Treatment of Plasmodium falciparum Malaria
Uncomplicated P. falciparum Malaria
For uncomplicated P. falciparum malaria, treat with oral artemisinin-based combination therapy (ACT), specifically artemether-lumefantrine or dihydroartemisinin-piperaquine, as first-line therapy. 1, 2, 3
First-Line Treatment Options
Artemether-lumefantrine (AL): Administer 4 tablets at 0 hours, 4 tablets at 8 hours on day 1, then 4 tablets twice daily on days 2 and 3 (total 6 doses over 3 days). 1, 2, 3
Dihydroartemisinin-piperaquine (DP): Administer 3 tablets daily for 3 days (for adults 36-75 kg) or 4 tablets daily for 3 days (for adults >75 kg). 1, 2, 3
Second-Line Treatment Options
Atovaquone-proguanil: Use when ACTs are contraindicated or in patients from Southeast Asia with suspected ACT resistance. 2, 3
- Dosing: 4 tablets daily for 3 days (for adults >40 kg), taken with a fatty meal. 3
Quinine sulfate plus doxycycline or clindamycin: Alternative regimen when ACTs are unavailable or contraindicated. 2, 3, 4
- Quinine: 648 mg (two capsules) every 8 hours for 7 days, taken with food. 4
- Plus doxycycline 100 mg twice daily for 7 days, or clindamycin 20 mg/kg every 8 hours for 7 days. 3
- Major caveat: Quinine should NOT be used for P. falciparum acquired in Southeast Asia due to resistance concerns. 3
- Serious adverse effects: Cinchonism, hypoglycemia, thrombocytopenia, HUS/TTP, and QT prolongation. 4
Severe P. falciparum Malaria
For severe P. falciparum malaria, immediately administer intravenous artesunate as a medical emergency—this is the only appropriate first-line treatment. 1, 2, 3
Criteria for Severe Malaria
Severe malaria is defined by any of the following criteria (note that parasitemia thresholds vary by guideline from 2-5% for non-immune patients): 1
- Neurological: Unarousable coma, multiple convulsions (>2 in 24 hours), prostration
- Cardiovascular/Respiratory: Shock (SBP <80 mmHg), pulmonary edema, ARDS (PaO2 <60 mmHg or SpO2 <92%)
- Renal: Creatinine >3 mg/dL or urine output <400 mL/24 hours
- Hematologic: Severe anemia (hemoglobin <7 g/dL with parasitemia >10,000/mL)
- Metabolic: Hypoglycemia (<40 mg/dL), acidosis (lactate >5 mmol/L)
- Hepatic: Jaundice (bilirubin >3 mg/dL with parasitemia >100,000/mL)
- Parasitemia: >2-5% depending on guideline (>2% for non-endemic travelers per most European guidelines, >5% per WHO for non-immune patients) 1
Treatment Protocol for Severe Malaria
Intravenous artesunate: 2.4 mg/kg IV at 0,12, and 24 hours, then daily until parasitemia is <1%. 1, 2, 3
If IV artesunate is unavailable: Use IV quinine as second-line therapy. 3
- Loading dose: 20 mg salt/kg over 4 hours
- Maintenance: 10 mg/kg over 4 hours every 8 hours, starting 8 hours after initiation of loading dose. 3
Monitoring Requirements
- Check parasitemia every 12 hours until decline to <1%, then every 24 hours until negative. 1
- Daily monitoring: Complete blood count, hepatic function, renal function, glucose, and blood gas analysis. 1
- Post-artemisinin delayed hemolysis (PADH): Monitor on days 7,14,21, and 28 after treatment—occurs in 37.4% of patients using strict definitions. 2, 3
Special Populations
Pregnancy
- Artemether-lumefantrine is safe in all trimesters of pregnancy and is recommended by WHO and CDC. 2, 3
- Multiple trials found no association between ACT treatment and congenital malformations or miscarriage in second/third trimester. 2
Renal Impairment
- For severe chronic renal impairment: One loading dose of 648 mg quinine followed 12 hours later by maintenance doses of 324 mg every 12 hours. 4
Hepatic Impairment
- No dose adjustment needed for mild-moderate hepatic impairment (Child-Pugh A-B), but monitor closely. 4
- Quinine contraindicated in severe hepatic impairment (Child-Pugh C). 4
Critical Warnings and Contraindications
QTc Prolongation
- Both artemether-lumefantrine and dihydroartemisinin-piperaquine can cause QTc interval prolongation. 2, 3
- Avoid in patients at risk for QTc prolongation or taking medications that prolong QTc. 2, 3
- Quinine is contraindicated in patients with prolonged QT interval—one fatal ventricular arrhythmia was reported. 4
Quinine-Specific Contraindications
- Absolute contraindications: Prolonged QT interval, myasthenia gravis, optic neuritis, known hypersensitivity (including history of thrombocytopenia, ITP, TTP, HUS, or blackwater fever). 4
- NOT approved for: Treatment or prevention of nocturnal leg cramps due to serious hematologic reactions including thrombocytopenia and HUS/TTP. 4
- Avoid in patients with neuropsychiatric disorders. 3
Common Pitfalls to Avoid
- Delayed diagnosis kills: P. falciparum malaria is frequently overlooked in non-endemic settings, and delayed diagnosis significantly increases mortality. 1, 2
- Fat requirement with artemether-lumefantrine: Failure to ensure adequate fat intake results in subtherapeutic levels and treatment failure. 2, 3
- Underestimating parasitemia: Different guidelines use thresholds between 2% and 5% to define severe malaria—err on the side of caution and treat as severe if parasitemia is >2% in non-immune travelers. 1, 2
- Geographic resistance patterns: Do not use quinine for P. falciparum acquired in Southeast Asia due to resistance. 3
- Fasting vs. fed state: Artemether-lumefantrine requires fatty food; dihydroartemisinin-piperaquine requires fasting—mixing these up compromises efficacy. 2, 3