6. CAPA Treatment—Current Paradigm
While it is currently unknown whether antifungal treatment of COVID-19 associated IPA translates into a survival benefit, diagnosis should in most cases trigger early antifungal treatment. Outside the hematologic malignancy setting, voriconazole remains the recommended first-line treatment for IPA [79,80]. However, besides its narrow therapeutic window and the requirement for therapeutic drug monitoring to ensure efficacy and prevent neuro and hepatotoxicity [81], drug–drug interactions may particularly limit the use of voriconazole in the ICU setting [82]. Being metabolized via CYP2C19, CYP2C9, and CYP3A4, voriconazole is among the drugs most frequently associated with major drug–drug interactions in the ICU [83]. Furthermore, it may show interactions with experimental COVID-19 therapies, including hydroxychloroquine, atazanavir, lopinavir/ritonavir and last but not least—although weaker—with remdesivir, which is also a substrate for CYP3A4, although its metabolism is primarily mediated by hydrolase activity [84]. Isavuconazole and liposomal amphotericin B are the primary alternative options for treatment of IPA in the ICU [79]. Compared to voriconazole, isavuconazole shows a more favorable pharmacokinetic profile, and is associated with fewer toxicities. However, it is also metabolized via CYP3A4 and could therefore be problematic, although drug–drug interactions are generally less a problem with isavuconazole than with voriconazole [85,86]. Liposomal amphotericin B is a broadly effective alternative treatment option, however, in the ICU renal insufficiency often complicates initiation or requires discontinuation of this antifungal agent. This concern is particularly relevant for patients infected by SARS-CoV-2 which has shown renal tropism and been described as a frequent cause of kidney injury [87]. While itraconazole is now rarely used to treat invasive aspergillosis, it has been shown to exhibit some antiviral activity, specifically as a cholesterol transport inhibitor, and was effective in a feline coronavirus model [88]. In addition, its novel oral SUBA formulation has great bioavailability [89], and itraconazole may therefore be an alternative option for treating COVID-19 associated IPA, although it shares the problem of drug–drug interactions with other triazoles. While currently available echinocandins are not considered first-line treatment options for invasive aspergillosis due to their limited antifungal activity against Aspergillus spp., they are generally well tolerated with limited drug–drug interactions and show at least fungistatic activity against Aspergillus hyphae [90]. Furthermore, they synergistic interactions with some other antifungals, making them an excellent choice for combination antifungal therapy [90]. New antifungal classes currently under development, namely fosmanogepix and olorofim [91], may have equal efficacy without the same burden of drug–drug interactions and toxicity, and may therefore overcome the limitations of currently available antifungals and become the preferred treatment options in the near future. If the reported high incidence of COVID-19 associated IPA in ICU patients is confirmed in larger studies, there may be justification for prophylaxis trials, for which not only triazoles and nebulized liposomal amphotericin B [52], but also another novel antifungal currently under development, rezafungin (i.e., once weekly echinocandin with improved activity against Aspergillus spp.), may be a candidate [92].