What do you need to know about emerging, antifungal medication-resistant dermatophyte infections?
Dr. Schwarzenberger is the physician editor of DermWorld. She interviews the author of a recent study each month.
By Kathryn Schwarzenberger, MD, FAAD, September 1, 2023
In this month’s Clinical Applications column, Physician Editor Kathryn Schwarzenberger, MD, FAAD, talks with Avrom S. Caplan, MD, FAAD, about his JAMA Dermatology paper, ‘Trichophyton mentagrophytes Internal Transcribed Spacer Genotype VIII.’
DermWorld: What is so new and important about ringworm today?
Dr. Caplan: Dermatophyte infections (aka “ringworm”) have been around for a very long time, and dermatologists have extensive experience diagnosing and treating these infections. What’s emerging and worrisome in recent years among dermatophyte infections is resistance to antifungal medications. Terbinafine-resistant Trichophyton rubrum and a newly identified dermatophyte, termed Trichophyton indotineae (also called Trichophyton mentagrophytes ITS genotype VIII, which I’ll get to below) are reported globally. The scope of the problem in North America was recently highlighted in a paper reviewing dermatophyte samples and antifungal susceptibility testing. This 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 a potential emerging issue that dermatologists here may increasingly encounter. An additional public health concern are reports of sexually transmitted tinea infections, including recent report out of France of Trichophyton mentagrophytes ITS genotype VII in men who have sex with men, highly suspected of being sexually transmitted. Even though it’s not one of the strains I’ll discuss today, we as doctors need to be aware of this because of the highly transmissible characteristic of resistant dermatophyte strains including T. indotineae and the potential for human-to-human spread via skin contact.
For the remainder of the interview, however, I’ll focus on T. indotineae. This pathogen is concerning in particular because it causes extensive lesions and is frequently resistant to terbinafine and sometimes resistant to multiple antifungal drugs. Also, what makes this infection challenging 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, 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.
DermWorld: Is this a new type of infection, or did we just start to recognize it? Any thoughts on where it came from or how it arose?
Dr. Caplan: It’s been reported at least since the mid-2010s, so it’s not “new,” but new compared to the time that dermatophytes have been around. We’ve learned a lot about this particular infection from our colleagues in India, who have been treating, studying, and reporting on T. indotineae for many years. Even though we reported the first two confirmed cases recently in New York City, I’m confident it’s been around longer than that. In fact, in our internal review, we probably had a case back in 2021, treated as tinea corporis, but with signals that it was likely T. indotineae (hindsight of course being 20/20). The patient was treated with itraconazole and cleared after failing terbinafine. She acquired the infection abroad, and the culture showed Trichophyton mentagrophytes. I’ll come back to why this is important. We also had a case in hindsight back in 2019 who has recently returned to clinic and is on itraconazole for now confirmed T. indotineae. In the more recently published paper highlighted above, when they reviewed their samples, they found a T. indotineae sample dating back to 2017.
As to where it came from, there are many discussions in the literature. In a French paper, it was reported that animals are a potential reservoir, yet transmission is primarily between humans. They further report that T. indotineae was present in India, Oman, Australia, and Iran from 2004-2013. According to another paper, the first sequence identified corresponds to a strain collected in India in 2004. But it isn’t entirely clear how this emerged. Besides how it might have emerged, there is a lot of discussion in the literature on the inappropriate use of topical combination creams with corticosteroids and antifungals, and whether these creams may be driving chronic and refractory infections.
Since we’re discussing emergence, we should also comment on the name. The nomenclature of dermatophytes can get pretty confusing, but the name “Trichophyton indotineae” also raises some points of discussion. The other name is based on a large study performed with dermatologists in India and scientists in Germany. That name is based on sequencing and termed “Trichophyton mentagrophytes ITS genotype VIII.” This is important for many reasons, one of which is the potential for missed diagnoses based on fungal cultures (see below). The other relates to naming conventions and trying to move away from geographic-based names. In this interview I use both terms, T. indotineae and T. mentagrophytes ITS genotype VIII.
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DermWorld: What should make us suspect infection with T. indotineae? Does it have any unique clinical features?
Dr. Caplan: Many clinical morphologies are reported including ring-on-ring appearances, “pseudoimbricata,” tinea incognito, pustular, papulosquamous, lichenoid, and others. 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. Patients can have extreme pruritus. In our case series, all but one patient have clear links to travel to or from areas where T. indotineae is widespread and endemic. This tells us that in patients with widespread, very itchy, inflamed, or atypically appearing tinea corporis, cruris, or facei, especially when traveling from endemic locations, we need to think about T. indotineae. One of our patients had no clear link to anyone traveling, suggesting the possibility of a locally acquired infection. Yet that is hard to confirm. We did not find other contacts with infection, and she had no travel history. In particular, and importantly, the family members of this patient did not acquire the infection from her. So, we may see this in patients with no clear travel history and need to be aware of this possibility.
DermWorld: How do we establish the diagnosis? Will a routine fungal culture give us this answer?
Dr. Caplan: We should be scraping for KOH evaluation and sending fungal cultures. A routine fungal culture will not confirm T. indotineae. The culture may read as Trichophyton mentagrophytes or Trichophyton interdigitale, as I point out in regard to our patient above in 2021. Yet, it may be Trichophyton indotineae (Trichophyton mentagrophytes ITS genotype VIII). Special testing is required to confirm the infection. That often requires specialized labs, which can be identified by contacting local public health authorities. Not all labs will have the capabilities for this testing.
DermWorld: Perhaps most importantly, how do we treat this infection? Is there any benefit/role for topical agents?
Dr. Caplan: There is a lot we still need to learn about treating this particular infection, yet we already know so much from our colleagues in India who have been tackling this challenging infection for a number of years. Their painstaking efforts have given us a lot of information on how we can approach treatment. T. indotineae is typically terbinafine resistant. It is often griseofulvin resistant as well. Reduced susceptibility to azoles is noted in some reports, though typically, the treatment of choice is itraconazole. The treatment duration can range widely for patients. Six to eight weeks is commonly reported, yet, in a recent study, very long treatment courses of 12 weeks or longer were also needed for some patients. Relapse can be seen even after high daily doses of itraconazole are used. Dermatologists should be aware of drug-drug interactions when prescribing itraconazole. For example, simvastatin and itraconazole are contraindicated. Thus, medication lists should be fully updated and checked. In addition, itraconazole has been associated with cardiac dysfunction. In patients with existing cardiac dysfunction, dermatologists should consult a cardiologist prior to prescribing. New symptoms of heart failure (e.g., shortness of breath, orthopnea, leg swelling) should be urgently evaluated while itraconazole is stopped. Dermatologists may also consider referrals to infectious disease doctors for assistance with treating T. indotineae and/or prescribing itraconazole. There is a role for topical agents as well. These can help. We use them in our patients, and they report benefit for itching and reduction of other symptoms. In patients where itraconazole doesn’t seem to be working, the next step isn’t entirely clear. This is rarely reported. Serum levels of itraconazole may guide therapy, but this is not well established in dermatophyte infections. Voriconazole has been reported in a case report of itraconazole failure. These patients also may require infectious disease input.
DermWorld: From a public health standpoint, is there anything we can/should be doing to help prevent the spread of this worrisome fungus?
Dr. Caplan: It’s important to be good stewards of antifungal medications. We should confirm fungal infections, treat to terminate the infection, and limit use of antifungals to fungal infections. It’s also important that we confirm T. indotineae or other resistant dermatophyte infections when suspected. That may mean better access to testing and increased utilization of testing in clinic. It also means that costs of testing are reimbursed appropriately. We also want to educate patients. Patients with tinea infections, especially T. indotineae, should avoid sharing garments, linens, and towels when infected. Minimizing skin-on-skin contact is also advisable during times of active infection. We also need to ask about family members who may have itchy rashes and ask them to come to clinic for evaluation. It is important to treat affected family members of patients as well. Taking a sexual history may also prove important considering the risk of spread from skin contact.
Avrom S. Caplan, MD, FAAD, is assistant professor of the Ronald O. Perelman Department of Dermatology at NYU Grossman School of Medicine, and co-director of the Sarcoidosis Program. He does not have any relevant financial and/or commercial conflicts of interest.
Their paper appeared in JAMA Dermatology.
Disclaimer: The views and opinions expressed in this article do not necessarily reflect those of DermWorld.
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