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Basic Principles of Antifungal Treatment
Published in Firza Alexander Gronthoud, Practical Clinical Microbiology and Infectious Diseases, 2020
Monitor signs of drug toxicity All antifungal drugs can cause hepatotoxicity, lowest risk seen with echinocandins.Azoles: Prolonged QT interval. Visual disturbances and encephalopathy can be seen with voriconazole. IV voriconazole can result in renal toxicity.Echinocandins: Low toxicity profile. Infusion-related reaction is a rare side effect.Amphotericin B: Infusion-related reaction (lower with liposomal amphotericin B), renal toxicity, hypokalaemia, hepatotoxicity.
Candida spp.
Published in Rossana de Aguiar Cordeiro, Pocket Guide to Mycological Diagnosis, 2019
Silviane Praciano Bandeira, Glaucia Morgana de Melo Guedes, Débora de Souza Colares Maia Castelo-Branco
The most recently described class of antifungal drugs is the echinocandins. These drugs act quite peculiarly by preventing the synthesis of glucans in the fungal cell wall by inhibiting the enzyme 1,3-β-glucan synthase. This unique mechanism significantly reduces the occurrence of side effects, since it targets a structure that does not exist in the host cells. This class includes the drugs caspofungin, micafungin, and anidulafungin. They are expensive, but are a good therapeutic options in cases of Candida fungemia (Akins, 2005; Pfaller et al., 2012).
Anidulafungin
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
A number of in vitro studies have reported paradoxical tolerance of Candida spp. exposed to high concentrations of echinocandins. With respect to anidulafungin, paradoxical growth occurs at concentrations > 4 μg/ml and appears to persist for at least 24 hours (Wiederhold, 2009; Maiolo et al., 2014; Chamilos et al., 2007). This “eagle-effect”-like phenomenon is conditional, as strains that display paradoxical growth exhibit normal susceptibility patterns when subcultures are re-challenged with drug (Stevens et al., 2004; Wiederhold and Lewis, 2007). The clinical relevance of this phenomenon remains to be determined. Anidulafungin and other echinocandins lack appreciable activity against pathogenic yeast species other than Candida, including Cryptococcus and Trichosporon (Espinel-Ingroff, 1993; Zhanel et al., 1997).
Meta-analysis of echinocandins combined with trimethoprim-sulfamethoxazole for treatment of Pneumocystis pneumonia
Published in Journal of Chemotherapy, 2023
Jiayu Guo, Zhongbao Chen, Chenyang Kong, Bo Yu, Tianyu Wang, Yalong Zhang, Yiting Liu, Jiangqiao Zhou, Tao Qiu
The drug of choice for the prevention and treatment of PCP is trimethoprim/sulfamethoxazole ([TMP/SMX] at a dosage of 15 to 20 mg of TMP/kg/day and 75 to 100 mg of SMX/kg/day). However, at present, drug resistance and poor curative effects have appeared in clinical practice [5]. Other treatments include Pentamidine, hydroxyethsulfonate, Atorvastone, Dapsone, Clindamycin, and Primaquine. However these drugs cause more adverse reactions than TMP/SMP [5,7,8]. Therefore, alternative drugs to treat PCP are needed. Echinocandins are large lipopeptide molecules, which were first discovered in 1974, and include caspofungin, micafungin, and anidulafungin. β-(1,3)-D glucose is one of the components of the fungal cell wall. Echinocandins can inhibit the synthesis of the fungal cell wall enzyme complex, β-(1,3)-D glucan synthase, thereby inhibiting the synthesis of the fungal cell wall and then playing a fungicidal role because the β-(1,3)-D glucan synthase catalysed subunit is expressed in the cell wall formed by the cysts of PCP, and echinocandins has high activity against PCP. The adverse events and toxicity of the echinocandins appear to be limited. Therefore, echinocandins can be used to treat PCP [9].
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
Until the end of the 20th century, azoles, polyenes, and flucytosine were mainly used to treat mycoses. These classes of drugs can cause serious side effects related to their hepato- and nephrotoxicity. In addition, many fungal strains have developed resistance to these antibiotics, which significantly reduces their efficacy6. In rare cases, cross-resistance to polyenes and azoles may occur, raising concerns about the future of antifungals targeting membrane ergosterol (polyens) and sterol synthesis (azoles)7. In addition, there are frequent drug-drug reactions associated with interactions of the aforementioned drugs and their metabolites in the body8. This has prompted the search for alternative agents to combat fungal infections. Echinocandins are a class of antifungal drugs that are fungicidal against many fungi including Candida species, but are fungistatic to the Aspergillus genus. This class of drugs has been found to cause milder side effects compared to polyenes and azoles9. The mechanism of action based on the inhibition of fungal-specific metabolic pathway and limited side effects have resulted in increasing interest and use of this class of drugs10.
Pneumocystis jirovecii: a review with a focus on prevention and treatment
Published in Expert Opinion on Pharmacotherapy, 2021
R. Benson Weyant, Dima Kabbani, Karen Doucette, Cecilia Lau, Carlos Cervera
Unlike many other fungi, PJ does not have ergosterol in its cell wall. This makes it immune to both the azoles and polyenes, two of the most frequently used antifungal classes. Echinocandins competitively inhibit β-1,3-D-glucan synthase and prevent the synthesis of β-1,3-D-glucan (BDG), a different component of fungal cell walls. Currently they are only available in parenteral form, owing to poor oral absorption. Most of what we know about their anti-pneumocystis properties is from animal models. Murine models have found echinocandins to be effective for prophylaxis and treatment of pneumocystis, with caspofungin and anidulafungin more effective that micafungin [105,106]. As discussed before, only the cyst form of pneumocystis species has BDG, and therefore echinocandins are not effective against the trophic form, the predominate form in the alveoli. By specifically targeting PJ cysts with anidulafungin, infected mice were unable to transmit PJ to other mice [106]. This suggests that the cyst form is essential for transmission of infection. However, in these same murine models the trophic form remains in the lungs after echinocandin treatment, allowing for the repopulation of cyst forms. This suggests that monotherapy may not be adequate, and echinocandins may be best suited as part of combination therapy. A theoretical drawback to echinocandin therapy, is that if started before the diagnosis of PJP is confirmed, it may decrease the sensitivity of stains that detect the cyst form such as Grocott’s methenamine silver stain [106].