Conclusions and Perspectives
In summary, the antifungal armamentarium now comprises primarily of lipid formulations of AmB, which have a wide spectrum but can cause renal impairment and have no oral bioavailability; azoles, which have, in most cases, a narrower spectrum, better tolerability, and oral options but carry significant drug interactions; and echinocandins, which display fungicidal activity but a narrower spectrum and no oral route. Unmet needs are therefore obvious but become even more striking when considering the rise of resistant fungi such as C. auris or azole-resistant strains of Aspergillus spp. Additional antifungals are currently in development and notable ones include the following:
Rezafungin (CD101), a new echinocandin with a very long half-life, allowing a once a week dosing. In vitro activity against Candida and Aspergillus is similar to that of other echinocandins. It has also shown activity against C. auris in mice. Activity against Pneumocystis seems to be more pronounced than that for the other echinocandins. In a murine model, rezafungin had similar efficacy to trimethoprim/sulfamethoxazole in preventing the development of Pneumocystis pneumonia by blocking the formation of both reproductive forms (trophic and cyst/asci) of Pneumocystis murina. Phase 3 studies have been initiated in invasive Candida infections (https://clinicaltrials.gov).
Ibrexafungerp (SCY-078) is an orally bioavailable β-D-glucan synthesis inhibitor that is not an echinocandin but a triterpenoid. Ibrexafungerp is active against Candida (including multidrug-resistant C. auris and C. glabrata), Aspergillus, and Pneumocystis. It is the only agent with modest activity against Lomentospora prolificans (formerly Scedosporium prolificans) but is inactive against the agents of mucormycosis and Fusarium spp. A phase 2 study of oral step down therapy after initial echinocandin treatment has been conducted in patients with invasive candidiasis.
PC945 is a triazole designed for inhalation with sustained lung penetration for the treatment of pulmonary aspergillosis. Preclinical studies show synergy between topical PC945 and systemic voriconazole or posaconazole. Clinical trials are ongoing in allergic asthma in patients infected by Aspergillus and Candida, in cystic fibrosis patients infected by Aspergillus, and for the early treatment of Aspergillus infections in lung transplant patients (https://clinicaltrials.gov).
Olorofim (F901318) is an inhibitor of dihydroorotate dehydrogenase. It belongs to the orotomide class. Despite lack of in vitro activity against Candida spp. and the agents of mucormycosis, olorofim has interesting potency against Aspergillus spp. including azole-resistant strains, Scedosporium spp., and various rare molds.[102–105]
VL-2397 (previously known as ASP2397) is a natural product discovered in Acremonium persicinum. VL-2397 is a ferrichrome-type siderophore chelating aluminum. Cellular uptake of VL-2397 in A. fumigatus is mediated by the fungal siderophore transporter Sit1. VL-2397 has demonstrated in vitro activity against Aspergillus species, including azole-resistant strains, and Fusarium species.[106,108] A phase 3 study was launched in invasive aspergillosis, but clinical development was terminated by business decision after enrollment of four patients (https://clinicaltrials.gov).
Manogepix (APX001A and formerly E1210) is an oral and IV broad-spectrum antifungal targeting the highly conserved fungal enzyme Gwt1.[109–112] Inhibition of Gwt1 blocks the inositol acylation of glycosylphosphatidylinositol-anchored proteins and compromises fungal wall integrity. Manogepix is active against most pathogenic fungi such as Candida spp. (including caspofungin-resistant strains but not C. krusei), C. neoformans, Aspergillus spp., Scedosporium spp., and other rare molds.[109,110]
While awaiting further improvement in our options to treat invasive fungal infections, a good understanding of the clinically relevant features of antifungals, which drive their use in terms of drug selection and management, is crucial for improving the prognosis of infected patients.
Semin Respir Crit Care Med. 2020;41(1):158-174. © 2020 Thieme Medical Publishers