Drug-resistant fungus is raising international concern

In late 2022, a patient arrived at Bellevue Hospital in New York City with a perplexing case of scaly, itchy skin lesions. Despite being treated for what was believed to be ringworm, or tinea, with multiple rounds of topical steroids and antifungal medications, the condition persisted.

The case came under the care of Dr. Avrom Caplan, a dermatologist and assistant professor at the NYU Grossman School of Medicine. Upon examining the patient, Dr. Caplan immediately recognized that this was no ordinary case of ringworm. Instead of just a few lesions, the patient’s thighs and buttocks were covered with numerous maddeningly itchy, striated disks, indicating an unusual and severe infection.

As a dermatologist, Dr. Caplan’s first instinct was to consider whether the patient was immunosuppressed, a common concern when faced with such an extensive case of tinea. However, this patient did not have any underlying immunosuppression.

Dr. Caplan prescribed four weeks of oral terbinafine, a widely used first-line antifungal drug. Surprisingly, the treatment had no effect. He then tried a month-long course of another oral antifungal, griseofulvin. While the plaques shrank, they did not completely disappear.

The patient's story revealed a crucial detail: the rash had first appeared during a visit to Bangladesh, where several of the patient’s relatives also suffered from similar rashes. The family had treated their conditions with over-the-counter antifungal and steroid combination creams, but the rash returned once the patient was back in the U.S.

Dr. Caplan grew increasingly uneasy with this case, which combined a travel-acquired infection, family contagiousness, and resistance to recommended drugs. Seeking answers, he consulted with dermatology residents at Bellevue, who had encountered another patient with similar crusty, ring-shaped patches extending up the abdomen and neck.

This patient, too, had not responded to oral terbinafine and required four weeks of itraconazole, a less preferred antifungal, to clear the rash. Disturbingly, this patient had not traveled recently, suggesting that the stubborn, spreading rash had been contracted locally.

Concerned by these cases, Dr. Caplan reached out to both the New York State Department of Health and the Centers for Disease Control and Prevention (CDC). Laboratory technicians at the state health department identified the cause as a newly named fungal species, Trichophyton indotineae. Dr. Caplan and his coauthors later described these cases—the first reported in the U.S.—in the CDC’s Morbidity and Mortality Weekly Report (MMWR).

The CDC had already been tracking the spread of highly transmissible, terbinafine-resistant dermatophytosis around the globe for several years. Reports from South Asia in the mid-2010s indicated the emergence of this persistent fungal infection, which then spread to Canada, East and Southeast Asia, Europe, and the Middle East.

In each location, patients exhibited persistent, expanding, and intensely itchy lesions that spread to uncommon areas of the body, including the face. The symptoms were unresponsive to extended courses of first-line antifungal drugs, and the CDC recognized that this diminished drug response would pose a significant public health challenge.

Dr. Jeremy A.W. Gold, an epidemiologist and medical officer in the CDC’s mycotic diseases branch, emphasized the potential impact of this emerging infection. “The estimated lifetime prevalence of ringworm is 1 in 4 people,” he noted. “This isn’t necessarily something that will kill people, but it really has the potential to spread widely and affect a lot of people’s lives.”

The situation in India provides a cautionary tale. Clinicians there have been grappling with an epidemic of T. indotineae for nearly a decade. In 2014, dermatologists in India began noticing atypical, widespread cases of nonresponsive dermatophytosis. A multicenter study conducted between 2014 and 2018 found that a high percentage of fungal isolates from skin infections showed diminished susceptibility to several antifungals, including 11% with some resistance to terbinafine. Over the years, this resistance has only increased.

Dr. Ramesh Bhat, a professor of dermatology at Father Muller Medical College in Mangalore, India, described the challenge: “Around 2014, we started seeing atypical, widespread manifestations of nonresponsive dermatophytosis.”

The rise of resistant ringworm led Indian researchers to form an informal network to share insights on these unusual cases. One key factor they identified was the misuse of topical corticosteroid, antifungal, and antibacterial combination creams. In India, where much of the population lacks access to specialists, it is common for individuals to self-treat with these creams, which are easily available over the counter.

Dr. Manjunath Shenoy, a professor and head of dermatology at Yenepoya Medical College in Mangalore, explained, “It’s very common that someone would not be treated by a dermatologist but would buy these creams.” The Indian government eventually took regulatory action against these over-the-counter combination creams, like the one used by Dr. Caplan’s patient. However, some products were reformulated to bypass the ban and returned to the market with powerful steroids still included.

Through conversations with patients, researchers in India realized how the widespread use of these creams contributed to the development of drug-resistant tinea. “These creams are used not only very widely but also erratically,” said Dr. Shyam Verma, a dermatologist in private practice in Gujarat. The potent steroid in the creams suppresses itching temporarily, leading patients to use them for a few days and then stop. This incomplete treatment results in a pool of patients who are not fully cured and continue to spread the infection.

Dr. Shenoy highlighted another issue: some individuals also use these steroidal creams for skin lightening, unknowingly making themselves more susceptible to fungal infections by inducing localized immune suppression.

Defining this emerging epidemic has relied heavily on case reports and surveys on recalcitrant dermatophytosis. In 2016, a hospital in Chandigarh reported that treatment-resistant dermatophytosis accounted for up to 10% of all new cases at their clinic. A study conducted by Dr. Shenoy and colleagues at 13 medical centers in India between 2017 and 2018 found treatment resistance in about 28% of more than 7,000 patients with dermatophytosis. By 2021, a survey of 459 dermatologists revealed that 52% had encountered treatment failure due to antifungal resistance.

Meanwhile, drug-resistant tinea has spread globally, reaching Australia and Latin America. A genetic sequence database search at the University of Texas Health Science Center at San Antonio, a leading fungal reference laboratory in the U.S., identified a resistant isolate from North America dating back to 2017, well before Dr. Caplan’s encounter with it in New York.

This spring, Dr. Caplan and his coauthors published a case series in JAMA Dermatology documenting 11 patients treated for T. indotineae in New York City between 2022 and 2023, most of whom had traveled to Bangladesh. The series included the two patients from Dr. Caplan’s initial report, both of whose terbinafine-resistant rashes eventually resolved with alternative antifungals.

At the University of Alabama at Birmingham, Dr. Boni Elewski, a professor and chair of dermatology, has treated three patients with probable treatment-resistant T. indotineae since 2020. She has also been consulted on other cases. Dr. Elewski has repeatedly faced the challenge of finding appropriate antifungals after first-line drugs failed, especially when next-line options were contraindicated or would violate antifungal stewardship guidelines.

“The problem is, we have only three drugs that have been out roughly since 1990,” she said, referring to terbinafine, itraconazole, and fluconazole. Newer antifungal drugs like voriconazole and posaconazole are generally reserved for systemic infections due to their significant side effects and high cost, making them unsuitable for routine use.

The lack of a robust antifungal arsenal and comprehensive fungal-infection surveillance are long-standing issues. The CDC has previously identified these factors as contributing to the unanticipated spread of invasive fungal infections such as Candida auris. Recognizing the global emergence of drug-resistant tinea and its potential link to travel, the CDC began drafting educational campaigns in collaboration with the American Academy of Dermatology (AAD).

In July 2024, the AAD launched an Emerging Diseases Resource Center on its website, featuring information on diagnosing and treating T. indotineae. The resource center also includes a new case registry for resistant dermatophytosis, an extension of a registry initially created for dermatologic manifestations of COVID-19 and later expanded to track mpox cases.

The objective of the registry is to collect data on presentations of resistant dermatophytosis and serve as an early-warning system. Dr. Esther Freeman, the registry’s principal investigator and director of global health dermatology at Massachusetts General Hospital, emphasized its importance.

“I think of the registry as a great place for hypothesis generation and a great place to rapidly collect data from many countries in a systematic way,” she said. “Our goal is to feed back to people who are on the front line: these are the risk factors you should be looking for, and these are the clinical patterns you should be looking for. And doing that on a global scale.”

The registry's arrival is timely. Dermatologists have observed other fungal dermatophyte species behaving in unusual ways. Since 2014, clinicians in Europe have reported severe infections caused by T. mentagrophytes genotype VII (TMVII) on patients' genitals, a rare location for dermatophytosis.

The first cases were reported among men and women who had visited clinics in Zurich, Switzerland, after sexual contact in Southeast Asia. These patients required two to ten weeks of oral terbinafine or itraconazole treatment, with some needing systemic prednisone to manage inflammation. Two patients were hospitalized due to the severity of their symptoms.

Other European case reports of TMVII infections linked to sexual contact or genital grooming emerged in 2019 and 2021. Dermatologists are particularly concerned about a case series published last year in the CDC’s journal Emerging Infectious Diseases.

This series involved 13 patients, mostly men who exclusively had sex with men, many of whom had traveled. The possibility that this fungal infection could spread through international social-sexual networks, similar to the mpox virus in 2022, is alarming. It took three weeks to four months of systemic treatment with terbinafine, itraconazole, or voriconazole to resolve some of these infections.

In New York, Dr. Caplan has treated a patient with a confirmed TMVII infection, described in JAMA Dermatology in June 2024. This case could be a harbinger of future challenges. “TMVII thus far seems to respond to terbinafine,” Dr. Caplan said. “But one of my worries is, what happens if TMVII meets TMVIII, T. indotineae, and picks up its resistance patterns? What is the potential that that is going to spread?”

The AAD’s new registry is designed to prompt clinicians to report details of dermatophyte infections beyond T. indotineae that exhibit unusual treatment resistance and increased transmissibility. The site is now open for submissions, and investigators are eagerly waiting to see what data might emerge.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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