The iron-chelating drug deferoxamine mesylate (DFO) is active against Pneumocystis carinii in vitro and in rat and mouse models of P. carinii pneumonia. Because DFO has a short half-life, daily divided or continuous dosage was expected to improve the dose response, as is the case with DFO treatment of malaria. Therefore, results of single daily intraperitoneal injections were compared with results of an evenly divided four-timesdaily dosage and the efficacy of delivery with implanted infusion pumps. The highest bolus dosage (1,000 mg kg ؊1 of body weight day
؊1) was as effective as the standard combination of trimethoprim with sulfamethoxazole. Unexpectedly, very little improvement was observed with the divided or continuous dosage, and several mechanisms that could account for this are discussed.Pneumocystis carinii is a fungus that causes P. carinii pneumonia (PCP), an opportunistic infection of considerable importance for AIDS and other immunosuppressive conditions (9). Although the standard agents for treatment, pentamidine and a combination of trimethoprim and sulfamethoxazole (TMP-SMZ), have high response rates, they often produce severe side effects which necessitate cessation of therapy in more than 60% of AIDS patients (5). Better-tolerated modes of treatment are needed. Deferoxamine mesylate (DFO) is a very potent hexadentate iron chelator used routinely since the 1960s to treat iron overload in -thalassemia patients (12). It is also used to remove aluminum from kidney dialysis patients (3). In both of these types of patients DFO has been well tolerated for prolonged periods. DFO is also active against P. carinii in vitro (17) and is therapeutic in animal models of PCP, although very high dosages, i.e., up to 1,000 and 400 mg kg Ϫ1 of body weight day
Ϫ1, are required for rats (4) and mice (17), respectively. In contrast, the usual clinical dose ranges from 40 to 60 mg kg
Ϫ1. Since the half-life (t 1/2 ) of DFO is about 10 to 20 min (10, 15) and the daily bolus dosage was used in the previous studies, administration by divided doses or by continuous infusion was expected to improve markedly the dose response, as has been observed for treatment of malaria (13, 18).
MATERIALS AND METHODS
Materials.The following materials were used: DFO, available as Desferal, Ciba Pharmaceuticals Co., Summit, N.J.; a pediatric suspension of TMP-SMZ, Barre-National, Baltimore, Md.; a water-soluble preparation of dexamethasone sodium phosphate for injection (10 mg ml Preparation of immunosuppressed rats. Specific-pathogen-free Sprague-Dawley rats were acquired from Taconic Farms (Germantown, N.Y.), placed in a barrier colony, and given multiple antibiotics to avoid other opportunistic infections as previously described (14) except that on arrival the rats were also given a single injection of penicillin G (6,000 IU) plus procaine. The animals were immunosuppressed by the addition of dexamethasone to the drinking water (1.5 mg liter Ϫ1 ), a regimen which was continued for all animals throughout the experiment.Induction of P...