Postgraduate Medical Journal (September 1979) 55, 608-610 Failure of treatment in chronic dermatophyte infections R. J. HAY M.R.C.P. Department ofMicrobiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT Summary (Roth, Sallman and Blank, 1959). It seems, there- A proportion of dermatophyte infections fail to fore, that the effectiveness of griseofulvin is depen- respond to normally adequate courses of griseofulvin dent on host factors such as the immune response and tropical antifungal therapy. The organism Tricho- and a normal turnover of epidermis which tends to phyton rubrum was isolated from 96°o of 50 patients shed the organism into the environment. studied, but no instances of in vitro resistance were Griseofulvin remains a useful drug, surprisingly seen. Of these patients, 57%o had an underlying free of side effects in the doses normally used condition, commonly hay fever/asthma, atopic eczema, (Livingood et al., 1960). Gastric intolerance, head- collagen disease or ichthyosis. Defective delayed type aches, urticaria and rashes, and leucopenia have hypersensitivity responses and leucocyte migration been described. inhibition to the specific antigen, trichophytin, were The patients described here had chronic dermato- demonstrated. Immediate type hypersensitivity was phyte infections, often of many years' standing. The seen in 58% and this was partially suppressible with clinical presentation was remarkably constant and chlorpheniramine and cimetidine. The relationship the very rare variants, dermatophyte mycetoma and between these abnormalities and failure of treatment is systemic dermatophytosis, were not seen. The discussed. clinical, immunological and pharmacological data are presented and their relevance to treatment Introduction failure is discussed. It is a common experience amongst dermatologists that certain types of dermatophyte infection fail to Materials and methods respond to a normally adequate course of the drug Fifty patients were seen in the out-patient depart- griseofulvin given in a dose of one g daily for at least ment of St John's Hospital for Diseases of the Skin, 3 months. This occurs even where the influence of London. A full clinical assessment was made and nail involvement, which is notoriously slow to laboratory isolation of the causative organism respond, is excluded. carried out. Minimal inhibitory concentrations of Griseofulvin is a metabolic by-product of several griseofulvin were measured by comparing the growth species of the mould Penicillium, e.g. P. griseofulvum, of the organisms in serial dilutions of the drug. Skin and the discovery that it was active against dermato- tests were performed on all patients using tricho- phyte fungi in vivo was a therapeutic advance of phytin (Bencard Ltd, Middlesex) and in appropriate great importance (Gentles, 1958). It is absorbed in cases the immediate reaction was suppressed using adequate amounts after oral administration, the either an equal volume of chlorpheniramine maleate serum levels depending on a number of variables (Piriton injection, 10 mg/ml) given concurrently including the size of the griseofulvin particles, e.g. with the intradermal antigen or cimetidine (Taga- microcrystalline form (Crounse 1963), and the met) 200 mg 4 times daily by mouth for 2 days before timing of the dose in relation to a meal. However, the skin test. there are 2 findings of particular relevance here. The method used in the leucocyte migration inhi- Firstly, griseofulvin has been shown to be selectively bition test has already been described (Hay and accumulated in the stratum corneum where the Brostoff, 1977). The test was carried out in sterile fungal invasion occurs (Epstein, Shah and Riegel- plastic chambers and peripheral blood leucocytes man, 1972). Drug levels in this layer may be several were used. Griseofulvin levels were kindly measured times greater than in serum and follow excretion of by Glaxo Laboratories Ltd. the drug in the sweat. Secondly, it was observed that in vitro high levels of griseofulvin (up to 30 ,ug/ml) Results failed to kill pellets of dermatophytes and the drug In 48 patients the organism isolated was Tricho- was limited in its effect in this system to fungistasis phyton rubrum. One patient, with tylosis, was in- 0032-5473/79/0900-0608$02.00 © 1979 The Fellowship of Postgraduate Medicine Treatment failure in dermatophytosis 609 fected with Epidermophyton floccosum and one other, other dermatophyte infections, usually T. mentagro- with chronic mucocutaneous candidiasis, with phytes, where 75% showed DTH. Of the patients Microsporum canis. with chronic dermatophyte infections tested 85% In 10 organisms isolated from patients and studied (total 19) showed poor leucocyte-migration inhibi- forresistance to griseofulvin, the minimum inhibitory tion, i.e. a migration index > 0'8. This poor concentrations ranged from 1.5 to 6-3 mg/l. These response suggests a defect in the production of values did not differ significantly from control values. migratory inhibitory factor (MIF) in response to Out of 50 patients studied 34 were male and 16 trichophytin. In contrast, the control group of female, with a mean age of 44 years (range 17-76 patients with other dermatophyte infections had good years). In 41 patients, the infection was of the dry responses, 95% with a migration index < 0-8. non-inflammatory variety with moccasin distribu- The ability to suppress the immediate type tion and involvement of at least 2 of the following response to intradermal trichophytin with cimetidine sites: palms, soles, toe-webs, finger- or toe-nails, and or chlorpheniramine is shown in Table 1. Although groins. Four patients had bullae either between toes there is partial suppression no delayed reactions or on the soles. Four had isolated tinea corporis and were uncovered one had tinea capitis. In the 28 had an condi- TABLE 1. Effect of histamine blocking agents on trichophytin group, (57%o) underlying test (immediate reaction) tion. The commonest was asthma or asthma/hay fever or atopic eczema of varying severity (16 Weal* Flare* disease or patients); collagen rheumatoid arthritis Nil 48+21 170+42 was seen in 2 and another patient was on systemic Chlorpheniramine 28 + 20 113 + 46 corticosteroid therapy; 5 patients had an epidermal Cimetidine 34 +19 62 + 26 disorder such as tylosis or non-bullous ichthyosiform Chlorpheniramine + cimetidine 17 + 9 43 ± 22 more were erythroderma and 2 found to have severe * Mean (10 patients) radii2 (mm3) intermittent claudication. The associated clinical conditions can therefore be broadly grouped into In all but 2 patients whose serum griseofulvin diseases associated with immune defects and dis- levels were studied, adequate values were obtained. orders of keratinization or circulation. Of 8 patients Both patients subsequently admitted failing to take with persistent tinea corporis, 6 (75%/) had an the tablets. In one patient, with non-bullous ich- underlying condition - chronic mucocutaneous can- thyosiform erythroderma, levels of griseofulvin in didiasis (1), systemic lupus erythematosus (1), ich- stratum corneum were found to be at least 5 times thyosis (1), atopic eczema (2), mycosis fungoides (1), the serum concentration. 2 were normal (both Chinese). In Caucasian patients with persistent tinea corporis it may be advisable to Discussion search for an underlying disease. The outcome of treatment in a dermatophyte No abnormalities were found in serum biochem- infection depends on the ability of the drug to istry apart from raised circulating IgE levels in 4 inhibit the fungus coupled with the ability of the host patients. to destroy it, set against the organism's resistance. The reasons for the repeated failure to detect From this study it does not appear that drug resist- specific circulating antibodies to dermatophytes by ance is an important factor. The serum levels of all available methods, e.g. immunodiffusion, com- griseofulvin were also adequate, although the plement fixation, and immunofluorescence, have presence of conditions, such as ichthyosis, where been reviewed recently (Grappel, Bishop and Blank, epidermal turnover is abnormal, amongst the pre- 1974). However, the affinity of antibodies present disposing diseases might suggest that defective in dermatophyte infections for epithelial tissue has distribution of the drug could be important. been demonstrated (Hopfer, Grappel and Blank, However, epidermal turnover as well as cellular 1975), and this aspect is currently under investiga- immunity are important host responses to infections. tion. It is possible that this accounts for the absence Increased epidermal labelling has been demonstrated of demonstrable circulating antibodies. Several in the vicinity of dermatophyte infections using workers have emphasized defective cellular immune autoradiography (Berk, Penneys and Weinstein, responses in some of these patients (Hanifin, Ray 1976). A defect in epidermal growth would be and Lobitz, 1974; Jones, Reinhardt and Rinaldi, important in determining chronicity of an infection. 1974). Likewise, the defect of cellular immunity reported Within the group studied only 12% showed de- here and elsewhere (Hay and Brostoff, 1977) may layed hypersensitivity (DTH) to intradermal tricho- also be relevant. The mechanisms underlying the phytin, whereas 58% had immediate responses. defective cellular responses in this system are This contrasts with the responses in patients with complex and speculative and include the disruption 610 R. J. Hay of normal T-lymphocyte