Abstract
Microsporum canis is the dermatophyte most commonly responsible for ringworm in cats. The purpose of this paper was to evaluate the in vivo efficacy of oral terbinafine (Lamisil; Sandoz) in the treatment of feline ringworm caused by M canis, and to consider this drug as an alternative to griseofulvin or imidazoles. Fifteen cats infected with M canis were treated orally once daily with 30 mg/kg of terbinafine over a 2-week period. All treated animals were checked for dermatophytes on the last day of treatment, a month later and 3 months after the last administration of the drug. Only 12 cats could be used in the whole trial and 11 of these (92%) showed a complete cure. Terbinafine could be an effective alternative to griseofulvin when fungal resistance or idiosyncrasic intolerance are shown and, compared with griseofulvin, could give a faster rate of cure and less relapses.
Microsporum canis is the dermatophyte most commonly responsible for ringworm in cats. This zoophilic fungus has a broad spectrum of hosts and is the predominant cause of human tinea corporis and tinea capitis in Italy (Flammia et al 1995), with the cat serving as the main reservoir. The importance of cats as the source of this dermatophyte in humans is due to the high prevalence of asymptomatic carriers and to feline habits such as sleeping on beds and divans. In these places arthrospores shed by infected animals are difficult to remove and can remain viable in the environment for up to 18 months. The cats affected by M canis may undergo spontaneous remission, but the infection can be persistent for 18 months to 4 years (Moriello 1990) and over such a period the risk of the spread of infection is high. For these reasons a safe and effective treatment for infected cats is required.
Among the antifungal agents now available terbinafine (Lamisil; Sandoz, Milan, Italy) shows a good activity against a broad range of dermatophytes (Balfour & Faulds 1992). This compound is also available in an oral form and its mechanism of action, which is responsible for its fungicidal effects, consists of the inhibition of squalene epoxidase, an essential step in fungal ergosterol synthesis. This drug shows several interesting features such as good penetration into infected tissues, a high efficacy after short duration of treatment in chronic infections of cutaneous tissues, and good tolerance. In common dermatological practice terbinafine is employed topically or systemically (Hay et al 1991, Matsumoto et al 1995, Evans 1997, Krafchik & Pelletier 1997), but its use in veterinary medicine seems to be limited to animal models (Petranyi et al 1984). There is only one study on the effect of pharmacokinetics in cats (Mala 1995), which shows that terbinafine is safe and reaches adequate plasma levels quickly. However, terbinafine has not been used in the treatment of feline ringworm.
This antifungal drug requires treatment periods considerably shorter than other drugs and it would be indicated in chronic, recalcitrant dermatophyte infections such as feline ringworm due to M canis.
The purpose of this paper was to evaluate the in vivo efficacy of oral terbinafine in the treatment of feline ringworm caused by M canis and to consider this drug as an alternative to griseofulvin or imidazoles.
Materials and methods
Animals
Fifteen cats naturally infected with M canis were examined. The diagnosis was made by culturing samples of hair drawn with a sterile brush. The subjects were European cats (nos 1–14) and a Persian cat (no. 15), which consisted of seven males and eight females, aged between 6 months and 5 years. Two of the cats (nos 14 and 15) were household cats, while the others (1–13) lived in a shelter. At physical examination the animals showed different signs of microsporiasis. Detailed data are reported in Table 1. The duration of treatment varied from 2 to 4 weeks except for cats 14 and 15. These animals had been previously treated unsuccessfully with griseofulvin (Fulcin; SIT, Pavia, Italy) (cat 14) (40 mg/kg for 20 days) and in the first instance with griseofulvin ultramicrosize (Gris-PEG; Herbert) (10 mg/kg for 60 days) then with itraconazole (Sporanox, Janssen Cilag, Latina, Italy) (three courses of 15 days with 2 mg/kg), (cat 15). The duration of the clinical signs was 7 months in cat 14 and more than 1 year in cat 15.
General information about the cats treated with terbinafine
The owners' informed consent was given and all the animals were treated with terbinafine at a dosage of 30 mg/kg. The health status of all the animals was followed by a clinician and, if adverse effects were observed, the treatment was interrupted.
Control animals
Four naturally infected untreated subjects were used as controls; three of them (cats 16–18) came from the same shelter and the fourth (cat 19) was a stray cat naturally infected with M canis. All the animals showed signs of ringworm such as alopecia and crusts (cats 16 and 18), scales and crusts (cat 17) and scales only (cat 19). The animals were checked for clinical signs and submitted to cultural examinations.
Treatment
Terbinafine was administered orally once a day at a dosage of 30 mg/kg for a 2-week period. A further week of therapy was administered to cats that scored heavily positive cultures when brushed a month from the end of the treatment. The dosage was empirically adjusted from that used by Petranyi et al (1987) in the therapy of experimentally induced M canis infection in guinea pigs. The medication was adapted for each cat by weighing and breaking the tablets commercially available for humans to reach the requested dosage.
Mycology
Hair samples taken from the cats by brushing technique (McKenzie 1963) were cultured onto Mycobiotic agar (Difco Laboratories, Detroit, MI, USA) and the Petri dishes were incubated at 25°C for 10 days. Microsporum canis was identified by its macro and microscopical features, following the criteria published by Rebell and Taplin (1979). All the treated animals were submitted to cultural controls for dermatophytes; the first check (C1) was on the last day of treatment, the second (C2) a month later and the third (C3) 3 months after the last administration of the drug. Cats with heavily positive cultures at the C2 stage were not checked at C3, but were submitted to a further week of therapy, followed by cultural controls a week after the end of the treatment (C3′) and a month (C4) and 3 months (C5) later, respectively. The plates were incubated for 15 days, and if growth was absent after such a period the cultures were regarded as negative and the plates discarded.
Results
Only 12 cats (nos 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 14 and 15) could be used throughout the whole trial, and 11 of these (92%) showed a complete cure. Cat 10 showed adverse reactions to the treatment, vomiting at 30 min after the second and third administration of the drug; the cat was therefore withdrawn from the trial. Cats 1 and 4 died during the trial: cat 1 died from a parvovirus infection, immediately after stage C3′, cat 4 died from FIP virus infection and stage C3 could therefore not be completed.
At stage C1 all the cats had positive cultures for M canis, and no resolution of any clinical signs. At stage C2 cats 5, 9, 11 and 12 showed a complete clinical and aetiological recovery; cats 3, 4, 6, 7, 8, 13 and 14 showed a dramatic decrease in the number of reisolated colonies, while the clinical signs were mild; and the cats 1, 2 and 15 needed a further week of therapy, still being heavily infected.
At stage C3 cats 3, 6, 7, 8, 13 and 14 appeared to have completely recovered. At stage C3′ cat 1 remained symptomatic and scored positive in cultural examinations even though it had a low mycotic burden; cat 2 showed a complete remission of signs and M canis was not isolated; and cat 15 did not have any improvement in its clinical or mycological status. Cat 10 showed heavy positive controls (C1, C2, and C3) until the end of the trial. The control group also yielded heavy positive cultures and did not show any clinical improvement. The results are summarized in Table 2.
Detailed cultural results of the controls performed on the treated cats
Cat 10 has been included (therapy interrupted)
A strong correlation between the clinical signs and positive culture isolation was observed and M canis was not isolated when the subjects showed remission of signs, suggesting that no animals became asymptomatic carriers of the dermatophyte.
Discussion
Terbinafine is the first oral antimycotic with a primarily fungicidal action against dermatophytes (Petranyi & Mieth 1988). It is widely used in human dermatology in the treatment of tinea capitis, corporis, cruris and onychomycosis, with high and fast mycological cure rates reported. Its use in veterinary medicine is not yet documented, except in a study of an experimental model of dermatophytosis in guinea pigs, where a 100% mycological cure was achieved at a dosage of 6 mg/kg for Trichophyton mentagrophytes and 40 mg/kg for M canis (Petranyi et al 1987). Mala (1995) suggested that therapeutical plasma levels of the drug were obtained with a dosage of 10 mg/kg per os in a trial with uninfected cats, but data on M canis-infected cats are not yet available. In our study we have used a dosage of 30 mg/kg per day, taking into consideration the lack of information available on the tissue concentration, especially in stratum corneum, dermis, epidermis and hair, which are more relevant than blood levels in cutaneous antifungal therapy (Meihof 1993; Faegermann et al 1990). The necessity of increasing the dosage to 30 mg/kg in order to reach concentration far above the minimum fungicidal concentration for the main dermatophytes in the target tissues was due to the fact that the absorption of terbinafine ranges from 20 to 90% in many mammalian species (Petranyi et al 1983) and that a large number of the derivatives found in the plasma after liver metabolism are antimycotically inactive metabolites (Battig et al 1987). Furthermore, Petranyi et al (1987) studying the activity of terbinafine in the therapy of experimental microsporosis in guinea pigs, found that 100% of clinical and mycological cure rates were obtained with 40 mg/kg of oral terbinafine for 9 days.
This dosage of oral terbinafine gave good results, with clinical and mycological cure in 11 of the 12 (92%) cats treated and checked for the whole period of the trial. The drug was well tolerated except in cat 10. This aspect reflects the keratinophylic and lipophylic character of the drug which, according to Faegermann et al (1990), reached high levels in and around the hair follicles, in the stratum corneum and sebum with concentrations far above the minimum inhibitory concentration. Such concentrations may therefore be present for 2–3 weeks after the therapy is discontinued.
A negative culture result was also achieved in cat 14, which was previously treated with griseofulvin but with poor results. Cat 15 did not reach a mycological cure, but the same result was previously obtained with griseofulvin and itraconazole.
Fourteen days of therapy was adequate for most of the cats while cats 1, 2 and 15 needed one more week of treatment. No asymptomatic carriers were observed.
Treatment with terbinafine could be considered as an alternative to griseofulvin when fungal resistance or idiosyncrasic intolerance (mostly characterized by anorexia, vomiting, diarrhoea or bone marrow suppression) are shown and, compared to this drug, could allow faster rates of cure and less relapses, since griseofulvin is a fungistatic compound. Terbinafine therapy could be administered in the cases where griseofulvin is not recommended because of its teratogenicity or potential toxicity. However, further well-controlled studies should be performed on cats with immunosuppression and/or kittens under the age of 12 weeks.
The drug is available in Italy in 125 and 250 mg tablets but is not approved for veterinary use. It is also expensive—it would therefore be necessary to reformulate preparations for veterinary use in order to make the cost more affordable for owners.