Etiological prevalence and antifungal sensitivity patterns of dermatophytosis in India – A multicentric study

Plain Language Summary

Dermatophytosis is a prevalent problem in the Indian scenario due to the hot and humid climate. The various antifungal agents currently available for treatment are terbinafine, itraconazole, fluconazole, luliconazole, etc. This study was conducted to assess dermatophytes’ prevalence, clinical types of dermatophyte fungal infection, and in vitro antifungal drug susceptibility against dermatophytes. A total of 395 patients with dermatophytosis were enrolled from five cities across India. All patients were subjected to clinical examination and investigations. The results indicated that T. rubrum was the most common in India, followed by T. mentagrophytes. Tinea corporis was the most common clinical type of dermatophytosis. The mean minimum inhibitory concentration (MIC) of terbinafine was above the reference range, while it was within the range for itraconazole; griseofulvin had the lowest mean MIC. Luliconazole presented the lowest mean MIC values across different regions, particularly Delhi and Kolkata. Data from this study will help clinicians to choose a suitable antifungal agent during treatment.

Introduction

Dermatophytosis continues to be the most common cause of superficial fungal infection worldwide.^1,2 Reports indicate that the epidemiology of dermatophytes varies among countries and even within different regions in the country.² It is more prevalent in developing, particularly in tropical and subtropical countries like India, evidently due to the hot and humid climatic conditions.³ In addition to climatic factors, geographic location, health-care system, overcrowding, urbanization, population migration, environmental and personal hygiene culture, the prevalence of virulent species, socioeconomic conditions, individual immune system, etc., may also affect the epidemiology and incidence of dermatophyte infections.^3,4

The various antifungal agents currently available in clinical use against dermatophytes are terbinafine, itraconazole, fluconazole, luliconazole, etc. Even though antifungal agents’ inappropriate use may result in resistant strains, their activity against dermatophytes has not yet been fully explored. The research outlining the antifungal susceptibility of common dermatophyte species in India is inadequate, posing a therapeutic challenge to practitioners.⁵ Furthermore, despite the high incidence and clinical relevance, multicentric evidence depicting the present-day clinico-epidemiological patterns of dermatophytosis across India is scarce. The magnitude of the concern thus demands studies across different geographic locations within India to increase the generalizability of the data.

Hence, considering the nature of region-wise species variability and the recent rise in antifungal therapeutic failure observed clinically, in this multicentric study, we assessed the etiological prevalence of pathogenic dermatophytes, clinical types of dermatophyte fungal infections, and in vitro antifungal drug susceptibility testing against dermatophytes to understand the variation in minimum inhibitory concentrations (MICs) levels of antifungals among dermatophytes.

Methods

In this cross-sectional, multicentric study, patients were enrolled from five different cities (Mumbai, Delhi, Kolkata, Lucknow and Hyderabad) across 13 centers in India between July 2018 and January 2019. The Royal Pune Independent Ethics Committee approved the study. All patients with dermatophyte infections visiting the outpatient department during this period were screened. A total of 395 consecutive patients aged between 18 and 65 years (~30 from each center), clinically suspected with dermatophyte skin infection (excluding infection at the sites of nails, palms, soles and scalp) with recurrent cases of tinea and other atypical presentations, receiving antifungal treatment, and willing to have minimum three days washout period before antifungal drug susceptibility testing of the clinical specimen (fungal isolate), were recruited. Patients with a non-mycotic pathology in the area of fungal infection or any condition that, in the investigator’s opinion, does not justify the patient’s inclusion in the study were excluded from the study.

All patients provided written consent in the patient authorization form to participate in the study. A detailed history was obtained from all patients, who were then subjected to clinical examinations and investigations, including a wet preparation for direct microscopic examination, fungal culture and antifungal susceptibility tests.

Results

Male preponderance was observed (63.8%) among 395 cases studied. The mean age of the study population was 36.6 ± 13.76 years. Most patients were in the 18–30 years group (n = 165), followed by 31 to 40 years (n = 87), > 50 years (n = 76) and 41 to 50 years (n = 67). About 91.6% of patients had previous episodes of dermatophyte infection. A family history of skin diseases was reported in 82 (20.8%) patients, of which only 50 (12.7%) were on treatment.

Clinical types

Tinea corporis was the most common presentation (282 [71.4%]), followed by tinea cruris (245 [62.0%]), tinea pedis (35 [8.9%]) and tinea capitis (25 [6.3%]) [Figure 1]. Infected sites for > 5% of patients were groin (51 [12.9%]), abdomen (28 [7.1%]) and buttock and groin (20 [5.1%]).

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Figure 1:

Clinical presentation (n = 395)

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Region-wise antifungal drug susceptibility

Antifungal susceptibility was tested across India’s five different cities (Mumbai, Kolkata, Delhi, Lucknow and Hyderabad) [Figure 2]. Griseofulvin had the lowest MIC values across regions (0.19 [0.082] μg/mL). Among the topical antifungals, luliconazole showed the lowest mean MIC values across India’s different regions, particularly Delhi and Kolkata. Amorolfine also showed the least mean MIC values in Kolkata and Delhi. None of the patients from Hyderabad reported high MIC for terbinafine. The percentage of patients with high MIC for terbinafine was significantly higher from coastal areas (Mumbai and Kolkata) versus noncoastal [P = 0.0017].

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Figure 2:

Region-wise mean minimum inhibitory concentration values

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Although the MIC of itraconazole was within the range, the upper side of a higher limit was found in the majority of the patients from Hyderabad (77.3%), and lowest from Mumbai (61.3%). T. rubrum and T. mentagrophytes were the commonly reported organisms across all five regions of India. Within species, T. mentagrophytes was predominant in Mumbai and Kolkata compared to other cities (Delhi, Lucknow and Hyderabad).

Discussion

Considering the widespread prevalence of various cutaneous mycoses in a tropical country like India, primarily due to its hot and humid climate, it is essential to understand the patterns of etiology and clinical presentations. Furthermore, numerous antifungal-resistant strains causing superficial mycoses have emerged over the recent past which may be attributed to many years of underuse, overuse and misuse of antifungal medication.^13,14 Hence, the development of an expound antifungal profile may help control the transmission of the infection, in turn, the impact of resistant fungal strains in the near future. The present, one of its kind multicentric studies was intended to understand the clinical manifestations of dermatophytosis, dermatophyte species distribution and their susceptibility patterns in different regions across India.

Most enrolled patients were in the age group of 18–30 years, followed by 31–40 years which agrees with India’s reported literature on dermatophytosis-centric studies.^15-18 In concordance with the previous studies, male preponderance was noted.^17,19 The higher incidence in young males could be attributed to their increased physical activity, predisposing them to increased sweating. The lower incidence among females seen in this study could be attributed to their hesitation to consult physicians and the financial dependence on males.

Tinea corporis (72%) and tinea cruris (62%) were the most commonly reported clinical presentations. This observation is supported by the studies of Hanumanthappa et al.²⁰ Sharma et al.¹⁷, Agarwal et al.²¹ and others;^22,23 however, variation in clinical manifestation is also reported in the literature.^16,24 Low prevalence of tinea unguim reported in this study could be due to the fact that scrapping was not taken from the nail, resulting in less reporting of tinea unguim. Further, an increase in the prevalence of tinea facie was noted in this study compared to the recent past,^22,24,25 which could be ascribed to the activities such as using common towels for the bath by all family members. Tinea infections indeed lead to personal discomfort, and antifungal treatment regimens can last for a reasonably long duration (3–6 months).²⁶ To prevent the unnecessary usage of toxic drugs, regular surveillance of antifungal susceptibility patterns in patients should be carried out in their long-term interest.²⁷

In this study, the commonly reported clinical features were itching, scaling, dryness, inflammation, a lesion with central clearing surrounded by an advancing, red, scaly, elevated border (ringworm lesions) and erythema, as reported by Gupta et al.²⁸ Furthermore, in accordance with the earlier study, infected sites for more than 5% of patients were groin, abdomen and buttock and groin.²⁸

The literature indicates that the KOH positivity rate varies between 35.6% and 88.6%, and the rate of culture positivity between 36% and 53.6% which was confirmed in our case.^15,19,29,30 Shenoy et al. in 2008 showed positive results in 53% of cases by microscopy and 35% cases by culture.³¹ In another study in North India, KOH mount and culture showed positive results in 53.5% and 61.2% of patients.³² In our study, the KOH positivity rate was 88.4%, and the culture positivity rate was 44.1%. The inter-laboratory difference in the techniques of sampling and KOH examinations might account for the difference in microscopic and culture findings, making it essential that all the KOH negative samples should be cultured.

Trichophyton species have been a principal causative agent of dermatophytosis than the other two genera, Microsporum and Epidermophyton. In our study also, among dermatophytes, the genus Trichophyton represented the majority of the isolates of dermatophytes. T. rubrum was the most predominant fungal isolate (68.4%), as reported by other studies from India, followed by T. mentagrophytes (29.3%).^33-35 This highlights the emergence of T. mentagrophytes as a codominant fungal isolate. Recent studies from India have also reported the emergence of T. mentagrophytes as the dominant^36-38 or codominant fungal isolate.^33-35 In our study, within species, T. mentagrophytes was predominant in coastal cities such as Mumbai and Kolkata compared to noncoastal cities (Delhi, Lucknow and Hyderabad). A similar study from India also reported a higher prevalence of T. mentagrophytes from the coastal area.³⁹ This could be attributed to the humid climate in the coastal cities which has been indicated as an essential component for T. mentagrophytes.⁴⁰ Apart from humidity, other factors such as temperature, trauma and internal factors such as host-parasite relationships, host susceptibility and immunological factors are also indicated as probable reasons for this recent shift in prevalence.^36,40,41 Further, within species, the prevalence of T. rubrum was significantly higher in patients with less than 50 years of age, while the prevalence of T. mentagrophytes was higher in patients with more than 50 years of age.

Out of seven antifungal agents tested in this study, high MIC values were reported only for terbinafine. High MIC for terbinafine was reported only in 20 (11.5%) patients out of 174. The overall mean high MIC value reported for terbinafine could be attributed to high individual patients’ data of these 20 patients. Higher MIC values were noted in both T. mentagrophytes (0.256 μg/ml) and T. rubrum (0.256 μg/ml), suggesting the virulent nature of T. mentagrophytes and T. rubrum. Furthermore, 88.5% of patients had MIC within range for terbinafine. Hence, the clinician must consider the plausible reasons such as virulence potential of the infecting species, clinical type of dermatophytosis and external factors such as heat, humidity, sweating, type of clothing and the pharmacological factors such as the quality of the drug, compliance, pharmacokinetics and absorption of the drug to understand the recalcitrant infection better.⁴²

The region-wise comparison indicated that none of the patients from Hyderabad reported high MIC value for terbinafine. The majority of the patients with high MIC with terbinafine were from coastal areas (Mumbai and Kolkata). This has been confirmed by other studies, including from different locations.^43-45

Among all antifungal agents, griseofulvin reported the lowest mean MIC value. This is an encouraging trend considering the recently reported increasing clinical resistance cases to oral antifungal among Indian patients. Vardai Pai et al. had also reported lower MIC of systemic griseofulvin and topical amorolfine than fluconazole.⁴⁶

All 174 (100%) patients were susceptible to griseofulvin, itraconazole, luliconazole, sertaconazole, amorolfine and eberconazole. In our study, the mean MIC of griseofulvin (range 0.25–1 μg/mL) for Delhi and Kolkata was 0.120 μg/mL, for Mumbai μg/mL and Lucknow, it was 0.240 μg/mL and for Hyderabad, it was 0.180 μg/mL. Further, newer oral drugs like itraconazole did not report high MIC in any patient. All the causative agents reported in our study were found to be susceptible to itraconazole. The median MIC (μg/ml) of itraconazole (range 0.05–1 μg/mL) for all 174 patients was 1.0 μg/ml. However, though the MIC of itraconazole was within the range, the upper side of the higher limit was found in the majority of patients from Hyderabad (77.3%). A similar trend was noted in other regions as well. This indicates the need to optimize the use of itraconazole, emphasizing on the right dose and duration of treatment, considering the present effectiveness of oral itraconazole in our routine clinical practice. Moreover, this is the last drug in the current armamentarium, and hence rational use of itraconazole is the need of the hour.

Among topical antifungals, luliconazole showed an encouraging trend in terms of lowest mean MIC values in different regions from India, Delhi and Kolkata. Similarly, sertaconazole reported the lowest mean MIC values in Hyderabad as compared to other areas. For amorolfine, the lowest mean values were reported for Kolkata, followed by Delhi and Mumbai.

These data indicate a variation in the susceptibility of fungal isolates from different regions of India which demands the need for fungal culture and antifungal susceptibility tests to identify the causative fungi and chose the effective antifungal treatment in the early stages of infection. However, clinically successful treatment does not always correlate with the MIC value of antifungals which may be illustrated by the “90–60 rule,” which states that infections due to susceptible strains respond to appropriate therapy in 90% of cases. In contrast, infections due to resistant strains respond in approximately 60% of patients.²

Conclusion

Dermatophytosis is a prevalent problem in the Indian scenario due to the hot and humid climate and low socio-economic status. Varied etiological agents, along with regional variations, make the management of this common cutaneous condition challenging. T. rubrum was found to be the most common, and T. mentagrophytes the emerging/codominant fungal isolate in India. Tinea corporis was the most common clinical type of dermatophytosis. Mean MIC value of terbinafine was above the reference range, while it was within the range for itraconazole; griseofulvin had the lowest mean MIC. Luliconazole presented the lowest mean MIC values across different regions, particularly Delhi and Kolkata. The data generated from this study will enable clinicians to select an appropriate antifungal agent, optimizing existing oral and topical antifungal agents used in different regions of India. However, further studies on larger samples are warranted to correlate the MIC values with clinical outcomes to define the MIC breakpoints which will help adapt to therapeutic choices with high chances of success.