An open label, single arm, pilot study to evaluate the safety, tolerability, and efficacy of daily fluconazole 150 mg in subjects suffering from Tinea cruris and Tinea corporis

Dattatray Gopal Saple; Sushrut Save; Devesh Kumar; Suneet Sood

doi:10.12688/f1000research.127138.2

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Research Article

Revised

An open label, single arm, pilot study to evaluate the safety, tolerability, and efficacy of daily fluconazole 150 mg in subjects suffering from Tinea cruris and Tinea corporis

[version 2; peer review: 3 approved with reservations, 2 not approved]

Dattatray Gopal Saple¹, Sushrut Save¹, Devesh Kumar², Suneet Sood ³

PUBLISHED 06 Dec 2024

Author details Author details

¹ La’Mer Clinic, Mumbai, Maharashtra, 400014, India
² Innovate Research, Noida, Uttar Pradesh, 201301, India
³ Department of Surgery, School of Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, 57000, Malaysia

Dattatray Gopal Saple
Roles: Conceptualization, Investigation, Methodology, Writing – Review & Editing

Sushrut Save
Roles: Data Curation, Investigation, Writing – Review & Editing

Devesh Kumar
Roles: Conceptualization, Funding Acquisition, Project Administration, Writing – Review & Editing

Suneet Sood
Roles: Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Pathogens gateway.

Abstract

Background

Dermatophytes are the most common superficial fungal infections worldwide and are treated with prescribed regimens of terbinafine and itraconazole, or with weekly doses of fluconazole. Dermatologists are increasingly encountering treatment failures, and experts suggest that standard treatment regimens are not applicable anymore. We planned an open-label study to evaluate the results of fluconazole 150 mg daily for 8 weeks in patients with tinea cruris and tinea corporis.

Methods

Patients were enrolled from the La’Mer Clinic, Mumbai, India. We included adult subjects with uncomplicated dermatophytosis confirmed by microscopic examination of skin scrapings. Pregnancy, poor renal function, and recent exposure to anti-fungal therapy were exclusion criteria. Patients were reviewed on days 14, 28 and 56. The treating doctor scored the severity of erythema, scaling, and pruritus on a four-point scale: absent, mild, moderate, and severe. Of 107 subjects screened, 100 were finally included in the study. Eleven were lost to follow up and one subject withdrew consent.

Results

The site of disease was body alone in 29, groin alone in 7, and both body and groin in 64 cases. At 5 weeks, 98%, 100%, and 97% of patients had no scaling, erythema, and pruritus, respectively. Skin scrapings showed 100% mycological cure. In one patient the alanine transaminase level rose from 54.9 to 100.2 U/L, and qualified as a grade 1 adverse event not requiring intervention. No other significant adverse events were noted.

Conclusions

Our results suggest that fluconazole 150 mg daily for eight weeks effectively treats dermatophytosis. This regimen is safe and well-tolerated even in patients with co-morbidities. Fluconazole is about eight times less expensive than itraconazole or terbinafine and may be the preferred therapy.

Registration

The trial was registered with Clinical Trials Registry, India (Registration number CTRI/2020/06/026110) on 24 June 2020. FDC Company, India, provided financial support for the study.

Keywords

Dermatophytes, skin infections, fungal infections, Tinea capitis, antifungal agents, itraconazole, terbinafine, tropical diseases, erythema, scaling, pruritus

Corresponding author: Suneet Sood

Competing interests: FDC Company provided financial support for the medicines and laboratory tests. S Sood is a consultant for Innovate Research, the contract research organization that assisted DGS in the drug trial.

Grant information: This work was funded by FDC Company, India.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2024 Saple DG et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Saple DG, Save S, Kumar D and Sood S. An open label, single arm, pilot study to evaluate the safety, tolerability, and efficacy of daily fluconazole 150 mg in subjects suffering from Tinea cruris and Tinea corporis [version 2; peer review: 3 approved with reservations, 2 not approved]. F1000Research 2024, 11:1446 (https://doi.org/10.12688/f1000research.127138.2) First published: 07 Dec 2022, 11:1446 (https://doi.org/10.12688/f1000research.127138.1) Latest published: 06 Dec 2024, 11:1446 (https://doi.org/10.12688/f1000research.127138.2)

Revised Amendments from Version 1

From the Conclusions, we have removed the line which states that fluconazole should be preferred first-line therapy.

See the authors' detailed response to the review by Kabir Sardana
See the authors' detailed response to the review by Clara Gómez and Enrique Alberdi

Introduction

Dermatophytes are the commonest superficial fungal infections worldwide. They include three genera of fungi: Trichophyton, Epidermophyton, and Microsporum.¹ Treatment of localized lesions involves the use of topical antifungals such as luliconazole, sertaconazole, clotrimazole, terbinafine and others, or oral agents such as itraconazole, terbinafine, and griseofulvin.² Oral agents effective against dermatophytes include the azoles (e.g., itraconazole, fluconazole) and the allylamines (terbinafine). The azoles act at the fungal P-450 pathway to prevent the formation of ergosterol, an important biomembrane lipid.³

However, practicing dermatologists are increasingly encountering treatment failures, and reports of recalcitrant dermatophytosis have begun to appear in the literature. Yamada et al.,⁴ showed in 2017 that as many as 17% of Trichophyton strains showed reduced susceptibility to terbinafine. Monod and Mehul⁵ reviewed the literature to show that mutant strains of Trichophyton were responsible for this decreased sensitivity. Poojary et al.,⁶ noted a sudden unexplained surge of difficult-to-treat dermatophytosis in India, and experts gradually have come to suggest that standard treatment regimens are probably not applicable anymore.⁷^,⁸

Fluconazole has traditionally not been used routinely in the treatment of dermatophytosis.¹^,⁷ There are increasing reports of inadequate response to therapy, relapses, recurrence and resistance to available antifungal drugs like terbinafine, itraconazole and griseofulvin. We therefore planned a study to determine the results of fluconazole therapy in cases of dermatophytosis. Using fluconazole 150 mg daily for 8 weeks, we evaluated clinical parameters and mycological cure rates in patients with tinea cruris and tinea corporis.

Methods

Ethics

Written informed consent was taken from subjects prior to their inclusion in the study. This study was approved by the Vision Independent Ethics Committee, Mumbai (independent Government-approved Ethics Committee), per its letter dated 13 June 2020. The study was registered with the Clinical Trials Registry – India on 24 June 2020 (registration number CTRI/2020/06/026110).

Study design

This research was a prospective, open label, single-center, non-comparative study.

Study population

We enrolled 100 patients with dermatophytosis (tinea cruris and tinea corporis) visiting the outpatient department of La’Mer Clinic, Mumbai, considering this number to be adequate for a pilot study. All the subjects were enrolled after they gave written informed consent. The first patient was enrolled on 22 July 2020 and the last subject was enrolled on 24 August 2021.

Inclusion and exclusion criteria

We included subjects with dermatophytosis confirmed by fungal hyphae in a 10% potassium hydroxide (KOH) preparation of skin scraping. Subjects were aged 18 to 65 years old.

We excluded patients with secondarily infected or eczematized lesions, and those who had received any type of oral or topical anti-fungal therapy within 14 days prior to baseline visit. We also excluded patients who were immunosuppressed, had a creatinine clearance < 30 ml/minute, patients who were pregnant or lactating, and those with any severe medical comorbidity. Diabetes was not an exclusion criterion unless it was uncontrolled.

Intervention

All patients were administered fluconazole 150 mg daily for 8 weeks.

Measurements

In the screening visit (“Visit 1”, day -4 to day 1) patients were examined and baseline full blood counts, renal function tests, liver function tests and urine physical, chemical and microscopy studies were carried out. Urine pregnancy tests were conducted in female patients. Fluconazole therapy was started in eligible subjects on the day of enrolment (“Visit 2”). They were then reviewed clinically and microbiologically on days 14 ± 2, 28 ± 2, and 56 ± 2 (“Visit 3”, “Visit 4”, and “Visit 5”).

Clinical review consisted of a subjective evaluation of three parameters: erythema, scaling, and pruritis. The treating doctor (GDS) scored the severity of each parameter on a four-point scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe.

Mycological review consisted of examination of a 10% KOH preparation of a skin scraping under direct microscopy. The result of the examination was reported as absent or present for fungal hyphae. Fungal culture was not carried out.

Patients received an investigational product compliance diary card on which they were advised to record medication intake and adverse events. The treating doctor (GDS) reviewed diary entries at every visit.

On the final visit (day 56), the treating doctor also carried out a urine analysis and blood examination for full blood count, renal function tests and liver function tests.

Alterations of aminotransferase levels were graded according to the criteria described by the US Department Of Health And Human Services per their 2017 document.⁹

Data analysis

The data were analyzed by simple mathematical calculation of response rates.

Results

Demographics

100 subjects were finally included in the study ( Figure 1). The mean age was 40 years old (SD 11.6). A total of 46 of the 107 subjects were female.

Figure 1. CONSORT 2010 flow diagram of study patients.

Twenty two patients had comorbidities, of which the commonest were diabetes and hypertension ( Table 1).¹⁰

Table 1. List of comorbidities. CAD, coronary artery disease.

Comorbidity	Number
Allergic Asthma	1
Diabetes	3
Hypertension	9
Diabetes & Hypertension	2
Diabetes, Hypertension & CAD	3
Hypertension & CAD	1
Hypothyroidism	3

The site of disease was body (Tinea corporis) alone in 29, groin (Tinea cruris) alone in 7, and both body and groin in 64 cases.

Response to treatment

Scaling, erythema, pruritus, and mycological results improved over the 5 visits, as shown in the charts below.

Scaling

Scaling was present in all patients at enrolment. The number of patients with severe scaling, and the severity of scaling decreased with treatment. At fifth visit (56 days), 86 of 88 patients had no scaling; the other two had mild residual scaling ( Figure 2).

Figure 2. Progress of the scaling parameter over time.

The numbers are percentages of the total number of patients available for assessment.

Erythema

Erythema was present in 97 of the 100 patients at enrolment. By the end of the fifth visit the erythema had disappeared in all cases ( Figure 3).

Figure 3. Progress of the erythema parameter over time.

The numbers are percentages of the total number of patients available for assessment.

Pruritus

Pruritus was present in all patients at enrolment. By the end of the fifth visit the pruritus had disappeared in 97% of cases ( Figure 4).

Figure 4. Progress of the pruritus parameter over time.

The numbers are percentages of the total number of patients available for assessment.

Thus, the overall clinical cure rate was 97%, with two patients having mild residual scaling, and three having mild pruritus.

Mycological cure

Skin scrapings were examined for fungal hyphae on visits 1, 3, 4 and 5. By the fifth visit, mycological cure was 100% ( Figure 5).

Figure 5. Progress of the skin microscopy over time.

The numbers are percentages of the total number of patients available for assessment. KOH, potassium hydroxide.

Adverse events

One patient had an elevation of serum creatinine to 1.22 mg/dl (laboratory normal 0.67-1.17). This change did not reach the threshold to be considered an adverse event.

Mild elevations of liver enzymes were noted in a few patients between visit 1 and visit 5. ( Table 2). Six patients, none with comorbidity, had alanine aminotransferase (ALT) levels above the upper limit of normal. In five, the levels just barely exceeded the upper limits of normal and did not reach the threshold for being considered Grade 1 adverse events. In one, the ALT level rose from 54.9 to 100.2 U/L, and qualified as a grade 1 adverse event only,⁹ not requiring intervention. Eight patients, two with comorbidity, had mild elevations of serum aspartate aminotransferase levels. The changes did not meet the criteria for being considered adverse events ( Table 2).

Table 2. Changes in liver enzymes with treatment.

Patient nos.^a	Serum ALT (Lab normal 5–45 U/L)	Serum AST (Lab normal 5–40 U/L)
2^b	54.9 ➔ 100.2	37.7 ➔ 43.1
12^b	40.7 ➔ 64.9	21.8 ➔ 49.2
23^b	26.3 ➔ 58.6	27.8 ➔ 40.4
40^c	No change	30.8 ➔ 41.8
52^d	No change	15.6 ➔ 51.9
77^b	40.9 ➔ 47.0	36.0 ➔ 40.4
88^b	24.0 ➔ 61.2	18.7 ➔ 46.6
97^b	39.7 ➔ 58.9	21.8 ➔ 53.7

a In no other patient did the change meet the threshold to be considered an adverse event;

b Patients had no comorbidity;

c hypertension;

d diabetes. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Discussion

Dermatophytosis affects 20-25% of the world’s population.¹¹ The prevalence is likely much higher in India¹² and is certainly increasing to alarming, almost panicky levels.⁸^,¹³

The burden of recalcitrant dermatophytosis is growing in India, with an estimated 3-10% of cases being difficult-to-treat.¹^,⁷^,¹⁴^–¹⁶ Almost every major dermatological conference has begun to devote an entire session to the discussion of dermatophytosis.¹⁴ Reports are also appearing from other parts of the world about the worrying increase in resistance.¹¹^,¹⁷

The emergence of recalcitrant tinea is almost certainly encouraged by the non-adherence to the treatment regimen and shorter duration of the regimen.¹⁶^,¹⁸ A species shift to Trichophyton indotineae is another likely cause of the observed recalcitrance.¹⁹ Taking in consideration the significant number of recalcitrant cases, one of us (DGS) decided to conduct a trial of daily dose fluconazole for patients with dermatophytosis.

Response to fluconazole

This study shows that at present one may expect a reliable response to oral fluconazole in a 150 mg daily dose regimen lasting five weeks. While there are several reports of the efficacy of weekly fluconazole for dermatophytosis,²⁰ there is a paucity of literature regarding the daily use of fluconazole in dermatophytosis, and the clinicians have been discouraged from its use for treating this condition. The usual recommended dose is 150 mg once a week. At this dose the cure rates vary from 64%²¹ to about 90%.²²^,²³ On the other hand, the daily dosing ensures that the drug concentrations consistently exceed the minimum inhibitory concentrations (MICs) required to kill the fungus. This result should come as no surprise: fluconazole is among the triazoles that is known to be effective in treating dermatophytosis. Indeed, members of an expert panel recently indicated that fluconazole and terbinafine were their preferred systemic choice of antifungal agents for children.¹³

Fluconazole is about eight times less expensive than itraconazole or terbinafine, therefore if the therapeutic effect is similar fluconazole may be the preferred therapy, as it is likely to ensure patient compliance for a long time. Considering that nearly 70% of infections occur in the low and very low income socioeconomic groups,²⁴ cost becomes a critical factor in deciding the medication.

It is also worthy of note that fluconazole accumulates in the stratum corneum²⁵ and its levels are very high when compared to other azoles.²⁶ The in vitro MIC₉₀ levels of fluconazole are 16–32 micrograms/ml,²⁷^,²⁸ depending on the species. In the stratum corneum the tissue concentrations of fluconazole are more than the MICs for most dermatophytes, and the drug is eliminated 2–3 times more slowly than from the blood.²⁹ Daily doses of fluconazole achieve levels of 66 micrograms/gram, about three times as high as levels after weekly doses,²⁵ which explains why daily fluconazole is so effective in the treatment of dermatophytosis. Sardana et al.,²⁶ and others reviewed the literature on the pharmacokinetics of antifungal agents, and stated that the distribution of itraconazole and terbinafine, being highly lipophilic, depended on the presence of sebum. Though itraconazole and terbinafine achieved MIC₉₀ inhibition at lower levels in laboratory studies, these drugs also achieved lower levels in the skin.³⁰ Standard antifungal sensitivity test (AFST) methods involving in vitro and animal data are unreliable for predicting clinical outcomes, and there is the suggestion that fluconazole might be the preferred drug, especially for sites that secrete less sebum or in persons with intrinsically dry skin (such as diabetics).²⁶ Khurana et al.,³¹ in a recent review, pointed out that the 60–90 hour elimination half-life of fluconazole would be insufficient antifungal cover if the drug was given once weekly. We believe that it is likely that these properties of fluconazole provide a strong rationale for a daily dose regimen.

Safety

Several studies have shown that fluconazole is well tolerated at daily doses of up to 1,600 mg.²³^,³²^–³⁶ Hepatotoxicity is described, but rare, and in most cases is self-limiting. Mild elevations in serum aminotransferase levels occur in up to 5% of patients. These patients are asymptomatic and do not require discontinuation of the medication.³⁷ In our cases none of the patients developed any significant adverse effect. The drug was well-tolerated even in patients who had existing comorbidities. Except in one patient, the transaminases remained stable, and showed a minimal elevation in only about 5% of patients.

Cross-reactivity of fluconazole with other azoles is unlikely, but fluconazole should nevertheless be used with caution in patients who have had adverse effects from itraconazole and related compounds.³⁷ It is good to remember that fluconazole inhibits the cytochrome P450 enzyme CYP 3A4, and may cause interactions with drugs that are metabolized by this enzyme, though it is a less potent inhibitor of the pathway than are itraconazole and posaconazole.³⁸

Conclusions

Our results suggest that fluconazole in a dose of 150 mg daily for eight weeks effectively treats dermatophytosis, with a clinical efficacy of 97% and a mycological cure rate reaching 100%. The eight-week daily dose regimen is safe and well-tolerated, even in patients with co-morbidities. In view of the severe concerns about the applicability of existing recommendations for dermatophytosis, dermatologists should consider this regimen as a viable option. There is also a need for a large comparative study with itraconazole and terbinafine.

Strengths and weaknesses

This study evaluates the efficacy of an inexpensive and safe drug, fluconazole, in the management of a major health disorder. The enrolled patients were carefully evaluated, and an attempt was made to ensure that the readings were as objective as was possible. Patients were also examined microbiologically to corroborate the clinical findings.

In a single center private clinic, it was not feasible to carry out fungal cultures due to financial limitations. However, we did not encounter any case that would require us to ask for fungal culture and anti-fungal sensitivity tests. Additionally, even expert panels do not recommend cultures except in recalcitrant cases.¹³

We also were not able to blind the measurement of the clinical responses to the drug.

Data availability

Underlying data

Harvard Dataverse: Replication Data for: FLUCONAZOLE_150. https://doi.org/10.7910/DVN/P7DLSU.¹⁰

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).

Acknowledgements

We acknowledge and thank Innovate Research, Mr. Shailendra Meena, Dr. Piyush Kumar Pandey, Mr. Shaitan Singh and Ms. Charanpreet Arora who have provided administrative support to the study.

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Version 2

VERSION 2 PUBLISHED 07 Dec 2022

Author details Author details

Dattatray Gopal Saple
Roles: Conceptualization, Investigation, Methodology, Writing – Review & Editing

Sushrut Save
Roles: Data Curation, Investigation, Writing – Review & Editing

Devesh Kumar
Roles: Conceptualization, Funding Acquisition, Project Administration, Writing – Review & Editing

Suneet Sood
Roles: Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing

Competing interests

FDC Company provided financial support for the medicines and laboratory tests. S Sood is a consultant for Innovate Research, the contract research organization that assisted DGS in the drug trial.

Grant information

This work was funded by FDC Company, India.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

version 2

Revised

Published: 06 Dec 2024, 11:1446

https://doi.org/10.12688/f1000research.127138.2

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Published: 07 Dec 2022, 11:1446

https://doi.org/10.12688/f1000research.127138.1

© 2024 Saple DG et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Saple DG, Save S, Kumar D and Sood S. An open label, single arm, pilot study to evaluate the safety, tolerability, and efficacy of daily fluconazole 150 mg in subjects suffering from Tinea cruris and Tinea corporis [version 2; peer review: 3 approved with reservations, 2 not approved]. F1000Research 2024, 11:1446 (https://doi.org/10.12688/f1000research.127138.2)

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Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions

Version 2

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Reviewer Report 25 Jul 2025

Saumya Panda, Jagannath Gupta Institute of Medical Sciences and Hospital (JIMSH), Kolkata, India

Not Approved

https://doi.org/10.5256/f1000research.175612.r396719

There were several methodological and reporting limitations in the study:

1. The first author appears to have played a central role as the treating physician, assessor, and primary reporter. It would be helpful to clarify the contributions of the other co-authors.

2. There was 100% mycological cure. This is a bit reality-defying, as in the current context of recalcitrant dermatophytosis, there is hardly a molecule showing complete susceptibility, particularly in tinea corporis and cruris, of which the major responsible organism in India seems to be Trichophyton indotineae/Trichophyton mentagrophytes Genotype VIII.¹

3. Also, in the context of the supposed rationale of the usage of fluconazole, namely its preference for concentration in the stratum corneum rather than in the sebum, the sites of occurrence to favour the effectiveness of fluconazole should have been palms and soles. So, the authors should have tested the molecule in tinea pedis and tinea mannum, rather than tinea cruris and tinea corporis.

4. The very important information of whether there was any concomitant medication used has not been reported.

5. Similarly, whether there was any previous treatment with any antifungals, or if there was a wash-off period, has not been stated either.

6. Beats me why a CONSORT flow chart has been provided. This is not an RCT. It is just a pilot open trial.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

No

References

1. Leeyaphan C, Saengthong‐aram P, Laomoleethorn J, Phinyo P, et al.: Therapeutic Outcomes in Patients WithTrichophyton indotineae : A Systematic Review and Meta‐Analysis of Individual Patient Data. Mycoses. 2025; 68 (4). Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: dermatology, clinical dermatology, mycology, artificial intelligence applications

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report 22 Jul 2025

Paulo Henrique Fonseca Carmo, Department of Genetics, Microbiology and Immunology, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil

Approved with Reservations

https://doi.org/10.5256/f1000research.175612.r396715

The authors conducted a pilot study to assess the safety, tolerability, and efficacy of daily fluconazole (150 mg) in patients with dermatophytosis. The manuscript introduces an interesting perspective by revisiting fluconazole therapy for this condition. However, several points of the manuscript ... Continue reading

Please revise the statement regarding the taxonomy of dermatophytes. Dermatophytes comprise more than three genera; this should be corrected (10.1007/s11046-016-0073-9).
Scientific names should be italicized throughout the manuscript.
The introduction would benefit from highlighting the rising incidence of dermatophytosis caused by Trichophyton indotineae, an emerging species known for reduced susceptibility to terbinafine.
The rationale for choosing a fluconazole-based therapy should be clearly stated. Why was fluconazole selected over other antifungal agents? A stronger justification for the study’s therapeutic approach is needed.

Methods

Please detail and reference the methodologies used for evaluating renal and liver function, as well as urine analyses (physical, chemical, and microscopic).
A correlation analysis between biochemical parameters and evaluation timepoints could provide additional statistical significance into treatment-related trends. I suggest using the Fisher’s t-test.
Are the dermatophytes identified? Did you perform antifungal susceptibility assays with the isolated strains?

Results and Discussion

Figure captions should be more comprehensive, detailed and self-contained.
The layout of Table 2 lacks clarity. I suggest adding columns for AST and ALT levels before and after treatment.
Is there any observable relationship between the clinical response and the dermatophyte species involved? This would offer insight into species-specific treatment outcomes.
The discussion would benefit from comparisons with other in vitro, in vivo, and clinical studies. There is a meta-analysis published in 2022 that could contextualize the findings and reinforce the study’s relevance (10.18231/j.ijced.2022.023).

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

No
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Yes

References

1. de Hoog G, Dukik K, Monod M, Packeu A, et al.: Toward a Novel Multilocus Phylogenetic Taxonomy for the Dermatophytes. Mycopathologia. 2017; 182 (1-2): 5-31 Publisher Full Text
2. Shendge P, Desai A, Kesare S: The use of fluconazole in the treatment of superficial fungal infections- A meta-analysis. IP Indian Journal of Clinical and Experimental Dermatology. 2022; 8 (2): 101-106 Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Mycology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Reviewer Report 03 Mar 2025

David W Denning, The University of Manchester, Manchester, England, UK

Approved with Reservations

https://doi.org/10.5256/f1000research.175612.r367763

This is an interesting paper reviving the previously studied idea of using fluconazole for dermatophytosis. In the early days of fluconazole development in the late 1980’s several studies were done by Pfizer, using low dose fluconazole. The company was very concerned about liver toxicity, as for ketoconazole, and wanted to avoid ‘crashing the drug’ by using what are now standard doses. So 50mg and 100mg dose studies were common. Then it became apparent that the greater need and financial value lay in Candida infections (oral, esophageal and systemic) as well as cryptococcal meningitis, as this was the time when AIDS was exploding in numbers and before any antiretroviral therapy. So cutaneous infections were ‘dropped’ and not applied for as indications.

See the following studies (not all of which require to be referenced, but a fully discussion of dose and duration is required):
https://pubmed.ncbi.nlm.nih.gov/8181207/
https://pubmed.ncbi.nlm.nih.gov/2365398/
https://pubmed.ncbi.nlm.nih.gov/1486705/
https://pubmed.ncbi.nlm.nih.gov/1562699/
https://pubmed.ncbi.nlm.nih.gov/9568414/
https://pubmed.ncbi.nlm.nih.gov/9155961/
https://pubmed.ncbi.nlm.nih.gov/9762826/
https://pubmed.ncbi.nlm.nih.gov/24347774/
https://pubmed.ncbi.nlm.nih.gov/29459592/

The study is an open study, without any independent verification of response, leaving it open to a critique of observer bias. Nonetheless the outcomes are strikingly good. This referee believes that 100mg daily would have produced an equivalent result, which the author does not address in his discussion, in terms of cost. In many countries, fluconazole 150mg is available as single doses over the counter for women with VVC, and is disproportionately expensive as a result.

A significant limitation of the work of the work is the lack of cultures and knowledge of which fungi were implicated. In particular, it is important to know of Trichophyton indotineae was the causative agent.

Recommendations.
1. The author adds a brief summary of the prior work with fluconazole into the introduction, and in more detail in the discussion. A mention of the in vitro activity against different dermatophytes is required.
2. The authors are more critical of the dose of fluconazole selected, and address the possibility of lower doses and shorter durations, based on prior literature.
3. A limitations paragraph is required.
4. Caution about efficacy in T. indotineae infections is required: https://pubmed.ncbi.nlm.nih.gov/32538466/

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

References

1. Lospalluti M, Barile F, Pantaleo AK, Conese M, et al.: [Comparative evaluation of fluconazole 50 mg and 100 mg versus itraconazole 100 mg in the treatment of dermatomycoses].Clin Ter. 1994; 144 (2): 129-38 PubMed Abstract
2. Zucchi A, De Panfilis G, Allegra F: [Fluconazole in the treatment of dermatomycoses. Clinical experience].G Ital Dermatol Venereol. 1990; 125 (1-2): I-III PubMed Abstract
3. Suchil P, Gei FM, Robles M, Perera-Ramírez A, et al.: Once-weekly oral doses of fluconazole 150 mg in the treatment of tinea corporis/cruris and cutaneous candidiasis.Clin Exp Dermatol. 1992; 17 (6): 397-401 PubMed Abstract | Publisher Full Text
4. Montero-Gei F, Perera A: Therapy with fluconazole for tinea corporis, tinea cruris, and tinea pedis.Clin Infect Dis. 1992; 14 Suppl 1: S77-81 PubMed Abstract | Publisher Full Text
5. Stary A, Sarnow E: Fluconazole in the treatment of tinea corporis and tinea cruris.Dermatology. 1998; 196 (2): 237-41 PubMed Abstract | Publisher Full Text
6. Faergemann J, Mörk NJ, Haglund A, Odegård T: A multicentre (double-blind) comparative study to assess the safety and efficacy of fluconazole and griseofulvin in the treatment of tinea corporis and tinea cruris.Br J Dermatol. 1997; 136 (4): 575-7 PubMed Abstract
7. Nozickova M, Koudelkova V, Kulikova Z, Malina L, et al.: A comparison of the efficacy of oral fluconazole, 150 mg/week versus 50 mg/day, in the treatment of tinea corporis, tinea cruris, tinea pedis, and cutaneous candidosis.Int J Dermatol. 1998; 37 (9): 703-5 PubMed Abstract | Publisher Full Text
8. Thaker SJ, Mehta DS, Shah HA, Dave JN, et al.: A comparative study to evaluate efficacy, safety and cost-effectiveness between Whitfield's ointment + oral fluconazole versus topical 1% butenafine in tinea infections of skin.Indian J Pharmacol. 2013; 45 (6): 622-4 PubMed Abstract | Publisher Full Text
9. Sultana T, Saha SK, Hossain M, Ajmeri S, et al.: Current Trends of Using Systemic Antifungal Drugs and their Comparative Efficacy in Tinea Corporis and Tinea Cruris in Outpatient Department of Dermatology in a Tertiary Level Hospital.Mymensingh Med J. 2018; 27 (1): 52-56 PubMed Abstract
10. Singh S, Chandra U, Anchan VN, Verma P, et al.: Limited effectiveness of four oral antifungal drugs (fluconazole, griseofulvin, itraconazole and terbinafine) in the current epidemic of altered dermatophytosis in India: results of a randomized pragmatic trial.Br J Dermatol. 2020; 183 (5): 840-846 PubMed Abstract | Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Fungal diseases and antifugal therapy

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Version 1

VERSION 1

PUBLISHED 07 Dec 2022

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Reviewer Report 02 May 2024

Clara Gómez, Institute of Physical Chemistry Blas Cabrera, CSIC, Madrid, Spain

Enrique Alberdi, Private clinic Dr. Alberdi, Madrid, 28020, Spain

Approved with Reservations

https://doi.org/10.5256/f1000research.139613.r263418

The paper “An open label, single arm, pilot study to evaluate the safety, tolerability, and efficacy of daily fluconazole 150 mg in subjects suffering from Tinea cruris and Tinea corporis” by Dattatray Gopal Saple, Sushrut Save, Devesh Kumar and Suneet Sood, is a clinical trial which aims to evaluate the effects of a dermatologic treatment based on fluconazole 150 mg daily for 8 weeks in patients with uncomplicated dermatophytosis. Treatment was very effective and also safe and well tolerated.
The text is clear, the figures and tables are consistent. The conclusions are adequately supported by the results and are important as they indicate that a very high and prolonged dose of fluoconazole is effective and safe.

There are MINOR concerns and suggestions that should be addressed by the authors.

* If Kurana et al (ref. 31) pointed out that elimination half-life of fluconazole is between 60-90 hours in the stratum corneum, applying fluconazole every 3 days for example for 3 months would also be effective and much safer in terms of side effects and interactions. Why didn't the authors consider also carrying out an intermediate treatment between the already established one (150 mg weekly for 6 months) and the one shown here, to determine if it is also effective?
* Another aspect to consider is the importance of determining a priori the type of dermatophyte causative of the disease, since difficulty in eradicating the disease depends on the genus and specie of the causative dermatophyte. Establishing a pattern of dosage as a function to the causative agent could allow the reduction of the dose proposed by the authors in certain patients and thus increase the safety of the treatment.

*Abstract
Methods: remove the sentence “Of 107 subjects…withdrew consent”
Results: change “At 5 weeks” by “At fifth visit (56 days)”
Conclusions: remove the sentence “Fluconazole is… preferred therapy” because it is not a conclusion of the study.
Keywords: introduce fluconazole, tinea cruris, tinea corporis. Remove tinea capitis

*Discussion
Remove epigraphs
Fourth paragraph: lasting eight weeks

*Figure 1 can be deleted since it is a clinical study with patients assigned to a single group (there is no randomization).

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Not applicable
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Fungal infection; Photodynamic therapy

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

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Author Response 12 Dec 2024

Suneet Sood, Department of Surgery, School of Medicine, International Medical University, Bukit Jalil, 57000, Malaysia

12 Dec 2024

Author Response

We wish to thank the reviewer for her comments.
To respond:
Comment: Why didn't the authors consider also carrying out an intermediate treatment between the already established one (150 mg ... Continue reading We wish to thank the reviewer for her comments.
To respond:
Comment: Why didn't the authors consider also carrying out an intermediate treatment between the already established one (150 mg weekly for 6 months) and the one shown here, to determine if it is also effective? Another aspect to consider is the importance of determining a priori the type of dermatophyte causative of the disease, since difficulty in eradicating the disease depends on the genus and specie of the causative dermatophyte.
Response: We agree to both comments. However, this was an exploratory, pilot study to determine if there were enough grounds to carry out in-depth studies of fluconazole in dermatophytosis. In view of the increasing reports of resistance across the world, it was not considered worthwhile in the beginning to consider the intermediate treatment. Now that we have evidence of efficacy and safety, our next step will be to study the organisms and the appropriate dosages.

Comment: *Abstract. Methods: remove the sentence “Of 107 subjects…withdrew consent”. Results: change “At 5 weeks” by “At fifth visit (56 days)”. Conclusions: remove the sentence “Fluconazole is… preferred therapy” because it is not a conclusion of the study. Keywords: introduce fluconazole, tinea cruris, tinea corporis. Remove tinea capitis
Response: We agree, and we appreciate the observations. The text has been changed accordingly.

Comment: *Discussion: Remove epigraphs; Fourth paragraph: lasting eight weeks. *Figure 1 can be deleted since it is a clinical study with patients assigned to a single group (there is no randomization).
Response: We have made most of the changes as suggested. It may be clearer to maintain Figure 1, however.
We wish to thank the reviewer for her comments.
To respond:
Comment: Why didn't the authors consider also carrying out an intermediate treatment between the already established one (150 mg weekly for 6 months) and the one shown here, to determine if it is also effective? Another aspect to consider is the importance of determining a priori the type of dermatophyte causative of the disease, since difficulty in eradicating the disease depends on the genus and specie of the causative dermatophyte.
Response: We agree to both comments. However, this was an exploratory, pilot study to determine if there were enough grounds to carry out in-depth studies of fluconazole in dermatophytosis. In view of the increasing reports of resistance across the world, it was not considered worthwhile in the beginning to consider the intermediate treatment. Now that we have evidence of efficacy and safety, our next step will be to study the organisms and the appropriate dosages.

Comment: *Abstract. Methods: remove the sentence “Of 107 subjects…withdrew consent”. Results: change “At 5 weeks” by “At fifth visit (56 days)”. Conclusions: remove the sentence “Fluconazole is… preferred therapy” because it is not a conclusion of the study. Keywords: introduce fluconazole, tinea cruris, tinea corporis. Remove tinea capitis
Response: We agree, and we appreciate the observations. The text has been changed accordingly.

Comment: *Discussion: Remove epigraphs; Fourth paragraph: lasting eight weeks. *Figure 1 can be deleted since it is a clinical study with patients assigned to a single group (there is no randomization).
Response: We have made most of the changes as suggested. It may be clearer to maintain Figure 1, however.
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response 12 Dec 2024

Suneet Sood, Department of Surgery, School of Medicine, International Medical University, Bukit Jalil, 57000, Malaysia

12 Dec 2024

Author Response

We wish to thank the reviewer for her comments.
To respond:
Comment: Why didn't the authors consider also carrying out an intermediate treatment between the already established one (150 mg ... Continue reading We wish to thank the reviewer for her comments.
To respond:
Comment: Why didn't the authors consider also carrying out an intermediate treatment between the already established one (150 mg weekly for 6 months) and the one shown here, to determine if it is also effective? Another aspect to consider is the importance of determining a priori the type of dermatophyte causative of the disease, since difficulty in eradicating the disease depends on the genus and specie of the causative dermatophyte.
Response: We agree to both comments. However, this was an exploratory, pilot study to determine if there were enough grounds to carry out in-depth studies of fluconazole in dermatophytosis. In view of the increasing reports of resistance across the world, it was not considered worthwhile in the beginning to consider the intermediate treatment. Now that we have evidence of efficacy and safety, our next step will be to study the organisms and the appropriate dosages.

Comment: *Abstract. Methods: remove the sentence “Of 107 subjects…withdrew consent”. Results: change “At 5 weeks” by “At fifth visit (56 days)”. Conclusions: remove the sentence “Fluconazole is… preferred therapy” because it is not a conclusion of the study. Keywords: introduce fluconazole, tinea cruris, tinea corporis. Remove tinea capitis
Response: We agree, and we appreciate the observations. The text has been changed accordingly.

Comment: *Discussion: Remove epigraphs; Fourth paragraph: lasting eight weeks. *Figure 1 can be deleted since it is a clinical study with patients assigned to a single group (there is no randomization).
Response: We have made most of the changes as suggested. It may be clearer to maintain Figure 1, however.
We wish to thank the reviewer for her comments.
To respond:
Comment: Why didn't the authors consider also carrying out an intermediate treatment between the already established one (150 mg weekly for 6 months) and the one shown here, to determine if it is also effective? Another aspect to consider is the importance of determining a priori the type of dermatophyte causative of the disease, since difficulty in eradicating the disease depends on the genus and specie of the causative dermatophyte.
Response: We agree to both comments. However, this was an exploratory, pilot study to determine if there were enough grounds to carry out in-depth studies of fluconazole in dermatophytosis. In view of the increasing reports of resistance across the world, it was not considered worthwhile in the beginning to consider the intermediate treatment. Now that we have evidence of efficacy and safety, our next step will be to study the organisms and the appropriate dosages.

Comment: *Abstract. Methods: remove the sentence “Of 107 subjects…withdrew consent”. Results: change “At 5 weeks” by “At fifth visit (56 days)”. Conclusions: remove the sentence “Fluconazole is… preferred therapy” because it is not a conclusion of the study. Keywords: introduce fluconazole, tinea cruris, tinea corporis. Remove tinea capitis
Response: We agree, and we appreciate the observations. The text has been changed accordingly.

Comment: *Discussion: Remove epigraphs; Fourth paragraph: lasting eight weeks. *Figure 1 can be deleted since it is a clinical study with patients assigned to a single group (there is no randomization).
Response: We have made most of the changes as suggested. It may be clearer to maintain Figure 1, however.
Competing Interests: No competing interests were disclosed. Close
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Reviewer Report 30 Apr 2024

Kabir Sardana, ABVIMS & Dr RML Hospital, New Delhi, India

Not Approved

https://doi.org/10.5256/f1000research.139613.r263427

There are major methodological constraints and the results that the author propose are not correct as in India fluconazole never leads to 1005 cure rates.

1 -The use of antifungal drugs is based on AFSST and without MIC data using a drug makes no sense. Multiple studies from India have shown that the MIC to fluconazole is very high. Up to 1:128. Also while it does achieve high levels in the stratum corneum they are not higher than the prevalent MIC needed. This drug almost always fails.

There is no pre data or lab data to tell us the prevalent MIC in their study.

2 - Dose - fluconazole 150 mg daily for 8 weeks.
There is no rationale for this dose. Unless the authors can demonstrate that this dose achieves high levels in the s corneum than 50/100 mg.

3. To expect a “mycological cure of 100%” just on fluconazole is not plausible. As this drug has been repeatedly been shown to be ineffective in dermatophytosis. Unless there was a topical synergistic drug given, which is very likely. In fact most patients use topical luliconazole which is highly potent and could be the cause of the results. There is no data of the same.
Also it is inexplicable why the authors could not culture as this was a sponsored study. I would have been happy to see the MIC to other drug specially itraconazole and terbinafine.

4 - Discussion:
There are many inconsistent statements made, especially in regard to itraconazole which is now universally in India the preferred line of treatment. Even the cost has come down with the novel SUBA preparation.

In essence the 100% efficacy as a monotherapy seems unlikely. Without a culture MIC and AFFST data the preference for fluconazole seems a bit arbitrary, it would have been much better if, in the absence of a AFSST you could have actually tried itraconazole and fluconazole in two arms as your results are converse to the prevalent practice in India.

Is the work clearly and accurately presented and does it cite the current literature?

No
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

No source data required
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

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Author Response 06 Dec 2024

Suneet Sood, Department of Surgery, School of Medicine, International Medical University, Bukit Jalil, 57000, Malaysia

06 Dec 2024

Author Response
We would like to thank the reviewer for the meticulous review.

Here are our responses to the reviewer’s comments:

Comment: In India fluconazole never leads to 100% cure ... Continue reading
We would like to thank the reviewer for the meticulous review.

Here are our responses to the reviewer’s comments:

Comment: In India fluconazole never leads to 100% cure rates.
Response: This is true at traditional doses. That, indeed, was the very reason for a study using higher doses.

Comment: Multiple studies from India have shown that the MIC to fluconazole is very high. Up to 1:128. Also while it does achieve high levels in the stratum corneum they are not higher than the prevalent MIC needed.
Response: Respectfully, we wish to differ. We have shown, in the Discussion, that according to some authors at least the in vitro MIC90 levels of fluconazole are 16–32 micrograms/ml, that the tissue concentrations, and that the drug is eliminated 2–3 times more slowly than from the blood. All of these reports suggest at least the justification for a pilot study.

Comment: There is no pre data or lab data to tell us the prevalent MIC in their study. 2 – Dose fluconazole 150 mg daily for 8 weeks. There is no rationale for this dose. Unless the authors can demonstrate that this dose achieves high levels in the s corneum than 50/100 mg.
Response: MIC levels have previously been established.[1, 2] We are not making the claim that MIC levels previously established apply in this case. However, the entire purpose of a pilot trial such as this one is to determine if there is reason to conduct in-depth studies like tissue levels and in vitro MIC levels. That said, if we had known in advance that fluconazole would be effective, we would certainly have carried out the microbiological studies to confirm the reason for its efficacy. Now that we are aware that fluconazole is effective in these doses, there is every reason to carry out follow up research.

Comment: To expect a “mycological cure of 100%” just on fluconazole is not plausible. As this drug has been repeatedly been shown to be ineffective in dermatophytosis. Unless there was a topical synergistic drug given, which is very likely. In fact most patients use topical luliconazole which is highly potent and could be the cause of the results. There is no data of the same. Also it is inexplicable why the authors could not culture as this was a sponsored study. I would have been happy to see the MIC to other drug specially itraconazole and terbinafine.
Response: Admittedly, this drug has not been effective in once-weekly doses. But, as observed by Professor Sardana himself,[3] fluconazole in daily doses is likely to be effective. Indeed, it would not be too inaccurate to say that it was his comment about the possibility of daily fluconazole being the “ideal drug” that was the inspiration for this pilot trial.

Comment: There are many inconsistent statements made, especially in regard to itraconazole which is now universally in India the preferred line of treatment. Even the cost has come down with the novel SUBA preparation. In essence the 100% efficacy as a monotherapy seems unlikely. Without a culture MIC and AFFST data the preference for fluconazole seems a bit arbitrary, it would have been much better if, in the absence of a AFSST you could have actually tried itraconazole and fluconazole in two arms as your results are converse to the prevalent practice in India.
Response: We do not deny that itraconazole is available, and has advantages, and that we could have compared the two drugs in two treatment arms. However, this really was not our study. Our study was exploratory, a pilot study as pointed out in the title itself, intended to determine if fluconazole was effective in daily disease. Our study does not arrive at the conclusion that fluconazole is better or worse than other drugs.

References

Felton T, Troke PF, Hope WW: Tissue penetration of antifungal agents. Clin. Microbiol. Rev. 2014; 27: 68–88.

Pathania S, Rudramurthy SM, Narang T, et al.: A prospective study of the epidemiological and clinical patterns of recurrent dermatophytosis at a tertiary care hospital in India. Indian J. Dermatol. Venereol. Leprol. 2018; 84: 678–684.

Sardana K, Arora P, Mahajan K: Intracutaneous pharmacokinetics of oral antifungals and their relevance in recalcitrant cutaneous dermatophytosis: Time to revisit basics. Indian J. Dermatol. Venereol. Leprol. 2017; 83: 730–732.
We would like to thank the reviewer for the meticulous review.

Here are our responses to the reviewer’s comments:

Comment: In India fluconazole never leads to 100% cure rates.
Response: This is true at traditional doses. That, indeed, was the very reason for a study using higher doses.

Comment: Multiple studies from India have shown that the MIC to fluconazole is very high. Up to 1:128. Also while it does achieve high levels in the stratum corneum they are not higher than the prevalent MIC needed.
Response: Respectfully, we wish to differ. We have shown, in the Discussion, that according to some authors at least the in vitro MIC90 levels of fluconazole are 16–32 micrograms/ml, that the tissue concentrations, and that the drug is eliminated 2–3 times more slowly than from the blood. All of these reports suggest at least the justification for a pilot study.

Comment: There is no pre data or lab data to tell us the prevalent MIC in their study. 2 – Dose fluconazole 150 mg daily for 8 weeks. There is no rationale for this dose. Unless the authors can demonstrate that this dose achieves high levels in the s corneum than 50/100 mg.
Response: MIC levels have previously been established.[1, 2] We are not making the claim that MIC levels previously established apply in this case. However, the entire purpose of a pilot trial such as this one is to determine if there is reason to conduct in-depth studies like tissue levels and in vitro MIC levels. That said, if we had known in advance that fluconazole would be effective, we would certainly have carried out the microbiological studies to confirm the reason for its efficacy. Now that we are aware that fluconazole is effective in these doses, there is every reason to carry out follow up research.

Comment: To expect a “mycological cure of 100%” just on fluconazole is not plausible. As this drug has been repeatedly been shown to be ineffective in dermatophytosis. Unless there was a topical synergistic drug given, which is very likely. In fact most patients use topical luliconazole which is highly potent and could be the cause of the results. There is no data of the same. Also it is inexplicable why the authors could not culture as this was a sponsored study. I would have been happy to see the MIC to other drug specially itraconazole and terbinafine.
Response: Admittedly, this drug has not been effective in once-weekly doses. But, as observed by Professor Sardana himself,[3] fluconazole in daily doses is likely to be effective. Indeed, it would not be too inaccurate to say that it was his comment about the possibility of daily fluconazole being the “ideal drug” that was the inspiration for this pilot trial.

Comment: There are many inconsistent statements made, especially in regard to itraconazole which is now universally in India the preferred line of treatment. Even the cost has come down with the novel SUBA preparation. In essence the 100% efficacy as a monotherapy seems unlikely. Without a culture MIC and AFFST data the preference for fluconazole seems a bit arbitrary, it would have been much better if, in the absence of a AFSST you could have actually tried itraconazole and fluconazole in two arms as your results are converse to the prevalent practice in India.
Response: We do not deny that itraconazole is available, and has advantages, and that we could have compared the two drugs in two treatment arms. However, this really was not our study. Our study was exploratory, a pilot study as pointed out in the title itself, intended to determine if fluconazole was effective in daily disease. Our study does not arrive at the conclusion that fluconazole is better or worse than other drugs.

References

Felton T, Troke PF, Hope WW: Tissue penetration of antifungal agents. Clin. Microbiol. Rev. 2014; 27: 68–88.

Pathania S, Rudramurthy SM, Narang T, et al.: A prospective study of the epidemiological and clinical patterns of recurrent dermatophytosis at a tertiary care hospital in India. Indian J. Dermatol. Venereol. Leprol. 2018; 84: 678–684.

Sardana K, Arora P, Mahajan K: Intracutaneous pharmacokinetics of oral antifungals and their relevance in recalcitrant cutaneous dermatophytosis: Time to revisit basics. Indian J. Dermatol. Venereol. Leprol. 2017; 83: 730–732.
Competing Interests: No competing interests were disclosed. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 06 Dec 2024

Suneet Sood, Department of Surgery, School of Medicine, International Medical University, Bukit Jalil, 57000, Malaysia

06 Dec 2024

Author Response
We would like to thank the reviewer for the meticulous review.

Here are our responses to the reviewer’s comments:

Comment: In India fluconazole never leads to 100% cure ... Continue reading
We would like to thank the reviewer for the meticulous review.

Here are our responses to the reviewer’s comments:

Comment: In India fluconazole never leads to 100% cure rates.
Response: This is true at traditional doses. That, indeed, was the very reason for a study using higher doses.

Comment: Multiple studies from India have shown that the MIC to fluconazole is very high. Up to 1:128. Also while it does achieve high levels in the stratum corneum they are not higher than the prevalent MIC needed.
Response: Respectfully, we wish to differ. We have shown, in the Discussion, that according to some authors at least the in vitro MIC90 levels of fluconazole are 16–32 micrograms/ml, that the tissue concentrations, and that the drug is eliminated 2–3 times more slowly than from the blood. All of these reports suggest at least the justification for a pilot study.

Comment: There is no pre data or lab data to tell us the prevalent MIC in their study. 2 – Dose fluconazole 150 mg daily for 8 weeks. There is no rationale for this dose. Unless the authors can demonstrate that this dose achieves high levels in the s corneum than 50/100 mg.
Response: MIC levels have previously been established.[1, 2] We are not making the claim that MIC levels previously established apply in this case. However, the entire purpose of a pilot trial such as this one is to determine if there is reason to conduct in-depth studies like tissue levels and in vitro MIC levels. That said, if we had known in advance that fluconazole would be effective, we would certainly have carried out the microbiological studies to confirm the reason for its efficacy. Now that we are aware that fluconazole is effective in these doses, there is every reason to carry out follow up research.

Comment: To expect a “mycological cure of 100%” just on fluconazole is not plausible. As this drug has been repeatedly been shown to be ineffective in dermatophytosis. Unless there was a topical synergistic drug given, which is very likely. In fact most patients use topical luliconazole which is highly potent and could be the cause of the results. There is no data of the same. Also it is inexplicable why the authors could not culture as this was a sponsored study. I would have been happy to see the MIC to other drug specially itraconazole and terbinafine.
Response: Admittedly, this drug has not been effective in once-weekly doses. But, as observed by Professor Sardana himself,[3] fluconazole in daily doses is likely to be effective. Indeed, it would not be too inaccurate to say that it was his comment about the possibility of daily fluconazole being the “ideal drug” that was the inspiration for this pilot trial.

Comment: There are many inconsistent statements made, especially in regard to itraconazole which is now universally in India the preferred line of treatment. Even the cost has come down with the novel SUBA preparation. In essence the 100% efficacy as a monotherapy seems unlikely. Without a culture MIC and AFFST data the preference for fluconazole seems a bit arbitrary, it would have been much better if, in the absence of a AFSST you could have actually tried itraconazole and fluconazole in two arms as your results are converse to the prevalent practice in India.
Response: We do not deny that itraconazole is available, and has advantages, and that we could have compared the two drugs in two treatment arms. However, this really was not our study. Our study was exploratory, a pilot study as pointed out in the title itself, intended to determine if fluconazole was effective in daily disease. Our study does not arrive at the conclusion that fluconazole is better or worse than other drugs.

References

Felton T, Troke PF, Hope WW: Tissue penetration of antifungal agents. Clin. Microbiol. Rev. 2014; 27: 68–88.

Pathania S, Rudramurthy SM, Narang T, et al.: A prospective study of the epidemiological and clinical patterns of recurrent dermatophytosis at a tertiary care hospital in India. Indian J. Dermatol. Venereol. Leprol. 2018; 84: 678–684.

Sardana K, Arora P, Mahajan K: Intracutaneous pharmacokinetics of oral antifungals and their relevance in recalcitrant cutaneous dermatophytosis: Time to revisit basics. Indian J. Dermatol. Venereol. Leprol. 2017; 83: 730–732.
We would like to thank the reviewer for the meticulous review.

Here are our responses to the reviewer’s comments:

Comment: In India fluconazole never leads to 100% cure rates.
Response: This is true at traditional doses. That, indeed, was the very reason for a study using higher doses.

Comment: Multiple studies from India have shown that the MIC to fluconazole is very high. Up to 1:128. Also while it does achieve high levels in the stratum corneum they are not higher than the prevalent MIC needed.
Response: Respectfully, we wish to differ. We have shown, in the Discussion, that according to some authors at least the in vitro MIC90 levels of fluconazole are 16–32 micrograms/ml, that the tissue concentrations, and that the drug is eliminated 2–3 times more slowly than from the blood. All of these reports suggest at least the justification for a pilot study.

Comment: There is no pre data or lab data to tell us the prevalent MIC in their study. 2 – Dose fluconazole 150 mg daily for 8 weeks. There is no rationale for this dose. Unless the authors can demonstrate that this dose achieves high levels in the s corneum than 50/100 mg.
Response: MIC levels have previously been established.[1, 2] We are not making the claim that MIC levels previously established apply in this case. However, the entire purpose of a pilot trial such as this one is to determine if there is reason to conduct in-depth studies like tissue levels and in vitro MIC levels. That said, if we had known in advance that fluconazole would be effective, we would certainly have carried out the microbiological studies to confirm the reason for its efficacy. Now that we are aware that fluconazole is effective in these doses, there is every reason to carry out follow up research.

Comment: To expect a “mycological cure of 100%” just on fluconazole is not plausible. As this drug has been repeatedly been shown to be ineffective in dermatophytosis. Unless there was a topical synergistic drug given, which is very likely. In fact most patients use topical luliconazole which is highly potent and could be the cause of the results. There is no data of the same. Also it is inexplicable why the authors could not culture as this was a sponsored study. I would have been happy to see the MIC to other drug specially itraconazole and terbinafine.
Response: Admittedly, this drug has not been effective in once-weekly doses. But, as observed by Professor Sardana himself,[3] fluconazole in daily doses is likely to be effective. Indeed, it would not be too inaccurate to say that it was his comment about the possibility of daily fluconazole being the “ideal drug” that was the inspiration for this pilot trial.

Comment: There are many inconsistent statements made, especially in regard to itraconazole which is now universally in India the preferred line of treatment. Even the cost has come down with the novel SUBA preparation. In essence the 100% efficacy as a monotherapy seems unlikely. Without a culture MIC and AFFST data the preference for fluconazole seems a bit arbitrary, it would have been much better if, in the absence of a AFSST you could have actually tried itraconazole and fluconazole in two arms as your results are converse to the prevalent practice in India.
Response: We do not deny that itraconazole is available, and has advantages, and that we could have compared the two drugs in two treatment arms. However, this really was not our study. Our study was exploratory, a pilot study as pointed out in the title itself, intended to determine if fluconazole was effective in daily disease. Our study does not arrive at the conclusion that fluconazole is better or worse than other drugs.

References

Felton T, Troke PF, Hope WW: Tissue penetration of antifungal agents. Clin. Microbiol. Rev. 2014; 27: 68–88.

Pathania S, Rudramurthy SM, Narang T, et al.: A prospective study of the epidemiological and clinical patterns of recurrent dermatophytosis at a tertiary care hospital in India. Indian J. Dermatol. Venereol. Leprol. 2018; 84: 678–684.

Sardana K, Arora P, Mahajan K: Intracutaneous pharmacokinetics of oral antifungals and their relevance in recalcitrant cutaneous dermatophytosis: Time to revisit basics. Indian J. Dermatol. Venereol. Leprol. 2017; 83: 730–732.
Competing Interests: No competing interests were disclosed. Close
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Version 2

VERSION 2 PUBLISHED 07 Dec 2022

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	1	2	3	4	5
Version 2 (revision) 06 Dec 24			read	read	read
Version 1 07 Dec 22	read	read

Kabir Sardana, ABVIMS & Dr RML Hospital, New Delhi, India
Clara Gómez, Institute of Physical Chemistry Blas Cabrera, CSIC, Madrid, Spain

Enrique Alberdi, Private clinic Dr. Alberdi, Madrid, Spain
David W Denning, The University of Manchester, Manchester, UK
Paulo Henrique Fonseca Carmo, Universidade Estadual Paulista (UNESP), Botucatu, Brazil
Saumya Panda, Jagannath Gupta Institute of Medical Sciences and Hospital (JIMSH), Kolkata, India

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4 Views

25 Jul 2025 | for Version 2

Saumya Panda, Jagannath Gupta Institute of Medical Sciences and Hospital (JIMSH), Kolkata, India

4 Views Cite this report Responses(0)

Not Approved

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

No

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

dermatology, clinical dermatology, mycology, artificial intelligence applications

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2 Views

22 Jul 2025 | for Version 2

Paulo Henrique Fonseca Carmo, Department of Genetics, Microbiology and Immunology, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil

2 Views Cite this report Responses(0)

Approved With Reservations

Please revise the statement regarding the taxonomy of dermatophytes. Dermatophytes comprise more than three genera; this should be corrected (10.1007/s11046-016-0073-9).
Scientific names should be italicized throughout the manuscript.
The introduction would benefit from highlighting the rising incidence of dermatophytosis caused by Trichophyton indotineae, an emerging species known for reduced susceptibility to terbinafine.
The rationale for choosing a fluconazole-based therapy should be clearly stated. Why was fluconazole selected over other antifungal agents? A stronger justification for the study’s therapeutic approach is needed.

Methods

Please detail and reference the methodologies used for evaluating renal and liver function, as well as urine analyses (physical, chemical, and microscopic).
A correlation analysis between biochemical parameters and evaluation timepoints could provide additional statistical significance into treatment-related trends. I suggest using the Fisher’s t-test.
Are the dermatophytes identified? Did you perform antifungal susceptibility assays with the isolated strains?

Results and Discussion

Figure captions should be more comprehensive, detailed and self-contained.
The layout of Table 2 lacks clarity. I suggest adding columns for AST and ALT levels before and after treatment.
Is there any observable relationship between the clinical response and the dermatophyte species involved? This would offer insight into species-specific treatment outcomes.
The discussion would benefit from comparisons with other in vitro, in vivo, and clinical studies. There is a meta-analysis published in 2022 that could contextualize the findings and reinforce the study’s relevance (10.18231/j.ijced.2022.023).

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

No
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Yes

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Mycology

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4 Views

03 Mar 2025 | for Version 2

David W Denning, The University of Manchester, Manchester, England, UK

4 Views Cite this report Responses(0)

Approved With Reservations

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Fungal diseases and antifugal therapy

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Reviewer Report

16 Views

02 May 2024 | for Version 1

Clara Gómez, Institute of Physical Chemistry Blas Cabrera, CSIC, Madrid, Spain

Enrique Alberdi, Private clinic Dr. Alberdi, Madrid, 28020, Spain

16 Views Cite this report Responses(1)

Approved With Reservations

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Not applicable
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Fungal infection; Photodynamic therapy

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Author Response

12 Dec 2024

Suneet Sood, Department of Surgery, School of Medicine, International Medical University, Bukit Jalil, 57000, Malaysia

We wish to thank the reviewer for her comments.
To respond:
Comment: Why didn't the authors consider also carrying out an intermediate treatment between the already established one (150 mg weekly for 6 months) and the one shown here, to determine if it is also effective? Another aspect to consider is the importance of determining a priori the type of dermatophyte causative of the disease, since difficulty in eradicating the disease depends on the genus and specie of the causative dermatophyte.
Response: We agree to both comments. However, this was an exploratory, pilot study to determine if there were enough grounds to carry out in-depth studies of fluconazole in dermatophytosis. In view of the increasing reports of resistance across the world, it was not considered worthwhile in the beginning to consider the intermediate treatment. Now that we have evidence of efficacy and safety, our next step will be to study the organisms and the appropriate dosages.

Comment: *Abstract. Methods: remove the sentence “Of 107 subjects…withdrew consent”. Results: change “At 5 weeks” by “At fifth visit (56 days)”. Conclusions: remove the sentence “Fluconazole is… preferred therapy” because it is not a conclusion of the study. Keywords: introduce fluconazole, tinea cruris, tinea corporis. Remove tinea capitis
Response: We agree, and we appreciate the observations. The text has been changed accordingly.

Comment: *Discussion: Remove epigraphs; Fourth paragraph: lasting eight weeks. *Figure 1 can be deleted since it is a clinical study with patients assigned to a single group (there is no randomization).
Response: We have made most of the changes as suggested. It may be clearer to maintain Figure 1, however.

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17 Views

30 Apr 2024 | for Version 1

Kabir Sardana, ABVIMS & Dr RML Hospital, New Delhi, India

17 Views Cite this report Responses(1)

Not Approved

Is the work clearly and accurately presented and does it cite the current literature?

No
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

No source data required
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Respond to this report

Responses (1)

Author Response

06 Dec 2024

Suneet Sood, Department of Surgery, School of Medicine, International Medical University, Bukit Jalil, 57000, Malaysia

We would like to thank the reviewer for the meticulous review.

Here are our responses to the reviewer’s comments:

Comment: In India fluconazole never leads to 100% cure rates.
Response: This is true at traditional doses. That, indeed, was the very reason for a study using higher doses.

Comment: Multiple studies from India have shown that the MIC to fluconazole is very high. Up to 1:128. Also while it does achieve high levels in the stratum corneum they are not higher than the prevalent MIC needed.
Response: Respectfully, we wish to differ. We have shown, in the Discussion, that according to some authors at least the in vitro MIC90 levels of fluconazole are 16–32 micrograms/ml, that the tissue concentrations, and that the drug is eliminated 2–3 times more slowly than from the blood. All of these reports suggest at least the justification for a pilot study.

Comment: There is no pre data or lab data to tell us the prevalent MIC in their study. 2 – Dose fluconazole 150 mg daily for 8 weeks. There is no rationale for this dose. Unless the authors can demonstrate that this dose achieves high levels in the s corneum than 50/100 mg.
Response: MIC levels have previously been established.[1, 2] We are not making the claim that MIC levels previously established apply in this case. However, the entire purpose of a pilot trial such as this one is to determine if there is reason to conduct in-depth studies like tissue levels and in vitro MIC levels. That said, if we had known in advance that fluconazole would be effective, we would certainly have carried out the microbiological studies to confirm the reason for its efficacy. Now that we are aware that fluconazole is effective in these doses, there is every reason to carry out follow up research.

Comment: To expect a “mycological cure of 100%” just on fluconazole is not plausible. As this drug has been repeatedly been shown to be ineffective in dermatophytosis. Unless there was a topical synergistic drug given, which is very likely. In fact most patients use topical luliconazole which is highly potent and could be the cause of the results. There is no data of the same. Also it is inexplicable why the authors could not culture as this was a sponsored study. I would have been happy to see the MIC to other drug specially itraconazole and terbinafine.
Response: Admittedly, this drug has not been effective in once-weekly doses. But, as observed by Professor Sardana himself,[3] fluconazole in daily doses is likely to be effective. Indeed, it would not be too inaccurate to say that it was his comment about the possibility of daily fluconazole being the “ideal drug” that was the inspiration for this pilot trial.

Comment: There are many inconsistent statements made, especially in regard to itraconazole which is now universally in India the preferred line of treatment. Even the cost has come down with the novel SUBA preparation. In essence the 100% efficacy as a monotherapy seems unlikely. Without a culture MIC and AFFST data the preference for fluconazole seems a bit arbitrary, it would have been much better if, in the absence of a AFSST you could have actually tried itraconazole and fluconazole in two arms as your results are converse to the prevalent practice in India.
Response: We do not deny that itraconazole is available, and has advantages, and that we could have compared the two drugs in two treatment arms. However, this really was not our study. Our study was exploratory, a pilot study as pointed out in the title itself, intended to determine if fluconazole was effective in daily disease. Our study does not arrive at the conclusion that fluconazole is better or worse than other drugs.

References

Felton T, Troke PF, Hope WW: Tissue penetration of antifungal agents. Clin. Microbiol. Rev. 2014; 27: 68–88.
Pathania S, Rudramurthy SM, Narang T, et al.: A prospective study of the epidemiological and clinical patterns of recurrent dermatophytosis at a tertiary care hospital in India. Indian J. Dermatol. Venereol. Leprol. 2018; 84: 678–684.
Sardana K, Arora P, Mahajan K: Intracutaneous pharmacokinetics of oral antifungals and their relevance in recalcitrant cutaneous dermatophytosis: Time to revisit basics. Indian J. Dermatol. Venereol. Leprol. 2017; 83: 730–732.

View more View less

Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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An open label, single arm, pilot study to evaluate the safety, tolerability, and efficacy of daily fluconazole 150 mg in subjects suffering from Tinea cruris and Tinea corporis

Abstract

Background

Methods

Results

Conclusions

Registration

Keywords

Revised Amendments from Version 1

Introduction

Methods

Ethics

Study design

Study population

Inclusion and exclusion criteria

Intervention

Measurements

Data analysis

Results

Demographics

Figure 1. CONSORT 2010 flow diagram of study patients.

Table 1. List of comorbidities. CAD, coronary artery disease.

Response to treatment

Scaling

Figure 2. Progress of the scaling parameter over time.

Erythema

Figure 3. Progress of the erythema parameter over time.

Pruritus

Figure 4. Progress of the pruritus parameter over time.

Mycological cure

Figure 5. Progress of the skin microscopy over time.

Adverse events

Table 2. Changes in liver enzymes with treatment.

Discussion

Response to fluconazole

Safety

Conclusions

Strengths and weaknesses

Data availability

Underlying data

Acknowledgements

References

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