What are the recommended treatment guidelines for uncomplicated and severe Plasmodium falciparum malaria in an otherwise healthy non‑pregnant adult, including recommendations for pregnancy (first trimester versus later trimesters), children, and second‑line therapy options?

Malaria Treatment Guidelines

First-Line Treatment for Uncomplicated P. falciparum Malaria in Non-Pregnant Adults

Artemether-lumefantrine (AL) is the WHO-endorsed first-line artemisinin-based combination therapy for uncomplicated P. falciparum malaria, with cure rates of 96-100%. 1

Dosing and Administration

• Artemether-lumefantrine: 4 tablets at hour 0,4 tablets at hour 8 on day 1, then 4 tablets twice daily on days 2 and 3 (total 24 tablets over 72 hours for patients >35 kg). 1
• Critical administration requirement: AL must be taken with a fatty meal or drink to achieve adequate absorption; failure to do so is the most common cause of treatment failure due to subtherapeutic drug levels. 1
• Alternative first-line option: Dihydroartemisinin-piperaquine (DP) 3 tablets once daily for 3 days (36-75 kg) or 4 tablets once daily for 3 days (>75 kg), taken on an empty stomach (fasting condition). 1

Important Safety Considerations

• Both AL and DP can prolong the QTc interval and should be avoided in patients with baseline QTc prolongation risk or those receiving other QT-prolonging medications. 1
• Post-artemisinin delayed hemolysis (PADH) occurs in 37.4% of patients when strict diagnostic criteria are applied; monitor hemoglobin, haptoglobin, and lactate dehydrogenase on days 7,14,21, and 28 after treatment. 1

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Second-Line Treatment Options

When ACTs are contraindicated (QTc prolongation risk) or for travelers from Southeast Asia with suspected ACT resistance, atovaquone-proguanil is the recommended second-line therapy. 2, 1

• Atovaquone-proguanil dosing: 4 tablets daily for 3 days (patients >40 kg), taken with a fatty meal or drink. 1
• Third-line rescue regimens: Quinine sulfate plus doxycycline (quinine 750 mg three times daily for 3-7 days plus doxycycline 100 mg twice daily for 7 days) or quinine plus clindamycin, reserved for patients who cannot receive first- or second-line agents. 1
• Mefloquine is not recommended for P. falciparum acquired in Southeast Asia due to documented resistance, is contraindicated in patients with neuropsychiatric history, and has been excluded from UK and French national guidelines. 1

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Treatment of Severe P. falciparum Malaria

Intravenous artesunate (2.4 mg/kg) is the WHO-recommended first-line therapy for severe malaria and should be administered as a medical emergency. 1

WHO Criteria Mandating IV Artesunate (Any One Criterion)

• Impaired consciousness (Glasgow Coma Scale <11) or multiple convulsions 1
• Acute respiratory distress syndrome or circulatory shock 1
• Severe anemia (hemoglobin <7 g/dL in non-immune patients) 1
• Clinical jaundice with organ dysfunction 1
• Hypoglycemia (<40 mg/dL) or metabolic acidosis (lactate >5 mmol/L) 1
• Acute kidney injury (serum creatinine >3 mg/dL) 1
• Hyperparasitemia (>4-5% in non-immune patients) 1
• Abnormal bleeding or hemoglobinuria 1

Dosing Protocol

• 2.4 mg/kg IV at 0,12, and 24 hours, then once daily until peripheral parasitemia falls below 1% and the patient can tolerate oral medication. 1
• After clinical improvement, complete treatment with a full oral ACT course (preferably AL or DP). 1

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Treatment in Pregnancy

First Trimester

Women with uncomplicated malaria during the first trimester should be treated with either mefloquine or quinine plus clindamycin as first-line options. 3

• When neither mefloquine nor quinine plus clindamycin is available, artemether-lumefantrine should be considered as an alternative, with cure rates of 98.2%. 3
• Critical principle: Never delay treatment waiting for preferred medications, as untreated malaria causes far greater harm than any theoretical artemisinin risks. 3
• Quinine plus clindamycin: Quinine 750 mg three times daily for 3-7 days plus clindamycin 20 mg/kg every 8 hours for 7 days, though associated with higher rates of tinnitus, dizziness, and vomiting compared to ACTs. 3

Second and Third Trimesters

Artemether-lumefantrine is recommended by WHO and CDC as first-line treatment for uncomplicated malaria in the second and third trimesters, at the same doses used for non-pregnant women, with cure rates ≥94.9%. 4, 3

• AL performs equal to or better than quinine-based regimens, with a pooled risk ratio of treatment failure of 0.41 (95% CI 0.16-1.06) compared to non-ACTs. 4
• Meta-analyses found no association between ACT treatment and congenital malformations or miscarriage in second/third trimester. 1, 3
• AL has superior tolerability compared to quinine, with significantly lower rates of tinnitus, dizziness, and vomiting. 4

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Treatment of Non-Falciparum Malaria

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

Chloroquine is the drug of choice for uncomplicated non-falciparum malaria in chloroquine-sensitive regions, with a total dose of 25 mg base/kg over 3 days (600 mg, 600 mg, and 300 mg at 0,24, and 48 hours). 2, 4

• In chloroquine-resistant regions (Papua New Guinea, Indonesia, Sabah where failure exceeds 10%), ACTs are recommended. 2
• Dihydroartemisinin-piperaquine is superior to chloroquine or AL in preventing P. vivax recurrence over 42 days (RR 0.32,95% CI 0.24-0.43). 1, 5

Radical Cure to Prevent Relapse

Following blood schizontocidal treatment for P. vivax or P. ovale, primaquine or tafenoquine must be administered to eliminate liver hypnozoites and prevent relapse. 1

• Critical safety requirement: Test for G6PD deficiency before administering 8-aminoquinolines to prevent severe hemolysis. 1
• Primaquine reduces the risk of first-time relapse by 80%. 1
• Patients with mild to moderate G6PD deficiency (30-70% activity) can receive primaquine 45 mg once weekly for 8 weeks. 1
• Both primaquine and tafenoquine are absolutely contraindicated during pregnancy. 1, 3

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Pediatric Dosing (Weight-Based)

• Artemether-lumefantrine: 4 tablets per dose for children >35 kg, following the adult schedule (0 h, 8 h, then twice daily on days 2-3), with the same fatty meal requirement. 1
• Dihydroartemisinin-piperaquine: 3 tablets once daily for 3 days for children weighing 36-75 kg (fasting condition). 1
• Atovaquone-proguanil: 3 tablets daily for 3 days for children <40 kg, taken with a fatty meal. 1

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Resistance Considerations and Regional Variations

Artemisinin partial resistance has been documented in Rwanda, Uganda, the Horn of Africa, and the Greater Mekong sub-region, each with distinct K13 mutations; however, overall ACT efficacy remains high in most regions. 1

• In the Greater Mekong sub-region where established ACT resistance exists, atovaquone-proguanil should be used as first-line therapy. 1
• Late treatment failures with AL (13.9% of cases) are often linked to suboptimal dosing in patients with higher body weight, which reduces lumefantrine exposure. 1
• Swiss guidelines recommend extending AL treatment to 5 days (four additional doses) in patients with high body weight or suspected malabsorption. 2

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Critical Pitfalls to Avoid

• Failure to co-administer a fatty meal with AL is the most frequent cause of treatment failure; patients must receive a fatty meal or drink with every dose. 1
• Confusing the feeding requirements of AL (fat) and DP (fasting) compromises drug efficacy; clear patient instructions are essential. 1
• Delays in recognizing severe disease—especially when hyperparasitemia thresholds vary (2-5%)—should prompt immediate IV artesunate treatment. 1
• Baseline ECG assessment and avoidance of concomitant QT-prolonging agents are critical when prescribing AL or DP. 1
• Not testing for G6PD deficiency before administering primaquine or tafenoquine can lead to severe hemolysis. 1