Recent advances in the management of fungal infections.
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Biomedical subjects
Publications and source records attributed to R J Hay.
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Human peripheral polymorphonuclear neutrophils exhibited potent cytotoxic activity against the dermatophyte fungi Tricophyton quinckeanum and T. rubrum as assessed by inhibition of fungal replication in Sabouraud's agar. Monocytes also showed cytotoxic activity, but this was less pronounced than that of neutrophils, while lymphocytes had no toxic effect. Cytotoxicity showed a linear relationship to the target cell:effector cell ratio, with significant killing detected at a ratio of one neutrophil to one fungal cell. Fungal killing was optimal at incubation times of 2-24 hr for T. rubrum and 2-48 hr for T. quinckeanum. Thereafter, neutrophils were unable to prevent fungal replication while remaining viable. cytotoxicity was markedly reduced by sodium azide, an agent that inhibits haem enzymes, and by catalase, but not by heat-inactivated catalase or superoxide dismutase. The fungicidal activity of neutrophils and monocytes was greatly increased by stimulation with phorbol myristate acetate (PMA) or with concanavalin A (Con A) compounds known to stimulate the secretion of lysosomal enzymes and the production of highly reactive oxygen intermediates. The cytotoxic activity of monocytes to T. quinckeanum, but not to T. rubrum, was also increased by Con A treatment. Neutrophil and monocyte phagocytosis of dermatophytes was demonstrated by electron microscopy studies. Disrupted T. quinckeanum and T. rubrum germlings were identified in the cytoplasm of the phagocytic cells, and similarly disruption of hyphae surrounded, but not engulfed, by neutrophils was also observed. These studies suggest that phagocytosis and/or oxidative products of the respiratory burst of neutrophils and monocytes may be implicated in the killing of dermatophytes in vivo.
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The clinical features of 86 tropical ulcers in 64 subjects seen in hospitals and rural clinics in Zambia are described. Pre-ulcerative lesions were identified. 85% of the patients came from subsistence farming families. Few wore shoes but more than a quarter wore clothes below the knee at some time. No association with dental caries or gingivitis was observed. Ulcers were seen in some clinically well-nourished individuals of appropriate weight for height and occurred in areas where animal protein was plentiful. Family studies showed that concurrent cases within households were uncommon.
The successful isolation of anaerobes largely depends on adequate transportation of the specimens after collection. We are investigating the role of anaerobes in the pathogenesis of tropical ulcer and have used Hungate tubes with pre-reduced peptone yeast broth and agar as a transportation system. The medium included 0.05% cysteine and 0.03% sodium formaldehyde sulphoxylate as an Eh buffer. Resazurin 1 microgram/ml seved as an Eh indicator. We found the tubes convenient to use and very reliable at maintaining anaerobiasis.
Twelve (34%) of thirty-five patients with an active infection on the palms or soles caused by Hendersonula toruloidea or Scytalidium hyalinum were found to have circulating antibodies to these organisms by counter immunoelectrophoresis or immunodiffusion, compared with 9% of uninfected controls. In every instance there was cross-reactivity between the positive patients' sera and the heterologous non-dermatophyte antigen. Using crossed and intermediate gel immunoelectrophoresis it was found that cytoplasmic extracts of H. toruloidea and S. hyalinum showed 34 and 41 precipitin peaks respectively, most of which were shared by both organisms. No cross-reactions were observed between the non-dermatophyte cytoplasmic extracts and hyperimmune animal antisera raised to Trichophyton rubrum, Trichophyton interdigitale, Aspergillus fumigatus or Candida albicans. Exoantigens prepared from the two non-dermatophytes showed similar cross-reactivity between the two species. It appears that H. toruloidea and S. hyalinum are very similar in antigenic structure, a finding which lends support to the view that they may be closely related. They are also antigenically distinct from other pathogenic fungi which commonly infect skin, a fact which may be useful in their cultural identification as well as their recognition in tissue specimens.
There is a wide variety of highly effective topical antifungal agents available for the treatment of dermatophytosis. In more widespread infections or those involving hair or nails oral therapy with griseofulvin or ketoconazole can be used. With both forms of therapy certain types of dermatophyte infection are clinically resistant to treatment. These include onychomycosis, infections of the sole caused by T.rubrum and certain forms of tinea capitis (e.g. favus) or tinea corporis. In future consideration needs to be given to find the optimum duration and frequency of treatment and better methods of allowing penetration of drugs into nails and heavely keratinised sites.
The drugs used in the treatment of superficial mycoses include substances with an indirect affect on the organisms such as the keratolytics as well as antifungal compounds. The antifungals include specific inhibitory compounds such as the polyene or imidazole antibiotics and substances with a wider spectrum of antiseptic activity. High cure rates (80-90%) can be achieved by most specific antifungals although this can be affected by the host response and the location of the infection. The orally active antifungals used in superficial disease, ketoconazole and griseofulvin, can be used in conditions unresponsive or inaccessible to topical therapy, such as chronic superficial candidosis and tinea capitis. However, the treatment of onychomycosis, particularly affecting toe nails, is highly unsatisfactory. There is therefore an important place for new drugs and new methods of applying them in the treatment of superficial (local) mycoses.
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Foot infection has been studied in 514 coal miners: 70% of men had some evidence of infection but dermatophyte fungi accounted for only one-third of those affected; Gram-negative bacilli accounted for much of the remaining pathology. Itching and cracking were more severe in those with dermatophytes than in those with Gram-negative bacilli. Duration of service in the industry correlated with increasing dermatophyte infection, but not with bacillary infection. Wetness of the feet predisposed to bacillary infection but not to dermatophyte infection. There was no evidence of an association of atopy with either form of infection.
The merits of oral ketoconazole and griseofulvin in dermatophytosis have been compared in a double blind study on 74 patients with 152 infected sites. The initial daily doses were 200 mg and 500 mg respectively, but these were doubled after 3 months if there was an inadequate clinical response. Treatment was continued either until clinical and mycological remission was achieved or a year of therapy had been given. Seventy-five per cent (total 80) and 74% (total 72) of all infected sites treated with ketoconazole and griseofulvin respectively were cleared of infection. However, in toe nail infections the respective cure rates were only 21% and 17%. Ketoconazole appeared to act more rapidly in curing tinea corporis or tinea cruris due to Trichophyton rubrum, whereas griseofulvin was superior in T. interdigitale infections. No serious side-effects were encountered in either treatment group. In view of the slight risk of drug-induced hepatitis, ketoconazole is best reserved as a second-line drug for toe nail infections unless there are specific indications, such as griseofulvin intolerance. In these cases liver function tests should be monitored regularly throughout therapy.
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