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 areas 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 antibacterial 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. efficacy profile27. In a study by Clerico et al25, 40 patients with In a study on 417 women with vaginal candidi- tinea versicolor, candidiasis or dermatophytosis asis, published in 201232, the efficacy and tolera- were treated with 2% fenticonazole or miconazole bility of treatment with a vaginal capsule of 600 cream. Clinical response was observed in 16 out mg of fenticonazole were evaluated. Patients were of 20 patients (80%) in the group treated with re-evaluated on day 1, 7 and 28 after treatment. fenticonazole, versus 14/20 patients (70%) in the After seven days, a significant reduction in symp- group treated with miconazole. toms (vaginal discharge and itching) was observed. A multi-center, double-blind study2 was con- Microbiological control with vaginal smear docu- ducted on 100 patients with cutaneous fungal in- mented a complete response in 385/417 women fections, in order to compare the efficacy and tol- (92.3%). After one week of treatment, 84 women erability of spray formulations of fenticonazole have repeated the therapy for persistent symptoms 2% and naftifine 1%. The patients were treated or positive smear. At day 28, complete recovery once a day for 2 to 4 weeks. Candida albicans was reported in 392 patients (94%), and only one was present in 33.3% of patients in fenticonazole patient showed worsening of symptoms. Side ef- group and 20.8% in naftifine group. At the end of fects were infrequently reported, and mainly con- treatment, only 3 (6.3%) and 5 (10.4%) patients – sisted of moderate redness of the vulva and vagina, out of the 48 evaluated in each group – still had and a slight itching during the first days of therapy. a positive mycological examination. The evalua- In a recent study35 on reproductive-aged pa- tion of the symptoms showed a marked improve- tients with acute vaginal candidiasis, 54 women ment with respect to baseline: 90% of patients received one 600-mg vaginal fenticonazole cap- in each group were considered cured or greatly sule. Seven of them had acute complicated vulvo- improved. Follow-up data showed that, among vaginal candidiasis and received a second 600-mg patients cured or greatly improved at the end of fenticonazole capsule on day 4 after treatment ini- treatment, only 1 patient (3.2%) on fenticonazole tiation. In a subsequent stage of investigation, 57 and 2 patients (6.3%) on naftifine experienced patients with acute vaginal candidiasis were given mycological relapse. 2 intravaginal fenticonazole capsules (days 1 and

2751 F. Tumietto, L. Giacomelli

4). Overall, the response rates were 100% in the Trichomonas vaginalis, with fenticonazole 600 first stage of the study and 97% in the second. mg or 1000 mg, respectively. In a prospective study36, 80 patients with con- With more specific reference to tolerability, firmed vulvovaginal candidiasis were random- fenticonazole – in any formulation – was very ly assigned to either intra-vaginal tablet fenti- well tolerated for up to 4-6 weeks. The most com- conazole (600 mg) or oral fluconazole (150 mg). mon adverse event was burning, in most cases of Two sequential doses of azoles were given 3 days short duration and mild-to-moderate, occurring in later (short-course treatment). At 30 days after about 7% of patients26,27,29-32,39. However, this ad- treatment, 32/40 patients (80%) in fenticonazole verse event has been reported in <1% of patients group and 31/40 patients (77.5%) in the fluco- in four studies26,21,31,39, and was already present at nazole group were cured. Vulvovaginal pruritus baseline in most cases. was reduced in a lower time in patients assigned to fenticonazole than in those receiving fluco- The Future of Topical Treatments of nazole (2.3 days vs. 4.5 days, p=0.047). Superficial Mycoses: Antifungal In a multicenter, prospective, open-label Stewardship in Dermatology and study39, fenticonazole (1 g vaginal suppositories Gynaecology once daily on days 1 and 3), was used for the Antimicrobial resistance is a worldwide issue treatment of mixed vulvovaginal infections with with large clinical and economic impact. The se- Candida albicans, Trichomonas vaginalis, and/ lection of resistant strains may eventually lead to or Gardnerella vaginalis. The rate of eradication the increased prevalence of non-albicans Candida of Candida albicans at day 8 was 90% (26/29); strains, with variable sensitivity and even full re- 28 days later, no recurrence was reported, while sistance to azoles. This problem is rapidly emerg- the success rate was 73% for G. vaginalis, and ing, mainly for two reasons. First, because oral 77% for mixed infection. In addition, a signifi- antifungal medications are prescribed in most cant improvement in signs and symptoms were cases at low doses or inappropriately. A recent observed at day 8, as compared with baseline analysis42 revealed that 12.6% of outpatient visits (p<0.05). Overall similar results were reported in in the United States led to the prescription of an other studies on patients with vulvovaginal can- antibiotic, and 30% of these prescriptions can be didiasis29,31,32, with fenticonazole resulting in an considered inappropriate. improvement of the signs (erythema, edema) and The direct-to-consumer sales might then fur- symptoms (itching, burning) within a couple of ther complicate the problem of inappropriate use: days since the first administration and complete it has been shown that only one-third of patients resolution of some or all of symptoms in 52-100% with a self-diagnosed vulvovaginal candidiasis of patients within one week. infection purchasing an over-the-counter (OTC) Fenticonazole has also an antibacterial activity drug for treatment had a laboratory-confirmed di- against Gram-positive bacteria and an antiparasit- agnosis43. In the US, clotrimazole and miconazole ic action against Trichomonas vaginalis15,16. were the first topical antifungal drug available as In three studies conducted in patients with OTC, since 1991. A trend to a decrease in aver- vaginal trichomoniasis, fenticonazole vaginal age annual rates of visits at physician office for capsules 600 mg or 1000 mg administered as a symptoms of vaginitis and vulvovaginal candi- single dose, with34 or without vaginal wash for diasis has been observed, clearly linked with the 5 days, or daily for 2 days without vaginal wash OTC availability. However, and not surprisingly, eradicated all organisms in 28-65% of patients at trends in antifungal prescriptions increased in fa- 7 days; eradication of Trichomonas vaginalis and vour of oral azoles, such as fluconazole. It means Candida spp was seen in 100% of patients at day that women firstly self-treated infections with 7. A single dose of fenticonazole 1000 mg was OTC drugs (and it was correct only in one third of significantly more effective on Trichomonas than cases), and then their gynaecologists prescribed 600 mg single dose (p<0.01) 40,41. preferentially oral azoles44. On the other hand, it In the case of mixed infections, two open-label must be acknowledged that in many countries it is studies (600 mg as a single dose, or 1000 mg on impossible to guarantee a correct microbiological days 1 and 3) demonstrated the complete eradica- diagnosis for vulvovaginitis. Moreover, there is an tion in 45% of patients after 7-8 days38,39. At tri- increasing tendency to prescribe oral medications al endpoint, 96% and 90% of patients eradicated as a first-line therapy, although current guide- Candida albicans, and 67% and 70% eradicated lines indicate the equivalent topical therapy to

2752 Fenticonazole: as the first-step of antifungal stewardship program oral treatment in superficial infections44. Indeed, temic antifungal drugs of high cost. However, the topical therapies are proven to be as effective as high number of prescriptions of some systemic systemic treatments in uncomplicated fungal in- oral azoles (in particular fluconazole and itracon- fections. In addition, oral formulations expose azole) is almost ignored by community medicine the intestinal microbiota to the active compound, and hospitals. Noteworthy, hospitals may be the thus promoting the selection of resistant strains. ideal setting to organize ASPs because they can On these bases, it can be suggested that the use of be easily controlled and refer to a single pharma- topical anti-mycotic drugs with a broad spectrum cy structure, which represents the fundamental of action, such as fenticonazole, either as an OTC support for their realization. However, ASPs are or RX medication, can be considered a cost-effec- difficult to implement in hospitals and have a poor tive solution, allowing woman with symptomatic acceptance49. However, the use of antibiotics in vaginal discharge to successfully cure infections hospitalized patients represents only 38.5% of the of different etiology minimizing the risk of se- total market of antibiotics, while the largest part lecting drug-resistant strains45. of the antibiotic market is administered to outpa- Emergence of resistant strains is a well-known tients and is, therefore, more difficult to control50. issue in clinical microbiology, and it is raising An effective ASP must be designed and con- dramatically also in fungal infections. As an ex- structed with a comprehensive vision, i.e. by ample, most recently, the emergence of Candida including all prescription contexts, from gener- auris was reported. This fungus can cause inva- al practitioners to specialist offices and referral sive infections, associated with high mortality and acute care hospitals. is often resistant to the three classes of antifungal To date, ASPs were mainly implemented in drugs (azoles, echinocandins and polyenes). C. acute-care hospitals, but inappropriate antibi- auris was first described in 2009 in Japan, and otic use and high prevalence of multi-resistant afterwards reports of infections, including sys- organisms are also common in long-term care temic ones, have been published from Colombia, facilities (LTCF) or community medicine. On India, Israel, Kenya, Kuwait, Pakistan, South the other hand, the ASP strategies used in the Africa, South Korea, Venezuela, and the United acute-care hospitals cannot be automatically Kingdom46. Infections often occur as nosocomial extrapolated to LTCFs or general community outbreaks, affecting patients of any age. A large medicine due to the differences in patients and part of isolates is fluconazole resistant, and am- available resources51. In fact, high-cost drugs photericin B and echinocandin resistance rates (new azoles, echinocandins and lipid formu- are approximately 30%-40% and approximately lations of polyenes) are generally only used in 5%-10%, respectively. Not less than 50% of iso- hospitals. However, it is necessary to pay atten- lates are multidrug resistant (considering multi- tion to all prescription contexts, and especially drug resistant those strains resistant to 2 or more to the outpatient setting which is often the most antifungal classes). Pandrug resistant isolates relevant in terms of market share. In the case of were reported. Preferential treatment regimens superficial fungal infections, it should be taken are unknown. Mortality rates are high, up to 70% into account that inexpensive drugs such as fen- during candidemia47. ticonazole are available and represent suitable Antimicrobial Stewardship Programs (ASPs) and effective options within an ASP. The avail- may represent a solution to minimize the devel- ability of non-systemic drugs as fenticonazole, opment of resistance48. with proven efficacy in the treatment of uncom- The Infectious Diseases Society of America plicated infections, and without a significant (IDSA), the Society for Healthcare Epidemiolo- impact on the microbiota should be highlight- gy of America (SHEA), and the Pediatric Infec- ed with greater strength in the guidelines and tious Diseases Society (PIDS) defined ASP as reference documents issued by the national and “coordinated interventions designed to improve international scientific societies. Fenticonazole and measure the appropriate use of [antibiotic] is an antifungal drug for topical use which has agents by promoting the selection of the optimal shown a broad spectrum of action and a high ef- [antibiotic] drug regimen including dosing, dura- ficacy for the treatment of mucocutaneous can- tion of therapy, and route of administration”. didiasis and fungal infections of the skin. Given In the field of ASPs for antifungal therapies, also the availability of different formulations, the international debate is mostly focused on the fenticonazole can certainly be considered a cor- optimization of the prescription and use of sys- nerstone in the effective treatment of non-severe

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2754 Fenticonazole: as the first-step of antifungal stewardship program

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