Is there a role for sulphamethoxazole (SMX) plus pyrimethamine in the treatment of severe malaria?

Sulphamethoxazole Plus Pyrimethamine Has No Role in Severe Malaria Treatment

Sulphamethoxazole plus pyrimethamine (co-trimoxazole) should not be used for the treatment of severe malaria, as intravenous artesunate is the first-line treatment of choice for this life-threatening condition. 1, 2

First-Line Treatment for Severe Malaria

• Intravenous artesunate is the recommended first-line treatment for all forms of severe malaria according to the WHO and should be administered as a medical emergency 1
• Artesunate has been shown to provide faster parasite clearance time and shorter ICU stays compared to quinine in severe malaria cases 1
• Artesunate should be administered for 3 doses, followed by a switch to an oral artemisinin-based combination therapy (ACT) once the patient is clinically improved with parasitemia <1% 1

Alternative Options When Artesunate Is Unavailable

• Intravenous quinine can be used as an alternative when artesunate is unavailable, though it is associated with more adverse effects 2, 3
• There is no evidence supporting the use of sulphamethoxazole-pyrimethamine (co-trimoxazole) for severe malaria treatment in any current guidelines 1, 2

Role of Sulphamethoxazole-Pyrimethamine in Malaria Treatment

• Sulphamethoxazole-pyrimethamine combinations (such as Fansidar) are only mentioned as possible second-line drugs for uncomplicated malaria in areas with chloroquine resistance, not for severe malaria 1
• These combinations are primarily used for uncomplicated malaria when first-line treatments fail, not as initial therapy for severe disease 1
• Cross-resistance exists between trimethoprim and pyrimethamine at the molecular level, potentially limiting effectiveness 4

Clinical Management of Severe Malaria

• Severe malaria requires prompt recognition and treatment as a medical emergency with continuous monitoring of cardiocirculatory, pulmonary, renal, and metabolic parameters 1
• Parasitemia should be monitored every 12 hours after starting treatment until decline to <1%, then every 24 hours until negative 1
• Fluid management should be carefully controlled to avoid pulmonary or cerebral edema 1, 2
• Antibiotics should only be started if concomitant bacterial infection is suspected and continued only if blood cultures are positive 1

Important Considerations

• Exchange blood transfusion is no longer indicated in severe malaria with the availability of artesunate 1
• Acetaminophen (1g every 6 hours for 72 hours) may have a reno-protective effect in acute kidney injury associated with severe malaria 1
• Restrictive fluid management is generally recommended to avoid pulmonary or cerebral edema 1, 2

Research on Co-trimoxazole in Malaria

• While some research has examined co-trimoxazole for uncomplicated malaria, showing similar efficacy to sulfadoxine-pyrimethamine, these studies did not include severe malaria cases 5, 6
• One study found that pyrimethamine combined with co-trimoxazole had only a 47.8% clearance rate of asexual parasitemia in chloroquine-resistant malaria, which is inadequate for severe disease 7
• Co-trimoxazole is primarily used as prophylaxis in HIV-positive patients in malaria-endemic regions, not as treatment for active severe malaria 6

In conclusion, the management of severe malaria requires immediate treatment with intravenous artesunate as the first-line therapy. There is no established role for sulphamethoxazole plus pyrimethamine in the treatment of severe malaria based on current guidelines and evidence.