What are the recommended artesunate dosing regimens for severe and uncomplicated acute malaria in adults, children, and pregnant women, and what are the alternative parenteral treatments if artesunate is unavailable?

Artesunate Dosing for Acute Malaria

Severe Malaria – Intravenous Artesunate

Intravenous artesunate at 2.4 mg/kg body weight is the first-line treatment for severe malaria and must be administered immediately as a medical emergency at 0,12, and 24 hours, then continued daily until the patient can tolerate oral medication and parasitemia falls below 1%. 1, 2

Dosing Schedule for Severe Disease

• Initial three doses: 2.4 mg/kg IV at 0 hours, 12 hours, and 24 hours 1, 2
• Subsequent doses: 2.4 mg/kg IV once daily after the first 24 hours until all stopping criteria are met 1
• Minimum treatment: At least three IV doses must be given before switching to oral therapy, even if the patient appears improved 1

Criteria for Switching to Oral Therapy

Do not discontinue IV artesunate until ALL of the following are met: 1

• Patient is hemodynamically stable and conscious
• Able to tolerate oral intake
• Peripheral parasitemia has declined to <1% of red blood cells

Completion of Treatment

• After meeting stopping criteria, immediately begin a full 3-day course of oral artemisinin-based combination therapy (ACT) 1, 2
• Preferred oral options: artemether-lumefantrine or dihydroartemisinin-piperaquine 1, 2
• The oral ACT course is mandatory for the complete three days regardless of how many IV artesunate days were administered 1

Alternative Parenteral Treatment When Artesunate Unavailable

If IV artesunate is unavailable, use intravenous quinine dihydrochloride as second-line therapy: 1

• Loading dose: 20 mg salt/kg over 4 hours
• Maintenance: 10 mg/kg over 4 hours starting 8 hours after initiation, then every 8 hours
• Switch to oral therapy only after completing at least 48 hours of IV treatment 1

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Uncomplicated Malaria – Oral Artemisinin-Based Combination Therapy

Artemether-lumefantrine is the WHO-endorsed first-line regimen for uncomplicated P. falciparum malaria and is safe in all trimesters of pregnancy. 3, 2

Artemether-Lumefantrine (AL) Dosing

For adults and children >35 kg: 2

• 4 tablets at hour 0
• 4 tablets at hour 8 on day 1
• 4 tablets twice daily on days 2 and 3 (total 24 tablets over 72 hours)
• Critical requirement: Must be taken with a fatty meal or drink to achieve adequate absorption; omission leads to subtherapeutic levels and treatment failure 2

Extended regimen consideration: Swiss guidelines recommend extending AL treatment from 3 to 5 days in patients with high body weight or suspected malabsorption to prevent treatment failure 4

Dihydroartemisinin-Piperaquine (DP) Dosing

Alternative first-line option with longer post-treatment prophylactic effect: 2

• For patients 36-75 kg: 3 tablets once daily for 3 days
• For patients >75 kg: 4 tablets once daily for 3 days
• Must be taken on an empty stomach (fasting condition) 2
• Superior to AL in preventing P. vivax recurrence (RR 0.32,95% CI 0.24-0.43) 2

Second-Line Therapy When ACTs Contraindicated

Atovaquone-proguanil is recommended for patients with contraindications to ACTs (e.g., QT prolongation risk) or travelers from Southeast Asia with suspected ACT resistance: 4, 2

• Dosing: 4 tablets daily for 3 days (patients >40 kg)
• Must be taken with a fatty meal or drink 2

Third-Line/Rescue Regimens

Quinine-based combinations are reserved for patients who cannot receive first- or second-line agents: 4, 2

• Quinine sulfate plus doxycycline: quinine 750 mg three times daily for 3-7 days plus doxycycline 100 mg twice daily for 7 days 2
• Quinine sulfate plus clindamycin: quinine 750 mg three times daily for 3-7 days plus clindamycin 20 mg/kg every 8 hours for 7 days 4, 2
• These regimens have inferior tolerability with higher rates of tinnitus, dizziness, and vomiting 2

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Special Populations

Pregnant Women

Artemether-lumefantrine is recommended for uncomplicated P. falciparum malaria in all trimesters of pregnancy per WHO and CDC guidelines. 3, 2

• Multiple trials found no association between ACT treatment and congenital malformations or miscarriage in second/third trimester 2
• For severe malaria, IV artesunate remains the treatment of choice 1

Children

Weight-based dosing for children: 2

• Artemether-lumefantrine: 4 tablets per dose for children >35 kg, following adult schedule (same fat-meal requirement applies)
• Dihydroartemisinin-piperaquine: 3 tablets once daily for 3 days for children 36-75 kg (fasting condition)
• IV artesunate for severe malaria: 2.4 mg/kg at 0,12,24 hours, then daily (same as adults) 5

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Critical Monitoring Requirements

During Treatment

Parasitemia monitoring: 1

• Check peripheral blood smears every 12 hours until parasite density falls below 1%
• After reaching <1%, check every 24 hours until negative
• An initial rise in parasite density during the first 24 hours does not constitute treatment failure 1

Laboratory monitoring: 1

• Complete blood count, liver function tests, renal function tests, and serum lactate measured daily

Post-Treatment Surveillance

Post-artesunate delayed hemolysis (PADH) monitoring is mandatory: 1, 4

• Check hemoglobin, haptoglobin, and lactate dehydrogenase on days 7,14,21, and 28 after completion of IV artesunate
• PADH occurs in 10-15% of patients treated with IV artesunate (up to 37.4% using strict definitions) 3, 1

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Common Pitfalls to Avoid

Failure to co-administer fatty meals with artemether-lumefantrine is the most frequent cause of treatment failure – patients must receive a fatty meal or drink with every AL dose 2

Confusing feeding requirements: AL requires fat, DP requires fasting – mixing these compromises drug efficacy 2

Premature discontinuation of IV artesunate: Do not stop after only three doses if the patient cannot yet tolerate oral intake or if parasitemia remains ≥1%; continue once-daily IV dosing until all criteria are met 1

Shortening the oral ACT regimen: A complete 3-day course is mandatory after IV artesunate cessation, regardless of how many IV days were given 1

Delaying PADH monitoring: This complication can arise up to four weeks post-treatment and requires systematic surveillance 1, 4

Both AL and DP can prolong the QTc interval – assess baseline QTc and avoid co-administration with other QT-prolonging agents 2

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Resistance Considerations

Artemisinin partial resistance has been documented in Rwanda, Uganda, the Horn of Africa, and the Greater Mekong sub-region with distinct K13 mutations, though overall ACT efficacy remains high in most regions 3, 2

For patients from Southeast Asia (especially Greater Mekong sub-region): Consider atovaquone-proguanil as first-line therapy due to high levels of ACT resistance 3, 4

Late treatment failures occur in 13.9% of cases with artemether-lumefantrine – inadequate dosing related to body weight can affect therapeutic concentrations, particularly with lumefantrine 4