An update on the myriad antifungal resistance mechanisms in dermatophytes and the place of experimental and existential therapeutic agents for Trichophyton complex implicated in tinea corporis and cruris.

INTRODUCTION: There is an epidemic emergence of increased resistance in dermatophytes with to antifungal drugs with ergosterol1 (Erg1) and Erg11 mutations to terbinafine and azoles. Apart from mutations, mechanisms that predict clinical failure include efflux pumps, cellular kinases, heat shock proteins (Hsp), and biofilms. Apart from itraconazole and SUBATM (Super-Bioavailable) itraconazole, measures that can be used in terbinafine failure include efflux-pump inhibitors, Hsp inhibitors and judicious use of antifungal drugs (topical + systemic) combinations. AREAS COVERED: A PubMed search was done for the relevant studies and reviews published in the last 22 years using keywords dermatophytes OR Trichophyton, anti-fungal, resistance, mechanism and fungal AND resistance mechanisms. Our aim was to look for literature on prevalent species and we specifically researched studies on Trichophyton genus. We have analyzed varied antifungal drug mechanisms and detailed varied experimental and approved drugs to treat recalcitrant dermatophytosis. EXPERT OPINION: Apart from administering drugs with low minimum inhibitory concentration, combinations of oral and topical antifungals (based on synergy data) and new formulations of existing drugs are useful in recalcitrant cases. There is a need for research into resistance mechanism of the existent Trichophyton strains in therapeutic failures in tinea corporis & cruris instead of data derived from laboratory strains which may not mirror clinical failures.

Treatment recalcitrant cases of tinea corporis/cruris caused by T. mentagrophytes - interdigitale complex with mutations in ERG11 ERG 3, ERG4, MDR1 MFS genes & SQLE and their potential implications.

BACKGROUND: Recalcitrant dermatophyte infections are being reported from various parts of the world due to varied causes including strain variation, steroid misuse, SQLE mutations, and variable quality of itraconazole pellet formulations. The oral drug preferred in endemic areas is itraconazole, to which MIC levels remain low, and clinical failures to itraconazole reported defy a sound scientific explanation. OBJECTIVES: The objective of the study was to conduct a proteomic and genomic analysis on isolates from therapeutically recalcitrant case with isolation of gene mutations and enzymatic abnormalities to explain azole failures. METHODS: Trichophyton mentagrophyte interdigitale complex strains were isolated from seven clinically non-responding tinea corporis/cruris patients, who had failed a sequential course of 6 weeks of terbinafine 250 mg QD and itraconazole 100 mg BID. After AFST 1 strain, KA01 with high MIC to most drugs was characterized using whole genome sequencing, comparative proteomic profiling, and total sterol quantification. RESULTS: Sterol quantification showed that the standard strain of Trichophyton mentagrophytes (MTCC-7687) had half the ergosterol content than the resistant KA01 strain. Genomic analysis revealed mutations in SQLE, ERG4, ERG11, MDR1, MFS genes, and a novel ERG3 mutation. Proteomic analysis established the aberrant expression of acetyl Co-A transferase in the resistant strain and upregulation of thioredoxin reductase and peroxiredoxin. CONCLUSION: Our findings demonstrate possible reasons for multidrug resistance in the prevalent strain with mutations in genes that predict terbinafine (SQLE) and azole actions (ERG4, ERG11, ERG3) apart from efflux pumps (MDR1, MFS) that can explain multidrug clinical failures.

A prospective real-world study evaluating serum levels of arginine and cysteine in women with chronic telogen effluvium: do we really need blanket prescription of amino acid supplementation?

Amino acids form a major component of hair fibres and are prescribed routinely in the form of nutritional supplements in patients with chronic telogen effluvium (CTE). Such a practice is based on assumption of a nutritional deficiency state in such patients. In this prospective study, we evaluated the serum levels of cysteine and arginine in 30 women with CTE and in healthy controls. We found no significant difference between the two groups in terms of serum arginine levels. Cysteine levels were higher in patients with CTE (P < 0.001). No correlation was found between levels of serum amino acids (cysteine and arginine) and either diet type (vegetarian or not) or body mass index, and no significant correlation between levels of the two amino acids and severity of disease. Our work suggests that arginine and cysteine deficiency is not present in women with CTE. Supplementation is unlikely to be of any benefit in nutrient-replete populations and only adds to the cost of therapy.

Adjunctive use of saturated solution of potassium iodide (SSKI) with liposomal amphotericin B (L-AMB) in mucormycosis achieves favorable response, shortened dose and duration of amphotericin: A retrospective study from a COVID-19 tertiary care center.

PURPOSE: Second wave of COVID-19 pandemic was associated with an unprecedented rise in cases of mucormycosis, treatment of which has been challenging owing to the availability and side effects associated with amphotericin. METHODS: All patients presenting with rhino-orbital cerebral mucormycosis (ROCM) following COVID-19 infection between April 2021 to June 2021 were included in this retrospective interventional study. Primary objective was to assess the clinical response with combination of intravenous liposomal amphotericin B (4-5 mg/kg/day) and saturated solution of potassium iodide (SSKI) given orally along with surgical debridement. RESULTS: Twenty-five patients of ROCM were treated with the regimen. Mean age and fasting blood sugar levels were 53.48 years and 239.64 mg/dL respectively. All patients had history of intake of steroids with a mean daily dose of 86.39 mg of prednisolone equivalent. 88% of patients had a "proven" diagnosis of mucormycosis. Cultures were positive in 52% of patients with Rhizopus arrhizus as the predominant species. The mean daily dose of amphotericin received was 268 mg/day with a mean duration of 9.52 days. Mean daily dose of SSKI was 2.57 g. 21 patients (84%) had stabilization of disease at week 8 and achieved cure at the end of treatment whereas the mortality rate was 16%. Factors that significantly affected outcome were eye and central nervous system (CNS) involvement on presentation. CONCLUSION: SSKI, with its remarkably low cost and safety profile, makes it a potential adjuvant drug that may help achieve the twin benefits of shortened duration and dose of LAMB.

Role of nutritional supplements in selected dermatological disorders: A review.

BACKGROUND: While a plethora of literature continues to be published on the role of nutritional agents both in lay press and indexed journals, the data is not on a firm footing and leaves the dermatologist in a quandry and the patient confused. The various agents include vitamins, minerals, amino acids, antioxidants, diets & gluten. A proper knowledge of the role of nutritional supplements in dermatological diseases can be a useful tool in advising the patients and in certain cases ameliorating the disorder. PATIENTS/METHODS: Literature review of last 15 years was made using the terms "diet in dermatology," "nutrition and skin," "nutritional supplements in dermatology," "nutritional agents and acne," "nutritional agents and alopecia," and "nutritional agents and psoriasis." RESULTS: While there are multiple publications on the use of nutritional supplements for amelioration of skin diseases, most of them are based on either associations or in vitro studies, but very few transcend the rigors of a clinical trial or the holey grail of a double-blinded randomized controlled trial. There seem to be some evidence in acne, psoriasis, telogen effluvium, urticaria & vitiligo. Coeliac disease and dermatitis herpetiformis have a strong link with diet. Rosacea has a strong link with certain foods, but the other disorders like melasma, aphthous stomatitis do not have any scientifically validated association with diet. CONCLUSIONS: Our updated review examines the role of nutritional supplements and antioxidants in various dermatological disorders. We have found that there are varying levels of evidence with notable associations of low glycemic diet & acne, fish oil & weight loss with psoriasis, fish oils & probiotics with atopic dermatitis & vitamins & botanical extracts with vitiligo. The evidence for diet and nutrition in bullous disorders and photoageing is scarce. The role of low histamine diet in urticaria is useful in select cases of episodic urticaria. Rosacea is triggered by hot and spicy food . Apart from gluten and Dermatitis Herpetiformis, no diet can be considered disease modifying in our reveiw. The lack of comparison of nutritional or dietary modiffication with conventional validated agents, makes the data difficult to translate in real world patient management.

A Prospective Study Examining the Effect of Selected Topical and Systemic Drugs on Pruritus Grading System Score and STAT 6 Expression in Patients of Prurigo Nodularis.

Background: Prurigo nodularis (PN) is a chronic dermatologic condition presenting as multiple papulonodular lesions occurring with intense pruritus. Though numerous agents (topical, systemic, phototherapy and biological drugs) have been tried, the outcomes are variable. Objectives: The aim of this study was to assess the role of topical and systemic therapies in primary PN by comparing the Pruritus Grading System (PGS) score at baseline and 1 month post-therapy. Materials and Methods: Of 86 diagnosed cases of PN, 49 cases of primary PN were clinically graded by Pruritus Grading System Score (PGSS), and assessed histopathologically by IHC staining (STAT-1, 3, and 6). Apart from topical agents, oral nortriptyline (mild grade), methotrexate (moderate grade) and thalidomide (severe grade) were administered, whereas doxepin was administered for itching. The PGSS was assessed after 1 month of therapy. Results: Among 49 patients of PN, the majority of patients showed a significant decrease in PGSS (P = <0.001) in 1 mont, which correlated with STAT-6 expression. The combination of different topical and oral agents resulted in a statistically significant change in severity, though individual drugs did not achieve statistically significant results. Conclusion: A combination of selected oral and topical agents can effectively control the severity of PN within one month, and this was found to correlate with STAT 6 expression.

Complete cure of Fusarium solani sp. complex onychomycosis with Qs NdYAG treatment.

The incidence of non dermatophytic mould (NDM) onychomycosis (OM) has been steadily increasing Fusarium spp is the most common cause of NDM OM in most geographical locations. Fusarium spp and other NDMs are largely resistant to commonly used anti-fungals. The successful use of laser and light based devices has been demonstrated in dermatophytic OM, but there is no previous report of their successful use in any NDM OM. We describe a patient with OM caused by Fusarium solani spp, who was clinically (with a normal appearing nail) and mycologically (with negative microscopy and culture on repeated samples) cured of her infection following treatment with 2 sessions of Qs NdYAG (532nm and 1064nm) given 1 month apart.

A prospective study comparing ultrapulse CO2 laser and trichloroacetic acid in treatment of Xanthelasma palpebrarum.

BACKGROUND: Xanthelasma Palpebrarum is a type of xanthoma which presents as cosmetic concern. OBJECTIVE: To compare the efficacy of 30% TCA and UpCO2 laser in XP. METHODS AND MATERIALS: Fifty patients with XP were categorized clinically into three groups. Patients in each group were alternately allocated to 30% TCA (Group A) and laser (Group B). TCA was applied weekly (maximum: 12 sessions), and laser sessions were given monthly (maximum: three sessions). The primary outcome measures were total patients cured, the number of sessions, and mean VAS at the end of treatment. The secondary outcome measures were total duration of treatment, side effects, and recurrence in follow-up (6 months) (P < 0.05 significant). RESULTS: In Group A, 14 of 25 and in Group B, 25 of 25 patients achieved complete cure (P < 0.05). The mean VAS was lower for Group A (patient: 4.56 vs. 5.36; physician: 4.64 vs. 5.44) [P < 0.05] with significant difference only for group III patients. Mean number of sessions was less with laser group (1.56 vs. 9.74), except in group I. There was no significant difference in pigmentary changes and recurrence. CONCLUSION: For clinically mild lesions, both TCA and laser are good options, but laser is a better option for severe lesions. Recurrence is a concern with both modalities.

A rapid tattoo removal technique using a combination of pulsed Er:YAG and Q-Switched Nd:YAG in a split lesion protocol.

BACKGROUND: Tattoo removal has evolved over the years and though Q-switched laser is the 'workhorse' laser, it invariably requires multiple sittings, which are dependent on numerous factors, including the skin colour, location of the tattoo, age of the tattoo, colour of pigment used, associated fibrosis and the kind of tattoo treated. Though ablative lasers, both pulsed CO2 and Er:YAG, have been used for recalcitrant tattoos, very few studies have been done comparing them with pigment-specific lasers. Our study was based on the premise that ablating the epidermis overlying the tattoo pigment with Er:YAG could help in gaining better access to the pigment which would enable the Q-switched laser to work effectively with less beam scattering. OBJECTIVE: A study of rapid tattoo removal (RTR) technique using a combination of pulsed Er:YAG and Q-Switched Nd:YAG in a split lesion protocol. MATERIALS AND METHODS: This prospective study was undertaken during 2010-13 at a laser Clinic in the Maulana Azad Medical College, New Delhi. A total of 10 patients were recruited, 5 of amateur tattoo and 5 of professional tattoo. After informed consent each tattoo was arbitrarily 'split' into two parts. One part was treated with QS Nd:YAG laser(1064 nm) and the other part with Er:YAG laser immediately followed by the QS Nd:YAG. The laser treatments were repeated at 6-week intervals until the tattoo pigment had cleared. On the combination side in subsequent sittings only the QS Nd:YAG was used, to minimize repetitive ablation. To ensure consistency in the intervention methods a trained dermatologist who was independent of the treatment delivery randomly rated 10% of the procedures. RESULTS: The mean improvement achieved by the Q-switched laser (2.93) was less than the combination laser (3.85) side (p = 0.001) and needed more sessions (3.8 vs. 1.6; p = 0.001). There was a statistically significant difference in the improvement on the combination side till the second session. On the combination side patients required a maximum of 2 sessions, while the Q-switched laser required 3-5 sessions for appreciable lightening. CONCLUSION: From our study it was concluded that use of a pulsed ablative laser may help in rapid removal of tattoos in conjunction with QS lasers with minimal side effects and can be used as a RTR.

An observational study of methionine-bound zinc with antioxidants for mild to moderate acne vulgaris.

APC is a novel methionine-based zinc complex with antioxidants that has been used in acne as a nutritional supplement. This is based on the proven role of zinc and antioxidants in improving acne, specially the inflammatory lesions. The objectives of this study are to explore the efficacy, safety, and tolerability of APC in acne patients with mild to moderate facial acne vulgaris. In this exploratory trial, 48 patients were treated with oral APC thrice a day for 3 months followed by a 4-week treatment-free period. At the end of treatment (Week 12), there was a statistically significant improvement in the global acne count (p < 0.05), which began after 8 weeks (p < 0.05). Almost 79% (38/48) of the patients had 80-100% improvement. There was a significant reduction in pustules (8 weeks (p < 0.05) and 12 weeks (p < 0.001)), and papules and closed comedones (8 weeks (p < 0.05) and 12 weeks (p < 0.001)). Only two patients had side effects. The current data indicate that treatment with oral APC thrice daily for 12 weeks in patients with mild to moderate facial acne vulgaris is efficacious and well tolerated. As the onset of action is late, concomitant topical therapy can enhance the results.

Therapeutic trials for systemic sclerosis: an update.

The pathogenesis of systemic sclerosis (SSc) is complex, and the final story is yet to be elucidated. The clinical heterogeneity of the disease, its various autoimmune and antibody profiles, its long course and tendency for spontaneous cure makes the design of clinical trials difficult. The overwhelming need in this disease is to diagnose it early and identify those patients who will benefit most from early, aggressive treatment. We attempt to review data from recent clinical trials and the lessons derived.

Malignant transformation of donovanosis (granuloma inguinale) in a HIV-positive patient.

Donovanosis is endemic in various parts of the world. Although donovanosis has been reported to co-exist with the human immunodeficiency virus (HIV) infection, to our knowledge there have been no reports of co-existent squamous cell carcinoma (SCC) in an HIV positive patient. In our case the patient did not respond to treatment for donovanosis and on biopsy we realized that the patient had coexistent SCC, which is hitherto unreported with granuloma inguinale.