Supplement

Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers

4. Prevention of malaria in special hosts

a. Malaria Prevention in Children

Travellers should be clearly advised of the risks involved in taking young children to areas with drug-resistant falciparum malaria. Children are at special risk of malaria, since they may rapidly become seriously ill. In order to reduce the risk of infection when travel to malarial areas is unavoidable, all children, including those who are breast-fed, should be well protected against mosquito bites and receive appropriate malaria chemoprophylaxis.

Protection from bites should include alteration of the itinerary to limit time spent in malarial regions as well as to avoid outdoor activities after dusk. Pyrethroid-treated netting may be used for more than just beds (e.g., over strollers, playpens, and cradles) to protect the very young from bites. For ALL children travelling to malarial regions, particular attention should be paid to other personal protective measures, such as protective and treated clothing as well as effective insect repellents (see Section 2). These recommendations may differ from common practices in other areas of the world, such as Canada, where serious insect-borne disease is less of a concern.

All infants and children should be prescribed an appropriate antimalarial drug if they are at risk of infection. Infants do not receive sufficient medication through breast milk to protect them, and therefore they should be prescribed antimalarial drugs even though their mother is receiving chemoprophylactic medication. Ensuring that young children take antimalarial agents may be difficult because of the lack of pediatric formulations and the unpleasant taste. Malaria tablets may be crushed and mixed with chocolate syrup, jam, cereal, or bananas to mask the taste. Sufficient tablets should be prescribed to allow for a few doses that may be vomited or spat out. Emesis is more frequent among children, and therefore parents must be given clear instructions as to when doses should be repeated. For small doses, the pharmacist may be asked to pre-cut tablets in order to increase the accuracy of dosing and/or crush and insert into capsules. Parents must be aware that antimalarial drugs should be protected from sunlight and high humidity. As with all medication, they should be kept out of reach of infants and children and stored in childproof containers to avoid a potential fatal overdose.

Chloroquine remains the preferred agent for chemoprophylaxis in areas with chloroquine-sensitive malaria. Although it is not available in Canada, chloroquine sulfate (for example, Nivaquine) is widely available as a syrup in malaria-endemic areas. The syrup is often more easily administered than tablets. Physicians should calculate the dose to be administered according to body weight, as the volume will vary with the different concentrations of chloroquine base that may be found in suspensions available abroad.

Mefloquine is the drug of choice in chloroquine-resistant regions, although there are no studies that specifically analyze its bioavailability and rate of metabolism in children. Although the manufacturer recommends that mefloquine not be given to children weighing < 5 kg, it should be considered for prophylaxis of all children at high risk of acquiring chloroquine-resistant P. falciparum, at a dose of 5 mg base/kg once weekly (see Section 9, Table 8). Young children seem to be less likely to suffer major neuropsychiatric side effects from mefloquine.

Atovaquone/proguanil has been licensed for the treatment of malaria in children > 11 kg (25 lb) or aged > 3 years. However, it is available in many countries for use in this age group for both treatment and prophylaxis, and its safety is supported by clinical trials; in the United States atovaquone/proguanil can be used for the treatment of malaria in children weighing 5 kg (11 lb) (A 1 - evidence-based medicine recommendation, see Appendix II). Currently, it is licensed in Canada for prophylaxis in those weighing > 40 kg. Doxycycline can be used in children > 8 years of age, with attention to contraindications and precautions.

There is no safe and effective chemoprophylactic regimen licensed for children < 8 years who travel to mefloquine-resistant areas where Thailand borders with Myanmar (Burma) and Cambodia, in western Cambodia, and eastern Myanmar. However, as in adults, atovaquone/proguanil may be considered on the basis of its documented efficacy when used as treatment for malaria in these regions.

Recommendations

1. If possible, young children should avoid travel to areas with significant transmission particularly of chloroquine-resistant malaria (C III - evidence-based medicine recommendation).
2. Personal protective measures should be strongly encouraged for all children who travel to malaria-endemic areas (A I - evidence-based medicine recommendation).
3. Young children travelling to or residing in chloroquine-sensitive areas should use chloroquine as chemoprophylaxis (A I - evidence-based medicine recommendation).
4. For young children travelling to or residing in chloroquine-resistant areas, mefloquine is the drug of choice for chemoprophylaxis (A I - evidence-based medicine recommendation). An alternative is atovaquone/proguanil, although it is not licensed in Canada for this use.
5. There is no safe and effective chemoprophylaxis regimen licensed for children < 8 years old who travel to mefloquine-resistant areas where Thailand borders with Cambodia and Myanmar (Burma), although atovaquone/proguanil may be considered.

b. Malaria Prevention in Pregnancy

Malaria increases the risk of maternal and neonatal death, miscarriage, and stillbirth. In addition, low birth weight is more frequent among women who are taking ineffective prophylaxis (A 1 - evidence-based medicine). Pregnant women should defer travel to malaria-endemic areas, particularly to areas with risk of acquisition of drug-resistant falciparum malaria. If travel cannot be avoided, special care should be taken to avoid mosquito bites (see Section 2), and chemoprophylaxis should be used.

Doxycycline is contraindicated for malaria prophylaxis during pregnancy and lactation because of adverse effects on the fetus, including discoloration and dysplasia of the teeth, and inhibition of bone growth. Primaquine is contraindicated during pregnancy because the drug can be passed trans-placentally to a G6PD-deficient fetus and cause hemolytic anemia in utero. Whenever radical cure or terminal prophylaxis with primaquine is indicated during pregnancy, chloroquine should be given once a week until delivery, at which time primaquine may be given. Atovaquone/proguanil is not currently recommended during pregnancy unless the potential benefit outweighs the potential risk to the fetus (for example, for a pregnant woman who is at significant risk of acquiring P. falciparum malaria in an area of multidrug-resistant strains).

According to current data, mefloquine is safe for chemoprophylaxis after the first trimester, with no evidence of increased teratogenic effects. Although study results are conflicting, some suggest that there may be an increased rate of spontaneous abortion, particularly during the first trimester. It is prudent to recommend avoidance of pregnancy for 3 months after completion of mefloquine chemoprophylaxis because of the long half-life. However, if a woman who is receiving mefloquine prophylaxis becomes pregnant this is not an indication for termination of pregnancy. If there is an unavoidable risk of chloroquine-resistant malaria during the first trimester of pregnancy, the risks of malaria to the mother and fetus should be weighed against the small risks associated with mefloquine. Chloroquine and proguanil are known to be safe in pregnancy, although they are significantly less effective than mefloquine in preventing chloroquine-resistant P. falciparum.

Recommendations

1. If possible, pregnant women should avoid travel to areas with significant transmission particularly of chloroquine-resistant malaria (C III - evidence-based medicine recommendation).
2. Personal protective measures should be strongly encouraged for all pregnant women who travel to malaria-endemic areas (A I - evidence-based medicine recommendation).
3. Pregnant women travelling to or residing in chloroquine-sensitive areas should use chloroquine as chemoprophylaxis (A I - evidence-based medicine recommendation).
4. Mefloquine is effective and safe for prophylaxis beyond the first trimester of pregnancy and is recommended where exposure to chloroquine-resistant falciparum malaria is unavoidable (AI - evidence-based medicine recommendation).
5. Women who plan to travel to areas with chloroquine-resistant falciparum malaria during the first trimester of pregnancy should have an individual risk assessment and counsel from a travel medicine or tropical diseases specialist (A III - evidence-based medicine recommendation).
6. The combination of chloroquine and proguanil is safe in pregnancy but is significantly less effective against chloroquine-resistant malaria than mefloquine. In view of the serious consequences of malaria in pregnancy, utilization of this suboptimal antimalarial combination would not routinely be recommended (A I - evidence-based medicine recommendation).
7. There is no safe and effective licensed chemoprophylaxis regimen for pregnant women who travel to mefloquine-resistant areas where Thailand borders with Cambodia and Myanmar (Burma).

c. Prophylaxis while Breast-feeding

Because the quantity of antimalarial medication transferred in breast milk is insufficient to provide adequate protection against malaria, infants who require chemoprophylaxis should receive the recommended dosages of appropriate antimalarial drugs. The very small amount of chloroquine, mefloquine, and proguanil secreted in the breast milk of lactating women is not thought to be harmful to a nursing infant. There is no information on the amount of primaquine that enters human breast milk; therefore, the infant should be tested for G6PD deficiency before primaquine is given to a woman who is breast-feeding. Because data are not yet available on the safety and efficacy of atovaquone/proguanil in infants weighing < 11 kg (25 lbs), the medication should not be given to a woman who is breast-feeding an infant less than this weight unless the potential benefit to the woman outweighs the potential risk to the infant (for example, a lactating woman who has acquired P. falciparum malaria in an area of multidrug-resistant strains and who cannot tolerate other treatment options).

d. Malaria Prevention in the Medically Compromised Host

Travellers with underlying medical conditions present a special challenge, for a wide variety of reasons. These include the potential for increased susceptibility to and severity of malaria, the deleterious impact of malaria on the underlying condition, and the complexity of potential interactions between antimalarial and other medications.

Immunocompromised hosts

1. HIV/AIDS: Early studies of the interaction between HIV and P. falciparum resulted in conflicting conclusions but were limited by poor design or the small numbers of subjects. More recent data suggest a two-way relation between these two organisms. In vitro and human data indicate that malaria infection stimulates HIV-1 replication, resulting in increased viral loads that persist for weeks after the infection. Thus, malaria may speed the clinical progression of HIV disease. It has also been shown that infants born to co-infected women have a higher mortality rate than those born to women with either HIV/AIDS or malaria alone. Conversely, a recent, well-designed study has shown that those infected with HIV have an increased risk of Plasmodium parasitemia and clinical malaria infection. Infection risk and parasite density increase as the immune status deteriorates (A I - evidence-based medicine). Malaria treatment failure may be more likely in those with HIV/AIDS, as shown in Ugandan children < 5 years of age. Treatment of HIV often includes multiple antiretroviral drugs, several of which (especially protease inhibitors) may interact with antimalarial drugs or cause adverse effects. The result may be increased toxic effects from or reduced efficacy of either the antiretroviral agent or the antimalarial medication. Consultation with a travel or tropical medicine expert is advised.
2. Asplenia: The spleen facilitates phagocytosis and promotes removal of parasitized red blood cells. Animal models suggest that asplenia exacerbates malaria disease. Fatal malaria has been reported in those with asplenia, although it may be more important in non-immune (e.g., travellers) than semi-immune populations. It is presumed that Plasmodia species cause more severe disease in travellers with functional or anatomic asplenia and, therefore, maximal preventive measures should be recommended. Standby self-treatment may be considered in addition to prophylactic measures if remote regions are being visited, where access to care is limited. Fever in an asplenic individual may represent malaria or infection with an encapsulated bacterial organism, so empiric therapy for both may need to be instituted (B III - evidence-based medicine recommendation).
3. Other immunosuppressive conditions: Little has been documented about the natural history of malaria in individuals with other immunocompromising conditions. The clinical course of malaria in these individuals is presumably similar to or worse than in other people. However, the practitioner should also consider any immunosuppressive medications that are being used, many of which are metabolized in the liver by the microsomal enzymes and thus may interact with certain antimalarial medications.

Other Conditions

1. Cardiovascular: Mefloquine is contraindicated in those with cardiac arrhythmias or conditions that may predispose to arrhythmia. Doxycycline should not be used in patients taking warfarin because of potentiation of the latter's effect. There is a single case report of possible interaction between proguanil and warfarin, therefore a trial of atovaquone/proguanil with testing of INR (International Normalized Ratio) may be prudent until more information becomes available.
2. Neuropsychiatric: Seizure disorders may be exacerbated by chloroquine and mefloquine, so alternative agents should be used. Febrile seizures in children are not thought to be a risk factor or contraindication for these drugs. Concurrent use of anti-convulsant drugs that are liver-metabolized may decrease serum levels of doxycycline, and a dosage adjustment is recommended (see Section 3f). Mefloquine is associated with exacerbation of psychiatric conditions, including depression and anxiety disorders, and should be avoided if these illnesses are identified.
3. Hepatic or renal dysfunction: Moderate to severe hepatic or renal dysfunction may result in significant alteration in antimalarial medication levels. If either the liver or kidneys are compromised, then there must be careful consideration given to the selection and dosing of medications for the prophylaxis and treatment of malaria. Consultation with a travel or tropical medicine specialist is recommended.

Recommendations

1. Consultation with a travel medicine or tropical disease specialist is advised for anyone with a significant medical condition or immunosuppression (B III - evidence-based medicine recommendation).
2. All compromised travellers must be made aware of their degree of risk and should review the necessity of the trip along with options to alter the itinerary and their behaviour to reduce malaria risk as much as possible (B III - evidence-based medicine recommendation).
3. Personal protective measures for malaria prevention must be emphasized (A III - evidence-based medicine recommendation).
4. Carefully selected antimalarial chemoprophylaxis should be used for those at unavoidable risk of the disease (A I - evidence-based medicine recommendation).
5. In compromised travellers at high risk of severe disease, the option of standby self-treatment with malaria medication should be discussed. This should be offered in addition to chemo-prophylaxis for use in case of fever if the traveller is going to be in a remote area or an area where safe and effective care is not promptly available. Broad spectrum antibiotics are also important in asplenic patients, since infections with bacteria and Plasmodia may be indistinguishable and sometimes co-exist (B III - evidence-based medicine recommendation).

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