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

Abstract

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...

Amphotericin B lipid complex therapy of experimental fungal infections in mice

“…The relative failure of oral agents like itraconazole and fluconazole was somewhat surprising, because they have been reported to be effective in the therapy of experimental fungal infections in mice (5,11,25). In the current study, the model infections were designed to present a formidable challenge to the test agents, to reflect the severe problems that these systemic mycoses often present in seriously ill individuals.…”

Efficacy of the triazole D0870 in a murine model of systemic histoplasmosis

“…In the study described here we examined the utility of D0870 as a therapy for experimental systemic histoplasmosis in immunocompetent mice. Fluconazole was chosen as the comparison drug on the basis of the results of clinical trials that demonstrated the clinical improvement of immunocompetent patients with histoplasmosis treated with fluconazole (3), in addition to the efficacy of fluconazole shown in animal models of histoplasmosis (6,10,11).…”

Discovery and development of new antimicrobial agents

“…The antimicrobial treatment period for such infection models may be longer than the routine PD50 experiments, since many infections in immunosuppressed patients are chronic in nature and require treatment over a period of time longer than 48 h. Chronic protection studies of this type often require different criteria for measuring successful therapy compared with routine PD50 studies that usually record lethality. These criteria can include counting viable microbial cells in one or more infected organs of animals sacrificed during, or at the completion of, a course of therapy (91). Measurement of microbial cell clearance from infected tissues is another way of assessing how well a test antibiotic might work in many of the serious infections encountered in humans.…”

“…Furthermore, with the increased incidence of immunosuppressed patients seen in hospitals today, there is a major need for new antimicrobial agents that provide adequate therapy in patients lacking an intact immune system (57,98,134). Therefore, new infection models have been developed in immunosuppressed animals that measure the efficacy of antimicrobial agents against bacterial and fungal pathogens found in immunosuppressed patients (6,91,132). Usually, the animals are chemically immunosuppressed with repeated doses of agents such as dexamethasone or cyclophosphamide before challenge with a lethal inoculum of test organism (91,132).…”

“…Therefore, new infection models have been developed in immunosuppressed animals that measure the efficacy of antimicrobial agents against bacterial and fungal pathogens found in immunosuppressed patients (6,91,132). Usually, the animals are chemically immunosuppressed with repeated doses of agents such as dexamethasone or cyclophosphamide before challenge with a lethal inoculum of test organism (91,132). The antimicrobial treatment period for such infection models may be longer than the routine PD50 experiments, since many infections in immunosuppressed patients are chronic in nature and require treatment over a period of time longer than 48 h. Chronic protection studies of this type often require different criteria for measuring successful therapy compared with routine PD50 studies that usually record lethality.…”