Emerging Fungal Infections Demand All-Out Approach

As the number of drug-resistant and other troublesome tinea infections grows, perhaps the only certainty is that these are not the tinea subtypes that most providers studied in medical school. As dermatologists, public health officials, and infectious disease specialists scramble to raise awareness about prevention and treatment, challenges ranging from a dearth of testing facilities and data to payer pushback over longer therapeutic courses remain.

Dermatophyte Discourse Changing

“Trichophyton indotineae is changing the way we talk about dermatophyte infections,” Avrom S. Caplan, MD, assistant professor in the Department of Dermatology at New York University, New York City, said in an interview. Called T mentagrophytes VIII (TMVIII) before a 2020 report in the journal Mycopathologia proposed the name T indotineae, this species requires clinicians to expand their conception of how tinea looks, acts, and responds to treatment.

Boni E. Elewski, MD, professor and chair of dermatology, at The University of Alabama at Birmingham, saw her first case of probable T indotineae in a patient in early 2020. “He was covered with fine scale, and he itched all over. I thought he had atopic dermatitis. This didn’t look like any tinea. His face, arms, back, and legs were scaly.”

Nevertheless, KOH and biopsy confirmed dermatophytosis. Culture (performed at the Center for Medical Mycology [CMM] in Cleveland) identified T mentagrophytes. Back then, Elewski told Medscape Medical News, labs did not routinely go beyond genus and species. But based on the patient’s symptoms, history of unresponsiveness to terbinafine, borderline sensitivity to fluconazole, and travel to India and Spain, Elewski strongly suspected T indotineae.

The patient refused itraconazole, to which the fungus was sensitive, and did not respond to fluconazole 400 mg daily. Ultimately, he was lost to follow-up. “Last I saw him,” said Elewski, “he was not cured.”

Tracking Cases

Because T indotineae does not require reporting to public health agencies, said Jeremy Gold, MD, MS, a medical officer with the US Centers for Disease Control and Prevention (CDC) Mycotic Diseases Branch in Atlanta, “there is no official public health surveillance keeping track of exactly how many cases have occurred.” The same is true for TMVIIand terbinafine-resistant T rubrum, which are also on the rise. Regarding T indotineae, authors from the University of Texas Health Science Center at San Antonio retrospectively reported 21 terbinafine-resistant isolates from North America in the July 2023 Journal of Clinical Microbiology.

Caplan has seen approximately 12 T indotineae cases to date, including the first two confirmed US cases, which he and co-authors, including Gold, reported in the CDC’s Morbidity and Mortality Weekly Report in May 2023. T indotineae is likely underreported, he said, because it eludes standard culture-based techniques, and identifying it requires molecular testing, which is available at only a handful of labs nationally.

To help educate providers, in July, the American Academy of Dermatology (AAD) and the International League of Dermatological Societies unveiled an Emerging Diseases Resource Center, which includes resources for providers and a registry for reporting confirmed and suspected resistant dermatophytes.

“Our goal is to provide easy-to-access and easy-to-understand resources to healthcare providers,” Esther Freeman, MD, PhD, told Medscape Medical News. She is director of Global Health Dermatology at Massachusetts General Hospital, associate professor of dermatology at Harvard Medical School, both in Boston, and chair of the AAD’s Emerging Diseases Task Force.

“Our resources include an algorithm for when to suspect a drug-resistant case and how to think through treatment options. We cover issues related to diagnosis and treatment, as well as linking to our case registry reporting system,” said Freeman.

The new registry resides within the AAD’s existing COVID-19, Mpox, and Emerging Infections Registry. “Our registry efforts have already captured 2500 COVID-19 and mpox cases from 72 different countries,” Freeman said. For all these infections, she added, “we hope that real-time data analysis of cases worldwide will provide information that helps physicians recognize and treat cases.”

Consistent with the registry’s approach, said Caplan and Gold, there is no silver bullet for battling dermatophyte resistance. What is needed, said Gold, is a coordinated approach involving public health officials, dermatologists, primary care providers, infectious disease specialists, pharmacists, and patients. “It’s going to be a team effort to address the challenge of emerging complex dermatophytosis,” he said.

Resistant T rubrum 

“The biggest difference with T rubrum resistance is you may not see that widespread infection that we see with T indotineae,” said Caplan. T rubrum is probably the most common dermatophyte that dermatologists see, added Elewski, who encounters a resistant case at least monthly. One such patient, featured in a 2020 British Journal of Dermatology research letter, cleared on itraconazole and ciclopirox cream but subsequently returned with itraconazole-resistant T rubrum because he had been doctor-shopping for the drug intermittently for years, she said. He cleared on posaconazole 300 mg daily, then was lost to follow-up.

TMVII

A 2023 Emerging Infectious Diseases report highlighted the potential for this dermatophyte to spread among men who have sex with men (MSM), presenting as an itchy, scaly rash affecting the pubic, genital, and buttocks skin. “People don’t generally think of a fungal infection as something that could behave like a sexually transmitted infection (STI),” said Gold.

Caplan and coauthors reported the first confirmed US TMVII case in JAMA Dermatology in June 2024. Many experts suspect that unreported US cases existed previously, he said. “When it circulates in Europe and there’s so much travel, it’s probably here too.”

The fact that T indotineae was formerly called TMVIII has created confusion, added Caplan. “I’ve had patients say, ‘I’m worried I have that resistant ringworm that’s spreading among MSM.’ Whenever we talk about STIs and introduce the word ‘resistant,’ that comes with the potential for stigma, anxiety, and concern.” Fortunately, he said, TMVII has shown no resistance to first-line antifungals.

Why the Rise

Gold said, “We don’t know for sure why we’re seeing these different drug-resistant species popping up.” One possibility, he said, is the common misuse and overuse of topical antifungals — especially those available overseas in combination with high-potency steroids, such as clobetasol. Consumers use these products for a few weeks until symptoms resolve, then reapply them off and on over years, fueling resistance, said Gold.

“We are worried that with warming temperatures, there’s potential to see expansion of the geographic range of epidemic fungi,” he added. “That could be part of what has fueled recent increases in resistant dermatophytes. But it’s hard to prove.”

Climate change may be behind the emergence of Candida auris, according to a 2022 article in The Lancet Regional Health – Americas. This potentially fatal multidrug-resistant infection spreads easily among sick patients in healthcare facilities, according to a CDC information page on C auris.

Confirming Dermatophyte Infection

“A biopsy will only confirm the presence of fungus,” said Elewski. “Here you will need a lab that knows how to do a fungal culture.” Most state laboratories can do this, she said, as can some hospitals and special labs such as CMM in Cleveland.

It takes a Clinical Laboratory Improvement Amendments–certified lab to perform KOH prep in-house, added Caplan, plus up-to-date gear and knowledge of where and how to scrape and what to look for microscopically. Moreover, identifying T indotineae requires molecular testing available at only a handful of laboratories — listed on the AAD Emerging Dermatophytes webpage — nationwide.

Nevertheless, said Caplan, nailing down a diagnosis can guide treatment, often supplanting empirically prescribed antifungal steroid creams. “Those are probably not going to help. And people may be using those on areas of the body they shouldn’t. Both the clinical clues and the steps to make the diagnosis need to come together. But that’s often easier said than done, especially in a busy practice.”

Identifying resistance requires antifungal sensitivity testing, he added, which few labs perform. “Practically speaking,” said Elewski, “if the patient failed terbinafine, I would try itraconazole. You don’t necessarily need proof” of resistance. But if a patient does not respond to itraconazole and terbinafine clinically, she said that she might consider fungal susceptibility testing.

Treatment Tips

To address any resistant dermatophyte, Elewski recommended getting comfortable with itraconazole. For decades, she said, dermatologists have avoided itraconazole because terbinafine typically costs patients $10 for 3 months. “Itraconazole could be $200 per month,” said Elewski. Because of potential drug-drug interactions and absorption issues — and a boxed warning regarding congestive heart failure — physicians historically reserved itraconazole for severe fungal infections.

Itraconazole labeled dosing for onychomycosis is 200 mg daily for 12 weeks. Elewski favors a two-pronged attack, often combining an -azole antifungal with topical ciclopirox.

Another element that emerging tinea pathogens share is slower response to treatment. For T indotineae, reports appearing in the Journal of the American Academy of Dermatology in 2022 and 2024 suggest duration from 6-8 weeks up to 20 weeks.

To avoid recurrences of resistant T rubrum, Elewski treats for a year. However, she has problems getting itraconazole approved, when often it is the only agent that works. “I’ve written more letters than I like to insurance companies” to document terbinafine failure, she said.

Rarely, said Gold, dermatophyte infections resist both terbinafine and itraconazole. Next-line agents such as voriconazole, which some dermatologists have used for resistant T indotineae, can be much harder to tolerate, with more drug interactions, he said.

And because itraconazole, voriconazole, and posaconazole are all triazoles, added Elewski, the latter two might not work better than the former. But because these drugs might outperform itraconazole in selected cases, she said, “that’s when you want to do fungal susceptibility testing.”

TMVII is so new, said Caplan, that optimal therapy duration remains unclear. “One of the challenges with TMVII is when it gets into the genital skin, it’s a hair-bearing area. And based on various grooming practices, there’s an opportunity for the tinea to get deeper into the hair follicle and dermis. That may also be true of T indotineae.”

Anemic Arsenal

Unfortunately, said Gold, the arsenal of antifungals available in the United States remains limited. “Depending on how you count, there are only three to four classes of antifungal drugs designed to treat severe or invasive infections. So whenever we hear about a new fungal pathogen that’s causing resistant infections, it causes public health concern.”

Promising drugs in development include olorofim (F2G) and fosmanogepix (Basilea), according to Gold. However, he said, the development of these drugs to date has targeted invasive fungal infections such as aspergillosis. In June 2023, the US Food and Drug Administration rejected the new drug application for olorofim, requesting additional data and analyses. Regarding fosmanogepix, a double-blinded noninferiority phase 3 trial in invasive yeast infections was recently launched, according to a September 24 press release.

Gold, Caplan, and Elewski reported no relevant financial disclosures. Freeman is a COVID-19 co-author for UpToDate and chair of the AAD Emerging Diseases Task Force.

John Jesitus is a Denver-based freelance medical writer and editor.