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 mouse-derived Pneumocystis carinii. The development of a highly reproducible fatal P. carinii pneumonia occurred within 10 weeks (mean survival time +/- SEM = 72.2 +/- 1.2 days). Continuous administration of dexamethasone (2 mg/liter in the drinking water) exacerbated the rate of onset 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 scores (graded assessments of immunofluorescent cysts on lung impression smears) suggesting that infection scoring accurately and rapidly reflects the severity of P. carinii pneumonia in SCID mice. These studies led to the development of a drug screening protocol in which Pneumocystis-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 were evaluated either for: a) prophylaxis (continuously from day 1 post infection) or b) treatment (from day 21 post infection) until day 42 post infection, when all mice were killed and infection scores determined. Co-trimoxazole (at 250 mg sulfamethoxazole + 50 mg trimethoprim/kg/day) given in the drinking water was found to be highly effective in both the prophylaxis and treatment of mouse P. carinii pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)
Comley
J C
JC
Biology Division, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Sterling
A M
AM
D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D008168:Lung / Q000382:microbiology; D051379:Mice; D016513:Mice, SCID; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy*; D013420:Sulfamethoxazole / Q000627:therapeutic use; D014295:Trimethoprim / Q000627:therapeutic use; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use
D000935:Antifungal Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014295:Trimethoprim; D013420:Sulfamethoxazole