In vitro determination of the combination of ciclopirox and terbinafine in the treatment of dermatophytosis.

INTRODUCTION: The cases of dermatophytosis are increasing and they are associated with a higher number of therapeutic failures leading the doctor to prescribe combinations of antifungals as therapy. The objective was to evaluate the interaction of terbinafine and ciclopirox, the most commonly antifungals used in the clinic, in dermatophyte isolates. METHODOLOGY: The minimum inhibitory concentrations (MIC) of ciclopirox and terbinafine were determined by the broth microdilution method according CLSI and the checkerboard assay was used to evaluate the interaction between the antifungal agents. RESULTS: For terbinafine the mic50 was 0.125 ug/mL and mic90 was 0.250 ug/mL. For ciclopirox the values were 2.0 ug/mL for mic50 and 4.0 ug/mL for mic90. No synergistic interaction was observed for the dermatophyte isolates tested. CONCLUSION: These results suggest that the use of terbinafine in combination with ciclopirox, which is widely used in the clinic, may not be a good choice for the treatment of onychomycosis.

Prior selection of itraconazole in the treatment of recalcitrant Trichophyton indotineae infection: Real-world results from retrospective analysis.

BACKGROUND: The number of terbinafine-resistant Trichophyton indotineae is increasing in recent years while the treatment is still a matter to discuss. OBJECTIVES: To explore the best therapeutic approach, we present real-world treatment of T. indotineae infection by analysing publicly available data. METHODS: We have reviewed all published articles, mainly including case reports and case series, on the drug-resistant T. mentagrophytes complex by using the key search terms to search the databases. RESULTS: We enrolled 25 articles from 14 countries, including 203 times of treatment information for 113 patients. The cure rate of itraconazole 200 mg per day at the fourth, eighth and the twelfth week were 27.27%, 48.48% and 54.55%, respectively, which was significantly higher than terbinafine 250 mg per day (8.77%, 24.56% and 28.07%) and even 500 mg/d terbinafine. Griseofulvin 500-1000 mg for 2-6 months may be effective while fluconazole had no record of successful treatment. Voriconazole and ravuconazole had potential therapeutic efficacy. Topical therapy alone showed limited therapeutic efficacy, but the combination with oral antifungals can be alternative. CONCLUSION: Oral itraconazole 200 mg per day for 4-8 weeks was the most effective treatment out of these commonly used antifungal drugs, and can be prior selection.

Azorean Black Tea (Camellia sinensis) Antidermatophytic and Fungicidal Properties.

The treatment of dermatophytoses, the most common human fungal infections, requires new alternatives. The aim of this study was to determine the antidermatophytic activity of the aqueous Azorean Black Tea extract (ABT), together with an approach to the mechanisms of action. The phytochemical analysis of ABT extract was performed by HPLC. The dermatophytes susceptibility was assessed using a broth microdilution assay; potential synergies with terbinafine and griseofulvin were evaluated by the checkerboard assay. The mechanism of action was appraised by the quantification of the fungal cell wall chitin and ß-1,3-glucan, and by membrane ergosterol. The presence of ultrastructural modifications was studied by Transmission Electron Microscopy (TEM). The ABT extract contained organic and phenolic acids, flavonoids, theaflavins and alkaloids. It showed an antidermatophytic effect, with MIC values of 250 µg/mL for Trichophyton mentagrophytes, 125 µg/mL for Trichophyton rubrum and 500 µg/mL for Microsporum canis; at these concentrations, the extract was fungicidal. An additive effect of ABT in association to terbinafine on these three dermatophytes was observed. The ABT extract caused a significant reduction in ß-1,3-glucan content, indicating the synthesis of this cell wall component as a possible target. The present study identifies the antidermatophytic activity of the ABT and highlights its potential to improve the effectiveness of conventional topical treatment currently used for the management of skin or mucosal fungal infections.

[Top 4 Research Studies of the month for Italian Primary Care Physicians: November 2023.] / La Top 4 di novembre 2023. Gli studi clinici che vale la pena conoscere se lavori nelle cure primarie in Italia.

This monthly article provides a collection of summaries of the most relevant studies identified as POEMs (patient-oriented evidence that matters) for Italian primary care physicians. 1) Based on efficacy, safety, and cost, a regimen of terbinafine 250 mg once daily for 12 weeks, followed by a 12-week period of no therapy, and then a 4-week booster of terbinafine 250 mg is preferred for onychomycosis in adults for the outcome of complete cure at 1 year. 2) A high-quality randomized trial found that standard-course antibiotic therapy for children with uncomplicated urinary tract infection was superior to short-course therapy. However, the number needed to treat of 28 suggests that offering short-course therapy is not unreasonable, especially if there is good follow-up in the subsequent weeks. 3) An updated guideline of the American College of Physicians on screening of colorectal cancer adds 2 new recommendations. One is to consider not screening patients aged 45 to 49 years. The other recommendation is against screening using stool Dna, computed tomography colonography, capsule endoscopy, urine, or serum screening tests for colorectal cancer. 4) The US Preventive Services Task Force found additional evidence on the benefit of folic acid supplementation for preventing neural tube defects. Since the critical period starts at least 1 month before conception, the task force recommends a daily supplement of 0.4 mg to 0.8 mg folic acid for all women who plan to or could become pregnant.

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.

Evaluation of the efficacy of topical Terminalia chebula Retz. with vinegar in the treatment of tinea corporis: a non-inferiority randomized controlled trial.

OBJECTIVES: Unani physicians have suggested a wide range of anti-dermatophytic remedies, although the scientific evidence is scarce. Thus, the efficacy and safety of Terminalia chebula Retz. fruit powder mixed with vinegar was compared with terbinafine hydrochloride 1% cream in the treatment of tinea corporis in order to establish the non-inferiority of test drugs. METHODS: The primary outcome measures were change in the presence or absence of hyphae on KOH mount test, change in pruritus severity assessed on 100 mm VAS and change in physician's global assessment. Secondary outcome measure was change in the dermatology life quality index (DLQI). Hemograms, serum creatinine, serum bilirubin, and random blood sugar levels were measured at the baseline and after treatment to ensure the safety of the interventions. RESULTS: A per-protocol analysis was done on 40 participants (21 in the test group and 19 in the control group). The observed differences in the primary and secondary outcomes between the test and control groups were greater than the non-inferiority margin, signifying that the test drugs were not inferior. CONCLUSIONS: It may be inferred that the trial drug Terminalia chebula Retz. fruit powder mixed with vinegar is not inferior to terbinafine hydrochloride cream in the treatment of tinea corporis.

Trichophyton indotineae, from epidemiology to therapeutic.

Trichophyton indotineae is a newly described dermatophyte species. This fungal pathogen has recently emerged in India and is responsible for chronic or recurrent widespread superficial infections. Resistance to terbinafine is frequently associated to this pathogen and is related to point mutations in the gene encoding the squalene epoxidase. T. indotineae infections have been reported outside India, highlighting the risk of worldwide diffusion of this microorganism. Species identification and antifungal susceptibility determination are key points for infection control but still remain challenging. Systemic treatment is usually required and itraconazole is frequently prescribed in case of terbinafine resistance. This review summarizes main features of T. indotineae taxonomy, epidemiology, clinical manifestations, identification, antifungal profile, treatment and prevention.

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.

Efficacy and safety of 250 mg versus 500 mg oral terbinafine in the treatment of tinea corporis and cruris: A randomised, assessor-blinded comparative study.

Background Though higher doses of terbinafine are often prescribed to treat dermatophyte infections, it is unknown if such doses are more effective than the conventional dose because comparative data are unavailable. Aim To compare the efficacy and safety of a once-daily dose of oral terbinafine 250 mg with 500 mg along with topical clotrimazole in the treatment of tinea infections. Methods A randomised, assessor-blinded, comparative study was carried out. Each group of subjects were administered either 250 mg or 500 mg oral terbinafine once daily for four weeks, along with topical clotrimazole. Clinical improvement was assessed after two weeks and again after four weeks from treatment initiation. Result A total of 60 patients with tinea corporis and cruris were randomised into two groups receiving either 250 mg (group A) or 500 mg (group B) oral terbinafine, along with clotrimazole cream in both groups. Baseline clinical parameters such as lesional activity (papules, vesicles and pustules), degree of erythema, scaling and severity of itching were comparable between both treatment arms. At the first and second follow-ups, no significant differences were found in the clinical parameters between the two groups. At the end of two weeks 13.8% of group A and 14.3% of group B and after 4 weeks 25.9% of group A and 33.3% of group B participants became KOH negative (P = 1.00 and 0.76, respectively). No significant difference in culture negativity was reported at the end of therapy (four weeks) between the two treatment arms (P = 0.78). Overall cure rates were 20% and 33.3% in the two treatment arms respectively at the end of the study (P = 0.82). Conclusion Oral terbinafine 250 mg daily yielded a poor cure rate in tinea cruris and corporis after 4 weeks of treatment and an increased dose of 500 mg did not have any additional benefit.

Assessing the efficacy and safety of Unani pharmacopoeial formulations in dermatophytosis (quba) - a randomized controlled trial.

OBJECTIVES: The recent trends of rising unresponsive cases of dermatophytosis to conventional therapies pose a challenge in clinical practice. Unani medicine offers effective treatment for dermatophytosis. This study aimed to evaluate the efficacy and safety of the Unani herbo-mineral preparations Qurs-e-Asfar (QA) and Rogan-e-Narjeel (RN) in dermatophytosis. METHODS: This was a randomized, active-controlled and open-label clinical study. The participants diagnosed with dermatophytosis (n=78) randomized into treatment group (n=40) receiving oral QA (778 mg twice a day) and topical RN and control group (n=38) receiving oral Itraconazole (100 mg/day) and topical Terbinafine hydrochloride (1%) for 6 weeks. RESULTS: We found post-treatment improvement in itching by 86.3% vs. 78% (treatment vs. control group), erythema by 96.4% vs. 94.3%, scaling by 93% vs. 92.2% and peripheral raised margins by 82.3% vs. 81%. Furthermore, this study showed that the differences in the mean Total Signs and Symptoms Score (TSSS) and positive KOH mount were clinically and statistically significant (p<0.05) in both the groups. On comparing inter group, the differences in mean TSSS (p=0.07) and positive KOH mount (p=0.717) were found statistically insignificant. CONCLUSIONS: This study concludes that the formulations QA and RN were effective and safe in the treatment of dermatophytosis.

New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box® that present synergism with itraconazole.

BACKGROUND: Black fungi of the Herpotrichiellaceae family are agents of chromoblastomycosis and phaeohyphomycosis. There are few therapeutic options for these infections and it is common to associate antifungal drugs in their treatment. OBJECTIVES: To investigate the Medicines for Malaria Venture (MMV) Pathogen Box® for possible compounds presenting synergism with antifungal drugs used to treat black fungal infections. METHODS: An initial screening of the Pathogen Box® compounds was performed in combination with itraconazole or terbinafine at sub-inhibitory concentrations against Fonsecaea pedrosoi. Hits were further tested against eight Herpotrichiellaceae using the checkerboard method. FINDINGS: No synergism was observed with terbinafine. MMV687273 (SQ109) and MMV688415 showed synergism with itraconazole against F. pedrosoi. Synergism of these compounds was confirmed with some black fungi by the checkerboard method. SQ109 and itraconazole presented synergism for Exophiala dermatitidis, F. pedrosoi, F. monophora and F. nubica, with fungicidal activity for F. pedrosoi and F. monophora. MMV688415 presented synergism with itraconazole only for F. pedrosoi, with fungicidal activity. The synergic compounds had high selectivity index values when combined with itraconazole. MAIN CONCLUSIONS: These compounds in combination, particularly SQ109, are promising candidates to treat Fonsecaea spp. and E. dermatitidis infections, which account for most cases of chromoblastomycosis and phaeohyphomycosis.

Evaluation of the efficacy and safety of Unani Formulations in Pityriasis Versicolor: A randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Pityriasis Versicolor (PV) is a commonly encountered infection of the skin caused by Malassezia species. Despite effective conventional antifungal drugs, the prevention and treatment of PV remain a challenge. The Unani pharmacopoeial preparations Itrifal Hakim Ali (IHA) and Habb-e-Kalaf (HK) have been used in the treatment of PV for a long time. The Unani practitioners recommend these formulations for the successful treatment of PV in clinical practice. AIM OF THE STUDY: This study aimed to evaluate the efficacy and safety of Unani formulations IHA (oral) and HK (topical) in the treatment of PV. MATERIALS AND METHODS: A single centre, randomized, active-controlled, parallel-group and open-label clinical study was carried out in the outpatient departments of the National Research Institute of Unani Medicine for Skin Disorders, Hyderabad, India. The participants diagnosed with PV of any gender aged between 18 and 60 years were randomized into the test group (n = 37) to receive oral IHA (10g/day) and topical HK and the active control group (n = 35) to receive oral Itraconazole (100 mg/day) and local Terbinafine (1%) for the period of 6 weeks. Of them, 30 participants in each group completed the duration of the protocol therapy. The outcome of this study was based on a per-protocol analysis of the data. The efficacy of the interventions was measured by post-treatment change in subjective clinical symptoms/signs, mean TSSS, IGA score, direct microscopy of fungal elements and DLQI. The dermal safety was assessed by Berger/Bowman Scoring Scale and systemic safety was evaluated by Urinalysis, haematological and biochemical parameters. RESULTS: This study observed statistically and clinically significant post-treatment reduction in itching (test group vs. active control group; 73.4% vs. 89.1%), hypopigmentation (63.2% vs. 57.1%), hyperpigmentation (60% vs. 65.5%), and scaling (91.6% vs. 92.7%) (p < 0.001). The differences in mean TSSS (5.4 ± 0.63 vs. 5.60 ± 0.32), IGA score (2.07 ± 0.15 vs. 1.74 ± 0.08) and DLQI (9.6 ± 2.06 vs. 9.04 ± 2.7) were also found clinically and statistically significant (p < 0.001) in each group when compared baseline data to post-treatment. On inter-group comparison, the changes in mean TSSS and DLQI were not found statistically significant at p < 0.05. But, the change in the mean IGA score was significant (p = 0.03). Further, the mycological cure was observed in 100% and 76.7% of participants in the test group and the control group respectively. On comparing inter-group the effects of the interventions on direct microscopy were found statistically significant (p = 0.034). In addition, no significant change in urinalysis, biochemical and haematological parameters from baseline to post-treatment in each group was observed. CONCLUSION: This study concluded that the test drugs (IHA and HK) were safe and effective in the treatment of PV. The oral (IHA) and local (HK) Unani formulations were tolerated well by all the participants The efficacy and safety of the IHA and HK were comparable to the standard drugs (Itraconazole and Terbinafine).

Olive oil and clove oil-based nanoemulsion for topical delivery of terbinafine hydrochloride: in vitro and ex vivo evaluation.

In this article, formulation studies for terbinafine hydrochloride nanoemulsions, prepared by high-energy ultrasonication technique, are described. Pseudo-ternary phase diagram was constructed in order to find out the optimal ratios of oil and surfactant/co-solvent mixture for nanoemulsion production. Clove and olive oils were selected as oil phase. Based on the droplet size evaluation, maximum nanoemulsion region were determined for formulation development. Further characterization included polydispersity index (PDI), zeta potential, Fourier transform infrared (FT-IR) spectroscopy, morphology, pH, viscosity, refractive index, ex vivo skin permeation, skin irritation, and histopathological examination. Droplet sizes of optimized formulations were in colloidal range. PDI values below 0.35 indicated considerably homogeneous nanoemulsions. Zeta potential values were from 13.2 to 18.1 mV indicating good stability, which was also confirmed by dispersion stability studies. Ex vivo permeation studies revealed almost total skin permeation of terbinafine hydrochloride from the nanoemulsions (96-98%) in 6 hours whereas commercial product reached only 57% permeation at the same time. Maximum drug amounts were seen in epidermis and dermis layers. Skin irritation and histopathological examination demonstrated dermatologically safe formulations. In conclusion, olive oil and clove oil-based nanoemulsion systems have potential to serve as promising carriers for topical terbinafine hydrochloride delivery.

Review of the alternative therapies for onychomycosis and superficial fungal infections: posaconazole, fosravuconazole, voriconazole, oteseconazole.

Terbinafine and itraconazole are the most commonly used oral antifungals to treat onychomycosis and superficial dermatomycoses. Recently, poor response to oral terbinafine has been reported. We have summarized the most appropriate dosing regimens of posaconazole, fosravuconazole, voriconazole, and oteseconazole (VT-1161) to treat onychomycosis and superficial fungal infections. A structured search on PubMed and Google Scholar was conducted. Additionally, the bibliographies of selected articles were searched to identify relevant records. The number of records identified from the searches was 463, with 50 articles meeting the inclusion criteria for review. None of the new azoles are US FDA approved for onychomycosis treatment; however, an increasing number of studies have evaluated these agents. The efficacies (complete cure and mycologic cure) of the antifungal agents for dermatophyte great toenail onychomycosis treatment are terbinafine 250 mg/day × 12 weeks (Phase III trial) (38%, 70%), itraconazole 200 mg/day × 12 weeks (Phase III trial) (14%, 54%), posaconazole 200 mg/day × 24 weeks (Phase IIB) (54.1%, 70.3%), fosravuconazole 100 mg/day ravuconazole equivalent × 12 weeks (Phase III) (59.4%, 82.0%), and oteseconazole 300 mg/day loading dose × 2 weeks (Phase II), followed by 300 mg/week × 10 weeks (maintenance dose) (45%, 70%). Guidelines for monitoring are also presented.

Therapeutic efficacy of topically used luliconazole vs. terbinafine 1% creams.

OBJECTIVES: Dermatomycoses of zoophilic origin, especially those caused by Trichophyton mentagrophytes, often pose considerable therapeutic problems. This is reflected in the growing number of strains of this species with resistance to terbinafine caused by a mutation in the squalene epoxidase (SQLE) gene. Therefore, it is reasonable to look for alternative therapies to the commonly used terbinafine. The aim of the present study was to assess the in vivo effectiveness of topical therapy with luliconazole or terbinafine 1% cream. METHODS: Therapeutic efficacy was assessed using direct examination in KOH with DMSO, qPCR analysis with pan-dermatophyte primers and culturing. Moreover, in vitro susceptibility tests for luliconazole and terbinafine were performed. RESULTS: The results demonstrated significantly higher antifungal activity of luliconazole than terbinafine against dermatomycoses caused by T. mentagrophytes. The geometric mean of the MIC value for luliconazole against all T. mentagrophytes strains was 0.002 µg/ml, while this value for terbinafine was 0.004 µg/ml. In all studied cases, 28-day local therapy with luliconazole contributed to complete eradication of the aetiological agent of infection. CONCLUSIONS: Given the increasingly frequent reports of difficult-to-treat dermatophytoses caused by zoophilic terbinafine-resistant strains, the 1% luliconazole cream can be alternative solution in topical therapy.

Computationally guided high-throughput design of self-assembling drug nanoparticles.

Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib-glycyrrhizin and terbinafine-taurocholic acid both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug-loading capacities for a wide range of therapeutics.

[Tinea capitis: clinical features and therapeutic alternatives]. / Tinea capitis: aspectos clínicos y alternativas terapéuticas.

A descriptive observational and cross-sectional study was carried out. The clinical characteristics, etiologic agents, treatments and outcome of 33 cases of tinea capitis in the Mycology Unit at Francisco J. Muñiz Hospital of Buenos Aires City between January 2015 and December 2019 were analyzed. The median age of the patients was 7 years, 21 of whom were male, 3 were HIV-positive and 22 had pets. The isolated etiologic agents were the following: Microsporum canis in 22 cases, Trichophyton tonsurans in 8, Nannizzia gypsea in 2 and Trichophyton mentagrophytes in one patient. Suppurative tinea capitis (krion Celsi) was detected in 10 cases and the same number of patients presented other skin locations of their dermatophytosis in addition to those in the scalp. Twenty-one cases were orally treated with griseofulvin and 12 with terbinafine. Those patients with suppurative tinea capitis received drops of betamethasone by mouth besides the antifungal drugs. All patients had good clinical and mycological response to the treatments, all lesions disappeared, and mycological studies turned negative by the end of the treatments. We conclude that both drugs were effective for the treatment of tinea capitis; however, lesions in those cases receiving terbinafine involuted more slowly.