Abstract
Aspergillus fumigatus is a saprobic fungus that may cause allergic syndromes, chronic pulmonary aspergillosis (CPA), and acute invasive aspergillosis (IA). Many patients suffering from aspergillus diseases benefit from antifungal therapy. Itraconazole, voriconazole, posaconazole, and isavuconazole have been shown to be the most effective compounds for prevention and treatment of the various aspergillus diseases. The use of alternative antifungal drugs, i.e., liposomal amphotericin B, is limited by toxicity and the echinocandins by fungistatic activity, while both also require intravenous access. As a consequence, the triazoles have become the recommended option for first-line therapy and chemoprophylaxis. Unfortunately, the effective use of triazoles has been threatened by the emergence of resistance in A. fumigatus. In voriconazole-treated patients, day 42 survival was 21% lower in voriconazole-resistant IA compared with voriconazole-susceptible infection. As the number of available drug classes is already very limited, some aspergillus diseases, such as central nervous system IA, are virtually untreatable if caused by a triazole-resistant isolate.
Highlights
In voriconazole-treated patients, day 42 survival was 21% lower in voriconazole-resistant invasive aspergillosis (IA) compared with voriconazole-susceptible infection [4]
In a controlled experimental evolution design, many environmental azole fungicides were found to be active against A. fumigatus to very effectively select for resistance and, crucially, to cause cross-resistance to the medical triazoles in these populations without ever being exposed to them [20]
Resistance is found in all aspergillus diseases: invasive aspergillosis, ABPA, chronic colonization, aspergilloma
Summary
In a controlled experimental evolution design, many environmental azole fungicides were found to be active against A. fumigatus to very effectively select for resistance and, crucially, to cause cross-resistance to the medical triazoles in these populations without ever being exposed to them [20] Numerous studies have reported the presence of TR34/L98H, TR53, and TR46/Y121F/ T289A in clinical and environmental samples, single-resistance mutations have been found in settings not consistent with in-host resistance selection: the environment and from triazole-naïve patients. Patient route Resistance is primarily found in patients with a pulmonary cavity Recent or ongoing triazole therapy Isolates may have a fitness cost in culture Isogenic wild-type and resistant isolates may be found in consecutive samples from the same patient Resistance mutations include single mutations in the Cyp51A gene and non-Cyp51A (unknown) mutations
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