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To compare the safety and effectiveness of an investigational drug therapy (trimetrexate plus leucovorin calcium) with that of conventional therapy (sulfamethoxazole-trimethoprim) in the treatment of moderately severe Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, are HIV positive, or are at high risk for HIV infection. New treatments are needed to reduce the mortality rate from PCP in AIDS patients and to reduce the high relapse rate found after conventional therapy. Trimetrexate (TMTX) was chosen for this trial because it was found to be much more potent than sulfamethoxazole/trimethoprim (SMX/TMP) against the PCP organism in laboratory tests. Also TMTX, in combination with leucovorin (LCV), did not cause severe toxicity in a preliminary trial. It is believed that TMTX will be more effective than SMX/TMP in treating PCP and in preventing a recurrence of PCP. Preliminary studies suggest that aerosolized pentamidine (PEN) is likely to be effective in preventing a recurrence of PCP. Patients entered in the study are randomly assigned to TMTX / LCV or to SMX/TMP for a 21-day trial. For the first 10 days, the trial is double-blind (neither patient nor physician knows which drugs the patient is receiving), and drugs are given by intravenous infusion. TMTX is given once every 24 hours and LCV every 6 hours; SMX/TMP is given every 6 hours. Doses are determined by body size. After the first 10 days, LCV and SMX/TMP may be given orally. Doses are adjusted or treatment is changed to intravenous PEN if side effects are too severe. During the 21-day trial, zidovudine (AZT) may not be used because of possible increased bone marrow toxicity. AZT may be resumed as soon as the patient's white cell count is acceptable. Aerosolized PEN therapy is begun 7 - 10 days after completion of therapy for the acute episode. PEN is inhaled once weekly for 4 weeks, then every 2 weeks for 48 weeks.
Inclusion Criteria Concurrent Medication: Allowed: * Acetaminophen: * 650 mg prescribed as necessary for temperature \> 38.7 degrees C. Acetaminophen should not be prescribed as a standing order for more than 48 hours. Prior Medication: Allowed: * Zidovudine (AZT) as long as such therapy is suspended prior to randomization and not reinstituted until therapy for the acute episode is completed and the patient's white blood cell count is acceptable. * Other myelosuppressive therapies which may be handled in the same manner as AZT. * Prophylaxis for Pneumocystis carinii pneumonia (PCP). * Unequivocal diagnosis of Pneumocystis carinii pneumonia (PCP) by morphologic confirmation of three or more typical P. carinii organisms in sputum, bronchoalveolar lavage fluid, or lung tissue obtained by transbronchial or open-lung biopsy within 3 days before or after randomization. If morphologic confirmation is not possible prior to therapy, patients may be randomized if the investigator believes there is a high suspicion of PCP based on clinical presentation. If morphologic diagnosis cannot be established within 6 days of randomization, the patient will be withdrawn from study therapy. Resting (A-a) DO2 \< 30 torr on room air. Patient, parent, guardian, or person with power of attorney gives informed consent. Exclusion Criteria Co-existing Condition: Patients will be excluded for the following reasons: * History of Type I hypersensitivity (i.e., urticaria, angioedema, or anaphylaxis), exfoliative dermatitis, or other life-threatening reaction secondary to antibiotics containing sulfa, trimethoprim, or trimetrexate. * History of life-threatening pentamidine toxicity. Concurrent Medication: Excluded: * Other drugs for the treatment or prevention of AIDS or Pneumocystis carinii pneumonia (PCP). * Disalcid. * Aspirin. * Acetaminophen q4h as a standing order for more than 48 hours. Prior Medication: Excluded within 14 days of study entry: * Systemic steroids exceeding physiological replacement. * Other investigational drugs including ganciclovir. * Excluded within 6 weeks of study entry: * Another antiprotozoal regimen for this episode for therapy of active Pneumocystis carinii pneumonia (PCP). * Patients who are unable to have arterial blood gas analysis (ABG's) on room air. * Patients for whom a liter of intravenous fluid (5 percent dextrose in water) per 24 hours, which is required to maintain blinding, would be medically inadvisable.