The realm of dermatophytosis of the glabrous skin (tinea corporis, cruris or faciei) has undergone a tremendous change over the past few years. From being an infection responding promptly to short courses of antifungals before, increasing recalcitrance to treatment has been documented since 2017. The initial manifestation of a changing scenario was consequent to the slow clinical response to terbinafine.[1] Reports of terbinafine resistance attributed to mutations in the squalene epoxidase (SQLE) gene followed, along with attempts at modifying recommended systemic antifungal regimens to achieve improved therapeutic outcomes. However, the (undue) panic-stricken attempts at this have led to the use of irrational regimens of antifungals, leading not only to a potential increase in treatment-related adverse effects and cost, but also threatening antifungal stewardship attempts, with dire long-term consequences. In the following sections, we present an overview of the changing scenario of dermatophytosis in India and the world, with an emphasis on current updated evidence pertaining to the use of various systemic antifungals. The data search was limited to PubMed-cited articles.

   Trichophyton indotineae (T. indotineae): A novel species 

The emergence and widespread global spread of T. indotineae in less than a decade is alarming. The species has now spread beyond the Indian subcontinent to many other parts of Asia, as well as Europe and North America.[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12] In particular, high rates of antifungal resistance in this species have enlisted this pathogen as a multidrug-resistant clonal species.[13] The earliest studies from India identified T. interdigitale or T. mentagrophytes internal transcribed spacer (ITS) type VIII as the aetiologic agent of recalcitrant tinea infections.[14],[15],[16] Later, Kano and colleagues (2020) named these highly terbinafine-resistant T. strains as a new species, T. indotineae, which is distinct from the T. mentagrophytes or T. interdigitale complex.[17] Multilocus sequence typing and whole-genome sequencing distinctly delineate T. indotineae from T. mentagrophytes or T. interdigitale complex.[13],[18]

Furthermore, T. indotineae has been recorded as a clonal anthropophilic species, which is frequently associated with terbinafine resistance, conferred by mutations in the SQLE gene. Terbinafine-resistant T. indotineae isolates exhibit single-point mutations in the target gene squalene epoxidase, a key enzyme in the ergosterol biosynthetic pathway.[14],[19],[20] The single amino acid substitution Phe397Leu has been the most commonly reported substitution worldwide, followed by Leu393Phe, Leu393Ser and Phe415Val.[21] Overall, the true burden of T. indotineae infections is underestimated globally, as unequivocal identification of T. indotineae can only be performed using DNA sequencing, the facilities of which are not available in routine microbiology laboratories. A worryingly high rate of in vitro terbinafine resistance, ranging between 30 and 60%, has been reported in recent studies.[14],[19],[20] In addition, (in vitro) azole resistance has also been frequently identified with T. indotineae.

   Treatment Updates 

The following sections delve into past and recent evidence pertaining to the use of the main systemic antifungals in dermatophytic infection of the glabrous skin, with a summary of the existent data at the end of each section. This is followed by a critical analysis of some recent clinical trends in the management of tinea corporis or cruris. Owing to the nearly complete dominance of T. indotineae in studies from various parts of the country in the past few years (which have identified the organism to species level), it has been presumed that the included recent clinical (therapeutic) reports from the country, which do not provide species identification by sequencing, also probably pertain to T. indotineae.

   Terbinafine 

Mechanism of action: Terbinafine acts by the inhibition of the enzyme SQLE in a non-competitive manner. SQLE enzyme is encoded by gene ERG1, and it determines the earliest step in ergosterol synthesis in fungal cell membranes. This inhibits the production of 2, 3 oxidosqualene from squalene, resulting in a block in the ergosterol synthetic pathway, as well as an accumulation of squalene. A high concentration of squalene can consequentially lead to disruption of the fungal cell membrane and is possibly the reason for the drug's fungicidal effect.[22] Although most widely used for dermatophytosis, terbinafine has demonstrated activity against a wide range of filamentous, dimorphic and dematiaceous fungi, as well as yeasts.

Place in the treatment of dermatophytosis

Since its introduction, terbinafine has been the mainstay of treatment for dermatophytic infections. Terbinafine's acceptable safety profile, favourable pharmacokinetic profile and low drug interaction potential made it the drug of choice for dermatophytosis for decades. Although it was presumed that resistance to terbinafine is unlikely, owing to the low likelihood of development of the reported mechanism of a single-nucleotide substitution in the gene encoding SQLE protein (ERG1), developments in recent years have been to the contrary.[23],[24] While before 2017, there were only two confirmed cases of terbinafine resistance reported in the literature, since then there has been a slew of reports describing SQLE gene mutations in T. spp. from India and various parts of the world.[7],[8],[9],[10],[14],[25],[26]

Clinical evidence: From past and in the current context

At the time of the introduction of terbinafine, it was used in doses of 125–250 mg twice daily, while later a dose of 250 mg once daily came into clinical use.[27],[28] At a dose of 250 mg/day, the initial studies demonstrated high cure rates of 75–90% for tinea corporis or cruris.[27] Cole et al.[29] compared a higher dose of terbinafine 250 mg twice daily (BD) with griseofulvin in the same dose (both given for six weeks) and observed a cure rate of 87% with terbinafine versus 73% with griseofulvin. Subsequently, a high efficacy was reported with only one-week treatment with terbinafine 250 mg/day, and this was used as the standard treatment regimen until recently.[30]

Of late, however, this regimen has been observed to lead to inadequate clinical responses. Majid et al.[31] recruited 100 patients with mycologically confirmed tinea corporis and/or cruris and administered a standard dose of terbinafine 250 mg once daily for two weeks. At the end of this treatment period, 65% of patients were clinically and mycologically cured, while 30% of patients showed a persistent disease clinically, and 35% still showed positivity on culture. Over a further follow-up of 4 months, 22 (33.8%) of the cured patients had a relapse of infection. Interestingly, the body surface area involvement was similar across cured, failure and relapsed groups. Subsequently, in 2018, the first reports of T. species harbouring SQLE gene mutations were published from two centres in the country, explaining the lowered efficacy of the standard regimen.[14],[19]

To circumvent the reducing efficacy of standard terbinafine dosing, higher doses and longer durations of terbinafine started to be used empirically.[32],[33] This was followed by a clinical trial aimed at documenting the clinical response to longer durations or higher doses of terbinafine and correlating that with in vitro minimum inhibitory concentrations (MICs) and SQLE gene mutation analysis.[34] The study entailed treatment with terbinafine 250 mg once daily (OD) after confirmation by potassium hydroxide (KOH) mount of skin scrapings. On follow-up, if the patients achieved >50% clinical clearance by 3 weeks, the same dose was continued till cure (defined as clinical clearance and negative KOH smears). If not, the dose was increased to 250 mg twice a day (BD). In the third follow-up, that is after 3 weeks of terbinafine 250 mg BD dose, if the clinical clearance still remained below 50%, the patients were shifted to itraconazole, while if >50% clinical clearance was achieved with terbinafine 250 mg BD by this time point the same dose was continued. In each such group, the patients were treated till they achieved a clinical and mycological (negative KOH smears) cure. The authors observed that in the three groups thus formed, that is those cured using terbinafine 250 mg/day given for longer durations (group 1), those who achieved cure on increasing dose to 250 mg BD (group 2) and those who did not respond to either and were then treated with itraconazole (group 3), the difference in mean MICs was statistically significant.

Terbinafine has a linear pharmacokinetic profile of up to 750 mg of daily dose, implying that an increase in dose to this level would increase plasma levels proportionately and thus likely stratum corneum levels as well.[34] This could be a reason for the response in group 2, wherein the MICs were about five times higher than in group 1 (5.039 μg/ml in group 2 versus 1.515 μg/ml in group 1). Furthermore, comparing with in vitro MICs, it was observed that the odds of achieving cure with terbinafine in patients harbouring strains with MIC <1 μg/ml were 2.5 times the odds of achieving cure when infected with a strain exhibiting MIC >1 μg/ml, thus suggesting an MIC-dependent, and drug dose-dependent, response, as has been observed with other fungi as well.[35],[36],[37] Pertinent to this is the later observation by Shaw et al.[38] highlighting the absence of SQLE mutations in T. indotineae isolates with MIC <1 μg/ml. An interesting observation, however, was that five patients harbouring isolates with mutated SQLE gene were also cured with longer durations of terbinafine 250 mg/day (n = 3) or with updosing to 250 mg BD (n = 2), thus documenting the possibility of increasing drug exposure and circumventing fungal resistance mechanisms to some extent.[34] Overall, about 70% of patients responded to either 250 mg OD dose (50% of cases, mean duration of treatment 5.6 weeks) or on shifting to 250 mgBD dose (a further 20% of cases, mean total treatment duration (OD + BD)—7.8 weeks).

Examining these results and other reports wherein clinical response and in vitro susceptibility testing have been reported, it has been suggested that therapeutic success may be achieved with the drug up to an MIC of 4–5 μg/ml.[26],[39],[40],[41] This value is lower than the mean MICs for terbinafine reported from different centres across the country over the past few years and in line with the recently reported upper limit of wild-type (UL–WT) MIC of 8 μg/ml for terbinafine in Indian strains.[14],[19],[34],[38],[42],[43],[44] It is interesting to note that of the nine isolates from patients who failed higher dose or longer durations of terbinafine, eight had terbinafine MICs of ≥32 μg/ml.[34]

Unfortunately, there have not been any further studies examining the treatment duration required to achieve a cure with standard or higher doses of terbinafine since. Other recent studies on the drug have used fixed-duration treatment protocols (2–6 weeks) and are summarised below. While analysing these, it is important to remember that both frontline drugs for dermatophytosis (terbinafine and itraconazole) now require prolonged treatment durations to cure the infection, and estimation of cure rate at shorter lengths of time may provide a falsely low estimate of the drug's efficacy.[34]

Bhatia et al.[45] (2019) compared terbinafine 500 mg/day (dosing frequency not mentioned) with itraconazole 200 mg/day (dosing frequency not mentioned), both given for four weeks. The authors did not comment on clinical cure or complete cure, but reported that at the end of week 4, 91.8% of patients in the itraconazole group and 74.3% of patients in the terbinafine group achieved mycological cure, although the statistical significance of the result was not mentioned. The authors mention that scaling, pruritus and erythema reduced significantly in both groups after 4 weeks, though, interestingly, there was no significant difference in percentage reduction in these parameters among the two groups at week 4. The study also mentions results as per global clinical response comprising healed, marked improvement, considerable residual lesions (>50%), no change or worse categories. After 2 weeks, 74% of patients had 'marked improvement' in the terbinafine group, compared with none in the itraconazole group. In the latter group, 58% showed 'considerable residual lesions' at this time point. At 4 weeks, 92% in the itraconazole group versus 74% in the terbinafine group were adjudged as 'healed'. In a later study conducted on patients with recurrent tinea corporis or cruris, Verma et al.[46] reported a cure rate of 42.5% after treatment with 4 weeks of terbinafine 250 mg BD. A recurrence rate of 65% was observed in a follow-up period of 3 months.

Singh et al.[47] used body weight-based dosing of terbinafine (5 mg/kg/day) and reported a cure rate of 30.6% at 4 weeks. It was, however, later pointed out that the cure rates reported were probably miscalculated as the authors mention that 153 of 362 patients achieved cure, which gives a cure rate of 42.3% rather than 30.6% as mentioned in the article.[48] Notably, considering the average body weight of the Indian population, the dose used by the author corresponds to approximately 325 mg/day for males and 275 mg/day for females, likely explaining the low cure rates observed. The authors did not mention the range of doses or mean dose used as per the body weight of included patients, to corroborate this aspect.[47] The same author group reported a cure rate of 28% at 8 weeks using 7.5 mg/kg/day of terbinafine and a cure rate of 33.3% at 8 weeks with terbinafine 250 mg BD, in subsequent publications.[49],[50] The details of doses used in individual patients were not provided in the former.[49],[51]

Safety of standard and higher doses of terbinafine

At a dose of 250 mg/day, terbinafine is well tolerated, with occasional reports of hepatotoxicity.[52] At a higher dose of 250 mg BD, the incidence of adverse effects is reported to be similar to that with a dose of 250 mg OD.[53] A further higher dose of 500 mg BD, however, demonstrated an increased incidence of adverse effects, as compared to a dose of 250 mg BD, in 63 patients with lymphocutaneous sporotrichosis treated for up to 6 months.[54] Importantly, terbinafine has much fewer clinically significant drug interactions than azoles, except for drugs metabolised by CYP2D6 of which it is a known inhibitor.[55]

Summary

The evidence presented suggests low cure rates with a standard dose of 250 mg once daily. Superior efficacy (cure rates up to 70%) is reported with a dose of 250 mg BD, with longer treatment durations being associated with higher cure rates. Thus, the drug remains an important component of the antifungal armamentarium of clinicians. The same has been endorsed by the guidelines released by the Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) and the treatment workflow suggested for tinea corporis or cruris by the Indian Council of Medical Research (ICMR).[56],[57] Owing to its high safety profile, much lower risk of drug interactions than azoles and the tendency of resistance potentiation with azole use, terbinafine offers many advantages over azoles and must be used to its maximum potential in the wake of rising treatment recalcitrance owing to the uprise of T. indotineae.[58]

   Azoles 

Mechanism of action

Azoles act on ergosterol biosynthesis at the C-14 demethylation stage. This is a three-step oxidative reaction catalysed by the cytochrome P-450 enzyme—14 α-lanosterol demethylase (P-450DM), encoded by the gene ERG11.[59] This blocks the ergosterol synthesis pathway and leads to the accumulation of 14-methylated sterols, thus making the plasma membrane vulnerable to further damage and altering activity of membrane-bound enzymes, importantly those involved in nutrient transport and chitin synthesis.[60] Severe ergosterol inhibition also affects the 'sparking' function of ergosterol required for cell growth and proliferation.[61],[62] Diversion of the accumulated sterols to an alternate pathway leads to the formation of another metabolite—dienol, which is also fungistatic. Reduction of obtusifolione to obtusifoliol is also impaired, resulting in further accumulation of methylated sterol precursors.[63] The triazoles exhibit significant differences in their affinity for the lanosterol 14α-demethylase enzyme, accounting for their varying antifungal potency and spectrum of activity.[64]

   Itraconazole 

Since the drug was introduced in the 1980s, itraconazole has demonstrated high efficacy in tinea corporis or cruris, although till recently terbinafine was the more preferred drug for the condition. The drug has a favourable skin pharmacokinetic profile and attains high levels in stratum corneum, although oral bioavailability of the pellet formulation is poor and shows high inter-individual variations.[65],[66],[67] Cross-inhibition of several human CYP-dependent enzymes (CYP3A4, CYP2C9 and CYP2C19) is responsible for most of the clinical side effects and drug–drug interactions of itraconazole and other azoles. While the molecular reasoning for altered clinical responses to itraconazole is not yet defined, a recent experiment on clinical isolates obtained from clinical failure (to itraconazole and terbinafine) cases reported efflux pump activation with concomitant mutations in Erg11, Erg3 and Erg4 genes.[68]

Clinical evidence: From past and in the current context

Past literature: The earliest studies on itraconazole demonstrated the superiority of a 100 mg/day dose over 50 mg/day.[69],[70] Degreef et al.[71] (1987) randomly assigned 91 patients of tinea corporis or cruris to receive either itraconazole 50 mg or 100 mg daily, which continued till one week after clinical cure. The authors reported treatment durations, for achieving a cure, to range from 7 to 108 days (mean 43.2 days). The mycological response was seen in 92% of patients in the 100 mg group, versus 85% in the 50 mg group. A similar mean treatment duration of about 6 weeks was reported by Hay et al.[72] (1990) and Nuijten et al.[73] (1987). The latter also reported a mycological cure rate of 89% with itraconazole 100 mg/day, similar to the observations of Degreef et al. A much shorter 2-week course of itraconazole 100 mg OD was subsequently shown to produce a high clinical response rate (88%) and mycological cure rate (82%), 3–4 weeks after discontinuation of treatment,[74] and was thus recommended for clinical use.

Later, studies were conducted to examine whether a further increase in dose to 200 mg/day (given as two 100 mg capsules given at the same time) would improve clinical outcomes further. Parent et al.[75] (1994) were the first to compare itraconazole 200 mg OD (given for 7 days) with 100 mg OD (given for 15 days) in patients with tinea corporis and cruris. Clinical response (defined as a complete cure or marked improvement) was achieved in 93% of patients in the 200 mg group and 96% in the 100 mg group at the end of treatment, while the corresponding values for mycological cure were 87% and 83%, respectively. Thus, both dosage regimens were shown to be similarly effective. Similarly, Boonk et al.[76] (1998) compared the efficacy and safety of itraconazole 100 mg/day for 2 weeks and 200 mg/day for 1 week in a randomised, double-blind, parallel-group trial and found similar clinical and mycological responses between the two groups. At 6 weeks of follow-up, the mycological cure was achieved in 70% of patients in the 100 mg group, compared with 60% in the 200 mg group. The corresponding figures for clinical response were 80% and 73%, respectively.

Current scenario

Since the emergence of T. indotineae, there have been concerns about inadequate clinical response to standard dosage regimens of itraconazole, leading to an empiric use of higher doses among clinicians, unsupported by the literature.[77] Alongside, it has also been proposed that the inherent issues of low and variable bioavailability of the drug, along with documented quality variations, may be possible contributory factors, leading to erratic clinical responses.[78],[80],[81],[82],[83]

Recent studies have clearly established that short, fixed-duration treatment schedules previously recommended are unlikely to be successful in a majority of patients and cure rates with short durations remain low.[45],[49],[50],[81][Table 1] However, considering T. indotineae's largely low MICs to itraconazole as yet, the drug is expected to affect a successful therapeutic outcome in infections caused by the organism.

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Exploring optimal treatment durations for itraconazole

Although our understanding of T. indotineae's virulence mechanisms, which often lead to erratic clinical responses even with a drug to which it is seemingly susceptible, is not yet well understood, it is evident that prolonged treatment durations are essential to obtain a positive therapeutic outcome with itraconazole as well. Khurana et al.[84] conducted a double-blind randomised controlled trial on 149 patients to compare cure rates, treatment durations, safety profile, cost-effectiveness and relapse rates with 100, 200 and 400 mg/day of itraconazole given to treatment naïve patients of tinea corporis or cruris. The cure was defined as complete clinical clearance along with negative KOH smear examination from multiple sites, while the absence of significant clinical improvement (<50%) by 8 weeks or appearance of new lesions or extension of original lesions anytime during treatment was considered as treatment failure. Patients were followed up for a minimum of 8 weeks beyond cure to detect relapses. The dose of 200 mg was given as two capsules of 100 mg at the same time, and 400 mg dose was given as two capsules of 100 mg twice a day. Of the 126 patients who completed the study protocol, 116 were cured and 10 were termed failures as per the definition above, thus giving an overall cure rate of 92%. The difference in cure rates between the 100 mg and 200 mg groups (82% versus 93.2%) was statistically insignificant, while the difference between the 400 mg group and the other two groups was statistically significant. Patients who ultimately achieved a cure had achieved 93.4% clinical clearance by 8 weeks, compared with 75% clearance in those who ultimately failed treatment. Treatment durations ranged from 2 to 20 weeks, with a mean duration of 6.63 weeks. The mean treatment durations were not significantly different in the 100 mg and 200 mg groups (7.7 weeks vs 7.2 weeks), while that in the 400 mg group was significantly shorter (5.2 weeks). Interestingly, neither the cure rates nor the treatment durations were significantly associated with the extent of disease, history of tinea in the past and previous antifungal or steroid use. The rapidity of response in terms of achieving 50% clinical clearance was similar between the three groups, while the time to achieve 90% clinical clearance was significantly different between groups (4 weeks, 3.67 weeks and 2.7 weeks, respectively, for 100, 200 and 400 mg groups), although here too the difference between 100 mg and 200 mg groups was non-significant. However, 47.4% of patients relapsed after successful treatment, and interestingly, the relapse rates were not significantly different within the three dose groups.

Considering the prolonged treatment durations, and the high relapse rates within all groups (implying that many patients would require re-treatment for relapses later), the cost to achieve a cure becomes an important concern. Importantly, to achieve the end point of cure, the cost of treatment increased by 63% in the 200 mg group and 120% in the 400 mg group, over and above the cost to cure with 100 mg dose.

A total of 63 patients reported an adverse event on treatment, and this was significantly different between groups. The most common of the 85 adverse events reported were acidity (in 8%, 10.2% and 14% of patients in the 100, 200 and 400 mg groups, respectively), abdominal discomfort or pain (in 2%/8.2%/10% among the three groups) and constipation (in 4%/4.1%/10% of the patients).

To conclude the study findings, itraconazole demonstrated high efficacy at all doses, similar to older literature on the drug as previously discussed, but with much longer durations of treatment. Furthermore, in line with older literature, doses of 100 mg/day and 200 mg/day doses did not differ significantly in terms of cure rates. The treatment durations were also similar between the two groups, while relapse rates were high across all three dose groups.

What is the effect of itraconazole serum levels on clinical outcome?

In a bid to analyse the impact of serum levels achieved with doses of 100 mg, 200 mg and 400 mg per day of itraconazole on the final therapeutic outcome (cure or failure), Khurana et al.[66] measured trough (pre-dose) serum levels (on day 14) in 21 patients of tinea corporis or cruris randomly assigned to one of the three dose groups (seven in each group) using liquid chromatography–mass spectrometry method. Patients were treated till cure or failure, with preset definitions for both. Only two of 21 patients failed treatment, while the other 19 achieved cure with durations of treatment ranging between 3 and 14 weeks (mean 7.6 weeks). Serum levels were not significantly different between the 100 mg and 200 mg groups, while significantly higher levels were observed in the 400 mg group. This is in concordance with similar cure rates observed with the two dose groups, as discussed in the section above. Both failures had serum levels <0.2 μg/ml (below the detection limit). Notably, eight other patients with serum levels <0.2 μg/ml also achieved a cure. There were two confirmed relapses in the post-treatment follow-up period, and two patients could not be contacted further after treatment discontinuation. Both relapses occurred in the 400 mg dose group, with serum levels of 1.04 and 1.57 μg/ml. Thus, while a target trough concentration of 0.25–0.5 μg/ml and 1 μg/ml is recommended for the prevention and treatment (respectively) of invasive systemic fungal infections, a lower level may suffice for dermatophytic skin infections, possibly owing to the concentration of the drug in stratum corneum, the site of infection and largely low MICs of T. indotineae to itraconazole.[85],[86] However, there was no correlation between drug serum levels with treatment durations required to achieve a cure or with the incidence of relapses, although the sample size was likely small to comment on these aspects (unpublished data).

There have been two additional studies since, wherein serum itraconazole levels were measured and correlated with treatment response. Handa et al.[87] analysed itraconazole serum levels in patients on 200 mg of itraconazole for 7 days. This dose was variably prescribed as either a single 200 mg capsule or two 100 mg capsules taken together. The first analysis was conducted after 7 days, and the second analysis was conducted after 14 days of treatment initiation. Notably, it requires 14 days of continuous dosing for steady-state serum concentrations of itraconazole to be achieved.[88] The authors did not find a significant difference in mean pre-dose serum levels with clinical 'response' at 7 days, while at 14 days, serum analysis was conducted only in 'responders'. Interestingly, all mean pre-dose values observed at day 7 (responders and non-responders groups) were <0.2 ug/ml, while at 14 days the mean pre-dose value in 'responders' was 0.356 ug/ml. The study does not provide any data on a cure achieved, and hence, the desired final outcome, and the impact of serum levels on the same, remains unclear. Various brands of the drug were used, which compromises uniformity and could have possibly impacted the results. Furthermore, a treatment period of 4 weeks may be too short to accurately predict treatment success or failure, as previously discussed. Interestingly, a recent study has reported that the serum levels achieved by itraconazole 200 mg OD (two capsules of 100 mg taken at the same time) are higher than levels achieved by 100 mg BD dosing of the same pellet-based formulation (even though the clinical response is likely similar).[89]

Bhalavi et al.[81] also recently reported on the lack of correlation between itraconazole plasma levels and treatment response, assessed at 4 weeks, in patients with chronic dermatophytosis. The clinical response was compared with two plasma level groups of more than and less than 0.5 μg/ml (the lower limit of detection of the assay used in the study), rather than mean or individual values. Interestingly, the authors found a significant difference in cure rates with 200 mg/day of innovator, multinational and local generic formulations (given for 4 weeks each) although not between plasma levels achieved in either group.

Thus, analysing the literature above suggests that a low serum level (upwards of 0.2 μg/ml) may suffice for achieving a cure with itraconazole in patients with tinea of the glabrous skin, but this factor does not provide an explanation for the prolonged treatment durations, or the high incidence of relapses post-cure.

Summary

Itraconazole is likely the most effective drug for T. indotineae infections currently although, akin to terbinafine, this also requires prolonged treatment durations and is associated with significant relapses post-cure. In contrast to short, fixed-duration treatment regimens used over the past decades, treatment till cure is now essential, and the use of itraconazole in this way results in high overall efficacy, comparable with past literature on the drug. Contrary to popular clinical belief, the therapeutic response with 100 mg and 200 mg of itraconazole does not appear to be significantly different as has been evidently highlighted in older and recent literature. Acceptable cure rates upward of 80% are achieved by both doses, in mean durations of about 7–8 weeks. The pill burden to the patient, treatment cost and adverse effects must all be borne in mind while deciding itraconazole's dose, accounting for both the long treatment durations and the high relapse rates, which would necessitate re-treatment in future.

Role of Superbioavailable (SUBA) itraconazole

SUBA formulation of itraconazole provides improved bioavailability due to the incorporation of the drug in a pH-dependent polymeric matrix, which targets drug release in the proximal small intestine, the primary site of itraconazole's absorption.[90] This contrasts with the pellet-based conventional formulation wherein the dissolution, and thus absorption of the incorporated drug, is largely restricted to the stomach. The formulation achieves more consistent serum levels with 21% less inter-patient variation.[91] SUBA itraconazole obviates the requirement of an acidic environment for dissolution and thus the need for avoidance of concomitant gastric acid-lowering agents and overcomes the high food variability seen with conventional itraconazole formulations[90] SUBA itraconazole has been shown to have a relative bioavailability of 173% compared with conventional itraconazole, implying that 58 mg of SUBA itraconazole (95% CI, 52.6 mg to 64 mg) would provide drug exposure equivalent to 100 mg of conventional itraconazole.[91] Thus, both the 50 mg and 65 mg SUBA formulations would provide drug exposure similar to 100 mg of conventional itraconazole.

A comparison of recently launched SUBA preparation of 130 mg, with conventional itraconazole in doses of 100 mg BD and 200 mg OD (given as two capsules of 100 mg at one time) and SUBA itraconazole 100 mg OD (given as two capsules of SUBA itraconazole 50 mg formulation), demonstrated the bioequivalence of SUBA itraconazole 130 mg, as well as SUBA itraconazole 100 mg, with conventional itraconazole 200 mg OD (100 mg × two capsules).[89] The mean serum values observed (at 4 weeks of continuous dosing) were 1.042 μg/ml with conventional itraconazole 100 mg BD, 1.423 μg/ml with conventional itraconazole 200 mg OD, 1.534 μg/ml with SUBA itraconazole 130 mg OD and 1.107 μg/ml with SUBA itraconazole 100 mg OD, with a significant difference between the first (100 mg BD) and the latter three groups (conventional itraconazole 200 mg OD, SUBA itraconazole 130 mg and SUBA itraconazole 100 mg). The bioequivalence of SUBA 130 and 100 mg formulations with conventional itraconazole 200 mg OD was thus established. The serum values reported refer to the mean value of samples taken—before dosing (trough levels) and after 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after dosing. Serum trough levels are not separately mentioned in the report. The authors also compared cure rates achieved at 4 weeks and found no statistically significant difference among the four groups.[89]

Summary

As the drug in consideration remains the same, the choice between conventional and SUBA formulations is based on the pharmacokinetic profile of the two as detailed above. The expected clinical response to a SUBA formulation is logically similar to that expected with an equivalent dose of conventional itraconazole. A rationale for its use is the variation in the manufacturing process of itraconazole pellet formulations, which is (plausibly) obviated by the SUBA formulation, apart from the lower inter-individual variation in serum levels achieved by SUBA itraconazole and the lesser food effect.[80] As very low serum trough levels (see above) have been shown to suffice to achieve a cure in tinea corporis or cruris, using higher-dose formulations is unlikely to offer any added benefit.

   Voriconazole 

While there are occasional reports of both successful use[92],[93] and failure[94] of voriconazole in the treatment of tinea corporis or cruris, the drug must be sparingly used, if at all, as it is an important drug for life-threatening invasive mycoses.[95] Also, some recent studies have demonstrated voriconazole to have seemingly similar efficacy as other systemic antifungals discussed above, although methodological flaws within these cannot be ignored and better-designed studies are needed.

Chandrashekar et al.[96] used voriconazole (800 mg on day one followed by 200 mg BD for 2 weeks), along with varied topical (azole) antifungals (details not mentioned), and reported that 90% of patients had 'clearance' at 2 weeks, but the figure dropped to 75% at 6-week follow-up. The mycological cure was not documented. The six-week follow-up was based on telephonic contact in 15 of 40 patients. Notably, lower doses have been used in other reports.[92],[93] Khattab et al.[97] reported clinical cure in 83.3% and mycological cure in 86.7% of patients treated with voriconazole for 6 weeks. Another author group used 200 mg BD of voriconazole for 12 weeks and reported 88% 'full cures' and 12% 'partial cures', while the mycological cure was not commented upon.[98] Shahzad et al.[99] similarly reported voriconazole to have only 71% and 58% efficacy in the treatment of relapsing and 'resistant' cases of dermatophytosis, respectively.

Summary

Voriconazole's skin pharmacokinetics is not well understood, and its optimum dosimetry and safety profile for use in dermatophytic infections have not been established. Also, its pharmacokinetics displays high inter- and intraindividual variability, and the drug has a narrow therapeutic range.[92],[100] Voriconazole has a nonlinear pharmacokinetics, and there are known polymorphisms of its metabolising enzymes that risk toxicity or therapeutic failure.[101] Furthermore, the drug is prohibitively expensive, and large-scale use in a common condition risks resistance promotion. Finally, the drug's efficacy in the treatment of tinea corporis or cruris does not seem to be very impressive, based on the limited current literature. Further trials with robust methodology are required to form a definite opinion on the utility of this drug for dermatophytosis.

Fluconazole

Fluconazole was initially used in dermatophytic skin infections in a daily dose of 50 mg/day, although later a weekly dose of 150 mg was reported to be effective.[102],[103] However, the drug has a short stratum corneum elimination life of 60–90 hours and a low keratin binding avidity, implying the absence of a reservoir effect and a rapid loss of effect after treatment discontinuation.[104] Thus, adequate levels may not persist at the infection site with weekly dosing. There have been reports on clinical unresponsiveness to weekly fluconazole in the past, and most recent literature (including on T. indotineae) reports high in vitro MICs for the drug.[13],[14],[19],[34],[105] A recent study reported a cure rate of 42% at 8 weeks of treatment with 5 mg/kg of fluconazole given daily.[49]

Summary

Based on the past literature on fluconazole skin levels, a daily dose of the drug may be able to achieve stratum corneum levels to match the MICs of the prevalent species.[106] However, there is only sparse literature on such use of the drug in recent times, and the high MIC levels, with a lack of longevity of response due to poor keratin adherence, make it a poor choice for treatment in the current scenario.[104]

   Ketoconazole 

The literature on the use of this drug for tinea corporis or cruris is sparse. The earliest studies on ketoconazole demonstrated its superiority over griseofulvin.[107] The drug offered higher keratin adherence and shorter treatment durations as advantages over griseofulvin, the only other antifungal of utility in dermatophytosis at those times.[107] Robertson et al.[107] (1982) reported complete clearing of skin lesions within 30–97 days of ketoconazole (200–400 mg/day) in patients who had previously failed griseofulvin (2.5 g/day taken for at least 6 weeks). Among griseofulvin-naïve patients, most had 'clearing or marked improvement' by 10 weeks. Cox et al.[108] reported a cure rate of 63%, using a dose of 200–400 mg/day for a mean of 10 weeks. In another study on 454 patients with dermatophytic or yeast infections, 61% achieved clinical cure.[109] The authors mention that most patients had 'responded' within 8 weeks, with the median time to 'response' being 4 weeks. The drug was later withdrawn in some countries, and strict restrictions were put in place in some others in view of its hepatotoxic potential.[110]

There has been only one study on the drug since the emergence of T. indotineae. Arora et al. (2021)[111] reported a cure rate of 67.4% with a dose of 400 mg/day used for a mean duration of 9.4 weeks. Two patients developed (2–5 times of baseline) an increase in liver enzymes on treatment, while 37.9% of patients relapsed within a mean duration of 31.3 days.

Summary

The drug has retained its (moderate) efficacy over time. Treatment durations have been long as per older and recent literature. Although arguments have been raised against the ban imposed by some drug regulatory authorities on ketoconazole, the drug does not offer any advantage, either in terms of efficacy, treatment durations or relapse rates, over terbinafine and itraconazole, to warrant its wider use.

   Griseofulvin 

The drug requires prolonged treatment durations owing to the mechanism of action (i.e. inhibition of microtubule aggregation), which necessitates a long time to render dermatophytes non-viable due to their slow growth characteristics. Griseofulvin's low adherence to keratin and a 'washout' effect with sweating make its pharmacokinetics unfavourable for the treatment of dermatophytic infections.[104]

The data over the past decades, across countries, document high MICs for the drug. A recent Indian study found griseofulvin to be the 'most inactive' drug (in vitro) with a modal MIC of 32 μg/ml.[19],[112],[113],[114] An MIC of ≥3.0 μg/mL was previously proposed as indicative of relative griseofulvin resistance.[115] The low efficacy of the drug for tinea corporis or cruris has been documented previously. A comprehensive literature summary published in 1965 observed a cure rate of 64.8% for the treatment of tinea of the glabrous skin with griseofulvin.[116] Artis et al.[115] (1981) compared clinical outcomes in 43 patients prescribed griseofulvin (250 mg twice daily), with some being on the drug for years, and observed that 13 of 16 patients with tinea corporis failed treatment (failure defined as no substantial improvement after at least four months of treatment). In a review of all published trials, Lachapelle et al.[117] (1992) later documented a mycological cure rate of 67% in non-fixed-duration studies on griseofulvin and a clinical and mycological cure rate of 69% and 65%, respectively, in fixed-duration studies with the drug.

Since the advent of T. indotineae, there is only sparse literature on the drug but that too shows low efficacy.[7] A recent study noted a 14% cure rate at 8 weeks of treatment with 10 mg/kg of the drug.[49]

Summary

Griseofulvin requires prolonged treatment duration to clear dermatophytic infections. Cure rates with the drug have been low for decades and seem to have lowered further in recent times.

   Combination of Systemic Antifungals 

An assumption that the use of two or more effective drugs with different mechanisms of action will produce an improved outcome compared with the use of a single agent alone that is simplistic and unscientific and would likely result in drug interactions, added side effects and an increase in the overall cost of treatment.[118] With reducing efficacy of previously effective systemic antifungals, however, such combinations have been suggested and used without an evidence backing.[119],[120] However, to demonstrate and validate synergistic antifungal drug combinations, three sequential steps are essential, that is1) in vitro checkerboard testing or time-kill curve technique to look for possibly synergistic combinations, 2) in vivo animal model validation and 3) testing of the combination therapy in well-designed clinical trials as the final step to prove or disprove its utility.[51]

A recent paper from India examined the effect of various antifungal combinations on clinical isolates obtained from patients with tinea corporis or cruris who had no or minimal improvement after receiving 4 to 6 weeks of oral antifungals (itraconazole, terbinafine, fluconazole or ketoconazole) in approved or higher doses.[118] Four isolates with SQLE gene mutation and high MICs to terbinafine, and one wild-type strain, were evaluated further, and an in vitro synergistic effect was noted with combinations of itraconazole with luliconazole, terbinafine or ketoconazole.

It is important to remember that in vitro synergy may not convert to a similar in vivo effect, and only a few combinations showing in vitro synergy have shown higher efficacy than monotherapy in clinical trials on invasive mycoses.[121] Furthermore, strain-to-strain variations may occur warranting in vitro MIC data on larger sets of distinct isolates. These data can, however, be used to design feasible, appropriate and powerful clinical trials. It is surprising that although topical antifungals are routinely co-prescribed with systemic antifungals in the treatment of tinea corporis or cruris, no large-scale study has yet demonstrated the efficacy or superiority of the combination treatment (oral with topical antifungal) compared with systemic antifungal used alone. This contrasts with onychomycosis where combinations of topical and systemic antifungals have demonstrated greater efficacy than oral antifungal alone.[122],[123] Demonstrating the superiority (if any) of a combination of systemic and topical antifungal over an effective systemic antifungal alone, in the treatment of tinea of the glabrous skin, would require large numbers as any difference (if at all) is likely to be small.

Two recent studies examined the effect of systemic antifungal combinations in tinea corporis or cruris. Sharma et al.[124] compared terbinafine 250 mg OD and itraconazole 200 mg OD, with a combination of these two, and reported that at 3 weeks of treatment, more patients in the combination group had 'grade 4 improvement' (90% in the combination group versus 50% in the itraconazole group and 35% in the terbinafine group). The results on endpoints are, however, variably reported with 'grade 4 improvement' and 'cure' used interchangeably, although methodology describes the two terminologies differently. Interestingly, the 'cure rates or grade 4 improvement' reported for monotherapy are much higher than the cure rates reported at similar time points by other authors in recent studies [Table 1].

Another author group examined the efficacy of a combination of itraconazole 200 mg OD and terbinafine 250mg/day, with four other groups—terbinafine 250 mg OD, terbinafine 250 mg BD, itraconazole 100 mg BD and itraconazole 200 mg BD.[50] The authors reported the absence of a significant difference in cure rates between the combination group and itraconazole 200 mg and 400 mg groups, at both 4 weeks and 8 weeks of treatment. The cure rates in the combination group at these time points were 18.9% and 79.2% (at 4 weeks and 8 weeks, respectively), while those in itraconazole 200 mg and 400 mg groups were 17% and 76.6% and 19.6% and 80.4%, respectively. All itraconazole-containing groups demonstrated higher efficacy than the terbinafine groups at 4 and 8 weeks (cure rates of 23.4% and 33.3% cures with terbinafine 250 mg OD and BD, respectively, at 8 weeks). The lack of significant difference between the 200 mg and 400 mg groups contrasts with the study by Khurana et al.[84] where itraconazole 400 mg group showed significantly higher (final) cure rates than the 200 mg group. However, in this study too, the difference between 200 mg and 400 mg groups was not significant till week 8 of treatment, the time point of comparison used by Singh et al. (unpublished data).

Summary

Analysing existing literature, the combination of two systemic antifungals (itraconazole and terbinafine) does not seem to provide any advantage over itraconazole monotherapy, for the treatment of tinea corporis or cruris. Clinical studies comparing different systemic–topical antifungal combinations, based on the results of in vitro checkerboard interactions, are urgently needed to derive the maximum benefit out of the limited basket of drugs against dermatophytes.

   Use of Non-antifungal Drugs to Enhance the Action of Antifungal Drugs