Introduction: Dermatophyte infection has become extremely resistant and widespread in all parts of India during the past decade. A change in the major causative organism has been identified to be a major factor behind the change in the character of the infection. The epidemiological shift has been accompanied by large scale antifungal resistance. This review aims to take a look at the current status of evidence regarding the effectiveness of major antifungal molecules, with particular reference to the current epidemic-like scenario of resistant dermatophytosis in India. Methods: We have searched and included the relevant literature on “Dermatophytosis” from the PubMed, Scopus, and Google Scholar. Results: The current situation has also brought into focus the glaring lack of evidence-based guidelines for the management of dermatophytosis. The guidelines available previously had mostly been based on the western literature with the scarcity of studies from tropical countries such as India. Conclusion: The current guidelines of the management of dermatophytosis have lost their relevance in the present scenario and need to be replaced. However, without adequate studies we do not have robust data to formulate the new guidelines.
Keywords: Antifungal susceptibility test, evidence-based management, itraconazole, luliconazole, miconazole, terbinafine, Trichophyton indotinae, upper limit of wild type, voriconazole
| Introduction|| |
In little less than a decade, dermatophytic infection of the skin or tinea has managed to grab the attention of the medical fraternity. Its transformation from an easy-to-treat condition to a disease which is recalcitrant, persistent, and resistant to most treatments has baffled clinicians and scientists alike. Its relative refractoriness to treatment and chronicity leads to increased disease burden in the population and consequent increase in transmission as evidenced by the alarming rise in both the incidence and prevalence of tinea. The changing climatic conditions and misuse of corticosteroids cannot on their own explain the magnitude of this change and, at best, can be contributing factors.
A change in the nature of the causative organism has been suspected and slowly, but surely evidence is accumulating which confirms this suspicion. This change involves the replacement of Trichophyton rubrum, which had till recently been the most common isolate,,,,,,, by Trichophyton mentagrophytes which now accounts for the majority of cases.,,,, T. mentagrophytes as a group is complex with multiple clades which are very similar to each other and difficult to identify based on cultural characteristics alone. In certain studies, the most common organism isolated was labeled as Trichophyton interdigitale,, the anthropophilic subtype of T. mentagrophytes. These appear to have been misclassified and were actually T. mentagrophytes ITS genotype VIII, a new subtype of T. mentagrophytes which was identified by rDNA sequencing of the ITS gene. This variant, known as the Indian subtype, appears to be the most common isolate from the subcontinent.,, Currently, this subtype has been given the status of a new species named Trichophyton indotineae., Its increased transmissibility between humans and ability to survive for longer duration on inanimate objects, making fomites an important mode of transmission explains the explosive increase in the incidence of tinea.
The epidemiological shift in the causative Trichophyton species has been accompanied by another disconcerting phenomenon of antifungal resistance. Antifungal resistance is often difficult to demonstrate or determine due to the lack of established species-specific clinical breakpoints and epidemiologic cutoff values, which hinders the interpretation of the results of antifungal sensitivity test (AFST). The situation is complicated by the discordance between in vivo and in vitro susceptibility to various drugs. Clinical or in vivo resistance is dependent on a lot of host factors such as host immunity, individual pharmacokinetic variations, and compliance and is not a mere reflection of increased minimum inhibitory concentration (MIC) values. However, AFST for documenting in vitro resistance is logically the first step in predicting an emerging resistance and decreased response to a certain antifungal drug. Along with this, the determination of the resistance conferring genetic mutation and screening of isolates for its presence can go a long way in guiding the clinicians regarding appropriate choice of antifungals for the treatment of difficult-to-treat dermatophytosis. A PubMed search for studies documenting the MIC values to different antifungals among dermatophytes isolated from India using the standard CLSI or EUCAST reference standards yielded studies,,,,,,,,,, with a total of 1324 isolates (T. interdigitale-262, T. mentagrophytes-363, T. mentagrophytes interdigitale-547, T. rubrum-152). An increased MIC to various antifungals was noted in a significant number of isolates; however, absence of guidelines regarding the breakpoints and epidemiological cutoff values makes the interpretation of data difficult.
The current situation has also brought into focus the glaring lack of evidence-based guidelines for management of dermatophytosis. The guidelines available previously had mostly been based on western literature with scarcity of studies from tropical countries such as India. These have lost their relevance in the present scenario and need to be replaced. However, without adequate studies we do not have robust data to formulate the new guidelines. Efforts have been made to streamline and provide a standard guideline for the management of dermatophytosis based mostly on experiences and opinions of experts.,
| Terbinafine|| |
Terbinafine has, for a long time, been the antifungal of choice for the treatment of tinea.,,, However, the emergence of the newer subtype of T. mentagrophytes ITS VIII and acquisition of a resistance conferring mutation in the squalene epoxidase (SQLE) gene among the various Trichophyton species has rendered this drug ineffective in a large number of cases. In vitro analyses of the fungal isolates from the several parts of the country have shown a high MIC 90 values of 8 mg/l and high percentage (11.4%) of isolates above the upper limit of the wild type (UL-WT) for terbinafine. Resistance rates as high as 72% in T. mentagrophytes ITS type VIII and 44% in T. rubrum have been reported in another large pan India study. Data from various other studies in the Indian population also reflect a similar rise in the MIC values for terbinafine.,,, Several point missense mutations in the SQLE gene have been documented, of which Phe397 Leu substitution and Leu393Phe substitution were found to be associated with the highest MIC values. This phenomenon of increasing in vitro resistance to terbinafine is mirrored in the clinical setting where the cure rates with oral terbinafine have been disappointing in recent studies., The whistle-blower study in this regard was the large prospective cohort study on 500 patients by Singh and Shukla, where an abysmal cure rate of 2% (95% confidence interval 1.0–3.7) was obtained on an intention-to-treat analysis. A daily dose of 500 mg in two divided doses, instead of 250 mg once, did not appear to significantly improve the outcome. A nonblinded randomized trial on patients with recurrent dermatophytosis found that the addition of isotretinoin to terbinafine provided no added benefit. There are conflicting results regarding the efficacy of combined terbinafine 250 mg and itraconazole 200 mg/day, with one randomized controlled trial (RCT) showing significant improvement in clinical cure as compared to itraconazole or terbinafine given alone and another showing no significant difference between groups treated with the combination or itraconazole alone.
| Itraconazole|| |
It is a broad-spectrum triazole antifungal which has emerged as a savior in the current epidemic of terbinafine-resistant tinea. The drug has demonstrated consistently low MIC (0.25–0.5 μg/ml) against all the species of Trichophyton and a low percentage of isolates above the ULWT., Its in vivo efficacy has also been demonstrated in several clinical studies and RCTs with clinical cure or mycological cure in > 90% of cases.,,, In an alarming clinical report from a single center RCT, conducted in India among chronic and chronic relapsing tinea patients, limited effectiveness of all four oral agents: fluconazole, griseofulvin, itraconazole, and terbinafine was the key finding. In terms of cure rate and the number needed to treat itraconazole however was found to be most effective than the rest, followed by fluconazole daily, then terbinafine, and lastly griseofulvin. The combination of terbinafine with itraconazole does not provide any advantage over itraconazole alone. The clinical response to the drug depends on the levels achieved in the serum and skin. Itraconazole, being lipophilic usually shows high concentration in sebum rich area. Increasing the dose of the drug to 400 mg per day as compared to 200 mg per day does increase its serum levels. However, there are conflicting reports from two different RCTs if this increase in dosing leads to any improvement in clinical efficacy., Besides, there are doubts that capsules of 200 mg itraconazole may not be stable and may show an increased tendency to agglutinate. The absorption of itraconazole is unpredictable and shows wide individual variation. To circumvent this problem, newer drug delivery mechanisms have been developed. The super-bioavailable (SUBA) technology utilises the solid dispersion of the drug in a polymer that improves its dissolution as compared to its original crystalline form leading to better absorption and a relative improvement in the bioavailability by 173% as compared to conventional formulation. There is also a 21% decrease in inter-patient variability; however, absorption decreases by 27% when SUBA-itraconazole (S-ITZ) is taken with food., This formulation shows a 22% increase in plasma levels of the drug when co-administered with omeprazole, in stark contrast to the conventional formulation conventional itraconazole (C-ITZ) where omeprazole reduces both the Cmax and mean area under curve (AUC) by more than half. Bioequivalence studies reveal that 58 mg S-ITZ is equivalent to 100 mg of C-ITZ as per the AUC. S-ITZ is marketed in the strengths of 50 mg, 65 mg, 100, and 130 mg. Theoretically, S-ITZ should be effective in dermatophytosis, but there is a lack of adequate evidence to evaluate its appropriate dosing as well as comparative efficacy in the treatment of tinea in the Indian scenario. Till date, there is only one study from India comparing the safety and efficacy of S-ITZ to C-ITZ which concluded that S-ITZ showed better clearance of lesion. Besides being industry funded, the study was an open label one, with doubtful randomization and a high risk of bias, thus translating into poor quality evidence. Currently, the only Food and Drug Administration (FDA)-approved indications for S-ITZ include blastomycosis, histoplasmosis, and aspergillosis in patients intolerant or refractory to amphotericin B.
Resistance to itraconazole has been documented, although the mechanism in T. mentagrophytes ITS type VIII is not known, it may be similar to that seen in T. rubrum where decreased sensitivity to azoles has been attributed to the overexpression of several genes belonging to a superfamily of transporters capable of operating as azole efflux pumps.,
| Voriconazole|| |
A triazole antifungal very similar to itraconazole reported to have a very low MIC 90 value (0.25 mg/l) against T. mentagrophytes but a relatively high percentage of isolates above the UL-WT MIC (4.8%). In vivo it has been reported to be effective and relatively safe with clinical clearance in 75%–83% of cases after 6 weeks, with a low relapse rate. It has been reported to be superior to itraconazole alone or itraconazole with isotretinoin, with respect to clinical and mycological clearance and lower relapse rate. However, similarity to itraconazole explains the phenomenon of cross resistance where strains showing lower sensitivity to itraconazole also have a reduced sensitivity to voriconazole. A particular mutation (Ala448Thr substitution) confers resistance to both itraconazole and voriconazole. Considering the good response of T. mentagrophytes to ITZ and the phenomenon of cross resistance, it would possibly be prudent to avoid the rampant use of voriconazole which is a reserve drug for the treatment of systemic mycoses.
The other systemic antifungals such as griseofulvin and fluconazole have very high MIC values and currently are of limited use in the treatment of dermatophytosis due to very low cure rate, 42% for fluconazole and 14% for griseofulvin as demonstrated in an RCT.
| Luliconazole|| |
Luliconazole is an imidazole which inhibits lanosterol-14α-demethylase and consequently blocks ergosterol synthesis. In vitro luliconazole has been shown to have relatively low MICs against Trichophyton compared to most other topical antifungals. In a countrywide study involving 415 isolates, the MIC90 of this molecule was found to be low (0.125), although a high percentage (13.9%) of isolates above the UL-WT MIC was also noted. Compared to 1% terbinafine cream and 1% bifonazole cream, 1% luliconazole cream shows a higher clearance of dermatophytes in certain clinical studies., Amorolfine 0.25% was shown to be equally efficacious as luliconazole. In vitro, luliconazole has been found to have a synergistic effect with itraconazole. Luliconazole is an effective topical treatment in terbinafine-resistant strains of Trichophyton. Newer nanomaterial-based drug delivery systems are being developed which may improve the skin permeation and skin retention of the drug leading to improved efficacy.,
| Amorolfine|| |
A morpholine derivative, which inhibits both C14 reductase and C7–C8 isomerase activity, it has been reported to have low MIC90 of 0.06 mg/l. Clinically, it has been found to be effective, resulting in mycological cure in almost 80% of patients after 4 weeks of therapy. Comparison with other topical antifungals showed amorolfine to be as effective as luliconazole but slightly inferior to sertaconazole.,
Some other effective and safe topical antifungals are eberconazole,, ciclopirox olamine, and sertaconazole., Sertaconazole was shown to be more effective in comparison to amorolfine and eberconazole., Interestingly, miconazole an older antifungal was demonstrated to have a very low MIC (0.06 mg/l) against the prevalent Trichophyton species.
| Summary|| |
- T. mentagrophytes ITS type VIII (currently T. indotineae) is the predominant pathogen responsible for the epidemic of dermatophytosis in India.
- Several point mutations in the SQLE gene promoting resistance to terbinafine have rendered it relatively ineffective in the current scenario.
- Increasing the daily dose of terbinafine to 500 mg does not appear to significantly improve the outcome. Also, addition of isotretinoin to terbinafine does not provide any added benefit.
- Itraconazole is the current drug of choice for the treatment of dermatophytosis and shows low MIC and high efficacy.
- Regarding itraconazole, a dosage of 200 mg daily in two divided doses appears effective. There are no studies to determine the duration of treatment. However, usually, longer duration of 4 weeks to 6 weeks of treatment appears effective.
- Evidence regarding the efficacy of a daily dose of 400 mg of itraconazole (in two divided doses) is conflicting. However, it is pertinent to note that capsules containing 200 mg itraconazole may not be stable and may show an increased tendency to agglutinate.
- S-ITZ shows a greater bioavailability compared to the conventional form and remains unaffected by concomitant intake of proton-pump inhibitors. Intake of S-ITZ with food decreases absorption.
- Studies to prove the superior efficacy of S-ITZ over the conventional drug and to determine the effective and safe dose of S-ITZ for the treatment of dermatophytosis are lacking or are inadequate. Currently, this formulation is not approved by the FDA for treatment of any form of dermatophytosis. Hence, caution must be exercised regarding its use in the treatment of tinea.
- Resistance to itraconazole has been documented and care must be exercised to prevent its rampant misuse. The use of topical formulations of itraconazole as cream and shampoos is irrational and should be strongly discouraged.
- There is no conclusive proof regarding the superior efficacy of a combination of terbinafine and itraconazole over monotherapy with itraconazole.
- Regarding the other systemic antifungals, there are no studies to evaluate the efficacy of simultaneous use of any two systemic antifungals. Neither are there any studies evaluating the safety of such combinations. Hence, the practice of simultaneous administration of two oral antifungals should be avoided.
- Combination of a systemic and a topical antifungal may be advantageous and certain combinations such as itraconazole with luliconazole or ketoconazole have been shown in vitro to have synergistic effect.
Conflicts of interest
There are no conflicts of interest.
- Aparajita Ghosh: Drafting, editing, acting as guarantor.
- Saumya Panda: Drafting, editing, acting as guarantor, corresponding author.
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