F. Van Gerven

Itraconazole, a new triazole that is orally active in aspergillosis.

Itraconazole is a new orally active triazole derivative with broad-spectrum antifungal activity. This drug is effective in experimental aspergillosis and possesses in vitro activity against various species and strains of Aspergillus. Morphological destruction of inoculated hyphae and complete inhibition of hyphal outgrowth in culture is obtained from 0.07 micrograms ml-1 (10(-7)M) onward. These properties make itraconazole a likely candidate for clinical evaluation in disseminated aspergillosis. Images

Ketoconazole -- a new broad spectrum orally active antimycotic.

Oral treatment with ketoconazole prevented and cured artificial crop candidosis of the turkey, vaginal candidosis of the rat and skin candidosis of the guinea-pig. It was also highly effective against artificial systemic candidosis of the guinea-pig and chicken as well as against dermatophytoses of the guinea-pig.

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.

Detection of circulating galactomannan by Pastorex Aspergillus in experimental invasive aspergillosis

The performance of Pastorex Aspergillus, a new latex agglutination test for the detection of circulating galactomannan in the serum of patients with invasive aspergillosis, was evaluated in a blind trial in standardized guinea‐pig models of invasive aspergillosis and other invasive mycoses. In these animal models, the invasive nature of the fungal infection was confirmed by re‐isolation of the etiologic agent from the organs of every animal.

In Vitro and In Vivo Activities of the Novel Azole Antifungal Agent R126638

ABSTRACT R126638 is a new triazole agent with potent antifungal activity in vitro against various dermatophytes, Candida spp., and Malassezia spp. Its activity against Malassezia spp. in vitro was superior to that of ketoconazole, the agent currently used for the treatment of Malassezia-related infections. R126638 showed activity comparable to or lower than that of itraconazole against dermatophytes in vitro; however, in guinea pig models of dermatophyte infections, R126638 given orally consistently showed antifungal activity superior to that of itraconazole, with 50% effective doses (ED50s) three- to more than eightfold lower than those of itraconazole, depending on the time of initiation and the duration of treatment. The ED50 of R126638 in a mouse dermatophytosis model was more than fivefold lower than that of itraconazole. These data indicate that if the effects of R126638 seen when it is used to treat animals can be extrapolated to humans, the novel compound would be expected to show effects at doses lower than those of existing drugs and, hence, present a lower risk for side effects.

Oral and parenteral therapy with saperconazole (R 66905) of invasive aspergillosis in normal and immunocompromised animals.

Saperconazole (R 66905) is a broad-spectrum antifungal triazole with potent in vitro activity against Aspergillus spp. A total of 279 strains were tested in brain heart infusion broth. Development of the Aspergillus spp. was completely inhibited at 0.1 and 1 microgram of saperconazole per ml for 80.3 and 99.6% of the strains, respectively. Normal and immunocompromised guinea pigs were infected intravenously with Aspergillus fumigatus and treated orally, intravenously, or intraperitoneally with saperconazole or intraperitoneally with amphotericin B. Leukopenia, neutropenia, lymphocytosis, and monocytosis were obtained with mechlorethamine hydrochloride; leukopenia, neutrophilia, and lymphopenia were obtained with cyclophosphamide. Saperconazole was dissolved for oral treatment in polyethylene glycol and for parenteral treatment in cyclodextrins. Amphotericin B was given parenterally as Fungizone (E.R. Squibb & Sons). Treatment was given once daily for 14 days. An early starting treatment was efficacious, but the activity of saperconazole was maintained even when the onset of the treatment was delayed to the moribund state. The activity of saperconazole was not altered in immunocompromised animals. Saperconazole was clearly superior to amphotericin B and free of side effects. The oral and parenteral formulations of saperconazole were equipotent. The systemic activity of saperconazole in guinea pigs was confirmed in invasive aspergillosis in pigeons.

The anti-Malassezia furfur activity in vitro and in experimental dermatitis of six imidazole antifungal agents: bifonazole, clotrimazole, flutrimazole, ketoconazole, miconazole and sertaconazole

Summary. Bifonazole, clotrimazole, flutrimazole, ketoconazole, miconazole and sertaconazole were tested for their activity against 23 isolates of Malassezia furfur by agar dilution in vitro. Topical formulations of the same agents were evaluated for efficacy against M. furfur skin infections in guinea pigs in vivo. The most potent inhibitor in vitro was ketoconazole (geometric mean minimum inhibitory concentration 0.51 μg ml‐1), followed by bifonazole (8.1 μg ml‐1), then miconazole (14 μg ml‐1), clotrimazole (15 μg ml‐1) and flutrimazole (16 μg ml‐1), with sertaconazole the least active (52 μg ml‐1). In animal experiments involving three consecutive days of topical treatments, bifonazole 1% cream, clotrimazole 1% cream, flutrimazole 1% and 2% creams, ketoconazole 2% cream and shampoo and miconazole 2% cream all reduced M. furfur dermatitis lesion severity below that of untreated control animals; however, sertaconazole 2% gel and cream showed no reduction in lesion severity below control. The results confirm that ketoconazole is a more potent inhibitor of M. furfur in vitro than other topical antifungal agents of its class and suggest that sertaconazole is the least effective of such agents among those tested.

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.

Terconazole – A New Broad-Spectrum Antifungal

Terconazole, a new triazole ketal, is found to be highly active in vitro on a wide range of yeasts and mycelium-forming fungi. The in vitro activity depends largely on the medium used. In vitro it is a potent antifungal agent in preventing the morphogenetic transformation of the yeast into the (pseudo-)mycelium form of Candida albicans. In vivo terconazole is highly active in topical treatment of various experimental models of dermatophytosis and candidosis. It also possesses moderate oral broad-spectrum activity. No side effects were observed.

Effect of tissue invasion and treatment with itraconazole or amphotericin B on galactomannan levels in plasma of guinea-pigs with experimental invasive aspergillosis

The guinea-pig model of invasive aspergillosis was used to study the effect of the intensity of tissue invasion and of antifungal treatment on galactomannan levels in plasma. In untreated animals, galactomannan titres, determined with Pastorex Aspergillus, steadily increased and reached a maximum shortly before death. There was a significant correlation (P < 0·05) between this increase and that of the mean colony forming units of Aspergillus fumigatus in muscle, kidney, brain, peritoneum, eye and spleen, but not in skin, liver and lung. Pastorex Aspergillus detected galactomannan in 19/20 (95%) of the infected untreated animals. Uninfected guinea-pigs (160 samples) remained negative. In animals treated with itraconazole or amphotericin B, striking differences in antigenemia were observed between surviving and non-surviving animals. Only 5/25 surviving animals had detectable amounts of galactomannan in plasma, all on day 2 and one also on day 5, suggesting that successful treatment rapidly eradicated A. fu...