Combatting Anti-fungal Resistance: Selenium Sulfide as a Promising Solution in Tackling Tinea Versicolor and Seborrheic Dermatitis

In the world of microbes, the evolution of resistance to antimicrobial drugs is a process that is nearly inevitable. (1) While fungal resistance is not as pronounced as bacterial resistance, the economic impact associated with fungal infections remains significant. (2) Although the precise etiology of seborrheic dermatitis remains unclear, there is a strong correlation between the condition and the colonization of the skin by yeasts of the genus Malassezia. (3,4) Antifungal therapies that reduce the Malassezia population have been shown to be effective in managing the condition. (5) However, the development of resistance in these fungi poses a growing challenge in dermatological treatments or in treatment of Seborrheic Dermatitis (SD), necessitating continuous research and innovative therapeutic approaches to maintain treatment efficacy.

The rise of Antifungal Resistance or Emerging Challenges in anti-fungal resistance

The rate at which new anti-fungal medications are developed is low, while the prevalence of these diseases is rising quickly, and so is the growth of resistance to these medications. Ketoconazole, an imidazole compound, exhibits potent fungistatic activity against Malassezia, making it highly effective in treating dandruff and seborrheic dermatitis by inhibiting ergosterol synthesis in fungal cell membranes. (6,7) However, prolonged and widespread use of ketoconazole has become a significant concern, as it has led to the development of resistance in Malassezia species against this antifungal medication. (8) The antifungal resistance to azoles, was first reported in the 1980s. (9) Azole resistance may be primary (intrinsic) or secondary (acquired). (10) Both may be attributed to an increase in the prophylactic and irrational use of azole drugs, prolonged treatment regimens, agricultural use of azole fungicides for crop protection. (11) A study by Park et al. found M. restrica strains resisting ketoconazole in patients with dandruff. This study suggests that a common adaptive mechanism like tandem multiplication might be the mechanism underlying resistance in Malassezia against azole drugs. (8)(12) In another prospective study conducted at a Portuguese University Hospital's Dermatology Department over three years, researchers identified 86 Malassezia isolates from 182 volunteers, characterizing them by species through sequencing. Drug susceptibility, assessed using a broth microdilution assay (following Clinical Laboratory Standards Institute guidelines), revealed Malassezia sympodialis as the predominant species. A significant resistance to azoles was seen, evidenced by high MIC values and a wide range across isolates. This resistance highlights potential challenges in effectively treating Malassezia infections. (13)

A few other recent studies have highlighted a concerning rise in antifungal resistance among Malassezia species. These studies have reported isolates exhibiting high minimum inhibitory concentrations (MICs) against several azoles, which are commonly used antifungal agents. (14,15) This trend is particularly alarming given the prevalence of Malassezia in various skin and systemic infections, necessitating long-term antifungal treatments. The growing evidence of azole resistance underscores the need for continuous monitoring and research to develop effective treatment strategies and prevent further resistance.

Mechanisms of development of Anti-fungal resistance in Malassezia spp.

One of the primary challenges in treating Malassezia-related conditions is the development of antifungal resistance. (16) Clinical resistance, defined as an infection persisting or progressing despite appropriate therapy, was once rare but is now increasingly reported. (9,17) Resistance mechanisms include both intrinsic and acquired factors, such as altered gene expression, leading to decreased susceptibility to antifungal agents. (9) Mechanism of resistance in fungi include enzyme alterations, drug efflux, and mutations reducing drug binding. (18) Overexpression of major facilitator superfamily (MFS) and ATP-binding cassette (ABC) transporters enhances multidrug resistance by actively expelling antifungal agents through ATP hydrolysis or electrochemical gradients. (19–22) In Malassezia restricta, it has also been discovered that genomic duplications in ATM1 and ERG11, which encode iron-sulfur transporters, confer ketoconazole resistance. (8) Additionally, alterations in the fungal cell membrane composition can reduce the binding affinity of antifungal drugs, making them less effective. (23,24) Mutations in target enzymes, such as lanosterol 14α-demethylase, decrease susceptibility to azole antifungals by modifying the drug-binding site. (25) These adaptive changes enable Malassezia to survive in the presence of antifungal agents, posing a significant challenge to treatment efforts. This highlights the necessity for novel therapeutic strategies and the development of new antifungal agents to effectively manage Malassezia-related conditions. Additionally, exploring non- antifungal treatment options could provide alternative or adjunctive therapies, addressing the multifaceted nature of seborrheic dermatitis and potentially improving patient outcomes.

Role of Selenium sulfide

Selenium sulfide has been used for decades as an effective agent for dandruff, particularly in treating seborrheic dermatitis and tinea versicolor. (26) It disrupts the growth and replication of fungi by interfering with their cellular metabolism, specifically targeting the cell membranes of fungi like Malassezia, leading to their destruction. (27) Additionally, selenium sulfide works by generating reactive oxygen species (ROS), which further damages fungal cells. This multifaceted mechanism of action makes it difficult for fungi to develop resistance. (28) Clinical studies have demonstrated the efficacy of selenium sulfide in managing seborrheic dermatitis and tinea versicolor. For instance, a study by William Danby et al. highlighted its effectiveness in controlling dandruff through selenium sulfide shampoo. (29) Similarly, a study conducted by Rapaport, compared the efficacy of four anti-dandruff shampoos in 199 patients which resulted in substantial improvement of symptoms in patients who used the shampoo containing selenium sulfide as opposed to the other options. (30) Importantly, there is currently limited evidence of fungal resistance to selenium sulfide, making it a valuable alternative to azole antifungals, which have seen a rise in resistant fungal strains. This lack of significant resistance underscores selenium sulfide's potential as an alternative or adjunctive therapy in the management of fungal skin infections. The sustained effectiveness of selenium sulfide, despite widespread use, highlights its enduring place in the dermatological arsenal against fungal pathogens and reinforces its role in combating antifungal resistance. (31) As one of the oldest molecules, its underrated potential continues to offer promising outcomes in the fight against fungal infections such as Seborrheic Dermatitis and Tinea Versicolor. (31)

Conclusion

Antifungal resistance is a growing concern in dermatology, (12) particularly with the widespread use of azole compounds like ketoconazole. Malassezia species have demonstrated an ability to develop resistance to these treatments, complicating the management of conditions such as seborrheic dermatitis and tinea versicolor. (16) Selenium sulfide presents a promising alternative due to its potent antifungal, anti-inflammatory, and keratolytic properties. Its effectiveness against azole-resistant strains and the absence of significant resistance makes it a critical component in the dermatological treatment protocols. While there is not as much data available on resistance to selenium sulfide as there is for ketoconazole, its proven efficacy positions it as a superior option in combating fungal infections. Further research is needed to fully understand selenium sulfide's mechanisms and explore its potential in treating other fungal infections, ensuring it remains a frontline treatment option in the face of rising antifungal resistance.

For the use of a registered medical practitioner or a hospital or a laboratory only.

IND2327687 02 Sep 2024

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