Raulo Parmegiani

In vitro and in vivo activities of SCH 56592 (Posaconazole), a new triazole antifungal agent, against Aspergillus and Candida

ABSTRACT SCH 56592 (posaconazole), a new triazole antifungal agent, was tested in vitro, and its activity was compared to that of itraconazole against 39 Aspergillus strains and to that of fluconazole against 275 Candida and 9 Cryptococcus strains. The SCH 56592 MICs for Aspergillus ranged from ≤0.002 to 0.5 μg/ml, and those of itraconazole ranged from ≤0.008 to 1 μg/ml. The SCH 56592 MICs for Candida andCryptococcus strains ranged from ≤0.004 to 16 μg/ml, and those of fluconazole ranged from ≤0.062 to >64 μg/ml. SCH 56592 showed excellent activity against Aspergillus fumigatus andAspergillus flavus in a pulmonary mouse infection model. When administered therapeutically, the 50% protective doses (PD50s) of SCH 56592 ranged from 3.6 to 29.9 mg/kg of body weight, while the PD50s of SCH 56592 administered prophylactically ranged from 0.9 to 9.0 mg/kg; itraconazole administered prophylactically was ineffective (PD50s, >75 mg/kg). SCH 56592 was also very efficacious against fluconazole-susceptible, -susceptible dose-dependent, or -resistantCandida albicans strains in immunocompetent or immunocompromised mouse models of systemic infection. The PD50s of SCH 56592 administered therapeutically ranged from 0.04 to 15.6 mg/kg, while the PD50s of SCH 56592 administered prophylactically ranged from 1.5 to 19.4 mg/kg. SCH 56592 has excellent potential for therapy against seriousAspergillus or Candida infections.

In vitro and in vivo activities of SCH 42427, the active enantiomer of the antifungal agent SCH 39304.

SCH 39304, a new triazole antifungal agent, is a 50:50 racemic mixture of two enantiomers, SCH 42427 and SCH 42426. The activities of these three compounds were compared in a series of in vitro and in vivo experiments. SCH 42427 was twofold more active in vitro against a variety of yeasts and dermatophytes than SCH 39304, while SCH 42426 was inactive (MICs greater than 64 micrograms/ml). In a systemic Candida albicans infection in mice, SCH 42427 administered orally (p.o.) (50% protective dose [PD50], 0.17 mg/kg of body weight; 50% effective dose, [ED50], 0.47 mg/kg) had greater efficacy than SCH 39304 (PD50, 0.21 mg/kg; ED50, 0.62 mg/kg) and SCH 42426 (greater than 100 mg/kg for PD50 and ED50). In a pulmonary Aspergillus flavus infection in mice, SCH 42427 p.o. (PD50, 13 mg/kg) was also more effective than SCH 39304 (18 mg/kg) and SCH 42426 (greater than 250 mg/kg). In a C. albicans vaginal infection in hamsters, SCH 42427 p.o. (ED50, 3.5 mg/kg) was more active than SCH 39304 (8.5 mg/kg) and SCH 42426 (320 mg/kg). Following topical administration, against a Trichophyton mentagrophytes infection in guinea pigs, SCH 42427 was about 2-fold more active than SCH 39304 and about 100-fold more active than SCH 42426. These and other results indicated that SCH 42427 is the active enantiomer, responsible for all the antifungal activity observed with SCH 39304.

Comparative in vitro and in vivo evaluation of N-D-ornithyl amphotericin B methyl ester, amphotericin B methyl ester, and amphotericin B.

N-D-Ornithyl amphotericin B methyl ester (O-AME), a semisynthetic derivative of amphotericin B methyl ester (AME), was compared with amphotericin B (AMB) and AME. In vitro, O-AME was more active than the other two against Candida spp. and other fungi and was only slightly affected by inoculum size, addition of serum, or changes in pH. In vivo, the dose of O-AME required to produce a 10,000-fold reduction of Candida albicans in a mouse kidney infection was similar to that of AMB and 1/10 that of AME. After intravenous treatment of infected mice and rats and subcutaneous treatment of mice, average 50% protective doses for O-AME and AMB were similar. Acute intravenous 50% lethal doses in mice indicated that O-AME was one-ninth as toxic as AMB but twice as toxic as AME. Acute renal function tests in rats indicated that Sch 28191 was less than 1/10 as toxic as AMB and slightly more toxic than AME. On this basis, the calculated advantage relative to AMB (with AMB equal to 1) was 8 for O-AME and 1.5 for AME.

Antifungal Properties of 2-Alkenoic Acids and 2-Bromo Alkanoic Acids

The antifungal activity of homologous series of 2-alkenoic and 2-bromo alkanoic acids was determined against Aspergillus niger, Trichoderma viride, Myrothecium verrucaria, and Trichophyton mentagrophytes and compared with data on analogous alkanoic and 2-fluoro alkanoic acids. The fungitoxicity of all of the series of compounds was determined by chain length, pH of the medium, and presence or absence of adsorbents such as serum albumin. The order of toxicity on a molecular basis, by using a scale where the most active series is 1.0, is 2-bromo alkanoic acids (1.0) > 2-fluoro alkanoic acids (1.2) > alkanoic acids (1.4) > 2-alkenoic acids (2.5).

Antifungal Activity of 5-, 7-, and 5,7-Substituted 2-Methyl-8-Quinolinols

2-Methyl-8-quinolinol and sixteen 5-, 7-, and 5,7-substituted derivatives with fluoro, chloro, bromo, iodo, nitro, and amino substituents were tested for in vitro antifungal activity against five fungi, Aspergillus niger, A. oryzae, Trichoderma viride, Myrothecium verrucaria, and Trichophyton mentagrophytes. The 5,7-dichloro and 5,7-dibromo derivatives were the most fungitoxic of the compounds tested. With the exception of these two compounds and 5-iodo-2-methyl-8-quinolinol, the 2-methyl analogues were less active than the corresponding 8-quinolinols.

Comparison of SCH 39304, fluconazole, and ketoconazole for treatment of systemic infections in mice.

SCH 39304 was compared with fluconazole and ketoconazole in a systemic Candida albicans infection in mice (10(6) CFU per mouse). Results were based on survival rates and CFU in kidneys following once-daily oral treatment of 2, 5, or 10 days duration. In normal mice, SCH 39304 (dose to reduce kidney counts by 4 log units, 0.5 mg/kg of body weight) was 3 and 200 times more active than fluconazole and ketoconazole, respectively. In immunocompromised mice (gamma irradiation, 600 rads), SCH 39304 (dose to reduce kidney counts by 4 log units, 1.3 mg/kg) was 35 and greater than 100 times more active than fluconazole and ketoconazole, respectively. In normal mice, when the infecting inoculum varied from 10(5) to 10(7) CFU, only a fivefold increase in the dose to reduce kidney counts by 4 log units was observed with SCH 39304. Excellent protection was also seen when mice were treated with a single oral dose of SCH 39304 up to 24 h prior to infection with C. albicans. Studies in a systemic C. albicans infection model indicated that SCH 39304 is equally efficacious following either oral or intravenous administration. In a systemic Aspergillus flavus infection, mice treated with SCH 39304 (5 mg/kg) survived twice as long (16 days) as those treated with fluconazole (50 mg/kg) or controls did.