The Growing Issue of Antifungal Resistance in Scalp Fungal Infections: A Closer Look at Tinea Capitis

20 % of Dermatophytes Resistant to Fluconazole; 12 % Resistant to Terbinafine.

Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. Examples of these include tinea corporis, tinea unguium, tinea facei, tinea pedia, tinea cruris and tinea capitis.

It is estimated that around 10-15% of people around the world get infected by dermatophytes at some point in their lives. Tinea capitis (TC) is the fungal infection of the scalp cause by dermatophytes. We’ll come back to this concept.

A REVIEW OF ANTIFUNGALS AND RESISTANCE 

Griseofulvin was FDA approved in 1959. It interferes with microtubule formation impairing fungal cell growth and fungal cell division. Ever since the introduction of griseofulvin, it has been increasingly clear that a small proportion of patients do not respond to antifungal drugs. Some patients have been noted to have infections associated with increased minimum inhibitory concentrations to griseofulvin. This indicates drug resistance.

Resistance to “Azole” drugs

In addition to resistance to griseofulvin, resistance has been noted with azole drugs as well. Azole drugs inhibit the α-demethylase enzyme in the fungal cell membrane, thereby blocking the biosynthesis of ergosterol biosynthesis.

The molecular mechanisms that cause antifungal resistance include many different mechanisms including reduced uptake of drug, active transportation of the drug out of the cell and modified drug metabolic degradation of the cell. Overexpression of genes encoding ABC transporters, give rise to multidrug efflux outside the cell.

Another reason for dermatophyte resistance is the point mutation in the ERG11 gene that codes for lanosterol 14a-demethylase which causes the blockage of the binding capacity of the azole drug to its target.

Resistance to Terbinafine

Terbinafine is an allylamine antifungal that inhibits squalene epoxidase. This prevents the formation of ergosterol and causes accumulation of squalene. This weakens the cell wall of the fungus. Resistance to the drug terbinafine is increasingly noted as we’ll see in a moment.

The first case of terbinafine resistant Trichophyton rubrum was recorded in North America by Mukherjee et al. in 2003. The paper showed that terbinafine resistant isolates showed normal susceptibilities to antifungals such as itraconazole, fluconazole and griseofulvin, but they were crossresistant to several other known squalene epoxidase inhibitors, such as naftifine, butenafine, tolnaftate and tolciclate, suggesting a target specific mechanism of resistance to allylamines. The Mukherjee paper did not propose a mechanism for the resistance.

Subsequent studies in 2004 by Favre indicated that it was alterations in the squalene epoxidase (SE) gene that contributed to resistance.

The Terbinafine Resistance Story of 2018

The terbinafine resistance story changed again with news form India in 2018. Data from India showed high terbinafine resistance in isolates initially named “Trichophyton interdigitale.   In that year,  Singh et al. reported a resistance rate of 32% among T. interdigitale strains in India. The Trichophyton was renamed  T. indotineae,

In 2020, Ebert et al. conducted an epidemiological study across 8 different locations in India. This study included 402 patients with clinically suspected dermatophytosis. Among the isolates, 314 (78%) were identified as T. mentagrophytes, eighteen (5%) were from the T. interdigitale/mentagrophytes group and nineteen (5%) were T. rubrum.   Among these isolates, terbinafine resistance was found in 71%. There was also increased MICs for voriconazole and itraconazole (indicating resistance). They observed that azole resistance was more frequent in terbinafine susceptible strains than in resistant ones. This study showed a concerning rate of terbinafine resistance in India. This has only increased since the 2018 report.

Resistance continues to be a major issue in India  – however worldwide spread is now appreciated. The authors propose that the unchecked availability of inexpensive and irrational corticosteroid–antifungal–antibacterial combinations sold over the counter in India contributed to the resistance.

Resistance is most likely to be seen Trichophyton mentagrophytes (mainly) and some cases are caused by T. rubrum. Although resistance was first noted in India, many parts of the world are showing resistance to terbinafine. Terbinafine-resistant T. rubrum has been documented in the United States  and resistant T. mentagrophytes has been reported in India, Germany, Poland, and Iran.

James Hay in his article, “The Spread of Resistant Tinea and the Ingredients of a Perfect Storm” says that this is “evolving into a global public health crisis.”

Most cases of terbinafine resistance have been tinea corporis, tinea cruris, tinea inguium, tinea pedis, tinea facie.

Overall the current rate of terbinafine resistance with various trichophyton may be as high as 30 % in India.  Resistance rates up to 20% in trichophyton species may be present in other part of the world.

What factors might be contributing to the emergence and spread of antimicrobial-resistant dermatophytes?

• Overuse of over-the-counter topical antifungal creams

• Inappropriate use of topical steroid creams

• Inappropriate prescription of antifungal drugs

• Inadequate adherence to prescribed courses of antifungal medication

• Global travel and migration

Why is it difficult to track antifungal resistant dermatophyte infections?

The true number of antimicrobial-resistant dermatophyte cases is difficult to estimate because antifungal susceptibility testing is not widely available. Furthermore, it is not mandatory to report antimicrobial-resistant dermatophyte cases is not required in the United States

Tinea capitis specific resistance

Reports about 10 years ago highlighted the emerging resistance to tinea capitis.

More recent work by Ayodele et al highlighted the emerging resistance to T. rubrum. A 2020 study by Sacheli et al highlighted the terbinafine resistance seen in Europe with Trichophyton mentagrophytes. The authors stated that the monitoring of terbinafine resistance among dermatophytes seems necessary now.

In 2022 Abastabar published on tinea capitis in Iran. TC was diagnosed in diagnosed in 75 children (79.8%) and 19 adults (20.2%) by direct microscopy and culture. Frequency of TC was significantly more among males (66 males = 70.2% vs 28 females = 29.8%). The prevalent age group affected was 5-9 years (39.36%).

MIC values of isolates showed susceptibility to all antifungal agents, except for fluconazole and griseofulvin. Two resistant T. mentagrophytes isolates harbored missense mutations in SQLE gene and therefore resistance to terbinafine.

The exact proportion of terbinafine resistant tinea capitis worldwide is not clear but may not be insignificant . Ghannoum suggested that 3.5% strains of dermatophytes causing TC are found to be resistant to fluconazole globally. Terbinafine resistance may be somewhere in the estimate of 10-20%

Zeeshan et al 2023

Authors from Karachi, Pakistan set out to determine the epidemiological profile of dermatophytes among patients of tinea capitis and their susceptibility pattern to the two antifungal drugs fluconazole and terbinafine. The goal of the study was to highlight the current status of antifungal resistance in dermatophytes among the local population.

Between August and December 2019 samples of hair and skin were taken from the scalp of tinea capitis patients regardless of age and gender. Demographic details were collected and the samples were processed for direct microscopy and mycological culture. Antifungal susceptibility testing for fluconazole and terbinafine was performed.

Results

Of the 207 patients, 115(55.5%) were males, and 114(55.1%) were children. 196 (94.7%) participants were from low socio-economic strata, 10(4.8%) belonged to middle-income group, while 1(0.5%) patient was from high-income group. Non-inflammatory type of lesions were found in 107(51.7%) cases. Cervical and occipital lymphadenopathy was noted in 31 (15%) and 11 (5.3%) cases, respectively.

The most common presenting complaint was alopecia 141(68.1%), followed by dandruff or scaling 132(63.6%), pruritus 108 (52.2%) and painful pustules 87(42%)

Overall, 106 (51.2%) samples showed fungal growth and 101(48.8%) specimens did not grow any fungal organisms. Among the growth-positive cases, 61 (57.6%) constituted dermatophytes, while non-dermatophytes were isolated in 45 (42.4%) cases.

What dermatophytes were uncovered as causes of tinea capitis in Pakistan?

Among the dermatophyte cases, T. violaceum accounted for 21(34.4%) cases, followed by T. mentagrophytes 18(29.5%), T. tonsurans 9(14.8%), T. soudanense 3(4.9%), T. verrucosum 3(4.9%), M. canis 3(4.9%), T. rubrum 2(3.3%) and M. gypseum 2(3.3%)

FLUCONAZOLE RESISTANCE

The rate of resistance in dermatophytes to fluconazole was 12 (19.7%). Among dermatophytes, highest resistance to fluconazole was noted in T. mentagrophytes 7(38.9%), followed by T. violaceum 4 (19%) and T. rubrum 1(50%).

 

TERBINAFINE RESISTANCE

7(11.5%) dermatophytes showed resistance to terbinafine. Highest rate of resistance was seen in T. mentagrophytes 4 (22.2%), followed by T. violaceum 3 (14.3%).

Conclusion and Summary of Zeeshan Study 2023

Trichophyton violaceum was the most common pathogen responsible for tinea capitis in this study from Pakistan and was found in 34.4 % of dermatophyte cases. This was followed by trichophyton mentagrophytes in 29.5%. Resistance to fluconazole and terbinafine among dermatophytes was recorded in 19.7% and 11.5% of dermatophyte isolates, respectively.

Antifungal resistance to either terbinafine or fluconazole was predominantly seen in trichophyton violaceum and trichophyton mentagrophytes.

REFERENCE

Zeesha F.The rising menace of antifungal resistance in dermatophytes among the patients of tinea capitis. J Pak Med Assoc. 2023 Jan;73(1):43-48.

D M L Saunte et al. Emerging antifungal treatment failure of dermatophytosis in Europe: take care or it may become endemic. J Eur Acad Dermatol Venereol . 2021 Jul;35(7):1582-1586.

Bishnoi  A, Vinay  K, Dogra  S. Emergence of recalcitrant dermatophytosis in India. [Comment in Lancet Infect Dis. 2018;18:718–9.]. Lancet Infect Dis. 2018;18:250–1.

Kano  R, Kimura  U, Kakurai  M, Hiruma  J, Kamata  H, Suga  Y, et al. Trichophyton indotineae sp. nov.: a new highly terbinafine-resistant anthropophilic dermatophyte species. Mycopathologia. 2020;185:947–58

Hay, RJ The Spread of Resistant Tinea and the Ingredients of a Perfect Storm. Dermatology. 2022;238(1):80-81

B K Chen  et al. Tinea capitis update: a continuing conflict with an old adversary. Curr Opin Pediatr. 2001 Aug;13(4):331-5.

Ayodele  EH et al. PREVALENCE, IDENTIFICATION AND ANTIFUNGAL SUSCEPTIBILITY OF DERMATOPHYTES CAUSING TINEA CAPITIS IN A LOCALITY OF NORTH CENTRAL NIGERIA. Afr J Infect Dis. 2020 Dec 14;15(1):1-9.

Rosalie Sacheli  etla. Belgian National Survey on Tinea Capitis: Epidemiological Considerations and Highlight of Terbinafine-Resistant T. mentagrophytes with a Mutation on SQLE Gene. J Fungi (Basel). 2020 Sep 29;6(4):

Mahdi Abastabar et al. Iranian National Survey on Tinea Capitis: Antifungal Susceptibility Profile, Epidaemiological Characteristics, and Report of Two Strains with a Novel Mutation in SQLE Gene with Homology Modeling, Mycopathologia. 2022 Aug 18.

Bishnoi  A, Vinay  K, Dogra  S. Emergence of recalcitrant dermatophytosis in India. [Comment in Lancet Infect Dis. 2018;18:718–9.]. Lancet Infect Dis. 2018;18:250–1.

Mukherjee, P.K.; Leidich, S.D.; Isham, N.; Leitner, I.; Ryder, N.S.; Ghannoum, M.A. Clinical Trichophyton rubrum strain exhibiting primary resistance to terbinafine. Antimicrob. Agents Chemother. 2003, 47, 82–86. [CrossRef]

Favre, B.; Ghannoum, M.A.; Ryder, N.S. Biochemical characterization of terbinafine-resistant Trichophyton rubrum isolates. Med. Mycol. 2004, 42, 525–529. [CrossRef]

Singh, A.; Masih, A.; Khurana, A.; Singh, P.K.; Gupta, M.; Hagen, F.; Meis, J.F.; Chowdhary, A. High terbinafine resistance in Trichophyton interdigitale isolates in Delhi, India harbouring mutations in the squalene epoxidase gene. Mycoses 2018, 61, 477–484. [CrossRef] [PubMed]

Ebert, A.; Monod, M.; Salamin, K.; Burmester, A.; Uhrlaß, S.; Wiegand, C.; Hipler, U.C.; Krüger, C.; Koch, D.; Wittig, F.; et al. Alarming India-wide phenomenon of antifungal resistance in dermatophytes: A multicentre study. Mycoses 2020, 63, 717–728. [CrossRef]

Ghannoum, M. Azole resistance in dermatophytes: prevalence and mechanism of action. J Am Podiatr Med Assoc. 2016; 106:79- 86. doi: 10.7547/14-109.