The fading boundaries between patient and environmental routes of triazole resistance selection in Aspergillus fumigatus

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 [1,2].Unfortunately, the effective use of triazoles has been threatened by the emergence of resistance in A. fumigatus [3].In voriconazole-treated patients, day 42 survival was 21% lower in voriconazole-resistant IA compared with voriconazole-susceptible infection [4].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. How is triazole resistance selected in A. fumigatus?Triazoles represent a stress factor to the fungus that can be overcome by genetic adaptation, i.e., the acquisition of heritable modifications through natural selection, enabling the fungus to survive and reproduce in the azole-containing environment.Mutation is thus an important requirement for adaptation as genetic variations are created that might be better suited to survive in the presence of azoles.A. fumigatus can benefit from three reproduction modes that create this variation [5].Asexual sporulation allows spontaneous mutations to occur in each one of the many produced spores, while, in addition, extensive genetic reshuffling takes place through recombination during sexual and parasexual reproduction.Asexual sporulation is abundant in A. fumigatus, but the frequency and conditions that support (para)sexual reproduction remain largely unknown [5].When A. fumigatus is exposed to triazoles in experimental conditions, resistance mutations may emerge both through asexual reproduction and sexual reproduction [6], indicating that both modes enable adaptation to the azole environment.Resistance generally comes with a fitness cost and reduced growth rates are observed in resistant isolates recovered from triazole-treated patients when grown in the absence of triazoles [5,7].Although these isolates have an advantage in the azole environment, they will