The efficacy and tolerance of pentamidine aerosol were evaluated in the prophylaxis and therapy of murine Pneumocystis carinii pneumonia. P. carinui pneumonia was induced in rats by corticosteroid immunosuppression. Pentamidine was administered three times weekly via a Bird micronebulizer. The actual amount of pentamidine inhaled was estimated by monitoring the ventilation of the rats during the aerosol administration. Pentamidine levels in blood, lung, liver and kidney samples were determined by high-pressure liquid chromatography after completion of the treatment. Efficacy was evaluated by examination of lung imprints. In the prophylactic treatment, 4.8-and 8.6-mg/kg doses of aerosolized pentamidine administered three times weekly for 7 weeks were effective in preventing P. carinui pneumonia in 80 and 100% of the rats, respectively. In the therapeutic studies, a 14.6-mg/kg dose of aerosolized pentamidine administered three times weekly for 3 weeks was effective both in curing the pneumonia and in clearing P. carinii cysts in 70% of the rats. In the remaining animals, although the pneumonia was cured, the cysts persisted. A dose-dependent effect of the drug was demonstrated in both prophylactic and therapeutic treatments. High lung/kidney and lung/liver ratios of pentamidine levels were demonstrated and were associated with good clinical, biological, and histologic tolerance.More than 10,000 cases of Pneumocystis carinii pneumonia have been reported in the United States to the Centers for Disease Control since the emergence of the acquired immunodeficiency syndrome epidemic (5). P. carinii infection is confined to the lungs. Trimethoprim-sulfamethoxazole (TMP-SMZ) and pentamidine are the two drugs which are routinely used in treating human P. carinii pneumonia. However, the parenteral administration of pentamidine is hampered by frequent local intolerance and major systemic side effects due to its high level of extrapulmonary deposition. TMP-SMZ side effects are also frequent, especially in acquired immunodeficiency syndrome patients. Since preliminary data on aerosolized pentamidine pharmacokinetics were available (E. M. Bernard, H. P. Donelly, H. P. Koo, and D. Amstrong, Program Abstr. 25th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 552, 1985), we tested the feasibility, tolerance, and efficacy of pentamidine aerosol in the prophylaxis and therapeutic treatment of murine P. carinii pneumonia.MATERIALS AND METHODS Animal model of P. carinii pneumonia. Male SpragueDawley rats (Charles River Breeding Laboratories, St. Aubin, France), weighing 200 to 250 g, were housed in groups of five in conventional cages with standard rat chow (no. A03; Usine Alimentation Rationelle, Villemoisson, France) and water ad libitum. Rats were weighed weekly.Rats were immunosuppressed by subcutaneous injections of 25 mg of cortisone acetate (Hydrocortisone; HoechstRoussel, Paris, France) twice weekly, until death or sacrifice. Doxycycline (Vibramycine; Pfizer Inc., Paris, France) was subcutaneously injected at a dose ...