J. Fransen

The in vitro antifungal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum and their efficacy as a shampoo in the treatment of experimental pityrosporosis in guinea pigs

The fungistatic and fungicidal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum, a yeast thought to play a pathogenic role in seborrheic dermatitis and dandruff, was assessed in Dixon broth for Pityrosporum ovale and Sabouraud broth for Pityrosporum pachydermatis. Ketoconazole inhibited growth at concentrations ranging from 0.001 to 1 micrograms/ml. For zinc pyrithione and selenium sulfide higher concentrations were needed. In a guinea pig model the efficacy of treatment with four shampoos (Nizoral [Jansen], EDS Zinc [Schering], Zinkan [Lederle], and Selsun [Abbott]) was compared. The animals were inoculated for 7 consecutive days on intact skin. The lesions were scored for erythema, folliculitis, and hyperkeratosis 24 hours after the last inoculation and after treatment. Final evaluations were made 13 days after infection (10 days after last shampoo application). Treatment with undiluted and diluted (1:10) shampoos showed consistently superior clinical and mycologic results for Nizoral shampoo. None of the shampoos produced side effects.

Treatment of Experimental Zygomycosis in Guinea Pigs with Azoles and with Amphotericin B

Nonpredisposed Albino guinea pigs were infected intravenously with Rhizopus microsporus var. rhizopodiformis or with Rhizopus oryzae. Both strains were highly pathogenic. They killed all control animals between days 4 and 7 and between days 5 and 9 after infection, respectively. All animals presented invasion of almost all internal organs and skin eruptions developing into ulcers. Oral treatment with ketoconazole, itraconazole, fluconazole or saperconazole was inefficacious. Parenteral treatment with amphotericin B prolonged survival and was life-saving in 9 out of 12 guinea pigs infected with Rh. microsporus var. rhizopodiformis and in 5 out of 12 infected with Rh. oryzae. More active therapy is needed.

Histopathology of experimental systemic candidosis in guinea-pigs

Unpretreated Albino guinea-pigs were infected intravenously with Candida albicans. Cutaneous candidosis with (pseudo-) hyphal outgrowth in the hair shafts and in the keratinized layers of the epidermis developed as a consequence of systemic dissemination. The spread of the infection was followed by cultures and by gross- and micropathological study of various organs of different animals during a follow-up period of 35 days. The possible relationship of organ invasion by C. albicans and skin candidosis is discussed.

Therapeutic Efficacy of Itraconazole in Systemic Candidosis in Guinea Pigs

Fifty non-immunocompromised guinea pigs were infected by the intravenous route with 8,000 blastospores of Candida albicans per gram body weight: 26 were treated orally with the excipient, 12 with itraconazole at 1.25 mg X kg-1 and 12 at 5 mg X kg-1, once daily for 14 days starting on the day of infection. Hematology was checked for all animals before infection and on days 7, 14 and 17 after infection. Histopathological examinations were done for 2 animals of each group on days 7, 14 and 17. The infection and the therapeutic efficacy were checked by clinical observation, at autopsy and by cultures of organs. Itraconazole was highly active at both concentrations, resulting in clinical cure, negativation of cultures, normalisation of the blood picture and absence of fungal elements and presence of only small remnants of lesions on days 14 and 17 in some organs. No drug-related side effects were observed.

Experimental Zygomycosis Due to Rhizopus spp. Infection by Various Routes in Guinea‐Pigs, Rats and Mice

Summary:  Streptozotocin‐diabetes was induced in Swiss mice and in Wistar rats. Hematological examination was performed before streptozotocin was administered, and for 5 weeks afterwards. Leukocytosis was present in all animals. Severe diabetes was found, and it persisted during the 13‐week follow‐up period. Serum glucose levels were controlled weekly. Nondiabetic animals infected by inhalation or by intranasal instillation with Rhizopus microsporus var. rhizopodiformis remained negative as well as diabetic animals infected by inhalation. In the intranasally instilled mice and rats, 33% and 67% respectively contracted severe zygomycosis. Non‐compromised guinea‐pigs and mice were infected intravenously or intraperitoneally with Rhizopus microsporus var. rhizopodiformis or Rh. oryzae. The guinea‐pig infected with small inocula was more sensitive than the mouse, and developed fatal zygomycosis with invasion of almost all organs and production of erythematous ulcerative skin eruptions. Fatal disease was also obtained in mice infected intravenously, but not intraperitoneally. Anatomopathology of the various organs and lesions revealed profuse invasion of various organs including brain, lungs, blood vessels, etc. Large coenocytic hyphae were present. In the lungs and the spleen of the guinea‐pig and in the pelvic cavity of the mouse, various forms of large vesicles and sporangium‐like elements were observed. The hyphae were in general distorted, broad, irregular and rarely septated. The infection of guinea‐pigs with Rhizopus spp. is proposed as a model for the study of the infection. It presents all aspects of zygomycosis that may occur in man and animals, especially in compromised or largely exposed individuals.

Oral treatment with ketoconazole in systemic candidosis of guinea-pigs: microbiology, hematology and histopathology

Non-pretreated Albino guinea-pigs were infected intravenously with Candida albicans and treated orally either with placebo or ketoconazole. The 17-day follow-up of the fungal dissemination was based upon hematology, on gross and microscopic lesions and on the demonstration of the fungus by culture techniques. The efficacy of ketoconazole, both with regard to the quantity and the morphology of fungi in various organs and the tissue-healing process are discussed. The treatment of human systemic candidosis will also be considered. No side-effects due to the therapy were observed in these experiments.

Experimental Candidosis in Animals and Chemotherapy

Members of the genus Candida are widely spread. They are present as endosaprophytes in the gastrointestinal tract of man and the majority of animals or as exosaprophytes in the environment. Various Candida spp. may be responsible for pathological manifestations, but Candida albicans is considered to be the species with the highest potency for morbidity and mortality, mainly in immunocompromised individuals or when predisposing, known or unknown, factors or regimens are present. Any organ may be infected, but superficial infections constitute by far the highest incidence.

Animal Models of Mycoses Caused by Fungi that Produce Yeast- and Hyphal Forms

Various predisposing factors and immunodepressing agents are used in animal models to enhance fungal pathogenicity and to lead to more homogenous invasion of fungi. In this study the influence of cyclophosphamide, hydrocortisone acetate, prednisolone acetate, mechlorethamine hydrochloride, antibiotics, deferoxamine and others is described. The most drastic effects occurred with mechlorethamine hydrochloride pretreatment, which resulted in permanent neutropenia in the guinea-pig, but not in the mouse. Irreversible diabetes was obtained in mice and rats with streptozotocin. The injection of the iron chelator deferoxamine led rapidly to fatality in zygomycosis. Deferoxamine is also a potent antagonist of amphotericin B. Various experimental mycoses were induced by fungi presenting differences in morphology, including candidosis: systemic and in pregnancy in various animal species, intestinal, corneal and cutaneous in guinea-pigs and vaginal in rats. In Fusarium and Aspergillus keratitis, Malassezia infection, sporotrichosis, penicilliosis, paracoccidioidomycosis, cryptococcosis, zygomycosis and dermatophytosis in guinea-pigs at least two different morphological forms were present. This was also the case for chromoblastomycosis in mice and for histoplasmosis in mice and guinea-pigs. The broad-spectrum activity of itraconazole was clearly demonstrated in animal models where the morphology of the fungi in human infections was mimicked.