March 01, 2024
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In January, the CDC warned physicians to be cautious when prescribing topical antifungals in light of the recent detection of antimicrobial-resistant superficial fungal infections in the United States.
The warning accompanied new findings from a review of topical antifungal prescriptions filled by Medicare Part D beneficiaries in 2021, which found that nearly half of the more than 6 million prescriptions were written by just 10% of prescribers.
Many patients with fungal infections are diagnosed months later than they should be, according to Andrej Spec, MD. Source: Andrej Spec, MD, MSCI
As part of the warning, the CDC encouraged providers to confirm a patient’s fungal diagnosis before prescribing topical antifungals.
“[Everyone] has probably experienced a fungal infection in their life — athlete’s foot, jock itch, ringworm on your arm. One out of four of us get one of these things almost every year. We’re just constantly exposed to fungi,” Tom M. Chiller, MD, MPHTM, chief of the CDC’s Mycotic Diseases Branch, said in an interview.
Tom. M. Chiller
“They’re not a big deal — they’re cosmetic, they itch, they’re usually easy to treat and they go away. You dry things out, you use a little powder or a little cream. But now, we have a different scenario: What if those same little bothersome fungi do not respond to the cream, the drying, the powder? I’m concerned, and that’s why we’re trying to raise awareness.”
Other, less common fungal infections — like the emerging, often multidrug-resistant yeast Candida auris — are more serious, able to cause meningitis and deadly bloodstream infections.
We checked in with Chiller and other experts to survey the landscape of fungal diseases in the U.S. and get an update on the antifungal pipeline.
Limited surveillance
According to the CDC, the actual burden of fungal diseases in the U.S. is difficult to estimate because many cases go undiagnosed and because national public health surveillance is limited. Delays in diagnoses are also common, according to Andrej Spec, MD, MSCI, associate professor of medicine and associate director of the infectious disease clinical research unit at Washington University School of Medicine in St. Louis.
Andrej Spec
“Many patients are diagnosed months later than they actually should be diagnosed,” Spec said. He noted high rates of missed diagnoses of histoplasmosis and cryptococcus as examples.
“All of those add up to some very bad outcomes,” he said, adding that some patients are “permanently missed” — meaning, they ultimately die of an undiagnosed fungal infection.
There have been efforts to estimate the burden of fungal infections, both globally and in the U.S., according to Stephanie Kurdach, MS, an infectious disease analyst at GlobalData.
“Often, estimates rely on retrospective data from hospital-based surveillance, disease registries and peer-reviewed literature,” Kurdach said. “This is the case in the U.S., where there is no national public health surveillance for infections such as ringworm, vaginal candidiasis, aspergillosis and cryptococcosis.”
GlobalData estimated that, in 2022, there were around 3.08 million incident cases of invasive fungal infections in 16 countries with major pharmaceutical markets — including the U.S., which had 72,505 cases that year. Additional estimates project that the number of cases will increase to approximately 3.14 million in 2027, including an increase to 74,946 cases in the U.S.
Like case counts, deaths caused by fungal infections can also be difficult to estimate. The results of a review published in The Lancet Infectious Diseases in January estimated global deaths related to invasive fungal infections to be 3.8 million annually, including 2.5 million that were directly attributable to the infections. The CDC estimates that there were 7,199 deaths from fungal diseases in the U.S. in 2021, but the agency said that is likely an underestimate.
One aspect fungal infections that researchers were able to quantify, however, was an increase in hospitalizations and in-hospital mortality in the U.S. during the COVID-19 pandemic.
A study conducted by Jeremy A.W. Gold, MD, MS, a medical officer in the CDC’s Mycotic Diseases Branch, and colleagues showed that hospitalizations involving fungal infections increased 8.5% each year from 2019 to 2021, and that mortality rates for patients hospitalized with COVID-19-related fungal infections were around four times higher than mortality rates for patients with fungal infections that were not associated with COVID-19.
Priority pathogens
In 2022, WHO published its first-ever list of fungal priority pathogens, listing 19 fungi that “represent the greatest threat to public health.” The report categorized three threat levels: critical-, high- and medium-priority pathogens.
Pathogens on the “critical” list include Aspergillus fumigatus, C. auris, Candida albicans and Cryptococcus neoformans. High-priority pathogens include Candida parapsilosis, Candida tropicalis, eumycetoma-causative agents, Histoplasma species, Mucorales, Fusarium species and Nakaseomyces glabrata (formerly Candida glabrata). The medium-priority pathogens list includes Coccidioides species, Cryptococcus gattii, Lomentospora prolificans, Paracoccidioides species, Pichia kudriavzeveii (formerly Candida krusei), Pneumocystis jirovecii, Scedosporium species and Talaromyces marneffei.
“All have their own problems,” Spec said. “But the one that I think is really worth calling out is Candida auris. It has a very high attack rate and a high level of resistance with a relatively quick pathway to becoming totally drug resistant — literally resistant to every single drug that we have on the market.”
C. auris has emerged as an important cause of hospital infections in the U.S. First identified in 2009 in Japan, it has now been reported on every continent except Antarctica. Research has shown that it emerged on several continents around the same time.
The first U.S. cases of C. auris were reported in 2016. Since then, cases have increased dramatically. Data published last year in Annals of Internal Medicine showed a 59% increase from 2019 to 2020 and a 95% increase from 2020 to 2021. Over that time, 17 U.S. states identified their first cases of C. auris.
Additionally, data showed that the number of cases with resistance to echinocandins — the first-line therapy for invasive candidiasis and most C. auris infections — was about three times higher in 2021 than in 2019 and 2020.
According to Healio | Infectious Disease News Editorial Board member George R. Thompson, MD, professor of medicine at the University of California, Davis, another aspect of C. auris that makes it especially dangerous is that it can spread easily in hospitals.
“It lives on surfaces, then infects the next person in that room. So, it’s an infection control issue,” Thompson said.
One study published last year showed how quickly C. auris can contaminate health care environments near infected patients. In the study, researchers collected samples from C. auris carriers at five body sites and from several surfaces in their room before and after disinfection. Among the 41 known carriers, C. auris contamination was detected on 32.2% of room surfaces before disinfection and 20.5% of room surfaces by 4 hours after disinfection.
‘They’re all around us’
Something that sets fungal infections apart from other infectious diseases is that absolutely everyone is at risk, Spec said.
“A significant portion of the fungal infections that I manage are people with no predisposing medical history, and I think those are the ones that tend to be the most misdiagnosed because nobody realizes that they’re actually at risk,” he said.
With Aspergillus, for example, it is nearly impossible to not be exposed, Chiller said. Although most people do not get sick, Aspergillus can cause health problems in high-risk patients, including those with lung diseases or weakened immune systems, according to the CDC.
“I always like to tell people, ‘Take a deep breath. You just inhaled 100 spores of Aspergillus,” Chiller said. “They’re all around us. We’re breathing them in all the time.”
The universal risk makes managing fungal infections that much more crucial. According to Kurdach, major obstacles in the management of fungal infections include insufficient awareness, inadequate diagnostics and a lack of effective antifungal drugs.
Data derived from WHO.
“Misdiagnoses or untimely diagnoses of fungal infections contribute to millions of deaths each year, fueled by a lack of awareness from health care professionals and the absence of widespread diagnostic testing,” she said.
Currently available tests that rely on fungal cultures can identify only about one-third of people who have a fungal infection, Kurdach said. Blood culture tests identify only approximately 40% of life-threatening Candida infections, she added.
“This is then compounded by antifungal resistance, which is a growing concern, especially among patients with invasive infections,” Kurdach said. “In fact, there have been reported cases of pan-resistance to all three classes of commonly prescribed antifungal drugs among patients with Candida auris infections.”
A report published in 2021 provided the first evidence that pan-resistant strains of C. auris may have been transmitted in U.S. hospitals.
Update on antifungal pipeline
There are four main antifungal classes — echinocandins, polyenes, pyrimidine analogues and triazoles. Many antifungals in these classes remain first-line treatments, but new antifungals are seen as crucial to combating emerging pathogens and resistance.
According to Kurdach, the emergence of azole resistance has become a serious threat, and is due, in part, to the use of fungicides in the environment — particularly for A. fumigatus infections.
“As Aspergillus becomes exposed to azole fungicides in the environment, resistant microbes can survive, multiply and infect vulnerable individuals,” she said.
Kurdach explained that Aspergillus can become resistant if a patient with a chronic fungal infection takes an azole antifungal over a long period of time. As Aspergillus becomes exposed to the drug, the fungus can become resistant and multiply.
“Antifungal-resistant infections are difficult to treat and can be life-threatening,” she said. “According to the CDC, individuals infected with azole-resistant Aspergillus fumigatus infections are up to 33% more likely to die from the infection compared to patients who can be treated with azoles.”
Currently, the antifungal pipeline contains over 190 products in development, according to GlobalData. For critical-priority pathogens — Cryptococcus, Aspergillus and Candida — GlobalData identified 17 drugs in late-stage development.
One that Kurdach finds particularly interesting is LimmaTech Biologics’ Candi-5V, a pentavalent biconjugate vaccine candidate currently in phase 1/2 testing for women with recurrent vulvovaginal candidiasis, which is typically caused by C. albicans. Kurdach noted that there are currently no approved vaccines for any fungal infection.
Rezafungin, an echinocandin, was approved for use in the U.S. in 2023 for the treatment of candidemia and invasive candidiasis and is now in phase 3 testing for the prevention of Candida, Aspergillus and Pneumocystis infections in adults undergoing allogeneic blood and marrow transplants, one of the highest risk patient groups, Kurdach noted.
Data from the STRIVE trial showed that 75.8% of participants with candidemia and/or candidiasis who received 400 mg of rezafungin weekly and 77.4% who received 400 mg and then 200 mg of rezafungin weekly experienced clinical cure by day 14 of treatment compared with 71.4% who received caspofungin. The ReSTORE trial showed rezafungin was as effective as caspofungin against candidemia and/or invasive candidiasis, with 55 of 93 patients on rezafungin and 57 of 94 patients on caspofungin experiencing cure by day 14 of treatment.
“For invasive candidiasis, I think that this will be really helpful,” Thompson said.
Thompson said there is also excitement about olorofim, which has not been approved by the FDA. It has activity against molds like Coccidioides species, Histoplasma species, Scedosporium species and Lomentospora prolificans, he said, calling it a potential “game changer” for these types of molds, for which there are currently no good treatment options.
In addition to developing new therapies, Kurdach said other top priorities for fungal disease management should be increasing awareness and developing widespread diagnostic tools.
“Increasing awareness is a vital first step because serious fungal infections can become deadly relatively quickly,” she said. “For example, invasive Candida bloodstream infections have a mortality rate of approximately 40% within the first 30 days. Therefore, it is crucial that health care providers recognize the possible presence of a fungal infection, and that a proper diagnosis is made as early as possible.”
References:
- CDC. Aspergillosis. https://www.cdc.gov/fungal/diseases/aspergillosis/index.html. Last reviewed Dec. 27, 2022. Accessed Feb. 24, 2024.
- CDC. Impact of fungal diseases in the United States. https://www.cdc.gov/fungal/cdc-and-fungal/burden.html. Last reviewed March 2, 2023. Accessed Feb. 24, 2024.
- Cidara Therapeutics. Cidara Therapeutics and Melinta Therapeutics announce FDA approval of Rezzayo (resafungin for injection) for the treatment of candidemia and invasive candidiasis. Published March 22, 2023. Accessed Feb. 15, 2024.
- Cidara Therapeutics. Cidara Therapeutics reports positive topline results from phase 2 STRIVE trial of lead antifungal rezafungin. https://www.cidara.com/news/cidara-therapeutics-reports-positive-topline-results-from-phase-2-strive-trial-of-lead-antifungal-rezafungin/. Published March 19, 2018. Accessed Feb. 15, 2024.
- Denning DW, et al. Lancet Infect Dis. 2023;doi:10.1016/S1473-3099(23)00692-8.
- Gold JAW, et al. Emerg Infect Dis. 2023;doi:10.3201/eid2907.221771.
- Lyman M, et al. Ann Intern Med. 2023;doi:10.7326/M22-3469.
- Lyman M, et al. MMWR Morb Mortal Wkly Rep. 2021;doi:10.15585/mmwr.mm7029a2.
- Nelson R. Lancet Microbe. 2023;doi:10.1016/S2666-5247(23)00143-X.
- Sansom SE, et al. Clin Infect Dis. 2023;doi: 10.1093/cid/ciad752.
- Thompson GR, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)02324-8.
- WHO. WHO fungal priority pathogens list to guide research, development and public health action. Published Oct. 25, 2022. Accessed Feb. 15, 2024.
- WHO releases first-ever list of health-threatening fungi. https://www.who.int/news/item/25-10-2022-who-releases-first-ever-list-of-health-threatening-fungi. Published Oct. 25, 2022. Accessed Feb. 15, 2024.
For more information:
Tom M. Chiller, MD, MPHTM, can be reached at [email protected].
Stephanie Kurdach, MS, can be reached at [email protected].
Andrej Spec, MD, MSCI, can be reached at [email protected].
George R. Thompson, MD, can be reached at [email protected].
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Sources/Disclosures
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Source:
Healio Interviews
Disclosures:
Chiller, Gold and Kurdach report no relevant financial disclosures. Spec reports receiving grant funding from Astellas. Thompson reports serving on advisory boards or being a consultant in clinical trials for Astellas, Cidara, Melinta, Mundipharma, F2G and Pfizer.
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