Efficacy of continuous flucytosine infusion against Candida lusitaniae in experimental hematogenous murine candidiasis.

Candida lusitaniae may cause life-threatening infections in the immunocompromised host and may be resistant to amphotericin B. Flucytosine (5-FC) is very active against C. lusitaniae isolates in vitro, while the in vivo response of murine infection to 5-FC is not as good. To evaluate the hypothesis that this discrepancy may be primarily due to the short half-life of 5-FC in mice, we compared the same total dosage of 75 mg of 5-FC per kg of body weight per day given by bolus injections or infused continuously via a subcutaneously implanted pump in immunosuppressed CF1 mice infected with C. lusitaniae. The fungal titers in the kidneys of mice treated with the continuous 5-FC infusion were significantly lower (P < or = 0.05) than those in the kidneys of mice that received bolus injections once or thrice daily. The antifungal activity of 5-FC against murine candidiasis is best evaluated when the drug is administered by continuous infusion.

Effects of cyclophosphamide and ceftriaxone on gastrointestinal colonization of mice by Candida albicans.

Adult male Crl:CD1 (ICR) mice were fed chow containing Candida albicans to induce sustained gastrointestinal colonization by the yeast. Groups of mice were rendered neutropenic with cyclophosphamide and subsequently received ceftriaxone, while other groups received normal saline and served as controls. Stool cultures were obtained immediately before and at the end of treatment. The administration of cyclophosphamide substantially increased the C. albicans counts in the stools of mice. The addition of ceftriaxone to the cyclophosphamide regimen did not significantly increase the level of gastrointestinal colonization by C. albicans. There was no evidence of Candida dissemination to internal organs.

SCH 51048, a new antifungal triazole active against hematogenous Candida krusei infections in neutropenic mice.

Candida krusei is increasingly recognized as an opportunistic pathogen in immunocompromised patients and is inherently resistant to fluconazole. We tested the in vivo efficacy of SCH 51048, an investigational antifungal triazole, in experimental hematogenous murine infection caused by two C. krusei isolates and compared its activity with those of amphotericin B and fluconazole. CF1 mice were immunosuppressed with cyclophosphamide and cortisone acetate and were challenged intravenously with infecting inocula of each C. krusei isolate. Treatment with SCH 51048 (50 or 100 mg/kg of body weight per day orally) or amphotericin B (2 mg/kg/day intraperitoneally) significantly prolonged the survival of infected mice and significantly reduced fungal titers in the kidneys (P < or = 0.05). Treatment with fluconazole (100 mg/kg/day orally) had no effect. Both dosages of SCH 51048 were as effective as amphotericin B in improving survival, but the higher dosage was significantly (P < or = 0.05) better in reducing the fungal burden in the kidneys of infected animals. A dose-dependent response was observed with SCH 51048 treatment, especially in organ clearance. Our results indicate that SCH 51048 is the first triazole that has in vivo activity against experimental infection with C. krusei and deserves further evaluation.

Activities of D0870, a novel triazole, against Candida lusitaniae and Trichosporon beigelii in experimental murine infections.

Candida lusitaniae and Trichosporon beigelii may cause life-threatening infections in the immunocompromised host and may be resistant to amphotericin B. We assessed the activities of a new triazole, D0870, against one T. beigelii and four C. lusitaniae strains, in comparison with those of fluconazole and amphotericin B. Immunosuppressed CF1 mice, intravenously infected with each fungal strain, received 3 days of therapy with oral D0870 (5 or 25 mg/kg of body weight daily), fluconazole (5 to 50 mg/kg daily), or parenteral amphotericin B (1 or 2 mg/kg daily). Survival was significantly prolonged and kidney fungus titers were reduced in mice treated with D0870 compared with untreated mice (P < or = 0.05). Treatment with D0870 was significantly more effective than that with amphotericin B or fluconazole in animals infected with two of the C. lusitaniae strains and equally effective for the remaining two C. lusitaniae strains and the T. beigelii strain. Fluconazole and amphotericin B failed to improve the survival of mice infected with one and two C. lusitaniae strains, respectively. D0870 was active against all the organisms tested, including those resistant to fluconazole and amphotericin B.

Comparative efficacies of amphotericin B, triazoles, and combination of both as experimental therapy for murine trichosporonosis.

We assessed the activities of amphotericin B deoxycholate, liposomal amphotericin B, fluconazole, and SCH 39304 against 10 strains of Trichosporon beigelii in mice with hematogenous infections. Cyclophosphamide-immunosuppressed CF1 male mice were challenged intravenously with a lethal inoculum of T. beigelii (5 x 10(6) conidia per mouse) and were assigned to different treatment groups or were left untreated. Amphotericin B deoxycholate (1 mg/kg of body weight and liposomal amphotericin B (1, 5, and 10 mg/kg) were given parenterally once daily. Escalating doses (5, 10, and 20 mg/kg/day) of fluconazole and SCH 39304 were tested. We also compared the activity of amphotericin B deoxycholate plus fluconazole (1 and 10 mg/kg/day, respectively) with that of each agent alone. Fluconazole significantly prolonged the survival of mice infected with each of the 10 strains tested. Amphotericin B deoxycholate achieved various responses, improving the outcomes in mice infected with seven of the strains. Liposomal amphotericin B was not more effective than amphotericin B deoxycholate against the two strains tested. Both fluconazole and SCH 39304 reduced the kidney fungal counts in a dose-dependent pattern, with SCH 39304 being more active than fluconazole against one of the two strains tested. The activity of the combination of amphotericin B deoxycholate plus fluconazole appeared to be superior to that of either agent alone, especially in reducing the kidney fungal burden. Fluconazole is more active than amphotericin B deoxycholate against experimental murine trichosporonosis.

Efficacy of escalating doses of liposomal amphotericin B (AmBisome) against hematogenous Candida lusitaniae and Candida krusei infection in neutropenic mice.

Immunosuppressed CF1 mice were infected intravenously with two strains of Candida krusei and four strains of Candida lusitaniae (two of which were resistant to amphotericin B). Mice were treated with 1 or 2 mg of amphotericin B desoxycholate per kg of body weight per day or escalating doses of liposomal amphotericin B (8 to 30 mg/kg/day) or were left untreated. Higher doses of liposomal amphotericin B were as effective as standard dose of amphotericin B desoxycholate in prolonging survival but were significantly more effective in reducing the fungal burden in the kidneys of animals infected with both C. krusei strains and the C. lusitaniae strains that were susceptible to amphotericin B desoxycholate. This advantage of liposomal amphotericin B therapy could not be demonstrated in mice infected with the C. lusitaniae strains that were resistant to amphotericin B desoxycholate.

Correlation between in vitro and in vivo activity of antifungal agents against Candida species.

The correlation between antifungal susceptibility testing and in vivo response to antifungal therapy was examined in experimental murine candidiasis. In vitro susceptibility testing was done using a microbroth dilution method. Twenty-two Candida albicans, 4 Candida lusitaniae, and 2 Candida krusei isolates were tested against fluconazole, flucytosine, and amphotericin B. In vivo antifungal activity was tested in murine hematogenous candidiasis. Normal CF1 mice were infected with each of the C. albicans strains; immunosuppressed CF1 mice were inoculated with C. lusitaniae or C. krusei. Mice received various doses of antifungal agents, and survival was monitored for 21 days. Kidney fungal burden was examined on day 4. Antifungal therapy significantly prolonged survival and reduced tissue counts in animals infected with organisms susceptible to the agent tested (P < .05). In vitro resistance to a drug predicted its lack of in vivo activity. These results appear to correlate well with outcome of murine hematogenous candidiasis.

Comparison of the efficacy of polyenes and triazoles against hematogenous Candida krusei infection in neutropenic mice.

Candida krusei is reported to cause serious infections in immunocompromised patients, particularly those receiving prophylaxis with antifungal azoles. Treatment of this infection can be very challenging. The efficacy of amphotericin B, liposomal amphotericin B (three dosages), fluconazole, and D0870 (a new experimental oral bis-triazole) was assessed in a CF1 mouse model of hematogenous C. krusei infection. Increased survival time and reduced kidney fungal burden were achieved with treatment with amphotericin B at 2 mg/kg/day and liposomal amphotericin B at 8 and 15 mg/kg/day. D0870 at 25 mg/kg/day increased survival time but had no effect on clearance from organs, while the survival and clearance from organs of mice treated with fluconazole at a dose of 100 mg/kg/day did not differ from those of untreated animals. These findings suggest that deoxycholate and liposome-encapsulated amphotericin B are active against disseminated C. krusei infection in neutropenic mice and confirm the in vitro and in vivo resistance of this species to fluconazole.