Efficacy of Isotretinoin in Treating Fungal Infections: A Systematic Review

Infections caused by superficial fungi are among the most prevalent diseases in humans. They impact approximately 20-25% of the worldwide population. In humans, dermatophytes are the predominant factor causing superficial fungal diseases [1]. In recent years, there has been an increase in incidence particularly in tropical countries with a concomitant increase in chronic and recurrent dermatophytosis [2]. A significant disparity exists between the treatment needed in the current situation and the established treatment guidelines [3]. The cornerstone of therapy consists of topical and systemic antifungal agents. In the current context, topical antifungal agents have a restricted impact on adults. In contrast, systemic antifungals have been linked with reduced cure rates, increased adverse effects, several drug interactions and the development of drug resistance in various regions of the country [4]. Conversely, contemporary antifungals such as itraconazole, which formerly exhibited elevated cure rates, are now failing to achieve an acceptable clinical cure. Various strategies have been employed to overcome this problem including prolonging the period of treatment, increasing normal antifungal doses, using multiple antifungals concurrently and using penetration-enhancing agents [3]. Isotretinoin (13-cis-retinoic acid) has been suggested in several studies to contribute to the management of fungal infections through mechanisms that are primarily indirect rather than directly fungicidal. Its keratolytic properties enhance epidermal turnover and desquamation of the stratum corneum, thereby reducing fungal burden and potentially improving the efficacy of concomitant antifungal agents such as itraconazole. In addition, isotretinoin reduces sebum production and modifies the cutaneous microenvironment, factors that may limit fungal persistence in certain conditions [4,5].

Isotretinoin has gained extensive application in clinical practice and current attention has turned to its potential antifungal properties. Although isotretinoin was first created and widely used to treat acne vulgaris, its effects on microbial colonization, sebaceous gland activity and epidermal differentiation have sparked interest in its potential uses outside of acne. Given that keratinization irregularities, sebum production and biofilm formation impact a number of superficial fungal illnesses, these documented pharmacological actions offer a convincing justification for examining isotretinoin as an adjuvant therapy approach [6,7].

Fungal biofilms are integral to the pathogenesis of superficial mucosal and potentially fatal systemic mycosis [6]. Fungal cells embedded in biofilms exhibit greater resistance to antifungal agents and host immunological defences compared to their planktonic equivalents. Consequently, fungal proliferating in biofilms can endure within the host, resulting in severe infections [8]. Consequently, there is an immediate necessity to devise innovative therapeutic approaches to inhibit biofilm formation and dismantle established biofilms. Retinoids may offer a new strategy to inhibit and diminish the growth of biofilm in this scenario. Currently, while it has been demonstrated that these compounds possess antibacterial and anti-biofilm properties in bacterial cultures, there is a lack of data about their potential application against biofilm-associated fungal infections [9]. The combined administration of oral isotretinoin and oral itraconazole is proved to be effective in treating chronic persistent and recurrent dermatophytosis. Isotretinoin was believed to aid in eradicating the organisms by enhancing the proliferation of the epidermis, resulting in the desquamation of keratinocytes [10].

The evidence for isotretinoin as an adjuvant treatment for fungal infections is still dispersed across various fungal illnesses, study designs and treatment approaches, despite the drug's increasing popularity. To the best of our knowledge, no prior systematic review has thoroughly compiled the clinical data pertaining to the use of isotretinoin, either alone or in conjunction with antifungal medications, throughout the range of fungal infections and fungal-associated dermatoses. Thus, the purpose of this systematic review is to identify existing data gaps and future research goals while critically assessing the clinical applicability, safety and efficacy of isotretinoin in fungal infections.

Study Protocol and Focussed Research Question

The Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) standards [11], were adhered to in the systematic review selection of studies, synthesis and subsequent research findings. The research question was: "What is the comparative effectiveness of isotretinoin and antifungal therapies in treating skin fungal infections?" This would allow for the assessment of scientific documentation, the identification of specific clinical challenges, the recognition of gaps in the current literature and the evaluation of the need for additional research.

Information Sources and Search Strategy

An extensive search was performed in the PubMed, Scopus, Web of Science and Google Scholar databases, covering the last decade from January 2015 to December 2024. Only articles in the English language were incorporated into the searches. The lists of references of the original research and review articles were also screened for forward citations. After reviewing the literature, the following Medical Subject Headings (MeSH) phrase combination was used: (“Isotretinoin” OR “13-cis-Retinoic Acid” OR “Retinoids” OR “Retinoic Acid”) AND (“Fungal infections” OR “Fungal Diseases” OR “Mycoses” OR “Fungal biofilm” OR “Mucor” OR “Fonsecaea” OR “Dermatophytosis” OR “Candidiasis” OR “Seborrheic Dermatitis” OR “Pityriasis versicolor” OR “Tinea” OR “Mycosis fungoides”) AND (“Therapeutic effect” OR “Adverse effects” OR “Side effects” OR “Treatment outcome” OR “Efficacy” OR “Clinical cure” OR “Mycological cure” OR “Remission” OR “Recurrence”). The reference lists of the chosen studies were carefully examined to find any articles that were missing from internet databases.

Eligibility Criteria

The selection of eligible studies adhered to the PICOS criteria (Population, Intervention, Comparator, Outcome and Study design).

Inclusion Criteria

• Population: Individuals of any age, sex or ethnicity who had fungal infections were included
• Intervention: Research utilizing isotretinoin as a specific treatment for fungal infections
• Comparator: Any antifungal medicine or treatment for fungal infections other than isotretinoin. Nonetheless, the review also incorporated studies that did not employ a comparator

• Outcome: Research examining the direct and indirect effects of isotretinoin on fungal infections
• Study Design: All case reports, case series and clinical studies that discussed the application of isotretinoin in fungal illnesses were included

Exclusion Criteria

Non-English-language publications and studies on other diseases not associated with fungal pathogens were not included in this review. Studies performed in ambulatory environments or rehabilitation facilities were excluded. Systematic and narrative reviews, animal studies, editorial comments and expert opinions were also excluded.

Study Selection and Data Extraction Process

Two reviewers conducted a thorough search and screened according to the predetermined qualifying criteria of the review using online screening tool (Rayyan.ai). The titles and abstracts of the research studies were assessed and publications not meeting the criteria were excluded. Experts independently assessed the selected full-text articles. The reviewers arrived at a unanimous conclusion after a third reviewer had been invited in to mediate the conflicts between the two. The first author, journal, study title, year of publication, geographic area, study design, isotretinoin intervention regimen, employed antifungal therapies and study outcomes were gathered using a predefined data collection framework.

Data Synthesis

A quantitative meta-analysis was not possible due to the variability of trial designs, illness conditions, isotretinoin regimens, comparator therapies and outcome measures. As a result, the results were narratively summarized. Randomized controlled trials and comparative clinical studies were regarded as greater levels of evidence than case reports and case series, depending on the study design. To make it easier to compare the therapeutic benefits across research, results were categorized by type of fungal disease whenever possible.

Quality Appraisal

Risk of Bias (RoB) was appraised using the Cochrane Collaboration method ROBINS-I [12], which classifies bias as low, moderate, serious, critical or no information. The tool includes confounding bias, participant selection bias, intervention categorization bias, deviation from intended intervention bias, missing data bias, outcome assessment bias and selective reporting bias. Overall RoB for each study was categorized: Low RoB was given when all requirements were met. A moderate RoB was assigned to studies that did not meet any domains. When at least one domain had significant issues in any of the domains, it was considered a serious RoB. Critical concerns in at least one area indicate a critical RoB for the investigation. A study with no information and no evident evidence of serious or critical RoB was awarded no information.

Based on study quality according to the Cochrane Handbook for Systematic Reviews of Interventions, the RoB 2.0 tool was utilized to evaluate the RoB of RCTs as low, with some concerns or high [13]. These include randomization bias, departures from intended interventions, missing outcome data, measurement bias and reported result selection bias. Low RoB in all categories indicates low bias in the study. The overall RoB of the study is considered to have some concerns when the trial is determined to raise some issues in at least one domain. A study has a high RoB if it is regarded to be at high RoB in at least one area for this result or to have some issues for many domains that impair confidence in the result.

Two hundred forty-nine articles concerning the use of isotretinoin for fungal infections were identified. Titles and abstracts of 152 studies were evaluated, resulting in 54 studies deemed eligible for full-text evaluation. Thirty-eight studies were removed due to a lack of focus on fungal infections and inadequate target interventions. Finally, this review considered 16 studies [14-29] (Figure 1).

Figure 1: PRISMA (2020) Flow Chart of the Reviewed Studies

Among them, three were case reports [14,19,28]. The findings of our investigation are encapsulated in Table 1. Four research [15,17,21,24,25] focused on dermatophytosis, three [16,26,27,29] on seborrhoeic dermatitis and two each on pityriasis versicolor [14,28] and tinea [18,20,23] and one each on chromoblastomycosis [19] and mycosis fungoides [22]. There were four studies from India [15,21,23,25], three from Brazil [14,26,29], two each from China [16,19], Turkey [22,28] and Iraq [17,27] one each from Pakistan [20], Egypt [18] and Bangladesh [24].

Khattab et al. [18] administered treatment to patients with chronic recurrent/recalcitrant tinea utilizing the combined administration of oral itraconazole and isotretinoin, itraconazole monotherapy and voriconazole monotherapy, revealing cure (clinical) rates of 53.3% for the itraconazole group, 70% for the itraconazole/isotretinoin group and 83.3% for the voriconazole group. Mycological cure observed in the itraconazole, itraconazole/isotretinoin and voriconazole cohorts were 56.7, 83.3 and 86.7%, respectively. A statistically significant difference was observed across the three cohorts, favouring voriconazole against the combination group. A comparable study by Alhamdi and Alhamdi indicated a clinical cure rate of 97.5% for the combined administration of isotretinoin and itraconazole, accompanied by a notably low recurrence rate of 12.8%. In contrast, patients receiving itraconazole alone exhibited a cure rate of 53.7% and a relapse rate of 68.1%, with insignificant adverse effects disclosed. Rahman [24] performed a clinical trial to determine the efficacy of an oral monthly pulse regimen of itraconazole (200 mg twice/day for 7 days every month) that was combined with an everyday low dose of isotretinoin (20 mg) for the management of persistent superficial dermatophytosis. The treatment resulted in a 90% clinical cure rate and a 95% mycological cure rate, with no hematologic or biochemical variations seen.

A retrospective study [16] revealed that patients with moderate-to-severe seborrhoeic dermatitis who were administered either 20 mg or 10 mg of oral isotretinoin daily for 2-6 months, had a substantial decrease in the seborrhoeic dermatitis symptom scale in comparison with baseline measurements. Furthermore, there was no notable disparity in the results of these two groups. Kamamoto et al. [29] conducted an RCT among patients with moderate-to-severe seborrhoeic dermatitis contrasted isotretinoin 10 mg administered every other day to topical therapy, demonstrating that isotretinoin considerably reduced scalp pruritus and sebum production while enhancing quality of life relative to topical application. Taslidere et al. [22] observed that the combined use of narrow-band UVB and isotretinoin was not beneficial to narrow-band UVB therapy alone in terms of improved clinical outcomes and apoptotic induction. Nevertheless, recovery commenced sooner in the isotretinoin combined with the narrow-band UVB group. Verma et al. [21] also asserted that incorporating isotretinoin with terbinafine offers no further advantage in the management of those with recurrent dermatophytosis. The mycological cure rate in the isotretinoin and itraconazole cohort in the clinical trial by Priyadarshi et al. [15] was 97.5%. The cure rate was significantly higher than that stated in prior studies by various researchers [17,18,24,25] indicating that daily administration of 20 mg oral isotretinoin for two months provides additional advantages in the treatment of superficial dermatophytic infections. Furthermore, the relapse rate found by Priyadarshi et al. [15] was substantially lower in the isotretinoin and itraconazole group (2.6%) than documented in many other studies [17,18,24,25], emphasizing the relevance of oral isotretinoin in the alleviation of relapse if administered for a prolonged period. According to Yazici et al. [28], a case was successfully managed with oral isotretinoin (20 mg/day) for two months and a year-long remission was attained.

Henceforth, isotretinoin, whether administered as monotherapy or alongside existing antifungal medications, may serve as an intriguing option for innovative therapeutic or preventative antifungal strategies; thereby addressing the significant clinical challenge of fungal drug resistance.

Although several studies reported favorable outcomes with isotretinoin, these findings should be interpreted cautiously, as a substantial proportion of the evidence was derived from small sample sizes, open-label studies, observational designs and case reports.

Quality Assessment of the Reviewed Studies

Out of the six studies appraised using the ROBINS-I tool, three studies [14,19,28] exhibited a low RoB and three other studies [16,18,20] demonstrated a serious RoB (Figure 2).

Figure 2: ROBINS-I Tool for Evaluating the Risk of Bias of the Reviewed Non-Randomized Studies

Figure 3 illustrates the RoB across the non-randomized studies.

Figure 3: ROBINS-I Tool for Determining the Risk of bias across the Reviewed Non-Randomized Studies

The RoB 2.0 tool revealed that all the assessed studies [17,21-27,29] exhibited high RoB, except for one study [15] that raised some concerns (Figure 4).

Figure 4: ROB 2.0 tool for determining the risk of bias of the reviewed randomized controlled trials

The RoB across the evaluated RCTs is depicted in Figure 5. The predominance of studies with high or serious risk of bias limits confidence in the reported efficacy outcomes and highlights the need for cautious interpretation of the available evidence.

Figure 5: ROB 2.0 Tool for Determining the Risk of Bias Across the Reviewed Randomized Controlled Trials

The effectiveness of isotretinoin as a treatment for superficial mycoses is demonstrated by data from the reviewed clinical trials. Nevertheless, some of the reviewed studies [18,21,22] found isotretinoin ineffective in treating fungal infections than that of the comparison group. Further, Kamamoto et al. [26] documented equal effectiveness with isotretinoin and anti-seborrheic shampoo for the control of seborrhea/seborrheic dermatitis. Dermatophytic infections are rising globally, ascribed to a complicated interaction among host, fungus, medication and environment [30]. Additional significant causes comprise humid and elevated climatic conditions, the unregulated application of topical corticosteroid combinations, heightened utilization of broad-spectrum antibiotics, widespread usage of antifungal agents in agriculture and the rise of antifungal medication resistance [31]. Recurrences following an apparent resolution are also prevalent [32]. Multiple approaches have been employed to promote cure rates, including escalating the dosage of Dermatophytes inhibit keratinases and non-specific proteolytic enzymes, which are key virulence agents and exhibit their peak potency at acidic Ph [33]. Consequently, growth is contingent upon the skin pH, which, being acidic, provides an ideal setting for the fungus. Elevated transepidermal water loss and compromised skin barrier function are associated with increased skin Ph [34]. The elevation of skin pH due to treatment with retinoid compounds may limit the formation of dermatophytes. Ultimately, retinoids are widely regarded as stimulants of both humoral and cellular immunity and can augment antibody synthesis by activating T-helper cells. The cell surface antigens of T lymphocytes and natural killer cells were documented to be elevated following retinoid treatment in vitro [35]. Conversely, dermatophytes possess strategies that enable them to circumvent the host response such as a decrease in inflammation and phagocytosis [36,37]. Therefore, retinoids may mitigate certain immunosuppressive effects of the dermatophyte [5].

The medication causes atrophy of sebaceous glands and diminishes sebum production by up to 90%. Kraus et al. [38] documented that sebum production drops back to roughly 40% of the initial level within a month of therapy ending and it seldom regains its original levels. The concept may elucidate the sustained long-term remission achieved using isotretinoin medication. In the literature, isotretinoin has been successfully used to treat hidradenitis suppurativa, pityrosporum folliculitis, seborrhoeic dermatitis and persistent acne through the same approach [39,40]. Layton et al. [41] found that most patients exhibited long-term improvement in acne management following low-dose isotretinoin therapy, in addition to the well-established effectiveness of isotretinoin at doses of 0.5-1.0 mg/kg/day in the management of acne by Mandekou-Lefaki et al. [42]. Similarly, Geissler et al. [43] indicated that a minimal dosage of isotretinoin, specifically 2.5 mg administered three times/week, is beneficial in managing seborrhoea.

Ardeshna et al. [5] claimed superior outcomes for combination therapy utilizing isotretinoin and itraconazole in the management of recurrent dermatophytosis. Bartell et al. [44] also documented similar outcomes in the management of Tinea versicolor and were the first to see an incidental remission of a pre-existing skin infection lasting nine months following the administration of oral isotretinoin (40 mg twice daily) for acne vulgaris. Abraham and Piguet [45] documented two instances of Malassezia dermatosis that were well managed with oral isotretinoin (20 mg/day) in conjunction with topical ketoconazole. A recent systematic review [46] demonstrated that isotretinoin is more efficacious than oral itraconazole, antifungal shampoo or salicylic acid-incorporated soap in alleviating seborrhoeic dermatitis symptoms, even at modest dosages. Isotretinoin is an efficacious treatment for moderate-to-severe seborrhoeic dermatitis and is typically well-tolerated and safe [46]. Conversely, a retrospective investigation [47] has indicated that five patients who received isotretinoin treatment for acne later experienced seborrhoeic dermatitis-like skin eruptions.

The prevalence of obstinate recurrent infections caused by dermatophytes is approaching endemic status [5]. Our observation offers up possibilities for more research to address the utility of oral isotretinoin in recurrent dermatophytosis, even though we do not advise its routine usage for treating dermatophytes. Isotretinoin is excreted from the body by the desquamation of the stratum corneum during epidermal regeneration. Given that isotretinoin influences epidermal cell dynamics and enhances cell turnover, the concurrent treatment of isotretinoin and itraconazole would probably lead to expedited elimination of itraconazole from the dermis [48]. Consequently, we propose that comprehensive studies examining the impact of isotretinoin on the drug metabolism of itraconazole, specifically the variance in drug concentrations within the stratum corneum and sebum with and without the concomitant use of isotretinoin, should be conducted to further validate the integration of oral retinoids into antifungal treatment.

While several studies suggested potential benefits of isotretinoin, the overall certainty of the evidence remains limited because many included studies were characterized by small sample sizes, methodological limitations and high or serious risk of bias. Consequently, the reported benefits should be regarded as preliminary rather than definitive. Evidence from randomized controlled trials and comparative clinical studies was considered more clinically informative, whereas findings from case reports and case series should be regarded as hypothesis-generating and require confirmation in larger controlled investigations.

Cheilitis is the predominant side effect of isotretinoin, succeeded by eczema, fatigue and mood alterations. Laboratory studies reveal an elevation in total cholesterol and serum triglyceride levels. Mild and well-tolerated side effects are common. Nonetheless, the well-established teratogenicity of isotretinoin is an important safety concern; therefore, it should not be used during pregnancy or lactation [49]. In addition, regular clinical and laboratory monitoring is necessary throughout treatment because of its potential effects on lipid profiles and liver function. These considerations may reduce the practicality of isotretinoin as an adjunctive therapy for fungal diseases, particularly when safer conventional antifungal alternatives are available.

The adverse effects associated with isotretinoin predominantly involved mucocutaneous ailments including dry skin, skin fragility, erythema, xerosis, rashes, cracked lips, dry and sore mouth, insatiable thirst, cheilitis and nasal dryness. However, all of them are transitory and not serious. Furthermore, isotretinoin treatment has an impact on liver function tests and lipid profiles with a higher likelihood of increasing lipid levels than liver enzymes. In almost all the studies reviewed, the abnormalities in liver markers and lipid profiles were normalized immediately after discontinuation of the medication, in line with the findings of a recent single-arm meta-analysis [50]. Retinoid-induced myositis must be acknowledged in the clinical setting, as it presents a diagnostic difficulty due to the various aetiologies linked to myopathic disorders [51]. These undesirable effects signify individual reactions to a medication [29]. Comprehending the adverse events spectrum and effectively communicating it to the patient enhances the probability of adherence to the prescribed dose regimen and the utilization of supplementary treatment, which may mitigate or eradicate undesirable consequences.

From a clinical perspective, isotretinoin should not currently be considered a routine treatment for superficial fungal infections. Conventional antifungal agents remain the standard of care because of their established efficacy, safety profile and broader evidence base. Based on the currently available evidence, isotretinoin may be considered only as a selective adjunctive option in carefully chosen cases, particularly recurrent or treatment-resistant conditions and only after careful evaluation of potential risks and benefits.

Future Recommendations

Traditional antifungal drugs still remain the first-line treatment due to the proven efficacy, safety profile and solid research background. Considering the current level of evidence, isotretinoin should be limited to a selective adjunctive treatment in well-selected cases, particularly recurrent and resistant to treatment and after a comprehensive evaluation of possible risks and benefits. Future Recommendations Future research should focus on specific fungal diseases, rather than combining several diseases in a single study design. In particular, recurrent dermatophytosis and moderate-to-severe seborrhoeic dermatitis seem to be the most promising areas for further research. Well-designed double-blind randomized controlled trials are needed to determine the optimal dosing schedules, duration of treatment, recurrence rates and long-term safety outcomes. Further studies investigating the mechanisms are also needed to determine whether the beneficial effects of isotretinoin are due to changes in the skin environment or rather direct effects on the fungus’s ability to cause disease and form biofilms.

Despite its potential as an adjunctive treatment for selected fungal disorders, isotretinoin currently functions primarily as a supportive rather than a standalone therapy. The most encouraging evidence has been observed in recurrent dermatophytosis and seborrhoeic dermatitis; however, the available literature remains limited by small sample sizes, clinical heterogeneity and methodological limitations. Conventional antifungal agents should therefore remain the cornerstone of treatment. Further disease-specific, adequately powered, double-blind randomized controlled trials are required to clarify the efficacy, safety and optimal clinical role of isotretinoin in fungal diseases.

Limitations

This review should be considered in the context of the literature available. The number of studies eligible for inclusion was relatively small, reflecting the early stage of research on isotretinoin in fungal diseases. Moreover, clinical and methodological heterogeneity was introduced due to variations in fungal diseases, study designs, treatment regimens, outcome measures and follow-up durations. A number of studies had incomplete reporting of outcomes, including recurrence rates, adverse effects and long-term follow-up data, which limited the ability to directly compare across studies. Consequently, a quantitative meta-analysis and formal certainty-of-evidence assessment were not feasible. Nevertheless, the systematic inclusion of diverse study designs enabled a comprehensive overview of the currently available evidence and helped identify recurring patterns, potential therapeutic applications and important areas for future investigation. Therefore, while the findings should be interpreted with appropriate caution, they provide a valuable foundation for the design of future well-controlled studies evaluating isotretinoin as an adjunctive antifungal therapy.

1. Sharmeen, A. et al. “Study of Effect of Oral Itraconazole with 2% Sertaconazole Cream versus Oral Terbinafine with 2% Sertaconazole Cream in Dermatophytosis.” International Journal of Research in Dermatology, vol. 9, no. 5, 2023, pp. 274-281. https://doi.org/10.18203/issn. 2455-4529.IntJResDermatol20232542.
2. Sahoo, A.K. and R. Mahajan. “Management of Tinea Corporis, Tinea Cruris and Tinea Pedis: A Comprehensive Review.” Indian Dermatology Online Journal, vol. 7, no. 2, 2016, pp. 77-86. https://doi.org/10.4103/2229-5178.17 8099.
3. Singh, S.K. et al. “Efficacy of Terbinafine and Itraconazole in Different Doses and in Combination in the Treatment of Tinea Infection: A Randomized Controlled Parallel Group Open Labeled Trial with Clinico-Mycological Correlation.” Indian Journal of Dermatology, vol. 65, no. 4, 2020, pp. 284-289. https://doi.org/10.4103/ijd.IJD_548_19.
4. Khattab, F. et al. “Update in the Treatment of Recalcitrant Dermatophytosis.” Annals of the Romanian Society for Cell Biology, vol. 25, no. 6, 2021, pp. 16012-16017.
5. Ardeshna, K.P. et al. “Successful Treatment of Recurrent Dermatophytosis with Isotretinoin and Itraconazole.” Indian Journal of Dermatology, Venereology and Leprology, vol. 82, no. 5, 2016, pp. 579-582. https://doi.org/10.4103/ 0378-6323.183632.
6. Cosio, T. et al. “Retinoids in Fungal Infections: From Bench to Bedside.” Pharmaceuticals, vol. 14, no. 10, 2021. https:// doi.org/10.3390/ph14100962.
7. Paichitrojjana, A. and A. Paichitrojjana. “Oral Isotretinoin and Its Uses in Dermatology: A Review.” Drug Design, Development and Therapy, vol. 17, 2023, pp. 2573-2591. https://doi.org/10.2147/DDDT.S427530.
8. Kowalski, C.H. et al. “Fungal Biofilm Architecture Produces Hypoxic Microenvironments That Drive Antifungal Resistance.” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 36, 2020, pp. 22473-22483. https://doi.org/10.1073/pnas. 2003700117.
9. Tan, F. et al. “Bactericidal and Anti-Biofilm Activity of the Retinoid Compound CD437 Against Enterococcus faecalis.” Frontiers in Microbiology, vol. 10, 2019. https://doi.org/ 10.3389/fmicb.2019.02301.
10. Seebacher, C. et al. “Updates on the Epidemiology of Dermatophyte Infections.” Mycopathologia, vol. 166, nos. 5-6, 2008, pp. 335-352. https://doi.org/10.1007/s11046-008-9100-9.
11. Page, M.J. et al. “The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews.” BMJ, vol. 372, 2021. https://doi.org/10.1136/bmj.n71.
12. Sterne, J.A. et al. “ROBINS-I: A Tool for Assessing Risk of Bias in Non-Randomised Studies of Interventions.” BMJ, vol. 355, 2016. https://doi.org/10.1136/bmj.i4919.
13. Higgins, J. et al. “Chapter 8: Assessing Risk of Bias in a Randomized Trial.” Cochrane Handbook for Systematic Reviews of Interventions, version 6.4, updated August 2023, Cochrane, 2023. https://training.cochrane.org/ handbook/current/chapter-08.
14. Veasey, J.V. et al. “Oral Isotretinoin for the Treatment of Chronic Pityriasis Versicolor: Case Report and Literature Review.” Anais Brasileiros de Dermatologia, vol. 99, no. 4, 2024, pp. 639-642. https://doi.org/10.1016/j.abd.2023. 08.014.
15. Priyadarshi, D. et al. “Safety and Efficacy of Oral Itraconazole versus Combination with Oral Isotretinoin in Superficial Dermatophytosis: A Randomised Clinical Trial.” Journal of Clinical and Diagnostic Research, vol. 17, no. 5, 2023, pp. WC01-WC05.
16. Yanfei, Z. et al. “Efficacy and Safety of Oral Isotretinoin in the Treatment of Moderate to Severe Seborrheic Dermatitis: A Retrospective Study.” International Journal of Dermatology, vol. 62, no. 6, 2023, pp. 759-763. https:// doi.org/10.1111/ijd.16582.
17. Alhamdi, D.K. and K.I. Alhamdi. “Efficacy and Safety of Adding Low-Dose Isotretinoin to Itraconazole in the Treatment of Chronic Recurrent Dermatophytosis among Sample of Iraqi Patients: An Open-Labelled Therapeutic Clinical Comparative Study.” Indian Journal of Dermatology, vol. 67, no. 5, 2022. https://doi.org/10.4103/ijd. ijd_332_22.
18. Khattab, F. et al. “Voriconazole Is Superior to Combined Itraconazole/Isotretinoin Therapy and Itraconazole Monotherapy in Recalcitrant Dermatophytosis.” Mycoses, vol. 65, no. 12, 2022, pp. 1194-1201. https://doi.org/ 10.1111/myc.13517.
19. Lan, Y. et al. “Retinoid Combined with Photodynamic Therapy against Hyperkeratotic Chromoblastomycosis: A Case Report and Literature Review.” Mycoses, vol. 64, no. 1, 2021, pp. 18-23. https://doi.org/10.1111/myc. 13190.
20. Naseemullah et al. “Efficacy of Itraconazole vs Itraconazole Plus Isotretinoin in Treatment of Chronic Tinea.” Pakistan Journal of Medical & Health Sciences, vol. 15, no. 10, 2021, pp. 3316-3318.
21. Verma, K.K. et al. “Oral Isotretinoin Combined with Oral Terbinafine Versus Oral Terbinafine Alone to Treat Recurrent Dermatophytosis: An Open-Label Randomised Clinical Trial.” Indian Dermatology Online Journal, vol. 12, no. 6, 2021, pp. 820-825. https://doi.org/10.4103/idoj. IDOJ_167_21.
22. Taşlıdere, N. et al. “Effects of Narrow-Band UVB Alone and in Combination with Isotretinoin on Apoptosis and Its Clinical Implications in Early Stage Mycosis Fungoides.” Journal of the Turkish Academy of Dermatology, vol. 14, no. 1, 2020, pp. 6-11. https://doi.org/10.4274/jtad.galenos. 2020.36854.
23. Kaushik, K. “To Compare Efficacy of Oral Isotretinoin and Itraconazole Combination with Salicylic Acid 30% Chemical Peel for Tinea Corporis and Tinea Cruris.” International Journal of Current Research, vol. 11, no. 12, 2019, pp. 8936-8939. https://doi.org/10.24941/ijcr.374 58.12.2019.
24. Rahman, M.H. “Role of Itraconazole Pulse Therapy with Adjuvant Isotretinoin in Treating Recurrent and Recalcitrant Dermatophytosis.” Gulf Journal of Dermatology and Venereology, vol. 26, no. 2, 2019, pp. 11-14.
25. Arora, R. and A. Solanki. “Comparative Efficacy of Monotherapy of Oral Itraconazole and Oral Itraconazole with Isotretinoin in Chronic and/or Resistant Superficial Dermatophytosis.” Paripex - Indian Journal of Research, vol. 7, no. 6, 2018, pp. 9-11.
26. Kamamoto, C.S.L. et al. “Cutaneous Fungal Microbiome: Malassezia Yeasts in Seborrheic Dermatitis Scalp in a Randomized, Comparative and Therapeutic Trial.” Dermato-Endocrinology, vol. 9, no. 1, October 2017. https://doi.org/10.1080/19381980.2017.1361573.
27. Meran, A.D. and M.Y. Saeed. “Efficacy and Safety of Low Dose Oral Isotretinoin in Comparison with Oral Itraconazole in the Treatment of Seborrheic Dermatitis among Patients Attending Erbil Dermatology Teaching Center in Erbil City.” Zanco Journal of Medical Sciences, vol. 22, no. 3, 2018, pp. 420-426.
28. Yazici, S., B.E. Baskan and H. Saricaoglu. “Long-Term Remission of Recurrent Pityriasis Versicolor with Short-Term Systemic Isotretinoin Therapy.” Journal of Dermatology & Cosmetology, vol. 2, no. 2, 2018, pp. 94-95. https://doi.org/10.15406/jdc.2018.02.00050.
29. de Souza Leão Kamamoto, C. et al. “Low-Dose Oral Isotretinoin for Moderate to Severe Seborrhea and Seborrheic Dermatitis: A Randomized Comparative Trial.” International Journal of Dermatology, vol. 56, no. 1, 2017, pp. 80-85. https://doi.org/10.1111/ijd.13408.
30. Rajagopalan, M. et al. “Expert Consensus on the Management of Dermatophytosis in India (ECTODERM India).” BMC Dermatology, vol. 18, no. 1, 2018. https://doi. org/10.1186/s12895-018-0073-1.
31. Monod, M. “Antifungal Resistance in Dermatophytes: Emerging Problem and Challenge for the Medical Community.” Journal de Mycologie Médicale, vol. 29, no. 4, 2019, pp. 283-284. https://doi.org/10.1016/j.mycmed. 2019.100913.
32. Majid, I. et al. “Relapse after Oral Terbinafine Therapy in Dermatophytosis: A Clinical and Mycological Study.” Indian Journal of Dermatology, vol. 61, no. 5, 2016, pp. 529-533. https://doi.org/10.4103/0019-5154.190120.
33. Tsuboi, R. et al. “Isolation of a Keratinolytic Proteinase from Trichophyton mentagrophytes with Enzymatic Activity at Acidic pH.” Infection and Immunity, vol. 57, no. 11, 1989, pp. 3479-3483. https://doi.org/10.1128/iai.57. 11.3479-3483.1989.
34. Thune, P. et al. “The Water Barrier Function of the Skin in Relation to the Water Content of Stratum Corneum, pH and Skin Lipids. The Effect of Alkaline Soap and Syndet on Dry Skin in Elderly, Non-Atopic Patients.” Acta Dermato-Venereologica, vol. 68, no. 4, 1988, pp. 277-283.
35. Prabhala, R.H. et al. “Enhancement of the Expression of Activation Markers on Human Peripheral Blood Mononuclear Cells by In Vitro Culture with Retinoids and Carotenoids.” Journal of Leukocyte Biology, vol. 45, no. 3, 1989, pp. 249-254. https://doi.org/10.1002/jlb.45.3.249.
36. Martinez-Rossi, N.M. et al. “Antifungal Resistance Mechanisms in Dermatophytes.” Mycopathologia, vol. 166, nos. 5-6, 2008, pp. 369-383. https://doi.org/10.1007/s11 046-008-9110-7.
37. Ogawa, H. et al. “Dermatophytes and Host Defence in Cutaneous Mycoses.” Medical Mycology, vol. 36, suppl. 1, 1998, pp. 166-173.
38. Kraus, S.J. “Stress, Acne and Skin Surface Free Fatty Acids.” Psychosomatic Medicine, vol. 32, no. 5, 1970, pp. 503-508. https://doi.org/10.1097/00006842-197009000-00008.
39. Cowley, N.C. et al. “The Permissive Effect of Sebum in Seborrhoeic Dermatitis: An Explanation of the Rash in Neurological Disorders.” British Journal of Dermatology, vol. 122, no. 1, 1990, pp. 71-76. https://doi.org/10.1111/j. 1365-2133.1990.tb08241.x.
40. Friedman, S.J. “Pityrosporum Folliculitis: Treatment with Isotretinoin.” Journal of the American Academy of Dermatology, vol. 16, no. 3, pt. 1, 1987, pp. 632-633. https://doi.org/10.1016/S0190-9622(87)80117-2.
41. Layton, A.M. et al. “Isotretinoin for Acne Vulgaris-10 Years Later: A Safe and Successful Treatment.” British Journal of Dermatology, vol. 129, no. 3, 1993, pp. 292-296. https:// doi.org/10.1111/j.1365-2133.1993.tb11849.x.
42. Mandekou-Lefaki, I. et al. “Low-Dose Schema of Isotretinoin in Acne Vulgaris.” International Journal of Clinical Pharmacology Research, vol. 23, nos. 2-3, 2003, pp. 41-46.
43. Geissler, S.E. et al. “Very Low Dose Isotretinoin Is Effective in Controlling Seborrhea.” Journal der Deutschen Dermatologischen Gesellschaft, vol. 1, no. 12, 2003, pp. 952-958. https://doi.org/10.1046/j.1365-2303.2003.00108.x-i1.
44. Bartell, H. et al. “Tinea Versicolor Clearance with Oral Isotretinoin Therapy.” Journal of Drugs in Dermatology, vol. 5, no. 1, 2006, pp. 74-75.
45. Abraham, S. and V. Piguet. “An Unusual Presentation of Malassezia Dermatosis.” Dermatology, vol. 212, no. 1, 2006, pp. 4-6. https://doi.org/10.1159/000089014.
46. King, A. et al. “Isotretinoin for the Management of Moderate-to-Severe Seborrheic Dermatitis: A Systematic Review.” Journal of the American Academy of Dermatology, vol. 89, no. 5, 2023, pp. 1063-1066. https://doi.org/10. 1016/j.jaad.2023.07.010.
47. Barzilai, A. et al. “Seborrheic Dermatitis-Like Eruption in Patients Taking Isotretinoin Therapy for Acne: Retrospective Study of Five Patients.” American Journal of Clinical Dermatology, vol. 9, no. 4, 2008, pp. 255-261. https://doi.org/10.2165/00128071-200809040-00005.
48. Srivastava, A. and S.K. Kothiwala. “Isotretinoin May Affect Pharmacokinetics of Itraconazole in the Skin: Is It Rational to Combine Both for the Treatment of Dermatophytosis?” Indian Journal of Dermatology, Venereology and Leprology, vol. 83, no. 1, 2017, pp. 68-69. https://doi.org/10. 4103/0378-6323.194292.
49. Brzezinski, P. et al. “Adverse Effects of Isotretinoin: A Large, Retrospective Review.” Dermatologic Therapy, vol. 30, no. 4, 2017. https://doi.org/10.1111/dth.12483.
50. Kapała, J. et al. “Adverse Events in Isotretinoin Therapy: A Single-Arm Meta-Analysis.” International Journal of Environmental Research and Public Health, vol. 19, no. 11, 2022. https://doi.org/10.3390/ijerph19116463.
51. Rivillas, J.A. et al. “Myositis Induced by Isotretinoin: A Case Report and Literature Review.” American Journal of Case Reports, vol. 21, 2020. https://doi.org/10.12659/AJCR. 917801.

Table 1: Summary Characteristics of the Reviewed Studies

NR – Not reported; NA – Not applicable; SDASI - Seborrheic dermatitis area severity index; PV - Pityriasis versicolor; RCT – Randomized comparative trial; ALA-PDT - 5-aminolevulinic acid-based photodynamic therapy; DLQI - Dermatology Life Quality Index; IQR –Interquartile range