Clinico-mycological study of onychomycosis and in vitro antifungal susceptibility of Trichophyton rubrum.

Onychomycosis, a fungal nail infection, is primarily caused by dermatophytes, yeasts, and non-dermatophyte moulds (NDMs). The incidence of this disease and the predominance of specific pathogens vary across different regions and evolve. This study aimed to elucidate the epidemiology of onychomycosis and the pattern of causative pathogens in Beijing, and to ascertain the in vitro antifungal susceptibility profiles of Trichophyton rubrum against itraconazole (ITR), terbinafine (TER), and fluconazole (FLU). Involving 245 patients of onychomycosis with positive fungal culture results, the study implemented internal transcribed spacer (ITS) sequencing of ribosomal DNA (rDNA) on all collected samples. The mean age of the participants was 37.93 ± 13.73 years, with a male-to-female ratio of 1.53:1. The prevalence of toenail infections was significantly higher than that of fingernails. Distal and lateral subungual onychomycosis (DLSO) were the most frequent clinical classifications. PCR results indicated that dermatophytes were the most prevalent pathogens, followed by yeasts and NDMs, among which T. rubrum was the most dominant dermatophyte. TER demonstrated high sensitivity to T. rubrum. However, in clinical settings, some patients with onychomycosis exhibit a poor response to TER treatment. The relationship between in vitro antifungal sensitivity and clinical effectiveness is complex, and understanding the link between in vitro MIC values and clinical efficacy requires further investigation.

Long-term follow-up study of the efficacy of fosravuconazole in the treatment of onychomycosis in elderly patients.

Onychomycosis is a chronic and intractable disease whose prevalence increases during aging. In elderly patients, if onychomycosis is left untreated and progresses to a severe stage it may cause functional decline of the lower limbs due to foot pain. This could lead to a decline in activities of daily living and secondary impairment such as cognitive decline. Thus, the treatment of onychomycosis in elderly patients is important. We have previously shown that fosravuconazole is relatively safe and effective for onychomycosis in elderly patients. In the present study, we continued the follow-up study and investigated the efficacy of re-administration of fosravuconazole in patients with recurrent onychomycosis. One hundred and twenty-five patients aged ≥65 years who had been initially diagnosed with onychomycosis at our hospital's dermatology department, and who had responded well to fosravuconazole at 48 weeks after the initial treatment, were followed up until 144 weeks after the start of the initial treatment. Patients who experienced a recurrence within 24 weeks after the start of the follow-up were assigned to the short-term recurrence group, and those who experienced a recurrence after 24 weeks were assigned to the long-term recurrence group. All patients in both groups were re-treated with fosravuconazole to evaluate its efficacy. The short-term and long-term recurrence groups consisted of 17 (14.3%) and 10 (8.4%) patients, respectively. There were no significant differences in mean age and sex ratio between the two groups. There were no serious adverse effects in either group, and the toenail opacity ratio was significantly reduced after 12 weeks of re-treatment in both groups. The short-term and long-term recurrence groups were significantly more likely to have wedge-shaped onychomycosis and total dystrophic onychomycosis, respectively. The results suggest that re-administration of fosravuconazole is safe and as effective as the first administration for elderly patients with recurrent onychomycosis. This study was registered at UMIN-CTR (UMIN000053516).

Photodynamic therapy for recalcitrant plantar warts: Case reports and a literature review.

Plantar wart is one of the most recalcitrant types of cutaneous warts with a high recurrence rate. Recalcitrant plantar warts are resistant to traditional treatments such as cryotherapy. Photodynamic therapy (PDT) is a modern, non-invasive method utilized to treat benign and malignant skin disorders. Several previous studies have reported the effective application of PDT treatment for plantar warts. We reported three cases of recalcitrant plantar warts successfully treated with PDT.

Effects of additional oral fosravuconazole l-lysine ethanolate therapy following inadequate response to initial treatment for onychomycosis: A multicenter, randomized controlled trial.

Onychomycosis, a superficial fungal infection, develops when dermatophytes infect nail plate and beds. Fosravuconazole l-lysine ethanolate (F-RVCZ), a fourth-generation azole antifungal agent with potent antifungal activity and few drug interactions, was highly effective in a clinical trial, with a complete cure rate of 59.4% at 48 weeks after treatment initiation. However, some patients were not completely cured. To achieve a higher complete cure rate, additional therapy needs to be examined. We aimed to examine (i) the criteria for additional F-RVCZ therapy in patients with an inadequate response to initial F-RVCZ treatment for onychomycosis; (ii) the timing of additional therapy; and (iii) the effects of additional treatment. This was a multicenter, open-label, three-arm randomized clinical trial. Patients with onychomycosis were orally administered an approved dose of F-RVCZ for 12 weeks, and its efficacy was assessed at week 24. Patients who demonstrated ≥55% reduction in nail involvement ratio at week 24 were included in Group X and followed up. Patients with <55% reduction were randomly assigned to follow-up (Group A) or additional treatment (Group B) groups. The complete cure rate at week 72 in Group X was 73.3%. In Groups A and B, the complete cure rates were 29.6% and 46.7%, respectively, and were significantly different (P = 0.0414, odds ratio 2.08). During the study, 63 adverse drug reactions were recorded in 59 of the 318 patients (18.6%), for which a causal relationship with F-RVCZ could not be ruled out. In Group B, three of 75 patients (4.0%) experienced three adverse drug reactions, all observed during additional treatment; none were serious. A high complete cure rate is possible without additional F-RVCZ treatment when nail involvement decreases by ≥55% at week 24; however, when the reduction is <55% at week 24, additional F-RVCZ treatment should be considered to improve the cure rate.

Number of Affected Nails Is the Primary Determinant of Efinaconazole 10% Solution Usage for Onychomycosis.

Good adherence to treatment is necessary for the successful treatment of onychomycosis and requires that an appropriate amount of medication be prescribed. Most prescriptions for efinaconazole 10% solution, a topical azole antifungal, are for 4 mL per month but there are no data on patient factors or disease characteristics that impact how much medication is needed. Data from two phase 3 studies of efinaconazole 10% solution for the treatment of toenail onychomycosis were pooled and analyzed to determine monthly medication usage based on the number of affected toenails, percent involvement of the target toenail, body mass index (BMI), and sex. Participants with two or more affected nails required, on average, >4 mL of efinaconazole per month, with increasing amounts needed based on the number of nails with onychomycosis (mean: 4.39 mL for 2 nails; 6.36 mL for 6 nails). In contrast, usage was not greatly impacted by target toenail involvement, BMI, or sex. Together, these data indicate that the number of affected nails should be the major consideration when determining the monthly efinaconazole quantity to prescribe. J Drugs Dermatol. 2024;23(2):110-112.    doi:10.36849/JDD.7676.

Dupilumab treatment improves signs, symptoms, quality of life, and work productivity in patients with atopic hand and foot dermatitis: Results from a phase 3, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Despite high disease burden, systemic treatment options for patients with atopic hand and/or foot dermatitis (H/F AD) are limited. OBJECTIVES: To evaluate efficacy and safety of dupilumab in H/F AD using specific instruments for assessing disease severity on hands and feet. METHODS: In this multicenter phase 3 trial, adults and adolescents with moderate-to-severe H/F AD were randomized to dupilumab monotherapy (regimen approved for generalized AD), or matched placebo. The primary endpoint was proportion of patients achieving Hand and Foot Investigator's Global Assessment score 0 or 1 at week 16. Secondary prespecified endpoints assessed the severity and extent of signs, symptom intensity (itch, pain), quality of life, and sleep. RESULTS: A total of 133 patients (adults = 106, adolescents = 27) were randomized to dupilumab (n = 67) or placebo (n = 66). At week 16, significantly more patients receiving dupilumab (n = 27) than placebo (n = 11) achieved Hand and Foot Investigator's Global Assessment score 0 or 1 (40.3% vs 16.7%; P = .003). All other prespecified endpoints were met. Safety was consistent with the known AD dupilumab profile. LIMITATIONS: Short-term, 16-week treatment period. CONCLUSION: Dupilumab monotherapy resulted in significant improvements across different domains of H/F AD with acceptable safety, supporting dupilumab as a systemic treatment approach for this often difficult to treat condition.

Real-life experience with dimethylfumarate in palmoplantar psoriasis: A multicentre retrospective Italian study.

Palmoplantar (PP) psoriasis is considered one of the most hard-to-treat areas with important impact on patients' quality of life, and few data are available about the efficacy of dimethylfumarate (DMF) on these areas. In our noninterventional multicentre retrospective cohort study of patients with PP psoriasis treated with DMF, effectiveness was evaluated as mean pp Psoriasis Area and Severity Index (ppPASI) reduction and as proportion of patients that reach ppPASI 75 at 4, 12, 24 and 48 weeks. The reduction in ppPASI was 23.5% at w4, 49.7% at w12, 69.1% at w24 and 81.1% at w48. pp Investigator's Global Assessment (ppIGA) 0/1 was reached by 5 patients (10.64%) at w4, 10 patients (23.8%) at w12, 11 patients (40.7%) at w24 and 12 patients (60%) at w48 confirming that DMF could represent an effective therapy in patients affected by PP psoriasis. Overall, the treatment was well tolerated although only 24 patients made it to 24 weeks of therapy and 28 patients completed the observation period at 48 weeks. None of the patients reported adverse events requiring discontinuation of the drug. However, this discontinuation rate is in line with clinical trials and real-world evidence.

Effectiveness and safety of oral terbinafine for dermatophyte distal subungual onychomycosis.

INTRODUCTION: Terbinafine has been a cornerstone in dermatophyte infection treatment. Despite its global efficacy, the emergence of terbinafine resistance raises concerns, requiring ongoing vigilance. AREAS COVERED: This paper focuses on evaluating the efficacy and safety of terbinafine in treating dermatophyte toenail infections. Continuous and pulse therapies, with a 24-week continuous regimen and a higher dosage of 500 mg/day have demonstrated superior efficacy to the FDA approved regimen of 250 mg/day x 12 weeks. Pulse therapies, though showing comparable effectiveness, present debates with regards to their efficacy as conflicting findings have been reported. Safety concerns encompass hepatotoxicity, gastrointestinal, cutaneous, neurologic, hematologic and immune adverse-effects, and possible drug interactions, suggesting the need for ongoing monitoring. EXPERT OPINION: Terbinafine efficacy depends on dosage, duration, and resistance patterns. Continuous therapy for 24 weeks and a dosage of 500 mg/day may enhance outcomes, but safety considerations and resistance necessitate individualized approaches. Alternatives, including topical agents and alternative antifungals, are to be considered for resistant cases. Understanding the interplay between treatment parameters, adverse effects, and resistance mechanisms is critical for optimizing therapeutic efficacy while mitigating resistance risks. Patient education and adherence are vital for early detection and management of adverse effects and resistance, contributing to tailored and effective treatments.

Onychomycosis.

Onychomycosis is a fungal infection of the nail, and the most common nail infection worldwide, causing discoloration and thickening of the nail plate. It is predominantly caused by dermatophytes. Clinical presentation is polymorphous. Diagnosis must be confirmed by mycological examination before initiating any therapy. Management is an ongoing challenge, often requiring several months' treatment, with a high risk of recurrence. Treatment must be adapted to clinical presentation and severity and to the patient's history and wishes. Debridement of all infected keratin is the first step, reducing fungal load. Systemic treatments are more effective than topical treatments, and combining the two increases the cure rate. Terbinafine is the drug of choice for dermatophyte onychomycosis, due to low drug interaction and good cost-effectiveness. Itraconazole and fluconazole are broad-spectrum antifungals that are effective against dermatophytes, yeasts, and some non-dermatophytic molds. Recurrence rates for onychomycosis are high. Prophylactic application of topicals and avoiding walking barefoot in public places may help prevent recurence.

Efficacy of topical trichloroacetic acid 100% either alone or combined with topical tioconazole 28% versus systemic itraconazole in the treatment of onychomycosis.

BACKGROUND: Treatment of onychomycosis is still challenging and warrants the development of new treatment strategies. Different trials were conducted to increase the penetration and efficacy of topical antifungals aiming at finding an alternative treatment especially when systemic antifungals are contraindicated. OBJECTIVES: To evaluate the efficacy of trichloroacetic acid (TCA) 100% either alone or combined with topical tioconazole 28% versus itraconazole pulse therapy in the treatment of onychomycosis. PATIENTS/METHODS: Forty-five patients with onychomycosis were divided into three groups: group (A) treated by topical TCA 100% for 12 sessions, group (B) treated by TCA 100% for 12 sessions combined with topical tioconazole 28% for 18 weeks and group (C) treated by itraconazole (400 mg/day for 1 week/month for 4 months). RESULTS: TCA 100% combined with topical tioconazole 28% showed the highest therapeutic response; however, the difference between the groups was statistically insignificant. Mycological cure (negative culture) was reported in 66.7% of group B versus 60% of group A and 40% of group C at the 20 week. CONCLUSIONS: TCA 100% is an effective and safe treatment option for onychomycosis especially when combined with antifungals. This modality is promising in the treatment of onychomycosis especially with the increased resistance to different antifungals.

Receipt survey of prescription continuation rates for patients with onychomycosis and web-based survey of dermatologists on prescribing policies for onychomycosis therapeutics.

Onychomycosis can be treated with topical and oral medications. However, it is important to appropriately select these medications according to the type and severity of the disease and ensure treatment is continued for the recommended duration. In Japan, treatment options for onychomycosis have increased in recent years. Moreover, in 2019, the guidelines for dermatomycosis treatment were revised. In this study, we conducted a receipt survey to clarify the actual treatment status of onychomycosis cases as indicated by the continuation rates of prescribed treatment drugs, together with a web-based survey to ascertain the prescribing policy of dermatologists regarding drugs for onychomycosis treatment. In agreement with past surveys, this receipt survey showed that the prescription continuation rate for oral medications was higher than that for topical medications. The 1-year prescription continuation rate for topical onychomycosis medications was found to be low (<10%). The web-based survey showed that the percentage of physicians who prescribed oral medications as their first choice increased by approximately 10% for each disease type, compared with the results of the previous survey conducted around 7 years ago. However, the study also confirmed that topical drugs are still prescribed for some disease types for which oral drugs are better suited. To ensure complete cure without patient drop-out, oral drugs with a high probability of achieving complete cure and a high continuation rate should be prescribed for patients with onychomycosis.

Medium-term antifungal effects of methylene blue versus flavin mononucleotide in the treatment of moderate toenail onychomycosis.

BACKGROUND: Methylene blue (MB) and flavin mononucleotide (FMN)-mediated photodynamic therapy (PDT) have demonstrated local antimicrobial effect, but no direct comparative study has been published so far for the treatment of toenail onychomycosis. OBJECTIVES: To directly compare the short and medium-term efficacy of MB versus FMN as photosensitizers in PDT for toenail onychomycosis by applying them in a 40% w/w urea cream in two different dye concentrations. METHODS: Forty toenails with distal and lateral subungual moderate onychomycosis due to dermatophyte fungi were randomised to receive 10 weekly sessions of PDT mediated by four topical formulations including MB or FMN at two different concentrations: Group I: 0.1% w/w MB; Group II: 2% w/w MB; Group III: 0.1% w/w FMN; and Group IV: 2% w/w FMN. Photographs were used for onychomycosis severity index (OSI) estimation allowing clinical assessment at any point of the study. Microscopic and microbiological evaluations were carried out at baseline, 27- and 35-week follow-ups. Side effects were recorded along with patient satisfaction. RESULTS: At week 27, mycological cure rates were 60%, 30%, 50% and 40% and complete cure rates were 0%, 20%, 10% and 20%, for Groups I, II, III and IV respectively. At week 35, mycological cure rates were 70%, 70%, 70% and 60% and complete cure rates were 30%, 50%, 70% and 30%, for Groups I, II, III and IV respectively. All cream formulations were safe and patients were fairly satisfied. CONCLUSIONS: Results of the present work confirm PDT as a therapeutic alternative for onychomycosis. Although all cream formulations were safe and effective, with a good degree of satisfaction, higher cure rates were obtained with 2% w/w MB cream and 0.1% w/w FMN cream.

Comparing the Efficacy for Pulse Versus Continuous Dose Terbinafine Therapy in Patients With Onychomycosis.

Recently, treatment outcomes in patients with toenail onychomycosis have improved considerably due to more effective oral antifungal medications such as terbinafine and itraconazole. These medications can either be used continuously for several weeks at a lower dose or intermittently (pulsed) at a higher dose. Previous literature comparing pulse and continuous therapy has generated mixed results.  Our study aims to compare the efficacy, in terms of clinical cure rate, of continuous vs pulse dose terbinafine regimens for toenail onychomycosis. Sixty patients with onychomycosis of Fitzpatrick skin types IV to VI, between 15 and 65 years of age, were divided into a continuous treatment group receiving 250 mg terbinafine once daily for 12 weeks and a pulse treatment group receiving 250 mg twice daily terbinafine for 1 week repeated every 4 weeks for 12 weeks. Each patient was followed up at weeks 4, 8, and 12.  Efficacy of the continuous treatment group was significantly greater at 76.67% compared with 26.67% in the pulse treatment group. Thus, we conclude that the clinical cure rate of a continuous dose regimen of terbinafine is a superior treatment option for toenail onychomycosis. However, we also suggest further studies including combinations of multiple agents and hybrid regimen models for the optimal onychomycosis treatment.   J Drugs Dermatol. 2023;22(10):     doi:10.36849/JDD.7323R1.

Relative impact of traditional vs. newer oral antifungals for dermatophyte toenail onychomycosis: a network meta-analysis study.

BACKGROUND: There is a paucity of evidence regarding the relative therapeutic efficacy of treatments for onychomycosis. OBJECTIVES: We determined the relative efficacy of monotherapies for dermatophyte toenail onychomycosis with Bayesian network meta-analyses (NMAs). METHODS: We searched PubMed, Scopus, EMBASE (Ovid) and CINAHL to identify studies that investigated the efficacy of monotherapy with oral antifungals for dermatophyte toenail onychomycosis in adults. In this paper, 'regimen' corresponds to a given agent and its dosage. The relative effects and surface under the cumulative ranking curve (SUCRA) values of the various regimens were estimated; evidence quality was assessed at the study level and across networks. RESULTS: Data from 21 studies were used. Our two efficacy-related endpoints were: (i) mycological and (ii) complete cure at 1 year; safety--related endpoints were: (i) 1-year count of any adverse event (AE), (ii) 1-year odds of discontinuation due to any AE, (iii) 1-year odds of discontinuation due to liver issues. Thirty-five regimens were identified; the newer agents among these included posaconazole and oteseconazole. We compared the efficacy of newer regimens with traditional ones like 'terbinafine 250 mg daily for 12 weeks' and 'itraconazole 200 mg daily for 12 weeks. We found that an agent's dosage was associated with its efficacy; for example, the 1-year odds of mycological cure with terbinafine 250 mg daily for 24 weeks (SUCRA = 92.4%) were significantly greater than those of terbinafine 250 mg daily for 12 weeks (SUCRA = 66.3%) (odds ratio 2.62, 95% credible interval 1.57-4.54). We also found that booster regimens can increase efficacy. Our results showed that some triazoles could be more effective than terbinafine. CONCLUSIONS: This is the first NMA study of monotherapeutic antifungals - and their various dosages - for dermatophyte toenail onychomycosis. Our findings could provide guidance for the selection of the most appropriate antifungal agent, especially amid the growing concerns about terbinafine resistance.

Outcome of fosravuconazole treatment for onychomycosis refractory to topical antifungal agents.

Fosravuconazole L-lysine ethanolate (F-RVCZ) is an oral antifungal agent approved in Japan for the treatment of onychomycosis. We treated 36 patients (mean age 77.6 years) with onychomycosis that had been refractory to long-term topical treatment. The patients took F-RVCZ (100 mg ravuconazole) once daily for a mean of 11.3 weeks, and were followed up for an average of 48 weeks (mean 48.3 ± 2.1 weeks). The mean rate of improvement of the affected nail area at 48 weeks was 59.4%, and 12 patients achieved complete cure. Patients with total dystrophic onychomycosis (TDO) showed a significantly lower improvement rate than those with distal and lateral subungual onychomycosis (DLSO), and those with an affected nail area of 76%-100% at the first visit showed a significantly lower improvement rate than those with an affected nail area of 0%-75%. Six patients had adverse events necessitating treatment discontinuation, but the symptoms and laboratory data improved without specific treatment in all of them. The data suggest that F-RVCZ would be effective in various age groups, including the elderly, and even in patients with onychomycosis refractory to long-term topical antifungal treatment. It was also suggested that its early use in mild cases might achieve a higher rate of complete cure. Furthermore, the average cost of oral F-RVCZ therapy was lower than that for topical antifungal agents. Therefore, F-RVCZ is considered to be much more cost-effective than topical antifungal agents.

Efficacy and safety of a new medicated nail hydrolacquer in the treatment of adults with toenail onychomycosis: A randomised clinical trial.

BACKGROUND: A new water-soluble formulation with ciclopirox has shown a higher penetration than other ciclopirox nail lacquers currently marketed, thus providing a higher concentration of ciclopirox into the nail. OBJECTIVE: To evaluate the efficacy and safety of a new ciclopirox nail hydrolacquer compared with its vehicle and an active comparator (hydroxypropyl chitosan-based 80 mg/g ciclopirox nail lacquer) for the treatment of toenail fungal infection. METHODS: Phase III, multicenter, randomised, double-blind, clinical trial in patients with distal mild to moderate toenail onychomycosis due to dermatophyte fungi. Patients were randomised to apply topically a ciclopirox nail hydrolacquer, its vehicle or a reference product once daily for 48 weeks with a follow-up period of 4 weeks up to week 52. RESULTS: A total of 381 patients were included. No statistically significant differences were observed between patient groups in the proportion of subjects achieving a complete cure. At week 52, a higher percentage of patients in the ciclopirox nail hydrolacquer group achieved a mycological cure (negative for culture and DTS/KOH test, with results: 32.0% ciclopirox nail hydrolacquer, 23.2% vehicle and 27% reference product, respectively), and similar results were found for improvement (mycological cure and reduction of diseased nail ≥20%, with results: 27.2% ciclopirox nail hydrolacquer, 21.6% vehicle and 20.6% reference product, respectively). Regarding mycological results, only ciclopirox nail hydrolacquer demonstrated significant statistical superiority versus vehicle negativizing dermatophyte culture (p = .039) with no recurrences, relapses or re-infections in a four-week follow-up patients with complete cure. The safety profile was comparable to the vehicle and reference product and consistent with the previously reported. CONCLUSIONS: A new water-soluble formulation for a ciclopirox nail lacquer showed similar efficacy to the reference product to eradicate toenail onychomycosis and superiority in the mycological cure defined by negative culture, thus preventing reinfections and recurrences. Efficacy and safety data demonstrate the positive benefit-risk profile of this new topical antifungal preparation. [Correction added on 13 April 2023, after first online publication: The results and conclusions in the Abstract contained incorrect information and were revised in this version.].