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Ketoconazole
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Using the CLSI in vitro susceptibility testing of filamentous fungi (M38), some strains of Aspergillus spp. may be sensitive to ketoconazole. However, the MIC breakpoints for antifungals have not been defined. Similarly, the agents that cause chromoblastomycosis (Cladosporium, Fonsecaea, and Phialophora spp.) may be susceptible to ketoconazole. Its action against the zygomycetes of the order Mucorales, such as the genera Cunninghamella, Rhizopus, Absidia, and Mucor, is poor (Eng et al., 1981; Almyroudis et al., 2007). Zygomycetes of the order Entomophthorales of the genera Basidiobolus and Conidiobolus are sometimes sensitive (Drouhet and Dupont, 1983; Van Cutsem, 1983; Yangco et al., 1984). Fusarium spp. are generally resistant to ketoconazole (Reuben et al., 1989). Madurella spp. and Pseudallescheria boydii, which are causes of eumycetoma, may be sensitive to ketoconazole (Venugopal et al., 1990; Gilgado et al., 2006, respectively). It is highly active against many strains of the dermatophytes, including Microsporum, Trichophyton, and Epidermophyton spp. (Venugopal et al., 1993; Zhanel et al., 1997; Fernández-Torres et al., 2001).
The potential role of interleukin-37 in infectious diseases
Published in International Reviews of Immunology, 2020
Gamal Allam, Asmaa M. Gaber, Sarah I. Othman, Adel Abdel-Moneim
Eumycetoma is a chronic granulomatous subcutaneous inflammatory disease resulting from infection with Madurella mycetomatis (M. mycetomatis) and affecting deep subcutaneous tissues and bones leading to massive destruction, deformities and disabilities [73]. A recent study has demonstrated that eumycetoma patients showed higher circulating levels of IL-37. In addition, serum levels of IL-37 were positively correlated with diameters of mycetoma lesions and negatively correlated with levels of IL-1β. However, the levels of IL-1β were negatively correlated with diameters of lesions, and unit increment in IL-1β decreases the levels of IL-37 by 35.28 pg/ml. The study concluded that high levels of IL-37 may have a negative impact on eumycetoma progression and clinical outcomes [74].
Echinocandins – structure, mechanism of action and use in antifungal therapy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mateusz Szymański, Sandra Chmielewska, Urszula Czyżewska, Marta Malinowska, Adam Tylicki
Echinocandins are recommended as a treatment for patients suffering from an invasive infection caused mainly by Candida, Aspergillus species and some other pathogenic fungi50 (Table 4). These antibiotics also act on biofilm-forming yeasts especially on the Candida genus64. Relative to Candida species, echinocandins exhibit fungicidal activity manifested by significant cell enlargement and distortion, which contributes to inhibition of cell proliferation. Against Aspergillus species (A. fumigatus, A. flavus, A. niger, and A. terreus), echinocandins exert fungistatic effects by causing irregular growth of the hyphae with multiple branched tips and distended cells, preventing the pathogen from spreading beyond the initial site of infection65–67. Echinocandins are also active against some species of Penicillium and Paecilomyces. To a lesser extent, they show activity against Madurella, Wangiella, Sporothrix, Exophiala, Scedosporium, Pseudallescheria and Fonsecaea genera68. These antibiotics used without additional antifungal compounds are not effective for the treatment of mycoses caused by Mucorales, Cryptococcus, Fusarium, Rhizpous and Trichosporon genera69,70. The cell wall of the above-mentioned fungal genera contains mainly β-(1,6)-d-glucans, which limits their sensitivity to echinocandins69. The activity of these antibiotics against representatives of the genera Histoplasma, Blastocystis and Coccidioides is also limited71.
Novel avenues for identification of new antifungal drugs and current challenges
Published in Expert Opinion on Drug Discovery, 2022
Innovative molecules from recent years also include rezafungin [75] (Figure 5), which is a new echinocandin with good solubility and long half-life. It is comparable with other echinocandins and has activity against Candida sp. and Aspergillus sp., including echinocandin-resistant C. auris isolates and azole-resistant Aspergillus isolates [76–78]. Olorofim [79] (Figure 5) is a representative of a completely new group of orotomides that has entered a clinical trial [80]. It inhibits dihydroorotate dehydrogenase and thus prevents the synthesis of pyrimidines. The agent is effective against Aspergillus sp., Scedosporium sp., Lomentospora prolificans, Fusarium, Blastomyces, Coccidioides, Histoplasma, Microascus, Scoulariopsis sp., Penicillium, Paecilomyces, Purpureocillium, Talaromyces, and Madurella, including azole and amphotericin B resistant strains/isolates. Unfortunately, it has no activity against yeasts and Mucorales [81,82]. Fosmanogepix [83] (in a clinical study [84]) is an N-phosphonooxymethylene prodrug of manogepix (see both in Figure 5), which is a model molecule of a new antifungal group of substituted isoxazolylaminopyridine glycosylphosphatidylinositol inhibitors [85,86] that show selective antifungal activity by inhibiting the fungal enzyme Gwt1, which causes inactivation of posttranslational modifications of mannoproteins [87], affects the cell wall integrity of the fungal cell, reduces the ability to adhere, invade host tissues, and increases the recognition of the fungus by immune cells. The molecule has a broad therapeutic index [88]. Thanks to its new mechanism of action, manogepix retains its efficacy against many resistant strains, including echinocandin-resistant Candida and azole-resistant Aspergillus. It is active against a wide variety of fungi and is currently being evaluated for the treatment of invasive candidiasis, aspergillosis, coccidiosis, and fungal infections caused by Scedosporium, Fusarium, L. prolificans, and Mucorales [84–88]. Ibrexafungerp [89] (Figure 5), a triterpene derivative of enfumafungin, was approved by the FDA on 1 June 2021 for the treatment of echinocandin- or azole-resistant vulvovaginal candidiasis [90,91]. The advantage of ibrexafungerp over parenteral caspofungin, micafungin, and anidulafungin is the oral route of administration. It blocks all subunits (FKS1, FKS2, Rho1) of β-1,3-glucan synthase in contrast to echinocandins [92,93]. Some other prepared compounds were overviewed, for example, by Billamboz et al. [94] and Rauseo et al. [95].