Dermatophytosis is the most common superficial fungal infection worldwide. In recent years, superficial mycoses have become increasingly resistant to current antifungals; specifically, high incidences of chronic infection, reinfection, and treatment failure have been reported.

Therefore the importance of detecting drug resistance in clinical practice and accordingly apply modified strategy in treating such cases would be beneficial to the patient.

Treatment resistant dermatophytoses caused by Trichophyton rubrum (T. rubrum) or Trichophyton mentagrophytes (T. mentagrophytes)/Trichophyton indotineae have recently emerged as a global public health issue.

Terbinafine is an allylamine antifungal administered orally or topically as a first-line therapy for the treatment of dermatophyte cutaneous infections and onychomycosis however resistance to terbinafine remains largely present.

This review will focus on the phenomenon of resistance to antifungals encountered in dermatophytes, with a special focus on terbinafine resistance.

Resistance to azoles will also be considered. A clinical review of lesions caused by these resistant dermatophytes will be presented and alternative therapies will be discussed.

CAUSATIVE PATHOGENS FOR DERMATOPHYTOSIS

Recent literature indicates a global rise in resistance of Trichophyton rubrum, Trichophyton mentagrophytes, and T. interdigitale known causes of tinea infections, to terbinafine. 

The epidemiological shift from T rubrum to T mentagrophytes/T interdigitale as the dominant pathogen in tinea patients now a day.

Resistance poses an alarming challenge due to the limited availability of systemic antifungals. Additionally, a potential long-term consequence of untreated tinea infections is postinflammatory hyperpigmentation, particularly in patients with darker Fitzpatrick skin types. 

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

The emergence of terbinafine resistance is increasingly reported and has been linked to:

• Overuse of the topical antifungal creams
• Inappropriate use of topical steroid creams
• Widespread use of this drug alone, or in combination with topic steroids
• Inappropriate prescription of antifungal drugs
• suboptimal dosing
• incomplete treatment courses
• Inadequate adherence to prescribed courses of antifungal medication
• Global travel and migration
• An altered immune response of the host
• Microbiological (in vitro) resistance of the causative fungi

Triazole resistance was more frequent in terbinafine-sensitive isolates, while terbinafine resistance was more frequent in triazole-sensitive isolates. This may be because patients were treated with either terbinafine or azole, but not with both classes of drugs.

Indeed, limited effectiveness of 4 oral antifungals (fluconazole, griseofulvin, itraconazole, and terbinafine), but itraconazole has shown better efficacy than the others in certain cases.

FUNGAL IDENTIFICATIONS

·        Antifungal susceptibility testing (AFST)

·        PCR-ELISA

Resistance to antimycotics is phenotypically determined by antifungal susceptibility testing (AFST). However, AFST is not routinely performed for dermatophytes and no breakpoints classifying isolates as susceptible or resistant are available.

The key to selecting an effective antifungal therapy for a recalcitrant infection is identification of the infectious organisms(s) and testing susceptibility of the organism(s) to antifungal drugs. Routine AFST should be considered to determine the most effective treatment, especially if there is failure to therapy.

MANAGEMENT OF RESISTANCE CASES

Clinicians should be more judicious in prescribing or recommending oral or topical antifungal therapy.

Given the limited selection of antifungals, it is paramount to mitigate resistant cases. Mitigation proposals include:

·        good skin hygiene,

·        proper (higher) dosing

·        longer duration of antifungals,

·        susceptibility testing, and

·        combination therapy.

Combinations therapy

Therapeutic choices are limited for the control of fungal diseases, and it is tempting to combine several drugs to achieve better therapeutic efficacy.

Combination therapy may be an option to improve the outcome of terbinafine-resistant dermatophytosis.

Combination such as:

o   2 systemic antifungals,

o   a systemic and topical antifungal, and/or

o   a topical keratolytic).

·        The use of combination therapy is an effective strategy to overcome the emergence of antifungal resistance.

·        Moreover, antifungal combinations can increase the efficacy of the treatment in case of synergistic interactions between the two partner drugs.

·        Combination therapy can also reduce toxicity by decreasing the antifungal dosages and improving the pharmacokinetics of one or both molecules.

·        Combination and sequential therapy regimens are options, but both require active monitoring for hepatic and renal function, drug interactions, and other adverse effects.

Several combinations have previously been tested against dermatophytes in vitro.

·        Itraconazole in combination with amorolfine or cyclopiroxolamine showed good results.

·        Oral itraconazole in addition to topical ciclopirox may be beneficial to some patients.

Combination of Terbinafine with Itraconazole against Isolates of Trichophyton Species:

In this study, the authors found that the combination of itraconazole with terbinafine was synergistic for 50% of the tested isolates, even when the tested isolate was resistant to terbinafine (57% of synergy). 

In conclusion, the in vitro results of synergistic interactions of terbinafine and itraconazole against terbinafine-resistant Trichophyton in the present study are promising.

T. mentagrophytes also had reduced susceptibility to azoles from different regions.

Higher Doses and Longer duration

Increasing terbinafine exposure through higher doses or longer durations has been proposed to overcome treatment failure and could protect azole-based antifungal drugs from developing resistance. 

Terbinafine resistance when given in the standard doses (250 mg once a day for 2 weeks) is being increasingly seen with partial or no response to treatment.

Antifungal resistance is due to a decrease in effective drug concentration because of extensive accumulation of terbinafine in the skin and adipose tissue. Hence, higher concentration of terbinafine 500 mg/day has seen found to be more effective.

Summary of Alternative Therapies for Terbinafine Resistant Strains

·        Use of prolonged therapy based on other antifungals azoles for example itraconazole, voriconazole has to be considered to treat terbinafine resistant dermatophyte strains giving rise to extended tinea corporis.

·        Increasing the dose of terbinafine (500mg/day) when resistance is suspected in extended tinea corporis.

·        Switch to itraconazole as continuous therapy (200 mg/day) or as a pulse therapy.

·        An increase of the dose of itraconazole to 300–400 mg/day should be considered in cases of azole resistance associated with terbinafine resistance.

·        Use of topical therapy with systemic therapy for better efficacy.

The duration of the therapy should be between 8–12 weeks and up to one year in cases of multidrug-resistant dermatophytoses.

Focus on Resistance to Azoles in Dermatophytes

Resistance to azoles has been reported infrequently until now, but some cases have been described, often together with allylamine resistance.

Methylene blue photodynamic therapy: A treatment option for terbinafine resistant Trichophyton species