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Antimicrobial Agents and Chemotherapy, July 2000, p. 1874-1877, Vol. 44, No. 7
California Institute for Medical Research,
San Jose, California 95128; Department of Medicine, Division of
Infectious Diseases, Santa Clara Valley Medical Center, San Jose,
California 95128; and Department of Medicine, Division of
Infectious Diseases and Geographic Medicine, Stanford University,
Stanford, California 94305
Received 20 September 1999/Returned for modification 23 January
2000/Accepted 1 April 2000
Sordarin derivatives (Glaxo Wellcome) are a new class of compounds
that selectively inhibit fungal protein synthesis and have a broad
spectrum of activity. Systemic coccidioidomycosis was established in
female CD-1 mice infected with Coccidioides immitis, and
therapy was begun on day 4 with either GM193663, GM211676, GM237354,
fluconazole, or no treatment; compounds were given twice daily orally
for 19 days at 20 or 100 mg/kg/day. The serum pharmacokinetics of the
compounds were studied in uninfected mice. The MICs of GM193663,
GM211676, and GM237354 for C. immitis were 1.56, 0.39, and
0.39 µg/ml, respectively, and the minimum fungicidal concentrations were 6.25, 3.13, and 0.39 µg/ml, respectively. Peak serum levels (sampled at 1 to 2 h) after a single 50-mg/kg dose were 9.8 µg/ml for GM193663, 13 µg/ml for GM211676, and 6.0 µg/ml for
GM237354. No accumulation occurred after 19 days of dosing, and peak
levels were lower at 3.2 µg/ml for GM193663, 4.0 µg/ml for
GM211676, and <2.5 µg/ml for GM237354. We estimate that the
t1/2 for each compound in serum is <2 h. In
vivo, all compounds showed dose-responsive efficacy, significantly
prolonging survival over the control groups (100% lethal dose); 80 to
100% of the mice given the 100-mg/kg doses of fluconazole or a GM drug
survived. All 100-mg/kg/day regimens were equivalent. At 20 mg/kg/day,
GM211676 was equivalent to 100 mg of fluconazole/kg/day, indicating
that GM211676 was ~5-fold more efficacious. No mice surviving the 49 days of the experiment were free of infection. All drugs 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 regimens in the reduction of burden in all organs. C. immitis was
susceptible both in vitro and in vivo to the GM compounds, which were
found to be equivalent or superior to fluconazole. These results are encouraging, indicating that further testing in other models of fungal
disease is warranted.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Efficacies of Sordarin Derivatives GM193663, GM211676, and
GM237354 in a Murine Model of Systemic
Coccidioidomycosis
*
Corresponding author. Mailing address: Division of
Infectious Diseases, Santa Clara Valley Medical Center, 751 South
Bascom Ave., San Jose, CA 95128-2699. Phone: (408) 998-4557. Fax: (408) 998-2723. E-mail: Karl.Clemons{at}slip.net.
Antimicrobial Agents and Chemotherapy, July 2000, p. 1874-1877, Vol. 44, No. 7
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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