How should Plasmodium falciparum malaria be treated in adults (uncomplicated and severe), children, and pregnant women?

Treatment of Plasmodium falciparum Malaria

Uncomplicated P. falciparum Malaria in Adults

Treat uncomplicated P. falciparum malaria with artemisinin-based combination therapy (ACT), specifically artemether-lumefantrine or dihydroartemisinin-piperaquine as first-line options. 1, 2

First-Line Treatment Options

Artemether-lumefantrine (AL):

• Dosing: 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, 2
• Critical requirement: Must be taken with a fatty meal or drink to ensure adequate absorption—failure to do so leads to subtherapeutic drug levels and treatment failure 1, 2, 3
• Cure rates: 96-100% 2, 3
• Can be used in all trimesters of pregnancy per WHO and CDC 1, 2, 3

Dihydroartemisinin-piperaquine (DP):

• Dosing: 3 tablets daily for 3 days (36-75 kg) or 4 tablets daily for 3 days (>75 kg) 1, 2
• Must be taken in fasting condition 1, 3
• Superior to artemether-lumefantrine in preventing P. vivax recurrence (RR 0.32,95% CI 0.24-0.43) 2, 4
• Longer half-life provides additional benefit in areas where P. vivax co-exists 2, 4

Important caveat: Both AL and DP can cause QTc interval prolongation and should be avoided in patients at risk of QTc prolongation or taking medications that prolong QTc 1, 2, 3

Second-Line Treatment

Atovaquone-proguanil:

• Dosing: 4 tablets daily for 3 days (>40 kg) 1, 3
• Must be taken with a fatty meal or drink 1
• Use when ACTs are contraindicated or in patients from Southeast Asia with suspected ACT resistance 1, 2
• Relatively slower-acting regimen compared to ACTs 1

Third-Line Options

Quinine sulfate plus doxycycline or clindamycin:

• Reserved for patients with contraindications to first and second-line drugs 1, 2
• Inferior tolerability with higher rates of tinnitus, dizziness, and vomiting 3

Mefloquine:

• Not to be used against P. falciparum acquired in Southeast Asia 1
• Contraindicated in patients with neuropsychiatric history 1
• Not considered a treatment option in UK and French guidelines 1

Severe P. falciparum Malaria in Adults

Treat severe malaria immediately with intravenous artesunate as a medical emergency. 2, 3

Treatment Protocol

• Dosing: 2.4 mg/kg IV at 0,12, and 24 hours, then daily until parasitemia <1% 2, 3
• Monitoring: Check parasitemia every 12 hours until <1%, then every 24 hours until negative 3
• Transition to oral therapy: Once patient improves clinically (parasitemia <1%) and can take oral medications, complete treatment with a full course of oral ACT (artemether-lumefantrine or dihydroartemisinin-piperaquine) 2, 3
• Post-treatment surveillance: Monitor for post-artemisinin delayed hemolysis (PADH) on days 7,14,21, and 28 after treatment, as it occurs in 37.4% of patients 2, 3

Criteria for Severe Malaria

Severe malaria is defined by the presence of any of the following: impaired consciousness, prostration, multiple convulsions, acute respiratory distress syndrome, circulatory shock, acute kidney injury, clinical jaundice plus evidence of vital organ dysfunction, abnormal bleeding, hemoglobinuria, severe anemia (in non-immune subjects), serum creatinine >3 mg/dL, and hyperparasitemia 1

Controversial threshold: Parasitemia thresholds vary between 2-5% across different guidelines; hyperparasitemia >4% was the most frequent criterion for ICU admission in European studies 1

Treatment in Children

Use the same ACT regimens as adults, with weight-based dosing adjustments. 1, 2

• Artemether-lumefantrine: 4 tablets per dose for children >35 kg, following the same schedule as adults 1
• Dihydroartemisinin-piperaquine: 3 tablets daily for 3 days for children 36-75 kg 1
• Atovaquone-proguanil: 3 tablets daily for 3 days for children <40 kg 1

Treatment in Pregnant Women

Artemether-lumefantrine is the recommended treatment for uncomplicated P. falciparum malaria in all trimesters of pregnancy. 1, 2, 3

Evidence Supporting Use in Pregnancy

• Cure rates in third trimester: 94.9-100% 3
• Performs equal to or better than quinine-based regimens (pooled RR of treatment failure 0.41,95% CI 0.16-1.06) 3
• Multiple trials and meta-analyses found no association between ACT treatment and congenital malformations, miscarriage, stillbirth, preterm birth, or low birth weight in second/third trimester 2, 3
• Superior tolerability compared to quinine 3
• CDC formally updated recommendations in 2018 to include artemether-lumefantrine for second and third trimesters 3

First Trimester Considerations

There remains uncertainty over the safety of artemisinin derivatives in the first trimester; they should not be used unless there are no effective alternatives 5

Contraindications in Pregnancy

Primaquine and tafenoquine are absolutely contraindicated during pregnancy and breastfeeding due to risk of hemolysis. 6, 2

Adjunctive Therapy: Primaquine for Transmission Reduction

Add a single low dose of primaquine (0.25 mg/kg) to ACT treatment to reduce transmission of P. falciparum. 6

Key Points About Primaquine Use

• Always combine with appropriate ACT; never use as monotherapy 6
• Significantly lower dose than the 14-day regimen (0.5 mg/kg/day) used for P. vivax/P. ovale radical cure 6
• G6PD testing must be performed before administration due to risk of hemolysis in G6PD-deficient individuals 6, 2
• For severe malaria, consider primaquine only after patient improves and can take oral medications 6
• Coadministration with chloroquine boosts primaquine blood levels 6

Critical Pitfalls to Avoid

• Delayed diagnosis and treatment significantly increases mortality 2, 3
• Failure to ensure adequate fat intake with artemether-lumefantrine results in subtherapeutic drug levels and treatment failure 2, 3
• Not testing for G6PD deficiency before administering primaquine can lead to severe hemolysis 6, 2
• Underestimating parasitemia levels can lead to incorrect classification of disease severity 1
• Ignoring QTc prolongation risk with ACTs in susceptible patients 1, 2, 3

Emerging Resistance Concerns

Artemisinin partial resistance has emerged in Rwanda, Uganda, and the Horn of Africa, with independent emergences of different K13 mutants in each region 7. However, current evidence suggests that the efficacies of leading ACTs remain excellent in most areas 7. The Greater Mekong sub-region has established ACT resistance, requiring alternative treatment strategies 1.