Antifungals
Sarah H. Wakelin, Howard I. Maibach, Clive B. Archer in Handbook of Systemic Drug Treatment in Dermatology, 2015
Most imidazole antifungal drugs are only formulated for topical use (clotrimazole, miconazole, econazole) to treat the skin and nails. Ketoconazole is the exception, but is no longer recommended for systemic use due to the risk of hepatotoxicity. Triazoles (itraconazole, fluconazole, voriconazole, posaconazole) are used systemically and have a higher specificity against fungal cytochrome P450 (CYP450) than imidazoles and less human toxicity. Fluconazole has good activity against fungal yeast forms but lacks activity against moulds, whereas itraconazole has a wider spectrum of action, but less reliable bioavailability. Vorioconazole and posaconazole are used for invasive fungal infections. The adverse effects of voriconazole include hepatitis, hair loss, nail changes, phototoxicity and squamous cell carcinoma.
History of antifungals
Mahmoud A. Ghannoum, John R. Perfect in Antifungal Therapy, 2019
Posaconazole, a hydroxylated analogue of itraconazole, was developed by the Schering-Plough Research Institute and approved for use in 2006 [64]. Posaconazole is effective against opportunistic and endemic fungi, such as Aspergillus spp., Zygomycetes, and Candida species [64,65]. Posaconazole has been shown to be superior to amphotericin B, fluconazole, and itraconazole against most common fungal pathogens in in vitro and animal studies [66]. It is approved for prophylaxis of invasive fungal infections (aspergillosis and candidiasis) in immunocompromised patients and for the treatment of oropharyngeal candidiasis. Recently, a delayed-release formula was created that allows patients to be dosed once to twice daily in the hospital or at home [67].
Posaconazole
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 in Kucers’ The Use of Antibiotics, 2017
Posaconazole has excellent activity against filamentous fungi, demonstrating MICs approximately twofold lower than itraconazole or voriconazole (Table 157.1). The spectrum of activity includes common Aspergillus spp., including A. fumigatus, A. flavus, and A. niger (Diekema et al., 2003; Sabatelli et al., 2006). Posaconazole is also active against A. terreus, a species with frequent resistance to amphotericin B (Lass-Florl et al., 2009). A notable aspect of posaconazole activity is against the emerging Mucorales group of fungi (Almyroudis et al., 2007; Diekema et al., 2003; Pfaller et al., 2002). However, MICs to posaconazole are higher for these organisms, especially Mucor spp. (MIC90, 2–16 µg/ml) and Rhizopus spp. (MIC90, 1–8 µg/ml), than those observed for other filamentous fungi in the Aspergillus genus. Posaconazole has in vitro activity against other filamentous fungi, such as Penicillium spp., Paecilomyces spp., Trichosporon spp., Bipolaris spp., Saprochaete spp., and Acremonium spp. (Diekema et al., 2003; Pfaller et al., 2002). Similar to other triazole drugs, posaconazole MICs to Fusarium spp. are high (MIC50, 8–16 µg/ml) (Diekema et al., 2003; Sabatelli et al., 2006).
Evaluating posaconazole, its pharmacology, efficacy and safety for the prophylaxis and treatment of fungal infections
Published in Expert Opinion on Pharmacotherapy, 2022
Paraskevi Panagopoulou, Emmanuel Roilides
Posaconazole has obtained an important position in the antifungal drug armamentarium. Having activity against both yeasts and filamentous fungi beyond Aspergillus spp., it can serve as a broad-spectrum antifungal agent for prophylaxis and empiric therapy. Indeed, its oral formulation is ideal for long-term treatment of patients with susceptible fungi including molds. In particular, its activity against Mucorales makes it an important adjunct to antifungal therapy in invasive mucormycosis. The delayed-release tablet formulation that was developed and studied more recently has been an advantage in the long-term prophylactic administration as it has better bioavailability characteristics than the previously existing oral solution. Posaconazole has been proved to be an excellent oral agent for prophylaxis of invasive fungal diseases especially of those caused by filamentous fungi.
Acute kidney injury: an unusual complication of posaconazole use
Published in Journal of Chemotherapy, 2018
Akaninyene Otu, Felix Bongomin, Chris Kosmidis, David W. Denning
Posaconazole has potent activity against Aspergillus species and is an effective agent for the prevention and treatment of a range of invasive fungal infections. Felton et al.6 reported the first use of posaconazole in the long-term treatment of 79 patients with chronic pulmonary aspergillosis (CPA) in 2010. Adverse reactions were observed in 12 patients (15%) (nausea in 5, rash in 5, headache in 1, and lethargy in 1), leading to discontinuation of treatment in 9 patients. In immunocompromized and critically ill patients with refractory invasive fungal diseases, long-term (>6 months) therapy with posaconazole was not shown to increase the risk of any individual adverse event. The most common treatment-related adverse events in these patients were nausea (8%) and vomiting (6%).8 Isavuconazole is a much newer novel triazole agent with utility in treatment of CCPA that does not contribute to a prolonged QT interval, has fewer drug–drug interactions; and does not require dose adjustments in patients with hepatic or renal impairment.9,10
Azole resistance in Aspergillus species: promising therapeutic options
Published in Expert Opinion on Pharmacotherapy, 2021
Shirisha Pasula, Pranatharthi H. Chandrasekar
Aspergillus fumigatus can cause a wide variety of pulmonary fungal diseases, including hypersensitivity pneumonitis, acute invasive aspergillosis (IA), chronic pulmonary aspergillosis (CPA), and allergic bronchopulmonary aspergillosis (ABPA) [1]. The triazoles, itraconazole, isavuconazole, posaconazole, and voriconazole are antifungal agents with potent activity against A. fumigatus. Itraconazole and voriconazole are the preferred agents in patients with chronic pulmonary aspergillosis. Voriconazole and isavuconazole have been studied as first-line agents for the treatment of invasive aspergillosis. Posaconazole is mainly used for prophylaxis against invasive fungal infections in patients with hematological diseases [2–4]. There is an increasing global concern for azole resistance creating difficulty in choosing reliable effective antifungal regimen and is associated with increased mortality. This paper reviews epidemiology, mechanisms and detection of azole resistance, and therapeutic options for azole-resistant Aspergillus infections.
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