Malaria Site: Combinations Of Antimalarial Drugs

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Combinations of Antimalarial Drugs

Early and effective chemotherapy for malaria has a pivotal role in reducing morbidity and mortality especially since a vaccine is unlikely to emerge within the next decade. Multidrug resistance has been reported from most parts of the world and as a result, monotherapy or some of the available combination chemotherapies for malaria are either ineffective or less effective. New antimalarial regimens are, therefore, urgently needed and antimalarial combination chemotherapy is widely advocated. Antimalarial combinations can increase efficacy, shorten duration of treatment (and hence increase compliance), and decrease the risk of resistant parasites arising through mutation during therapy.

Combination therapy with antimalarial drugs is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and different biochemical targets in the parasite. The concept of combination therapy is based on the synergistic or additive potential of two or more drugs, to improve therapeutic efficacy and also delay the development of resistance to the individual components of the combination.

Artemisinin based combinations are known to improve cure rates, reduce the development of resistance and they might decrease transmission of drug-resistant parasites. The total effect of artemisinin combinations (which can be simultaneous or sequential) is to reduce the chance of parasite recrudescence, reduce the within-patient selection pressure, and prevent transmission.

Antimalarial Drug Combinations
Artemisinin based combinations
Artesunate + Chloroquine
Efficacy		Very high chloroquine failure rates (>60%) and sub-optimal efficacy of the combination (<85% cure rate)
Status		Not approved; Not a viable option in areas with pre-existing moderate to high levels of P. falciparum resistance to Chloroquine
Artesunate + Amodiaquine
Efficacy and advantages	Better efficacy than amodiaquine alone (cure rate >90%); Well tolerated
Disadvantages	?Neutropenia; Pharmacokinetic mismatch
Dose	Artesunate 4mg/kg and amodiaquine 10mg base/ kg once a day 3 days
Status	Approved
Artesunate + Mefloquine
Efficacy and advantages	In use for many years and the first-line treatment in several parts of SE Asia
Disadvantages	Pharmacokinetic mismatch; Mefloquine induced neuropsychiatric effects, cardiotoxic effects, incidents of vomiting in children; but combination with artesunate results in less adverse reactions than the use of mefloquine alone
Dose	Artesunate (4mg/kg once daily) for 3 days + mefloquine (25mg base/kg) as a split dose of 15mg/kg on Day 2 and 10mg/kg on Day 3. (Alternatively 8mg/kg mefloquine daily for three days)
Status	Not approved; Not considered a viable option as first-line therapy in Africa
Artesunate + Sulfadoxine/Pyrimethamine (SP)
Efficacy and advantages	Well tolerated; Efficacy dependent on the level of pre-existing resistance to SP
Disadvantages	Pharmacokinetic mismatch; adverse effects to SP
Dose	Artesunate 4mg/kg once daily for 3 days and SP single dose of 25mg/kg and 1.25mg/kg respectively
Status	Approved (in areas where SP efficacy is high); Resistance to SP limits the use
Artemether + Lumefantrine (Coartem,^TM Riamet^TM)
Efficacy and advantages	As effective, and better tolerated, as artesunate plus mefloquine; No serious adverse reactions documented
Disadvantages	?Irreversible hearing impairment
Dose	Artemether 1.5mg/kg and Lumifantrine 9mg/kg at 0, 8, 24, 36, 48 and 60 hours
Status	Approved; Not recommended for use in pregnancy and lactating women
Chlorproguanil + Dapsone + Artesunate (Dacart^TM)
Status	Withdrawn at development stage by GSK for fears of hemolytic anemia in G6PD deficiency [See Press Release, News Report, Another Report]
Nosten F, White NJ. Artemisinin-Based Combination Treatment of Falciparum Malaria. Am. J. Trop. Med. Hyg., 77(Suppl 6), 2007, pp. 181�192 Full Text Bosman A, Mendis KN. A Major Transition in Malaria Treatment: The Adoption and Deployment of Artemisinin-Based Combination Therapies. Am. J. Trop. Med. Hyg., 77(Suppl 6), 2007, pp. 193�197. Full Text

Non-Artemisinin based Combinations
Sulfadoxine-pyrimethamine based combinations
Sulfadoxine-pyrimethamine (SP)
Efficacy and advantages	Single dose; Cheap
Disadvantages	Drug resistance; Serious adverse effects
Dose	Sulfadoxine 25mg/kg and Pyrimethamine 1.25mg/kg as single dose
Status	Not approved; Considered as single drug
SP + Chloroquine
Advantages	Cheap; Similar pharmacokinetic profiles, with varied modes of action on different biochemical targets in the parasite
Disadvantages	Drug resistance; Serious adverse effects to SP
Dose	Chloroquine 25mg/kg over 3 days; SP single dose as above
Status	Not approved; an be used where resistance to SP is not a problem
SP + Amodiaquine
Advantages	Similar pharmacokinetic profiles
Disadvantages	Adverse effects of amodiaquine and SP
Dose	Amodiaquine 10mg/kg daily for 3 days; SP single dose as above
Status	Approved (In areas where efficacy of both amodiaquine and SP remain high - countries in West Africa)
SP + Quinine
Advantages	Effective where resistance to SP is not a problem
Disadvantages	Drug resistance; Serious adverse effects
Dose	Quinine 15mg/kg 12 hourly for 3 days; SP single dose as above
Status	Not approved
SP + Mefloquin (Fansimef^TM)
Advantages	Fixed dose pill, single dose
Disadvantages	Not an additive or synergistic combination; Each drug has a different pharmacokinetic profile; Expensive; Resistance known
Dose	Mefloquine 15mg/kg and SP as above single dose
Status	Not approved; Not recommended for general use since 1990
Atovaquone + Proguanil (Malarone^TM)
Advantages	Synergistic activity; Good safety and tolerability in children and adults
Disadvantages	High cost; Restricted availability; Contra-indicated in case of hypersensitivity or renal insufficiency
Dose	Atovaquone 20mg/kg and Proguanil 8mg/kg once daily for 3 days
Status	Approved; Highly efficacious against P. falciparum, including strains that are resistant to chloroquine and mefloquine, with cure rates of 94-100%
*Chlorproguanil + Dapsone (LapDap^TM)*
Advantages	Well tolerated; Efficacious
Disadvantages	Dapsone induced methaemoglobinaemia and haemolysis in G6PD deficiency; Potential cross-resistance with SP
Dose	Chlorproguanil 2mg/kg and Dapsone 2�5mg/kg once daily for 3 days
Status	Withdrawn by GSK for fears of hemolytic anemia in G6PD deficiency [See Press Release, News Report, Another Report]
Quinine based Combinations
Quinine + Tetracycline
Advantages	Efficacious
Disadvantages	7-day course, multiple doses daily; Cinchonism; Tetracyclines contraindicated in children and pregnant women; Emergence of resistance
Dose	Quinine 10mg/kg 8 hourly and Tetracycline 4mg/kg 6 hourly for 7 days
Status	Not approved; Difficult to recommend as a first-line treatment for uncomplicated malaria
Quinine + Clindamycin
Advantages	Good efficacy; Safe in children and pregnant women; Lesser risk of resistance
Disadvantages	Cinchonism
Dose	Quinine 15mg/kg 12 hourly and Clindamycin 5mg/kg 12 hourly for 3 days
Status	Not approved
New Combinations
Piperaquine + Dihydroartemisinin + Trimethoprim (Artecom^TM) and Artecom^TM plus Primaquine (CV8^TM) (CV = China-Viet Nam)
Advantages	Efficacy consistently above 93%
Disadvantages	Animal toxicology studies indicate additive toxicity; No serious adverse events observed in human studies
Status	Trials; May prove to be more affordable
Chlorproguanil+ Dapsone + Artesunate (CDA^TM or Lapdap plus^TM )
Status	No adequate data available yet
Fosmidomycin+ Clindamycin
Advantages	Both drugs act on the parasite's apicoplast; Rapid clearance and 100% cure rates reported
Status	Trials on

Conclusions:

Clinical experience for many of the combinations is limited and more studies are needed
Artemisinin-based combinations produce rapid clinical and parasitological cure, parasite resistance is yet to be documented, reduce gametocyte carriage rate, and are generally well tolerated. However, the cost of treatment could be higher by a factor of up to 10-fold and this may be a hindrance in poor communities.
Based on available safety and efficacy data, the following therapeutic options are available now and have potential for deployment (in prioritized order) if costs were not an issue:
1. Artemether-lumefantrine (Coartem^TM)
2. Artesunate (3 days) plus amodiaquine
3. Artesunate (3 days) plus SP in areas where SP efficacy remains high
4. SP plus amodiaquine in areas where efficacy of both amodiaquine and SP remain high. This is mainly limited to countries in West Africa.
These combination options need continued documentation of safety and efficacy as part of any potential implementation process, especially among very young children, pregnant women, and breastfeeding mothers and their babies.
Options that are not recommended for policy at this time include:

Chloroquine-based combinations (CQ + SP and CQ + artesunate)

One-day treatment of artesunate + SP

Mefloquine-based combinations (e.g. mefloquine plus artesunate) in areas of high malaria transmission

One-day treatment of artesunate plus mefloquine in the acute phase of a complex emergency or malaria epidemics

References:

Antimalarial Drug Combination Therapy: Report of a WHO Technical Consultation. 4-5 April 2001. Available at http://mosquito.who.int/cmc_upload/0/000/015/082/use_of_antimalarials2.pdf

http://www.paho.org/English/AD/DPC/CD/mal-adct.htm
Kremsner PG, Krishna S. Antimalarial combinations. Lancet. 2004 Jul 17;364(9430):285-94.

Treatment of P. falciparum

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Last Updated: Mar 05, 2008

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