Summary of recommendations for the prevention of malaria by the Committee to Advise on Tropical Medicine and Travel (CATMAT)

Background: On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. Objective: To provide guidelines on risk assessment and prevention of malaria Methods: CATMAT reviewed all major sources of information on malaria prevention, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidencebased medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. Recommendations: Used together and correctly, personal protective measures (PPM) and chemoprophylaxis very effectively protect against malaria infection. PPM include protecting accommodation areas from mosquitoes, wearing appropriate clothing, using bed nets pre-treated with insecticide and applying topical insect repellant (containing 20%–30% DEET or 20% icaridin) to exposed skin. Selecting the most appropriate chemoprophylaxis involves assessment of the traveller’s itinerary to establish his/her malaria risk profile as well as potential drug resistance issues. Antimalarials available on prescription in Canada include chloroquine (or hydroxychloroquine), atovaquone-proguanil, doxycycline, mefloquine and primaquine. Introduction Malaria is a serious infection caused by five different species of the genus Plasmodium: falciparum, vivax, ovale, malariae and knowlesi. Malaria is transmitted by the bite of infected female anopheline mosquitoes. In 2009, 35% of Canadian travellers who went to a destination other than the United States visited a country that presented a risk of malaria, an increase of 131% from 2000 (1-2). Between September 2009 and September 2011, 94 cases of malaria were diagnosed among returned Canadian travellers (3). 119 | CCDR – 3 April 2014 • Volume 40-7 According to the Centers for Disease Control and Prevention (CDC), malaria risk for travellers from the United States (4-6) varied as follows:  Highest in west Africa and parts of Oceania;  Moderate for other parts of Africa, parts of South America and South Asia;  Lower for much of Central America, the Caribbean, Mexico and other parts of Asia and South America;  Minimal in urban centres of southeast Asia and Central and South America, and in large resort areas in the Caribbean and Mexico. The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to tropical disease and health risks associated with international travel. This is a summary of the CATMAT Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers, developed for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill (7). These guidelines include a full description of the recommendations on risk assessment and prevention of malaria, a disease that is still uncommon in Canada.


Introduction
Malaria is a serious infection caused by five different species of the genus Plasmodium: falciparum, vivax, ovale, malariae and knowlesi.Malaria is transmitted by the bite of infected female anopheline mosquitoes.
In 2009, 35% of Canadian travellers who went to a destination other than the United States visited a country that presented a risk of malaria, an increase of 131% from 2000 (1)(2).Between September 2009 and September 2011, 94 cases of malaria were diagnosed among returned Canadian travellers (3).
According to the Centers for Disease Control and Prevention (CDC), malaria risk for travellers from the United States (4-6) varied as follows:  Highest in west Africa and parts of Oceania;  Moderate for other parts of Africa, parts of South America and South Asia;  Lower for much of Central America, the Caribbean, Mexico and other parts of Asia and South America;  Minimal in urban centres of southeast Asia and Central and South America, and in large resort areas in the Caribbean and Mexico.
The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to tropical disease and health risks associated with international travel.This is a summary of the CATMAT Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers, developed for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill (7).These guidelines include a full description of the recommendations on risk assessment and prevention of malaria, a disease that is still uncommon in Canada.

Methods
The Malaria Subcommittee, a working group of CATMAT, developed the guidelines.Each member is a volunteer, and none declared a relevant conflict of interest.Each chapter was updated by one to two members of the subcommittee and reviewed and approved by the full membership of CATMAT.The update was based on a thorough review of the literature.In addition, the Malaria Subcommittee reviewed all major sources of information on malaria prevention and treatment, including the World Health Organization (8), Centers for Disease Control and Prevention (CDC) (6) and the Health Protection Agency Advisory Committee on Malaria Prevention (9).The Malaria Subcommittee reviewed recent research, and national and international epidemiological data in order to tailor the recommendations to the Canadian context.Influencing factors include drug licensure, Canadian-specific travel patterns and related malaria epidemiology, and the anticipated values and preferences of travellers and health care providers.The evidence-based medicine recommendations for prevention of malaria were developed with associated rating scales for the strength and quality of the evidence.
CATMAT has taken into consideration both the need for protection and the potential for adverse effects of chemoprophylaxis.The guidelines also emphasize the varying degrees of endemicity in different regions.The health care provider should be properly informed to be able to provide appropriate guidance for the individual traveller.

Recommendations
The evidence-based CATMAT recommendations for malaria prevention are summarized in Table 1.A discussion of some of the key recommendations follows.
Table 1: Evidence-based medicine recommendations for prevention of malaria Recommendation EBM rating 1   1.Properly used malaria chemoprophylaxis is very effective (6).

A I
2. Travellers should receive expert advice on malaria risks and strategies to avoid mosquitoes (10).

B III
3. A detailed review of the travel itinerary to determine the expected level of malaria endemicity and duration of exposure is essential to provide an accurate risk assessment for travellers (6,10,11).

B III
4. An assessment of the traveller's health and risk tolerances is also important in making malaria prevention recommendations.

A I
8. Atovaquone-proguanil and doxycycline are the drugs of choice for travellers to areas with mefloquine-resistant malaria.

A I
9. Primaquine is recommended for malaria chemoprophylaxis for travellers to regions with chloroquine resistance who are not willing or able to use atovaquone-proguanil, doxycycline or mefloquine.

A I
10. Standby malaria treatment with atovaquone-proguanil or quinine and doxycycline is recommended for travellers who are more than a day away from malaria diagnostic help.

C III
11. Doxycycline is an antibiotic and should never be co-administered with any live, oral bacterial vaccines.Vaccination with live oral typhoid or cholera vaccines should be completed at least three days before the first dose of choloroquine, atovaquone-proguanil or mefloquine.

B III
12. Concurrent use of chloroquine interferes with antibody response to intradermal administration of human diploid cell rabies vaccine.If intradermal rabies vaccine is administered to someone taking chloroquine, it is recommended that post-vaccine rabies antibodies be obtained to verify an adequate immunologic response.

B III
13. Use insecticide-treated bed nets.A I 14. Use topical repellents on exposed areas of skin to prevent arthropod bites and to reduce the risk of exposure to malaria-carrying mosquitoes.

A I
15. Products registered in Canada that contain 20%-30% DEET (N,N-Diethyl-meta-toluamide) or 20% icaridin should be the first choice for Canadian travellers.

A II
16. Products that contain p-menthane-3,8-diol (a chemical originally derived from the lemon eucalyptus plant) and that are registered in Canada should be considered second-choice topical repellents.

A II
17.Other active ingredients currently registered in Canada (e.g.citronella and soybean oil) are either not widely available and/or do not provide sufficiently long protection times against bites.These products are not recommended for protecting travellers against the bites of vectors.

E II
18. Protect work and accommodation areas against mosquitoes by using screening on doors, windows and eaves (the open area between the roof and wall), eliminating holes in roofs and walls, and closing other gaps around a building.

B I
Recommendation EBM rating 1   19.Wear insecticide-treated clothing.B II 20.Wear appropriate clothing (e.g.full-length, loose-fitting and light-coloured clothing with sleeves rolled down and pants tucked into socks or boots).

B III
21. Do not use/rely on other insecticide-based approaches, such as insecticide coils that are burned, insecticide vaporizers, aerosols and space sprays, and insecticide-treated bed sheets.

E III
22. PPM that are either ineffective or that have not been convincingly shown to be efficacious against arthropod vectors and related diseases are not recommended.These include electronic (ultrasonic) devices; wristbands, neckbands and ankle bands impregnated with repellents; electrocuting devices ("bug zappers"); odour-baited mosquito traps; Citrosa plant (geranium houseplant); orally administered vitamin B1; and skin moisturizers that do not contain an approved repellent active ingredient.

Risk assessment
CATMAT suggests a two-component process for malaria risk assessment: an exposure assessment and a host assessment.
An exposure assessment evaluates the probability of being bitten by infected mosquitoes.It takes three factors into account:  Expected level(s) of endemicity in the travel itinerary;  Presence/predominance of P. falciparum;  Duration of exposure.
A host assessment evaluates the traveller's health in relation to the potential hazard(s) of clinical malaria and the indications for specific malaria chemoprophylactic agents while taking into account personal preferences regarding risk management.Factors to consider include the following:  General health of the traveller;  Drug-drug interactions;  Likelihood of access to appropriate medical care;  Risk tolerance and individual preferences.
The completed risk assessment can be used to decide whether to use malaria chemoprophylaxis and which chemoprophylactic agent to prescribe:  If malaria risk is minimal and the incidence of P. falciparum is nil or very low, CATMAT recommends using chemoprophylaxis (with PPM) for a stay longer than two weeks. If malaria risk is minimal and the incidence of P. falciparum is higher, CATMAT recommends chemoprophylaxis (with PPM) for a stay longer than one week.
Travellers who decide not to use chemoprophylaxis have a higher risk of malaria but lower risk of chemoprophylaxis-associated adverse effects; the opposite is true for those who decide to use it.
A country-by-country characterization of malaria transmission areas is available in the complete guidelines (7).
The Appendix provides chemoprophylaxis recommendations for the top 25 destinations with risk of malaria transmission that are visited by Canadians.

Personal protective measures
 The risk of being bitten by a mosquito can be reduced by using physical and/or chemical barriers.Travellers should also be encouraged to plan activities during periods when risk is reduced (e.g. during the daytime where the principal vectors are active in the evening) and to visit areas where transmission is less likely (e.g.urban centres, highland areas > 2000 m/6500 ft).

Prescribing antimalarial drugs
Prescribe antimalarial chemoprophylaxis only after completing an individual risk assessment.For detailed descriptions of chemoprophylaxis and of chemotherapy see Chapter 8 of the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers (7).Selecting the most appropriate chemoprophylactic agent involves the following: 1. Evaluate the traveller's exact travel itinerary to determine his or her malaria risk profile.

Review the advantages and disadvantages of different regimens:
 Take into account the traveller's health status, other medications and the risks and character of adverse drug effects. Consider only those medications that are least likely to exacerbate any past or present medical problem(s).
3. Present all the available options to the traveller and, unless any medication is contraindicated, let travellers choose which first-line malaria chemoprophylactic regimens they prefer.4. Select the appropriate dosage of the medication:  Explain the dosing schedule, including the need to take the drug before, during and after visiting the area of risk, the desirability of taking the drug at the same time each day and advice on whether the prescribed medication should be taken with food, as well as any precautions regarding drug-specific side effects (e.g.sun exposure with doxycycline) (41-47).
5. Suggest a drug trial to check for possible medication-associated adverse reactions.6. Discuss strategies to change medication if serious adverse effects arise during travel.
 Advise the traveller to continue to take the prescribed malaria medication if it is well tolerated regardless of negative anecdotes about it.Long-term use of the chemoprophylactic agents currently recommended in Canada does not result in additional risks of severe adverse effects.
Discuss the importance of seeking medical advice urgently if a fever develops while the traveller is in a malariaendemic area or within one year of leaving.

Selecting antimalarial drugs for specific regions of drug resistance
Monitor appropriate sources (e.g.Public Health Agency of Canada, CDC, ProMED) to stay abreast of new information about malaria risks before giving pre-travel care.This is especially relevant for minimal-risk regions because changes may directly affect the recommendations for chemoprophylaxis.Hydroxychloroquine (Plaquenil ® ) is an acceptable equivalent alternative (51), as are the three drugs used in chloroquine-resistant areas (see below).

Chloroquine-resistant regions:
Most of sub-Saharan Africa, South America, Oceania and Asia.See below for regions that are both chloroquine-and mefloquine-resistant.

Chloroquine-and mefloquine-resistant regions:
Various countries in Asia, Africa and the Amazon basin.However, it is a significant problem only in rural, wooded regions where Thailand borders with Myanmar (Burma), Cambodia and Laos, and in southern Vietnam.
Atovaquone-proguanil (44,53,54) Doxycycline (44,53,54) Note: See the Appendix, 'Malaria risk and recommended chemoprophylaxis in top 25 malaria-endemic travel destinations visited by Canadians in 2012', or a more complete list in the Canadian Recommendations for the Prevention and Treatment of Malaria among International Travellers (7).

Discontinuing antimalarial drugs
Fatal malaria has occurred in travellers who have discontinued all chemoprophylaxis or effective chemoprophylaxis in favour of something less protective (24,51,55,56).Discontinuation of all chemoprophylaxis is NOT a reasonable option.
Other travellers and/or health care providers may suggest changing or stopping antimalarial medication.For the most part, such advice should be ignored or questioned.Medications used in other areas of the world may be less effective, may be associated with serious adverse effects or may not be manufactured to Canadian standards.Examples include proguanil alone (Paludrine ® ), pyrimethamine (Daraprim ® ), dapsone-pyrimethamine (Maloprim ® ) and mefloquine-sulfadoxine-pyrimethamine (Fansimef ® ).
However, if the traveller experiences significant adverse events because of the chemoprophylactic agent, the medication can be changed, especially if the advice is provided by a health care provider (preferably the one who provided the initial advice).

Adherence to chemoprophylaxis
The reasons for non-adherence include lack of knowledge that malaria was a threat; fear of or past experience with adverse effects of chemoprophylactic agents; the false belief that prior malaria infections have conferred long-term immunity; the cost of medications; and confusion arising from contradictory recommendations.However, there is little information on how to enhance adherence.
Health care providers themselves need to be properly informed to be able to provide appropriate guidance (58).Travellers who use one qualified information source, such as a family physician trained in travel medicine, are significantly more likely to be compliant with malaria prophylaxis than those who collect information from multiple sources that could contradict each other (58,59).

Summary
A summary of the key changes made to the 2014 Guidelines are noted in Table 3.

Table 3: Summary of key additions and changes to the 2014 Guidelines pertaining to prevention of malaria (7)
Additions 1.The addition of a length-of-stay threshold for use of malaria chemoprophylaxis so that health care providers can better tailor individualized risk assessments (see Chapter 2).
2. A new insect repellent, 20% icaridin, is recognized as an equivalent to DEET as a first-line choice for mosquito repellent (see Chapter 3).
3. The guidelines have been expanded for populations requiring special attention -children, migrants, expatriates and travellers visiting friends and relatives, women who are pregnant or breastfeeding, and travellers with comorbidities (Chapter 5).

A new "Malaria
Card" that can be given to travellers with information about their malaria chemoprophylaxis and an important reminder to seek medical attention in the event of a fever illness after travel.

Changes
1. Chapter 4, "Prevention -Chemoprophylaxis Regimens," has been refined to make it easier to navigate the drug choices available.These changes include a simplified, step-wise approach to selecting malaria prophylaxis; comprehensive listings of medications and malaria risk by country/area in tabular form; and expanded explanation of the differences in approaches to malaria prophylaxis in other jurisdictions.
2. Chapter 8, "Drugs for the Prevention and Treatment of Malaria," includes an update on primaquine use for malaria prophylaxis and prevention; additional up-to-date information on pediatric dosing of atovaquone/proguanil; and general updates to Table 8.11: Drugs (generic and trade name) for the treatment and prevention of malaria.
Revisions have also been made to the following sub-sections related to malaria prevention: chloroquine and mefloquine (with increased emphasis on selection or avoidance of this drug according to individual tolerability).

E II 1
EBM = Evidence based medicine.The EBM ratings are as follows: Strength of recommendation: A = Good evidence to support a recommendation for use B = Moderate evidence to support a recommendation for use C = Poor evidence to support a recommendation for or against use D = Moderate evidence to support a recommendation against use E = Good evidence to support a recommendation against use Quality of evidence: I = Evidence from at least one properly randomized, controlled trial II = Evidence from at least one well-designed clinical trial without randomization; from cohort or case-controlled analytic studies, preferably from more than one centre; from multiple time series; or from dramatic results in uncontrolled experiments III = Evidence from opinions of respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees (36)(37)(38)(39)(40)Screening on doors, windows, eaves and other gaps in the building(28)(29)(30); o Bed nets treated with insecticide(31)(32)(33); o Full-length, loose-fitting and light-coloured clothing (clothes can also be treated with insecticide).Chemicalbarriersrepelmosquitoesand/or kill them(34,35).The main chemical modalities currently available are topical insect repellents for use on exposed skin and insecticides that impregnate bed nets and clothing(36)(37)(38)(39)(40).

Table 2 : Selecting antimalarial drugs for specific regions of drug resistance
Most transmission in provinces east of the Panama Canal toward the border with Colombia.P. falciparum resistance to chloroquine has been reported in Darién and Kuna Yala (San Blas).ATQ-PG, DOXY or MFQ.21 Pakistan All areas at elevations < 2000 m.Risk is due to both P. vivax and P. falciparum.Risk lower in the north, including Islamabad, especially during winter months because of cool temperatures.In general, risk is higher in more easterly regions of Indonesia: in particular, the provinces of East Nusa Tenggara, Maluku, North Maluku, Papua (Irian Jaya) and West Papua.There is also risk on LombokIsland and the rural areas of KalimantanIsland (Borneo).There is a low risk of transmission in rural Java and Bali and sporadic cases reported among travellers to rural areas of Bali.In the other parts of the country, there is malaria risk in some districts.