Supplement

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

2. Prevention

Four components of malaria prevention should be discussed with the traveller:

1. the risk of acquiring malaria
2. personal protective measures to prevent mosquito bites
3. chemoprophylactic drugs (where appropriate)
4. the need to seek early diagnosis and treatment of a febrile illness

a. Risk of Acquiring Malaria

All travellers to malarial areas need to be aware of the risk of malaria infection, how they can best protect themselves, and the need to urgently seek medical advice if they have a fever. Travellers staying overnight in rural areas may be at highest risk.

Malaria transmission occurs in most of subSaharan Africa and New Guinea; in large areas of Southern Asia; in parts of Southeast Asia, Oceania, Haiti, and Central and South America; and in limited areas of Mexico, the Dominican Republic, North Africa and the Middle East. Appendix I provides country-specific information on malaria risk and recommended chemoprophylaxis. This information is derived from the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), and the International Association for Medical Assistance to Travellers (IAMAT). While this is the most accurate information at the time of publication, many factors, such as variations in local reporting rates and surveillance, may significantly affect the reliability of these data.

Malaria transmission occurs primarily between dusk and dawn, corresponding to the biting habits of the Anopheles mosquito. The risk of transmission is increased in rural areas and varies seasonally in many locations, being highest at the end of the rainy season. Risk is proportional to the duration of an individual's exposure. Transmission decreases at altitudes above 2000 m (6500 feet).

Travel to urban and tourist areas of Southeast Asia, and Central and South America are considered to entail minimal risk, whereas urban travel in other malaria-endemic regions, such as subSaharan Africa, the Indian subcontinent, and New Guinea (Papua New Guinea [PNG] and Papua [Irian Jaya]) may be associated with significant risk of infection. In the last decade, the spread of drug-resistant malaria and the prevalence of infection, especially with P. falciparum, have grown steadily. For example, malaria cases are at record levels on the Indian subcontinent, where an increasing proportion are due to drug-resistant P. falciparum.

Retrospective studies of large numbers of travellers have provided an approximation of malaria risk during a 1-month stay without chemoprophylaxis: Oceania (PNG, Papua [Irian Jaya], Solomon Islands and Vanuatu) 1:30 or higher, subSaharan Africa 1:50, Indian subcontinent 1:250, Southeast Asia 1:1,000, South America 1:2,500 and Central America 1:10,000. It is noteworthy that the highest risk areas for malaria are Oceania, Africa and, to a lesser extent, the Indian subcontinent.

b. Personal Protective Measures to Prevent Mosquito Bites

READERS SHOULD NOTE THAT THE FOLLOWING RECOMMENDATIONS ARE INTENDED FOR CANADIANS TRAVELLING INTERNATIONALLY TO AREAS OF MALARIA RISK AND MAY DIFFER FROM HEALTH CANADA'S (PEST MANAGEMENT REGULATORY AGENCY) RECOMMENDATIONS FOR DOMESTIC USE OF INSECTICIDES AND REPELLENTS.

All travellers to malaria-endemic regions are advised to use personal protective measures to reduce the risk of bites from Anopheles mosquitoes. Any measure that reduces exposure to the evening and night-time feeding Anopheles mosquito will reduce the risk of malaria. Risk reduction behaviour is maximized by using an integrated approach involving personal protective measures:

• avoid mosquitoes, e.g., by staying in an insect-proof area during the period of the day when mosquitoes bite.
• prevent the bites of mosquitoes through
  • physical barriers, e.g., clothing, bed nets
  • chemical barriers, e.g., repellents, insecticides

Avoiding Mosquitoes

Important measures to avoid mosquitoes are as follows:

• minimizing entry of mosquitoes into work and accommodation areas. This includes having screens that are in good repair on windows and doors; doors that close properly and tightly; and walls and roof that are "without holes" (C III - evidence-based medicine recommendation, see Appendix II).
• staying in a mosquito-protected area during the time(s) of the day when local mosquitoes are actively biting (C III - evidence-based medicine recommendation).
• not travelling to a locale during the season most strongly (or only) associated with transmission of malaria (C III - evidence-based medicine recommendation).

Physical Barriers

If mosquitoes cannot bite, then malaria cannot be transmitted; the aim is to reduce the amount of unprotected skin available to the mosquito. Approaches to the prevention of bites comprise physical and chemical barriers. Physical barriers include:

• Clothing: Wearing long-sleeved shirts (sleeves down, buttoned/zipped up, tucked into pants) and long pants (tucked into socks or footwear) may inhibit or prevent mosquito bites. Light-coloured clothing may be less attractive to some mosquitoes and make mosquitoes more noticeable (B II - evidence-based medicine recommendation).
• Mosquito net: Sleeping under a mosquito net is well established as a useful barrier against mosquito bites, but mosquitoes may still bite through the mesh (if the traveller's skin is against the net). The treatment (impregnation) of mosquito netting with insecticide (e.g., permethrin) substantially increases the protection afforded by the net (A I - evidence-based medicine recommendation).

Chemical Barriers

Two types of chemical barrier may be used to reduce the risk of malaria: repellents and insecticides. Repellents do not kill mosquitoes but, rather, affect them in such a way that the mosquito will not bite, whereas insecticides act primarily by killing a mosquito upon contact. These approaches are not mutually exclusive, i.e., some products may act as both a repellent and an insecticide:

• Repellents: There are a number of repellent chemicals and formulations for skin application available in Canada and an even larger number available in other countries. Repellents available for sale in most (if not all) Western nations have been reviewed for effectiveness and safety on the basis of national regulations by Health Canada's Pest Management Regulatory Agency (PMRA) and, in the United States, by the Environmental Protection Agency. Where testing has been done, some repellents have been found to be more effective than others against certain arthropod species.

• DEET: The repellent DEET (N,N-diethyl-3-methylbenzamide, also known as N,N-diethyl-m-toluamide) is generally acknowledged as the most effective of the currently available repellents (A I - evidence-based medicine recommendation). DEET has been used as a repellent since 1946 by the US military and is estimated to be used several hundred million times by North Americans each year alone. Scientific reviews have concluded that, when used as directed, DEET has an excellent safety record (A I - evidence-based medicine recommendation).

The higher the concentration of DEET in the repellent formulation, the longer the duration of protection; however, this relation reaches a plateau at about 30% to 35%. For a given DEET concentration, DEET formulations that are "extended duration" (ED), or microencapsulated, provide longer protection times, likely with less DEET absorption. ED DEET is also more cosmetically acceptable. However, these formulations are not currently available in Canada, although they are in the United States.

Regulatory agencies in Western nations may differ regarding the recommended maximum concentration of DEET, especially for children*. However, it must be recognized that, in comparison to Canada, the risks posed by malaria in other parts of the world are substantial. The traveller to a malarious area should employ any and all measures to reduce the risk. CATMAT is satisfied that, for travel outside of Canada where the risk of malaria outweighs the risk of any important adverse reaction to DEET, the threshold for use of DEET should be low.

CATMAT recommends that concentrations of DEET up to 35% can be used by any age group. For children, alternative personal protective measures, such as insecticide-impregnated mosquito nets, should be the first line of defence, especially for infants < 6 months of age. Portable mosquito nets, including self-standing nets, placed over a car seat, a crib, playpen, or stroller provide an insect-protected environment for infants. However, as a complement to the other methods of protection, the judicious use of DEET should be considered for children of any age. Recent medical literature from Canada suggests that DEET does not pose a significant or substantial extra risk to infants and children.

The reapplication intervals on the label of DEET formulations are a general guide only, since there are many variables, such as sweating, affecting the duration of effectiveness. As a general rule, the reapplication interval is a function of mosquito biting activity, so that if biting is noted before the interval on the label has expired, then reapplication of DEET is recommended.

ED DEET formulations (up to 35%) have useful advantages over other formulations and, overall, are preferred (A II - evidence-based medicine recommendation).

DEET/sunscreen combination products are not generally recommended, as DEET can decrease the efficacy of sunscreens by 34%. As well, the recommendations for application of DEET and sunscreens are diametrically opposed (i.e. use sunscreen liberally and often - use DEET sparingly and only as often as required). If application of both is necessary, the Canadian Dermatology Association recommends that the sunscreen be applied first and allowed to penetrate the skin for 20 minutes, followed by application of DEET (A II - evidence-based medicine recommendation).

"Natural-based" repellents: Most repellents containing "natural" products are effective for shorter durations than DEET (Table 1) and for this reason are not considered the preferred products for protecting against mosquito bites. For example, oil of citronella products can repel mosquitoes, but the duration of protection is very short (generally less than an hour, often less than 30 minutes). Therefore, citronella-containing repellents are not recommended (E II - evidence-based medicine recommendation).

P-menthane-3,8-diol, a synthetic analogue of lemon eucalyptus oil, has been registered as an insect repellent ("OFF! Botanicals Lotion Insect Repellent 1") by the PMRA. However, the period of protection afforded by this product is less than for ED DEET products, and it is not approved for use on children < 3 years of age. There are data to indicate that it is reasonably effective against mosquitoes that carry malaria. P-menthane-3,8-diol may be considered a second-line alternative repellent when DEET use is not possible (e.g., for people allergic to DEET) (A II - evidence-based medicine recommendation).

Table 1.
Comparative efficacy of selected insect repellents

Active ingredient	Formulation	Brand*	Duration of efficacy† (hrs)	Level of evidence
DEET < 10%	Pump spray, aerosol, gel, lotion	Cutter Skedaddle Skintastic (OFF)	1-3	A I
DEET 10%-30%	Pump spray, aerosol, lotion, stick	Cutter Backwoods Cutter Backyard Cutter Outdoorsman Deep Woods OFF! Muskol OFF!	4-6	A I
DEET 20%-35%	Lotion (microencapsulated slow release)	Sawyer Ultrathon	8-12	A I
Citronella oil 5%-15%	Pump spray, lotion, oil, towelette	Buzz Away Green Ban Herbal Armor Natrapel	0.3-0.5 (20-30min)	E II
Lemon eucalyptus oil 10%-30%	Lotion	OFF! Botanicals Lotion Insect Repellent 1	2-5	A II
Soybean oil 2%	Oil	Bite Blocker	1.4	A II
Bayrepel 10%-20% (Picaridin/ Hepidanin)	Pump spray, aerosol	Autan	3-5 (10%) 8-10 (20%)	A II
*NOTE : These products are presented as examples only and are not necessarily endorsed by Health Canada. † Most testing of repellency duration under field conditions is performed with Aedes species mosquitoes. Data regarding testing of DEET against Anopheles mosquitoes demonstrate shorter duration of efficacy, closer to the lower limits of the ranges in this table, compared with Aedes mosquitoes. Testing data for citronella oil and soybean oil are available only for Aedes species mosquitoes, and testing data for lemon eucalyptus oil and Bayrepel suggest equivalency of repellency between Aedes and Anopheles species mosquitoes.

Soybean oil 2% "Blocker" products are equivalent to 5% to 10% DEET in efficacy, with products repelling mosquitoes for 1 to 4 hours and black flies for 5 to 10 hours. Soybean oil has low toxicity, has no age-associated restrictions on use, and is non-irritating. It may therefore also be considered an alternative to DEET, albeit one with a substantially shorter protection time and without a long history of use. Importantly, CATMAT is unaware of scientific studies in which soybean repellents have been tested for effectiveness against malaria-transmitting mosquito vectors; therefore, soybean repellents are considered, at best, a third-line repellent where malaria presents a significant risk (A II - evidence-based medicine recommendation). Although there are currently four Blocker products containing soybean oil registered and approved for use in Canada (www.biteblocker.ca), they are not widely available in retail outlets.

Other, synthetic repellents: Bayrepel, a piperidine derivative also known as KBR 3023 and marketed under the trade name Autan, has been in use in Europe for several years. It has demonstrated action against a variety of mosquito species, including those that carry the malaria parasite, with durations of protection comparable to 15% to 50% DEET (A II - evidence-based medicine recommendation). Toxicologic analysis suggests no bio-accumulation and rapid renal excretion with no significant toxic effects reported. Although recommended by the WHO and registered with the Environmental Protection Agency (United States) in 2002, this product has not been evaluated by the PMRA, and there are currently no registered products available in North America (www.autan.co.uk).

Insecticides

Treated mosquito nets: All travellers with itineraries to locales outside Canada that are endemic for malaria should be strongly encouraged to use pyrethroid (e.g., permethrin, delta-methrin, lambda-cyhalothrin, cyfluthrin, alpha-cypermethrin) insecticide-impregnated mosquito nets unless their sleeping quarters are well-screened or otherwise protected from mosquitoes (A I - evidence-based medicine recommendation). Pyrethroids may kill mosquitoes directly after they land on impregnated netting, or repel them. In either case, the end result is protection against mosquito bites and malaria. Pyrethroid-impregnated nets are significantly more effective in preventing malaria than untreated nets and are safe for children and pregnant women (A I - evidence-based medicine recommendation). The duration of efficacy of pyrethroid-impregnated nets varies from several months to 1 year, depending on the product used (Appendix III and Table 2). While pyrethroids are generally considered to be of low mammalian toxicity, care should be taken when impregnating the permethrin or equivalent product into the net: follow the label instructions, use impervious gloves, and allow the net to dry before use (Appendix III). The PMRA does not currently register pyrethroid treatments for bed nets.

Table 2.
Comparative efficacy of pyrethroid insecticides for use on nets*

Active ingredient	Formulation	Brand**	Duration of efficacy† (mos)	Level of evidence
Permethrin EC 55%	Emulsified concentrate	Peripel	6	A I
Deltamethrin SC 1%	Suspension concentrate	K-Orthrine	12	A I
Deltamethrin 400 mg	Tablet	K-O Tab	12	A I
Lambda-Cyhalothrin CS 2.5%	Capsule suspension	Icon	9	A I
Cyfluthrin EW 0.05%	Water emulsion	Solfac	6-9	A I
Alpha-Cypermethrin SC 10%	Suspension concentrate	Fendona	6-9	A I

*Based on studies of insecticide-treated mosquito nets used for the prevention of malaria in subSaharan Africa
**NOTE: These products are presented as examples only and are not necessarily endorsed by Health Canada.
†Durations of efficacy not applicable to pyrethroid impregnation of clothing; deltamethrin residual efficacy maintained after three to four washings of impregnated net whereas the efficacy of other pyrethroids is lost after one to two washings.

• Treated clothing: Pyrethroid treatment of clothing will also reduce the risk of malaria (Appendix III). As with mosquito net treatments, the PMRA does not currently register permethrin clothing treatments, but several products are available in the United States. These usually consist of 0.5% permethrin in an aerosol or pump spray. Treatment of clothing with the 0.5% permethrin aerosol or pump spray is generally effective at preventing mosquito bites for at least 2 weeks, assuming regular laundering practices (e.g., through six machine washings). A long-acting DEET formulation applied to exposed skin together with pyrethroid-impregnated clothing are considered to be complementary, i.e., using both will greatly enhance protection against biting arthropods (A II - evidence-based medicine recommendation).

• Ineffective personal protective measures against insects: There are additional products that are marketed as safe, "natural" and/or effective measures to substantially reduce the risk of mosquito bites. However, CATMAT's assessment is that the following products do not have sufficient scientific basis to recommend them, or there is sufficient scientific evidence to indicate that the product is not useful (E II - evidence-based medicine recommendation). These include electronic (ultrasonic) devices, wristbands/neckbands/anklebands impregnated with repellents (whether for animal or human use), electrocuting devices (i.e., "bug zappers"), odour-baited mosquito traps, the Citrosa plant (i.e., geranium houseplant), oral vitamin B1, and Avon Skin-So-Soft (IR3535).

C. Chemoprophylactic Drugs (where appropriate)

Recommendations for chemoprophylaxis of malaria should be based on several factors:

• individual risk assessment
• distribution of drug-resistant malaria
• safety and efficacy of chemoprophylactic regimens (see Section 3, Chemoprophylactic Regimens).

Individual risk assessment

Several factors need to be assessed when selecting an appropriate chemoprophylactic regimen before travel. The travel itinerary should be reviewed in detail and compared with known areas of malaria transmission within a country to determine the likelihood that the traveller will be at risk of acquiring malaria. The specific activities (e.g., rural travel, night-time exposure, unscreened accommodations) of the individual while in the malarial region(s) should be considered in estimating risk. The health of the individual (e.g., age, pregnancy, medication, and chronic illness) also needs to be considered in order to determine the risk of severe disease if malaria were to occur and to choose an appropriate antimalarial drug for chemoprophylaxis.

The following should be considered in the individual risk assessment:

1. Will the traveller be exposed to malaria?
2. Will the traveller be in a drug-resistant P. falciparum zone?
3. Will the traveller have prompt access to medical care (including preparation of blood films with sterile equipment and prompt, accurate interpretation) if symptoms of malaria were to occur?
4. Are there any contraindications to the use of a particular antimalarial drug?
5. Is the traveller at increased risk of severe malaria disease, e.g., a young child, asplenic individual, pregnant woman?

Distribution of drug-resistant malaria (see Figure 1a and Appendix I)

Chloroquine-resistant P. falciparum is widespread in all malaria-endemic areas of the world, except for Mexico, the Caribbean, Central America (north of the Panama Canal), parts of China, and parts of the Middle East. P. falciparum malaria resistant to chloroquine AND mefloquine is still rare except in Thailand, on the borders with Cambodia and Myanmar (Burma). Resistance to Fansidar® (sulfadoxine-pyrimethamine) is now common in the Amazon basin, parts of subSaharan Africa and Southeast Asia. Chloroquine-resistant P. vivax is also an important problem, particularly in Papua New Guinea, Papua (Irian Jaya), Vanuatu, Myanmar, and Guyana. Strains of P. vivax with reduced response to primaquine are reported from widely divergent areas, including Papua New Guinea, Somalia, and India.

CATMAT considers there to be minimal risk of malaria in urban centres of Southeast Asia, and Central and South America. Malaria transmission falls at altitudes exceeding 2000 m (6500 feet) and is virtually non-existent over 3000 m (10 000 feet).

d. Early Diagnosis and Treatment

All travellers should be informed that malaria should be suspected if unexplained fever occurs during or after travel. Medical attention should be sought as soon as possible, and the traveller should request that a thick and thin blood film be promptly (i.e., immediately) obtained and examined for malaria parasites. If the initial blood film is negative and the traveller remains symptomatic, then the blood film should be repeated in 12 to 24 hours. The most important factors that determine the survival of patients with falciparum malaria are early diagnosis and prompt initiation of appropriate treatment.

Appendix IV provides a checklist for the preparation of travellers to malarial areas.

* Health Canada's PMRA allows concentrations only up to 30% to be sold; it recommends that concentrations over 10% not be applied to children < 12 years of age and that application only be three times /day.

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