Pyrimethamine and G6PD Deficiency in Immunocompromised Patients with Toxoplasmosis
Pyrimethamine can be used cautiously in patients with G6PD deficiency, as pyrimethamine itself does not typically cause hemolysis, but the sulfonamide component (sulfadiazine) commonly combined with it poses significant hemolytic risk and should be avoided in G6PD-deficient patients.
Key Clinical Considerations
Primary Treatment Strategy
For G6PD-deficient patients with toxoplasmic encephalitis, use pyrimethamine plus clindamycin with leucovorin as the preferred alternative regimen 1. This combination avoids sulfonamides entirely while maintaining efficacy against toxoplasmosis.
The standard pyrimethamine-sulfadiazine combination, while highly effective, must be avoided because sulfadiazine can trigger severe hemolytic anemia in G6PD-deficient patients 1.
Pyrimethamine monotherapy at adequate serum levels (≥500 ng/ml) has demonstrated efficacy in experimental models, though it is not recommended as standard practice 2.
Dosing and Monitoring Requirements
Acute treatment dosing: Pyrimethamine 2 mg/kg/day for 2-3 days (loading), then 1 mg/kg/day, combined with clindamycin 5.0-7.5 mg/kg orally 4 times daily (maximum 600 mg/dose) 1.
Mandatory leucovorin supplementation: 10-25 mg daily to prevent bone marrow suppression, which is pyrimethamine's primary dose-limiting toxicity 1, 3.
Weekly complete blood counts are essential during daily pyrimethamine therapy to detect neutropenia, anemia, or thrombocytopenia 1, 3. Continue leucovorin for 1 week after stopping pyrimethamine due to its long half-life 1.
Critical Pitfalls to Avoid
Never use TMP-SMZ (trimethoprim-sulfamethoxazole) in G6PD-deficient patients, as the sulfamethoxazole component poses the same hemolytic risk as sulfadiazine 1.
Do not use dapsone, which is another alternative for toxoplasmosis prophylaxis but causes significant hemolysis in G6PD deficiency 1.
Be aware that pyrimethamine has a narrow therapeutic window and requires careful dose titration 3. Signs of folate deficiency (megaloblastic anemia, glossitis) mandate dose reduction or temporary discontinuation 3.
Prophylaxis Considerations
For primary prophylaxis in patients with CD4 counts <100 cells/mm³, pyrimethamine 50 mg three times weekly with folinic acid 15 mg can be considered, though it is less effective than TMP-SMZ when used alone 4.
Lifelong suppressive therapy is mandatory after completing acute treatment to prevent relapse, using pyrimethamine plus clindamycin with leucovorin 1, 5.
Alternative Considerations
Atovaquone (1,500 mg orally twice daily with meals) combined with pyrimethamine and leucovorin represents another sulfa-free option, though pediatric data are limited 1.
Azithromycin (900-1,200 mg/day) with pyrimethamine and leucovorin has been used in sulfa-allergic adults but lacks pediatric studies 1.
Special Populations
Pregnant women with G6PD deficiency: Pyrimethamine should be used with extreme caution due to teratogenicity (Category C), particularly in the first trimester 1, 3. Consider deferring pyrimethamine-containing regimens until after pregnancy if clinically feasible 1.
Pediatric patients: The pyrimethamine-clindamycin combination can be used with appropriate weight-based dosing adjustments 1.
Hematologic Toxicity Profile
Pyrimethamine causes reversible bone marrow suppression through folate antagonism, not hemolysis 1, 3.
One case report documented hemolytic anemia associated with toxoplasmosis itself (not pyrimethamine) that responded to pyrimethamine treatment 6.
The combination of pyrimethamine with other myelosuppressive agents (zidovudine, methotrexate, proguanil) increases bone marrow toxicity risk 3.