mycoses Diagnosis,Therapy and Prophylaxis of Fungal Diseases Review article Isoconazole nitrate: a unique broad-spectrum antimicrobial azole effective in the treatment of dermatomycoses, both as monotherapy and in combination with corticosteroids Stefano Veraldi Department of Pathophysiology and Transplantation, University of Milan, I.R.C.C.S. Foundation, Ca Granda Ospedale Maggiore Policlinico, Milan, Italy Summary Fungal skin infections, or dermatomycoses, are associated with a broad range of pathogens. Involvement of gram-positive bacteria is often suspected in dermatomyco- ses. Inflammation plays an important role in dermatomycoses, displaying a close association between frequent inflammation and reduced skin-related quality of life. Isoconazole nitrate (ISN) is a broad-spectrum antimicrobial agent with a highly effec- tive antimycotic and gram-positive antibacterial activity, a rapid rate of absorption and low systemic exposure potential. ISN is effective against pathogens involved in dermatomycoses, with minimum inhibitory concentrations well below the concentra- tion of ISN in skin and hair follicles. The combination of the corticosteroid diflucorto- lone valerate with ISN (Travocortâ) increases the local bioavailability of ISN. Compared with ISN monotherapy, Travocort has a faster onset of antimycotic action, faster relief of itch and other inflammatory symptoms, improved overall therapeutic benefits and earlier mycological cure rate. Travocort is effective in the treatment of inflammatory mycotic infections, and also in the eradication of accompanied gram- positive bacterial infections. The rapid improvement observed with Travocort treatment, combined with favourable safety and tolerability, results in higher patient satisfaction, and therefore, can be an effective tool to increase treatment adherence in patients with dermatomycoses accompanied by inflammatory signs and symptoms. Key words: isoconazole nitrate, diflucortolone valerate, mycoses, antifungals, Travocort, Travogen increasing.2,3 In most cases, management of the infec- Introduction tion with a topical antifungal agent is effective using one of the two main classes: azoles and allylamines.4,5 Widespread utility of antifungals The azoles are the most widely used antifungal drugs.4 Dermatophytoses, commonly known as ringworm or Azoles act primarily by inhibiting the fungal cytochrome tinea, are superficial fungal infections caused by derma- P450 enzyme (CYP450), 14a-demethylase. There are tophytes, a group of keratinophilic fungi that infect the two groups of azoles in current clinical use: the imidaz- skin, hair and nails.1 Dermatophyte infections are extre- oles, which have a two-nitrogen azole ring and are mely common and are estimated to affect more than 20 predominantly used topically (isoconazole, bifonazole, –25% of the world’s population, and their prevalence is clomidazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, tio- conazole) and the triazoles, which have three nitrogens Correspondence: Stefano Veraldi, Department of Pathophysiology and in the azole ring and are primarily used for systemic Transplantation, University of Milan, 20122 Milan, Italy. administration (fluconazole, itraconazole, voriconazole, Tel.: +39 02 55035109. Fax: +39 02 50320779. and fosfluconazole, posaconazole, terconazole).4,6 E-mail: [email protected] Recently, a systematic review of 104 randomised = Submitted for publication 21 December 2012 controlled studies (N 15 795) evaluated the efficacy Accepted for publication 2 January 2013 of 16 topical antifungal agents vs. placebo in the © 2013 Blackwell Verlag GmbH Mycoses, 2013, 56 (Suppl. 1), 3–15 doi:10.1111/myc.12054 S. Veraldi treatment of cutaneous candidiasis and tinea versi- its molecular structure, (RS)-1-[2-[(2,6-dichlorobenzyl) color, tinea corporis, tinea cruris and tinea pedis.7 oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole) ISN A pooled subanalysis of mycological cure rate effi- belongs to the N-substituted imidazole group of azoles, cacy (N = 3044) demonstrated the consistent superi- and is closely related to miconazole (Table 1).8 ority of topical azoles over placebo, with an estimated pooled odds ratio of 10.25 (95% CI 6.88– Antimicrobial properties of isoconazole 15.27) favouring azoles. Moreover, no differences were nitrate found in safety and tolerability in all direct compari- sons made between antifungals and placebo or among The most common pathogens relevant in superficial antifungal classes. The results of this meta-analysis fungal infections are dermatophytes (~70%), yeasts justify the use of topical antifungal drugs over pla- (~35%), and non-dermatophytic moulds (<10%).2,9–16 cebo, irrespective of the drug evaluated, pharmaco- Most dermatophytoses involve more than one type of logical class, dosages, concentration, therapeutic pathogen from the Trichophyton, Microsporum or Epi- regimen adopted, duration of the treatment, diagnosed dermophyton species.2,3,17 In addition, dermatomycoses dermatomycosis and efficacy outcome taken into are often accompanied by bacterial superinfections, consideration. which can be caused by a mixture of different bacte- ria, but most often involve bacteria belonging to the Staphylococcus spp.17,18 Therefore, from a clinical point Isoconazole nitrate of view, there is a need for an antimicrobial treatment Isoconazole nitrate (ISN) belongs to the azole class of that is effective across a broad spectrum of pathogens, antifungal agents and is the active ingredient in the and displays both antifungal and antibacterial activity. topical drugs Travocortâ and Travogenâ (Bayer ISN has a broad spectrum of antimicrobial activity HealthCare/Intendis GmbH), which were specifically against dermatophytes, pathogenic yeasts (including developed to treat superficial fungal diseases. Based on the causative organism of pityriasis versicolor), Table 1 Molecular characteristics of isoconazole nitrate. Characteristic Description Reference Isoconazole nitrate Molecular structure ((RS)-1-[2-[(2,6-dichlorobenzyl)oxy]-2 [43] -(2,4-dichlorophenyl)ethyl]-1H-imidazole) Molecular formula C18 H14 Cl4 N2O [43] Main metabolites 2,4-Dichloromandelic acid and 2-(2,6-dichlorobenzyloxy)-2 -(2,4-dichlorophenyl)-acetic acid Physicochemical parameters pKA 6.68 [81] Log P 5.6 [81] Spectrum of activity Dermatophytes, pathogenic yeasts, [82] pathogenic filamentous fungi, gram-positive bacteria and trichomonads Formulation for topical use Travogen 1% w/w isoconazole nitrate (10 mg gÀ1) [61] cream (white to faintly yellow) for topical use Travocort 1% w/w isoconazole nitrate (10 mg gÀ1) and 0.1% w/w diflucortolone valerate (1 mg gÀ1) cream (white to faintly yellow) for topical use Molecular structure Isoconazole nitrate Cl –––– N CH2 CH O CH2 HNO3 N Cl Cl Cl © 2013 Blackwell Verlag GmbH 4 Mycoses, 2013, 56 (Suppl. 1), 3–15 Broad antimicrobial activity of isoconazole nitrate filamentous fungi, moulds, gram-positive bacteria such and one by Geotrichum candidum), clinical and myco- as Corynebacterium minutissimum, the causative organism logical cure was observed in 47 of the 49 patients of erythrasma8,19,20 (Table 2 and Table 3). treated with 1% ISN cream: 29 patients were cured in 3–4 weeks, 15 patients in 5–6 weeks and 3 patients in 8 weeks.22 In another study, coal miners with toe- Spectrum of clinical antifungal action nail and foot infections due to Hendersonula toruloidea, The broad antifungal efficacy of ISN has been demon- Scytalidium hyalinum and dermatophytes such as Trich- strated in numerous clinical investigations. In patients ophyton rubrum, Trichophyton mentagrophytes and Epi- with dermatomycoses, caused by dermatophytes like dermophyton floccosum were treated with 1% ISN Microsporum spp., Trichophyton spp., Epidermophyton cream. Clinical cure rate was 80% after 6 weeks of spp., Candida albicans, and other species (Malassezia fur- treatment.23 fur), monotherapy with 1% ISN cream, solution or spray, either once or twice daily resulted in cure rates Antifungal activity in vitro ranging from 96 to 100%.21 Furthermore, in 54 patients with tropical dermatomycoses (one patient Results of in vitro studies have helped explain the highly with a dermatomycosis caused by Trichosporum beigelii effective clinical antifungal profile of ISN. Table 2 Table 2 Antimycotic action of isoconazole nitrate.69 Isoconazole nitrate concentration Minimum inhibitory in the stratum corneum 1 h after Class of microorganism Species concentration (MIC) (lgmlÀ1)69 topical application26 Dermatophytes Trichophyton mentagrophytes 0.4 2500–3500 lgmlÀ1 Trichophyton rubrum 0.2 Microsporum gypseum 1.6 Microsporum canis 0.8 Epidermophyton floccosum 1.6 Yeasts Candida albicans 6.3 Candida albicans (isolate 130) 0.12–4 83 Candida parapsilosis 1.6 Candida krusei 3.1 Torulopsis glabrata 6.3 Moulds Aspergillus fumigatus 0.8 Aspergillus flavus 6.3 Aspergillus niger 0.4 Table 3 Summary of the minimal inhibition concentration (MIC) of isoconazole nitrate for different gram-positive bacteria. Kessler et al. [8] Czaika et al. [20] Isoconazole nitrate concentration in the stratum corneum 1 h after Gram-positive bacteria MIC (lgmlÀ1) MIC (lgmlÀ1) topical application26 Staphylococcus aureus 6.3 18 2500–3500 lgmlÀ1 MR Staphylococcus aureus 32 Staphylococcus epidermidis 6 Staphylococcus haemolyticus 24 Staphylococcus hominis 15 Streptococcus salivarius 3 Streptococcus viridans (MÆr) Staphylococcus faecalis 50.0 Staphylococcus/Micrococc. species 3.1 Bacillus cereus 19 Corynebacterium tuberculostearicum 4 Propionibacterium