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Antifungal drug resistance: Significance and mechanisms
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Sharvari Dharmaiah, Rania A. Sherif, Pranab K. Mukherjee
Resistance against terbinafine, the commonly used allylamine, is rare. However, Mukherjee et al. [115] reported the first instance of terbinafine resistance in dermatophytes. The in vitro antifungal susceptibilities of six clinical T. rubrum isolates obtained sequentially from a single onychomycosis patient who failed oral terbinafine therapy (250 mg/day for 24 weeks) were determined by broth microdilution and macrodilution methodologies. The MICs of terbinafine for these strains were >4 µg/mL, whereas they were <0.0002 µg/mL for the susceptible reference strains, and MFCs for all six strains were >128 µg/mL, and 0.0002 µg/mL for the reference strain. Since PCR amplification analyses did not reveal any differences between the isolates, and the MIC of terbinafine for the baseline strain (cultured at the initial screening visit and before therapy was started) was increased by 4000-fold, this was identified as a case of primary resistance to terbinafine, acquired during the course of therapy. These terbinafine-resistant isolates exhibited normal susceptibilities to clinically available antimycotics, including itraconazole, fluconazole, and Griseofulvin, but were cross-resistant to several other known squalene epoxidase inhibitors, including naftifine, butenafine, tolnaftate, and tolciclate, suggesting a target-specific mechanism of resistance.
Non-dermatophytic onychomycosis
Published in Archana Singal, Shekhar Neema, Piyush Kumar, Nail Disorders, 2019
Terbinafine, the main representative of the allylamine class, was approved for the treatment of onychomycosis in 1991 in the United Kingdom. Terbinafine is highly effective against dermatophytes and some yeasts, but has low efficacy against NDM.13 Terbinafine is both fungicidal and fungistatic. Terbinafine interferes with ergosterol synthesis by inhibiting squalene epoxidase, an enzyme that catalyzes the conversion of squalene to squalene epoxide. This inhibition results in the accumulation of squalene in the cell cytoplasm and the deficiency in ergosterol. Terbinafine owe its fungicidal activity to squalene accumulation, which leads to lipid droplets within the cytoplasm, disruption of the cells’ homeostasis, and the release of lytic enzymes, while its fungistatic activity is a result of ergosterol deficiency. Terbinafine is incorporated in the nail plate through the nail bed and nail matrix.30 Terbinafine levels in the nail can be detected for six months after cessation of therapy.14 The acceptable dosage for onychomycosis is 250 mg a day for 3–4 months.
Candida
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Synthetic allylamines cause disruption of ergosterol synthesis as they are reversible, noncompetitive inhibitors of squalene epoxidase (ERG1). This enzyme catalyzes the conversion of squalene into 2,3-squalene epoxide. Inhibition of this enzymatic activity leads to squalene accumulation, causing an increase in yeast cell membrane permeability and cell death. The main members of this group are terbinafine and naftifine. These antifungal drugs are used for both systematic and topical treatment and are widely used in superficial skin and nails in Candida infection.22,60,62 Moreover, terbinafine has high fungicidal activity on itraconazole-resistant yeast.62
Antifungal resistance in superficial mycoses
Published in Journal of Dermatological Treatment, 2022
Aditya K. Gupta, Maanasa Venkataraman
Terbinafine is widely used to treat dermatophyte infections such as onychomycosis due to its high efficacy (39). Terbinafine resistance has been predominately attributed to point mutations in the squalene epoxidase (SQLE) gene whose product is the drug target for terbinafine (29). A unique mechanism of resistance exhibited by T. rubrum and T. interdigitale was documented, where elevated expression of salicylate 1-monooxygenase (salA) gene increased terbinafine resistance (40). Furthermore, molds such as Aspergillus fumigatus, may also exhibit terbinafine resistance due to the extra-plasmidial copies of the SQLE gene (40). Molecular biology techniques such as real-time polymerase chain reaction (RT-PCR), mutation, and gene expression analysis, could provide insight into the novel mechanisms of the fungal pathogens against terbinafine (29,40).
Development, optimization and characterization of nanoemulsion loaded with clove oil-naftifine antifungal for the management of tinea
Published in Drug Delivery, 2021
Adel F. Alghaith, Sultan Alshehri, Nabil A. Alhakamy, Khaled M. Hosny
Naftifine, a primary topical antimycotic drug with allylamine structure, is active against a broad spectrum of dermatophytes belonging to Trichophyton and Microsporum spp. and has shown good activity against Candida and Aspergillus spp. (Cuenca-Estrella et al., 2006). It is believed to exert a fungicidal effect through squalene epoxidase inhibition in fungi, thus diminishing ergosterol biosynthesis (Monk & Brogden, 1991). In contrast to other antifungal drugs like azoles, naftifine is highly selective to ergosterol biosynthesis and does not affect drug metabolism in the liver even if a significant portion reaches the systemic circulation (Lee et al., 2007). Although naftifine is well tolerated, it was reported to cause some mild inflammations and stinging sensation, which might affect patient compliance (Altmeyer et al., 1990).
Evaluation of efficacy and safety of oral terbinafine and itraconazole combination therapy in the management of dermatophytosis
Published in Journal of Dermatological Treatment, 2020
Priyanka Sharma, Mala Bhalla, Gurvinder P. Thami, Jagdish Chander
In the present study, a combination of terbinafine 250 mg and itraconazole 200 mg daily was found to have a significantly higher clinical and mycological cure rate of 90% at 3 weeks as compared to monotherapy with the same drugs. The in vitro as well as clinical synergism between terbinafine and itraconazole has been well documented against isolates of Fonsecaea, Candida albicans, Aspergillus, Scedosporium, Fonsecaea, and various other dematiaceous molds (9–11). However, the clinical or in vitro synergism of this combination has not yet been established in the treatment of tinea cruris or corporis or dermatophyte isolates. The combination of terbinafine 250–1000 mg/day and itraconazole 200–400 mg/day for 2–7 months has also been found to be effective in the treatment resistant cases of chromoblastomycosis (10). Theoretically, inhibition of squalene epoxidase and lanosterol 14-demethylase by terbinafine and itraconazole, respectively, results in dual and sequential inhibition of fungal ergosterol biosynthesis which serves as a bioregulator of membrane fluidity and integrity of fungal cells (20).