It is appropriate to start empiric therapy for P jirovecii pneumonia if the disease is suspected clinically; however, in both AIDS patients and non-AIDS patients with mild to moderately severe disease, continued treatment should be based on a proved diagnosis because of clinical overlap with other infections, the toxicity of therapy, and the possible coexistence of other infectious organisms. Oral trimethoprim-sulfamethoxazole (TMP-SMZ) is the preferred agent because of its low cost and excellent bioavailability in both AIDS patients and non-AIDS patients with mild to moderately severe disease. Patients suffering from nausea and vomiting or intractable diarrhea should be given intravenous TMP-SMZ until they can tolerate the oral formulation. Clinically significant resistance of Pneumocystis to TMP/SMZ is rare, although increasing rates of mutations have been reported in the DHPS and DHFR genes that mediate TMP-SMZ resistance. The best-studied second-line option is a combination of primaquine and clindamycin, although dapsone/trimethoprim, pentamidine, and atovaquone have been used. Therapy should be continued with the selected medication for at least 5–10 days before considering changing agents, as fever, tachypnea, and pulmonary infiltrates persist for 4–6 days after starting treatment. Some patients have a transient worsening of their disease during the first 3–5 days, which may be related to an inflammatory response secondary to the presence of dead or dying organisms. Early addition of corticosteroids may attenuate this response (see below). Some clinicians prefer to treat episodes of AIDS-associated Pneumocystis pneumonia for 21 days rather than the usual 14 days recommended for non-AIDS cases.
There are strong data indicating that TMP-SMZ is the optimal first-line therapy for Pneumocystis pneumonia. The dosage of TMP/SMZ is 15–20 mg/kg/day (based on trimethoprim component) given orally or intravenously daily in three or four divided doses for 14–21 days. Patients with AIDS have a high frequency of hypersensitivity reactions (approaching 50%), which may include fever, rashes (sometimes severe), malaise, neutropenia, hepatitis, nephritis, thrombocytopenia, hyperkalemia, and hyperbilirubinemia.
A meta-analysis suggested that primaquine, 15–30 mg orally daily, plus clindamycin, 600 mg three times orally daily, is the best second-line therapy with superior results when compared with pentamidine. Primaquine may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
The use of pentamidine has decreased as alternative agents have been studied. This medication is administered intravenously (preferred) or intramuscularly as a single dose of 3–4 mg (salt)/kg/day for 14–21 days. Pentamidine causes side effects in nearly 50% of patients. Hypoglycemia (often clinically inapparent), hyperglycemia, hyponatremia, and delayed nephrotoxicity with azotemia may occur. Rarely, a variety of other severe adverse reactions may occur, including anemia, thrombocytopenia, ventricular arrhythmias, and fatal pancreatitis. Blood glucose levels should be monitored. Inadvertent rapid intravenous infusion may cause precipitous hypotension.
Atovaquone is FDA approved for patients with mild to moderate disease who cannot tolerate TMP-SMZ or pentamidine, but failure is reported in 15–30% of cases. Mild side effects are common, but no serious reactions have been reported. The dosage is 750 mg orally two times daily for 21 days. Atovaquone should be administered with a fatty meal.
Trimethoprim, 15 mg/kg/day in three divided doses daily, plus dapsone, 100 mg/day, is an alternative oral regimen for mild to moderate disease or for continuation of therapy after intravenous therapy is no longer needed.
Based on studies done in patients with AIDS, prednisone is given for moderate to severe pneumonia (when PaO2 on admission is less than 70 mm Hg or oxygen saturation is less than 90%) in conjunction with antimicrobials. The addition of corticosteroids in such patients is associated with significant reduction in morbidity and mortality; administration of adjunctive corticosteroids within 72 hours is preferred. The dosage of prednisone is 40 mg twice daily orally for 5 days, then 40 mg daily for 5 days, and then 20 mg daily until therapy is completed (total course, 21 days). The role of prednisone in non-AIDS patients is less clear, although observational studies suggest that adjunctive corticosteroids are associated with reduced mortality in non-AIDS patients with Pneumocystis pneumonia and severe hypoxia (PaO2 60 mm Hg or less).