Fighting fungi

By Allison Evans, Assistant Managing Editor, June 1, 2024

A patient presents with widespread, pruritic, scaly, and erythematous plaques of what appears to be tinea corporis. It may be routine to prescribe an antifungal cream or oral agent based on the visual clinical clues. Dermatophyte infections (aka “ringworm” or tinea) have been around for a very long time, and dermatologists have extensive experience diagnosing and treating these infections. However, with increasing resistance to antifungal treatments, physicians may need to adjust their approach to treating dermatophytosis.

Dermatophytosis is an infection of the hair, skin, or nails caused by a dermatophyte, which is most commonly of the Trichophyton genus, resulting in infections such as tinea corporis, tinea pedis, and onychomycosis, among others. Superficial fungal skin infections have an estimated lifetime prevalence of more than 20% worldwide.

Dermatophytosis accounts for many outpatient visits due to fungal diseases, said Aditya K. Gupta, MD, PhD, MBA/HCM, MA, FECMM, FAAD, FRCPC, professor in the department of medicine at the University of Toronto. “We could see more patients being referred to specialists by primary care providers due to recurrent infections, and unlike bacterial infections, we have fewer treatment options for these newly emerged pathogenic fungi.”

As dermatologists, we’re the experts and leaders in the field of skin disease, said Avrom S. Caplan, MD, FAAD, assistant professor at NYU’s Grossman School of Medicine. “With the emergence of recalcitrant superficial skin infections, as leaders in this area of skin disease and experts on skin and skin health, we really do have a stake and a role in helping to understand this emerging problem.”

Why is resistance developing?

In 2021, the World Health Organization (WHO) listed antimicrobial resistance as one of the 10 global health issues to track, including fungi and antifungals specifically as elements to be included in the surveillance. Recent research shows that incorrect use of topical antifungals and antifungal-corticosteroid combinations is likely contributing to the global emergence and spread of severe antimicrobial-resistant superficial fungal infections, which have also been detected in the United States, according to a CDC report.

The application of topical steroids to a fungal infection has also been part of the problem, said Boni Elewski, MD, FAAD, James Elder professor and chair of dermatology at the University of Alabama, and should be avoided. “Additionally, people who have a fungal infection often don’t treat until it’s completely resolved. They treat until they feel better, even though the fungus may still be living on them.”

Shari Lipner, MD, PhD, FAAD, associate professor of clinical dermatology, associate attending physician, and director of the nail division at the New York-Presbyterian Hospital/Weill Cornell Medical Center, agreed. “Antifungal resistance is likely developing due to empiric prescribing of antifungals, inadequate treatment courses, and nonadherence to therapy. Antifungal resistance to both terbinafine and itraconazole has been reported globally. Resistant fungal organisms are likely to become widespread and invasive, leading to increased infection rates and promoting global disease spread.”

When to suspect resistance?

“When a patient fails therapy, there is often a constellation of clinical and microbiological factors to consider. The former includes insufficient dosing and lack of compliance, while the latter includes innate or acquired drug resistance mechanisms in these pathogens,” said Dr. Gupta.

“As far as we know, terbinafine-resistant T. rubrum and terbinafine-sensitive onychomycosis clinically look identical, but terbinafine-resistant T. rubrum onychomycosis will not improve with three months of oral terbinafine.” Dermatologists who suspect antifungal resistance are encouraged to contact local health departments or the CDC for help in confirming these infections.

Awareness and certain signs may suggest an antifungal-resistant dermatophyte infection, explained Dr. Lipner, who has been working with the CDC on this issue. “If a patient has widespread tinea corporis that does not respond to topical antifungals or oral terbinafine therapy, an antifungal-resistant dermatophyte infection should be suspected.” Additionally, Dr. Lipner noted that recent travel to the Middle East or South Asia, or contact with someone from this area, could suggest exposure to a resistant T. indotineae strain.

“While it would be ideal to be able to have all fungal strains identified via molecular sequencing, there isn’t laboratory capacity for this to become a reality. For public health purposes, for research, for investigation, it’s important to get the identification,” Dr. Caplan said. “But for clinical treatment, if dermatologists are seeing somebody who has traveled from a high prevalence area of the world; if they’re reporting multiple people in their household or multiple contacts have similar tinea infections; if it’s an atypical look of a dermatophyte infection, noninflammatory, widespread, and very itchy; if people are reporting that they have used other oral antifungal medicines that don’t seem to be working, then I think suspicion should go up that maybe what we’re dealing with is one of the infections by T. indotineae or terbinafine-resistant T. rubrum.”

“If a culture grows T. mentagrophytes or T. interdigitale, but all the clinical clues are there that it’s T. indotineae, then maybe genetic confirmation isn’t necessary for empiric treatment, but would be important to ascertain where possible,” added Dr. Caplan.

An emerging threat: T. indotineae

The emergence and spread of antimicrobial-resistant superficial fungal infections has led to large outbreaks of extensive, recalcitrant skin infections in South Asia that frequently do not respond to topical antifungals or first-line oral therapies, including terbinafine. This emergence and spread are likely exacerbated by the overuse and misuse of topical antifungals, including over-the-counter options, which may also include antibiotics and high-potency corticosteroids (doi: 10.15585/mmwr.mm7301a1).

Since the mid-2010s, resistant dermatophytosis has emerged as a major health concern in India and reached troubling levels. Trichophyton indotineae is a newly identified dermatophyte mold that has been associated with a near epidemic level of chronic, refractory, and severe dermatophyte infections in areas of South Asia — and has now been reported globally, wrote Dr. Caplan and colleagues in a JAMA Dermatology article. The spread can be traced to immigration, travel, and local transmission.

T. mentagrophytes internal transcriber space (ITS) genotype VIII was renamed T. indotineae and classified as a separate species in 2020 after scientists determined that these Trichophyton strains were sufficiently different from T. mentagrophytes.

Many clinical morphologies are reported including ring-on-ring appearances, “pseudoimbricata,” tinea incognito, pustular, papulosquamous, lichenoid, and others, Dr. Caplan said. “Scaly concentric plaques and erythematosquamous morphology with active red borders is reported in a review article, but lesions may also be present elsewhere, including the axilla, and can be quite widespread.”

T. indotineae enters the U.S.

On Feb. 28, 2023, Dr. Caplan notified public health officials of two patients who had severe tinea that did not improve with oral terbinafine treatment, raising concern for potential T. indotineae infection. The patients shared no epidemiologic links (doi: 10.15585/mmwr.mm7219a4).

Dr. Caplan reported that the first patient was a pregnant woman with no travel history, suggesting she picked up the infection locally. The second patient, also a woman, had recently traveled to Bangladesh. The first patient had it on the neck, abdomen, pubic region, and thighs, while the second patient had it on the pubic region/groin and legs. The first patient was cured with itraconazole after failing two weeks of oral terbinafine. The second patient was eventually cured with an eight-week course of griseofulvin after failing four weeks of oral terbinafine and having a drug interaction with itraconazole.

The scope of the problem in North America was recently highlighted in a paper reviewing dermatophyte samples and antifungal susceptibility testing, noted Dr. Caplan. “A lab reviewed North American isolates sent to them from 2021 to 2022 and found 18.6% of isolates were resistant to terbinafine, including 21 T. rubrum and 21 T. indotineae isolates. As a reference lab, this may be an overrepresented sample, but it highlights an emerging issue that dermatologists here may increasingly encounter."

T. indotineae resistance

The global spread of terbinafine-resistant Trichophyton indotineae strains with mutations in the squalene epoxidase gene is a major issue, said Dr. Gupta.

“Terbinafine works by interfering with an enzyme in the fungus called squalene epoxidase, and fungi have evolved or mutated to have defects in this enzyme, so the fungus gets around it. You can give terbinafine, and no improvement occurs,” said Dr. Elewski, “and I think it’s more common than we probably think.”

According to Dr. Caplan, this dermatophytosis has a reportedly high level of resistance to terbinafine with decreased in vitro responsiveness to griseofulvin and fluconazole per reports in the literature. “The current treatment of choice is oral itraconazole, typically for a six- to eight-week duration or longer; however, relapse even after eight weeks of therapy with high doses of itraconazole has been reported.”

Dermatophytosis caused by T. indotineae often begins with tinea corporis, tinea cruris, or tinea genitalis as inflammatory or hyperpigmented scaly and itchy lesions, Dr. Gupta noted. “The majority of these infections prove to be resistant to conventional antifungals, including allylamines and, less frequently, azoles (itraconazole and fluconazole), thus, emphasizing the need for reassessing in nonresponsive patients.”

Since there are a limited number of antifungal agents available to treat dermatophytosis, the early detection of terbinafine resistance should be a prerequisite in the management of T. indotineae infections (doi: 10.3390/jof9070733).

“Travel history should be gathered, and suspicion raised when patients present with widespread, inflamed, or atypical appearing plaques of tinea, especially when they were refractory to first- or second-line therapies,” Dr. Caplan noted.

Culture-based identification techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale; correct identification requires genomic sequencing. Health care professionals who suspect T. indotineae infection should contact their state or local public health department for assistance with testing, Dr. Gupta said.

“What makes this infection challenging,” noted Dr. Caplan, “is the diagnostic confirmation and the many clinical morphologies it can take, which can confuse clinicians who may think, for example, that it is eczema. It is also challenging because symptomatically, tinea caused by T. indotineae can be very inflamed and itchy — though typically non-inflammatory — leading to patients seeking, or clinicians prescribing, topical corticosteroids. These, and other challenging aspects of these infections will require a coordinated effort among dermatologists, public health officials, and policymakers, including a focus on antifungal stewardship, testing/laboratory confirmation, treatment, and access to care for patients.”

Terbinafine resistance

“Since the recognition of resistant antifungal organisms is relatively new, there is limited data to guide us in treating these patients,” Dr. Lipner remarked.

“What has been particularly alarming is the increased incidence in terbinafine-resistant dermatophytes, which have been identified and isolated across the globe,” said Dr. Gupta. A study in Denmark estimated terbinafine resistance between 56-61% of samples reviewed in 2019-2020.

“Resistance can be detected using antifungal susceptibility testing that determines the minimum inhibitory concentration (MIC),” Dr. Gupta said. “An elevated MIC typically reflects a higher risk of resistance development leading to treatment failure. Molecular techniques, including sequencing and PCR can also be used to detect resistant mutations,” he noted.

“Over the past 10 years or so, we have been encountering T. rubrum terbinafine-resistant strains,” Dr. Lipner said. “This is definitely something to be worried about because if we lose terbinafine, we do not have many remaining treatment choices.”

Terbinafine resistance is the most concerning, said Dr. Gupta. “This drug is one of the cheapest in the U.S. since going generic and one of the most commonly prescribed antifungal agents across dermatology, family medicine, and pediatrics.”

While azoles are often used if terbinafine fails, they are contraindicated for many patients. “For patients with onychomycosis, who have contraindications to oral azoles, FDA-approved topical medications, including ciclopirox, tavaborole, and efinaconazole, are reasonable options,” stated Dr. Lipner. “For patients with tinea corporis, who have contraindications to oral azoles, griseofulvin is an option, but its efficacy may be limited,” she added.

For patients not able to take an oral azole, topical azoles (e.g., miconazole) and other classes of topical antifungal agents, for example hydroxypyridones (ciclopirox olamine), can be considered, said Dr. Gupta. “Oral and topical combination therapies are also recommended. When itraconazole and terbinafine are ineffective, consider off-label therapies such as fluconazole, voriconazole, or posaconazole. There is a growing amount of data to support the use of these triazoles in the appropriate setting.”

Treatment options

With increasing resistance to first-line agent terbinafine, dermatologists must reach for other therapies, although choices remain limited. Currently, there is growing evidence that itraconazole is an effective option for some of these terbinafine-resistant strains, although there are various reasons why patients may not be able to take the drug, including drug interactions (e.g., statins and antacids), potential for congestive heart failure, and inability to use if the patient is pregnant or breastfeeding.

“A lot of dermatologists haven’t even written a prescription for itraconazole because they’re more familiar with terbinafine. Both drugs were developed about 30 years ago and were pretty much used equally,” noted Dr. Elewski. While itraconazole is more expensive and has some drug interactions, Dr. Elewski has seen many instances in which a dermatophyte resistant to terbinafine will clear on itraconazole. “I usually prescribe 200 mg per day of itraconazole for at least two months for extensive tinea corporis.”

“We are seeing pan-resistance,” said Dr. Elewski, in which a dermatophyte is resistant to many treatments. “I have one patient with tinea corporis over his full body, and terbinafine and itraconazole didn’t work. I gave him both fluconazole and terbinafine at the same time, and he very slowly started clearing. I also have him on topical ciclopirox olamine, and he’s still slowly clearing. After months of treatment, he’s still not clear.”

There’s some literature from India that says a double dose of terbinafine may be effective. “So instead of giving one pill 250 mg per day, you give two pills or 500 mg per day,” said Dr. Elewski. “Itraconazole is the alternative and the intermittent method is 400 mg per day one week per month for several consecutive months. I tend to use itraconazole first but try the 500 mg of terbinafine as a backup plan if itraconazole can’t be used.”

For both onychomycosis and skin fungal infections, voriconazole, posaconazole, and ravuconazole are also being studied. “The emergence of resistant organisms is likely to spark interest in development of new antifungals, but approval of new drugs is a long, arduous process,” said Dr. Lipner.

Since there are only two major classes of antifungals available, there is currently an unmet need for the development of novel antifungals with new targets. “We’re running out of options,” Dr. Elewski said. “No one has developed an anti-fungal treatment for dermatophytosis in 30 years. We need new treatments.”

Looking forward

“At the policy level, a greater advocacy for antifungal stewardship practices is warranted to preserve the efficacy of our first-line agent,” Dr. Gupta said. “This includes advocating for the proper identification of the causative organism before starting treatment and additional testing for resistance (susceptibility testing, molecular testing) as appropriate.”

Antifungal stewardship is important in preventing antifungal resistance, said Dr. Lipner. “Mycological confirmation for suspected fungal infections is needed to make an accurate diagnosis and prescribe the most appropriate treatment.”

Dermatologists are encouraged to report fungal infections that are resistant to traditional antifungals to the local health department or the CDC at FungalOutbreaks@cdc.gov, Dr. Lipner said. “With patients having easy access to over-the-counter antifungals, treatment of non-fungal rashes with antifungals, and incomplete treatment courses, the resistance problem will likely worsen with new dermatophyte strains that are resistant to current treatments,” she added.

“Without surveillance programs to keep track of these cases, it is expected that we will continue to see resistant fungi in clinical practice,” Dr. Gupta agreed.

Dr. Elewski also notes the importance of educating patients about antifungal treatments. “I tell my patients that a big tube of medication is required so they have enough to treat for a full month to completely kill the fungus. You should not treat until the itch improves, but until that infection is completely gone. Small tubes found over the counter are generally not sufficient for a month supply that may be necessary to cure the problem.”

“We have to be good stewards of antifungal medicines the way we’re good stewards of antibiotics,” Dr. Caplan said in a Public Health On Call podcast. “We need to really focus on getting the correct diagnosis of a fungal infection, using medicines appropriately — topicals and oral antifungals. We need to think about how we’re going to approach this new type of fungal infection at multiple levels — with the physician, researchers, and state, local, and national health authorities all working together on this.”

Additional DermWorld Resources