Given the increasing resistance of dermatophytes to the various groups of available antifungal agents, antifungal susceptibility testing against dermatophytes is gaining importance. Minimum inhibitory concentration of antifungal agents helps to predict the likelihood of efficacy of the antifungal therapy.

The susceptibility profile of implicated dermatophytes to the antifungal agents can guide the clinician to choose the best antifungal agent with maximum efficacy, less toxicity and less expense.

Management of dermatophytosis is the biggest challenge faced by dermatologists today. Herein, authors have summarized the available therapeutic options, and have provided the rationale of using different molecules in the appropriate dose and duration.

General measures

• Patients should avoid sharing of garments, linens and towels, including bathroom napkins
• All the garments including undergarments and socks must be thoroughly washed daily in hot water and sun-dried (iron-pressed reverse if sun drying is not feasible)
• It is considered prudent to wear loose fitting cotton garments.
• Avoidance or minimization of close contact with child or spouse until adequate treatment is taken. Intimate contact with partner may be avoided during active infection.
• Avoidance of body-contact sports and swimming is preferable
• Simultaneous treatment of affected family members is vital.
• Examination of nails and feet is important to rule out reservoirs of infection.
• Patient needs to be advised to keep the skin, especially the folds, dry. Special attention should be given to toe web spaces
• If the patient is involved in physical activity or is in an environment where one tends to sweat a lot or has primary hyperhidrosis, having a bath twice daily helps. 

Indications of topical therapy include single lesions, elderly patients with significant comorbidities, infants and pregnancy.

An additional topical antifungal agent in a case where oral antifungal is administered concomitantly serves three purposes:

the local concentration of the topical antifungal increases the chances of clearance;

the purported anti-inflammatory and antimicrobial properties of the new topical antifungals help the cause; and

the patient satisfaction also increases.

Topical antifungals

Oldest and nonspecific agents include keratolytics-salicylic acid, lactic acid, Whitfield’s ointment and so on and antiseptics like gentian violet, castellani’s paint, potassium permanganate. These older topical agents have fallen out of favor for causing significant irritation and color changes barring Whitfield’s ointment which is often used in patients of moccasin tinea pedis.

Azoles useful in superficial dermatophytosis

These molecules are the first line topical agents these days, because of their promising effectiveness and low incidence of side effects. 

The available options in India from this group include miconazole, bifonazole, clotrimazole, ketoconazole, oxiconazole, sertaconazole, luliconazoleeberconazole, fenticonazole and fluconazole.

The oft-used topical azole antifungals are discussed below:

• Clotrimazole is satisfactorily effective in the management of intertriginous candidal infections but its efficacy in the current scenario of dermatophytes seems doubtful
• Oxiconazole is demonstrated to be effective with once daily dosing
• Sertaconazole is relatively lipophilic compared to other azoles, leading to a greater reservoir effect in the stratum corneum
• Luliconazole is the currently preferred topical agent amongst all the available molecules in India. One advantage of luliconazole is that it is effective once daily. Besides, it has demonstrated strong fungicidal activity at very low levels
• Butenafine and terbinafine were found to have better effectiveness, in comparison to clotrimazole, oxiconazole and sertaconazole, in a meta-analysis. But, the utility of terbinafine in our setting is questionable, owing to the recently discovered resistance to this group of molecules.
• In a study, amorolfine was found to equally effective as bifonazole. In another Indian study, it was found to be inferior to sertaconazole in terms of effectiveness. 
• Hydroxypyridilones - Ciclopirox 1% cream has been found to be better than clotrimazole 1% cream in the treatment of tinea pedis. 

There are regional differences across India in the use of systemic antifungal agents, namely, itraconazole, terbinafine, griseofulvin, ketoconazole and fluconazole.

However, itraconazole is the most preferred antifungal in the current scenario due to increasing cases of terbinafine failureIn a recently conducted randomized controlled trial in India among chronic and chronic relapsing tinea corporis, tinea cruris and tinea faciei patients, limited effectiveness of all four oral agents – fluconazole, griseofulvin, itraconazole and terbinafine was the key finding.

In terms of cure rates and the number needed to treat, among the four, itraconazole was found to be the most effective agent, followed by fluconazole daily, then terbinafine and lastly griseofulvin.

Terbinafine

According to some clinicians, terbinafine at a dose of 250 mg once daily for 4–6 weeks provides clinical cure. Presently, on account of increasing evidence of resistance, terbinafine is not preferred, although regional variability in the susceptibility and clinical responses exist.

In a randomized study comparing oral itraconazole versus oral terbinafine, mycological cure was seen in 91.8% after four weeks in the itraconazole group as compared to 74.3% of patients in the terbinafine group. Authors concluded that itraconazole and terbinafine were effective and safe.

A divided dose of 250 mg twice daily is preferred over 500 mg once daily since single dose defies the basic principles of pharmacokinetics/pharmacodynamics of the drug.

Itraconazole

With the increasing number of cases of recalcitrant dermatophytoses, itraconazole has undoubtedly stood out as the most favored molecule.

Itraconazole at a dose of 100 mg twice daily for a minimum duration of 2–4 weeks in naïve cases, and four weeks in recalcitrant cases was recommended in a consensus statement.

Fluconazole

Though not a preferred antifungal in the current scenario according to recent evidence, fluconazole has certain advantages like good oral absorption and lower cost. 

Griseofulvin

Recommended dosage of griseofulvin is 1 g per day for a period of four weeks according to western text books. Hot and humid climate that is prevalent in India may necessitate an increase in the duration more than the above mentioned four weeks duration.

Resistance to different antifungal agents

Griseofulvin resistance

Antifungal resistance to griseofulvin was first reported by Michaelides et al. in 1960 in patients with Trichophyton rubrum and Trichophyton tonsurans infection. A study from north India also reported tinea capitis patients not responding to the systemic antifungal agent, griseofulvin. Increasing reports of treatment failures with griseofulvin led to a shift in the treatment of choice towards azoles and allylamines, but still, some recommend it for the treatment of tinea capitis. Increased in vitro resistance to griseofulvin has been reported from across the world.

Azole resistance

Though clinical trials have shown that fluconazole is effective for the treatment of dermatophytosis, high minimum inhibitory concentrations demonstrated by in vitro studies, especially from recent studies from India criticizes its utility as the preferred agent and it needs clinical trials to confirm its effectiveness. Itraconazole is considered as one of the most effective azoles for the treatment of dermatophytosis. In vitro data also indicates that resistance to itraconazole is a rare phenomenon. In vitro antifungal susceptibility results showed that itraconazole was the most effective oral azole agent effective against dermatophytes isolated from north India. Most of the studies on in vitro susceptibility testing on topical azoles such as luliconazole, sertaconazole, efinaconazole and lanoconazole have shown that all have very potent in vitro activity with low minimum inhibitory concentrations

Allylamine resistance

Primary resistance to terbinafine in Trichophyton rubrum that resulted in treatment failure was first reported by Mukherjee et al., in 2003. In 2018, high terbinafine resistance was reported in 15 (17%) Trichophyton interdigitale (which can be considered to be the currently defined Trichophyton mentagrophytes VIII) and five (14.3%) of Trichophyton rubrum isolates. In addition to Trichophyton rubrum, a mutation in the squalene epoxidase gene conferring resistance in Trichophyton tonsurans and Epidermophyton floccosum were also reported.