental models of invasive candidiasis and cryptococcosis. However, little is known regarding the clinical efficacy and safety of this agent, as published data from studies involving humans are not currently available.
    Keywords T-2307 ; aromatic diamidine ; in vitro susceptibility ; mitochondrial membrane ; mitochondrial membrane potential ; Candida ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Review of the Novel Investigational Antifungal Olorofim

    Nathan P. Wiederhold

    Journal of Fungi, Vol 6, Iss 122, p

    2020  Volume 122

    Abstract: The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium ... ...

    Abstract The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans , and Fusarium species are inherently less susceptible or intrinsically resistant to clinically available antifungals. Olorofim (formerly F901318) is the first member of the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. This agent inhibits dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising. This review describes the mechanism of action of olorofim, its in vitro spectrum of activity, and what is currently known about its pharmacokinetic profile and clinical efficacy.
    Keywords Olorofim ; F901318 ; invasive mold infections ; dihydroorotate dehydrogenase ; Aspergillus ; Scedosporium ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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