Activity of UK-49,858, a bis-triazole derivative, against experimental infections with Candida albicans and Trichophyton mentagrophytes

The effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans were studied. With respect to the extracellular growth of C. albicans, antifungal activity was measured in terms of MICs and minimal fungicidal concentrations as well as by determination of the concentration that effectively killed (>99.9%) C. albicans in the absence or presence (amphotericin B only) of serum. Amphotericin B was highly active in terms of killing, even at an increased inoculum size. In the presence of serum, amphotericin B activity was substantially reduced. For fluconazole, activity was restricted to inhibition of fungal growth, even after the inoculum size was reduced. With respect to the intracellular growth of C. albicans, antifungal activity was measured by using monolayers of murine peritoneal macrophages infected with C. albicans and was measured in terms of inhibition of germ tube formation as well'as effective killing (>99%) of C. albicans. Amphotericin B was highly active against C. albicans. At an increased ratio of infection, amphotericin B activity was slightly reduced. Fluconazole had no antifungal activity. Neither a reduction in the ratio of infection nor exposure of C. albicans to fluconaz'ole prior to macrophage ingestion resulted in activity against intracellular C. albicans by fluconazole. Previous exposure of C. albicans to amphotericin B resulted in increased intracellular activity of amphotericin B. The. intracellular antifungal activity of the combination of fluconazole with amphotericin B was les than that of amphotericin B alone. Amphotericin B showed fungicidal activity against C. albicans growing both extracellularly and intracellularly, whereas fluconazole inhibited growth only of extracellular C. albicans. A slight antagonistic effect between fluconazole and aiflphotericin B was found with respect to intracellular as well as extracellular C. albicans.Deep-seated candidal infections are an important cause of morbidity and mortality in immunocompromised patients (15,21,22). The current drug of choice for most systemic mycoses is still amphotericin B (AmB), but its use is restricted by a variety of toxic side effects (6,13,15,21,22). Consequently, there is a need for effective and less toxic drugs for the treatment of patients with these infections. One of these antifungal agents is the triazole fluconazole (Flu) (4,10,14,33,34,41). In vivo experimental studies suggested that Flu is active against disseminated candidiasis (8,9,29,31,32,35,37). Recently, the antifungal efficacy of Flu was demonstrated in persistently granulocytopenic rabbits when it was used for prevention or early treatment (39,40). Little is still known, however, on the role of Flu in the treatment of systemic candidiasis in immunocompromised patients. Since the host defense mechanisms in these patients are severely impaired, the intrinsic antifungal activity of the antifungal agent is of great importance for effective treatment. Unfortunately, standardized in vitro methods for assessment of ...

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Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans

Etten

Rhee

Kampen

et al. 1991

“…injection in treating normal AKR and C57BL/6 mice infected with Histoplasma capsulatum (7). Others have reported that fluconazole was more effective than the imidazole ketoconazole in treating normal mice (12,14) and rats (12,13) (14) reported that fluconazole was more than 20 times as effective as ketoconazole in C. albicans-infected mice that were immunocompromised by daily administration of dexamethasone. Fluconazole is an attractive antifungal agent in that (i) it is less toxic than amphotericin B, (ii) it is renally excreted, (iii) it readily penetrates cerebral spinal fluid, and (iv) it has a high serum half-life that can be maintained by daily oral administration (5).…”

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confidence: 99%

Comparison of fluconazole and amphotericin B in treating histoplasmosis in immunosuppressed mice

Kobayashi

Travis

Medoff

1987

Fluconazole (UK-49,858) was compared with amphotericin B in treating histoplasmosis in female AKR mice immunosuppressed with either cyclophosphamide or cortisone. Both drugs protected animals from a lethal challenge with Histoplasma capsulatum, but neither regimen resulted in cures since viable organisms were cultured from spleens of survivors.We have previously shown that the triazole fluconazole 858) given orally was as effective as amphotericin B given by intraperitoneal (i.p.) injection in treating normal AKR and C57BL/6 mice infected with Histoplasma capsulatum (7). Others have reported that fluconazole was more effective than the imidazole ketoconazole in treating normal mice (12,14) and rats (12,13) (14) reported that fluconazole was more than 20 times as effective as ketoconazole in C. albicans-infected mice that were immunocompromised by daily administration of dexamethasone. Fluconazole is an attractive antifungal agent in that (i) it is less toxic than amphotericin B, (ii) it is renally excreted, (iii) it readily penetrates cerebral spinal fluid, and (iv) it has a high serum half-life that can be maintained by daily oral administration (5). In the present study, we evaluated the efficacy of fluconazole and amphotericin B in the treatment of histoplasmosis in mice immunosuppressed with either cyclophosphamide or cortisone.For these studies, 6-to 8-week-old female AKR mice (average weight before beginning the experiment was 22 g) were purchased from Charles River Mouse Farms, Wilmington, Mass. All mice were housed and held for 1 week before experimentation. organisms per mouse in normal mice (7). The drug dosages for fluconazole were tested in twofold increments between 1.42 and 90.91 mg/kg per mouse, given twice a day in 0.5-ml volumes orally for a total of 6 consecutive days. For amphotericin B, the range of dosages tested was in twofold increments between 0.85 and 2.73 mg/kg per mouse, given every other day for a total of six injections by the i.p. route. Each dosage of drug was tested in groups of 10 animals, and the experiments were repeated at least three times with essentially the same results. The doses were calculated on the basis of milligrams per kilogram of average body weight of the animals at the start of therapy. According to procedures previously described (7), both fluconazole, given by gavage twice daily in 0.5-ml volumes for a total of 6 consecutive days, and amphotericin B, administered by i.p. injections on alternate days for a total of six injections begun 24 h after infection, protected the cyclophosphamide-induced leukopenic mice from fatal histoplasmosis (LD,00 dose of 5 x 105 organisms per mouse). The dosage of drugs that protected 50% of the infected mice (PD50) was 9.6 ± 2.9 mg/kg per day of fluconazole and 0.54 ± 0.1 mg/kg per day of amphotericin B (Table 1). With this drug regimen, the PD90 for fluconazole was 14.4 mg/kg per day and the PD,0 was 6.4 mg/kg per day; for amphotericin B, the PD%0 was 0.78 mg/kg per day and the PD20 was 0.31 mg/kg per day.We also studied the ef...

“…UK 49,858 has been shown to have a broader spectrum of activity then ketoconazole (6). For example, the doses of UK 49,858 that prevented death of 50% of mice given a lethal dose of Aspergillus flavus were 4-to 20-fold lower than ketoconazole doses in this model of infection (Troke et al IXth Int.…”

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“…Like ketoconazole, it is active when given orally and well tolerated by healthy human volunteers; doses of 1.4 mg/kg for 7 consecutive days and up to 0.7 mg/kg for 28 consecutive days have not shown any toxicity (Investigator's Reference Manual, Pfizer Inc., Groton, Conn., 1984). Orally administered UK 49,858 also appears to possess activity superior to that of ketoconazole in mice with lethal Candida albicans (6) and Aspergillus flavus (P. F. Troke, R. J. Andrews, M. S. Marriott, and K. Richardson (4). Saccharomyces cerevisiae (HLR), originally obtained from Hoffman-LaRoche, Inc., Nutley, N.J., was used as a drug control organism for our susceptibility studies.…”

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confidence: 99%

Comparison of the in vitro and in vivo activity of the bis-triazole derivative UK 49,858 with that of amphotericin B against Histoplasma capsulatum

Kobayashi¹,

Travis²,

Medoff³

1986

The antifungal activity of UK 49,858, a difluorophenyl bis-triazole derivative, was evaluated in vitro against seven strains of Histoplasma capsulatum and in vivo in AKR and C57BL/6 murine models of histoplasmosis. UK 49,858 had a lower toxicity for AKR and C57BL/6 mice than amphotericin B did. The therapeutic index of UK 49,858 was 4.3 for AKR mice and 7.1 for C57BL/6; with amphotericin B it was 2 for both mouse strains. Given orally, UK 49,858 compared favorably with amphotericin B given intraperitoneally in either AKR or C57BL/6 mice infected with H. capsulatum.