The Mystery of an Inflamed "Soul Patch".

A 20-year-old man had developed dermatitis on his scalp and facial hair between his lower lip and chin, his 'soul patch', for one month. He initially presented to urgent care, where the dermatitis was attributed to Herpes simplex infection, for which he was treated with both oral valacyclovir and topical acyclovir. When no change was observed, he consulted his pediatrician, who prescribed oral clindamycin and referred him to dermatology. Physical examination revealed a crusted plaque on an erythematous and edematous base at the lower cutaneous border of the lower lip (Figure 1). Examination additionally revealed an erythematous scaling plaque on the left temporal area with associated flaking, tenderness, and hair loss and left-sided cervical lymphadenopathy. A fungal culture grew Trichophyton mentagrophytes, but a bacterial culture did not grow. Further investigation revealed that he had a dog; however, no other animal contact to account for a fungal reservoir was present. He was successfully treated with oral terbinafine for 6 weeks, plus ketoconazole 2% shampoo and ketoconazole 2% cream with complete reso-lution (Figure 2).

Impact of new antifungal medications on onychomycosis prescriptions and costs in Japan: A nationwide claims database study.

Onychomycosis, a fungal nail infection, is a common dermatological condition in Japan, with a prevalence of approximately 5%-10%. Despite the introduction of new antifungal medications and updated treatment guidelines published in 2019, data on real-world prescription trends and the associated medical costs are limited. This study aimed to investigate the prescription patterns and medical costs of topical and oral antifungal medications for onychomycosis in Japan from fiscal years 2014 to 2021 using the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data. We analyzed the annual prescription volumes and medical costs of four antifungal medications: efinaconazole, luliconazole, fosravuconazole, and terbinafine. The prescription volume of efinaconazole, a topical medication launched in 2014, rapidly increased and dominated the market share. Fosravuconazole, an oral medication introduced in 2018, showed an increasing trend, coinciding with a decline in efinaconazole prescriptions. Terbinafine, a well-established oral medication, experienced a substantial decrease in prescription volume. The sex- and age-adjusted prescription volume per 100 000 population was higher among older adults, particularly for efinaconazole. The total medical costs for onychomycosis treatment more than doubled in fiscal year 2015 compared with that for 2014, mainly driven by efinaconazole prescriptions, and exceeded 30 billion Japanese yen in fiscal years 2019-2021. The costs slightly decreased in fiscal years 2020 and 2021, possibly due to the introduction of fosravuconazole. The predominance of topical prescriptions, especially in older adults, raises concerns regarding adherence to the Japanese guidelines that recommend oral antifungals as the first-line treatment for onychomycosis. The substantial increase in medical costs also highlights the economic burden of onychomycosis and the need for cost-effective treatment strategies. This study provides valuable insights into the real-world prescription trends and medical costs of onychomycosis treatment in Japan, suggesting an opportunity to assess potential gaps between guideline recommendations and clinical practice.

PILOT STUDY OF INTRACOELOMIC TERBINAFINE IMPLANTS IN GREATER SIRENS (SIREN LACERTINA).

Chytridiomycosis caused by Batrachochytrium dendrobatidis (Bd) has been documented in greater sirens (Siren lacertina) in the wild and in the pet trade. This study evaluated the use of terbinafine-impregnated implants for chytridiomycosis prophylaxis in greater sirens exposed to Bd. Implants were placed intracoelomically in both control (blank implant, n = 4) and treatment (24.5 mg of terbinafine implant, n = 4) groups. Sirens were exposed to Bd zoospores via 24-h immersion bath at 1 and 2 mon postimplant placement. Blood was collected monthly for plasma terbinafine levels, and skin swabs were collected weekly for Bd quantitative PCR. Animals with terbinafine implants had detectable concentrations of plasma terbinafine ranging from 17 to 102 ng/ml. Only one terbinafine-implanted animal had a peak concentration above the published minimum inhibitory concentration for terbinafine against Bd zoospores (63 ng/ml); however, it is unknown how plasma terbinafine concentrations relate to concentrations in the skin. There was no difference between the two treatment groups in clinical signs or Bd clearance rate, and no adverse effects from implants were observed. These findings indicate using intracoelomic drug implants for drug delivery in amphibians is safe; however, terbinafine efficacy in preventing Bd chytridiomycosis in sirens remains unclear. Further investigation of the use of intracoelomic implants and identification of effective drugs and doses in other amphibian species against Bd and other infectious diseases is warranted, as this may provide a practical method for long-term drug delivery in wildlife.

Clinical Course, Antifungal Susceptibility, and Genomic Sequencing of Trichophyton indotineae.

Importance: Trichophyton indotineae is an emerging dermatophyte causing outbreaks of extensive tinea infections often unresponsive to terbinafine. This species has been detected worldwide and in multiple US states, yet detailed US data on infections with T indotineae are sparse and could improve treatment practices and medical understanding of transmission. Objective: To correlate clinical features of T indotineae infections with in vitro antifungal susceptibility testing results, squalene epoxidase gene sequence variations, and isolate relatedness using whole-genome sequencing. Design, Setting, and Participants: This retrospective cohort study of patients with T indotineae infections in New York City spanned May 2022 to May 2023. Patients with confirmed T indotineae infections were recruited from 6 New York City medical centers. Main Outcome and Measure: Improvement or resolution at the last follow-up assessment. Results: Among 11 patients with T indotineae (6 male and 5 female patients; median [range] age, 39 [10-65] years), 2 were pregnant; 1 had lymphoma; and the remainder were immunocompetent. Nine patients reported previous travel to Bangladesh. All had widespread lesions with variable scale and inflammation, topical antifungal monotherapy failure, and diagnostic delays (range, 3-42 months). Terbinafine treatment failed in 7 patients at standard doses (250 mg daily) for prolonged duration; these patients also had isolates with amino acid substitutions at positions 393 (L393S) or 397 (F397L) in squalene epoxidase that correlated with elevated terbinafine minimum inhibitory concentrations of 0.5 µg/mL or higher. Patients who were treated with fluconazole and griseofulvin improved in 2 of 4 and 2 of 5 instances, respectively, without correlation between outcomes and antifungal minimum inhibitory concentrations. Furthermore, 5 of 7 patients treated with itraconazole cleared or had improvement at the last follow-up, and 2 of 7 were lost to follow-up or stopped treatment. Based on whole-genome sequencing analysis, US isolates formed a cluster distinct from Indian isolates. Conclusion and Relevance: The results of this case series suggest that disease severity, diagnostic delays, and lack of response to typically used doses and durations of antifungals for tinea were common in this primarily immunocompetent patient cohort with T indotineae, consistent with published data. Itraconazole was generally effective, and the acquisition of infection was likely in Bangladesh.

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.

Determination of terbinafine in healthy Chinese human plasma using a simple and fast LC-MS/MS method and its application to a bioequivalence study.

A rapid, simple, and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was validated for the determination of terbinafine concentrations in the plasma of healthy Chinese subjects. Terbinafine-d7 was used as the internal standard (IS), and the acetonitrile protein precipitation method was selected. The processed samples were chromatographically separated with a C18 column. The mobile phases were 0.1% formic acid (FA) in water (A), and methanol (B), respectively, and the gradient elution program was used with a flow rate of 0.8 mL/min. Quantification was achieved by positive electrospray ionization containing multiple reaction monitoring (MRM) transitions of m/z 292.5 â†’ 141.1 for terbinafine and m/z 299.5 â†’ 148.1 for IS. The calibration curve range was 2.00-1200 ng/mL; the intra- and inter-batch precision (coefficient of variation, %CV) was <8.2%, with the accuracy deviation (relative error, %RE) of -6.5% to 10.2%. The selectivity, sensitivity, extraction recovery, matrix effect, dilution reliability, carryover, and stability were within the acceptable range. This method was successfully applied to a bioequivalence study that orally administered 125 mg of terbinafine hydrochloride tablets in 84 healthy Chinese subjects.

Onychomycosis: Rapid Evidence Review.

Onychomycosis is a chronic fungal infection of the fingernail or toenail bed leading to brittle, discolored, and thickened nails. Onychomycosis is not just a cosmetic problem. Untreated onychomycosis can cause pain, discomfort, and physical impairment, negatively impacting quality of life. Onychomycosis should be suspected in patients with discolored nails, nail plate thickening, nail separation, and foul-smelling nails. Accurate diagnosis is important before initiating treatment because therapy is lengthy and can cause adverse effects. A potassium hydroxide preparation with confirmatory fungal culture, periodic acid-Schiff stain, or polymerase chain reaction is the preferred diagnostic approach if confirmative testing is cost prohibitive or not available. Treatment decisions should be based on severity, comorbidities, and patient preference. Oral terbinafine is preferred over topical therapy because of better effectiveness and shorter treatment duration. Patients taking terbinafine in combination with tricyclic antidepressants, selective serotonin reuptake inhibitors, atypical antipsychotics, beta blockers, or tamoxifen should be monitored for drug-drug interactions. Topical therapy, including ciclopirox 8%, efinaconazole 10%, and tavaborole 5%, is less effective than oral agents but can be used to treat mild to moderate onychomycosis, with fewer adverse effects and drug-drug interactions. Nail trimming and debridement used concurrently with pharmacologic therapy improve treatment response. Although photodynamic and plasma therapies are newer treatment options that have been explored for the treatment of onychomycosis, larger randomized trials are needed. Preventive measures such as avoiding walking barefoot in public places and disinfecting shoes and socks are thought to reduce the 25% relapse rate.

Failure of Warfarin Anticoagulation Therapy after Administration of Oral Terbinafine.

Warfarin is widely used anticoagulant drug for a variety of diseases (thromboembolic disease, atrial fibrillation, etc.). It has three most important parallel metabolic pathways, CYP1A2, CYP3A4 and CYP2C9. Terbinafine is a potent CYP2D6 inhibitor. A possible drug interaction could lead to an increased pharmacological effect of the above drugs. Enzyme induction with CYP3A4, CYP2C9, CYP1A2 inducers may have occurred. Case report: We present a case report of an 88-year-old male patient who has been successfully anticoagulated with warfarin due to atrial fibrillation. He was orally administered terbinafine to treat onychomycosis. Two weeks after initiation of this drug the patient experienced dizziness and feelings of instability, for which he was admitted to the neurology department. A low-efficient INR level was found at the baseline, presumably due to warfarin interaction with terbinafine. The induction of liver enzymes lasts 10-14 days, which matches the introduction of the antifungal agent. Conclusion: Combined therapy with warfarin and oral terbinafine is actually rarely prescribed but, if used, their interaction can have serious consequences in many clinical situations for which anticoagulation therapy with warfarin is indicated.

EFFICACY OF SUBCUTANEOUS IMPLANTS TO PROVIDE CONTINUOUS PLASMA TERBINAFINE IN HELLBENDERS (CRYPTOBRANCHUS ALLEGANIENSI) FOR FUTURE PROPHYLACTIC USE AGAINST CHYTRIDIOMYCOSIS.

Batrachochytrium dendrobatidis (Bd) is an important fungal pathogen present in wild hellbender (Cryptobranchus alleganiensis) populations that appears to cause disease during novel exposure and acute stress. Hellbender repatriation efforts are ongoing to combat declining populations, but mortality by chytridiomycosis (disease from Bd) after release has been reported. The goal was to determine whether a safe antifungal agent could be administered and provide prolonged plasma concentrations without repeated handling. A subcutaneous implant impregnated with 24.5 mg of terbinafine was tested in three juvenile eastern hellbenders (C. a. alleganiensis) raised in human care, and plasma terbinafine concentrations were recorded from weekly to biweekly for 141 days. Plasma concentrations were variable, with peak plasma concentrations of 1,610, 112, and 66 ng/ml between 28 and 56 days postimplant. Although all hellbenders achieved plasma concentrations above the published minimum inhibitory concentration for terbinafine against Bd zoospores (63 ng/ml) at several time points, only one individual remained above this threshold for more than two consecutive time intervals. Results show the potential for these implants as a prophylaxis for chytridiomycosis in captive-to-wild hellbender releases. However, further investigation will be needed to determine the plasma concentrations required to achieve prophylaxis in vivo and implant reliability.

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.

In Vitro Sensitivity Analysis of the Gastrointestinal Dissolution Profile of Weakly Basic Drugs in the Stomach-to-Intestine Fluid Changing System: Explanation for Variable Plasma Exposure after Oral Administration.

An in vitro methodology for simulating the change in the pH and composition of gastrointestinal fluid associated with the transition of orally administered drugs from the stomach to the small intestine was developed (the stomach-to-intestine fluid changing system (the SIFC system)). This system was applied to in vitro sensitivity analysis on the dissolution of weakly basic drugs, and the obtained results were discussed in relation to the intrasubject variability in the plasma exposure in human bioequivalence (BE) study. Three types of protocols were employed (steep pH change: pH 1.6 FaSSGF → pH 6.5 FaSSIF, gradual pH change: pH 1.6 FaSSGF → pH 6.5 FaSSIF, and high gastric pH: pH 4.0 FaSSGF → pH 6.5 FaSSIF). Regardless of the protocols and the forms of drug applied in active pharmaceutical ingredient powder or formulation, dissolution profiles of pioglitazone after fluid shift were similar and the final concentrations in FaSSIF were approximately equal to the saturation solubility in FaSSIF, supporting its small intrasubject variance in human BE study. In contrast, dissolved concentration of terbinafine in the SIFC system became less than half in the high gastric pH protocol than that in other protocols, suggesting the fluctuation of gastric pH as one of the factors of high intrasubject variance of terbinafine in human. Plasma exposure of telmisartan was highly variable especially at the high dose. Although the dissolution of telmisartan in the SIFC system was greatly improved by formulation, it considerably fluctuated during fluid shift especially at the high dose, which corresponds well to in vivo results.

Effect of Different Nail Penetration Enhancers in Solid Lipid Nanoparticles Containing Terbinafine Hydrochloride for Treatment of Onychomycosis.

Onychomycosis is considered a stubborn nail fungal infection that does not respond to conventional topical antifungal treatments. This study aimed to develop and characterize novel solid lipid nanoparticles (SLNs) formulae containing terbinafine HCl (TFH) and loaded with different nail penetration enhancers (nPEs). Three (nPEs) N-acetyl-L-cysteine, thioglycolic acid, and thiourea were used. Characterization of the prepared formulae was done regarding particle size, zeta potential, polydispersity index (PDI), entrapment efficiency (EE%), physical stability, in vitro release study, infrared (FT-IR), and their morphological structures. The selected formulae and the marketed cream Lamifen® were compared in terms of their antifungal activity against Trichophyton rubrum as well as their nail hydration and their drug uptake by the nail clippers. Thiourea was the nPE of choice; formulae (N2 and N8), with thiourea, were considered the optimum TFH SLNs containing nPEs. They were selected for their optimum particle size of 426.3 ± 10.18 and 450.8 ± 11.45 nm as well as their highest EE% of 89.76 ± 1.25 and 90.35 ± 1.33, respectively. The in vitro microbiological screening of the antifungal activity of these two formulae showed significantly larger zones of inhibition in comparison with the marketed product. The ex vivo screening of the drug uptake of the two selected formulae was significantly higher than that of the marketed product. The nPE formulae present a very promising option as they showed optimum physicochemical characterization with high antifungal activity and high drug uptake as well as good nail hydration effect.

Efficacy and safety of topical terbinafine 10% solution (MOB-015) in the treatment of mild to moderate distal subungual onychomycosis: A randomized, multicenter, double-blind, vehicle-controlled phase 3 study.

BACKGROUND: Onychomycosis is a recalcitrant fungal nail infection. Topical antifungal agents may be preferred over systemic agents due to lack of systemic adverse effects. OBJECTIVE: To investigate the efficacy and safety of topical terbinafine 10% solution (MOB-015) for the treatment of distal and lateral subungual onychomycosis. METHODS: In a multicenter, double-blind, phase III, North American study, patients with mild to moderate distal and lateral subungual onychomycosis involving 20% to 60% of at least 1 great toenail were randomized to once daily application of MOB-015 or matching vehicle for 48 weeks. The primary efficacy variable was complete cure, while the secondary efficacy variables were mycological cure and treatment success. Safety evaluations were also performed. RESULTS: At week 52, the mycological cure (negative culture and potassium hydroxide microscopy) rate in the MOB-015 and vehicle groups was 69.9% and 27.7%, respectively (P < .001), and complete cure (0% clinical disease involvement and mycological cure) was achieved in 4.5% and 0% of patients, respectively (P = .0195). At least 1 adverse event leading to discontinuation of treatment occurred in 2.8% of patients in the MOB-015 group and in 4.2% in the vehicle group. LIMITATION: The follow-up period after end of treatment may not be sufficient to accurately reflect cure in distal and lateral subungual onychomycosis. CONCLUSIONS: MOB-015 is a treatment option for onychomycosis with an adverse event profile similar to vehicle.

Severe onychomycosis management with oral terbinafine in a kidney transplantation setting: Clinical follow-up by image analysis.

BACKGROUND: Severe onychomycosis treatment in kidney transplant recipients (KTR) is challenging because of drug interactions and adverse events. Tacrolimus remains the antirejection treatment (ART) of choice in kidney transplantation but tolerance with systemic terbinafine for the management of severe onychomycosis has not been studied. OBJECTIVE: This study illustrates severe onychomycosis management in a kidney transplantation setting and investigates systemic terbinafine tolerance profile in KTR. PATIENTS/METHODS: We retrospective analysed clinical data of KTR with a confirmed diagnosis of severe onychomycosis. RESULTS: We retrieved a total of 29 KTR with severe onychomycosis needing an oral treatment to manage onychomycosis. In 55.1% (16/29) KTR, altered renal biological parameters or lack of guidelines to manage severe onychomycosis were the main reasons to deterring clinicians from prescribing oral treatments. 13 patients received an oral terbinafine treatment (9, 3 and 1 with a tacrolimus, cyclosporine and everolimus-based ART, respectively). Clinical and biological follow-up did not reveal severe drug interactions. ART blood levels showed significant variations in 2 patients without clinical consequences in renal graft. Two patients reported mild adverse events but after only one dose of terbinafine. Using an open-source image analysis program, clinical evolution of onychomycosis could be retrospectively quantified and followed up. CONCLUSIONS: The results presented here suggest that oral terbinafine can be proposed to treat severe onychomycosis with an acceptable tolerance profile in KTR with different ART such as tacrolimus and highlight the need of multicentric studies to establish guidelines for onychomycosis treatment in KTR.