Fenticonazole: an Effective Topical Treatment for Superficial Mycoses As the First-Step of Antifungal Stewardship Program
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European Review for Medical and Pharmacological Sciences 2017; 21: 2749-2756 Fenticonazole: an effective topical treatment for superficial mycoses as the first-step of antifungal stewardship program F. TUMIETTO1, L. GIACOMELLI2 1Infectious Diseases Unit Teaching Hospital S. Orsola-Malpighi, Alma Mater Studiorum University of Bologna, Bologna, Italy 2Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy Abstract. – The resistance of microorgan- infections are defined as infections in which the isms to antimicrobial drugs is a major issue for pathogen is confined to the superficial layer, with public health, with important consequences in minimal or no histological signs1. terms of morbidity, mortality and resource use. The dermatophyte or ringworm infections, su- The phenomenon is so serious that in some ar- eas of the world resistant strains to all available perficial candidosis of the mouth, skin or genital drugs have been selected. tract and infections due to Malassezia, such as Many conditions may result in the development Pityriasis versicolor, are the main conditions. Tin- of resistance: they include the indiscriminate or ea affects external areas of the body. Candidiasis is inappropriate (e.g., for viral infection or coloniza- caused most often by the yeast Candida albicans, tion) use of antibiotics, the excessive duration of although in recent years, cases due to non-albicans the prescribed treatment regimens, as well as in- adequate dosing or administration routes. strains are increasing significantly. Candidiasis of- Resistance is well-known, but less studied, al- ten affects the genitals or inside of the mouth. so for infections caused by fungi. All these infections are usually diagnosed clin- In the last decade, an impressive outbreak ically. However, microbiological diagnosis is also of candidiasis due to non-albicans strains (with crucial, and it becomes mandatory when infec- variable patterns of resistance to azoles) was ob- tion by non-albicans strains of Candida species is served. This outbreak was likely associated with suspected. Treatment largely depends on the use inappropriate use of oral azoles for the treatment of non-complicated candidiasis, such as vulvo- of azole (imidazole/triazole) or allylamine anti- vaginal candidiasis or Candida dermatitis. fungals, applied in short courses topically or for In this setting, fenticonazole may represent an longer periods orally, depending on the site and effective topical drug for the treatment of mycot- severity of the infection. ic infections of skin and mucosa. Topical treat- In particular, topical antifungal treatment ment of superficial mycoses still holds a major with imidazole derivatives results in a relevant importance as it helps reduce the exposure to benefit for the treatment of superficial myco- oral systemic azoles – mainly fluconazole and 2 itraconazole – of intestinal microbiota, which ses . Among different therapies, fenticonazole represents the main human reservoir of yeasts. applied once- or twice daily appears at least This strategy can contribute to reduce the se- as effective as other topical antifungals (cyc- lection of resistant strains of Candida, within the lopyroxolamine, naftifine, and many imidazole context of a really-effective antifungal steward- derivatives) in the treatment of superficial skin ship program. mycoses and vulvovaginal candidiasis3,4. This Key Words: review presents and discusses current evidence Antimicrobial stewardship, Fenticonazole, Antimicro- on fenticonazole and the role of this molecule in bial drugs, Mycotic infections, Intestinal microbiota. clinical practice. Pharmacology Introduction Fenticonazole [alpha-(2,4-dichlorophenyl)-be- ta, N-imidazolylethyl 4-phenylthiobenzyl ether Superficial fungal infections or mycoses are nitrate] is an imidazole derivative that was de- common, treatable conditions. Superficial fungal veloped for the topical treatment of fungal infec- Corresponding Author: Fabio Tumietto, MD; e-mail: [email protected] 2749 F. Tumietto, L. Giacomelli Fenticonazole exerts also an interesting anti- bacterial activity, with a spectrum that comprises Gram-positive bacteria (such as Staphylococcus aureus, Staphylococcus epidermidis, Streptococ- cus spp.), which often super-infect the skin and vaginal infections14 and an antiparasitic action against Trichomonas vaginalis15,16. As a drug belonging to the class of imidazoles, where metronidazole is the prototype most com- monly used today, fenticonazole is also active against parasites such as Trichomonas vaginalis or some bacterial species such as Gardnerella Figure 1. Chemical structure of fenticonazole. vaginalis. The anti-Trichomonas action seems to be based on the cyto-lethal activity of a radical anion distinguished by a short half-life, produced under anaerobic conditions, while the antibacteri- tions. This molecule presents a wide spectrum of al activity would be linked to the effect of a selec- activity against dermatophytes and yeasts (Fig- tive cytotoxic oxidative metabolite17. ure 1)5,6. The acute toxicity after oral and topical Fenticonazole exerts antifungal activity by sub-chronic toxicity intake were studied in animal 18 three different mechanisms: (1) inhibition of the models . The acute oral LD50 in dogs, mice and release of protease acid by Candida albicans9,10; rats ranged between 1,000 mg/kg and 3,000 mg/ (2) alteration of the cytoplasmic membrane, via kg. Topical sub-chronic toxicity was studied in rats inhibition of the fungal P450 isozyme, which is and dogs, showing no histopathological abnormal- necessary to convert lanosterol to ergosterol, an ities following the administration of fenticonazole. essential component of fungal cell membrane Fenticonazole does not affect release and ac- synthesis11; and (3) blockade of cytochrome oxi- tivity of histamine, adrenaline, noradrenaline and dases and peroxidases7-12. acetylcholine, and vital functions such as blood A scanning electron microscopic study of pressure, heart rate, and pulmonary ventilation19. the effect of fenticonazole on cells of C. al- Two other pharmacological characteristics of bicans revealed the induction of cytoskele- fenticonazole are worth mentioning. The drug tal changes and alterations in the structure of is retained in the stratum corneum of the skin plasma membrane, more evident with increas- for a long time20, and it has peculiar pharmaco- ing concentrations of the molecule7. Moreover, kinetic properties that allow its accumulation in at concentrations close to the Minimal Inhib- the mucosal tissue as active drug up to 72 hours, itory Concentration (MIC), the inhibition of this allowing the formation of a reservoir of fen- the formation of pseudohyphae of C. albicans ticonazole and delaying consecutive administra- is observed8. Table I reports the MIC of fen- tions21. Furthermore, the determination of plasma ticonazole for different Candida strains, with levels of fenticonazole has confirmed that the other azoles as comparison13. drug is poorly absorbed at a systemic level22. Table I. Susceptibilities of 260 VVC isolates and quality control strains (EUCAST broth microdilution method). Isolate Fenticonazole Itraconazole Fluconazole Ketoconazole MIC50 range GM MIC50 GM MIC50 range GM MIC50 (µg/ml) (µg/ml) range (µg/ml) (µg/ml) (µg/ml) (µg/ml) range GM (µg/ml) (µg/ml) C. albicans 0.03-0.25 0.10 0.03-0.5 0.6 0.12-32 1.84 0.12-4.0 0.54 C. glabrata 0.03-0.5 0.28 0.03-0.5 0.10 2.0-≥64 7.51 2.0-8.0 2.13 C. parapsilosis 0.03-0.25 0.13 0.06-012 0.09 0.5-4 2.14 0.12-0.5 0.21 C. krusei 0.06-1 0.20 0.03-0.12 0.08 32-64 45.25 0.12-1 0.26 GM: geometric mean 2750 Fenticonazole: as the first-step of antifungal stewardship program Clinical Studies in Dermatology Clinical Studies in Gynaecology A number of open, controlled trials on fen- In the gynaecological setting, fenticonazole ticonazole are available in the dermatology was studied in the treatment of Candida vulvo- setting. Overall, clinical evidence shows that vaginitis26-36 and mixed infections34,37-39. the different formulations of fenticonazole are In all studies, the diagnosis was based on clin- effective in the treatment of cutaneous fungal ical history and presentation, direct mycological infection, and that the side effects are rare and examinations and cultures. However, no study to of mild severity. date evaluated recurring infections. A study conducted in 198723 on 30 patients Most studies were open label27,28,31,33-35,37-39 but with candidiasis, tinea versicolor and epider- four were double-blind, controlled or -single com- momycoses treated with fenticonazole once parator trials26,29,30,32,36. Four studies compared daily has documented a clinical and microbio- fenticonazole with clotrimazole26,29,30,32, and one logical response in all patients after 28 days of fenticonazole with fluconazole36. therapy (in the case of candidiasis and pityri- Nine studies were conducted on ovule formu- asis), and after 32 days in 8 out of 10 patients lations27,29,30,32-34,36-38; two studies with the combi- with epidermomycoses. nation of cream with ovules27,34; and one study on One large clinical trial, conducted in 198824, the combination of ovules and vaginal lavage39. was a multi-center, open-label trial in which fen- In more details, vaginal capsules (600 mg or 1 ticonazole cream, spray or powder were applied g as a single dose or 200 mg/day for three days), once or twice daily in 760 patients with super- 2% cream for 3 or 7 days, or a combination of ficial mycoses. The mycological negativity was capsules with cream or vaginal lavage, were ef- achieved by the fifth week of treatment, with a fective in the treatment of infections in 75-100% marked clinical response in patients with tinea of patients and allowed the eradication of Candida versicolor (100%) and candidiasis (95%). Twen- spp. in 70-100% of patients26-34,37. Eradication was ty-nine patients reported adverse events, but only obtained within one week in most studies27,29-33,37. 8 subjects were required to stop treatment. Fenticonazole 600 mg or 1 g as a single dose or Controlled clinical trials on the use of fenti- 200 mg/day for three days has shown a similar conazole led to similar results.