What is the recommended artesunate dosing regimen for severe Plasmodium falciparum malaria, including in children and pregnant women, and what are its adverse effects and alternative treatments?

Artesunate for Severe and Uncomplicated Malaria

Severe Plasmodium falciparum Malaria: Intravenous Artesunate is First-Line

Intravenous artesunate is the WHO-recommended first-line treatment for all forms of severe malaria and must be administered immediately as a medical emergency. 1, 2, 3

Dosing Regimen for Severe Malaria

• Administer 2.4 mg/kg IV at 0,12, and 24 hours, then once daily until parasitemia falls below 1% and the patient can tolerate oral medication. 1, 2, 3, 4
• Do not delay the first dose for any reason—including patient transfer or additional testing—because severe malaria is immediately life-threatening. 3
• After clinical improvement (parasitemia <1%, able to take oral medication), complete treatment with a full 3-day course of oral artemisinin-based combination therapy (ACT), preferably artemether-lumefantrine or dihydroartemisinin-piperaquine. 1, 2, 3, 4

Pediatric Dosing

• The same weight-based dosing applies to children: 2.4 mg/kg IV at 0,12, and 24 hours, then daily. 2, 3

Pregnant Women

• Intravenous artesunate is recommended for severe malaria in the second and third trimesters of pregnancy. 1, 2
• For the first trimester, the benefit-risk assessment favors artesunate in life-threatening severe malaria despite limited safety data. 1

Evidence Supporting Artesunate Over Quinine

• The SEAQUAMAT trial demonstrated a 35% reduction in mortality with artesunate compared to quinine, with the greatest benefit in patients with high parasite counts. 5
• The TropNet severe malaria study showed faster parasite clearance and shorter ICU stays with artesunate versus quinine. 1, 4

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Uncomplicated P. falciparum Malaria: Oral Artemisinin-Based Combination Therapy

Artemether-lumefantrine (AL) is the WHO and CDC first-line oral regimen for uncomplicated P. falciparum malaria in all age groups and all trimesters of pregnancy. 2, 4

Artemether-Lumefantrine Dosing

• Adults and children >35 kg: 4 tablets at 0 hours, 4 tablets at 8 hours on day 1, then 4 tablets twice daily on days 2 and 3 (total 24 tablets over 72 hours). 2, 4
• Critical: Must be taken with a fatty meal or drink (milk, yogurt, or food containing fat) to ensure adequate lumefantrine absorption; failure to do so causes subtherapeutic drug levels and treatment failure. 2, 4

Dihydroartemisinin-Piperaquine as Alternative

• Dosing: 3 tablets once daily for 3 days (patients 36–75 kg) or 4 tablets once daily for 3 days (patients >75 kg). 2, 4
• Must be taken on an empty stomach (fasting condition). 2, 4
• Dihydroartemisinin-piperaquine has a longer post-treatment prophylactic effect and is superior to artemether-lumefantrine in preventing P. vivax recurrence (RR 0.32,95% CI 0.24–0.43). 2

Pregnancy-Specific Recommendations

• Artemether-lumefantrine is safe and recommended for uncomplicated malaria in all trimesters of pregnancy per WHO and CDC guidelines. 1, 2, 4
• Multiple randomized trials and meta-analyses found no association between ACT treatment and congenital malformations or miscarriage in the second and third trimesters. 1
• Cure rates with artemether-lumefantrine in pregnant women are 99.3% (95% CI 96.0–99.9). 1

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Second-Line and Alternative Treatments

Atovaquone-Proguanil

• Recommended when ACTs are contraindicated (e.g., baseline QTc prolongation) or for travelers from Southeast Asia with suspected ACT resistance. 2, 4
• Dosing: 4 tablets daily for 3 days (patients >40 kg), taken with a fatty meal or drink. 2, 4

Quinine-Based Regimens (Third-Line)

• Quinine sulfate 750 mg three times daily 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. 2, 4
• Quinine has inferior tolerability with high rates of cinchonism (tinnitus, dizziness, vomiting), hypoglycemia, and thrombocytopenia. 4
• Quinine is not recommended for P. falciparum acquired in Southeast Asia due to documented resistance. 2, 4

Intravenous Quinine (If Artesunate Unavailable)

• Loading dose: 20 mg salt/kg over 4 hours, followed by 10 mg/kg over 4 hours starting 8 hours after initiation, then every 8 hours. 4
• Switch to oral therapy after at least 48 hours of IV treatment once the patient can tolerate oral intake. 4

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Monitoring During and After Treatment

Parasitemia Monitoring

• Check peripheral blood smears every 12 hours until parasitemia declines to <1%, then every 24 hours until negative. 1, 3, 4
• An initial increase in parasite density within the first 24 hours does not indicate treatment failure. 1, 3

Post-Artesunate Delayed Hemolysis (PADH)

• Monitor hemoglobin, haptoglobin, and lactate dehydrogenase on days 7,14,21, and 28 after IV artesunate treatment. 1, 2, 3, 4
• PADH occurs in 10–15% of patients (up to 37% with strict diagnostic criteria). 2, 3

Supportive Care in Severe Malaria

• Use restrictive fluid management to avoid pulmonary or cerebral edema without worsening kidney function. 1, 3, 4
• Acetaminophen 1 g every 6 hours for 72 hours may provide reno-protective benefit in acute kidney injury. 1, 3
• Start antibiotics only if bacterial co-infection is suspected; continue only if blood cultures are positive. 1, 3
• Exchange blood transfusion is not indicated and does not improve outcomes. 1, 3, 4

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Adverse Effects and Safety Considerations

QTc Prolongation

• Both artemether-lumefantrine and dihydroartemisinin-piperaquine can prolong the QTc interval; avoid in patients with baseline QTc prolongation risk or those taking other QT-prolonging medications. 2, 4
• Baseline ECG screening is advised in high-risk individuals. 2

Common Adverse Events

• Artesunate is generally well tolerated; adverse events are often difficult to distinguish from malaria symptoms. 5, 6
• Drug-induced vomiting occurs in approximately 2% of patients treated with artemether-lumefantrine. 7
• Headache, dizziness, and abdominal discomfort are reported but mild. 8

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Critical Pitfalls to Avoid

• Failure to administer artemether-lumefantrine with a fatty meal is the most common cause of treatment failure due to inadequate lumefantrine absorption. 2, 4
• Do not confuse the feeding requirements: artemether-lumefantrine requires fat, dihydroartemisinin-piperaquine requires fasting. 2
• Do not stop IV artesunate after only three doses if the patient cannot yet tolerate oral intake; continue once-daily IV dosing until oral tolerance and parasitemia <1% are achieved. 3
• Do not shorten the oral ACT regimen after IV artesunate; a complete 3-day course is mandatory. 3
• Delayed diagnosis and treatment of severe malaria significantly increases mortality; any WHO severe-malaria criterion mandates immediate IV artesunate. 2, 3, 4
• Do not delay PADH monitoring; systematic surveillance up to 28 days post-treatment is required. 3

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Resistance Considerations

• Artemisinin partial resistance with K13 mutations has been documented in Rwanda, Uganda, the Horn of Africa, and the Greater Mekong sub-region, but overall ACT efficacy remains high in most endemic areas. 2
• In Southeast Asia with established ACT resistance, atovaquone-proguanil is recommended as first-line therapy. 2