Emerging fungal threats and therapeutic strategies: A ‘changing fungal landscape’
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The landscape of invasive fungal infections (IFIs) is changing. Superficial mycoses account for much of the global prevalence, but IFIs are associated with a disproportionately high morbidity, mortality and economic burden.
Many factors have likely contributed to an increasing incidence of IFIs, including widespread use of immunomodulating therapies, more frequent nosocomial exposure, enhanced fungal identification capabilities, emergence of antifungal resistance and zoonotic fungal epidemics with human impact. Out of millions of fungal species worldwide, only 300 are known causes of disease, with 20 to 25 of these affecting humans on a frequent basis. Accurate IFI epidemiologic numbers are difficult to discern because of variation in definitions and reporting practices.
The CDC’s 2019 Antibiotic Resistance Threats in the United States report reflected growing concern about fungal infections. Candida auris is listed as an urgent threat and drug-resistant Candida a serious threat. Azole-resistant Aspergillus fumigatus is on the watch list. Only fluconazole-resistant Candida was in the initial 2013 CDC report. The effectiveness of current antifungal therapies — polyenes, flucytosine, azoles and echinocandins (as monotherapy or in combination) — against these organisms has plateaued with known gaps in spectra, toxicities and formulations. The steady rise in incidence, coupled with a limited therapeutic arsenal, remains a focus for further IFI research. In the interim, clinicians are faced with the tough task of determining optimal treatment modalities for two of the most clinically consequential emerging IFIs.
Drug-resistant Candida
Infections due to Candida species are associated with a wide variety of clinical manifestations, ranging from skin and soft tissue infections to disseminated bloodstream infections. Candida albicans historically has been considered the most pathogenic species and is still the leading cause of candidemia. However, non-albicans species now comprise more than 50% of bloodstream infections in many parts of the world. One non-albicans species, Candida auris, is alarming because of its association with nosocomial outbreaks and a predilection for epidemic spread despite vigilant infection control measures, ultimately behaving more like a bacterial multidrug-resistant organism than other Candida species. First described in 2009, C. auris — so named because it was first isolated from a patient’s ear canal in Japan — has since been isolated on six continents. Nineteen states in the U.S. have reported confirmed cases, totaling 1,092.
Bypassing the challenge of identification, treating invasive C. auris is exceedingly difficult because of unprecedented drug resistance. The Clinical & Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing have not established minimum inhibitory concentration breakpoints. The CDC has proposed the following breakpoints, conservatively based on those established for other species: 32 or more for fluconazole, 2 or more for amphotericin B ( 1.5 if using E-test), 4 or more for anidulafungin and micafungin and 2 or more for caspofungin. In the U.S., roughly 90% of C. auris isolates are resistant to fluconazole, around 30% are resistant to amphotericin B and less than 5% are resistant to echinocandins, which is congruent with resistance profiles from India, Pakistan, Venezuela and South Africa.
No systematic study has assessed the effectiveness of various antifungals against C. auris in humans. Echinocandins — comprising anidulafungin, caspofungin and micafungin — are the recommended first-line therapy. These agents work by blocking beta (1,3)-D-glucan synthase, an enzyme that is essential for the synthesis of beta (1,3)-D-glucan, a main component of the fungal cell wall. In mice with C. auris candidemia, micafungin was more efficacious than fluconazole and amphotericin B. In vitro investigations with echinocandins and azoles showed synergistic activity between micafungin and voriconazole against 10 C. auris strains. This was not reflected in other echinocandin and azole combinations. However, the site of infection is an important consideration. Echinocandins achieve poor concentrations in multiple sites, including cerebrospinal fluid, because of their high molecular weight, and minimal active drug is recovered from urine. The combination of amphotericin B, a polyene that acts by binding irreversibly to ergosterol-containing fungal membrane but has limited use due to adverse effects, and 5-flucytosine, a pyrimidine analog that interferes with fungal RNA and DNA metabolism, have been suggested for central nervous system infections and UTIs. New antifungal agents are on the horizon, namely ibrexafungerp — the first agent in the triterpenoid class of structurally distinct glucan synthase inhibitors — and rezafungin, part of the echinocandin family that achieves high plasma drug exposure, allowing for once-weekly administration. Both ibrexafungerp and rezafungin have shown activity against C. auris in early in vitro and in vivo experiments.
Azole-resistant Aspergillus fumigatus
Aspergillus is a ubiquitous mold that causes allergic, chronic and invasive disease, with most infections being caused by Aspergillus fumigatus. The survival rates of immunocompromised patients with invasive aspergillosis have significantly improved in part because of azole antifungals. This class comprises several agents with activity against aspergilli, including itraconazole, voriconazole, posaconazole and, more recently, isavuconazole. All have enteral options, easing administration practices, especially for long-term and ambulatory use. Erratic absorption, numerous drug-drug interactions and nonlinear pharmacokinetics (ie, itraconazole and voriconazole) can make assessment of drug levels difficult and confound efficacy. Azoles decrease synthesis of ergosterol by inhibiting a cytochrome P450-dependent enzyme, 14-alpha-demethylase.
Acquired azole resistance generally occurs by two routes: patient exposure with long-term azole therapy or via use of azole agricultural fungicide. Resistance mechanisms have been characterized by point mutations in the Cyp51A gene, which encodes the target enzyme of azoles. Resistant A. fumigatus isolates carrying either TR34/L98H or TR46/Y121F/T289A genes have been associated with environmental azole fungicide use, most commonly in patients without previous systemic azole exposure (64% to 71%). Azole-resistant A. fumigatus strains are common in Europe, but U.S. reports are limited, with the first case report in 2008.
All studies to date show that azole resistance is associated with treatment failure and mortality rates ranging between 50% and 100% in those with culture-positive azole-resistant invasive aspergillosis. Verweij and colleagues published an international expert opinion paper in 2015 with recommendations on the topic. Most experts recommended moving away from azole monotherapy when azole resistance is detected, in areas with confirmed environmental resistance and/or when azole resistance rates exceed 10%. Alternative therapy options include switching to liposomal amphotericin B or voriconazole in combination with an echinocandin. Seyedmousavi and colleagues demonstrated comparable efficacy of liposomal amphotericin B against invasive aspergillosis, including azole-resistant Aspergillus isolates (n = 3), indicating azole resistance does not diminish liposomal amphotericin B activity. Marr and colleagues showed a trend toward improved outcomes with voriconazole plus anidulafungin in comparison to voriconazole monotherapy, but susceptibility testing results of culture-positive patients were not reported. Preclinical data suggested the additive action of an azole-echinocandin combination might render an azole-resistant A. fumigatus more susceptible, but clinical evidence is needed to support this claim.
Conclusion
The changing fungal landscape is now one with drug resistance. C. auris and A. fumigatus are two of the most clinically consequential IFIs with limited treatment options. There are multiple unanswered questions regarding epidemiology, resistance mechanisms and the impact of the environment and climate change on the emergence of new fungal diseases and the re-emergence of old ones. Prevention of IFIs may be more effective than reactive efforts. The increasing prevalence of immunomodulating therapies and expansion of immunocompromised populations, along with known resistance development via use of agricultural fungicide use, warrants a One Health mentality to antifungal stewardship. As research investigates more efficient diagnostic methods and novel antifungal agents, fungal prophylaxis and treatment regimens require continued coordinated intervention for further optimization. The invasive fungal infection apocalypse is a threat if no action is taken.
- References:
- CDC. Antibiotic resistance threats in the United States, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed May 13, 2020.
- Forsberg K, et al. Med Mycol. 2019;doi:10.1093/mmy/myy054.
- Jeffery-Smith A, et al. Clin Microbiol Rev. 2018;doi:10.1128/CMR.00029-17.
- Marr KA, et al. Ann intern Med. 2015;doi:10.7326/M13-2508.
- Perfect JR. Nat Rev Drug Discovery. 2017;doi:10.1038/nrd.2017.46.
- Rauseo AM, et al. Open Forum Infect Dis. 2020;doi:10.1093/ofid/ofaa016.
- Seyedmousavi S, et al. Antimicrob Agents Chemother. 2013;doi:10.1128/AAC.02226-12.
- Van der Linden JW, et al. Emerg Infect Dis. 2015;doi:10.3201/eid2106.140717.
- Vermeulen E, et al. Curr Opin Infect Dis. 2013;doi:10.1097/QCO.0000000000000005.
- Verweij PE, et al. Drug Resist Updat. 2015;doi:10.1016/j.drup.2015.08.001.
- Webb BJ, et al. Open Forum Infect Dis. 2018;doi:10.1093/ofid/ofy187.
- For more information:
- Jennifer Ross, PharmD, is an infectious diseases clinical pharmacist at M Health Fairview University of Minnesota Medical Center. Ross can be reached at jross13@fairview.org.
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