Pneumocystis carinii pneumonia remains one of the most serious complications of immunosuppressed patients. In this study, the in vitro pharmacodynamic parameters of four
sordarin derivatives (GM 191519,
GM 237354,
GM 193663, and GM 219771) have been evaluated by a new quantitative approach and compared with the commercially available drugs
pentamidine,
atovaquone, and
trimethoprim-sulfamethoxazole (
TMP-SMX). In vitro activities and in vivo therapeutic efficacies of
sordarin derivatives against P. carinii were also evaluated. In vitro activity was determined by the broth microdilution technique, comparing the total number of microorganisms in treated and
drug-free cultures by using Giemsa staining. The in vitro maximum effect (E(max)), the
drug concentrations to reach 50% of E(max) (EC(50)), and the slope of the dose-response curve were then estimated by the Hill equation (E(max) sigmoid model).
Sordarin derivatives were the most potent agents against P. carinii, with EC(50)s of 0.00025, 0.0007, 0.0043, and 0. 025 microg/ml for GM 191519,
GM 237354,
GM 193663, and GM 219771, respectively. The EC(50)s of
pentamidine,
atovaquone, and
TMP-SMX were 0.025, 0.16, and 26.7/133.5 microg/ml, respectively. The results obtained with this approach showed
GM 237354 and GM 191519 to be approximately 35- and 100-fold more active in vitro than
pentamidine, the most active marketed compound. All
sordarin derivatives tested were at least 5,000-fold more active in vitro than
TMP-SMX. The three
sordarin derivatives tested in vivo-GM 191519,
GM 237354, and GM 219771-showed a marked therapeutic efficacy, defined as reduction of
cyst forms per gram of lung. GM 191519 was the most potent (daily dose reducing 50% of the P. carinii burden in the lungs [ED(50)], 0.05 mg/kg/day) followed by
GM 237354 and GM 219771 (ED(50)s, 0.30 and 0.49 mg/kg/day, respectively). Good agreement between in vitro parameters and in vivo outcome was obtained when P. carinii
pneumonia in rats was treated with
sordarin derivatives.