AEROSOL AND PARENTERAL PNEUMOCANDINS ARE EFFECTIVE IN A RAT MODEL OF PULMONARY ASPERGILLOSIS

The pneumocandins are semisynthetic analogs of echinocandin-like compo unds that have shown efficacy in animal models of systemic candidiasis , disseminated aspergillosis, and pneumocystis pneumonia. However, the most common form of Aspergillus infection in susceptible patients is pulmonary aspergillosis, which was not directly tested in the mouse mo dels used in the past, We have evaluated three pneumocandins, L-693,98 9, L-731,373, and L-733,560, in a rat model of pulmonary aspergillosis . Male Sprague-Dawley rats were treated for 2 weeks with cortisone and tetracycline and fed a low-protein diet before being inoculated via t he trachea with 10(6) conidia of Aspergillus fumigatus H11-20. In the absence of drug treatment, the animals developed a progressive, rapidl y fatal bronchopneumonia. All three pneumocandins at doses of 5 mg/kg (intraperitoneally [i.p.] every 12 h [q12h]) were effective in delayin g mortality in this model. Survival at day 7 postinfection was 20% amo ng controls (n = 10 for all groups), while it was 60, 80, and 90% in g roups that were treated with L-693,989, L-731,373, and L,-733,560, res pectively, In another trial, survival at day 7 postinfection was 25% a mong controls (n = 8 for all groups); it was 87.5% in a group treated with amphotericin B (0.5 mg/kg i.p. q12h) and was 100% in a group trea ted with L-733,560 (0.625 mg/kg i.p. q12h). In a separate trial, aeros ol L-693,989 administered 2 h before infection (5 mg/kg) delayed morta lity. Eight of the 10 animals treated with aerosol L-693,989 survived for 7 days, whereas only 2 of 10 control animals survived. We conclude that the pneumocandins we tested were highly effective in an animal m odel of pulmonary aspergillosis.