Clinically used antimicrobial drugs against experimental pneumocystosis, singly and in combination: analysis of drug interactions and efficacies.

We analyzed single drugs and combinations of drugs used clinically in the treatment of opportunistic infections and other conditions for their activities against Pneumocystis carinii pneumonia in immunosuppressed rats. When they were used alone, atovaquone, rifabutin, and dapsone were more active than clarithromycin or trimethoprim. Drug combinations were evaluated for synergistic activity by an analysis of variance model for two-way factorial experiments and a response surface model. Atovaquone combined with trimethoprim trimethoprim and some combinations of dapsone and clarithromycin was synergistic; however, the activities of combinations of atovaquone and rifabutin, atovaquone and clarithromycin, and atovaquone and dapsone were simply additive. Lovastatin, which inhibits 3-hydroxy-methylglutaryl coenzyme A reductase, was inactive whether it was used alone or in combination with other agents. None of the synergistic drug combinations was as effective as trimethoprim-sulfamethoxazole. We conclude that the rat model can be used to test combinations of anti-P. carinii agents for synergistic activity by well-established statistical techniques. While some combinations of clinically used antimicrobial drugs have enhanced anti-P. carinii activity, further studies are needed before clinical trials can be contemplated.

Immunodeficient and immunosuppressed mice as models to test anti-Pneumocystis carinii drugs.

Congenitally immunodeficient and immunosuppressed normal mice with naturally acquired Pneumocystis carinii infection were compared as models for testing anti-P. carinii drugs. Among the immunodeficient mice, mice with severe combined immunodeficiency disease (scid), which lack B and T cells, had higher levels of P. carinii pneumonia than did microMT mice, which lack K cells. Normal mice administered dexamethasone in the drinking water had more extensive pneumocystosis than mice administered parenteral methylprednisolone or hybridoma cells making a monoclonal antibody to CD4 cells. The standard anti-P. carinii drugs trimethoprim (TMP)-sulfamethoxazole (SMX), pentamidine, and atovaquone, which work well in rats and humans, worked well in the mice. Clindamycin and primaquine were effective in the scid and microMT mice but not in the immunosuppressed normal mice. High doses of epiroprim, an analog of TMP, appeared to enhance the activities of low doses of SMX and dapsone, while high doses of TMP did not; however, further studies are needed before definitive conclusions about the actions of these drugs can be drawn. Taken together, the data obtained in this study support the growing body of literature suggesting that the mouse is a valid alternative to the rat as a model for testing anti-P. carinii drugs. Additional differences involving the activities of individual drugs in these models will probably emerge as more experience is gained.

Guanylhydrazones in therapy of Pneumocystis carinii pneumonia in immunosuppressed rats.

Guanylhydrazones are cationic heteroaromatic drugs similar to the diamidines which are effective in the treatment of African trypanosomiasis and pneumocystosis. On the basis of their antitrypanosomal activity, different guanylhydrazones were selected for evaluation in a rat model of Pneumocystis carinii pneumonia. The most active compounds were the 2-(4'-formylphenyl)-1-methylimidazo-[1,2-a] pyridinium guanylhydrazones which, at a dose of 2 mg/kg/day, were about as effective as trimethoprim-sulfamethoxazole at a dose of 50 mg of trimethoprim per kg/day plus 250 mg of sulfamethoxazole per kg/day. The anti-P. carinii activity of these guanylhydrazone derivatives was found with parenteral but not with oral administration. The 1,3-arylene diketone bis(guanylhydrazones) were generally ineffective, although a triacetyl derivative showed some anti-P. carinii activity. Nitroimidazole guanylhydrazone derivatives were also ineffective. Attempts to improve the therapeutic efficacy of the different guanylhydrazones were limited by problems of toxicity. We conclude that some guanylhydrazone derivatives are potent anti-P. carinii drugs and that further studies should be pursued to develop safer compounds and investigate structure-activity relationships.