Supplement 2004 Canadian Recommendations for the Prevention and

Supplement 2004 Canadian Recommendations for the Prevention and
Canada Communicable Disease Report
ISSN 1188-4169
Volume : 30S1
June 2004
Supplement
Canadian Recommendations
for the Prevention and
Treatment of Malaria Among
International Travellers
2004
Our mission is to help the people of Canada
maintain and improve their health.
Health Canada
Suggested citation: Health Canada. Canadian recommendations for the
prevention and treatment of malaria among international travellers .
CCDR2004;30S1:1-62.
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¾¾ 2004 ¾¾
Canadian recommendations for the prevention
and treatment of malaria among international travellers
prepared by the
COMMITTEE TO ADVISE ON TROPICAL MEDICINE AND TRAVEL (CATMAT)
Any enquiries may be directed to the
Travel Medicine Program
Quarantine, Travel and Migration Health
Office of Public Health Security
Centre for Emergency Preparedness and Response
Health Canada
Telephone: (613) 957-8739 FAX: (613) 952-8286
¾¾ TABLE OF CONTENTS ¾¾
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iii
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3. Chemoprophylactic Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
a.
b.
c.
d.
e.
f.
Risk of Acquiring Malaria . . . . . . . . . . . . . . . . . . .
Personal Protective Measures to Prevent Mosquito Bites.
Chemoprophylactic Drugs (where appropriate) . . . . .
Early Diagnosis and Treatment . . . . . . . . . . . . . . .
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4. Prevention of Malaria in Special Hosts . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Malaria Prevention in Children. . . . . . . . . . . . . . . .
Malaria Prevention in Pregnancy . . . . . . . . . . . . . .
Prophylaxis While Breast-feeding . . . . . . . . . . . . . .
Malaria Prevention in the Medically Compromised Host.
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5. Malaria Prevention in the Long-term Traveller or Expatriate . . . . . . . . . . . . .
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6. Self-treatment of Presumptive Malaria. . . . . . . . . . . . . . . . . . . . . . . . . . .
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Discuss Common Errors Concerning Malaria Recognition and Management
Advise that Malaria Presents in Various Ways . . . . . . . . . . . . . . . . . . .
Indicate the Need to Seek Professional Medical Care As Soon As Possible . . .
Select the Self-treatment Drug with Care . . . . . . . . . . . . . . . . . . . . . .
Educate About Drugs to Avoid . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Step 1.
Step 2.
Step 3.
Step 4.
Step 5.
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a.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chloroquine-sensitive Regions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chloroquine-resistant Regions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chloroquine- and Mefloquine-resistant Regions . . . . . . . . . . . . . . . . . . . . . .
Primaquine Terminal Prophylaxis for Prevention of Relapses of P. vivax and P. ovale .
Selection of Antimalarial Drugs for Individual Travellers. . . . . . . . . . . . . . . . . .
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7. Malaria Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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i
8. Treatment of Malaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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a. General Principles of Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
b. Management of Falciparum Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
c. Management of Non-falciparum Malaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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9. Drugs for the Prevention and Treatment of Malaria . . . . . . . . . . . . . . . . . . .
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Appendices
Appendix I.
Appendix II.
Appendix III.
Appendix IV.
Appendix V.
Appendix VI.
ii
Malaria Risk by Geographic Area in Countries with Endemic Malaria .
Strength and Quality of Evidence Summary. . . . . . . . . . . . . . . .
Instructions for Insecticide Treatment of Bed Nets and Clothing . . . .
Checklist for Travellers to Malarial Areas . . . . . . . . . . . . . . . . . .
Frequently Asked Questions about Malaria . . . . . . . . . . . . . . . .
Contact Information for the Canadian Malaria Network . . . . . . . .
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47
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¾¾ PREFACE ¾¾
The prevention and treatment of malaria have changed considerably over the last decade,
primarily as a result of the development and spread of drug-resistant parasites and a
global resurgence of disease.
The following recommendations are guidelines prepared by the Malaria Subcommittee of
CATMAT for health care providers to assist travellers in preventing symptomatic
malaria and reducing the risk of severe illness or death from this infection.
The Travel Medicine Program at Health Canada provides a valuable resource for the
traveller and the travel medicine provider. Information concerning malaria and many
aspects of the health of travelling Canadians is available at www.travelhealth.gc.ca.
CATMAT Members
Ex-Officio Representatives
Dr. B. Ward (Chair); H. Birk; M. Bodie-Collins (Executive
Secretary); Dr. M-H Favreau; Dr. K. Gamble; Dr. S. Houston; Dr. S Kuhn; Dr. A.E. McCarthy; Dr. K. McClean;
Dr. P.J. Plourde; Dr. J.R. Salzman
Dr. R. Corrin (Therapeutic Products Directorate, Health
Canada); Dr. B. Dobie (Citizenship and Immigration Canada) Dr. E. Gadd (TPD); Dr. N. Gibson (Department of
National Defence); Dr. J. Given (Workplace Health and
Public Safety Programme, Health Canada);
Dr. P. Kozarsky (Centers for Disease Control and Prevention [CDC]); Dr. P. McDonald (Division of Anti-infective
Drugs); Dr. M. Parise (CDC); Dr. M. Tepper (Department of
National Defence); Ms. N. Theberge (Department of Foreign Affairs and International Trade)
Liaison Representatives
Dr. R. Birnbaum (Canadian Society for International
Health); Dr. C. Greenaway (Canadian Infectious Disease
Society); Dr. V. Marchessault (Canadian Paediatric Society
and National Advisory Committee on Immigration);
Dr. R. Saginur (Canadian Public Health Association);
Dr. P. Tietelbaum (Canadian Society for International
Health)
Member Emeritus
Dr. C.W.L. Jeanes
Malaria Subcommittee Members
Dr. A.E. McCarthy (Chair); Dr. K. Gamble; Dr. S. Kuhn;
Dr. P.J. Plourde; Dr. P. McDonald; Dr. M. Parise; Dr. N. Gibson; Dr. K. McLean; Dr. C. Greenaway; Dr. M. Tepper
iii
¾¾ PREAMBLE ¾¾
The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides Health
Canada with ongoing and timely medical, scientific, and public health advice relating to
tropical infectious disease and health risks associated with international travel.
Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and
the medical community caring for travellers.
Persons administering or using drugs, vaccines, insect repellents or other products should
also be aware of the contents of the product monograph(s) or other similarly approved
standards or instructions for use. Recommendations for use and other information set out
herein may differ from that set out in the product monograph(s) or other similarly
approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their
products only when used in accordance with the product monographs or other similarly
approved standards or instructions for use.
iv
¾¾ 1. INTRODUCTION ¾¾
Malaria is a common and serious infection caused by
four species of the genus Plasmodium: Plasmodium
falciparum, Plasmodium vivax, Plasmodium ovale, and
Plasmodium malariae. Infection with P. falciparum can
be fatal, and infections caused by P. vivax and P. ovale
can relapse from latent liver stages. All species of
malaria are transmitted by the bite of an infected
female Anopheles mosquito. Rarely, transmission may
occur by blood transfusion, by shared needle use, or
congenitally from mother to fetus. The disease is
characterized by FEVER and “flu-like” symptoms
such as myalgias, headache, abdominal pain, and
malaise. Rigors and chills often occur. The classically
described alternate-day fevers or other periodic fevers
are often not present. Severe malaria due to P.
falciparum may cause seizures, coma, and renal and
respiratory failure, and may lead to death. Malaria
deaths are frequently the result of delays in the diagnosis and treatment of the infection.
THE SYMPTOMS OF MALARIA ARE NON-SPECIFIC,
AND DIAGNOSIS IS NOT POSSIBLE WITHOUT A
BLOOD FILM.
The widespread resistance of P. falciparum to
chloroquine has complicated the prevention and
treatment of malaria. Drug-resistant strains of malaria
are now common in much of the world. The maps in
Figures 1a and 1b indicate the geographic distribution of P. falciparum malaria based on patterns of
resistance. These regions require frequent updating as
the malaria situation continues to evolve.
Figure 1a
Map showing malaria-endemic zones worldwide*
No malaria reported
No chloroquine resistance
Chloroquine resistance
Chloroquine and mefloquine resistance
*Visual aid only, see Appendix I, page 47, for specific country recommendations.
1
Figure 1b
Enlarged map of China and Thailand
showing patterns of malaria resistance*
Figure 2
Trends in reported malaria cases,
Canada, 1993-2002
China
Taiwan
Hainan
Myanmar
Thailand
Lao People's
Democratic Republic
Viet Nam
Cambodia
No malaria reported
Malaysia
No chloroquine resistance
Chloroquine resistance
Chloroquine and mefloquine resistance
*Visual aid only, see Appendix I, page 47, for specific country
recommendations.
As noted in Figure 2, the number of reported cases of
malaria in Canada peaked in 1997 and then
decreased. It is anticipated that the cyclical increase
in malaria cases will recur. However, it is estimated
that only 30% to 50% of cases are reported to public
health agencies, and therefore the true number of
imported cases into Canada is likely to be substantially higher. This assumption is supported by a
recent study of laboratory reporting in two Canadian
provinces, where only 52% to 71% of confirmed laboratory cases were reported to Health Canada. Canada’s rate of imported malaria continues to be 3 to 10
times the per capita rate of the United States, which
may reflect true differences in risk or may be a reporting artefact.
The majority of imported P. falciparum cases continue to be acquired in subSaharan Africa, and the
2
* Note 2001 and 2002 numbers are preliminary and subject to change.
majority of P. vivax cases are acquired in the Indian
subcontinent. The increased number of Canadian
malaria cases has been associated with severe and
fatal cases. There have been 11 malaria deaths
reported since 1997, all due to P. falciparum. As well,
since June 2001 there have been 25 cases of malaria
requiring parenteral quinine for treatment of severe
or complicated disease. Factors contributing to all of
these severe and fatal cases were noncompliance with
or failure to use appropriate chemoprophylactic
agents, delay in diagnosis and treatment, and incorrect therapy once a diagnosis had been reached.
Almost all malaria deaths in travellers are due to P.
falciparum. The overall case-fatality rate of imported
P. falciparum malaria varies from approximately 1%
to 5% and increases to 30% for those > 70 years of
age. Progression from asymptomatic infection to
severe and complicated malaria can be extremely
rapid, with death occurring within 36 to 48 hours.
The fatality rate of severe malaria is > 20% even when
the disease is managed in modern intensive care
units. The most important factors that determine
patient survival are early diagnosis and appropriate
therapy. The majority of infections and deaths due to
malaria are preventable.
¾¾ 2. PREVENTION ¾¾
Four components of malaria prevention should be
discussed with the traveller:
a. the risk of acquiring malaria
b. personal protective measures to prevent mosquito
bites
c. chemoprophylactic drugs (where appropriate)
d. 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
3
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
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).
Ÿ physical barriers, e.g., clothing, bed nets
Ÿ 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
4
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.
Ÿ DEET: The repellent DEET (N,N-diethyl-3-
methylbenzamide, also known as N,N-diethylm-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 insectprotected 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).
Ÿ “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
* 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.
5
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
AI
DEET 10%-30%
Pump spray, aerosol,
lotion, stick
Cutter Backwoods
Cutter Backyard
Cutter Outdoorsman
Deep Woods OFF!
Muskol
OFF!
4-6
AI
DEET 20%-35%
Lotion
(microencapsulated
slow release)
Sawyer
Ultrathon
8-12
AI
Citronella oil 5%-15%
Pump spray, lotion, oil, Buzz Away
towelette
Green Ban
Herbal Armor
Natrapel
0.3-0.5
(20-30 min)
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.
allergic to DEET) (A II – evidence-based medicine recommendation).
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
6
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.
Ÿ 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
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.
been evaluated by the PMRA, and there are
currently no registered products available in
North America (www.autan.co.uk/index.html).
§ Insecticides
Ÿ Treated mosquito nets: All travellers with itin-
eraries to locales outside Canada that are
endemic for malaria should be strongly encouraged to use pyrethroid (e.g., permethrin, deltamethrin, 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
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
AI
Deltamethrin SC 1%
Suspension concentrate
K-Orthrine
12
AI
Deltamethrin 400 mg
Tablet
K-O Tab
12
AI
Lambda-Cyhalothrin CS 2.5%
Capsule suspension
Icon
9
AI
Cyfluthrin EW 0.05%
Water emulsion
Solfac
6-9
AI
Alpha-Cypermethrin SC 10%
Suspension concentrate
Fendona
6-9
AI
*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.
7
Ÿ 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).
Ÿ 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
8
§ safety and efficacy of chemoprophylactic regi-
mens (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:
i.
Will the traveller be exposed to malaria?
ii. Will the traveller be in a drug-resistant P.
falciparum zone?
iii. 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?
iv. Are there any contraindications to the use of a
particular antimalarial drug?
v. 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 Cen-
tral 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.
9
¾¾ 3. CHEMOPROPHYLACTIC REGIMENS ¾¾
a. Introduction
Medications to reduce the risk of visitors acquiring
clinical malaria should be considered during evening
or overnight exposure in the following areas:
URBAN AND RURAL AREAS OF
(Higher risk) – subSaharan Africa (except most of
South Africa) and Oceania (including Papua New
Guinea, Papua, Solomon Islands and Vanuatu)
(Low to moderate risk) – Haiti, India, Bangladesh,
Pakistan, and Nepal (Terai region)
RURAL AREAS OF
Southeast Asia, Central and South America, and certain parts of Mexico, North Africa, and the Dominican Republic (adjacent to Haitian border).
Travellers should be informed that antimalarial medication can markedly decrease the risk of acquiring
symptomatic malaria. However, none of these agents
can guarantee complete protection against malaria.
Personal protective measures are an important adjunct
to malaria prevention, even for those taking
chemoprophylactic drugs (see Section 2, page 3, for
prevention). Symptoms due to malaria may occur as
early as 1 week after first exposure and as late as several years after travellers leave a malarial region
whether or not chemoprophylaxis has been used. Most
travellers who acquire P. falciparum infection will
develop symptoms within 3 months of exposure.
Falciparum malaria can be effectively treated early in
its course, but delay in therapy may result in a serious
and even fatal outcome.
FEVER OCCURRING IN A TRAVELLER WITHIN 3
MONTHS OF DEPARTURE FROM A MALARIA- ENDEMIC
AREA IS A MEDICAL EMERGENCY AND SHOULD BE
INVESTIGATED URGENTLY BY MEANS OF THICK AND
THIN BLOOD FILMS; IF SYMPTOMS PERSIST, THESE
FILMS SHOULD BE REPEATED TWICE AT 12 TO 24
HOUR INTERVALS IF THE PATIENT REMAINS
SYMPTOMATIC (SEE SECTION 8 AND FIGURE 3)
10
There is no global consensus on malaria chemoprophylactic regimens. During their travels many
individuals will encounter other travellers or health
care providers who will counsel them to change or
stop their antimalarial medication (especially
mefloquine), leaving them at high risk of acquiring
potentially life-threatening malaria. Travellers should
be warned of this possibility; as well, the antimalarial
guidelines and the risks and benefits of effective
chemoprophylaxis should be reinforced. Appendix V
(page 57), entitled “Frequently Asked Questions
about Malaria”, may aid the practitioner in answering
travellers’ questions. If desired, this text can be copied
and provided to the traveller.
Table 3 summarizes the different chemoprophylactic
options according to the presence of drug resistance.
See Section 9 for details regarding individual chemoprophylactic agents.
b. Chloroquine-sensitive Regions
Chloroquine-sensitive regions are those malarial
areas where chloroquine resistance has not been documented or is not widely present. These include
Haiti, the Dominican Republic, Central America
north of the Panama Canal, North Africa and parts of
the Middle East, and west/central China. See individual countries in Appendix I (page 47) for precise
recommendations.
Drug of choice: chloroquine (Aralen®) is the drug of
choice for travellers to areas with chloroquinesensitive malaria (A I – evidence-based medicine recommendation, see Appendix II). Chloroquine is
taken once weekly, beginning 1 week before entering
a chloroquine-sensitive malarial region, during the
period of exposure, and for 4 weeks after leaving the
malarial region.
Alternatives: For individuals unable to tolerate
chloroquine, atovaquone/proguanil, doxycycline, or
mefloquine should be used (see Section 3c, and Section 9).
c. Chloroquine-resistant Regions
The chloroquine-resistant regions refer to most of
Africa, South America, Oceania and Asia. See individual countries in Appendix I for specific recommendations. Note that some border areas of Thailand,
Myanmar, and Cambodia are also mefloquine-resistant regions (see Section 3d).
There are sufficient data in semi-immune and
non-immune hosts in various geographic locations to
conclude that atovaquone/proguanil, doxycycline,
and mefloquine are equally efficacious in the prevention of chloroquine-resistant malaria.
Drugs of choice: Atovaquone/proguanil, doxycycline,
or mefloquine (A I – evidence-based medicine recommendation); see Table 3 and Section 9 for details on
each medication.
Atovaquone/proguanil is taken daily, beginning 1
day before entering the malarial region, during the
period of exposure, and for 1 week after leaving the
malarial region.
Doxycycline is taken daily, beginning 1 day before
entering the malarial region, during the period of
exposure, and for 4 weeks after leaving the malarial region.
Mefloquine is taken weekly, beginning 1 week
before entering the malarial region, during the
period of exposure, and for 4 weeks after leaving the
malarial region.
Alternative: primaquine is taken daily, beginning 1
day before entry into the malarial region, during the
period of exposure, and for 4 weeks after leaving the
malarial region.
NOTE: Primaquine is CONTRAINDICATED in
G6PD (glucose-6-phosphate dehydrogenase) deficiency and CONTRAINDICATED in pregnancy. See
Table 8 for details on medication.
d. Chloroquine- and Mefloquineresistant Regions
Resistance to both chloroquine and mefloquine has
been reported sporadically from various countries in
Asia, Africa, and in the Amazon basin. However, it
has not been found to be a significant problem except
in rural, wooded regions where Thailand borders
with Myanmar (Burma) and Cambodia. These are
areas that are infrequently visited by tourists. See Figure 1b (page 2) for a map of this area. In addition to
chemoprophylaxis, personal protective measures
should be optimized.
Drug of choice: Doxycycline (see Table 3 and Section 9). Doxycycline is taken daily, beginning 1 day
before entering the malarial region, during the
period of exposure, and for 4 weeks after leaving the
malarial region.
Alternatives: There are no trials of alternative prophylactic agents for travellers to this region. Therefore
unnecessary travel to the area, especially by pregnant
women and children < 8 years of age, should be
avoided. Atovaquone/proguanil has been a successful
treatment for multi-drug resistant malaria in Thailand,
and therefore this medication may be considered for
travellers at risk in whom doxycycline is contraindicated or not tolerated. Atovaquone/proguanil is taken
daily, beginning 1 day before entering the malarial
region, during the period of exposure, and for 1 week
after leaving the malarial region.
11
Table 3.
Malaria chemoprophylaxis regimens for at-risk individualsa according to presence of drug resistance
b
Region
Drug(s) of choice
Alternatives
Chloroquine sensitive
Chloroquine
Chloroquine resistant
Atovaquone/proguanil, doxycycline, or Primaquinec
mefloquine
Chloroquine and mefloquine
resistant
Doxycycline
d
Atovaquone/proguanil, doxycycline,
mefloquine
Atovaquone/proguanil
a
IMPORTANT NOTE: Protection from mosquito bites (bed nets, insect repellents, etc) is the first line of defence against malaria for ALL travellers. In the
Americas and Southeast Asia, chemoprophylaxis is recommended ONLY for travellers who will be exposed outdoors in rural areas during evening or
night-time.
b
See text and Table 8 for adult and pediatric dosing information.
c
Contraindicated in G6PD (glucose-6-phosphate dehydrogenase) deficiency and in pregnancy.
d
Contraindicated in pregnancy, during breast-feeding, and in children < 8 years.
e. Primaquine Terminal Prophylaxis
for Prevention of Relapses of
P. vivax and P. ovale
P. vivax and P. ovale parasites can persist in the liver
and cause relapses for as long as 5 years after routine
chemoprophylaxis has been discontinued. Since most
malarial areas of the world (except Haiti and the
Dominican Republic) have at least one species of
relapsing malaria, travellers to these areas have some
risk of acquiring either P. vivax or P. ovale, although
actual risk for an individual traveller is difficult to
define. Primaquine decreases the risk of relapses by
acting against the persistent liver stages
(hypnozoites) of P. vivax and P. ovale. Primaquine
terminal prophylaxis is administered after the traveller has left a malaria-endemic area, usually during or
after the last 2 weeks of chemoprophylaxis. It is generally indicated only for people who have had prolonged exposure in malaria-endemic regions (e.g.,
long-term travellers or expatriates). Primaquine is
contraindicated in pregnant women and individuals
deficient in G6PD (see Table 3 and Section 9).
f. Selection of Antimalarial Drugs
for Individual Travellers
Malaria causes severe illness that may be lifethreatening. Mortality is at least 1% and increases to
20% or more in severe or complicated cases. Therefore it is always preferable to prevent the disease
12
rather than treat someone after symptoms develop.
Given the variety of choices in medication, a traveller
at risk of malaria should always be encouraged to use
chemoprophylaxis along with personal protective
measures against insect bites (see Section 2).
All antimalarial drugs have the potential to cause side
effects and should be prescribed only after completion of an individual risk assessment (as outlined in
Section 2, page 8), to ensure that only travellers truly
at risk of malaria infection receive antimalarial
chemoprophylaxis. In deciding between the various
chemoprophylactic options, the health care provider
must weigh the traveller’s underlying health status,
other medications, malaria drug efficacy, risks and
character of adverse drug reactions as well as the
individual’s preference against the likelihood that he
or she will be exposed to malaria.
Most users of antimalarial chemoprophylaxis will
have no or only minor adverse reactions. However,
preconceived ideas about side effects may profoundly
influence the traveller’s confidence in a particular
medication option and should be considered in the
selection process. If adverse events do occur, they can
have a significant impact not only on the traveller’s
health but also on his or her compliance with the
medication. One option available is a trial of medication in advance of travel to test for tolerability. To
keep adverse effects to a minimum, it is essential that
all travellers be educated about the dosing schedule,
including time of day and association with food, as
well as precautions regarding sun exposure or other
advice, depending on the drug used. Remember that
while several antimalarial drugs may be equally efficacious when studied in clinical trials, their effectiveness is a measure of protection offered in real life.
The more educated and compliant the patient, the
closer the effectiveness is to the efficacy of a given
chemoprophylactic agent.
Fatal malaria has occurred in travellers who have discontinued an effective antimalarial drug in favour of
one that is less protective. Therefore, travellers should
be warned to continue their malaria chemoprophylaxis
regardless of what they are told by other travellers. Different medications used in other areas of the world
may be less effective or associated with serious adverse
effects, and are not recommended. Examples include
proguanil alone (Paludrine®), pyrimethamine
(Daraprim®), dapsone/pyrimethamine (Maloprim®),
and mefloquine/sulfadoxine-pyrimethamine
(Fansimef®).
SUMMARY POINTS TO KEEP IN MIND
DURING THE DISCUSSION OF CHEMOPROPHYLAXIS INCLUDE THE FOLLOWING:
1. Inform patients that malaria can kill, but medications rarely cause serious adverse events if
selected and used with care.
2. Select a medication that is least likely to exacerbate any past or present medical problems.
3. Indicate that medication should be taken in
the recommended fashion to minimize significant side effects.
4. Discuss the option of a drug trial before the
trip to check tolerability, if this is a concern.
5. Discuss strategies to change medication if serious adverse effects should arise during the trip.
6. Do not try to talk someone into a particular
medication choice if there are alternatives that
are considered to be just as efficacious.
7. Recommend that, if a malaria medication is
tolerated well, the traveller should continue
taking it regardless of what others say.
13
¾¾ 4. PREVENTION OF ¾¾
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. Pyrethroidtreated 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
14
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 chloroquineresistant 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, page 43).
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 recommenda-
tion, 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
i.
If possible, young children should avoid travel to
areas with significant transmission particularly of
chloroquine-resistant malaria (C III – evidence-based medicine recommendation).
ii. Personal protective measures should be strongly
encouraged for all children who travel to
malaria-endemic areas (A I – evidence-based
medicine recommendation).
iii. Young children travelling to or residing in
chloroquine-sensitive areas should use
chloroquine as chemoprophylaxis (A I – evidence-based medicine recommendation).
iv. 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.
v. 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 transplacentally 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
15
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
i.
If possible, pregnant women should avoid travel
to areas with significant transmission particularly
of chloroquine-resistant malaria (C III – evidence-based medicine recommendation).
ii. Personal protective measures should be strongly
encouraged for all pregnant women who travel to
malaria-endemic areas (A I – evidence-based
medicine recommendation).
iii. Pregnant women travelling to or residing in
chloroquine-sensitive areas should use
chloroquine as chemoprophylaxis (A I – evidence-based medicine recommendation).
iv. 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).
v. 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).
vi. 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
16
suboptimal antimalarial combination would not
routinely be recommended (A I – evidence-based
medicine recommendation).
vii. 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 breastfeeding 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 com-
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).
plexity of potential interactions between antimalarial
and other medications.
Immunocompromised hosts
i.
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.
ii. 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
iii. 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
i.
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.
ii. 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.
iii. Hepatic or renal dysfunction: Moderate to
severe hepatic or renal dysfunction may result in
significant alteration in antimalarial medication
17
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
i.
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).
ii. 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).
18
iii. Personal protective measures for malaria prevention must be emphasized (A III – evidence-based
medicine recommendation).
iv. Carefully selected antimalarial chemoprophylaxis
should be used for those at unavoidable risk of
the disease (A I – evidence-based medicine
recommendation).
v. 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 chemoprophylaxis 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).
¾¾ 5. MALARIA PREVENTION IN THE ¾¾
LONG-TERM TRAVELLER OR EXPATRIATE
Modern prevention strategies have had a significant,
positive impact on the risk of mortality in long-term
expatriates, which was reported to be as high as 60%
among missionaries in West Africa during the 19th
century. However, the effort to develop unique, evidence-based guidelines for the long-term (> 6
months) traveller or expatriate is severely hampered
by a paucity of medical literature in this area.
Concerns encountered when addressing malaria prevention in long-term travellers and expatriates
include conflicting counsel regarding appropriate
chemoprophylaxis and self-treatment, the safety of
drugs used for chemoprophylaxis, fear of toxic effects
with prolonged use of medication, and lack of adherence to the use of personal protective measures. Confidence but lack of rigour in self-diagnosis coupled
with unreliable laboratory diagnosis in many developing countries have resulted in a misrepresentation
of drug efficacy by the long-term traveller/expatriate.
Data on the incidence of malaria and the effectiveness
and tolerance of currently recommended regimens
for long-term travellers are limited to the studies of
Peace Corps volunteers, in whom mefloquine was
well tolerated and was more effective than
chloroquine and proguanil in chloroquine-resistant
regions. At present, there is no evidence that
long-term use of therapies currently recommended
for short-stay travellers causes significant adverse
reactions. Doxycycline may be an exception, as studies have been confined to short-term travellers and
people using tetracyclines (at lower doses) as therapy
for skin conditions. In general, guidelines for the prevention of malaria in long-term travellers or expatriates should not deviate significantly from standard
recommendations for the short-term traveller.
A recent, self-reported summary of the malaria prevention strategies of 1192 long-term expatriates, representing a broad range of government and
non-government organizations in subSaharan Africa,
may provide some assistance in counselling
long-term travellers and expatriates. Overall, their
compliance rate was approximately 60%. Of those
receiving chemoprophylaxis, 54% reported changing
their prophylactic regimen, 22% because of adverse
effects. The severity of the adverse effects was not
associated with any specific drug, but the reported
incidence of neuropsychiatric side effects was 10%
among people taking chloroquine and proguanil as
compared with 17% in the mefloquine group.
Mefloquine was the only regimen for which participants reported a change in practice based on media
influence. Only a small number indicated that availability and cost were factors in their choice of prophylactic regimen. Participants who did not use
prophylaxis cited concerns about adverse reactions
and long-term effects as the primary reasons for their
choice. Personal protective measures were
suboptimal: only 38% had screened doors and windows, and 53% used mosquito netting (20% of which
were insecticide-treated nets).
There are no data available on self-diagnosis and
self-treatment of malaria in the long-term traveller or
expatriate population. Without training, there is no
reason to believe that the efficacy of these interventions will be any better than that demonstrated in the
general travel population. However, given that
long-term travellers and expatriates represent a reasonably homogeneous group, training in diagnosis
and self-treatment (see Sections 6 and 7), including
the use of rapid diagnostic tests for malaria, may
19
prove to be helpful in this population when access to
reliable, formal medical care is inadequate. Self-diagnostic kits that require refrigeration will limit access
to this technology in some regions.
Section 3e (page 12) addresses the use of primaquine
as terminal prophylaxis to decrease the risk of
relapses through its action against the liver stages of
P. vivax and P. ovale. Primaquine terminal prophylaxis is administered after the traveller has left a
malaria-endemic area, usually during or after the last
2 weeks of chemoprophylaxis. Terminal prophylaxis
with primaquine is generally indicated only for people who have had prolonged exposure in malariaendemic regions, such as expatriates or long-term
travellers. Primaquine is contraindicated in pregnant
women and individuals deficient in G6PD (see Section 9 for contraindications and precautions).
In conclusion, guidelines for the prevention of
malaria in long-term travellers or expatriates should
not deviate significantly from the recommendations
20
for short-term travellers (B III – evidence-based
medicine recommendation, see Appendix II). The
available data indicate that expatriates in high-risk
settings have not effectively used personal protective
measures (B II – evidence-based medicine). The
majority use a prophylactic regimen, but sound counsel does not always guide their choice: a significant
proportion is influenced by perception of risk rather
than documented problems. Thus the effectiveness of
current recommendations will be influenced by the
prevailing attitudes in the subculture in which the
long-term traveller or expatriate lives (C – evidencebased medicine). At present, there is insufficient evidence for the effectiveness of self-diagnosis with rapid
malaria test kits to recommend their routine use.
Primaquine should be given as terminal prophylaxis,
after consideration of precautions and contraindications, to long-term travellers or expatriates who
return from regions with P. vivax transmission (A I –
evidence-based recommendation).
¾¾ 6. SELF-TREATMENT ¾¾
OF PRESUMPTIVE MALARIA
Counsel regarding appropriate management of
malaria is of value for all travellers in regions where
malaria is highly endemic because reliable medical
attention may not be available. However, travellers to
high-risk regions should never rely exclusively on a
self-treatment regimen. Under some circumstances,
individuals at risk of malaria may be unable to seek
medical care within 24 hours and may not have
access to facilities that stock appropriate medications;
therefore, they require access to medication for
self-treatment of presumptive malaria.
All travellers should be advised that the signs and
symptoms of malaria are non-specific, that there is a
risk of other potentially serious illnesses mimicking
malaria, and that there are potential adverse reactions
to malaria therapy; thus self-treatment should never
be undertaken lightly. Consultation with a tropical
medicine expert is recommended before individuals
are advised to embark on a self-treatment program.
Training long-term travellers and expatriates to
become proficient in their practice of self-treatment is
difficult, and efforts should focus on those living in
areas where access to expert supervision and care of
high quality is limited, and where the threat of
malaria is significant. Ninety percent of global episodes of clinical malaria and deaths occur in
subSaharan Africa; therefore, particular attention
should be given to people travelling to that region.
Training should consist of the following steps:
Step 1 – Discuss Common Errors
Concerning Malaria Recognition and
Management
The consultant should discuss common errors that
have compromised the value of self-treatment:
§ Expatriates assume that they can recognize
malaria from the symptoms.
§ They do not consistently assume that fever is
malaria until proven otherwise.
§ They commonly mistake the anti-inflammatory
and antipyretic effect of chloroquine to signify
that they have successfully treated malaria.
§ They do not always choose an appropriate regi-
men –
Ÿ the drug administered for treatment is the
same as that used for prevention;
Ÿ single drug therapy is chosen over combina-
tion therapy;
Ÿ the dose used is often that used in the commu-
nity for “semi-immunes”;
Ÿ the drug used is often less effective than that
used for prevention, e.g., mefloquine for prevention, chloroquine for treatment.
21
Step 2 – Advise that Malaria Presents in
Various Ways
b. SEEK MEDICAL HELP AS SOON AS
POSSIBLE.
Travellers should be advised that the clinical presentation of malaria is variable and may mimic other diseases. An alternative diagnosis that requires treatment
may be present, particularly in travellers who have
been compliant with an appropriate chemoprophylaxis regimen. The most frequent symptoms of
malaria are fever, headache, and generalized aches
and pains. Fever, which may or may not be cyclical,
is almost always present. Malaria can be
misdiagnosed as influenza or another febrile illness,
so that an early and accurate diagnosis is essential.
Malaria is likely to be over-reported by laboratory
technicians; nevertheless, if malaria is diagnosed
there should be follow-up with medical management.
c. Chloroquine prophylaxis should be started.
Step 3 – Indicate the Need to Seek Professional Medical Care as Soon as Possible
Travellers should be told that self-treatment is NOT
considered definitive treatment but is a temporary, lifesaving measure while they seek medical attention.
Self-treatment for malaria should be undertaken only if
fever develops and professional medical care is not
available within 24 hours. After self-treatment, medical
attention should still be sought as soon as possible.
Step 4 – Select the Self-treatment Drug
with Care
When choosing a drug regimen for self-treatment,
safety, efficacy, and drug tolerance must be considered priorities. Individuals who are undergoing
chemosuppression should never attempt treatment
with the same drug, as there is the potential for additive toxicity and reduced efficacy.
Recommended Regimens
(NOTE: to be used only if fever develops and medical
care is not available within 24 hours)
1. For individuals in chloroquine-sensitive regions
who are not receiving chloroquine prophylaxis:
a. Self-treatment with chloroquine should be initiated (see Table 4, page 24).
22
2. For individuals in chloroquine-sensitive regions
who are already receiving chloroquine
prophylaxis:
a. Self-treatment with atovaquone/proguanil
should be initiated (see Table 4).
b. SEEK MEDICAL HELP AS SOON AS
POSSIBLE.
c. Chloroquine prophylaxis should be resumed.
3. For individuals in chloroquine- or chloroquineand mefloquine-resistant P. falciparum regions
who are not receiving atovaquone/proguanil
chemoprophylaxis:
a. Self-treatment with atovaquone/proguanil OR
quinine plus doxycycline should be initiated.
b. SEEK MEDICAL HELP AS SOON AS
POSSIBLE.
c. Atovaquone/proguanil, doxycycline, or
mefloquine should be started or resumed.
4. For individuals in chloroquine- or chloroquineand mefloquine-resistant P. falciparum regions
who are receiving atovaquone/proguanil
chemoprophylaxis:
a. Self-treatment with quinine plus doxycycline
should be initiated.
b. SEEK MEDICAL HELP AS SOON AS
POSSIBLE.
c. Atovaquone/proguanil should be resumed.
Travellers may not have access to drugs approved by
Health Canada when travelling in chloroquine- or
chloroquine- and mefloquine-resistant regions. Conversely, they may have access to medication endorsed
by the Roll Back Malaria Program that has not been
formally approved for use in Canada. The Roll Back
Malaria Program advocates the use of some fixed
combination therapies because they improve compliance and efficacy while reducing errors and the emergence of drug resistance (see Table 4).
Step 5 – Educate About Drugs to Avoid
Warn the traveller about the following drug regimens, which are no longer recommended for
self-treatment because of potential severe adverse
effects and/or poor efficacy:
§ Halofantrine (causes cardiac deaths)
§ Mefloquine (unacceptably high rates of severe
adverse events at treatment doses)
§ Fansidar® alone (sulfadoxine plus
pyrimethamine) (resistance)
§ Chloroquine plus Fansidar® (resistance,
ineffective)
Rapid detection of malaria using a simple dipstick
test may be available to some travellers. The sensitivity and specificity of these tests vary, from 50% to
90%. Furthermore, there are limited data about their
accuracy in the hands of non-experienced operators
and under non-refrigerated conditions in the tropics.
There are no rapid detection kits currently licensed in
North America (see Section 7).
§ Fansimef® (mefloquine plus Fansidar®)
(resistance)
23
24
Frequent:
nausea, vomiting,
abdominal pain, diarrhea, increased
transaminase levels
Rare:
seizures, rash
Frequent:
Cinchonism (tinnitus,
nausea, headache,
blurred vision),
hypoglycemia, nausea,
emesis
Occasional:
hypersensitivity, nerve
deafness, esophageal
ulcer (doxycycline)
Rare:
hemolysis
Not approved in pregnant women or
breast-feeding mothers
Contraindicated in presence of renal failure
(creatinine clearance <
30 mL/min)
Nausea and vomiting
common with malaria
and as side effect of
medication
Emesis may interfere
with success of
treatment
May need to
premedicate with Gravol
Children < 8 yr cannot
receive doxycycline
Contraindicated in
pregnancy
Complicated regimen
reduces compliance
Adverse reactions to
quinine common and
interfere with tolerance
and effectiveness
Safe for children > 5 kg
Resistance rare
Fixed combination
allows for simple treatment regimen
Excellent safety profile
Resistance to combined
therapy rare
Rapid parasite clearance
Readily available
Cheap
20 mg/kg atovaquone
AND
8 mg/kg proguanil daily
x 3 days
11-20 kg: 1 tablet daily
21-30 kg: 2 tablets daily
31-40 kg: 3 tablets daily
> 41 kg: 4 tablets daily
Quinine 7.5 mg base/kg
three times daily x 7
days
Doxycycline 1.5 mg/kg
twice daily x 7 days
< 25 kg or < 8 yrs:
contraindicated
25-35 kg or > 8 yr: 50 mg
bid
36-50 kg: 75 mg bid
> 50 kg: adult dose
1000 mg atovaquone
AND
400 mg proguanil
(4 tablets) once daily x 3
days
Quinine 250 mg base, 2
tablets three times daily
x 7 days
Doxycyline 100 mg
twice daily x 7 days
Quinine sulfate
PLUS
Doxycycline
Frequent:
nausea, emesis,
headache
Occasional:
skin eruptions
Rare:
nerve deafness,
photophobia,
myopathy, blood
dyscrasias, psychosis
and seizures
Adverse effects
Atovaquone/proguanil
(Malarone®)
Adult tablet: 250 mg
atovaquone plus 100
mg proguanil
Disadvantage
Widespread resistance
Should not be administered to people using
chloroquine for
prevention
Advantage
Safe in pregnancy
Treatment:
Safe for children
25 mg base/kg total
over 3 days
Long-term safety data
10 mg base/kg, then 5
mg base/kg in 6 hours,
then 5 mg base/kg daily
x 2 days
Pediatric dosage
1.5 g base over 3 days
600 mg base, then 300
mg base in 6 hours, then
300 mg base daily x 2
days
Adult dosage
Chloroquine
(Aralen®)
Tablet: 150 mg base
Drug, generic
(trade) name
Table 4. Drugs for the self-treatment of malaria
Approved by Health
Canada for treatment of
chloroquine- resistant
malaria
Approved by Health
Canada for treatment of
chloroquine- resistant
malaria
Approved by Health
Canada for treatment of
chloroquine-sensitive
malaria (Central America
and Haiti)
Not recommended for
self-treatment in other
regions because of risk
of mixed infection with
P. falciparum
Health Canada
approval status
25
Co-artemether
CoartemTM
TM
Riamet Novartis
Drug, generic
(trade) name
Artemether 20 mg
AND
Lumefantrine 120 mg
6 dose regimen standard for non-immune
travellers at 0 and 8
hours on day 1 and
twice daily on days 2
and 3
4 tablets per dose
Adult dosage
Artemether 20 mg
AND
Lumefantrine 120 mg
6 dose regimen standard for non-immune
travellers at 0 and 8
hours on day 1 and
twice daily on days 2
and 3
5 kg to < 15 kg: 1
tab/dose
15 to 24 kg: 2
tabs/dose
25 to 34 kg: 3
tabs/dose
> 35 kg: 4 tabs per
dose
Pediatric dosage
Safety profile from data
available suggests safe
for children > 5 kg
Resistance not
documented
Rapid parasite clearance
Drug widely distributed
in Africa
More readily available
and less expensive than
Malarone®
Better tolerated than
artesunate plus
mefloquine
No adjustment of dose
required for elderly and
renal failure
Lumefantrine does not
cause cardiac conduction disturbance
Advantage
Adverse effects
Frequent:
nausea, vomiting,
abdominal pain, fatigue
Occasional:
fever, rigors, anemia
(some adverse events
reported may be due to
malaria)
Disadvantage
Not in pregnant women
and breast-feeding
mothers
Two regimens (4 dose
and 6 dose) described
on product monograph
is confusing;
NOTE: the 4 dose regimen for semi-immunes
only
Not approved by
Health Canada but
endorsed by WHO (Roll
Back Malaria Program)
Health Canada
approval status
¾¾ 7. MALARIA DIAGNOSIS ¾¾
It is imperative that a travel history be obtained from
all patients with a history of fever, and that thick and
thin blood films for malaria be requested urgently for
all individuals who have travelled to or through a
malaria-endemic area. P. falciparum malaria usually
presents within 3 months of last exposure; however,
it may be delayed in patients who have taken
chemoprophylaxis. In addition, other types of
malaria, especially that caused by P. vivax, may occur
months and occasionally up to 5 years after travel in
endemic areas.
The treatment of malaria depends upon the species of
parasite and the level of parasitemia; therefore, every
effort should be made to determine these parameters
on an urgent basis. Since malaria is a reportable disease in all provinces/territories, physicians are
required to report all cases to the local public health
authority.
Occasionally, a single blood film examination may be
falsely negative for malaria parasites. Repeat blood
films over 48 hours (e.g., every 12 hours x 3) may be
required to exclude the possibility of malaria.
The examination of thick and thin blood films by an
experienced microscopist is essential for the diagnosis of malaria. The clinical presentation (history and
physical examination) of malaria is often nonspecific. When malaria is a consideration, especially
when the patient may be at risk of P. falciparum infection (whether chloroquine-sensitive or not), the laboratory diagnosis and quantification of the level of
parasitemia must be considered a medical emergency
and performed as soon as possible (< 24-hour turnaround time).
Not all laboratories are proficient in the diagnosis and
speciation of malaria. If appropriate expertise cannot
be ensured, then the patient should be treated empirically for chloroquine-resistant falciparum malaria and
an immediate referral of the patient or the specimen
should be made to a specialized facility. These facili-
26
ties can be identified through the Canadian Malaria
Network Centres, listed in Appendix VI.
While rapid diagnostic tests (RDTs) that use dipstick
techniques for the diagnosis of malaria are currently
being evaluated in the research setting, none is currently licensed for use in Canada. These RDTs are
based on antigen detection of trophozoites and are
targeted primarily at P. falciparum infections. Some
tests differentiate between infections with other species or between falciparum and non-falciparum infection. They are simple to perform and do not require
special equipment. They are rapid to interpret and
require minimal training to operate. On the other
hand, they may remain positive for up to 2 weeks
after microscopic clearance, they are relatively expensive compared with microscopy, and they are not
quantitative.
A WHO working group has reviewed the issues surrounding these test kits and identified further
research required and possible scenarios for their use.
One such scenario would be for self-treatment by
travellers to remote areas. Research to date would
suggest that this is not feasible, as interpretation by
lay people is inaccurate (D II – evidence-based medicine, see Appendix II). There are no data available on
self-diagnosis and self-treatment in the long-term
traveller or expatriate population. Without training,
there is no reason to believe that the efficacy of these
interventions will be any better than that demonstrated in the general travel population. However,
given that long-term travellers and expatriates represent a reasonably homogeneous group, training in
diagnosis and self-treatment (see Section 6), including the use of rapid diagnostic tests for malaria, may
prove to be helpful in this population when access to
reliable, formal medical care is inadequate. Self-diagnostic kits that require refrigeration will limit access
to this technology in some regions.
Polymerase chain reaction (PCR) techniques are also
rapidly emerging as a definitive diagnostic tool and
can demonstrate impressive sensitivity and specificity
(B I – evidence-based medicine). They are, however,
limited to laboratories that have the expertise and
equipment to conduct these analyses and are still primarily research tools. They are useful as an adjunct to
microscopy to confirm cases with low parasitemia
and uncertain species. This is particularly useful in
Canada, where the incidence of disease is quite low.
The Canadian Malaria Network Centres, identified in
Appendix VI, can direct clinicians to sites where this
technology is available.
Recommendations
i.
ii. Microscopy of Giemsa stained thick and thin
smears is the current gold standard for the laboratory diagnosis of malaria (A I – evidence-based
medicine). Wright’s stained thick and thin smears
are used in some laboratories but may miss parasite details that assist in speciation.
iii. PCR has a role in the confirmation of diagnosis
but is not accessible widely in a timely fashion, as
of yet.
iv. RDTs are of limited utility in the Canadian setting
and should not be used as a primary diagnostic
tool (DI – evidence-based medicine).
The diagnosis of malaria in a suspected case is a
medical emergency and requires accurate laboratory testing within a maximum of 24 hours (A I –
evidence-based medicine).
27
¾¾ 8. TREATMENT OF MALARIA ¾¾
Malaria, particularly that due to P falciparum, is a
medical emergency, and management includes immediate treatment and close follow-up. If the species is
not unequivocally identified, the case should be
treated as P. falciparum until further identification
and, if there is doubt about resistance patterns, P.
falciparum should be treated as chloroquine resistant.
In Canada, all patients with malaria due to P.
falciparum should be considered for admission to
hospital or should receive initial treatment in an
observation unit to ensure tolerance of treatment and
to confirm decreasing parasitemia with treatment.
Severe or complicated disease (see Table 5) requires
parenteral therapy and close clinical monitoring,
preferably in an intensive care unit. If required, assistance in the management of malaria cases can be
obtained through access to the Canadian Malaria
Network site in the appropriate area (a contact list is
available in Appendix VI).
a. General Principles of Management
The initial management of the patient depends on
many factors, including the infecting species of
malaria, the severity of infection, the patient’s age, the
pattern of drug resistance in the area of acquisition as
well as the safety, availability, and cost of antimalarial
drugs. The base-salt equivalents of selected
antimalarials are shown in Table 6.
Three questions need to be addressed in order to initiate effective treatment:
1. Is this infection caused by P. falciparum?
This is critical, as treatment varies according to the
species of malaria.
2. Is this a severe or complicated infection
(see Table 5)?
Severe or complicated malaria requires parenteral
therapy and sometimes an exchange transfusion.
28
Table 5. Criteria for severe falciparum malaria
EITHER
History of recent possible exposure and no
other recognized pathology
OR
Asexual forms of P. falciparum on blood smear
AND
Any one or more of the following 11 features:
1) Impaired consciousness or coma
2) Severe normocytic anemia
3) Renal failure
4) Pulmonary edema or adult respiratory distress
syndrome (ARDS)
5) Hypoglycemia
6) Circulatory collapse, shock
7) Spontaneous bleeding/disseminated
intravascular coagulation
8) Repeated generalized convulsions
9) Acidemia/acidosis
10) Hemoglobinuria
11) Parasitemia of > 5% (> 250 000/microlitre) in
non-immune individuals
Adapted from Management of Severe Malaria: A Practical Handbook. 2nd
ed. Geneva: World Health Organization, 2000.
3. Has the infection been acquired in an area of
known drug-resistant malaria (see Appendix 1)?
Therapy will have to be modified accordingly. When
in doubt, treat all falciparum malaria as drug resistant.
Treatment of malaria does not stop with selection of
appropriate antimalarial medications. For all cases of
malaria, medical follow-up must be ensured. Clinical
assessment and repeat malaria smears should be carried out daily until negative and again 7 and 28 days
after treatment, and at any time symptoms recur.
Table 6. Base/salt equivalents of selected
antimalarial drugs
Drug
treatment doses provided, or the patient should
be directed to a pharmacy that can fill the prescription appropriately.
Base (mg)
Salt (mg)
150.0
250.0
Chloroquine sulfate
100.0
136.0
Clindamycin hydrochloride
150.0
225.0
Severe P. falciparum
Mefloquine
250.0
274.0
Quinidine gluconate
5.0
7.5
10.0
15.0
8.0
12.0
16.0
24.0
Quinidine sulfateb
7.5
10.0
15.0
9.0
12.0
18.0
Quinine dihydrochloride
5.0
7.5
15.0
16.7
6.0
9.0
18.0
20.0
Severe P. falciparum infections, as defined by the criteria in Table 5, may have a mortality rate of 20% or
higher. Patients with these infections require immediate hospitalization and urgent, intensive medical
management. They are at risk of all the adverse outcomes defined in Table 5 as well as other adverse outcomes, including permanent neurologic deficits,
chronic renal insufficiency, and death.
250.0
300.0
Chloroquine phosphate
a
Quinine sulfate
a
Not available in Canada
Intramuscular preparation should not be used intravenously.
b
b. Management of Falciparum Malaria
The following guidelines have been derived, in part,
from the WHO Division of Control of Tropical Diseases (Management of Severe Malaria: A Practical
Handbook. 2nd ed. Geneva: World Health Organization, 2000). The interested reader is referred to this
document for a more detailed discussion of these
issues.
§ A detailed geographic history is essential to the
management of malaria. P. falciparum malaria
acquired in areas where drug resistance is known
to occur should be treated as chloroquine resistant.
§ As a general rule, all non-immune patients with
P. falciparum malaria, whether severe or not,
should be considered for admission to hospital in
order to ensure tolerance of antimalarial drugs
and to detect complications or early treatment
failure. If hospital admission is not planned, then
all cases must be observed during their first dose
of therapy to ensure that it has been tolerated
before discharge from the emergency department. Before discharge there must be further
§ An algorithm for the management of malaria is
presented in Figure 3.
All patients with severe P. falciparum infections and
those who are unable to tolerate drugs orally should
receive intravenous quinine (see Table 7) available 24
hours per day via the Canadian Malaria Network (see
Appendix VI for more information). Less optimally,
they can be treated with parenteral quinidine.
CATMAT prefers quinine because of the cardiotoxicity of quinidine, necessitating electrocardiographic monitoring and dose reduction with
cardiac toxic effects (infusion rates should be
decreased if the corrected QT interval is prolonged by
more than 25% of baseline). When quinine or
quinidine is administered to a patient who has taken
mefloquine or halofantrine in the previous 2 weeks,
there is a risk of drug-induced cardiac arrhythmia;
such patients should be monitored electrocardiographically.
Many ancillary treatments have been suggested for
the treatment of severe malaria, but few have been
objectively shown to improve outcome. Only
antipyretic drugs (acetaminophen) and
anticonvulsants (prophylactic phenobarbitol) have
been supported by sufficient evidence to warrant
their use. The use of steroids to treat severe or cerebral malaria has been associated with worse outcomes
and should be avoided (E I – evidence-based medicine recommendation, see Appendix II). In cases of
complicated P. falciparum infection (Table 5), or if
there is high parasitemia ($ 10%), exchange transfusion has been used on an experimental basis as a
29
Figure 3
Algorithm for the management of malaria
MALARIA SUSPECTED
IMMEDIATE: blood smear thick and thin,
blood culture, liver enzymes, glucose, serum creatinine, blood urea nitrogen
Malaria smear NEGATIVE
If symptoms (fever, ‘flu-like’ illness)
persist repeat malaria smears every 12
to 24 hours for a total of 3
Malaria smear POSITIVE
Determine species and percentage parasitemia
Falciparum species or species not known
Non falciparum malaria
Treat as per text
Indication for parenteral therapy (evidence of complicated malaria or servere nausea/vomiting)?
YES
Consider admission to intensive care unit.
Treat with parenteral quinine.
Change to oral therapy as soon as possible.
potentially life-saving procedure. When managing a
patient with severe or complicated falciparum
malaria, consultation with an infectious or tropical
disease expert is strongly recommended (see Appendix VI for contact information).
Uncomplicated P. falciparum
Uncomplicated cases of P. falciparum can become
severe over 12 to 24 hours if not treated and monitored properly. Infections unequivocally acquired in a
chloroquine-sensitive zone may be treated with
chloroquine alone (as per Table 8, page 43). Infections possibly or definitely acquired in drug-resistant
regions (most cases of P. falciparum malaria seen in
Canada) should be treated with atovaquone/
proguanil or quinine plus a second drug (preferably
30
NO
Treat with oral therapy.
Admit, or observe for a minimum of 8 hours.
Ideally, before discharge ensure no increase in parasitemia.
doxycycline). If the patient can tolerate quinine given
orally, then it and the second drug – either
doxycycline or, for those in whom doxycycline is
contraindicated, clindamycin – may be administered
simultaneously or sequentially (start quinine first). If
oral medication cannot be tolerated, then parenteral
quinine should be administered as per Table 7.
c. Management of Non-falciparum
Malaria (P. vivax, P. ovale, P. malariae)
Outside of New Guinea (Papua New Guinea and
Papua [Irian Jaya]), chloroquine remains the treatment of choice for malaria other than falciparum
malaria (as per Table 8 ). As with P. falciparum
malaria, response to treatment should be documented
with a repeat of thick and thin blood films on day 7
and day 28 after therapy, and at any time there is
recurrence of symptoms. A recurrence of parasitemia
< 30 days after treatment suggests chloroquine-resistant P. vivax; recurrence after $ 30 days suggests
primaquine resistance.
Recent reports have confirmed the presence and high
prevalence (80%) of chloroquine-resistant P. vivax in
Papua (Irian Jaya). Sporadic cases of chloroquineresistant P. vivax malaria have been reported elsewhere (e.g., in Indonesia, Papua New Guinea, the
Solomon Islands, Myanmar, and Guyana). At present,
chloroquine can no longer be relied upon either for
chemoprophylaxis or treatment of P. vivax acquired
in New Guinea, and the optimal treatment is
unknown. Although effective, a prolonged course of
quinine (> 3 days) is often required to cure P. vivax
infection from New Guinea, and it is poorly tolerated.
Mefloquine and halofantrine have been shown to be
efficacious in small clinical trials, but each is limited
by safety issues associated with therapeutic doses.
Standard chloroquine doses (25 mg base/kg every 72
hours) combined with high-dose primaquine (2.5 mg
base/kg every 48 hours) have been suggested as treatment for chloroquine-resistant P. vivax acquired in
Irian Jaya but have failed in cases from Guyana.
Expert advice from an infectious or tropical disease
specialist should be sought for the management of
these cases (see contact information, Appendix VI).
P. vivax and P. ovale have a persistent liver phase that
is responsible for relapses and is susceptible only to
treatment with primaquine or related drugs. Relapses
caused by the persistent liver forms may appear
months and, rarely, up to 5 years after exposure.
None of the currently recommended chemoprophylaxis regimens will prevent relapses due to
these two species of Plasmodium. In order to reduce
the risk of relapse following the treatment of symptomatic P. vivax or P. ovale infection, primaquine is
indicated to provide “radical cure”.
The possibility of G6PD deficiency should be
excluded before antirelapse therapy with primaquine
is given. In patients with known or suspected G6PD
deficiency, expert medical advice should be sought,
since primaquine may cause hemolysis in such
patients. Primaquine use is contraindicated in pregnancy. P. vivax or P. ovale infections occurring during
pregnancy should be treated with standard doses of
chloroquine (Table 8). Relapses can be prevented by
weekly chemoprophylaxis with chloroquine until
after delivery, when primaquine can be safely used
for mothers with normal G6PD levels.
Primaquine is not routinely recommended to prevent
relapsing malaria in asymptomatic returning travellers (terminal prophylaxis). However, it is generally
indicated for people with prolonged exposure in
malaria-endemic areas where vivax or ovale malaria
occurs (e.g., long-term travellers or expatriates, see
Section 5). For terminal prophylaxis, primaquine is
administered after the traveller has departed from a
malaria-endemic area, usually during or after the last
2 weeks of chemoprophylaxis (see Section 3 and
Table 8 for dosage recommendations).
P. vivax isolates with a decreased responsiveness to
primaquine are well documented in Southeast Asia
and, in particular, Papua New Guinea and Irian Jaya.
Recently, primaquine radical treatment failure has
been reported from Thailand and Somalia. Therefore,
the recommended dosage of primaquine to prevent
relapse has increased to 30 mg (0.5 mg/kg) daily for
14 days.
When P. vivax malaria relapses after primaquine therapy there are two issues to be considered: (1) the
treatment of the acute vivax malaria (see Table 8),
and (2) prevention of further relapses by a doubling
of the standard dose of primaquine, i.e., 30 mg (0.5
mg/kg) of primaquine base daily for 14 days (B I –
evidence-based medicine recommendation).
Blood infection with P. malariae may persist for many
years, but it is not life-threatening and is easily cured
by a standard treatment course of chloroquine (see
Table 8).
31
Table 7. Chemotherapy of severe OR complicated P. falciparum malaria
NOTE: A switch to oral therapy should be made as soon as possible.
A. If an infusion pump is available:
a
b
Quinine (base) 5.8 mg/kg loading dose (quinine dihydrochloride [salt] 7 mg/kg) intravenously by infusion
pump over 30 minutes followed immediately by 8.3 mg base/kg (quinine dihydrochloride [salt] 10 mg/kg)
diluted in 10 mL/kg isotonic fluid by intravenous infusion over 4 hours (maintenance dose), repeated 8 hourlyc
until the patient can swallow, then quinine tablets to complete 3 to 7 days of treatment (7 days for SE Asia).
B. Without an infusion pump:
a
b
Quinine (base) 16.7 mg/kg loading dose, (quinine dihydrochloride [salt] 20 mg/kg), by intravenous infusion
over 4 hours, then 8.3 mg base/kg (quinine dihydrochloride [salt] 10 mg/kg) diluted in 10 mL/kg isotonic fluid
by intravenous infusion over 4 hours (maintenance dose), repeated 8 hourlyc until the patient can swallow, then
quinine tablets to complete 3 to 7 days of treatment (7 days for SE Asia).
PLUS (either concurrently with quinine or immediately after)
1. Doxycycline: 100 mg orally twice daily for 7 days; pediatric dose = 2 mg/kg (to a maximum of 100 mg) twice daily;
contraindicated: pregnancy, breast-feeding or if age < 8 years.
OR
2. Atovaquone/proguanil: 4 tablets once daily for three days (see Table 8 for pediatric dosage).
OR
3. Clindamycin: 10 mg/kg (loading dose) intravenously, followed by 5 mg/kg every 8 hours until blood is clear of
sexual parasites (Note: Should be used only if patient is unable to take doxycycline or atovaquone/proguanil).
Note: Parenteral quinidine should be used only if parenteral quinine is unavailable. Because of increased risk of cardiac toxic effects with quinidine, cardiac monitoring is required. Parenteral quinidine gluconate may be obtained on a patient-by-patient basis with authorization from the Special
Access Programme, Therapeutic Products Directorate, Finance Building, 2nd Floor, Tunney’s Pasture, Ottawa, Ontario K1A 1B9, Address Locator
0202C1, (613) 941-2108 (08:30-16:30 hours EST), (613) 941-3061 (after hours), (613) 941-3194 (fax), Web site: www.hc-sc.gc/hpb-dgps/therapeut
a
Loading dose should not be used if patient received quinine, quinidine, or mefloquine within the preceding 24 hours.
b
Parenteral quinine dihydrochloride may be obtained through the Canadian Malaria Network (see Appendix VI for contact information).
c
Switch to oral therapy with quinine as soon as possible. In patients requiring > 48 hours of parenteral therapy, reduce the quinine maintenance dose by
one-third to one-half.
32
¾¾ 9. DRUGS FOR THE PREVENTION ¾¾
AND TREATMENT OF MALARIA
Travellers should be reminded that antimalarials, like
all drugs, have the potential to cause adverse effects.
These drugs should be prescribed after an individual
risk assessment (as outlined in Section 2) to ensure
that only those travellers truly at risk of malaria infection receive antimalarial chemoprophylaxis. Any
drugs taken for chemoprophylaxis should be used in
conjunction with personal protective methods to prevent mosquito bites (see Section 2). Most people
using antimalarial chemoprophylaxis will have no or
only minor adverse reactions, which can be minimized by careful adherence to dosing guidelines, precautions, and contraindications.
This chapter will review the drugs (in alphabetical
order) used for the prevention (chemoprophylaxis)
and treatment of malaria. This information is not
designed to be comprehensive. It is important to note
that product recommendations are subject to change,
and therefore providers should consult up-to-date
information, including recent drug monographs, for
any updates, particularly with respect to compatibility, adverse reactions, contraindications, and precautions. Further details and discussion on
recommendations concerning the use of these drugs
for chemoprophylaxis and treatment can be found in
Sections 3 and 8 respectively. Table 8 summarizes
information, including doses, for the antimalarial
drugs routinely used in Canada.
Figure 4 depicts the malaria lifecycle and the sites of
action of recommended chemoprophylactic drugs.
ATOVAQUONE/PROGUANIL (ATQ/PG)
Trade Name: Malarone®. Licensed in Canada for
malaria chemoprophylaxis in adults weighing > 40 kg
and for treatment of uncomplicated malaria in adults
and children.
Mechanism of Action: Atovaquone/proguanil is a
fixed drug combination of atovaquone 250 mg and
proguanil 100 mg, in a single tablet. The two components are synergistic, atovaquone inhibiting parasite
mitochondria and proguanil, along with its active
metabolite cycloguanil, causing inhibition of parasite
folate synthesis through effects on dihydrofolate
reductase. Atovaquone/proguanil is effective as a
causal (acting at the liver stage) as well as suppressive
(acting at the blood stage) prophylactic agent.
Atovaquone/proguanil must be taken DAILY. Because
of the causal effects, atovaquone/proguanil can be
discontinued 1 week after departure from a
malaria-endemic area.
Indications and Efficacy: For malaria chemoprophylaxis, atovaquone/proguanil has equal efficacy
(i.e., > 95%) to doxycycline and mefloquine against
chloroquine-resistant falciparum malaria (A I evidence-based medicine); it is also effective along the
borders of Thailand, where chloroquine and
mefloquine resistance is documented.
In clinical trials of treatment of acute, uncomplicated
P. falciparum malaria conducted in Southeast Asia,
South America, and Africa, the efficacy of the combination of atovaquone/proguanil (dosed once daily for
3 days) has exceeded 95%. As well, published case
reports have documented that it successfully treated
multidrug-resistant malaria that had failed to respond
to other therapies (AI – evidence-based medicine
recommendation, see Appendix II). Therefore,
atovaquone/proguanil, an effective and well-tolerated
therapy, is considered first-line treatment of noncomplicated P. falciparum infection, including
multidrug-resistant P. falciparum (A I – evidencebased medicine recommendation.
There is insufficient evidence at this time to recommend
atovaquone/proguanil for the routine treatment of nonfalciparum malaria, although limited data suggest efficacy for the treatment of P. vivax (C – evidence-based
medicine).
33
Figure 4. Malaria life cycle and primary areas of drug activity (modified from the U.S. Centers for
Disease Control and Prevention DPDx site: http://www.dpd.cdc.gov/dpdx/html.Malaria.htm)
Human Liver Stages
Liver cell
Infected
liver cell
Mosquito Stages
Ruptured
oocyst
Release of
sporozoites
Oocyst
Mosquito takes
a blood meal
(ingests sporozoites)
Exo-erythrocytic Cycle
Atovaquone/proguanil
Primaquine
Ruptured schizont
Schizont
Sporogenic Cycle
Human Blood Stages
Immature
trophozoite
(ring stage)
Ookinete
Macrogametocyte
Mosquito takes
a blood meal
(ingests gametocytes)
Erythrocytic Cycle
Microgamete entering
macrogamete
Mature
trophozoite
P. falciparum
Exflageltated
microgametocyte
Chloroquine
Doxycyline
Mefloquine
Ruptured
schizont
Primaquine
Schizont
Gametocytes
Infective Stage
Diagnostic Stage
P. vivax
P. ovale
P. malariae
Gametocytes
The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles
mosquito inoculates sporozoites into the human host❶. Sporozoites infect liver cells❷ and mature into
schizonts❸, which rupture and release merozoites❹. (Of note, in P. vivax and P. ovale a dormant stage
[hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks or even years
later.) After this initial replication in the liver (exo-erythrocytic schizogony A), the parasites undergo asexual
multiplication in the erythrocytes (erythrocytic schizogony B). Merozoites infect red blood cells❺. The ring
stage trophozoites mature into schizonts, which rupture releasing merozoites➏. Some parasites differentiate
into sexual erythrocytic stages (gametocytes)➐. Blood stage parasites are responsible for the clinical manifestations of the disease.
34
Daily atovaquone/proguanil can now be considered
as first-line chemoprophylaxis for travellers to areas
with multi-drug resistant falciparum malaria (with
attention to contraindications and precautions) (A I –
evidence-based medicine recommendation).
Adverse Effects, Contraindications and Precautions: Compared with other standard antimalarial
regimens, the atovaquone/proguanil combination for
chemoprophylaxis has demonstrated excellent safety
and tolerance. During treatment, the most frequent
adverse events are those associated with the gastrointestinal tract: approximately 8% to 15% of adults and
children experience nausea, vomiting, abdominal
pain, or diarrhea, and 5% to 10% develop transient,
asymptomatic elevations in transaminase and amylase
levels. Serious adverse events associated with
atovaquone/proguanil, such as seizure and rash, are
rare. Atovaquone has been associated with fever and
rash in HIV-infected patients, requiring discontinuation of therapy, and has been shown to be teratogenic
in rabbits but not in rat models (Food and Drug
Administration category C drug). Proguanil is well
tolerated, and although oral aphthous ulcerations are
not uncommon they are rarely severe enough to warrant discontinuing this medication.
Pregnancy, severe renal insufficiency (creatinine
clearance < 30 mL/min) and hypersensitivity to either
component are the only contraindications to
atovaquone/proguanil.
AZITHROMYCIN
TM
Trade Name: Zithromax
Mechanism of Action: Azithromycin is a macrolide
antibiotic that inhibits parasite protein synthesis.
Indications and Efficacy: Azithromycin has not
been shown to be very effective in the prevention of
malaria (AII – evidence-based medicine). Studies performed to date are small and suggest that azithromycin is less effective than atovaquone/proguanil,
doxycycline, mefloquine, or primaquine.
Azithromycin, which must be taken daily, should be
considered for chemoprophylaxis only in very selective groups.
There is insufficient evidence to recommend
azithromycin as an alternative antimalarial except
under circumstances in which other, more effective
and safer, medications are not available or are contraindicated (CI – evidence-based medicine
recommendation).
Adverse Effects, Contraindications and Precautions: Azithromycin is considered to be safe in pregnancy and for children, and is available in
suspension. However, in view of the serious consequences of malaria in pregnancy, use of this
suboptimal antimalarial would not routinely be
recommended.
CHLOROQUINE
Trade Name: Aralen®
Mechanism of Action: Chloroquine is a synthetic
4-aminoquinoline, which acts against the intraerythrocytic stage of parasite development. It interferes with the digestion of hemoglobin within the red
cell and leads to toxic metabolite formation within
the parasite’s food vacuole.
Indications and Efficacy: Chloroquine, taken once
weekly, is effective for malaria prevention and treatment in travellers to areas with chloroquine-sensitive
malaria (A I – evidence-based medicine recommendation). It remains the drug of choice for malaria
chemoprophylaxis of travellers to areas with
chloroquine-sensitive malaria and the drug of choice
for the treatment of chloroquine-sensitive falciparum
malaria, chloroquine sensitive P. vivax as well as P.
ovale and P. malariae infections. Chloroquine is suitable for people of all ages and for pregnant women.
There is insufficient drug excretion in breast milk to
protect a breast-feeding infant, and therefore nursing
infants should be given chloroquine (adjusted for
changing weight, see Table 8). Since overdoses are
frequently fatal, instructions for childhood doses
should be carefully followed, and the medication
should be kept out of the reach of children.
Weekly chloroquine plus daily proguanil is approximately 60% more efficacious in subSaharan Africa
than weekly chloroquine alone, but it is much less
efficacious than atovaquone/proguanil, doxycycline
35
or mefloquine (A I – evidence-based medicine recommendation) and is not routinely recommended for
Canadian travellers.
Adverse Effects, Contraindications and Precautions: Except for its bitter taste, chloroquine is usually well tolerated. Taking the drug with food may
reduce other mild side effects, such as nausea and
headache. Black-skinned people may experience generalized pruritus, which is not indicative of drug
allergy. Transient, minor visual blurring may occur
initially but should not be a reason to discontinue
chloroquine. Retinal toxic effects, which may occur
with long-term daily doses of chloroquine (> 100 g
total dose) used in the treatment of other diseases, is
extremely unlikely with chloroquine given as a
weekly chemoprophylaxis. Chloroquine may worsen
psoriasis and, rarely, is associated with seizures and
psychosis. Therefore, chloroquine should not be used
in individuals with a history of epilepsy or generalized psoriasis (C III – evidence-based medicine recommendation). Concurrent use of chloroquine
interferes with antibody response to intradermal
human diploid cell rabies vaccine.
CLINDAMYCIN
Trade Name: Dalacin C®
Mechanism of Action: Clindamycin is an antibiotic
that inhibits parasite protein synthesis.
Indications and Efficacy: Clindamycin is indicated
only for treatment of malaria in restricted circumstances. Clindamycin, although less effective than
doxycycline or atovaquone/proguanil, is used in combination with quinine for those unable to tolerate or
who have contraindications (e.g., pregnant women
and young children) to the use of first-line agents.
Adverse Effects, Contraindications and Precautions: The most frequent adverse events with
clindamycin are diarrhea and rash. Clostridium
difficile associated disease, including
pseudomembranous colitis, has been reported.
36
DOXYCYCLINE
TM
Trade Name: Vibra-Tabs
Mechanism of Action: Doxycycline is an antibiotic
that inhibits parasite protein synthesis.
Indications and Efficacy: Doxycycline is effective
for the prevention and treatment of chloroquineresistant P. falciparum. It has been shown to have
equivalent efficacy to atovaquone/proguanil and
mefloquine for the prevention of chloroquine-resistant P. falciparum (A I – evidence-based medicine).
Doxycycline is an efficacious chemoprophylactic
agent against mefloquine-sensitive and mefloquineresistant P. falciparum malaria (A I – evidence-based
medicine recommendation) but must be taken
DAILY to work. The major reason for doxycycline
failures is non-compliance with this daily regimen.
Adverse Effects, Contraindications and Precautions: Doxycycline may cause gastrointestinal upset
and, rarely, esophageal ulceration, which are less
likely to occur if the drug is taken with food and large
amounts of fluid. It should not be taken simultaneously with Pepto-bismol® or antacids. Because
doxycycline is photosensitizing, it may make the skin
burn more easily; use of a sunscreen that blocks
ultraviolet A rays may reduce this problem.
Doxycycline may also increase the risk of vaginal
candidiasis; therefore, women should carry antifungal
therapy for self-treatment of vaginal candidiasis.
Although tetracyclines and other antibiotics have
been cited as a cause of oral contraceptive failure, a
recent case-control analysis failed to demonstrate any
significant association. Concurrent use of doxycycline with barbiturates, carbamazapine, or
phenytoin may result in a 50% decrease in
doxycycline serum concentration because of induction of microsomal enzyme activity and resulting
reduction of the half-life of doxycycline. Adjustment
of doxycycline dosage may be necessary, using either
a twice daily dosing schedule (100 mg bid) or a single
dose of 200 mg daily.
Doxycycline is contraindicated during pregnancy, in
breast-feeding women, and in children < 8 years of
age. Although the long-term safety (> 3 months) of
doxycycline has not been established, historically, tetracycline derivatives have been used at lower doses
over many years for skin disorders.
MEFLOQUINE
Trade Name: Lariam®
Mechanism of Action: Mefloquine is a quinolinemethanol. It is a lipophylic drug that acts on the
intraerythrocytic asexual stages of parasite development causing degradation of hemozoin within the
food vacuole.
Indications and Efficacy: Mefloquine is an effective
chemoprophylactic and therapeutic agent against
drug-resistant P. falciparum. In Canada, it is routinely
recommended ONLY for chemoprophylaxis because
of the high rate of adverse effects with treatment
doses. It is one of the drugs of choice, along with
atovaquone/proguanil and doxycycline, for the prevention of malaria in travellers to chloroquine-resistant regions (A I – evidence-based medicine
recommendation).
There is no evidence that toxic metabolites of mefloquine accumulate, and long-term use of mefloquine
(> 1 year) by Peace Corps volunteers in Africa has
not been associated with additional adverse effects. It
is recommended, therefore, that the duration of use
of mefloquine NOT be arbitrarily restricted in individuals who tolerate this medication and are at risk of
acquiring malaria (B II – evidence-based medicine
recommendation).
For travellers who will be at immediate high risk of
drug-resistant falciparum malaria, consideration may
be given to the use of a loading dose of mefloquine.
Data from several trials indicate that mefloquine
taken once daily for 3 days before travel followed by a
once weekly dose is a well-tolerated and effective way
to rapidly achieve therapeutic blood levels (reaching
steady state levels in 4 days compared with 7 to 9
weeks with standard weekly dosing of mefloquine)
(A I – evidence-based medicine recommendation). In
controlled studies only about 1% to 2% of loading
dose recipients discontinued mefloquine, and most of
these did so during the first week. The loading dose
strategy also permits an assessment of drug tolerance
before travel and allows a change to a suitable alternative if required. Alternatively, if time permits,
mefloquine may be initiated up to 3 weeks before
travel in order to assess tolerance and achieve higher
blood levels before the traveller enters malariaendemic areas.
Adverse Effects: Mefloquine is generally well tolerated when used for chemoprophylaxis. Approximately 20% to 30% of travellers will experience side
effects from either mefloquine or chloroquine; most
of these are mild and self-limiting. The most frequent
minor side effects reported with mefloquine use are
nausea, strange vivid dreams, dizziness, mood
changes, insomnia, headache, and diarrhea. Approximately 1% to 4% of mefloquine users may have to
discontinue prophylaxis because of adverse effects, a
rate not significantly different from other chemoprophylaxis regimens. Over 13 million travellers have
used mefloquine prophylaxis, and severe reactions
(seizure, psychosis) to this drug are rare (reported
from 1 in 10,000 to 1 in 13,000 users). The great
majority of mefloquine users (95% to 99%) have
either no side effects or only mild and temporary
ones. Occasionally, a traveller (in particular, women)
will experience a less severe but still troublesome
neuropsychological reaction (e.g., anxiety, mood
change) to mefloquine (1 in 250 to 500 users),
requiring a change to an alternative drug. These reactions are almost always reversible. On occasions,
neuropsychological complaints have persisted long
after mefloquine has been stopped. Rare cases of suicidal ideation and suicide have been reported, though
no relation to drug administration has been confirmed.
37
When mefloquine is prescribed for prophylactic use,
individuals should be advised that if they experience
psychiatric symptoms such as acute anxiety, depression, restlessness, or confusion, these may be
prodromal to more serious adverse events. They
should report these adverse events immediately, the
drug should be discontinued, and an alternative medication should be substituted.
CATMAT does not routinely recommend mefloquine
for the treatment of malaria, because in treatment
doses (25 mg base/kg) it is less well tolerated. Severe
neuropsychiatric reactions are reported to be 10 to 60
times more frequent, occurring in 1/215 to 1/1,700
users of treatment doses of mefloquine.
Contraindications: These include known hypersensitivity or past severe reaction to mefloquine; history
of serious psychiatric disorder (e.g., psychosis, severe
depression, generalized anxiety disorder, schizophrenia or other major psychiatric disorders); and seizure
disorder.
Precautions: Precautions for the use of mefloquine
include use in children < 5 kg ; use in those with
occupations requiring fine coordination or activities
in which vertigo may be life-threatening, such as flying an aircraft; concurrent use of chloroquine or quinine-like drugs (halofantrine and mefloquine should
not be used concurrently, see Section 9); underlying
cardiac conduction disturbances or arrhythmia; and
first trimester of pregnancy.
There have been concerns regarding the co-administration of mefloquine and agents known to alter cardiac conduction, including beta-blockers, calcium
channel blockers, phenothiazines, non-sedating antihistamines, and tricyclic antidepressants. However, at
present these concerns remain theoretical, and the
concurrent use of these agents is not contraindicated.
A recent review of available data suggests that
mefloquine may be used in people concurrently taking beta-blockers if they have no underlying cardiac
arrhythmia.
38
Insufficient mefloquine is excreted in breast milk to
protect a nursing infant. Although the package insert
recommends that mefloquine not be given to children weighing < 5 kg, it should be considered for
children at high risk of acquiring chloroquineresistant P. falciparum malaria. There are no
pharmacokinetic data upon which to recommend a
correct dose for children weighing < 15 kg. The
WHO has suggested a chemosuppressive dose of 5
mg base/kg weekly for children weighing > 5 kg.
PRIMAQUINE
Trade Name: Primaquine (primaquine phosphate)
Mechanism of Action: Primaquine is an
8-aminoquinoline antimalarial that is active against
multiple life cycle stages of the plasmodia that infect
humans and has been used for over 50 years. Its
mechanism of action is incompletely understood.
However, it has activity against the developing liver
stages (causal effect) thereby preventing establishment of infection; against liver hypnozoites, preventing relapses in established P. vivax and P. ovale
infections; against blood stages; and against gametes,
thereby preventing transmission.
Indications and Efficacy: Evidence is accumulating
that primaquine is an effective chemosuppressive for
P. falciparum malaria (A I – evidence-based medicine
recommendation). Recent studies have shown efficacy in semi-immune and non-immune subjects,
although data for travellers and for varied geographic
regions are limited. Given at a dose of 0.5 mg/kg base
per day (adult dose 30 mg base per day) for 11 to 50
weeks, primaquine had a protective efficacy of 85% to
95% against both P. falciparum and P. vivax infections. Primaquine was better tolerated than other
standard chemoprophylactic regimens in people who
were not G6PD deficient. Because of the causal effects
of primaquine, it can be discontinued 1 week after
departure from a malaria-endemic area. All travellers
need to be evaluated for G6PD deficiency before
primaquine is initiated. This significantly complicates
the prescription process.
P. vivax and P. ovale parasites can persist in the liver and
cause relapses for as long as 5 years after routine
chemoprophylaxis has been discontinued. Since most
malarial areas of the world (except Haiti and the Dominican Republic) have at least one species of relapsing
malaria, travellers to these areas have some risk of
acquiring either P. vivax or P. ovale, although actual risk
for an individual traveller is difficult to define.
Primaquine decreases the risk of relapses by acting
against the liver stages of P. vivax and P. ovale.
Primaquine terminal prophylaxis is administered after
the traveller has left a malaria endemic area, usually during or after the last 2 weeks of chemoprophylaxis. Terminal prophylaxis with primaquine is generally
indicated only for people who have had prolonged
exposure in malaria- endemic regions (e.g., long-term
travellers or expatriates).
None of the other currently recommended chemoprophylaxis regimens will prevent relapses due to P.
vivax and P. ovale. In order to reduce the risk of
relapse following the treatment of symptomatic P.
vivax or P. ovale infection, primaquine is indicated to
provide “radical cure”. Primaquine should be initiated for radical cure after chloroquine therapy has
been completed and the acute febrile illness is over
(about 1 to 2 weeks).
P. vivax isolates with a decreased responsiveness to
primaquine are well documented in Southeast Asia
and, in particular, Papua New Guinea and Irian Jaya.
Recently, primaquine radical treatment failure has
been reported from Thailand and Somalia. On the
basis of increasing numbers of reports of resistance to
primaquine at the standard dose of 0.25 mg/kg, the
recommended dose has been increased to 30 mg
(0.5 mg/kg) of primaquine base daily for 14 days (B I
– evidence-based medicine recommendation).
Although not a first-line chemoprophylactic agent,
primaquine may be considered an alternative chemoprophylactic agent (with attention to contraindications and precautions) for those without G6PD
deficiency when other regimens are either inappropriate or contraindicated (AI – evidence-based
medicine recommendation).
Adverse Effects, Contraindications and Precautions: Primaquine is generally well tolerated but may
cause nausea and abdominal pain, which can be
decreased by taking the drug with food. More importantly, primaquine may cause oxidant-induced
hemolytic anemia with methemoglobinemia, particularly among individuals with G6PD deficiency, which
is more common in those of Mediterranean, African,
and Asian ethnic origin. As well, those receiving > 15
mg base/day have a greater risk of hemolysis. Therefore, ALL individuals should have their G6PD level
measured before primaquine therapy is initiated.
Primaquine is contraindicated in patients with severe
G6PD deficiencies. In mild variants of G6PD deficiency, primaquine has been used safely at a lower
dose for radical cure to prevent P. vivax and P. ovale
relapses (0.8 mg base/kg weekly; adult dose 45 mg
base weekly for 8 weeks); however, this reduced dose
is insufficient for chemoprophylactic activity. When
used at prophylactic doses (0.5 mg base/kg daily) in
children and men with normal G6PD activity, mean
methemoglobin rates (5.8%) were below those associated with toxicity (> 10%). Patients should be
advised to stop their medication and report to a
physician immediately if jaundice or abnormally dark
or brown urine is noted.
Primaquine use is contraindicated in pregnancy. P.
vivax or P. ovale infections occurring during pregnancy should be treated with standard doses of
chloroquine (Table 8). Relapses can be prevented by
weekly chemoprophylaxis with choloroquine until
after delivery, when primaquine can be safely used
for mothers with normal G6PD levels.
QUININE AND QUINIDINE
Mechanism of Action: These quinoline-containing
antimalarials are alkaloid derivatives of cinchona bark
that act on the intraerythrocytic asexual stage of the
parasite.
Indications and Efficacy: Quinine and quinidine are
indicated only for the treatment of malaria. Quinine
(or quinidine) should not be used alone: a second
drug such as doxycycline should be used concurrently (see Section 8).
39
Oral therapy with quinine (with a second agent) is
indicated for the treatment of non-complicated
falciparum malaria and as step-down therapy (with a
second agent) after parenteral treatment of complicated malaria. Oral quinidine is often used for these
purposes in children, because quinidine is easier to
suspend into liquid formulation.
Quinine is the preferred drug for parenteral therapy
of severe or complicated malaria (see Table 5, WHO
criteria) because of the significant cardiotoxic effects
associated with parenteral quinidine and the requirement for cardiac monitoring.
Adverse Effects, Contraindications and Precautions: Minor adverse events are common with quinine and quinidine use. These include cinchonism
(tinnitus, nausea, headache, blurred vision),
hypoglycemia, nausea, and vomiting. Occasionally,
hypersensitivity and nerve deafness have been
reported. Parenteral quinidine has the potential to
increase the QTc and therefore requires electrocardiographic monitoring.
OTHER DRUGS NOT AVAILABLE OR NOT
ROUTINELY RECOMMENDED IN CANADA
(IN ALPHABETICAL ORDER)
It is important for travellers and providers to understand that the medical management of malaria in
countries where the disease is endemic may differ significantly from management in Canada. In countries
where malaria is endemic there may be a limited
number of effective medications available for treatment, indeed some of the drugs used may be ineffective in non-immune travellers or be associated with
unacceptable adverse outcomes. As well, the level of
health care available in some of these countries may
put travellers at risk of other infectious diseases.
AMODIAQUINE is a 4-aminoquinoline that was first
introduced as an alternative to chloroquine. Unfortunately, resistance to this drug has followed the path
of chloroquine resistance.
40
ARTEMISININ AND DERIVATIVES are
endoperoxide-containing natural antimalarials from
sweet wormwood (Artemisia annua). They are being
used for the treatment of malaria in many parts of the
world. Artemesinin (qinghaosu) derivatives – including artesunate, artemether, arteether, and
dihydroartesinin – are available in oral, parenteral,
and suppository formulations. They are all metabolized to a biologically active metabolite, dihydroartemesinin, and have their antiparasitic effects on
the younger, ring-forming parasites. They thereby
decrease the numbers of late parasite forms that can
obstruct the host’s microvasculature.
All artemisinin preparations have been studied and
used for treatment only. They are not recommended
for prophylaxis because of their short half-life. For
the treatment of severe and complicated malaria, all
compounds are at least as efficacious as quinine.
Qinghaosu and its derivatives lead to faster clearance
times of parasites (mean: 32% faster) and fever
(mean: 17% faster) than do any other antimalarials.
In spite of the more rapid antiparasitic action of
qinghaosu compounds, these agents have not been
shown to decrease mortality as compared with
quinine.
Artemisinin-related compounds act rapidly against
drug-resistant P. falciparum strains but have high
recrudescence rates (about 10% to 50%) when used
as monotherapy for < 5 days. Recent studies have
examined longer durations of therapy (7 days), and
combinations of qinghaosu derivatives and
mefloquine to prevent recrudescence. In vitro synergy
has been demonstrated between artemisinin derivatives, mefloquine, and tetracycline. In Thailand, treatment with oral artesunate (over 3 to 5 days)
combined with mefloquine (15 to 25 mg/kg) was
more effective than mefloquine or artesunate alone.
Combination therapy results in > 90% cure rates of
primary and recrudescent P. falciparum infections.
Artemisinin derivatives have been used in over 1 million patients and are well tolerated. To date, there
have been two human cases of complete heart block
associated with their use, but most volunteer and
clinical studies have found no evidence of cardiac or
other toxic effects. Neurological lesions involving the
brainstem have been seen in rats, dogs, and primates
given repeated doses of artemisinin derivatives. To
date, no clinical neurologic events have been
observed in humans; however, studies addressing
cumulative toxic effects in humans have not been
performed. The safety of qinghaosu derivatives in
pregnancy has not been established.
Artemisinin and its derivatives are now available and
increasingly used in Southeast Asia and Africa; none
is licensed in Canada. Coartemether (Riamet in
Europe, Coartem in Africa) is a combination of
artemether and lumefantrine that is currently
licensed in some European countries and is becoming
widely distributed in Africa for the treatment of
malaria. Combinations of artesunate and mefloquine
appear to be the most active drug regimens for treatment of multidrug-resistant falciparum malaria in
Southeast Asia. There is concern that the quality of
artemisinin derivatives available in developing countries may be questionable, as they may not be produced in accordance with the good manufacturing
production standards required in North America.
Although there is good evidence that therapy with
artemisinin compounds is safe, questions about
cumulative neurologic toxicity require resolution.
Recommendations
i.
Artemisinin compounds are effective alternative
therapies for multidrug-resistant malaria (complicated and uncomplicated) (AI – evidence-based
medicine recommendation). However, at present,
there are insufficient toxicity data and evidence of
clinical superiority over standard therapy to routinely recommend these as first-line agents, particularly for P. falciparum infections acquired in
Africa.
ii. Artemisinin compounds should not be used for
chemoprophylaxis (C III – evidence-based medicine recommendation).
iii. Artemisinin compounds may be considered for
the treatment of laboratory-confirmed severe
falciparum malaria acquired in areas where P.
falciparum is known to be multidrug-resistant OR
for the treatment of falciparum malaria that fails
standard drug regimens. In such cases, they
should be used in combination with mefloquine
or tetracycline/doxycycline (A I – evidence-based
medicine recommendation).
HALOFANTRINE is a phenanthrene methanol derivative related to mefloquine and quinine. It is available
only in an oral formulation, which is limited by variable bio-availability. Halofantrine is not licensed in
Canada and has recently been withdrawn from the
world market because of concerns about cardiotoxicity. It does remain widely available in the tropics, and travellers should be made aware of the danger of this drug. The WHO has reported cardiac
deaths associated with the use of halofantrine and no
longer recommends its use.
Recommendations
i.
Halofantrine should not be used for self-directed
therapy (D II – evidence-based medicine
recommendation).
ii. Halofantrine is not indicated for the treatment of
multidrug-resistant malaria (combined resistance
to mefloquine and chloroquine) or for the treatment of recrudescent malaria (D II – evidencebased medicine recommendation).
iii. Travellers who inquire about halofantrine or who
are likely to encounter its use (e.g., in West
Africa) should be informed of its potential
cardiotoxic effects (C III – evidence-based medicine recommendation).
PROGUANIL should not be used as a single agent
for chemoprophylaxis. Proguanil is well tolerated.
Although oral aphthous ulcerations are not uncommon, they are rarely severe enough to warrant discontinuing this medication. Proguanil is considered
safe during pregnancy and breast-feeding, but insuffi-
41
cient drug is excreted in the milk to protect a nursing
infant.
PYRIMETHAMINE-SULFADOXINE (Fansidar®) is
a fixed drug combination antimetabolite that inhibits
parasite folate synthesis. Historically, this drug has
been used for treatment, including self-treatment, of
P. falciparum, but increasing resistance means that it
has limited utility for the treatment of P. falciparum
and is no longer recommended. Resistance has been
reported in the Amazon Basin, Southeast Asia, and
increasingly throughout Africa.
Pyrimethamine-sulfadoxine is not recommended by
CATMAT, the Centers for Disease Prevention and
Control, or WHO for chemoprophylaxis because of
the life-threatening complication of Stevens-Johnson
syndrome and toxic epidermal necrolysis.
42
PYRONARIDINE is a benzonaphthyridine synthesized in China in 1970, which has been used for the
treatment of P. vivax and P. falciparum for more than
20 years and has been shown to be effective in the
treatment of falciparum malaria in children in Cameroon. It has more gastrointestinal side effects than
chloroquine. There are insufficient data at present to
recommend the use of pyronaridine for the treatment
of malaria in non-immune travellers.
TAFENOQUINE is a long-acting, 8-aminoquinoline
with a half-life measured in weeks rather than hours.
Initial research has shown efficacy with weekly
chemoprophylaxis and evidence of causal prophylaxis. Studies are ongoing in semi- and non-immune
individuals. In the future, tafenoquine may provide
another option for chemoprophylaxis in those without G6PD deficiency.
43
Prevention:
5 mg/kg base weekly;
maximum 300 mg
Treatment:
25 mg base/kg total over
3 days
Prevention:
300 mg base once weekly
Treatment:
1.5 g base over 3 days
Prevention and treatment in chloroquinesensitive P.
falciparum areas
Treatment of P. vivax,
P. ovale, P. malariae
CHLOROQUINE
(Aralen®)
Tablet: 150 mg
base
Pediatric dosage
Adult tablets
Prevention:
11-20 kg: ¼ tablet daily
21-30 kg: ½ tablet daily
31-40 kg: ¾ tablet daily
> 40 kg: 1 tablet daily
Treatment:
20 mg/kg atovaquone
AND
8 mg/kg proguanil once
daily x 3 days
11-20 kg: 1 tablet daily
21-30 kg: 2 tablets daily
31-40 kg: 3 tablets daily
> 41 kg: 4 tablets daily
Adult dosage
Prevention and treat- Adult tablet:
ment of P. falciparum 250 mg atovaquone plus
100 mg proguanil
Prevention:
1 tablet daily
Treatment:
1000 mg atovaquone
AND
400 mg proguanil (4 tablets) once daily x 3 days
Indication
ATOVAQUONE /
PROGUANIL
(ATQ/PG)
(Malarone®)
Drug, generic
(trade) name
Frequent:
Pruritis in black-skinned
individuals, nausea,
headache
Occasional:
Skin eruptions, reversible
corneal opacity
Rare:
Nail and mucous membrane discoloration,
partial alopecia, photophobia, nerve deafness,
myopathy, retinopathy
with daily use, blood
dyscrasias, psychosis and
seizures
Long-term safety data for Most areas now report
prophylaxis
chloroquine resistance
Adverse effects
Frequent:
Nausea, vomiting,
abdominal pain, diarrhea,
increased transaminases
Rare:
Seizures, rash, mouth
ulcers
Disadvantage
Causal prophylaxis – only Daily dosing for
have to continue for 7
prophylaxis
days after exposure
Advantage
Table 8. Drugs for the treatment and prevention of malaria
44
Alternative treatment for P.
falciparum with a
second drug if standard therapy
contraindicated
Prevention and treatment of chloroquine-resistant
P. falciparum
DOXYCYCLINE
(Vibra-TabsTM)
Indication
CLINDAMYCIN
(Dalacin C®)
Drug, generic
(trade) name
Prevention:
100 mg once daily
Treatment:
100 mg twice daily for 7
days
Prevention:
no indication
Treatment oral:
300 mg base every 6 hr
for 5 days
Treatment IV:
10 mg/kg (loading dose)
intravenously, followed
by 5 mg/kg every 8 hours
until blood is cleared of
asexual parasites or oral
therapy is tolerated.
NOTE: Should only use if
patient is unable to take
doxycycline or ATQ/PG
Adult dosage
Advantage
Protection against
Prevention:
leptospirosis
1.5 mg base/kg once daily
(max 100 mg)
< 25 kg or < 8 yr: contraindicated
25-35 kg or 8-10 yr: 50 mg
36-50 kg or 11-13 yr: 75 mg
> 50 kg or > 14 yr: 100 mg
Treatment:
1.5 mg base/kg twice daily
(max. 200 mg daily)
< 25 kg or < 8 yr: contraindicated
25-35 kg or 8-10 yr: 50 mg
twice daily
36-50 kg or 11-13 yr: 75 mg
twice daily
> 51 kg or > 14 yr: 100 mg
twice daily
Safe in pregnancy and
Prevention:
young children
no indication
Treatment oral:
5 mg/kg three times per day
for 5 days
Treatment IV:
10 mg/kg (loading dose)
intravenously, followed by 5
mg/kg every 8 hours until
blood is cleared of asexual
parasites or oral therapy is
tolerated. NOTE: Should only
use if patient is unable to
take doxycycline or ATVPG
Pediatric dosage
Frequent:
Diarrhea, rash
Occasional:
Pseudomembranous
colitis
Rare:
Hepatotoxicity, blood
dyscrasias
Adverse effects
Daily dosing required for Frequent:
chemoprophylaxis
Gastrointestinal upset,
vaginal candidiasis,
photosensitivity
Occasional:
Azotemia in renal
diseases
Rare:
Allergic reactions, blood
dyscrasias, esophageal
ulceration
Lower efficacy than
atovaquone/proguanil
alone or combination of
doxycycline plus quinine
Disadvantage
Table 8. Drugs for the treatment and prevention of malaria (continued)
45
Prevention of
P. falciparum
Prevention of
chloroquine-resistant P. falciparum
Terminal prophylaxis
P. vivax and P. ovale
Radical cure for P.
vivax and P. ovale
infections
PRIMAQUINE
Indication
MEFLOQUINE
(Lariam®)
Drug, generic
(trade) name
Prevention:
Primary prophylaxis 30
mg base daily, see text
Terminal prophylaxis or
radical cure:
30 mg base/day for 14
days
Prevention:
250 mg base once weekly
Treatment:
not routinely recommended, see text
Adult dosage
Weekly dosing
Long-term safety data
Advantage
There have been occasional publicized cases of
severe intolerance to
mefloquine, which may
result in increased concern. If mefloquine is the
best choice but concern is
expressed, consider either
a loading dose or start 3
weeks before departure to
test for tolerability.
Disadvantage
Causal prophylaxis – only Daily dosing
Prevention:
Require G6PD* testing,
Primary prophylaxis 0.5 have to continue for 7
see text
mg base/kg daily, see text days after exposure
Terminal prophylaxis or
radical cure:
0.5 mg base/kg daily for
14 days
Prevention:
5 mg/kg weekly
< 5 kg: no data
5-9 kg: c tablet
10-19 kg: ¼ tablet 20-29
kg: ½ tablet
30-45 kg: ¾ tablet
> 46 kg: 1 tablet
Treatment:
not routinely recommended, see text
Pediatric dosage
Table 8. Drugs for the treatment and prevention of malaria (continued)
Occasional:
GI upset, hemolysis in
G6PD deficiency,
methemoglobinemia
Frequent:
Dizziness, headache, sleep
disorders, nightmares,
nausea, vomiting,
diarrhea
Occasional:
Sensory and motor
neuropathies, seizures,
abnormal coordination,
confusion, hallucinations,
forgetfulness, emotional
problems including anxiety, aggression, agitation,
depression, mood
changes, panic attacks,
psychotic or paranoid
reactions, restlessness
Rare:
Suicidal ideation and suicide (relation to drug
administration not
established)
Adverse effects
46
Prevention:
no indication
Treatment oral:
500 mg base three times
daily for 3-7 days (7 days for
S.E. Asia)
IV: see Table 7
QUININE SULPHATE
(Novoquinine®)
Prevention:
no indication
Treatment oral:
7.5 mg base/kg (max 500
mg base) three times daily
for 3-7 days (7 days for S.E.
Asia)
IV: see Table 7
Prevention:
no indication
Treatment:
See Table 7
Prevention:
no indication
Treatment:
see Table 7.
28 mg base/kg daily,
divided q 8 hourly.**
Pediatric dosage
Advantage
Parenteral therapy
requires cardiac
monitoring
Disadvantage
Similar to above
Frequent:
Cinchonism (tinnitus, nausea, headache, blurred
vision), hypoglycemia
Occasional:
Cardiac conduction disturbances, hypersensitivity
Rare:
Hemolysis
Frequent:
Vomiting, cramps, cinchonism (tinnitus, nausea,
headache, blurred vision)
Occasional:
Widening of QRS complex,
cardiac disturbance, fever,
delirium, rashes
Rare:
Acute hemolytic anemia
Adverse effects
*Glucose-6-phosphate dehydrogenase
**Suggested mixing instructions: to make 120 mL solution of concentration 8.3 mg base/mL combine 60 mL Orasweet and 60 mL Oraplus with 6 x 200 mg tablets of crushed
quinidine sulfate.
Prevention:
no indication
Treatment:
See Table 7
QUININE DIHYDROCHLORIDE
Adult dosage
Prevention:
no indication
Treatment:
see Table 7
Indication
QUINIDINE
GLUCONATE/
SULFATE
Drug, generic
(trade) name
Table 8. Drugs for the treatment and prevention of malaria (continued)
¾¾ APPENDIX I ¾¾
†
Malaria Risk by Geographic Area in Countries with Endemic Malaria
Country
Areas of risk within country
Recommended regimens
Afghanistan
All areas below 2000 m
First-line agent*
Algeria
One small focus in Ihrir
Chloroquine in risk area
Angola
All
First-line agent*
Argentina
Rural areas near Bolivian and Paraguay borders, lowlands of
Salta and JuJuy provinces, and lowlands of Misiones and
Corrientes Provinces
Chloroquine
Armenia
Risk limited to western border areas: Masis, Ararat, and Artashat
regions in Ararat district. No risk in tourist areas.
Chloroquine
Azerbaijan
Rural lowlands with highest risk in areas between Kura and
Arax rivers
Chloroquine
Bangladesh
All, except no risk in city of Dhaka
First-line agent*
Belize
Rural areas including resort areas, off shore islands, and forest
preserves, except no risk in Belize City
Chloroquine
Benin
All
First-line agent*
Bhutan
Risk in southern belt of five districts: Chirang, Samchi,
Samdrupjongkhar, Sarpang, and Shemgang
First-line agent*
Bolivia
Rural areas < 2500 metres, risk in departments of Beni,
Cochabamba, Chuquisaca, La Paz, Pando, Santa Cruz, and Tarija
First-line agent*
Botswana
Northern part of country (north of 21 South)
Brazil
Risk in Acre and Rondonia states, territories of Amapa and Roraima, First-line agent*
and in rural areas of Amazonas, Maranhao, Mato Grosso, Para
(except Belem City), and Tocantins. There is also transmission in
urban areas, including large cities such as Porto Velho, Boa Vista,
Macapa, Manaus, Santarem, and Maraba Note: No risk for travellers
to coastal states from the horn to Uruguay border and Iguassu Falls.
Burkina Faso
All
First-line agent*
Burundi
All
First-line agent*
Cambodia
All, except no risk in Phnom Penh. Malaria risk exists in
Angkor Wat.
First-line agent* (on western borders
- doxycycline or atovaquone/
proguanil)
Cameroon
All
First-line agent*
Cape Verde
Limited risk exists on Sao Tiago Island.
First-line agent*
Central African Republic
All
First-line agent*
Chad
All
First-line agent*
o
First-line agent*
Burma: see Myanmar
47
Country
Areas of risk within country
Recommended regimens
China
Rural areas only in Anhui, Fujian, Guangdong, Guangxi, Guizhou,
Hainan, Hubei, Hunan, Jiangsu, Jiangxi, Shandong, Shanghai,
Sichuan, Xizang, Yunnan and Zhejiang provinces/autonomous
regions. In provinces with risk, transmission only occurs during
warm weather. Transmission occurs < 1500 metres from July to
November north of 33o North, from May to December between
33o North and 25o N and throughout the year below 25o North.
Note: Travellers visiting cities and popular rural tourist routes,
including Yangtze river cruises, are generally not at risk and
require no prophylaxis.
Chloroquine
First-line agent* for Hainin
province,Yunnan province and
Guangxi province
Colombia
In general, rural areas only below 800 m, no risk in Bogota
and vicinity
First-line agent*
Comoros
All
First-line agent*
Congo
All
First-line agent*
Costa Rica
Risk in the provinces of Alajuela, Limon, Guanacaste, and Heredia. Chloroquine
No risk in Limon City.
Côte d’Ivoire (formerly
Ivory Coast)
All
First-line agent*
Democratic Republic
of Congo
All
First-line agent*
Djibouti
All
First-line agent*
Dominican Republic
All rural areas. Highest risk in areas bordering Haiti. Travellers visit- Chloroquine
ing resort areas are generally not at risk and require no
prophylaxis.
East Timor
All
First-line agent*
Ecuador
All areas less than 1500 metres (no risk in Guayaquil, Quito and
vicinity, the central highland tourist areas or the Galapagos
Islands)
First-line agent*
Egypt
Limited risk in El Faiyum area and part of Southern (upper) Egypt
(no risk in main tourist areas including Nile cruises)
None
El Salvador
Rural areas of the departments of Santa Ana, Ahuachapan, and La Chloroquine
Union.
Equatorial Guinea
All
First-line agent*
Eritrea
All, except no risk in Asmara and above 2000 metres
First-line agent*
Ethiopia
All, except no risk in Addis Ababa and above 2000 metres
First-line agent*
French Guiana
All
First-line agent*
Gabon
All
First-line agent*
Gambia
All
First-line agent*
Georgia
Risk in the southeastern part of the country, in the districts of
Lagodekhi, Sighnaghi, Dedophilistskaro, saraejo, Gardabani and
Marneuli in the Kakheti and Kveno Kartli regions. No risk in Tbilisi.
Chloroquine
Ghana
All
First-line agent*
Guatemala
Rural areas only, except no risk in central highlands above
1500 metres. No risk in Antigua or Lake Atitlan.
Chloroquine
Guinea
All
First-line agent*
48
Country
Areas of risk within country
Recommended regimens
Guinea-Bissau
All
First-line agent*
Guyana
High risk in all of interior regions. Sporadic cases reported in the
coastal region.
First-line agent*
Haiti
All
Chloroquine
Honduras
Rural areas only, including Roatan and other Bay Islands
Chloroquine
Hong Kong S.A.R. (China)
Urban areas: no risk, limited risk in extremely rural areas of S.A.R.
None
India
All areas below 2000 metres including Delhi and Bombay, except
no transmission in parts of the states of Himachal Pradesh,
Jammu, Kashmir, and Sikkim
First-line agent*
Indonesia
In general, rural areas only, except high risk in all areas of Irian Jaya First-line agent*
(western half of island of New Guinea). No risk in cities of Java and
Sumatra or resort areas in Java or Bali. Note: Transmission is
largely confined to rural areas not visited by most tourists. Risk
exists at the temple complex of Borobudur on Java.
Iran, Islamic Republic of
Rural areas only in the provinces of Sistan-Baluchestan, the
southern part of Kerman and Hormozgan
First-line agent*
Iraq
All areas in northern region: Duhok, Erbil, Basrah, Tamim, Ninawa
and Sulaimaniya province
Chloroquine
Kenya
All areas including game parks except low risk in city of Nairobi
and above 2500 metres
First-line agent*
Korea, Democratic People’s Republic of (North)
Limited malaria risk in some southern areas. No risk in Pyongyang. Chloroquine
Ivory Coast: see Côte
d’Ivoire
Korea, Republic of (South) Risk limited to demilitarized zone and to rural areas in the
northern parts of Kyonggi and Kangwon provinces along the
demilitarized zone
Chloroquine
Lao People’s Democratic
Republic
All areas, except no risk in city of Vientiane
First-line agent*
Liberia
All
First-line agent*
Madagascar
All
First-line agent*
Malawi
All
First-line agent*
Malaysia
Risk limited to rural areas only. No risk in urban or coastal areas,
no risk in Republic of Singapore.
First-line agent*
Mali
All
First-line agent*
Mauritania
All areas, except no risk in the northern areas of
Dakhlet-Nouadhibou and Tiris-Zemour
First-line agent*
Mauritius
Rural areas only, except no risk in Rodrigues Island
Chloroquine
Mayotte
All
First-line agent*
Mexico
Rural areas including rural resort areas of the following states:
Campeche, Chiapas, Chihauhua, Durango, Guerrero, Hidalgo,
Jalisico (mountainous northern area only), Michoacan, Nayarit,
Oaxaca, Quintana Roo, Sinaloa, Sonora and Veracrus. Risk also
o
o
o
exists in area between24 N and 28 N latitiude and 106 W and
110oW longitude. No risk along U.S. border. No malaria risk along
the Pacific and Gulf coasts.
Chloroquine
49
Country
Areas of risk within country
Recommended regimens
Morocco
Very limited risk in rural areas of Khouribga province. The cities of
Tangier, Rabat, Casablanca, Marrakech and Fes have no risk.
None
Mozambique
All
First-line agent*
Myanmar (formerly
Burma)
Rural areas. Note: Travellers to Yangon (Rangoon) and Mandalay
are not at risk and need no prophylaxis.
First-line agent*
Doxycyline or atovaquone/ proguanil
for borders with Thailand
Namibia
Risk in the northern regions and in Omaheke and Otjozondjupa
and along the Kavango and Kunene rivers
First-line agent*
Nepal
Rural areas in Terai District and hill districts below 1200 metres. No First-line agent*
risk in Kathmandu and typical Himalayan treks.
New Hebrides:
see Vanuatu
Nicaragua
Rural areas only, however risk occurs in the outskirts of Managua.
Chloroquine
Niger
All
First-line agent*
Nigeria
All
First-line agent*
Oman
Limited risk in remote areas of Musandam Province
First-line agent*
Pakistan
All areas below 2000 metres including cities
First-line agent*
Panama
Risk in rural areas of 3 provinces: Bocas del Toro, Darien and
San Blas. No risk in the Canal Zone or in Panama City.
Chloroquine in Bocas del Toro
First-line agent* in Darien, San Blas
and San Blas Islands
Papua New Guinea
All
First-line agent*
Paraguay
Risk in 3 departments: Alto Parana, Caaguazu, and Canendiyu
Chloroquine
Peru
Risk in all departments except Arequipa, Moquegua, Puno and
Tacna. Note: no risk for travellers visiting only Lima and vicinity,
coastal areas south of Lima, or the highland tourist areas (Cuzco,
Machu Picchu, Lake Titicaca).
First-line agent*
Philippines
Rural areas only, except no risk in Manila and province of Bohol,
Catanduanes and Cebu
First-line agent*
Rwanda
All
First-line agent*
Sao Tome and Principe
All
First-line agent*
Saudi Arabia
All areas in Western province, except no risk in the high altitude
areas of Asir province (Yemen border), and the urban areas of
Jeddah, Mecca, Medina and Taif
First-line agent*
Senegal
All
First-line agent*
Sierra Leone
All
First-line agent*
Solomon Islands
All
First-line agent*
Somalia
All
First-line agent*
South Africa
Risk in the low altitude areas of the Mpumalanga Province
(including Kruger National Park), Northern Province and
northeastern KwaZulu-Natal as far south as Tugelan River
First-line agent*
Sri Lanka
All rural areas except no risk in district of Colombo, Kalutara, and
Nuwara Eliya.
First-line agent*
Sudan
All
First-line agent*
Suriname
Rural areas only, except no risk in Paramaribo district and coastal
o
areas north of 5 North
First-line agent*
50
Country
Areas of risk within country
Recommended regimens
Swaziland
All lowland areas
First-line agent*
Syrian Arab Republic
Rural areas only (May to October) especially along northern
border. No risk in districts of Damascus, Deir-es-zor and Sweida.
Chloroquine
Tajikistan
Risk predominantly in southern border areas (Khatlon region);
Chloroquine
risk in some central (Dushanbe), western (Gorno-Badakhshan) and
northern (Leninabad) areas.
Tanzania,
United Republic of
All
First-line agent*
Thailand
Malaria risk exists throughout the year in rural, especially forested
and hilly, areas of the whole country, mainly towards the international borders (not visited by most travellers). There is no risk in
cities and the main tourist resorts (e.g., Bangkok, Chiangmai,
Chiang Rai, Pattaya, Phuket, and Ko Samui). Mefloquine resistance
reported from areas on borders with Myanmar and Cambodia.
Doxycycline or atovaquone/
proguanil for overnight exposure in
rural areas on border with Myanmar
and Cambodia.
Togo
All
First-line agent*
Turkey
Cukurova/Amikova areas and southeast Anatolia (May to
October). No risk in main tourist areas in west and south-west or
the Incirlik U.S. Air Force base.
Chloroquine
Turkmenistan
Risk in some villages from June to October in the Mary district
Chloroquine
Uganda
All
First-line agent*
Vanuatu (formerly
New Hebrides)
All
First-line agent*
Venezuela
Risk in the rural areas of the following states: Apure, Amazonas,
Barinas, Bolivar, Sucre, Tachira, and Delta Amacuro. Risk in Angel
Falls.
First-line agent*
Viet Nam
Rural areas only. No risk in Red Delta and coastal plain north of
Nha Trang
First-line agent*
Yemen
All except no risk at elevations above 2000 metres. No risk in Sanas First-line agent*
(2230 metres)
Zaire: see Democratic
Republic of Congo
Zambia
All
First-line agent*
Zimbabwe
All (including Victoria Falls) except no risk in cities of Harare and
Bulawayo
First-line agent*
Countries not listed are considered free of malaria.
†Adapted from CDC Health Information for International Travel 2001 and WHO International Travel and Health 2003.
*First-line agent (for chloroquine-resistant area) = atovoquone/proguanil; doxycycline or mefloquine (alphabetical listing).
51
¾¾ APPENDIX II ¾¾
Strength and Quality of Evidence Summary*
Category
Definition
Categories for the strength of each 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.
Categories for the quality of evidence on which recommendations are made
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 or respected authorities on the basis of clinical experience, descriptive studies, or
reports of expert committees.
*From Macpherson DW. Evidence-based medicine. CCDR 1994; 20:145-47.
52
¾¾ APPENDIX III ¾¾
Instructions for Insecticide Treatment of Bed Nets and Clothing
How to Treat Mosquito Nets with
Insecticides (adapted from PATH Canada)
Before travelling, individuals should inquire about
the availability of insecticides and should plan to purchase and apply these products at their destination.
Pre-impregnated mosquito nets are available from
PATH Canada (www.pathcanada.org) and are found
in some travel and mountain equipment stores in
Canada and the United States. These products are not
currently registered by the Pest Management Regulatory Agency (PMRA). For information regarding the
availability of insecticides in subSaharan Africa for
application onto clothing or nets, see the PATH Canada Website.
Always use metric measurements: centimetre (cm),
metre (m), millimetre (mm) millilitre (mL) and litre
(L). All nets should be clean and dry. Always wear
protective gloves when soaking a net in insecticide.
1. Calculate the area of the net, in square metres.
Consider a conical net as a triangle and a rectangular net as two rectangles.
How to measure a mosquito net:
Conical net
Lay the net flat:
§ Measure the total distance around the
curved base of the net (m)
§ Measure the height (m)
§ Multiply base x height = area of net
Rectangular net
Hang the net up:
§ Measure the area of the top = width x
length
§ Measure the area around the sides = height
x total distance around base of net
§ Add the two measurements together to
find the total area of the net
2. Calculate the amount of water absorbed by the
net, in millilitres or litres.
Using a bucket and a measuring container, measure 2 L of water into the bucket. Soak the net
until it is totally wet. Carefully wring out the net
over the bucket. When the net has stopped dripping, measure the water remaining in the bucket.
For example:
§ Original water in bucket (2 L) minus
remaining water in bucket (1.3 L) = water
absorbed by the net (0.7 L or 700 mL)
3. Calculate the amount of insecticide required
§ Obtain the highest quality product, in
original packaging, specifically designed
for use on mosquito netting. Avoid use of
products that have not undergone meticulous quality control. Do not use substitute
products.
§ Check the recommended dose of insecti-
cide. Read the instructions on the bottle or
check the following Table.
53
§ Check the concentration of the insecticide.
This follows the name of the insecticide.
For example, permethrin EC 50 contains
500 g of insecticide in each litre; this is
also known as a 50% solution.
Doses of commonly used insecticides
(in mg of insecticide per square metre of material – polyester)
Compound and
formulation
Permethrin EC
Deltamethrin SC
Deltamethrin tablet
Dose (mg of active
ingredient/square metre)
200-500
15-25
1 tablet per net
Lambda-cyhalothrin CS
10-15
Cyfluthrin EW
30-50
Alpha-cypermethrin SC
20
To calculate the amount of insecticide use the
following formula:
§ Dose (mg/unit metre) x area of net (in
square metres) to determine the amount of
insecticide required in mg (remember
there are 1000 mg per gram, 1000 mL per
litre, and 1 gram per mL).
§ Take amount of insecticide required
divided by the amount in mg of insecticide per mL of product (for example, a
product that contains 50% permethrin will
contain 500 g permethrin/litre and therefore 500 mg permethrin/mL) = amount of
insecticide required in mL.
For example:
If you want a dose of 200 mg/square metre on
an 11 square metre net and you are using a
product containing 50% permethrin w/w, you
would calculate the amount required as
follows:
§ 200 mg/square metre x 11 metres squared
= 2200 mg permethrin required.
§ 50% permethrin = 500 mg permethrin/mL.
§ 2200 mg divided by 500 mg/mL = 4.4 mL
of insecticide required to treat the net.
54
If you have found that your net absorbs 0.7
litre (700 mL) of water, add this amount of
water to the insecticide to make a final mixture.
4. Wear protective gloves when treating nets with
insecticide.
5. Measure the amount of water and insecticide
needed.
Wide-mouth containers, such as an empty margarine container (1 kg = approximately 1 litre), are
best for measuring large amounts of water. Insecticide can be measured using a 250 mL empty
container, which can be scored inside at 50 mL
intervals. For small amounts of insecticide a
syringe could be used.
6. Add the insecticide to the water and mix well.
Treatment should be performed out of doors or
in a well-ventilated area. Alternatively, you can
place the net in a plastic bag (making sure there
are no holes in the bag), add the insecticide and
water solution, knead well, and remove the
treated net from the bag for drying.
7. Dip the net into the solution until it is thoroughly
wet.
8. Wring the net out over a bowl and hang it up
until it has stopped dripping.
9. Dry the net.
Wet nets can be laid out flat to dry. Do not place
them in direct sunlight for more than a few
hours, as UV exposure may reduce the efficacy of
the insecticide.
10. Wash your hands and all equipment with soap
and water. Triple rinse any containers that will be
reused, and punch holes in containers or equipment that will be discarded to prevent their reuse
as drinking water containers.
11. Pour any waste insecticide down a pit latrine or
into a pit dug into the ground and NOT into a
river or pond, as pyrethroids are highly toxic to
fish and aquatic invertebrates.
For more information regarding application of insecticides onto mosquito netting, see PATH Canada
Website at <www.pathcanada.org>.
How to Treat Clothing with Insecticides
(adapted from Sawyer Products)
Before travelling, individuals should inquire about
the availability of insecticide and should plan to purchase and apply these products at their destination.
These products are not currently registered by the
PMRA.
1. Select an area that is well ventilated, but out of
the wind. Do not spray in an enclosed area.
2. Lay clothing flat on the ground, pin clothes on a
clothesline, drape over porch furniture and railings, or hang clothes on separate clothes hangers,
so that each garment can be easily sprayed and
allowed to thoroughly dry.
3. One treatment with permethrin spray will remain
effective for 2 weeks, including weekly
launderings. An amount of 100 mL (3 fluid
ounces) of permethrin spray will treat one complete set of garments (a pair of long-legged trousers and a long-sleeved shirt). Jackets,
windbreakers, and rain gear may be treated in the
same manner (caution: permethrin does not
adhere well to some synthetic fibres).
4. Wear protective gloves.
5. Spray one side of the garment for approximately
60 seconds holding the spray can or bottle
upright and 15-20 cm away from the surface.
Spray in a slow sweeping motion, similar to
spraying paint, to evenly coat the entire surface.
Turn the garment around to the other side and
repeat by spraying the second side for 60 seconds.
The surface of the clothing should be wetted but
not completely saturated with spray.
6. Hang garments up and allow the permethrin
treatment to dry for 2 hours, or 4 hours if conditions are very humid.
7. Treating other garments and gear (do not treat
underwear):
§ Socks can be treated with permethrin spray.
Lay socks on the ground or pin on a clothesline, and lightly spray the upper parts of
socks. Allow to dry for 2 or more hours.
§ Polyurethane-coated nylon (synthetic)
tent flaps and doors can be treated with
permethrin spray. Erect tent outdoors and
spray all tent flaps and doors until wetted.
Leave standing for 2 or more hours to dry.
8. After garments have dried, pack them as you normally would for your trip. You may also want to
roll up your treated clothes and store them in a
plastic bag to keep them dry. Pack tents as you
normally would.
For more information regarding application of insecticides onto clothing, see <www.permethrin-repellent.com>.
55
¾¾ APPENDIX IV ¾¾
Checklist for Travellers to Malarial Areas
The following is a checklist of key issues to be considered in advising travellers. The numbers in parentheses refer to those pages in the text where these
issues are discussed in detail.
a) Risk of malaria (Appendix I)
Travellers should be informed about their individual
risk of malaria infection and the presence of
drug-resistant P. falciparum malaria in their areas of
destination. Those who are pregnant, travelling with
young children, or who have medical conditions that
put them at increased risk (see Section 4) should
question the necessity of the trip.
b) Anti-mosquito measures (page 3)
Travellers should be instructed on how to protect
themselves against mosquito bites.
c) Chemoprophylaxis (page 10)
Travellers should be
1. questioned about medical conditions, drug allergies and other contraindications for drug use.
2. advised to start chemoprophylaxis before travel as
directed, and to use prophylaxis continuously
while in malaria-endemic areas and for 4 weeks
after leaving such areas (except for
atovaquone/proguanil and primaquine, which are
taken for 1 week after leaving such areas).
3. informed that antimalarial drugs can cause side
effects; if these side effects are serious, medical
help should be sought promptly and use of the
drug discontinued. Mild nausea, occasional vomiting or loose stools should not prompt discontinuation of chemoprophylaxis, but medical
advice should be sought if symptoms persist.
56
4. warned that they may acquire malaria even if they
use malaria chemoprophylaxis.
5. warned that they may receive conflicting information regarding antimalarial drugs overseas, but
that they should continue their prescribed medication unless they are experiencing moderate to
severe adverse effects.
d) In case of illness (Section 6)
Travellers should be informed that
1. symptoms of malaria may be mild, and that they
should suspect malaria if they experience a fever
or ‘flu like illness (unexplained fever).
2. malaria may be fatal if treatment is delayed.
3. medical help should be sought promptly if
malaria is suspected, and a blood film should be
taken and examined for malaria parasites on one
or more occasions (if possible, blood smears
should be brought home for review).
4. self-treatment (if prescribed) should be taken
only if prompt medical care is not available and
medical advice should still be sought as soon as
possible after self-treatment.
5. there is a need to continue to take chemoprophylaxis in cases of suspect or proven malaria.
e) Special hosts (Section 4)
1. Pregnant women, young children and those with
underlying medical conditions require special
attention because of the potential effects of
malaria illness and the contraindication of certain
drugs (for example, doxycycline in pregnant
women and young children).
(Adapted from International Travel and Health, World
Health Organization, Geneva, 1999).
¾¾ APPENDIX V ¾¾
Frequently Asked Questions About Malaria
From the Committee to Advise on Tropical Medicine and Travel, 2003
1. Is malaria a serious infection for healthy
people?
Malaria is a major killer worldwide and is the
principal life-threatening infectious disease that
Canadian travellers face when travelling to highrisk areas of the world. In recent years, there has
been a dramatic increase in malaria cases among
Canadian travellers, including several deaths.
2. Do all travellers to the developing world need
malaria prophylaxis?
Many destinations in the developing world are
either free of malaria or the risk is so low that
malaria prophylaxis is not needed. Furthermore,
some travellers to countries with known malaria
risk may not need to take malaria prophylaxis
because malaria transmission is often confined to
particular areas of a country (usually rural) and
may be seasonal. For example, most individuals
travelling only to urban centres or resort areas in
Central and South America or Southeast Asia do
not require malaria prophylaxis. However, ALL
travellers (adults and children) to any area with
any risk of malaria should use personal protective
measures, such as treated mosquito nets and
insect repellents, to avoid mosquito bites.
3. Should pregnant women, babies and children
receive malaria prophylaxis?
Pregnant women, babies and small children are at
particular risk of serious malaria; if they must go
to high-risk areas they should take malaria prophylaxis. Several effective prophylaxis regimens
are known to be safe in these groups. It is important to remember that drugs taken by nursing
mothers will not provide protection for the nursing child.
4. Do most people who take malaria prophylaxis
have serious side effects?
For travellers to high-risk areas, the risk of
acquiring malaria and dying is significantly
greater than the risk of experiencing a serious
side effect from malaria prophylaxis. The great
majority of people taking malaria prophylaxis
(95% to 99%) have either no side effects or only
mild and temporary ones, and in most studies
only 1% to 4% of people have to change to an
alternative drug because of side effects. These
reactions are almost always reversible. Death
from malaria, however, is not. The final choice of
which antimalarial drug to use should be based
on an individual risk assessment from a knowledgeable travel medicine provider, which should
include issues such as the drug’s effectiveness, the
traveller’s willingness to accept potential side
effects, the convenience of dosing (weekly versus
daily), the cost, and whether or not the traveller
has any contraindications to the drug.
5. Are there safer and/or more effective
antimalarial drugs available?
For high-risk regions of the world with
chloroquine-resistant malaria there are three
drugs that are equally effective and currently
licensed in Canada – atovaquone/proguanil
(Malarone®), doxycycline (Vibra-tab®), and
mefloquine (Lariam®). Each has advantages and
disadvantages. Travellers should be cautious
about drugs that are available and offered in
other countries, since these drugs may be ineffective or more toxic, such as chloroquine,
proguanil (Paludrine®), amodiaquine, pyrimethamine (Daraprim®), pyrimethamine plus
sulfadoxine (Fansidar®), pyrimethamine plus
57
dapsone (Maloprim®). Before departure, travellers should consult a health care provider with
knowledge of travel medicine for an informed
recommendation regarding malaria prophylaxis
for their planned itinerary.
ever, even short delays in the diagnosis of malaria
can make treatment more difficult and less
successful.
9. Once you are infected with malaria, are you
are infected for life?
6. If I take prophylaxis, will the malaria I get be
more resistant to treatment?
Appropriate treatment and follow-up can ensure
complete cure of malaria.
The prevention of malaria in travellers using prophylactic drugs does not promote the development of resistant malaria parasites. Appropriately
used prophylaxis can actually reduce resistance
by lowering the burden of malaria disease.
10. Is it true that individuals born and raised in a
malaria country are immune for life?
7. Is there a limited period in which one can take
prophylaxis safely?
There is no absolute time limit on how long one
can take any antimalarial prophylactic drug. The
small number of individuals who will experience
significant side effects from antimalarial drugs
usually do so within the first few weeks of use. If
side effects are significant, then an alternative
drug for malaria prevention should be used.
Many mild side effects decrease with continued
use of prophylaxis. If travellers consult a health
care provider with knowledge of travel medicine
early, then there may be time for a trial of the
malaria prophylaxis before departure, to ensure
tolerance.
8. Is it true that some malaria cannot be treated?
If identified early and treated appropriately,
almost all malaria can be completely cured. How-
58
Over time, individuals raised in areas where
malaria is common either die from the disease or
become partially immune to its most serious
manifestations. However, this immunity is short
lived once an individual leaves a malarial area.
Although avoidance of mosquito bites is important for protection (e.g., appropriate clothing,
screens and mosquito nets, repellents),
antimalarial prophylactic drugs are essential for
optimal protection in most settings. Any individual who has travelled to malarial areas and subsequently develops fever should urgently seek
medical advice (even if the fever appears many
months after returning to Canada) and request
blood films to rule out malaria.
Further information on issues related to travel
medicine and contact information for travel medicine providers in your area is available through
Health Canada’s Travel Medicine Program at
<www.travelhealth.gc.ca>.
¾¾ APPENDIX VI ¾¾
Contact Information for the Canadian Malaria Network
Parenteral quinine is the drug of choice for the treatment of severe and complicated malaria in Canada.
To facilitate the acquisition of parenteral quinine, the
Canadian Malaria Network (previously the Malaria
Centres of Excellence) was established in conjunction with Health Canada’s Travel Medicine Program
to pre-position parenteral quinine stocks across Canada for the treatment of individuals with severe or
complicated malaria. The main purpose of each of
these centres is to provide, through the pharmacy,
24-hour access to this life-saving drug. As an additional service, if requested, the designated physician
for each centre can provide assistance in management
of malaria cases. These centres also gather surveillance data for all patients treated with parenteral quinine. The surveillance data (collected at time of
diagnosis and on day 28) are essential in our efforts
to improve malaria prevention, diagnosis, and management in Canada. The following hospital centres
across Canada have been identified as participants in
the Canadian Malaria Network. Each Centre will
have depositories of parenteral quinine for the treatment of severe malaria and can provide guidance in
the management of malaria infections.
To obtain parenteral quinine, please contact the listed
pharmacy in your area. The designated physician for
each Centre can be used as a resource for any questions you may have with regard to the treatment of
malaria. For after-hours assistance please contact the
infectious disease consultant on call at the appropriate Centre.
Program Coordinator
Name:
Dr. Anne E. McCarthy
Dawna Garber, Research Nurse Coordinator
Address:
Director of Tropical Medicine and International
Health Clinic
Division of Infectious Diseases
Ottawa Hospital (General Campus)
501 Smyth Road
Ottawa, Ontario K1H 8L6
Ottawa Hospital
501 Smyth Road
Ottawa, Ontario K1H 8L6
Telephone #:
(613) 737-8184
(613) 737-8899 (x 72723)
Fax #:
(613) 737-8164
(613) 737-8580
E-mail:
amccarthy@ottawahospital.on.ca
dgarber@ottawahospital.on.ca
59
Participants, by Province
British Columbia
Name:
Dr. William Bowie
Dr. Tim Lau, Pharmacist
Address:
GF Stong Research Laboratory
Vancouver General Hospital
452D-2733 Heather Street
Vancouver, British Columbia V5Z 3J5
CSU Pharmaceutical Services
Vancouver Hospital and Health Sciences Centre
855 W 12th Ave.
Vancouver, British Columbia V5Z 1M9
Telephone #:
(604) 875-4147 or (604) 875-4111
(ID Physician on-call)
(604) 875-4111, local 63361
Fax #:
(604) 875-4013
(604) 875-5267
E-mail:
bowie@interchange.ubc.ca
ttlau@interchange.ubc.ca
Name:
Dr. Stan Houston
Amy Lau, Pharmacist
Address:
2E4.11 WC Mackenzie Health Sciences Ctr.
University of Alberta
Edmonton, Alberta T6G 2B7
University of Alberta Hospital Pharmacy
WMC OG1, 8440-112 Street
Edmonton, Alberta T6G 2B7
Telephone #:
(780) 407-7501
(780) 407-7707
Fax #:
(780) 407-7137
(780) 407-7690
E-mail:
shouston@ualberta.ca
Alau@cha.ab.ca
Name:
Dr. Susan M. Kuhn, Director
Dr. Dominique Van Schijndel, Pharmacist
Address:
Odyssey Travel and Tropical Medicine Clinic
Suite 208-2004-14th St. NW
Calgary, Alberta T2M 3N3
Alberta Children’s Hospital Pharmacy
1820 Richmond Road, SW
Calgary, Alberta T2T 5C7
Telephone #:
(403) 210-4770
(403) 229-7204
Fax #:
(403) 210-4775
E-mail:
Skuhn@MyTravelClinic.com
Alberta
Dominique.vanschijndel@calgaryhealthregion.ca
Saskatchewan
Name:
Dr. Karen McClean
Janet Harding, Pharmacist
Address:
Division of Infectious Diseases
Royal University Hospital
103 Hospital Drive
Saskatoon, Saskatchewan S7N 0W8
Royal University Hospital Pharmacy
103 Hospital Drive
Saskatoon, Saskatchewan S7N 0W8
Telephone #:
(306) 655-1000
(306) 655-2264 or (306) 655-1000
(hospital locating)
Fax #:
(306) 975-0383
E-mail:
karen.mcclean@usask.ca
60
hardingj@sdh.sk.ca
Participants, by Province
Manitoba
Name:
Dr. Pierre Plourde
Anita Richard, Pharmacist
Address:
Winnipeg Regional Health Authority
1800-155 Carlton Street
Winnipeg, Manitoba R3C 4Y1
St-Boniface Gen. Hosp. Pharmacy
409 Avenue Taché
Winnipeg, Manitoba R2H 2A6
Telephone #:
(204) 926-7079 or (204) 237-2053
(ID Physician on-call)
(204) 237-2161
Fax #:
(204) 926-8008
E-mail:
pplourde@wrha.mb.ca
Arichard@sbgh.mb.ca
Name:
Dr. Kevin C. Kain
Deo Bahadur, Pharmacist
Address:
The Toronto General Hospital
200 Elizabeth St. ENG-224
Toronto, Ontario M5G 2C4
The Toronto General Hospital
Pharmacy Department
200 Elizabeth St. ENG-260-D
Toronto, Ontario M5G 2C4
Telephone #:
(416) 340-3535
(416) 340-4800 ext. 6587
Fax #:
(416) 595-5826
(416) 340-3685
E-mail:
Kevin.Kain@uhn.on.ca
deo.bahadur@uhn.on.ca
Name:
Dr. Anne E. McCarthy
Kim Lamont, R.Ph. Tech.
Address:
Division of Infectious Diseases
Ottawa Hospital (General Campus)
501 Smyth Road, Ottawa, Ontario
K1H 8L6
Ottawa Hospital (General Campus)
Pharmacy Department
501 Smyth Road, Ottawa, Ontario
K1H 8L6
Telephone #:
(613)737-8184
(613) 737-2585
Fax #:
(613) 737-8164
(613) 737-8891
E-mail:
amccarthy@ottawahospital.on.ca
klamont@ottawahospital.on.ca
Name:
Dr. Shariq Haider
Gita Sobhi, Pharmacist
Address:
Division of Infectious Diseases
McMaster University Medical Centre
1200 Main Street West
Hamilton, Ontario L8S 4J9
McMaster University Pharmacy
1200 Main Street
Hamilton Ontario L8S 4J9
Telephone #:
(905) 521-2100 ext 73991
(after hours 905 521-5030)
(905) 521-2100 ext. 73447
Fax #:
(905) 521-5099
E-mail:
haider@mcmaster.ca
Ontario
sobhi@hhsc.ca
61
Participants, by Province
Quebec
Name:
Dr. Louise Côté
Luc Bergeron, Pharmacist
Address:
Microbiology & Infectious Diseases
Centre hospitalier
Universitaire du Québec
Pavillon CHUL
2705, boul. Laurier, PL S-413
Sainte-Foy, Québec G1V 4G2
Dept of Pharmacy
Centre hospitalier universitaire du Québec
Pavillon CHUL
2705, boul. Laurier, PL S-210
Sainte-Foy, Québec G1V 4G2
Telephone #:
(418) 656-4141 poste: 7882
(418) 656-4141 poste 7916
Fax #:
(418) 654-2147
E-mail:
micro.pchul@chuq.ulaval.ca
luc.bergeron@chuq.qc.ca
Name:
Dr. Brian Ward
Denise Kalyvas, Pharmacist
Address:
Montreal General Hospital
1650 Cedar Avenue
Room D7-153
Montreal, Québec H3G 1A4
Montreal General Hospital - Pharmacy
1650 Cedar Avenue, Room C1-200
Montreal, Québec H3G 1A4
Telephone #:
(514) 921-6953 or (514) 934-8075
(hospital locating)
(514) 937-6011 ext. 4933
Fax #:
(514) 934-8347
E-mail:
cybj@musica.mcgill.ca
Denise.kalyvas@muhc.mcgill.ca
Name:
Dr. David Haldane
Andrea Murphy, Pharmacist
Address:
Microbiology Laboratory
Mackenzie Building
VG Site, QE II HSC
5788 University Avenue
Halifax, Nova Scotia B1H 1V8
Pharmacy Department
VG Site, QE II HSC
1278 Tower Road
Halifax, Nova Scotia B3H 2Y9
Telephone #:
(902) 473-6624
(902) 473-6829
Fax #:
(902) 473-4432
E-mail:
David.Haldane@cdha.nshealth.ca
Nova Scotia
andrea.murphy@cdha.nshealth.ca
Newfoundland and Labrador
Name:
Dr. Chau Nguyen
Frank Pinsent, Pharmacist
Address:
Division of Infectious Diseases
General Hospital
The Health Care Corporation
300 Prince Philip Drive
St. John’s, Newfoundland A1B 3V6
Department of Pharmacy
Health Science Centre
300 Prince Philip Drive
St. John’s, Newfoundland A1B 3V6
Telephone #:
(709) 777-8437
(709) 777-6455
Fax #:
(709) 777-7655
(709) 777-8120
E-mail:
eskinner@mun.ca
hcc.pinf@hccsj.nf.c
62
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