Terbinafine: a review of its use in onychomycosis in adults

Terbinafine, an orally and topically active antimycotic agent, inhibits the biosynthesis of the principal sterol in fungi, ergosterol, at the level of squalene epoxidase. Squalene epoxidase inhibition results in ergosterol-depleted fungal cell membranes (fungistatic effect) and the toxic accumulation of intracellular squalene (fungicidal effect). Terbinafine has demonstrated excellent fungicidal activity against the dermatophytes and variable activity against yeasts and non-dermatophyte molds in vitro. Following oral administration, terbinafine is rapidly absorbed and widely distributed to body tissues including the poorly perfused nail matrix. Nail terbinafine concentrations are detected within 1 week after starting therapy and persist for at least 30 weeks after the completion of treatment. Randomized, double-blind trials showed oral terbinafine 250 mg/day for 12 or 16 weeks was more efficacious than itraconazole, fluconazole and griseofulvin in dermatophyte onychomycosis of the toenails. In particular, at 72 weeks' follow-up, the multicenter, multinational, L.I.ON. (Lamisil vs Itraconazole in ONychomycosis) study found that mycologic cure rates (76 vs 38% of patients after 12 weeks' treatment; 81 vs 49% of recipients after 16 weeks' therapy) and complete cure rates were approximately twice as high after terbinafine treatment than after itraconazole (3 or 4 cycles of 400 mg/day for 1 week repeated every 4 weeks) in patients with toenail mycosis. Furthermore, the L.I.ON. Icelandic Extension study demonstrated that terbinafine was more clinically effective than intermittent itraconazole to a statistically significant extent at 5-year follow-up. Terbinafine produced a superior complete cure rate (35 vs 14%), mycologic cure rate (46 vs 13%) and clinical cure rate (42 vs 18%) to that of itraconazole. The mycologic and clinical relapse rates were 23% and 21% in the terbinafine group, respectively, compared with 53% and 48% in the itraconazole group. In comparative clinical trials, oral terbinafine had a better tolerability profile than griseofulvin and a comparable profile to that of itraconazole or fluconazole. Post marketing surveillance confirmed terbinafine's good tolerability profile. Adverse events were experienced by 10.5% of terbinafine recipients, with gastrointestinal complaints being the most common. Unlike the azoles, terbinafine has a low potential for drug-drug interactions. Most pharmacoeconomic evaluations have shown that the greater clinical effectiveness of oral terbinafine in dermatophyte onychomycosis translates into a cost-effectiveness ratio superior to that of itraconazole, fluconazole and griseofulvin. CONCLUSION: Oral terbinafine has demonstrated greater effectiveness than itraconazole, fluconazole and griseofulvin in randomized trials involving patients with onychomycosis caused by dermatophytes. The drug is generally well tolerated and has a low potential for drug interactions. Therefore, terbinafine is the treatment of choice for dermatophyte onychomycosis.     

Itraconazole and terbinafine in perspective: from petri dish to patient

Objective To compare the antifungal activity of itraconazole and terbinafine in vitro and to relate them to their experimental in vivo activity and to their efficacy in patients with superficial fungal infections (tinea pedis and onychomycosis).Results Fungal infections such as onychomycosis and tinea pedis are often treated with oral antifungals. With the introduction of newer agents such as terbinafine and itraconazole, efficacy and safety have been improved. In vitro evaluation showed somewhat better results against dermatophytes for terbinafine than for itraconazole, but in vivo results were at least equivalent. Moreover, itraconazole is a broad-spectrum agent with higher cure rates for infections other than dermatophytosis (e.g. for Candida infections) than terbinafine, according to ex vivo studies. A review of all published clinical trials, comparing the efficacy and safety of terbinafine and itraconazole in a meta-analysis revealed similar and high cure rates (>70%) for both anti-fungal agents and similar adverse event profiles. Both treatments were safe and well tolerated.Conclusions Antifungal research has responded to the challenges of treating superficial infections by developing effective, well-tolerated, fast-acting antifungal therapies. The reduction in treatment duration has also led to improved patient's compliance. The most noticeable difference between itraconazole and terbinafine is the 1-week pulse concept of itraconazole in contrast to the continuous treatment concept of terbinafine.     

New antifungal agents.

This article, rather than presenting an overview of all available antifungal agents, has provided an update on new information about older agents, as well as evolving information about new agents, including those currently undergoing clinical trials. Among the azoles, ketoconazole will continue to be used as a major antifungal agent in dermatology, but one must keep up with its side effects and drug interactions. The place of the new triazole fluconazole in the treatment of cutaneous fungal infections needs to be clarified by additional controlled studies. Other agents on the horizon which are still undergoing investigation include itraconazole, which should be especially useful for dermatophyte (including tinea unguium) and candidal infections, sporotrichosis, and unusual infections such as aspergillosis and phaeohyphomycosis; and terbinafine, a member of the new class of antifungals called allylamines, which is an orally and topically active fungicidal agent that should be very useful for all types of dermatophyte infections. Research continues into the effectiveness of members of other classes of antifungals, including piritetrate, cilofungin, and amorolfine. In the 1990s, dermatologists should have safer, more effective antifungal agents for treating cutaneous fungal infections.     

Efficacy and tolerability of amorolfine 5% nail lacquer in combination with systemic antifungal agents for onychomycosis: A meta‐analysis and systematic review

The efficacy and safety of amorolfine 5% nail lacquer in combination with systemic antifungal agents in the treatment of the onychomycosis were evaluated. According to our meta‐analysis, combination treatment of amorolfine 5% nail lacquer and systemic antifungals can result in higher percentage of complete clearance of onychomycosis. It showed that the experimental combination group was more effective than monotherapy of the systemic antifungals [OR (odds ratio) = 1.97, 95%CI (95% confidence interval) = 1.44–2.69], and no more adverse events happened with the addition of amorolfine 5% nail lacquer (OR = .96, 95%CI = .56–1.63, p = .95). This effect strengthens the fact that amorolfine 5% nail lacquer in combination with systemic antifungal agents was better than the monotherapy of systemic antifungals like itraconazole and terbinafine.     

Onychomycosis

Onychomycosis is a frequent nail disease caused by dermatophytes, yeasts, and nondermatophyte molds. Trichophyton rubrum, T mentagrophytes, and Epidermophyton floccosum are the most common etiologic agents worldwide. Candida spp are the most frequent among the yeasts. Diagnosis is corroborated by direct microscopic examination, culture, and histomycology with periodic acid-Schiff stain. Other new methods of diagnosis are discussed. Treatment is based on oral antifungals: terbinafine, itraconazole, and fluconazole, including other emerging triazole drugs. Therapeutic outcome with ciclopirox and amorolfine lacquers alone and combined with systemic therapy are also reviewed, as well as the new nail enhancers and physical and chemical removal of the diseased nails.     

Stellenwert von Itraconazol in der Behandlung von Pilzinfektionen der Haut,Nägel und Schleimhäute

Itraconazole is an antifungal drug from the triazole group with distinct in vitro activity against dermatophytes, yeasts and some molds. Itraconazole has a primarily fungistatic activity. Itraconazole accumulates in the stratum corneum and in nail material due to its high affinity to keratin, as well as in sebum and vaginal mucosa. Together with terbinafine and fluconazole, itraconazole belongs to the modern highly effective systemic antifungal drugs with a favorable risk‐benefit ratio and for this reason is a preferred therapy option for fungal infections of skin, nails and mucous membranes. Compared to terbinafine in the treatment of fingernail and toenail fungal infections, itraconazole offers the advantage of a broad antifungal spectrum and better effectiveness against onychomycosis caused by yeasts yet appears inferior with regard to the more common dermatophyte infections. Itraconazole constitutes an important therapy option, along with fluconazole, terbinafine, ketoconazole and griseofulvin, for the treatment of dermatophyte infections of glabrous skin (tinea pedis, tinea manuum, tinea corporis and tinea cruris) in adults following unsuccessful topical therapy. In the oral therapy of tinea capitis, itraconazole plays an especially important role, in particular for disease caused by Microsporum canis (for children, however, only off‐label use is feasible currently). In the treatment of oropharyngeal candidiasis, candidiasis of the skin and vulvovaginal candidiasis, itraconazole and fluconazole are the preferred treatment options in cases in which topical therapy has proven unsuccessful.     

What defines the quality of patient care in tinea pedis?

OBJECTIVES: The aim of this study has been to evaluate patients with tinea pedis for their demographic data and attitudes affecting the treatment of disease, and to compare the in vitro activity of 10 antifungal agents and to relate them to their in vivo activity. METHODS: Patients with positive mycological examination were enrolled in the study, and a questionnaire comprised of 22 questions was administered. A mycological culture was carried out for each specimen. The antifungal susceptibility of the subcultured species was determined for griseofulvin, terbinafine, ciclopiroxolamine, fluconazole, ketoconazole, itraconazole, bifonazole, sulconazole, oxiconazole and miconazole with microdilution. RESULTS: Mycological cultures were carried out from 59 patients and there were 35 positive cultures (59.3%). The dermatophytes were Trichophyton rubrum (n = 25) and Trichophyton mentagrophytes (n = 3). The yeasts were Candida albicans (n = 7), Candida glabrata (n = 1) and Trichosporon (n = 2). In the minimum inhibitory concentration (MIC) study, the mean +/- standard error of the mean (SEM) MICs of the antifungals for T. rubrum were as follows: terbinafine 0.01 +/- 0.003, oxiconazole 0.16 +/- 0.05, sulkonazole 0.31 +/- 0.05, miconazole 0.45 +/- 0.15, itraconazole 0.74 +/- 0.01, ketokonazole 1.03 +/- 0.17, ciclopiroxolamine 1.30 +/- 0.12, bifonazole 1.94 +/- 0.51, griseofulvin 4.87 +/- 0.61, and fluconazole 17.91 +/- 3.67 microg/mL. CONCLUSION: Our study supports that azoles could be used as first-line treatment, as oxiconazole is very effective for both dermatophytes and C. albicans. Correlation between in vitro results and clinical outcomes of cases of dermatophytes is still to be established and interpretive breakpoints defined, in order to increase the quality of patient care in tinea pedis.     

The significance of itraconazole for treatment of fungal infections of skin, nails and mucous membranes

Itraconazole is an antifungal drug from the triazole group with distinct in vitro activity against dermatophytes, yeasts and some molds. Itraconazole has a primarily fungistatic activity. Itraconazole accumulates in the stratum corneum and in nail material due to its high affinity to keratin, as well as in sebum and vaginal mucosa. Together with terbinafine and fluconazole, itraconazole belongs to the modern highly effective systemic antifungal drugs with a favorable risk-benefit ratio and for this reason is a preferred therapy option for fungal infections of skin, nails and mucous membranes. Compared to terbinafine in the treatment of fingernail and toenail fungal infections, itraconazole offers the advantage of a broad antifungal spectrum and better effectiveness against onychomycosis caused by yeasts yet appears inferior with regard to the more common dermatophyte infections. Itraconazole constitutes an important therapy option, along with fluconazole, terbinafine, ketoconazole and griseofulvin, for the treatment of dermatophyte infections of glabrous skin (tinea pedis, tinea manuum, tinea corporis and tinea cruris) in adults following unsuccessful topical therapy. In the oral therapy of tinea capitis, itraconazole plays an especially important role, in particular for disease caused by Microsporum canis (for children, however, only off-label use is feasible currently). In the treatment of oropharyngeal candidiasis, candidiasis of the skin and vulvovaginal candidiasis, itraconazole and fluconazole are the preferred treatment options in cases in which topical therapy has proven unsuccessful.     

The efficacy and safety of terbinafine in children

In summary, terbinafine is a broad-spectrum allylamine, which has been used to treat superficial fungal infections including onychomycosis, and some systemic mycoses in adults. With a fungicidal activity, low minimum inhibitory concentration value, and high selectivity for fungal squalene epoxidase, terbinafine has demonstrated good efficacy in superficial fungal infections. Its lipophilic nature provides excellent, widespread absorption into hair, skin, and nails where it can eradicate fungal infection. Terbinafine has been shown to be effective and safe in several studies of the treatment of tinea capitis and onychomycosis in children. When treating Trichophyton tinea capitis the length of therapy may be 2 or 4 weeks. Microsporum tinea capitis may require somewhat higher or longer doses of terbinafine for adequate efficacy. These regimens still tend to be shorter than treatment with griseofulvin, and terbinafine may provide a higher compliance and a more cost-effective means of managing tinea capitis. It is possible that even higher cure rates and a shorter duration of therapy may be achieved following further optimization of treatment regimens that use a higher daily dosage of terbinafine than is currently recommended. The evidence is strongly in favor of using terbinafine to treat superficial fungal infections in children.     

Determination of the subungual antifungal activity of amorolfine after 1 month's treatment in patients with onychomycosis: comparison of two nail lacquer formulations

Onychomycosis is common worldwide, about 10% of all dermatomycosis being fungal infections of the nails.¹ Up until now no satisfactory topical treatment has been available. Therefore, the development of any new antifungal gives rise to high expectations with regard to its effectiveness in onychomycosis. Amorolfine is a phenylpropyl morpholine derivative which has been found to be more effective than imidazole derivatives and polyene antibiotics both in vitro and in experimental infections against dermatophytes and yeasts.^2,3
Amorolfine possesses two properties which give rise to hopes that it may be used to treat onychomycosis. First, it is effective at low concentrations,² and secondly, studies of in-vitro penetration on human nails show the presence of amorolfine in sufficient concentrations in the nail plate and the nail bed to give fungistatic and fungicidal levels.⁴ Furthermore, the persistence of amorolfine in the subungual keratin for 7 days⁵ would allow physicians to reduce the frequency of application.
Two different lacquer formulations, one methylene chloride-based and the other ethanol based, were developed as vehicles for amorolfine for treating onychomycosis with one or two applications per week. This study was carried out in order to test the bioequivalence of the two different lacquer formulations and to see whether the antifungal activity of amorolfine in the subungual area would last longer than 7 days, as shown in a previous study.⁵ The measurement of the antifungal activity in the subungual area will be taken as one of the criteria for penetration of amorolfine through the human nail.     

Topical antifungal treatment prevents recurrence of toenail onychomycosis following cure

Recurrence rates are high for onychomycosis, with prophylactic topical antifungal use proposed to counter recurrence. Although this is a reasonable action for many clinicians, few studies have been conducted on the efficacy of topical prophylaxis. A retrospective chart review (2010–2015) was conducted in patients receiving oral terbinafine or itraconazole for toenail onychomycosis. Following complete cure, a topical antifungal (amorolfine, bifonazole, ciclopirox olamine, or terbinafine spray) was used weekly as prophylaxis. Recurrence was recorded along with patient characteristics including demographics and concomitant medical conditions. Data from 320 patients were collected. Recurrence was significantly lower in patients receiving topical antifungal prophylaxis than in no prophylactic treatment following oral terbinafine (p < .001), but not itraconazole (p = .185). Regardless of oral treatment, the use of topical antifungals as prophylaxis (p < .001) decreased, and the number of affected toenails (p = .048) and family history of fungal infections (p < .001) increased the likelihood that recurrence would occur. This study supports the use of topical antifungal medications as prophylactic treatment to help prevent recurrence of toenail onychomycosis and suggests that those with a family history of fungal infections should be closely monitored.     

Treatment of tinea imbricata: a randomized clinical trial using griseofulvin, terbinafine, itraconazole and fluconazole

BACKGROUND: Griseofulvin has been the mainstay of treatment for tinea imbricata (TI) for decades; however, there have been few reports of efficacy of newer antifungals in the treatment of this condition. Many patients with TI have several obstacles to treatment due to their remote geographical locations and the primitive nature of their societies. OBJECTIVES: The aim of this study was to compare the efficacy of itraconazole, terbinafine and fluconazole with that of griseofulvin after 4 weeks of therapy. METHODS: Patients aged 12-76 years with the clinical diagnosis of TI were randomly assigned to one of four treatment groups: griseofulvin 500 mg twice daily for 4 weeks, terbinafine 250 mg daily for 4 weeks, itraconazole 200 mg twice daily for 1 week or fluconazole 200 mg once weekly for 4 weeks. Disease activity was monitored weekly. Laboratory measurements included monitoring complete blood count and liver function enzymes. Fifty-nine patients were included in the efficacy analysis: 13 in the fluconazole group, 15 in the griseofulvin group, 12 in the terbinafine group and 19 in the itraconazole group. RESULTS: Significant remission was achieved in the terbinafine and griseofulvin groups, lasting up to 8 weeks after cessation of therapy. The fluconazole group experienced no significant remission, and remission was of short duration in the itraconazole group. No adverse events were reported, and non-compliance with medications or follow-up was the only reason for removal from the study. CONCLUSIONS: Griseofulvin and terbinafine are effective in the treatment of TI. The decision of whether to treat at all and which medication to choose depends greatly on the extent of involvement, the social situation, and the availability of resources such as laboratory testing and follow-up.     

Terbinafine levels in serum, stratum corneum, dermis-epidermis (without stratum corneum), hair, sebum and eccrine sweat.

We determined terbinafine levels in serum, stratum corneum, dermis-epidermis (without stratum corneum), hair, sebum and eccrine sweat before, during and after 250 mg doses orally to volunteers once daily. Terbinafine is concentrated rapidly in stratum corneum (up to 9.1 micrograms/g of tissue) primarily by diffusion from the vascular system through the dermisepidermis. It also reaches high concentration in sebum (up to 45.1 micrograms/ml) after several days and continue to concentrate in sebum for up to two days after discontinuation of drug. Hair concentration reach levels of 2.6 micrograms/g of tissue indicating high drug levels in and around the hair follicle. It is not found in sweat. Plasma levels range between 0.1 and 1.0 micrograms/ml. There is a tenfold accumulation of drug in stratum corneum by day 2. Elimination of drug from tissue occurs with a half-life of 4 to 5 days and with the potential for drug levels above fungicidal concentrations for dermatophytes for more than 3 weeks. The tissue pharmacokinetic profile of terbinafine is similar to that of another lipophilic drug, itraconazole, but is very different from ketoconazole and griseofulvin. Higher levels of terbinafine are achieved than of either of the imidazoles and remain longer than griseofulvin.     

Oral Antifungal-Exacerbated Inflammatory Flare-Up Reactions of Dermatomycosis

Inflammatory flare-up reactions of some dermatomycoses, particularly those caused by zoophilic fungi, are typical and potentially severe adverse effects following the intake of some oral antifungals. However, this condition has not previously been reported with the most frequently used antifungals in dermatology, namely fluconazole, itraconazole, and terbinafine. In this report, we describe five patients, observed over a 10-year period, who presented with inflammatory exacerbations following oral antifungal therapy for dermatomycoses. We also review the literature on inflammatory reactions exacerbated by oral antifungal agents. Details of the patients' age, sex, occupation, and atopic background; the site of the lesion, its clinical and histologic features, and any systemic signs; the identity of the fungal pathogen; the antifungal agent taken by the patient; the time between drug intake and occurrence of the flare-up; the approach to management; and the outcome were documented for each patient. A PubMed literature search was also conducted, focusing on inflammatory exacerbations induced by griseofulvin, ketoconazole, itraconazole, fluconazole, and terbinafine. The patients were four farmers and one veterinarian (all male). All primary lesions were inflammatory dermatophytoses, including one kerion. Inflammatory exacerbation of the skin lesions started 12-24 hours after the intake of oral antifungals. Mild systemic changes, including slight fever and malaise, occurred in two cases. Itraconazole 400 mg/day was implicated as the causative agent in four cases and terbinafine 250 mg/day in one case. Mycologic cultures grew Trichophytonverrucosum in four cases. Antifungal treatment was discontinued in all patients. Oral and topical corticosteroids were administered to the two patients with systemic changes; the other three patients were treated with topical corticosteroids only. Two days after the onset of corticosteroids, lower doses of itraconazole (100 mg/day) and terbinafine (125 mg/day) were reintroduced. All lesions healed after 4-5 weeks. The PubMed search did not identify any articles that described inflammatory exacerbations of dermatomycoses induced by oral antifungals. Inflammatory flare-up of dermatomycoses is a rare but potentially severe cutaneous complication of oral antifungal use. Occupational contact with animals, inflammatory dermatomycoses, and zoophilic fungi represent common features in these patients. Although evidence-based data are not available, clinical experience shows that, in addition to antifungal therapy, topical and/or systemic corticosteroids are helpful to reduce the inflammatory reactions. The cases described in this article represent the first published report of oral antifungal-exacerbated inflammatory flare-up reactions of dermatomycosis in patients taking itraconazole or terbinafine.     

Onychomycosis: a new emerging infectious disease in childhood population and adolescents. Report on treatment experience with terbinafine and itraconazole in 36 patients

Background Onychomycosis is a rare disease in children with an estimated prevalence ranging from 0% to 2.6%. Thus far, only limited experience with itraconazole and terbinafine treatment in children with onychomycosis is available in the literature. Aim of the study Evaluation of treatment experience with itraconazole or terbinafine in childhood onychomycosis. Subjects Thirty‐six children and adolescents (aged 4–17 years, 18 males and 18 females) with clinical and mycologically proven onychomycosis were enrolled in the present study. Methods and outcome In 27 of 36 patients, the causative agent (Trichophyton rubrum in 26 cases and Trichophyton interdigitale in one patient) could be identified by means of cultivation. Nineteen patients were treated with itraconazole 200 mg once daily for 12 weeks, and 17 patients were treated with terbinafine for 12 weeks in a dosage according to their body weight, respectively. Clinical cure was achieved within 1 to 5 months after discontinuation in all patients treated with itraconazole and in all but two patients after cessation of terbinafine treatment. Neither in the itraconazole nor in the terbinafine group were serious adverse events reported.Clinical cure was achieved within 1 to 5 months after discontinuation in all patients treated with itraconazole and in all but two patients after cessation of terbinafine treatment. Neither in the itraconazole nor in the terbinafine group were serious adverse events reported. Conclusion To our experience, a mycological and clinical cure appears in children in a shorter time after treatment discontinuation (average 2–5 months) compared with adults. Itraconazole and terbinafine seem to be safe and effective in childhood onychomycosis; therefore, these antifungals seem to be potential alternatives to griseofulvin.     

In vitro antifungal susceptibility of dermatophyte strains causing tinea pedis and onychomycosis in patients with non‐insulin‐dependent diabetes mellitus: a case‐control study

Background The efficacy of antifungal treatment may be reduced and/or delayed in diabetic patients. To date, no study has investigated the in vitro antifungal susceptibility of dermatophytes in this patient group. Objective We aimed to determine the dermatophyte species causing tinea pedis and onychomycosis, and in vitro susceptibility of these dermatophytes to terbinafine, itraconazole, and fluconazole in patients with non‐insulin‐dependent diabetes mellitus. We compared the findings in diabetic patients with those in non‐diabetic individuals. Materials and methods One hundred patients with non‐insulin‐dependent diabetes mellitus and 100 otherwise healthy controls clinically suspected with tinea pedis and/or onychomycosis were included. Skin scrapings and/or nail clippings were taken and cultured on Sabouraud dextrose agar, mycobiotic agar, and dermatophyte test medium. In vitro antifungal susceptibility tests were carried out according to the Clinical and Laboratory Standards Institute (CLSI) M‐38P protocol with some modifications. Results Fifty‐seven samples of 54 diabetics and 50 samples of 50 controls grew dermatophytes. In both groups, Trichophyton rubrum was the most common isolate. Mean MIC values of terbinafine, itraconazole, and fluconazole for all of the isolated dermatophyte strains were similar in two groups (P > 0.05). The difference in mean MIC values of three antifungals for T. rubrum and T. mentagrophytes between two groups was not statistically significant (P > 0.05). Conclusions Dermatophyte types causing tinea pedis and onychomycosis, their frequency patterns, and in vitro activity of three antifungals against dermatophytes in diabetics are similar to the non‐diabetics. Terbinafine is the most active agent in vitro in both groups.     

Therapeutic Options for the Treatment of Tinea Capitis Caused by Trichophyton Species: Griseofulvin Versus the New Oral Antifungal Agents, Terbinafine, Itraconazole, and Fluconazole

Tinea capitis is a relatively common fungal infection of childhood. Griseofulvin has been the mainstay of management. However, newer oral antifungal agents are being used more frequently. A multicenter, prospective, randomized, single-blinded, non-industry-sponsored study was conducted in centers in Canada and South Africa to determine the relative efficacy and safety of griseofulvin, terbinafine, itraconazole, and fluconazole in the treatment of tinea capitis caused by Trichophyton species. The regimens for treating tinea capitis were griseofulvin microsize 20 mg/kg/day x 6 weeks, terbinafine [> 40 kg, one 250 mg tablet; 20-40 kg, 125 mg (half of a 250 mg tablet); < 20 kg, 62.5 mg (one-quarter of a 250 mg tablet)] x 2-3 weeks, itraconazole 5 mg/kg/day x 2-3 weeks, and fluconazole 6 mg/kg/day x 2-3 weeks. Patients were asked to return at weeks 4, 8, and 12 from the start of the study. Griseofulvin was administered for 6 weeks and the final evaluation was at week 12. Terbinafine, itraconazole, and fluconazole were administered for 2 weeks and the patient evaluated 4 weeks from the start of therapy. At this time, if clinically indicated, one extra week of therapy was given. There were 200 patients randomized to four treatment groups (50 in each group). At the final evaluation at week 12, the number of evaluable patients were griseofulvin, 46; terbinafine, 48; itraconazole, 46; and fluconazole, 46. Patients who discontinued therapy or were lost to follow-up were griseofulvin, 1/3; itraconazole, 0/4; terbinafine, 0/4; and fluconazole, 0/4. The causative organisms were Trichophyton tonsurans and T. violaceum species. Patients were regarded as effectively treated at week 12 if there was mycologic cure and either clinical cure or only a few residual symptoms. Effective treatment was recorded in, intention to treat, griseofulvin (46 of 50, 92.0%), terbinafine (47 of 50, 94.0%), itraconazole (43 of 50, 86.0%), and fluconazole (42 of 50, 84.0%) (p=0.33). Adverse effects were reported only in the griseofulvin group (gastrointestinal effects in six patients). Discontinuation from therapy due to adverse effects occurred only in the griseofulvin group (nausea in one patient). For the treatment of tinea capitis caused by the Trichophyton species, in this study, griseofulvin given for 6 weeks is similar in efficacy to terbinafine, itraconazole, and fluconazole given for 2-3 weeks. Each of the agents has a favorable adverse-effects profile.     

Antifungal susceptibilities of dermatophytic agents isolated from clinical specimens

The aim of this study was to investigate the susceptibility to four antifungal agents: ketoconazole, terbinafine, itraconazole and fluconazole, of the different species of dermatophyte strains isolated from clinical specimens. A total of 128 specimens were collected from toe nail, foot, inguinal region, trunk, hands and head. The dermatophytes tested included Trichophyton rubrum 108 (84.4%), Trichophyton mentagrophytes 11 (8.6%), Epidermophyton floccosum 5 (3.9%), Microsporum canis 2 (1.5%) and Trichophyton tonsurans 2 (1.5%). The mean minimum inhibitory concentrations (MIC) for the five species of dermatophytes ranged between 0.09-1.12 microg/mL for ketoconazole, 0.04-0.27 microg/mL for terbinafine, 0.08-0.43 microg/mL for itraconazole and 16.18-24.0 microg/mL for fluconazole. In vitro analysis of antifungal activity of these agents would also allow for the comparison between different systemic antifungals, which in turn may clarify the reasons for the lack of clinical response or serve as an effective therapy for patients with chronic infection.     

In vitro susceptibility testing of ciclopirox,terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes,and in vitro evaluation of combination antifungal activity

BACKGROUND: With the development of newer antifungal agents with activity against both yeasts and filamentous fungi, there is an increased need to develop and standardize in vitro assays that will evaluate the activity of antimycotics against filamentous fungi. In vitro analysis of antifungal activity of these agents would also allow for the comparison between different antimycotics, which in turn may clarify the reasons for lack of clinical response or serve as an effective therapy for patients with chronic infection. OBJECTIVES: To determine the in vitro susceptibility of fungal organisms to ciclopirox, terbinafine, ketoconazole and itraconazole and to evaluate the in vitro activity and mode of interaction of ciclopirox in combination with either terbinafine or itraconazole. MATERIALS AND METHODS: In the minimum inhibitory concentration (MIC) study 133 strains were evaluated, including dermatophytes (110 strains; 98 from Trichophyton spp.), Candida spp. (14 strains) and nondermatophyte moulds (nine strains). In vitro susceptibility testing was conducted in microbroth dilutions based on the National Committee for Clinical Laboratory Standards (NCCLS) M27-A proposed standard. The testing MIC ranges were 0.003-2 microg mL-1 for ciclopirox and terbinafine, and 0.06-32 microg mL-1 for itraconazole and ketoconazole. For inoculum preparation, dermatophytes were grown on Heinz oatmeal cereal agar slants. Inoculum suspensions of dermatophytes were diluted in RPMI 1640 (Sigma-Aldrich) with the desired final concentration being 2-5 x 103 c.f.u. mL-1. Once inoculated, the microdilution plates were set up according to the NCCLS M27-A method, incubated at 35 degrees C, and read visually following 7 days of incubation. For azole agents, the MIC was the lowest concentration showing 80% growth inhibition; for terbinafine and ciclopirox, the MIC was the lowest concentration showing 100% growth inhibition. In the synergy studies, 29 strains from nondermatophyte species were evaluated using a checkerboard microdilution method. The concentrations tested were: 0 and 0.06-32 microg mL-1 for itraconazole, and 0 and 0.003-4 microg mL-1 for both terbinafine and ciclopirox. Modes of interaction between drugs were classified as synergism, additivism, antagonism or indifference based on fractional inhibitory concentration index values (FIC index). Synergism was defined as an FIC index of < or = 0.50, additivity as an FIC index of < or = 1.0, and antagonism as an FIC index of > or = 2.0. The drug combination was interpreted as indifferent if neither of the drugs had any visible effect on the presence of the other drug. RESULTS: In the MIC study, the dermatophyte MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (0.04 +/- 0.02), terbinafine (0.04 +/- 0.23), itraconazole (2.28 +/- 7.42) and ketoconazole (0.83 +/- 1.99). The yeast MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (0.05 +/- 0.02), terbinafine (1.77 +/- 0.58), itraconazole (0.18 +/- 0.27) and ketoconazole (0.56 +/- 0.60). The non-dermatophyte fungi MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (1.04 +/- 2.62), terbinafine (1.04 +/- 0.95), itraconazole (17.87 +/- 16.75) and ketoconazole (10.69 +/- 13.09). In the synergy study, with ciclopirox in combination with terbinafine, mainly a synergistic or additive reaction was observed; there were no cases of antagonism. For ciclopirox in combination with itraconazole, there were some instances of additivism or synergism, with indifference in the majority of instances; there were no cases of antagonism. CONCLUSIONS: In vitro susceptibility testing indicates that ciclopirox may have a broad antimicrobial profile including dermatophytes, yeasts and other nondermatophytes. Terbinafine is extremely potent against dermatophytes. In vitro evaluation of activity of ciclopirox and terbinafine suggests many instances of synergy or additivism; for ciclopirox and itraconazole there may be indifference, synergy or additivism.     

Guidelines for the Management of Tinea Capitis in Children

Abstract: Practice guidelines for the treatment of tinea capitis (TC) from the European Society for Pediatric Dermatology are presented. Tinea capitis always requires systemic treatment because topical antifungal agents do not penetrate the hair follicle. Topical treatment is only used as adjuvant therapy to systemic antifungals. The newer oral antifungal agents including terbinafine, itraconazole, and fluconazole appear to have efficacy rates and potential adverse effects similar to those of griseofulvin in children with TC caused by Trichophyton species, while requiring a much shorter duration of treatment. They may be, however, more expensive ( Grading of recommendation A; strength of evidence 1a ). Griseofulvin is still the treatment of choice for cases caused by Microsporum species. Its efficacy is superior to that of terbinafine ( Grading of recommendation A; strength of evidence 1b ), and although its efficacy and treatment duration is matched by fluconazole ( Grading of recommendation A; strength of evidence 1b ) and itraconazole ( Grading of recommendation A; strength of evidence 1b ), griseofulvin is cheaper. It must be noted, however, that griseofulvin is nowadays not available in certain European countries (e.g., Belgium, Greece, Portugal, and Turkey).