Emerging treatment options for azole-resistant A. fumigatus
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Azole-resistant Aspergillus fumigatus has become an increasing problem worldwide over the last decade.
Azole-resistant A. fumigatus has been reported in up to 20% of isolates in some parts of the world and has been isolated on every continent except Antarctica. Unfortunately, the true rate of azole-resistant A. fumigatus is not well described because many laboratories do not have the capability to perform the necessary resistance testing.
Although azole-resistant A. fumigatus can occur from selective pressure during long-term treatment of infected patients, use of azoles in agriculture or farming has been a major factor in increasing resistance. Azole antifungals are commonly used to treat and prevent plant fungi because they are inexpensive, treat a wide variety of fungi and persist in the environment for prolonged periods of time. This makes them convenient to use and helps increase crop yields. Because Aspergillus species are found on decaying plant matter, resistant A. fumigatus has been found not only in commercially available soil, compost and mulch, but even in outdoor air.
Most of the new antifungal drugs approved over the past decade have been new drugs in existing antifungal classes. Because azoles are the mainstay of treatment for aspergillus infections, resistance complicates effective treatment. In azole-resistant strains, current treatment options include amphotericin B, echinocandins or combination therapy, but these alternatives are not optimal for A. fumigatus treatment. The antifungal research and development pipeline, however, includes several promising agents that may improve treatment of azole-resistant aspergillus infections, as well as other troublesome fungal infections.
Ibrexafungerp
Ibrexafungerp is the first novel antifungal FDA approved in the past 2 decades. It is a triterpenoid antifungal for vulvovaginal candidiasis treatment in adults and postmenarchal children.
Ibrexafungerp inhibits the biosynthesis of 1, 3-beta-D-glucan in the fungal cell wall. The binding sites for ibrexafungerp and the echinocandins differ with only a partial overlap, making cross-resistance between them less likely to occur. Ibrexafungerp retains activity against both azole-resistant Candida species and Aspergillus species. However, clinical trial data are lacking for its effectiveness with invasive pulmonary aspergillosis. In vitro, ibrexafungerp in combination with isavuconazole was shown to have synergistic activity. This combination also reduced the fungal burden and prolonged survival in a neutropenic rabbit model.
Currently, there is a phase 2 clinical trial evaluating the efficacy and safety of ibrexafungerp in combination with isavuconazole among people with invasive pulmonary aspergillosis (ClinicalTrials.gov identifier: NCT03672292). Ibrexafungerp is available as an oral 150 mg tablet, and an IV formulation is currently in development.
Fosmanogepix
Fosmanogepix is a prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1 that blocks glycosylphosphatidylinositol, which is important for building the fungal cell wall. Manogepix demonstrates broad-spectrum activity against yeasts and molds, including echinocandin-resistant Candida species and azole-resistant Aspergillus species. It also is active against pathogens with intrinsic resistance to other antifungals, such as Scedosporium, Fusarium and Lomentospora prolificans.
Manogepix has undergone phase 2 clinical trials for invasive candidiasis, for which it has shown good clinical outcomes. There is an ongoing phase 2 trial (NCT04240886) evaluating fosmanogepix in the treatment of invasive aspergillosis and other rare molds. This study is enrolling patients with limited treatment options due to expected or documented resistant pathogens, contraindications, intolerances or lack of clinical response to standard-of-care antifungal therapy. Fosmanogepix is being studied in IV and oral formulations. It has demonstrated good oral bioavailability (greater than 90%), which will be beneficial for intravenous to oral step-down therapy.
Olorofim
Olorofim is part of a new class of antifungals, the orotomides, developed to treat invasive aspergillosis and other mold infections. It is being developed in both IV and oral formulations. Olorofim inhibits fungal growth by inhibiting the fungal dihyroorotate dehydrogenase enzyme involved with pyrimidine synthesis. Although it is not considered to be a broad-spectrum antifungal, it does have activity against Histoplasma and Coccidioides species, Aspergillus species, including azole-resistant strains, and Scedosporium species. It also has good activity against L. prolificans, Rasamsonia species, Penicillium species and Scopularoiopsis species, which currently have limited treatment options.
Olorofim was designated a breakthrough therapy by the FDA for treatment of invasive mold infections for patients with limited or no treatment options, as well as for treatment of central nervous system coccidioidomycosis refractory to standard of care. Although there are no published clinical trials to date, there are several published case reports showing favorable outcomes. A phase 2b clinical trial for the treatment of invasive mold infections is underway (NCT03583164) that includes Aspergillus species with resistance to other available antifungals, or patients not responding to traditional therapy.
Opelconazole
Opelconazole is an inhaled broad-spectrum triazole antifungal drug. It is designed to be used in commercially available nebulizer systems. Although opelconazole is an azole, it possesses some characteristics that increase its lipophilicity, which results in high concentrations and retention in the lung. It also has slow systemic absorption, resulting in low plasma levels to help reduce systemic toxicity. Opelconazole has a broad spectrum, including many yeasts and molds. It has shown potent in vitro activity against azole-susceptible and azole-resistant A. fumigatus. Opelconazole has also shown promising synergistic activity when combined with systemically administered posaconaozle or voriconazole.
Opelconazole has been granted orphan drug, fast track and qualified infectious diseases product designations by the FDA for treating invasive pulmonary aspergillosis. A phase 2 trial (NCT05037851) for prophylaxis or pre-emptive therapy against pulmonary aspergillosis in lung transplant patients is underway.
Rezafungin
Rezafungin is a second-generation echinocandin that was designed to optimize its pharmacokinetics and reduce toxicity. Rezafungin is an analog of anidulafungin, which has a structural modification that results in a much longer half-life. Studies have shown that the mean half-life is approximately 80 hours after the first dose and 150 hours after subsequent doses. This long half-life allows rezafungin to be administered at extended intervals, usually weekly. It has a similar antifungal spectrum of activity as other echinocandins such as Candida species (including Candida auris), and A. fumigatus.
A phase 3 trial comparing rezafungin to caspofungin for treating candidemia/invasive candidiasis was recently completed, but results are not yet available. Rezafungin is also being studied for prevention of invasive fungal disease in adults undergoing allogeneic blood and marrow transplantation (NCT04368559), which will include Candida species, Aspergillus species and Pneumocystis jirovecii.
In the 2019 CDC Antibiotic Resistance Threats in the United States report, azole-resistant A. fumigatus was added to the watch list. Azole-resistant A. fumigatus is a global problem that will require a One Health approach to begin to address the problem and develop potential solutions. This is a complex situation that will need experts from human health, agricultural researchers and producers, policymakers, regulatory bodies and others, to work together. Although there are promising agents in the antifungal pipeline, the root cause of the increasing resistance rates needs to be adequately addressed to slow the spread of this troublesome pathogen.
- References:
- Burks C, et al. PLoS Pathog. 2021;doi:10.1371/journal.ppat.1009711.
- CDC Antibiotic resistance threats in the United States, 2019. https://www.cdc.gov/drugresistance/biggest-threats.html. Accessed June 10, 2022.
- Hoenigl M, et al. Drugs. 2021;doi:10.1007/s40265-021-01611-0.
- Pappas, et al. Open Forum Infect Dis. 2020;doi:10.1093/ofid/ofaa439.457.
- Patterson TF, et al. Clin Infect Dis. 2016;doi:10.1093/cid/ciw326.
- Petraitis V, et al. Antimicrob Agents Chemother. 2020;doi: 10.1128/AAC.02429-19.
- Verweij PE, et al. Fungal Biol Rev. 2020;doi:10.1016/j.fbr.2020.10.003.
- For more information:
- Jeff Brock, PharmD, MBA, BCPS AQ-ID, is an infectious disease pharmacy specialist at MercyOne Medical Center in Des Moines, Iowa. He can be reached at jbrock@mercydesmoines.org.
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