Investigation of the Efficacy of Micafungin in the Treatment of Histoplasmosis Using Two North American Strains of Histoplasma capsulatum

Hage, Chadi A.; Connolly, Patricia; Horan, Daniel J.; Durkin, Michelle; Smedema, Melinda; Żarnowski, Robert; Smith, Patricia; Wheat, L. Joseph

doi:10.1128/aac.01681-10

Cited by 24 publications

(18 citation statements)

References 16 publications

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“…No significant difference in the susceptibility to amphotericin B was found between the two Histoplasma morphologies (Fig. 5A), consistent with previous observations of amphotericin B effects on yeasts and mycelia (16). The variation in antifungal drug effects on the different morphologies underscores the importance of using the clinically relevant form (i.e., yeasts) for antifungal susceptibility profiling of Histoplasma.…”

Section: Methodssupporting

confidence: 78%

“…Differences in antifungal susceptibilities of Histoplasma yeasts cells compared to mycelia (16,17,20) raise the importance of standardizing methodologies for Histoplasma yeasts, the clinically relevant morphological form. Although CLSI has developed procedures for yeast-form fungal pathogens, these methods do not work for the culture of Histoplasma yeasts.…”

Section: Discussionmentioning

confidence: 99%

“…Early studies on the echinocandins suggested that this antifungal class, with very low host toxicity, could be effective against Histoplasma infections (13,18,19). However, some of these early reports were based on tests with the filamentous form, and subsequent in vitro susceptibility tests employing the yeast form demonstrated that the Histoplasma yeasts are comparatively resistant to the echinocandins (16,17,20). This morphology-based discrepancy in antifungal susceptibility is not limited to echinocandins and highlights the need to use the most appropriate cell type during antifungal testing (21).…”

mentioning

confidence: 99%

“…Both yeast-and filamentous-form Histoplasma cells are generally susceptible to polyenes and triazole-class antifungals in vitro (15)(16)(17). Early studies on the echinocandins suggested that this antifungal class, with very low host toxicity, could be effective against Histoplasma infections (13,18,19).…”

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confidence: 99%

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Quantitative Microplate-Based Growth Assay for Determination of Antifungal Susceptibility of Histoplasma capsulatum Yeasts

2015

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bStandardized methodologies for determining the antifungal susceptibility of fungal pathogens is central to the clinical management of invasive fungal disease. Yeast-form fungi can be tested using broth macrodilution and microdilution assays. Reference procedures exist for Candida species and Cryptococcus yeasts; however, no standardized methods have been developed for testing the antifungal susceptibility of yeast forms of the dimorphic systemic fungal pathogens. For the dimorphic fungal pathogen Histoplasma capsulatum, susceptibility to echinocandins differs for the yeast and the filamentous forms, which highlights the need to employ Histoplasma yeasts, not hyphae, in antifungal susceptibility tests. To address this, we developed and optimized methodology for the 96-well microtiter plate-based measurement of Histoplasma yeast growth in vitro. Using optical density, the assay is quantitative for fungal growth with a dynamic range greater than 30-fold. Concentration and assay reaction time parameters were also optimized for colorimetric (MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] reduction) and fluorescent (resazurin reduction) indicators of fungal vitality. We employed this microtiter-based assay to determine the antifungal susceptibility patterns of multiple clinical isolates of Histoplasma representing different phylogenetic groups. This methodology fulfills a critical need for the ability to monitor the effectiveness of antifungals on Histoplasma yeasts, the morphological form present in mammalian hosts and, thus, the form most relevant to disease.T he increasing incidence of fungal disease necessitates adequate and timely assessment of antifungal susceptibility to guide the selection and implementation of antifungal therapies. Consequently, the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) have established reference test methods for susceptibility to the major classes of antifungals, which include the polyenes, azoles, and the recently developed echinocandins (1, 2). These standards utilize broth macrodilution or microdilution assays for testing yeasts (M27-A3 [3] and E.DEF 7.1 [4]) and filamentous fungi (M38-A2 [5] and E.DEF 9.1 [6]). Procedures, including inoculum preparation, media, assay duration, and endpoint definitions, have now been established for testing some of the more commonly encountered yeast-form pathogenic fungi (i.e., Candida species and Cryptococcus). However, notably missing from the M27-A3 and E.DEF 7.1 standards for testing of yeasts are methods for testing the yeast forms of the dimorphic fungi.The dimorphic fungi that cause systemic disease are characterized by distinct yeast and filamentous morphological states (7,8). Temperature is the principal morphology-determining factor, with yeast forms characterizing infections in mammals (9). Histoplasma capsulatum is the most common clinically encountered dimorphic fungal pathogen in the United States, with an estimated 10,000 to 20,000...

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Section: Methodssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Quantitative Microplate-Based Growth Assay for Determination of Antifungal Susceptibility of Histoplasma capsulatum Yeasts

2015

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“…The third, and most recently developed, family of antifungals for invasive mycoses is the echinocandin class, which inhibits production of fungal cell wall ␤-1,3-glucan. Although the echinocandins are better tolerated than the polyenes and the azoles due to the uniqueness of ␤-1,3-glucan for fungi, the echinocandins are ineffective for the treatment of the fungal pathogens Cryptococcus neoformans and Histoplasma capsulatum (10)(11)(12).…”

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confidence: 99%

Identification of an Aminothiazole with Antifungal Activity against Intracellular Histoplasma capsulatum

Edwards

Kemski

Rappleye

2013

Antimicrob Agents Chemother

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As eukaryotes, fungi possess relatively few molecules sufficiently unique from mammalian cell components to be used as drug targets. Consequently, most current antifungals have significant host cell toxicity. Primary fungal pathogens (e.g., Histoplasma) are of particular concern, as few antifungals are effective in treating them. To identify additional antifungal candidates for the treatment of histoplasmosis, we developed a high-throughput platform for monitoring Histoplasma growth and employed it in a phenotypic screen of 3,600 commercially available compounds. Seven hit compounds that inhibited Histoplasma yeast growth were identified. Compound 41F5 has fungistatic activity against Histoplasma yeast at micromolar concentrations, with a 50% inhibitory concentration (IC 50 ) of 0.87 M, and has the greatest selectivity for yeast (at least 62-fold) relative to host cells. Structurally, 41F5 consists of an aminothiazole core with an alicyclic substituent at the 2-position and an aromatic substituent at the 5-position. 41F5 inhibits Histoplasma growth in liquid culture and similarly inhibits yeast cells within macrophages, the actual host environment of this fungal pathogen during infection. Importantly, 41F5 protects infected host cells from Histoplasmainduced macrophage death, making this aminothiazole hit compound an excellent candidate for development as an antifungal for Histoplasma infections.

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Antifungal Susceptibility Testing and Drug Discovery in the Dimorphic Fungus Histoplasma Capsulatum

Rappleye¹

2023

Methods in Molecular Biology

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Investigation of the Efficacy of Micafungin in the Treatment of Histoplasmosis Using Two North American Strains of Histoplasma capsulatum

Abstract: Micafungin alone and combined with liposomal amphotericin B was evaluated against two strains ofHistoplasma capsulatum. Micafungin was activein vitroagainst the mold but not the yeast form but was ineffectivein vivo. Micafungin appears to be ineffective in treatment of histoplasmosis.

Cited by 24 publications

References 16 publications

Quantitative Microplate-Based Growth Assay for Determination of Antifungal Susceptibility of Histoplasma capsulatum Yeasts

Quantitative Microplate-Based Growth Assay for Determination of Antifungal Susceptibility of Histoplasma capsulatum Yeasts

Identification of an Aminothiazole with Antifungal Activity against Intracellular Histoplasma capsulatum

Antifungal Susceptibility Testing and Drug Discovery in the Dimorphic Fungus Histoplasma Capsulatum

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