What is the recommended treatment for uncomplicated Plasmodium falciparum malaria in patients weighing ≥35 kg, and what are the options for severe falciparum malaria?

Treatment of Uncomplicated Plasmodium falciparum Malaria

For patients weighing ≥35 kg with uncomplicated P. falciparum malaria, artemether-lumefantrine (AL) is the WHO-endorsed first-line treatment: 4 tablets at hour 0,4 tablets at hour 8 on day 1, then 4 tablets twice daily on days 2–3, and must be taken with a fatty meal or drink to achieve therapeutic drug levels. 1

First-Line Artemisinin-Based Combination Therapy (ACT)

Artemether-Lumefantrine (AL)

• AL is recommended by WHO, CDC, and multiple guideline societies as first-line therapy for uncomplicated P. falciparum malaria in all age groups and all trimesters of pregnancy. 2, 1
• Dosing regimen: 4 tablets at time 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, 3
• Critical administration requirement: AL must be taken with a fatty meal or drink (milk, yogurt, or food containing at least 1.2 g fat). Failure to co-administer fat is the most common cause of treatment failure, resulting in subtherapeutic lumefantrine levels. 1, 3
• Efficacy: Cure rates of 96–100% in most settings, with PCR-adjusted failure rates <10%. 1, 4
• Adverse effects: Headache, vertigo, digestive disorders; can prolong QTc interval. 5

Dihydroartemisinin-Piperaquine (DP)

• DP is an alternative WHO-endorsed first-line ACT, preferred when longer post-treatment prophylactic effect is desired. 1
• Dosing regimen: 3 tablets once daily for 3 days (patients 36–75 kg) or 4 tablets once daily for 3 days (patients >75 kg). 1, 5
• Critical administration requirement: DP must be taken on an empty stomach (fasting condition)—the opposite of AL. 1, 5
• Efficacy: DP demonstrates superior efficacy compared to AL in preventing P. vivax recurrence over 42 days (RR 0.32,95% CI 0.24–0.43) and may offer better protection against reinfection. 1, 4
• Adverse effects: Similar to AL; can prolong QTc interval. 1, 5

QTc Prolongation Risk

• 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, 5, 3
• Baseline ECG screening is advised in high-risk individuals. 1

Second-Line Therapy

Atovaquone-Proguanil

• Atovaquone-proguanil is recommended by WHO as second-line therapy when ACTs are contraindicated or for travelers from Southeast Asia with suspected ACT resistance. 1, 5
• Dosing: 4 tablets daily for 3 days (patients >40 kg), taken with a fatty meal or drink. 1, 5
• Slower-acting than ACTs but well-tolerated. 1

Third-Line/Rescue Regimens

Quinine-Based Combinations

• Quinine sulfate combined with doxycycline or clindamycin is reserved for patients who cannot receive first- or second-line agents. 1
• Quinine + doxycycline: Quinine 750 mg three times daily for 3–7 days plus doxycycline 100 mg twice daily for 7 days. 1, 5
• Quinine + clindamycin: Quinine 750 mg three times daily for 3–7 days plus clindamycin 20 mg/kg every 8 hours for 7 days. 1
• These regimens have inferior tolerability with high rates of cinchonism (tinnitus, dizziness), hypoglycemia, and gastrointestinal side effects. 1

Mefloquine

• 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 malaria guidelines. 1

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. 2, 1

Diagnostic Criteria for Severe Malaria

Any of the following WHO criteria mandate immediate IV artesunate: 2, 1

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

IV Artesunate Dosing

• 2.4 mg/kg IV at 0,12, and 24 hours, then daily until parasite density falls below 1% and the patient can tolerate oral medication. 2, 1
• After clinical improvement, complete treatment with a full oral ACT course (preferably AL or DP). 2, 1

Post-Artesunate Monitoring

• Monitor for post-artesunate delayed hemolysis (PADH) on days 7,14,21, and 28 after treatment, which occurs in 10–37% of patients depending on diagnostic criteria used. 1, 3
• Check hemoglobin, haptoglobin, and lactate dehydrogenase during the first four weeks. 1

Special Populations

Pregnancy

• AL is safe for use in all trimesters of pregnancy according to WHO and CDC guidelines, with cure rates of 94.9–100% and no increased risk of congenital malformations or miscarriage. 1, 3
• Multiple trials and meta-analyses confirm safety in second and third trimesters. 1

Pediatric Dosing

• Same weight-based dosing as adults: 4 tablets per dose for children >35 kg, following the adult AL schedule with the same fat-meal requirement. 1
• DP: 3 tablets once daily for 3 days for children 36–75 kg (fasting condition). 1

Resistance Considerations

• Artemisinin partial resistance has been documented in the Greater Mekong sub-region, Rwanda, Uganda, and the Horn of Africa, each with distinct K13 mutations; however, overall ACT efficacy remains high in most regions. 1
• In areas with documented ACT resistance, WHO advisory groups recommend alternative treatment strategies guided by regional resistance data. 1
• Late treatment failures with AL have been reported in 13.9% of cases, often linked to suboptimal dosing in patients with higher body weight. 1

Common Pitfalls to Avoid

• Failure to co-administer a fatty meal with AL is the most frequent cause of treatment failure in clinical practice. Patients must receive explicit instructions to take every AL dose with fatty food or drink. 1, 3
• Confusing the feeding requirements of AL (requires fat) and DP (requires fasting) compromises drug efficacy. Clear patient instructions are essential. 1
• Delays in recognizing severe disease—especially when hyperparasitemia thresholds vary (2–5%)—can increase mortality. Any WHO criterion for severe malaria should prompt immediate IV artesunate treatment. 2, 1
• Not testing for baseline QTc prolongation or failing to avoid concomitant QT-prolonging agents when prescribing AL or DP can lead to cardiac complications. 1, 5
• Underestimating the importance of supervised first doses: For outpatient treatment, at minimum the first dose should be directly observed to ensure proper administration with food (for AL) and to monitor for immediate adverse reactions. 2