ARTIFICIAL INFECTIONS OF PNEUMOCYSTIS-CARINII IN THE SCID MOUSE AND THEIR USE IN THE IN-VIVO EVALUATION OF ANTIPNEUMOCYSTIS DRUGS

A model for the in vivo evaluation of antipneumocystis drugs has been developed in SCID mice infected intratracheally with cryopreserved mou se-derived Pneumocystis carinii The development of a highly reproducib le fatal P. carinii pneumonia occured within 10 weeks (mean survival t ime +/- SEM = 72.2 +/- 1.2 days). Continuous administration of dexamet hasone (2 mg/liter in the drinking water) exacerbated the rate of onse t of severe P. carinii pneumonia (mean survival time +/- SEM = 63 +/- 1.3 days) in SCID mice. The number of cysts per g of lung homogenate ( homogenate counts) were maximal with an inoculum of 20,000 cysts at 6 weeks post infection. Homogenate counts correlated with infection scor es (graded assessments of immunofluorescent cysts on lung impression s mears) suggesting that infection scoring accurately and rapidly reflec ts the severity of P. carinii pneumonia in SCID mice. These studies le d to the development of a drug screening protocol in which Pneumocysti s-free female SCID mice (20-25 g) were started on dexamethasone 7 days prior to IT inoculation with a single dose of 20,000 cysts. Drugs wer e evaluated either for: a) prophylaxis (continuously from day 1 post i nfection) or b) treatment (from day 21 post infection) until day 42 po st infection, when all mice were killed and infection scores determine d. Co-trimoxazole (at 250 mg sulfamethoxazole + 50 mg trimethoprim/kg/ day) given in the drinking water was found to be highly effective in b oth the prophylaxis and treatment of mouse P. carinii pneumonia. Co-tr imoxazole remained very effective in the prophylaxis P. carinii pneumo nia in the SCID mouse at 125 mg sulfamethoxazole + 25 mg trimethoprim/ kg/day p.o. and showed some enhancement of efficacy over sulfamethoxaz ole alone at 125 mg/kg/day p.o., suggesting limited synergy between su lfamethoxazole and trimethoprim. The results presented provide confirm ation of the usefulness and predictability of the model.