What is the treatment for malaria caused by Plasmodium (P.) parasites?

Treatment of Malaria Caused by Plasmodium Parasites

Artemisinin-based combination therapies (ACTs), specifically artemether-lumefantrine or dihydroartemisinin-piperaquine, are the first-line treatment for uncomplicated P. falciparum malaria, while intravenous artesunate is mandatory for severe malaria. 1, 2

Uncomplicated P. falciparum Malaria

First-Line Treatment: Artemether-Lumefantrine (AL)

• Administer artemether-lumefantrine as 4 tablets at 0 hours, 4 tablets at 8 hours on day 1, then 4 tablets twice daily on days 2 and 3. 1, 2
• AL must be taken with a fatty meal or drink to ensure adequate absorption—this is critical for therapeutic success. 1, 3
• Cure rates with AL range from 96-100% when properly administered. 3
• Failure to take AL with adequate fat intake is a common pitfall that leads to subtherapeutic drug levels and treatment failure. 1, 3

Alternative First-Line: Dihydroartemisinin-Piperaquine (DP)

• Administer 3 tablets daily for 3 days (36-75 kg) or 4 tablets daily for 3 days (>75 kg). 1, 2
• DP must be taken in a fasting condition, unlike AL. 1, 3
• DP demonstrates superior efficacy compared to AL for P. vivax malaria (HR 2.07 at day 42) and may be preferred in mixed infections. 4

Second-Line Treatment: Atovaquone-Proguanil

• Use atovaquone-proguanil when ACTs are contraindicated (e.g., risk of QTc prolongation) or in patients from Southeast Asia with suspected ACT resistance. 4, 1
• Administer 4 tablets daily for 3 days (>40 kg), taken with a fatty meal. 1
• Efficacy is 98.7% in clinical trials with 100% cure rate in combination therapy. 5

Third-Line Treatment: Quinine-Based Regimens

• Quinine sulfate 750 mg (3 tablets) for 3-7 days plus doxycycline 100 mg twice daily for 7 days, or plus clindamycin 20 mg/kg every 8 hours for 7 days. 1
• Avoid quinine in patients from Southeast Asia due to resistance concerns. 1

Severe P. falciparum Malaria

First-Line: Intravenous Artesunate

• Administer IV artesunate 2.4 mg/kg at 0,12, and 24 hours, then daily until parasite density is <1%. 1, 2
• Once the patient improves clinically and can take oral medication, complete treatment with a full course of oral ACT. 1, 2
• IV artesunate demonstrates faster parasite clearance and shorter ICU stays compared to quinine. 4

Second-Line: Intravenous Quinine

• If IV artesunate is unavailable, use IV quinine 20 mg salt/kg over 4 hours (loading dose), followed by 10 mg/kg over 4 hours every 8 hours. 1

Uncomplicated Non-falciparum Malaria

P. vivax, P. ovale, and P. malariae

• Chloroquine is the drug of choice in chloroquine-sensitive regions: total dose of 25 mg base/kg over 3 days (600 mg, 600 mg, and 300 mg at 0,24, and 48 hours). 4, 2, 3
• For travelers from chloroquine-resistant areas (Papua New Guinea, Indonesia, Sabah where resistance exceeds 10%), use ACTs instead. 4

Preventing Relapse in P. vivax and P. ovale

• Following blood schizontocidal treatment, administer primaquine or tafenoquine to eliminate liver hypnozoites and prevent relapse. 4, 2
• Test for G6PD deficiency before administering 8-aminoquinolines—this is mandatory to prevent hemolysis. 4, 2
• For mild to moderate G6PD deficiency (30-70% activity), use primaquine 45 mg once weekly for 8 weeks. 4
• Primaquine reduces relapse risk by 80% in P. vivax malaria. 4
• Both primaquine and tafenoquine are contraindicated during pregnancy. 4

Special Populations

Pregnancy

• AL can be used in all trimesters of pregnancy as endorsed by WHO and CDC. 4, 1, 2
• This recommendation is based on systematic review and individual data meta-analysis. 4

Patients with Vomiting or Diarrhea

• If vomiting occurs within 1 hour of dosing, repeat the dose immediately. 5
• Consider antiemetic use, though avoid metoclopramide as it reduces atovaquone bioavailability. 5
• In severe or persistent diarrhea/vomiting, alternative antimalarial therapy may be required as absorption is compromised. 5

Critical Safety Monitoring

Post-Artemisinin Delayed Hemolysis (PADH)

• Monitor for PADH on days 7,14,21, and 28 after treatment, particularly in patients treated for severe malaria. 1, 3
• PADH occurs in 1.9-37.4% of patients depending on diagnostic criteria used. 4

QTc Prolongation

• Both AL and DP can cause QTc interval prolongation—avoid in patients at risk or taking QTc-prolonging medications. 1, 2, 3

Drug Interactions

• Tetracycline reduces atovaquone levels by 40%—monitor parasitemia closely if co-administered. 5
• Rifampin and rifabutin reduce atovaquone levels by 50% and 34% respectively—concomitant use is not recommended. 5
• Proguanil potentiates warfarin—closely monitor coagulation tests when used together. 5

Common Pitfalls to Avoid

• Delayed diagnosis and treatment of P. falciparum malaria significantly increases mortality. 1, 2, 3
• Atovaquone-proguanil has not been evaluated for cerebral malaria or severe manifestations—patients with severe malaria are not candidates for oral therapy. 5
• Parasite relapse occurs commonly when P. vivax is treated with ACTs alone without primaquine for radical cure. 5
• In treatment failures or recrudescence after ACTs, use a different blood schizonticide class. 4, 5