Efficacies of sordarin derivatives GM193663, GM211676, and GM237354 in a murine model of systemic coccidioidomycosis

Sordarin derivatives (Glaxo Wellcome) are a new class of compounds that sel ectively inhibit fungal protein synthesis and have a broad spectrum of acti vity. Systemic coccidioidomycosis was established in female CD-1 mice infec ted with Coccidioides immitis, and therapy was begun on day 4 with either G M193663, GM211676, GM237354, fluconazole, or no treatment; compounds were g iven mice daily orally for 19 days at 20 or 100 mg/kg/day. The serum pharma cokinetics of the compounds were studied in uninfected mice. The MICs of GM 193663, GM211676, and GM237354 for C. immitis were 1.56, 0.39, and 0.39 mu g/ml, respectively, and the minimum fungicidal concentrations were 6.25, 3. 13, and 0.39 mu g/ml, respectively. Peak serum levels (sampled at 1 to 2 h) after a single 50-mg/kg: dose were 9.8 mu g/ml for GM193663, 13 mu g/ml fo r GM211676, and 6.0 mu g/ml for GM237354. No accumulation occurred after 19 days of dosing, and peak levels were lower at 3.2 mu g/ml for GM193663, 4. 0 mu g/ml for GM211676, and <2.5 mu g/ml for GM237354. We estimate that the t(1/2) for each compound in serum is <2 h, In vivo, all compounds showed d ose-responsive efficacy, significantly prolonging survival over the control groups (100% lethal dose); 80 to 100% of the mice given the 100-mg/kg dose s of fluconazole or a GM drug survived, All 100-mg/kg/day regimens were equ ivalent. At 20 mg/kg/day, GM211676 was equivalent to 100 mg of fluronazole/ kg/day, indicating that GM211676 was similar to 5-fold more efficacious. No mice surviving the 49 days of the experiment were free of infection. All d rugs dose responsively reduced the fungal burden in the spleen, liver, and lungs, and GM237354 at 100 mg/kg/day was superior to all of the other regim ens in the reduction of burden in all organs. C. immitis was susceptible bo th in vitro and in vivo to the GM compounds, which were found to be equival ent or superior to fluconazole, These results are encouraging, indicating t hat further testing in other models of fungal disease is warranted.