Efficacy of a New Triazole, BMS-207147, in a Model of Invasive Aspergillosis in Immunosuppressed, Neutropenic Rabbits.



Background: BMS-207147 (ER-30346) is a new triazole antifungal with activity versus Candida spp. (including many strains resistant to fluconazole), Cryptococcus neoformans, Aspergillus spp. and the important dermatophytic fungi. MFC/MIC ratios suggest that, like amphotericin B, BMS-207147 is fungicidal against many strains of aspergilli. We conducted a study to evaluate the efficacy of BMS-207147 in a well established rabbit model of invasive aspergillosis; this model employs a sublethal challenge which results in 50% mortality in saline treated controls. Method: Animals: New Zealand female white rabbits (2-3 kg); Immunosuppression: animals made neutropenic on Day 1 with IV cyclophosphamide (100 mg/kg) and then given steroids (triamcinolone 10 mg) daily to impair macrophage function; neutropenia persists for 7 days, nadir on day 4. Infection: IV challenge on Day 2 with 1.0 - 1.1 x 105} Aspergillus fumigatus conidia. Evaluation: mortality and quantitative colony counts of liver, kidney, lung and brain. Treatment: BMS-207147 30 mg/kg/d orally (BMS) (n=10), Amphotericin B 1 mg/kg/d IV (AmB) (n=4), Saline control IV (Con) (n=2) each given once daily x 6 days. Results: Mortality: BMS 0/10 (0%), AmB 0/4 (0%), Con 1/2 (50%). Mean colony counts (Std. Dev.) in CFU/g: Kidney: BMS 0.06 (+/-+/-0.13), AmB 0.60 (+/-+/-0.59), Con 1.72 (+/-+/-0.91); Liver: BMS 0.09 (+/-+/-0.20), AmB 0.41 (+/-+/-0.64), Con 2.82 (+/-+/-1.35); Lung: BMS 0.14 (+/-+/-0.26), AmB 0 (+/-+/-0), Con 2.44 (+/-+/-0.06); Brain: BMS 0.09 (+/-+/-0.14), AmB 0.30 (+/-+/-0.42), Con 0.80 (+/-+/-0.71) Conclusion: BMS-207147 is effective in this model of invasive aspergillosis and activity appears comparable to amphotericin B. Based on historical comparisons with other azoles tested in this model, BMS-207147 appears to be one of the most effective agents in this class. Clinical studies in humans are warranted.

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38th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 38th