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.

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.

A novel case of cutaneous squamous cell carcinoma at the site of previous sporotrichosis.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is a malignant tumor of epithelial keratinocytes, with a relatively reduced frequency of lymph node metastasis. Despite the fact that this tumor type is largely preventable, the incidence of cSCC is rising every year. Ultraviolet exposure is a major cause of cSCC and directly contributes to cSCC. Other known environmental risk factors include ionizing radiation, cigarette smoking, and certain chemical exposures. AIMS: In this study, we report a clinical case of cSCC with a novel causative factor. PATIENT/METHODS: The report describes a 72-year-old male who was seen for a dermatosis condition initially. Later, epidermal hyperplasia and granulomatous inflammation of the dermis was diagnosed based on skin biopsy. Fungal culture revealed the presence of Sporothrix schenckii which led to the diagnosis of fixed-type sporotrichosis. RESULTS: Four months of oral terbinafine (250 mg once a day) administration partially resolved the lesions. Patient was subsequently diagnosed with cSCC, and surgical resection with wider margins was performed. CONCLUSION: After a careful and rigorous exclusion of known risk factors, we confirmed that this incidence of cSCC was caused by chronic inflammation which followed fixed-type sporotricosis.

Use of terbinafine and risk of death in patients with prostate cancer: A population-based cohort study.

Terbinafine is used for the treatment of several superficial fungal infections. In silico analyses and animal models suggest that terbinafine might have an anti-tumor effect. We aimed to explore whether subsequent administration of terbinafine might be associated with a lower mortality rate in patients with prostate cancer. We identified patients diagnosed with prostate cancer between July 2005 and December 2014 from the Swedish Cancer Registry, and linked them to the Swedish Prescribed Drug Register to ascertain subsequent use of terbinafine. A total of 799 patients received oral treatment of terbinafine during the study period with a mortality rate of 18.6 per 1,000 person-years. Compared to patients who did not use terbinafine and adjusting for a range of confounding factors, patients that received oral treatment of terbinafine had a decreased risk of death from prostate cancer (HR, 0.53; 95% CI, 0.38-0.73) and a decreased risk of death overall (HR, 0.64; 95% CI, 0.52-0.77). To account for indication bias, we further identified 907 patients who received topical use of terbinafine. However, the risk of death from prostate cancer in patients with topical use of terbinafine was 0.92 (95% CI 0.74-1.12) and the risk of death overall was 1.03 (95% CI 0.91-1.17) as compared to the controls, which suggests that there was no association between risk of death in patients with prostate cancer with topical use of terbinafine. These findings suggest that this drug's potential anti-tumor effect needs to be explored further.

Antifungal mechanism of action of Schinus lentiscifolius Marchand essential oil and its synergistic effect in vitro with terbinafine and ciclopirox against dermatophytes.

OBJECTIVES: The aim of this study was to evaluate the antifungal, antichemotactic and antioxidant activities of Schinus lentiscifolius essential oil, as well as its combined effect with terbinafine and ciclopirox, against dermatophytes. METHODS: Essential oil was analysed by GC-MS. The antifungal activity and the mechanism of action were determined by broth microdilution, sorbitol and ergosterol assays, as well as scanning electron microscopy. The checkerboard method was used for evaluating the interactions with commercial antifungal agents. The antioxidant and antichemotactic activities were measured using the DPPH and the modified Boyden chamber methods, respectively. KEY FINDINGS: Chemical analysis revealed the presence of 33 compounds, the primary ones being γ-eudesmol (12.8%) and elemol (10.5%). The oil exhibited 97.4% of antichemotactic activity and 37.9% of antioxidant activity. Antifungal screening showed effect against dermatophytes with minimum inhibitory concentration values of 125 and 250 µg/ml. Regarding the mechanisms of action, the assays showed that the oil can act on the fungal cell wall and membrane. Synergistic interactions were observed using the combination with antifungals, primarily terbinafine. CONCLUSIONS: Schinus lentiscifolius essential oil acted as a chemosensitizer of the fungal cell to the drug, resulting in an improvement in the antifungal effect. Therefore, this combination can be considered as an alternative for the topical treatment of dermatophytosis.