2000 Canadian recommendations for the prevention and treatment of malaria among

2000 Canadian recommendations for the prevention and treatment of malaria among
ISSN 1188-4169
Canada Communicable Disease Report
Date of Publication: March 2000
Volume 26S2
Supplement
—–—
2000 —–—
Canadian recommendations
for the prevention and
treatment of malaria among
international travellers
Our mission is to help the people of Canada
maintain and improve their health.
Health Canada
This publication was produced by the Document Dissemination
Division at the Laboratory Centre for Disease Control, Health
Canada.
To obtain additional copies or subscribe to the Canada
Communicable Disease Report, please contact the Member
Service Centre, Canadian Medical Association,
1867 Alta Vista Drive, Ottawa ON, Canada K1G 3Y6.
Tel.: (613) 731-8610, ext. 2307; 888-855-2555 (toll free in
Canada and U.S.) or by FAX: (613) 236-8864.
This publication can also be accessed electronically via Internet
using a Web browser at http://www.hc-sc.gc.ca/hpb/lcdc
_______
2000
_______
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
Laboratory Centre for Disease Control
Tunney's Pasture
Ottawa, Ontario K1A 0L2
Telephone: (613) 957-8739 FAX: (613) 952-8286
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Table of Contents _______
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Prevention. . . . . . . . . . . . . . . . . . . . .
a. Risk of Acquiring Malaria . . . . . . . . . . .
b. Personal Measures to Prevent Mosquito Bites .
c. Chemoprophylactic Drugs (where appropriate)
d. Early Diagnosis and Treatment . . . . . . . .
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3. Chemoprophylactic Regimens . . . . . . . . . . . . . .
a. Introduction . . . . . . . . . . . . . . . . . . . . .
b. Chloroquine-Sensitive Regions. . . . . . . . . . . .
c. Chloroquine-Resistant Regions. . . . . . . . . . . .
d. Chloroquine- and Mefloquine-Resistant Regions . .
e. Primaquine Terminal Prophylaxis for Prevention of
Relapses of P. vivax and P. ovale . . . . . . . . . .
f. Antimalarial Drug Adverse Effects and Precautions .
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4. Prevention of Malaria in Special Hosts . . . . . . . . . .
a. Malaria Prevention in Children . . . . . . . . . . . . .
b. Malaria Prevention in Pregnancy. . . . . . . . . . . .
c. Malaria Prevention in the Immunocompromised Host .
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5. Malaria Prevention in the Long-Term Traveller or Expatriate . . . . . 17
6. Self Treatment of Presumptive Malaria . . . . . . . . . . . . . . . . . 19
7. Diagnosis of Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
8. Treatment of Malaria . . . . . . . . . . . . . . . . . . . . . . .
a. General Principles of Management. . . . . . . . . . . . . . .
b. Management of Falciparum Malaria . . . . . . . . . . . . . .
c. Ancillary Treatment of Severe Malaria . . . . . . . . . . . . .
d. Management of Non-Falciparum Malaria . . . . . . . . . . .
e. Prevention of Relapses of Malaria Due to P. vivax or P. ovale.
f. P. vivax Resistance to Primaquine . . . . . . . . . . . . . . .
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9. New Drugs for the Prevention and Treatment of Malaria . . . .
a. Atovaquone/Proguanil (Malarone®) for the Treatment and
Prevention of Malaria. . . . . . . . . . . . . . . . . . . . .
b. Primaquine and Tafenoquine for the Prevention of Malaria.
c. Artemisinin Derivatives (Qinghaosu) for the Treatment of
Drug-Resistant Malaria . . . . . . . . . . . . . . . . . . . .
d. Azithromycin for the Prevention of Malaria . . . . . . . . .
e. Halofantrine for the Treatment of Malaria . . . . . . . . . .
f. Pyronaridine for the Treatment of Malaria. . . . . . . . . .
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Appendix I: Malaria Risk by Geographic Area in Countries with
Endemic Malaria . . . . . . . . . . . . . . . . . . . . . . . . 30
Appendix II: Strength and Quality of Evidence Summary Sheet . . . . . . 34
Appendix III: Checklist for Travellers to Malarial Areas . . . . . . . . . . 35
Appendix IV: Misconceptions about Malaria and Mefloquine. . . . . . . . 37
Appendix V: Contact Information for Malaria Centres of Excellence . . . . 39
iv
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PREFACE _______
The prevention and treatment of malaria have changed considerably over the
last decade primarily as a result of the development and spread of drugresistant parasites and a global resurgence of disease.
The following recommendations are guidelines for health care providers to
assist travellers in preventing symptomatic malaria, and in reducing the risk
of severe illness or death from this infection.
The Travel Medicine Program at the Laboratory Centre for Disease
Control (Health Canada) provides a valuable resource for the traveller
and the travel medicine provider. Information is available 24 hours-a-day
through the FAXlink service (613-941-3900) or through the internet
(www.hc-sc.gc.ca/hpb/lcdc/osh/tmp_e.html).
CATMAT Members
CATMAT Liaison Representatives
Dr. B. Ward (Chairman); Dr. K. Kain* (Past
Chairman); H. Birk; M. Bodie-Collins (Executive
Secretary); Dr. S.E. Boraston; Dr. H.O. Davies;
Dr. K. Gamble; Dr. L. Green; Dr. J.S. Keystone;
Dr. K.S. MacDonald; Dr. P. Plourde; Dr. J.R.
Salzman; Dr. D. Tessier.
Dr. R. Birnbaum (CSIH); L. Cobb (CUSO);
Dr. V. Marchessault (CPS and NACI);
Dr. H. Onyett (CIDS); Dr. R. Saginur (CPHA);
Dr. F. Stratton (ACE).
CATMAT Ex-Officio
Dr. A.E. McCarthy (Chair); Dr. E. Gadd;
Dr. K. Gamble; Dr. L. Green; Dr. J.S. Keystone;
Dr. H. Lobel; Dr. K.S. MacDonald; Dr. H. Onyett;
Dr. M. Parise; Dr. P. Plourde.
Dr. E. Callary (HC); Dr. M. Cetron (CDC);
R. Dewart (CDC); Dr. E. Gadd (HC);
Dr. H. Lobel (CDC); Dr. A.E. McCarthy (DND);
Dr. M. Parise (CDC).
Members of Malaria Subcommittee
CATMAT Member Emeritus
Dr. C.W.L. Jeanes.
*CATMAT acknowledges the contribution of Dr. Kain to these guidelines.
Special thanks go to Dr. Phillipa McDonald (HC).
v
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1. INTRODUCTION _______
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 30 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, 1984-1997
1200
Number of cases
Cases
1000
800
600
400
China
200
0
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 30 for specific country recommendations.
As noted in Figure 2 (opposite), the number of
reported cases of malaria in Canada has risen more
than twofold since 1994, to a peak of 1,036 in
1997. However, it is estimated that only 30% to
50% of cases are reported to public health agencies; therefore the true number of imported cases
into Canada is likely to be substantially higher. It
is of note that 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 in
recent years were acquired in sub-Saharan Africa,
2
84
86
88
90
92
94
96
Year
and the majority of P. vivax cases were acquired in
the Indian subcontinent. The increased numbers
of Canadian malaria cases have been associated
with an increased number of malaria deaths: seven
from 1997 to 1999. All these deaths were due to
P. falciparum. Factors contributing to the deaths
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 over
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 managed in modern intensive
care units. The most important factors that determine patient survival are early diagnosis and
appropriate therapy. It should be emphasized
that the majority of infections and deaths due to
malaria are preventable.
_______
2. PREVENTION _______
Four components of malaria protection should be
discussed with the traveller:
a.
b.
c.
d.
the risk of acquiring malaria
personal measures to prevent mosquito bites
chemoprophylactic drugs (where appropriate)
the need to seek early diagnosis and treatment
for 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 develop a fever. Travellers
staying overnight in rural areas may be at highest
risk.
Malaria transmission occurs in most of sub-Saharan
Africa and New Guinea; in large areas of Southern
Asia; in parts of Southeast Asia, Oceania, Haiti,
Central and South America; and in limited areas
of Mexico, the Dominican Republic, North Africa
and the Middle East. Appendix I provides countryspecific information on malaria risk and recommended chemoprophylaxis. This information is
derived from World Health Organization (WHO)
and Centers for Disease Control and Prevention
(CDC) sources. 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 between dusk and
dawn, corresponding to the biting habits of the
female 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 2,000 metres (6,500 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 sub-Saharan
Africa, the Indian subcontinent, and New Guinea
(Papua New Guinea [PNG] and Irian Jaya) may
be associated with significant risk of infection. In
recent years, 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, Irian Jaya, Solomon Islands and
Vanuatu) 1:30 or higher, sub-Saharan 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 Measures to Prevent
Mosquito Bites
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 female Anopheles mosquito
will reduce the risk of acquiring malaria. Risk
reduction behaviour includes remaining in wellscreened or completely enclosed air-conditioned
areas, sleeping under insecticide-impregnated mosquito nets, wearing clothing (ideally insecticideimpregnated) that reduces the area of exposed
skin, and using insect repellent containing
diethyltoluamide (DEET).
The use of insect repellent on exposed skin,
particularly between dusk and dawn, is strongly
recommended. Of the insect repellents registered
in Canada, those containing DEET are the most
effective. Although the concentration of DEET
varies from product to product, repellency rates
are largely equivalent. In general, higher concentrations protect for longer periods of time, but
there is little advantage in the duration of repellency
with DEET concentrations > 50%, and there
may be additional risk of toxicity with higher concentrations. New microencapsulated products
3
containing 33% DEET are registered in Canada,
and they should provide 8 hours of protection. In
rare instances, application of insect repellents with
DEET has been associated with seizures in young
children. Therefore, in children, DEET 10% or
less should be applied sparingly to exposed surfaces only and washed off after the children come
indoors (see section 4a, page 14, Malaria Prevention
in Children).
ALL travellers at risk of acquiring malaria
should be strongly encouraged to use insecticideimpregnated mosquito nets (e.g. permethrin,
deltamethrin) unless their sleeping quarters
are well-screened or otherwise protected from
mosquitoes (A I – evidence-based medicine
recommendations – see Appendix II, page 34).
Permethrin or deltamethrin-impregnated nets are
significantly more effective in preventing malaria
than untreated bed nets and are safe for children
and pregnant women (A I – evidence-based medicine recommendations – see Appendix II, page
34). Impregnated bed nets are available in Canada
for use only by travellers while outside of Canada.
Permethrin treatment of clothing will also reduce
the risk of malaria infection. (A I – evidence based
medicine recommendation – see Appendix II,
page 34). Currently, pyrethroid pesticides such as
permethrin are not registered in Canada for use on
clothing, and travellers should plan to purchase
and apply these insecticides at their destination.
c. Chemoprophylactic Drugs
(where appropriate)
Recommendations for chemoprophylaxis of malaria should be based on:
•
•
•
individual risk assessment
distribution of drug-resistant malaria
safety and efficacy of chemoprophylactic
regimens (See section 3, page 6, 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 ac-
4
quiring malaria. The specific activities (e.g. rural
travel, night-time exposure, unscreened accommodations) of the individual while in the malaria
region(s) should be considered in estimating the
risk of contracting malaria. 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
then 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 for
severe disease with malaria, e.g. a young
child, asplenic individual, pregnant
woman?
Distribution of drug-resistant malaria
(see Figure 1 and Appendix I)
Chloroquine-resistant P. falciparum is now 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 sub-Saharan
Africa and Southeast Asia. Chloroquine-resistant
P. vivax is also becoming an important problem,
particularly in Papua New Guinea, Irian Jaya,
Vanuatu, Myanmar, and Guyana. Strains of
P. vivax with reduced response to primaquine
are now reported from widely divergent areas
including Papua New Guinea, Somalia, and
India.
CATMAT considers there to be minimal risk of
malaria in urban centres of Southeast Asia and
Central and South America. Malaria transmission
falls at altitudes exceeding 2,000 metres (6,500 feet)
and is virtually non-existent over 3,000 metres
(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 blood film be 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 III (page 35) provides a checklist for the
preparation of travellers to malarial areas.
5
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3. CHEMOPROPHYLACTIC REGIMENS _______
a. Introduction
Medications to reduce the risk of developing clinical malaria should be considered for visitors to the
following areas:
URBAN AND RURAL AREAS OF
(Higher risk) –sub-Saharan Africa (except most of
South Africa), and Oceania (including Papua New
Guinea, Irian Jaya, Solomon Islands and Vanuatu).
(Lower risk) – Haiti, India, Bangladesh, Pakistan,
and Nepal (Terai region).
EVENING OR OVERNIGHT EXPOSURE IN
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 although
antimalarials can markedly decrease the risk of
acquiring symptomatic malaria, NONE OF THESE
AGENTS CAN GUARANTEE COMPLETE
PROTECTION AGAINST MALARIA. Personal
protection 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 leaving a malaria region whether or not
chemoprophylaxis has been used. In most travellers who acquire P. falciparum infection, symptoms
develop 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 WITH THICK AND THIN BLOOD FILMS;
THESE SHOULD BE REPEATED 12 TO 24 HOURS
LATER IF THE PATIENT REMAINS SYMPTOMATIC.
6
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 antimalarials (especially mefloquine),
leaving them at high risk of acquiring potentially
life-threatening malaria. One should warn travellers of this possibility and reinforce the antimalarial
guidelines and the risks and benefits of effective
chemoprophylaxis. Appendix IV (page 37), entitled
“Misconceptions about malaria and mefloquine”,
may aid the practitioner in answering travellers’
questions.
Table 1 (page 7) summarizes the different chemoprophylactic regimens according to regions of drug
resistance. This information can be utilized along
with Appendix I (page 30) to determine the appropriate antimalarial for an individual traveller.
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, South America and most
of China. See individual countries in Appendix I
(page 30) for precise recommendations.
Drug of choice: chloroquine (Aralen® ) is the drug
of choice for travellers to areas with chloroquinesensitive malaria. Chloroquine is taken once weekly,
beginning 1 week before entering a chloroquinesensitive malarial region, during the period of
exposure, and for 4 weeks after leaving the malarial
region. (A I – evidence-based medicine recommendations – see Appendix II, page 34). Chloroquine is suitable for people of all ages and for
pregnant women (see section 3f, page 9, for contraindications and adverse effects). There is insufficient drug excretion in breast milk to protect
a breastfeeding infant, and therefore nursing
infants should be given chloroquine (adjusted
for changing weight, see Table 2, page 11). Since
chloroquine overdoses are frequently fatal, instructions for childhood doses should be carefully
TABLE 1
Malaria Chemoprophylaxis Regimens for At-Risk Individualsa According to Regions of Drug Resistance
Region
Alternatives
Drug(s) of Choiceb,c
Chloroquine sensitive
Chloroquine
1st Choice: mefloquine
2nd Choice: doxycyclined
Chloroquine resistant
Mefloquine
1st Choice: doxycyclined
2nd Choice: primaquinee or Malaronef
3rd Choice: chloroquine plus proguanilg
Chloroquine and mefloquine resistant
Doxycyclined
Malaronef
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 (1) Chloroquine and mefloquine are taken weekly, beginning 1 week before entering a malarial region, continued while in that region, and for 4 weeks after
departure from the malarial region.
(2) Doxycycline and proguanil are taken daily, starting 1 day before entering a malarial region, continued daily while in that region, and for 4 weeks after
departure.
(3) Primaquine and Malarone are taken daily, starting 1 day before entering a malarial region, continued during stay in that region, and for 1 week after
departure.
c Adult and pediatric dosing information provided in Table 2, page 11.
d Contraindicated in pregnancy, during breastfeeding and in those < 8 years.
e Contraindicated in G6PD deficiency and in pregnancy.
f Limited data, not currently licensed for chemoprophylaxis.
g Chloroquine plus proguanil is less effective than mefloquine or doxycycline in these areas.
Note: CATMAT does not recommend proguanil as a single agent for prophylaxis.
a
followed, and the medication should be kept out
of the reach of children.
Alternatives: For individuals unable to tolerate
chloroquine, mefloquine or doxycycline should
be used (see section 3f, page 9, for contraindications and adverse effects).
c. Chloroquine-Resistant Regions
The chloroquine-resistant regions refer to most
of Africa, South America, Oceania and Asia. See
individual countries in Appendix I (page 30) for
specific recommendations. Note that some border
areas of Thailand, Myanmar and Cambodia are
also mefloquine-resistant regions (see section 3d,
page 8).
Drug of choice: mefloquine is the drug of choice
for most travellers to chloroquine-resistant regions.
Mefloquine is an effective chemoprophylactic
and therapeutic agent against drug-resistant
P. falciparum. It is significantly more effective
than the combination of chloroquine and
proguanil for malaria chemoprophylaxis in subSaharan Africa (A I – evidence-based medicine
recommendations – see Appendix II, page 34).
Mefloquine is taken once weekly, beginning
1 week before entering a malarial region, continued
during the period of exposure, and for 4 weeks
after leaving the malarial region. There is no
evidence that toxic metabolites of mefloquine
accumulate, and long-term (> 1 year) use of
mefloquine 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 are at risk of acquiring malaria (B II – evidence-based medicine
recommendations – see Appendix II, page 34).
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 (as above)
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 recommendations –
see Appendix II, page 34). Only about 1% to 2%
7
of loading dose recipients discontinued mefloquine,
and most of these did so during the first week.
The loading dose strategy permits an assessment
of drug tolerance before travel and allows a change
to a suitable alternative if required. Alternatively,
when time permits, mefloquine may be initiated
up to 3 weeks before travel in order to assess tolerance and achieve higher blood levels before entry
to malaria-endemic areas.
Alternatives: For individuals unable to take
mefloquine, alternatives are doxycycline (alternative
of choice), primaquine (contraindicated in glucose6-phosphate dehydrogenase [G6PD] deficiency,
see section 9b, page 27), Malarone® (see section
9a, page 26) or, less optimally, chloroquine and
proguanil. In comparative trials in Irian Jaya and
Africa, doxycycline has been shown to be as effective as mefloquine (A I – evidence-based medicine
recommendations – see Appendix II, page 34).
Chloroquine plus proguanil is approximately 60%
more effective in sub-Saharan Africa than chloroquine
alone but it is less effective than doxycycline or
mefloquine (A I – evidence-based medicine recommendations – see Appendix II, page 34).
In some instances, one may need to consider
less well-established alternatives. Evidence is
accumulating that primaquine is an effective
chemosuppressive for P. falciparum malaria (A I –
evidence-based medicine recommendations –
see Appendix II, page 34). Recent studies have
shown efficacy in semi-immune and non-immune
subjects, although data for travellers and for varied
geographic regions are limited. Primaquine phosphate is given at adult doses of 30 mg (base) daily
and continued for 1 week after exposure. All
subjects need to be evaluated for G6PD deficiency
before primaquine is initiated. This significantly
complicates the prescription process (see section
9b, page 27). Daily Malarone® also shows promise
for chemoprophylaxis (A I – evidence-based
medicine recommendations – see Appendix II,
page 34), although there are only limited data
regarding its efficacy in non-immune travellers.
Malarone® is not currently licensed in Canada for
this indication.
In deciding between the alternative drugs, the
health care provider must weigh the drug efficacy,
risks and character of adverse drug reactions with
the likelihood that the traveller will be exposed to
chloroquine-resistant malaria. As discussed, such a
8
decision must take into account personal health
factors, destination and activities during travel.
d. Chloroquine- and Mefloquine-Resistant
Regions
Resistance to both chloroquine and mefloquine is
not a significant problem except in rural, wooded
regions where Thailand borders with Myanmar
(Burma) and Cambodia (areas infrequently visited
by tourists). See Figure 1b (page 2) showing map
of China and Thailand.
Drug of choice: doxycycline alone is the chemoprophylaxis of choice in these regions. It is taken
once daily (100 mg), beginning 1 day before
entering a malarial area, continued during the
period of exposure and for 4 weeks after exposure.
Doxycycline is an effective chemoprophylactic
agent against mefloquine-sensitive and mefloquineresistant falciparum malaria (AI – evidencebased medicine recommendations – see
Appendix II, page 34) but must be taken DAILY
to work. The main reason for doxycycline failure is
non-compliance with this daily regimen.
Alternatives: there are no proven alternatives for
travellers to this region in whom doxycycline is
contraindicated or not tolerated. Consultation
should be sought from a travel medicine specialist
and such travellers should be advised to re-evaluate
their travel plans. Limited data suggest that
Malarone® may become an alternative chemoprophylaxis in this situation.
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 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 following the last 2 weeks of
chemoprophylaxis. Terminal prophylaxis with
primaquine is generally indicated only for persons
who have had prolonged exposure in malariaendemic regions (e.g. long-term travellers or expatriates). Primaquine is contraindicated in pregnant
women and individuals deficient in G6PD (see
section 3f, below, for adverse effects and precautions).
f. Antimalarial Drug Adverse Effects and
Precautions
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 4) to ensure that only
travellers truly at risk of malaria infection receive
antimalarial chemoprophylaxis. Any antimalarial
drugs utilized for chemoprophylaxis should be used
in conjunction with personal protection methods
to prevent mosquito bites (see section 2, page 4).
Most users of antimalarial chemoprophylaxis will
have no or only minor adverse reactions. Careful
adherence to dosing guidelines and warnings will
decrease the risk of adverse events (see Table 2,
page 11).
Chloroquine
Except for its bitter taste, chloroquine is usually
well tolerated. Other mild side effects, such as
nausea and headache, may be reduced by taking
the drug with food. African-Canadians 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, are extremely unlikely with
chloroquine given as 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 recommendations –
see Appendix II, page 34). Concurrent use of
chloroquine interferes with antibody response to
intradermal human diploid rabies vaccine.
Mefloquine
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 dreams, dizziness, mood changes, insomnia,
headache, and diarrhea. Approximately 1% to 4%
of mefloquine users discontinue prophylaxis because
of adverse effects, a rate not significantly different
from other chemoprophylaxis regimens. Severe
neuropsychiatric reactions (psychosis, convulsions)
are infrequent with prophylactic doses and are
reported to occur in approximately 1/10,000 to
1/13,000 individuals. Less severe but nonetheless
troublesome neuro-psychologic adverse events
(anxiety, depression, nightmares, etc.) requiring
drug discontinuation are reported in < 1% of users.
In treatment doses (25 mg base/kg), which are not
routinely recommended by CATMAT, mefloquine
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 for the use of mefloquine
include
•
•
•
known hypersensitivity or past severe reaction
to mefloquine
history of serious psychiatric disorder (e.g.
psychosis or severe depression)
seizure disorder
Precautions for the use of mefloquine include the
following:
•
•
children < 5 kg
•
concurrent use of chloroquine or quinine-like
drugs (halofantrine and mefloquine should not
be used concurrently)
•
•
occupations requiring fine coordination or
activities in which vertigo may be lifethreatening, such as flying an aircraft
underlying cardiac conduction disturbances or
arrhythmia
first trimester of pregnancy
There have been concerns regarding the coadministration of mefloquine and agents known
to alter cardiac conduction, including beta
9
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 persons concurrently receiving
beta blockers if they have no underlying cardiac
arrhythmia.
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.
Doxycycline
Doxycycline is contraindicated during pregnancy,
in breastfeeding 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.
However, hepatic necrosis and serum sickness
have been associated with prolonged use of minocycline, a tetracyline derivative.
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. Doxycycline
10
is photosensitizing and may make the skin more
susceptible to sunburns. Using a sunscreen that
blocks ultraviolet A rays may reduce this problem.
Doxycycline may also increase the risk of candidal
infections of the vagina; 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 decreased doxycycline serum concentration due to
induction of microsomal enzyme activity and
resulting 50% reduction of the half-life of doxycycline. Adjustment of doxycycline dosage may be
necessary with either a twice daily dosing schedule
(100 mg bid) or 200 mg daily.
Proguanil
Proguanil should not be used as a single agent for
chemoprophylaxis. It is well tolerated, and although
oral aphthous ulcerations are not uncommon they
are rarely severe enough to warrant discontinuing
this medication. Proguanil is considered safe during pregnancy and breastfeeding, but insufficient
drug is excreted in the milk to protect a nursing
infant.
Primaquine
See section 9b (page 27).
Malarone®
See section 9a (page 26).
TABLE 2
Antimalarial Drugs (listed alphabetically), Doses, and Adverse Effectsa
Generic Name
Trade
Name
Packaging
Adult Dose
atovaquone/
proguanil
Malarone®
250 mg
atovaquone
AND
100 mg
proguanil
Prevention:
1 tablet daily
(see text)
Treatment:
1000 mg atovaquone AND
400 mg proguanil
(4 tablets) once daily x 3 days
chloroquineb
phosphate
Aralen®
150 mg
base
Prevention:
300 mg base once weekly
Treatment:
1.5 g base over 3 daysc
clindamycin
hydrochloride
Dalacin®
150 mg
base
Prevention:
no indication
Treatment oral:
300 mg base every 6 hr for
5 days
Treatment IV:
See Table 4 (page 23)
doxycyclined
Vibramycin®,
Vibra-Tabs®,
Doryx®
100 mg
Prevention:
100 mg once daily
Treatment:
1 tablet twice daily for 7 days
Pediatric Dose
Prevention:
11-20 kg: ¼ tab daily
21-30 kg: ½ tab daily
31-40 kg: ¾ tab daily
> 40 kg: 1 tab daily
(see text)
Treatment:
20 mg/kg atovaquone AND
8 mg/kg proguanil once daily x 3 days
11-20 kg: 1 tab daily
21-30 kg: 2 tabs daily
31-40 kg: 3 tabs daily
> 40 kg: 4 tabs daily
Prevention:
5 mg base weekly; maximum 300 mg
5-6 kg or < 4 mo: 25 mg base
7-10 kg or 4-11 mo: 50 mg base
11-14 kg or 1-2 yr: 75 mg base
15-18 kg or 3-4 yr: 100 mg base
19-24 kg or 5-7 yr: 125 mg base
25-35 kg or 8-10 yr: 200 mg base
36-50 kg or 11-13 yr: 250 mg base
> 50 kg or ³ 14 yr: 300 mg base
Treatment:
25 mg base/kg total over 3 days
Adverse
Effects
Frequent:
nausea, vomiting,
abdominal pain, diarrhea,
increased transaminases
Rare:
seizures, rash
Frequent:
pruritis in AfricanCanadian individuals,
nausea, headache
Occasional:
skin eruptions, reversible
corneal opacity, partial
alopecia
Rare:
nail and mucous membrane discoloration, nerve
deafness, photophobia,
myopathy, retinopathy
with daily use, blood
dyscrasias, psychosis and
seizures
Prevention:
Frequent:
no indication
diarrhea, rash
Treatment oral:
Occasional:
5 mg/kg three times per day for 5 days
pseudomembranous
colitis
Treatment IV:
See Table 4 (page 23)
Rare:
hepatotoxicity, blood
dyscrasias
Prevention:
Frequent:
1.5 mg base/kg once daily (max 100 mg)
GI upset, vaginal
candidiasis, photo<25 kg or < 8 yr: contraindicated
sensitivity
25-35 kg or 8-10 yr: 50 mg
36-50 kg or 11-13 yr: 75 mg
Rare:
allergic reactions, blood
>50 kg or ³ 14 yr:100 mg
dyscrasias, azotemia in
Treatment:
1.5 mg base/kg twice daily (max 200 mg daily) renal diseases, esophageal
ulceration
<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
> 50 kg or ³ 14 yr: 100 mg twice daily
11
Generic Name
mefloquine
Trade
Name
Lariam®
primaquinee
Packaging
Adult Dose
250 mg
base
Prevention:
250 mg base once weekly
Treatment:
not routinely recommended,
see text
15 mg base
Prevention: primary prophylaxis
30 mg base daily
(see text)
Terminal prophylaxis or
radical cure:
15 mg base/day for
14 daysf
Prevention:
200 mg daily
Treatment:
see text and atovaquone/
proguanil (above)
proguanilh
Paludrine®
100 mg
pyrimethaminesulfadoxine
Fansidar®
25 mg
pyrimethamine
and 500 mg
sulfadoxine
Prevention:
no indication
Treatment:
3 tablets
quinidine
gluconatej
Prevention:
no indication
Treatment:
See Table 4 (page 23)
quinidine
sulphate
Prevention:
no indication
Treatment:
See Table 4 (page 23)
Note: this is an intramuscular
preparation not recommended
for intravenous use
12
Pediatric Dose
Prevention:
5 mg/kg weekly
< 5 kg: no data
5-9 kg: 1/8 tablet
10-19 kg: ¼ tablet
20-29 kg: ½ tablet
30-45 kg: ¾ tablet
> 45 kg: 1 tablet
Treatment:
not routinely recommended, see text
Prevention:
primary prophylaxis
0.5 mg base/kg daily (see text)
Terminal prophylaxis or radical cure:
0.3 mg base/kg/day for 14 daysg
Prevention:
5-8 kg or < 8 mo: 25 mg (1/4 tablet) daily
9-16 kg or 8 mo-3 yr: 50 mg (1/2 tab) daily
17-24 kg or 4-7 yr: 75 mg (3/4 tablet) daily
25-35 kg or 8-10 yr: 100 mg (1 tab) daily
36-50 kg or 11-13 yr: 150 mg (1½ tabs) daily
> 50 kg or ³ 14 yr: 200 mg (2 tabs) daily
Treatment:
see text and atovaquone/proguanil (above)
Prevention:
no indication
Treatment:
2-3 mo: ¼ tablet
4-11 mo: ½ tablet
1-2 yr: ¾ tablet
3-4 yr: 1 tablet
5-9 yr: 1½ tablets
10-11 yr: 2 tablets
12-13 yr: 2½ tablets
³14 yr: 3 tablets
Prevention:
no indication
Treatment:
See Table 4 (page 23)
Prevention:
no indication
Treatment:
See Table 4 (page 23)
Note: this is an intramuscular preparation
not recommended for intravenous use
Adverse
Effects
Common:
transient dizziness,
diarrhea, nausea, vivid
dreams, nightmares, irritability, mood alterations,
headache, insomnia
Rare:
seizures, psychosis, prolonged dizziness
Occasional:
GI upset, hemolysis in
G6PD deficiency,
methemoglobinemia
Occasional:
anorexia, nausea, mouth
ulcers
Rare:
hematuria
Occasional:
headache, nausea, folate
deficiency
Rare:
Stevens-Johnson
syndrome, erythema
multiforme, toxic epidermal necrolysis
Frequent:
vomiting, cramps,
cinchonism (tinnitus,
nausea, headache, blurred
vision)
Occasional:
widening of QRS complex,
cardiac disturbance, fever,
delirium, rashes
Rare:
acute hemolytic anemia
similar to above
Generic Name
quinine
dihydrochloridej
b
c
d
e
f
g
h
i
j
k
Packaging
Adult Dose
Prevention:
no indication
Treatment:
See Table 4 (page 23)
Pediatric Dose
Prevention:
no indication
Treatment:
See Table 4 (page 23)
Adverse
Effects
Frequent:
cinchonism (tinnitus,
nausea, headache, blurred
vision), hypoglycemia
Occasional:
cardiac conduction disturbances, hypersensitivity
Rare:
hemolysis
similar to above
Prevention:
Prevention:
no indication
no indication
Treatmentk Oral:
Treatmentk oral:
2 tablets three times daily for 7.5 mg base/kg (max 500 mg base) three
3-7 days
times daily for 3-7 days (7 days for SE Asia)
(7 days for SE Asia)
For more details on adverse events and precautions see section 3f, page 9, and individual drug monographs. For treatment of severe malaria see Table 4
page 23.
Chloroquine sulfate (Nivaquine®) is not available in Canada, but is available in most malaria-endemic countries in both tablet and syrup form.
In adults, generally, 2 tablets twice daily on days 1 and 2, then 2 tablets on day 3 (total of 10 tablets).
Contraindicated in pregnancy, during breastfeeding and in those < 8 years.
Contraindicated in G6PD deficiency and pregnancy.
quinine
sulphate
a
Trade
Name
Novoquinine® 250 mg
base
Doses are increased to 30 mg base/day for primaquine-resistant P. vivax.
Doses are increased to 0.5 mg base/kg/day for primaquine-resistant P vivax.
NOTE: CATMAT does not recommend proguanil as a single agent for prophylaxis. These doses should be taken with weekly chloroquine (see page 11 for
chloroquine dosing).
Parenteral quinine is the drug of first choice for severe or complicated malaria. Parenteral quinidine is available through Health Canada’s Special Access
Program, see text.
Parenteral quinine is available through Malaria Centres of Excellence, see text and Appendix V.
Generally, treatment of chloroquine-resistant strains of P. falciparum acquired in Southeast Asia should include a longer course (7 days) of quinine or
quinidine and a second drug, as per Table 4, page 23.
13
_______
4. PREVENTION OF MALARIA IN SPECIAL HOSTS _______
a. Malaria Prevention in Children
Children are at special risk of malaria since they
may rapidly become seriously ill. If travel to
malarial areas is unavoidable, babies, including
breastfed infants, and children should be well protected against mosquito bites and should receive
malaria chemoprophylaxis. Travellers should be
clearly advised of the risks involved in taking
young children to areas with drug-resistant
falciparum malaria.
For ALL children travelling to malarial regions,
particular attention should be paid to personal
protection measures to reduce contact with mosquitoes (see section 2b, page 3). These include
the following: remaining in well-screened areas;
wearing clothes that cover most of the body;
using insecticide-impregnated mosquito nets
(available for cots and small beds); and using
insect repellents. The most effective repellents
contain diethyltoluamide (DEET), an ingredient
in many commercially available products. The
actual concentration of DEET varies among
repellents and can be as high as 95%; however,
repellents with DEET concentrations of 10% are
very effective and should last 3-4 hours. Rarely,
children exposed to DEET have developed toxic
encephalopathy (only 14 cases over 30 years of
DEET use and billions of applications every year).
The likelihood of adverse reactions can be minimized
by the following precautions: apply repellent
sparingly and only to exposed skin; avoid applying
high concentration products; avoid applying repellents to portions of children’s hands that are likely
to contact the eyes or mouth; never use repellents
on wounds or irritated skin; and wash repellenttreated skin after children come indoors. If a reaction to insect repellent is suspected, wash treated
skin and seek medical attention.
In Canada, DEET products are not recommended
for use in children < 2 years of age. However,
when living in a malaria endemic area, young
children are at risk of severe malaria and the risk
of severe disease outweighs the risk of appropriately applied DEET repellents.
14
Ensuring that young children take antimalarial
agents may be difficult because of the lack of
pediatric formulations. Malaria tablets may be
crushed and mixed with chocolate syrup, jam,
cereal or bananas to mask the taste. Tablets,
especially mefloquine, should be protected from
sunlight and high humidity once they have been
removed from the foil wrapper. All medication,
including antimalarials, should be kept out of reach
of children and stored in childproof containers to
avoid overdose, which may be fatal.
Chloroquine remains the preferred agent for chemoprophylaxis in areas with chloroquine-sensitive
malaria. Although it is not available in Canada,
chloroquine sulfate (Nivaquine®) is widely available
as a syrup in malaria endemic areas. The syrup is often more easily administered than tablets.
Mefloquine remains the drug of choice in
chloroquine-resistant regions, although there are
no studies that specifically analyze its bioavailability
and the rate of metabolism in children. Although
the manufacturer recommends that mefloquine
not be given to children < 5 kg, it should be considered for prophylaxis of all children at high risk
of acquiring chloroquine-resistant Plasmodium
falciparum at a dose of 5 mg base/kg once weekly
(see Table 2, page 12).
There is no safe and effective chemoprophylactic
regimen for children < 8 years who travel to
mefloquine-resistant areas along the Thai borders
with Cambodia and Myanmar (Burma).
Recommendations:
i.
If possible, young children should avoid travel
to areas with significant transmission particularly of chloroquine-resistant malaria (C III –
evidence-based medicine recommendations
– see Appendix II, page 34).
ii. Personal protection measures should be
strongly encouraged for all individuals who
travel to malaria-endemic areas (A I – evidencebased medicine recommendations – see
Appendix II, page 34).
iii. Young children travelling to or residing in
chloroquine-sensitive areas should use
chloroquine as chemoprophylaxis (A I –
evidence-based medicine recommendations
– see Appendix II, page 34).
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 recommendations
– see Appendix II, page 34).
v. The combination of chloroquine and proguanil
is safe in children, but is significantly less
effective against chloroquine-resistant malaria
(A I – evidence-based medicine recommendations – see Appendix II, page 34). There is
no safe and effective chemoprophylaxis regimen for children < 8 years old who travel to
mefloquine-resistant areas where Thailand borders with Cambodia and Myanmar (Burma).
b. Malaria Prevention in Pregnancy
Malaria increases the risk of maternal and neonatal death, miscarriage and stillbirth. Pregnant
women should defer travel to malaria-endemic areas
whenever possible, 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 2b,
page 3), and chemoprophylaxis should be used.
Chloroquine and proguanil are known to be safe
in pregnancy although they are not as effective as
mefloquine in preventing chloroquine-resistant
P. falciparum. This creates a dilemma for women
who are, plan to be, or become pregnant while in
malaria-endemic areas.
Recommendations:
i.
If possible, pregnant women should avoid
travel to areas with significant transmission
particularly of chloroquine-resistant malaria
(C III – evidence-based medicine recommendations – see Appendix II, page 34).
ii. Personal protection measures should be
strongly encouraged for all individuals who
travel to malaria-endemic areas (A I – evidencebased medicine recommendations – see
Appendix II, page 34).
iii. Pregnant females travelling to or residing in
chloroquine-sensitive areas should use
chloroquine as chemoprophylaxis (A I –
evidence-based medicine recommendations
– see Appendix II, page 34).
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 (A I – evidence-based medicine
recommendations – see Appendix II, page 34).
Doxycycline and primaquine are contraindicated during pregnancy, the latter because the
G6PD status of the infant cannot be evaluated.
Pyrimethamine-sulfadoxine (Fansidar®) is contraindicated in the last month of gestation and in the
first 2 months of breastfeeding. Malarone® is not
recommended during pregnancy.
v. Females 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 disease specialist (A III – evidence-based medicine recommendations – see Appendix II, page 34).
According to current data, mefloquine is safe for
chemoprophylaxis after the first trimester. When
used in treatment doses in the first trimester the
results of a recent study suggest that mefloqine may
be associated with an increased rate of spontaneous
abortions. Pregnancy should be avoided for 3 months
after completing mefloquine chemoprophylaxis
because of melfoquine's long half-life. However, the
occurrence of pregnancy while a woman is receiving
mefloquine prophylaxis is not an indication for
termination of pregnancy.
vi. The combination of chloroquine and proguanil
is safe in pregnancy, but is significantly less
effective against chloroquine-resistant malaria
than mefloquine (A I – evidence-based medicine recommendations – see Appendix II,
page 34). There is no safe and effective chemoprophylaxis regimen for pregnant women who
travel to mefloquine-resistant areas where
Thailand borders with Cambodia and
Myanmar (Burma).
15
c. Malaria Prevention in the
Immunocompromised Host
The immunocompromised traveller may be at
increased risk of severe disease from malaria
infections. If travel cannot be avoided, special
care should be taken to avoid mosquito bites (see
section 2b, page 3), and chemoprophylaxis should
be used (see section 3, page 6).
Asplenic individuals are at risk of severe disease
with organisms that require splenic clearance,
including malaria. Such individuals may become
rapidly ill and therefore should seek pretravel
consultation from a travel medicine or tropical
disease specialist. Consideration should be given
to the provision of self treatment for malaria (see
section 6, page 19) to be utilized in the event of a
febrile illness if medical care is not immediately
available.
Those with other forms of immunocompromise,
such as HIV or organ transplant recipients, may
16
also be at risk of severe disease from malaria. As
well, chemoprophylactic drugs may interfere with
other medications required for control of disease
or prevention of rejection. Therefore, pretravel
consultation with a travel medicine or tropical disease specialist is advised.
Recommendations:
i.
Individuals with immunodeficiency, including
those with asplenia, HIV infection or transplantation, should have an individual risk
assessment and counsel from a travel medicine
or tropical disease specialist (B III – evidencebased medicine recommendations – see
Appendix II, page 34).
ii. Personal protection measures should be strongly
encouraged for all individuals who travel to
malaria-endemic areas (A I – evidence-based
medicine recommendations – see Appendix II,
page 34).
5. MALARIA PREVENTION IN THE _______
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, evidenced-based guidelines for the longterm (> 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, safety of
drugs used for chemoprophylaxis, fear of toxic
effects with prolonged use of medication, and lack
of adherence to the use of personal protection
measures. Confidence but lack of rigour in selfdiagnosis coupled with unreliable laboratory
diagnosis in many developing countries has
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 have significant adverse reactions. Doxycycline may be an exception, as studies have been
confined to short-term travellers and persons using
tetracyclines (at lower dosage) for skin therapy.
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 1,192 long-term expatriates,
representing a broad range of government and
non-government organizations (NGOs) in subSaharan Africa, may provide some assistance in
counselling long-term travellers and expatriates.
Malaria prophylaxis was taken on a regular basis
by 75% of individuals with a compliance rate of
65%. Of those receiving chemoprophylaxis, 54%
reported changing their prophylactic regimen,
22% because of adverse effects. The severity of
side effects was not associated with any specific
drug, but the reported incidence of neuropsychiatric
side effects was 10% among persons taking
chloroquine and proguanil compared with 17%
in the mefloquine group. Mefloquine was the
only regimen on which participants reported a
change in practice based on media influence (see
Appendix IV, page 37, for information on malaria
myths and facts). Only a small number indicated
that availability and cost were factors in their
choice of prophylactic regimens. Participants who
did not use prophylaxis cited concerns about adverse reactions and long-term effects as the primary reasons for their choice. Personal protection
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 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
on diagnosis and self-treatment (see sections 7,
page 21, and 8, page 22), including the use of
rapid diagnostic tests for malaria, may prove to
be helpful in this population. Self-diagnostic kits
that require refrigeration will limit access to this
technology in some regions.
Section 3e (page 8) addresses the use of primaquine
as terminal prophylaxis to decrease 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 pro-
17
phylaxis with primaquine is generally indicated
only for persons who have had prolonged exposure
in malaria-endemic regions, such as expatriates or
long-term travellers. Primaquine is contraindicated
in pregnant women and individuals deficient in
G6PD (see section 9b, page 27, for contraindications and precautions).
In conclusion, guidelines for the prevention of malaria in long-term travellers or expatriates should
not deviate significantly from recommendations
for short-term travellers (B III – evidence based
medicine recommendation – Appendix II, page
34). The available data indicate that expatriates in
high-risk settings have not effectively utilized personal protection measures (B II – evidence-based
medicine recommendations – see Appendix II,
page 34). The majority are using a prophylactic
18
regimen, but sound counsel does not always guide
their choice; a significant proportion are influenced
by perception of risk rather than documented
problems. Therefore, the effectiveness of current
recommendations will be affected by the prevailing
attitudes in the subculture in which the long-term
traveller or expatriate lives (B II – evidence-based
medicine recommendations – see Appendix II,
page 34). 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
(see section 9b for contraindications and precautions) to long-term travellers or expatriates who
return from regions with P. vivax transmission (A I
– evidence-based medicine recommendations –
see Appendix II, page 34).
_______
6. SELF TREATMENT OF PRESUMPTIVE MALARIA _______
Most travellers will be able to obtain prompt
medical attention when malaria is suspected and
therefore will not require a self-treatment regimen. Under unusual circumstances, individuals at
risk of malaria may be unable to seek medical care
within 24 hours and may require self-treatment
for presumptive malaria. However, because of the
non-specific symptoms of malaria, the potentially
serious risk of incorrectly treating another disease
and the potential toxicity of malaria therapy, selftreatment should never be undertaken lightly;
consultation with a tropical medicine expert is
recommended before individuals begin selftreatment protocols.
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
chemoprophylaxis. 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.
Travellers for whom self-treatment has been
recommended 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 used only if travellers develop fever
and professional medical care is not available
within 24 hours. After self-treatment, medical
attention should still be sought as soon as possible.
Recommended Regimens* (to be used only
if fever develops and medical care is not available within 24 hours):
1. For individuals in chloroquine-sensitive
regions and not receiving chloroquine
prophylaxis: Self-treatment with chloroquine
should be taken (see Table 2, page 11). SEEK
MEDICAL HELP AS SOON AS POSSIBLE.
Chloroquine prophylaxis should be started.
2. For individuals in chloroquine-sensitive regions and already receiving chloroquine
prophylaxis: Self-treatment with Malarone®
should be taken (see Table 2, page 11). SEEK
MEDICAL HELP AS SOON AS POSSIBLE.
Chloroquine prophylaxis should be resumed.
3. In chloroquine- or chloroquine- and
mefloquine-resistant P. falciparum regions,
treatment recommendations for uncomplicated P. falciparum include the
following (see Table 2, page 11): Begin oral
Malarone® (see Table 2). SEEK MEDICAL HELP
AS SOON AS POSSIBLE. Mefloquine or other
appropriate prophylaxis should be resumed.
OR
Begin oral quinine and doxycycline (see Table 2,
page 11). SEEK MEDICAL HELP AS SOON AS
POSSIBLE. Mefloquine or other appropriate prophylaxis should be resumed.
OR
Begin oral quinine plus Fansidar® (see Table 2,
page 11) (Sub-Saharan Africa or Indian subcontinent only). SEEK MEDICAL HELP AS SOON AS
POSSIBLE. Mefloquine or other appropriate prophylaxis should be resumed.
Halofantrine (see section 9e, page 29) and mefloquine are not recommended for self-treatment
of malaria. In some countries, a combination of
mefloquine and Fansidar® is marketed under the
name Fansimef®, which should not be confused
with mefloquine. Fansimef® is not recommended
for the prevention or treatment of malaria. Individuals who are undergoing chemosuppression
should never attempt treatment with the same
drug, as there is the potential for additive toxicity
and reduced efficacy.
* If vomiting occurs within 30-60 minutes of dose, repeat full dose. If vomiting occurs 1-2 hours after dose, repeat
one half dose.
19
Rapid detection of malaria using a simple dipstick
test may be available to some travellers. The sensitivity and specificity of these tests in research
laboratories (> 90%) appear promising. However,
there are limited data about their accuracy in the
20
hands of non-experienced operators and under
non-refrigerated conditions in the tropics. There
are no rapid detection kits currently licensed in
North America.
_______
7. DIAGNOSIS OF MALARIA _______
FEVER OCCURRING IN A TRAVELLER WITHIN 3 MONTHS
OF DEPARTURE FROM A MALARIA-ENDEMIC AREA IS
A MEDICAL EMERGENCY AND SHOULD BE INVESTIGATED
URGENTLY WITH THICK AND THIN BLOOD FILMS;
THESE SHOULD BE REPEATED 12 TO 24 HOURS
LATER IF THE PATIENT REMAINS SYMPTOMATIC.
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 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 non-specific. When malaria is a consideration, especially when the patient may be at risk
of P. falciparum infection (whether chloroquinesensitive or not), the laboratory diagnosis and
quantification of the level of parasitemia must be
considered a medical emergency and be performed
as soon as possible (< 24-hour turnaround time).
Not all laboratories are proficient at 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. While dipstick methods for the
diagnosis of malaria are currently being evaluated
in the research setting, none is currently licensed
for use in Canada.
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 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, physicians are
required to report all cases to the local public
health authority.
21
_______
8. TREATMENT OF MALARIA _______
a. General Principles of Management
b. Management of Falciparum Malaria
This depends on 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. Three critical questions
need to be addressed in order to initiate effective
treatment:
The following guidelines have been derived, in part,
from the World Health Organization Division of
Control of Tropical Diseases (Severe and complicated
malaria. 2nd ed. Trans Roy Soc Trop Med Hyg
1990;84[Suppl 2]). The interested reader is referred
to this document for a more detailed discussion of
these issues.
1. Is this infection caused by P. falciparum?
This is critical, as treatment varies according to
the species of malaria.
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.
2. Is this a severe or complicated infection
(see Table 3, below)? Severe or complicated
malaria requires parenteral therapy and sometimes an exchange transfusion.
3. Has the infection been acquired in an area
of known drug-resistant malaria (see Appendix I, page 30)? Therapy will have to be modified accordingly.
When in doubt treat all falciparum malaria as
drug resistant.
TABLE 3
Criteria for Severe Falciparum Malaria
EITHER
History of recent possible exposure and no other recognized pathology
OR
Asexual forms of Plasmodium 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
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% in non-immune individuals
Adapted from Severe and complicated malaria. 2nd ed. Trans Roy Soc Trop
Med Hyg 1990;84(Suppl 2).
22
Severe P. falciparum infections, as defined by
the criteria in Table 3 may have a mortality rate of
20% or higher. These patients require immediate
hospitalization, and urgent, intensive medical
management. 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. All patients with severe P. falciparum
infections and those who are unable to tolerate
drugs orally should receive intravenous quinine or,
less optimally, quinidine (see Table 4, page 23).
In the treatment of severe malaria, parenteral
preparations of quinine and quinidine are equivalent. Quinine is preferred by CATMAT because
of the cardiotoxicity of quinidine. Patients treated
with intravenous quinidine should receive electrocardiographic monitoring, and infusion rates
should be decreased if the corrected QT interval is
prolonged by more than 25% of baseline. Intravenous quinine and quinidine are no longer readily
available in Canada.
Because of the potential for adverse outcome with
delays in acquiring parenteral malaria therapy,
every effort has been made to ensure that parenteral
quinine is available throughout Canada for the
treatment of severe malaria. A nation-wide network
of Malaria Centres of Excellence (see Appendix
V, page 39) is being established to facilitate the
storage and rapid distribution of parenteral quinine
for the treatment of severe P. falciparum infections.
TABLE 4
Chemotherapy of Severe Falciparum Malaria
NOTE: Quinine is the drug of choice. The four quinine and quinidine protocols listed below are equally efficacious and in all cases a switch
to oral therapy should be made as soon as possible.
A. If an infusion pump is available:
1. Quininea (base) 5.8 mg/kg loading doseb [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, repeated 8 hourly
(maintenance dose)c for up to 72 hours or until the patient can swallow, then quinine tablets to complete 3-7 days of treatment (7 days for SE Asia).
OR
2. Quinidined,e (base) 6.2 mg/kg loading doseb [quinidine gluconate (salt) 10 mg/kg] by intravenous infusion over 1 to 2 hours, followed by quinidine
(base) 0.0125 mg/kg/min [quinidine gluconate (salt) 0.02 mg/kg/min] by infusion pump (maintenance dose)c for up to 72 hours or until the patient can
swallow, then quinine tablets to complete 3-7 days of treatment (7 days for SE Asia).
B. Without an infusion pump:
1. Quininea (base) 16.7 mg/kg loading doseb [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, repeated 8 hourly (maintenance dose)c for
up to 72 hours or until the patient can swallow, then quinine tablets to complete 3-7 days of treatment (7 days for SE Asia).
OR
d,e
b
2. Quinidine (base) 15 mg/kg loading dose [quinidine gluconate (salt) 24 mg/kg] in a volume of 250 mL of normal saline infused over 4 hours
followed by a maintenance dosec, beginning 8 hours after the beginning of the loading dose, of quinidine (base) 7.5 mg/kg [quinidine gluconate (salt)
12 mg/kg] infused over 4 hours, every 8 hours for up to 72 hours or until the patient can swallow, then quinine tablets to complete 3-7 days of treatment
(7 days for SE Asia).
PLUS (either concurrently with quinine/quinidine 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,
breastfeeding or age < 8 years.
OR
2. Fansidar®: 3 tablets at one time (see Table 2 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 asexual parasites (ONLY IF UNABLE TO TAKE
DOXYCYCLINE, TETRACYCLINE OR FANSIDAR®).
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 Malaria Centres of Excellence (see Appendix V for contact information).
c Switch to oral quinine as soon as possible. In patients requiring more than 48 hours of parenteral therapy, reduce the quinine or quinidine maintenance
dose by one-third to one-half.
d Parenteral quinidine gluconate may be obtained on a patient-by-patient basis with authorization from the Special Access Program, Therapeutic Products
Programme, 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.ca/hpb-dgps/therapeut
e Quinidine should be used only if parenteral quinine is unavailable, see text. Cardiac monitoring is required.
The Centres will also provide expertise in the
management of malaria cases. As well, each Centre
will provide surveillance data to LCDC on cases
treated with parenteral quinine.
Parenteral quinidine gluconate dosing is provided
in Table 4. It is as effective as parenteral quinine
in the treatment of severe malaria, but the risk of
cardiotoxicity necessitates cardiac monitoring.
Parenteral quinidine gluconate can be obtained on
a patient-by-patient basis with authorization from
Health Canada’s Special Access Program, see footnote, Table 4, for contact information. Parenteral
quinidine sulfate is an intramuscular preparation
that is not recommended for intravenous use.
Uncomplicated P. falciparum infections unequivocally acquired in a chloroquine-sensitive zone
may be treated with chloroquine alone (as per
Table 2, page 11). Those infections that were
possibly or definitely acquired in drug-resistant
regions should be treated with Malarone® or quinine and a second drug. If the patient can tolerate
oral quinine, then it and the second drug – either
doxycycline, Fansidar®, or clindamycin – may be
administered simultaneously or sequentially (start
quinine first), either orally (as per Table 2, page 11)
or, if necessary, parenterally (as per Table 4). The
base-salt equivalents of selected antimalarials are
shown in Table 5 (page 24).
23
When quinine 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; if possible, such patients should be
monitored electrocardiographically.
Approximately 5% or more of patients may fail
treatment for falciparum malaria. Most patients
fail within 1 month of treatment. To ensure that
patients are cured, it is important to repeat a thick
and thin blood film on day 7 and day 28 after
therapy, and at any time there is recurrence of
symptoms.
TABLE 5
Base/Salt Equivalents of Selected Antimalarial Drugs
Drugs
Chloroquine phosphate
Chloroquine sulfatea
Clindamycin hydrochloride
Mefloquine
Quinidine gluconate
Quinidine sulfateb
Quinine dihydrochloride
Base (mg)
150
100
150
250
5.0
7.5
10
15
7.5
10
15
5
7.5
15
16.7
250
Quinine sulfate
a Not available in Canada
b Intramuscular preparation, should not be used intravenously.
Salt (mg)
250
136
225
274
8
12
16
24
9
12
18
6
9
18
20
300
c. Ancillary Treatment of Severe Malaria
Many ancillary treatments have been suggested
for the treatment of severe malaria, but few have
been objectively shown to improve outcome. Only
antipyretics (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
recommendations – see Appendix II, page 34).
In cases of complicated P. falciparum infection
(Table 3, page 22) or if there is high parasitemia
(³ 10%), exchange transfusion has been used on
24
an experimental basis as a 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 V, page 39, for contact information).
d. Management of Non-Falciparum
Malaria
Outside of New Guinea (Papua New Guinea and
Irian Jaya), chloroquine remains the treatment of
choice for malaria other than falciparum (as per
Table 2, page 11). Recent reports have confirmed
the presence and high prevalence (80%) of
chloroquine-resistant P. vivax in Irian Jaya. Sporadic
cases of chloroquine-resistant 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 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 (see sections 3f, page 9, and 9e,
page 29). Standard chloroquine doses (25 mg
base/kg/72 hours) combined with high dose
primaquine (2.5 mg base/kg/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.
As with falciparum malaria, response to treatment
should be documented with 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 less than 30 days after
treatment suggests chloroquine-resistant P. vivax;
recurrence after more than 30 days suggests
primaquine resistance.
e. Prevention of Relapses of Malaria Due
to P. vivax or P. ovale
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.
None of the currently recommended chemoprophylaxis regimens will prevent relapses due to these
two species of malaria. 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 is not
routinely recommended to prevent relapsing malaria in asymptomatic returning travellers (terminal prophylaxis). However, terminal prophylaxis
with primaquine is generally indicated for persons
with prolonged exposure in malaria-endemic
areas (e.g. long-term travellers or expatriates, see
section 5, page 17). For terminal prophylaxis
primaquine is administered after the traveller has
departed from a malaria-endemic area, usually
during or following the last 2 weeks of chemoprophylaxis. (See Table 2, page 11 for dosage recommendations).
Primaquine use is contraindicated in pregnancy.
P. vivax or P. ovale infections occurring during
pregnancy should be treated with standard doses
of chloroquine (Table 2, page 11). 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 generally well tolerated but may
cause nausea and abdominal pain; this may be
diminished by taking the drug with food. More
importantly, primaquine may cause oxidantinduced hemolytic anemia in those with a deficiency
of G6PD, as well as methemoglobinemia. Those of
Mediterranean, African, and Asian ethnic origin or
those receiving > 15 mg base/day have a greater
risk of hemolysis. All individuals should have their
G6PD level measured before primaquine therapy
is initiated.
Primaquine is contraindicated in those with
severe G6PD deficiency. In mild variants of G6PD
deficiency, primaquine has been used safely at
a lower dose (0.8 mg base/kg/week; adult dose
45 mg base once weekly for 6 weeks) for radical
cure of P. vivax or P. ovale malaria. 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). Patients should
be advised to stop their medication and report to a
physician immediately if jaundice or abnormally
dark or brown urine is noted.
f. P. vivax Resistance to Primaquine
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.
When P. vivax malaria relapses following primaquine therapy there are two issues to be considered: (1) the treatment of the acute vivax malaria
(see section 8d, page 24), and (2) prevention of
further relapses by doubling the standard dose
of primaquine, i.e. 30 mg (0.5 mg/kg/day) of
primaquine base daily for 14 days (B I – evidencebased medicine recommendations – see Appendix II, page 34).
Response to treatment should be documented
with 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 less than 30 days after treatment suggests
chloroquine-resistant P. vivax; recurrence after
more than 30 days suggests primaquine resistance.
25
_______
9. NEW DRUGS FOR THE PREVENTION _______
AND TREATMENT OF MALARIA
a. Atovaquone/Proguanil (Malarone®) for
the Treatment and Prevention of Malaria
Atovaquone (ATQ), a hydroxynapthaquinone,
is a member of a novel class of antimalarials first
described in the 1920s. ATQ is an analog of
ubiquinone, which selectively inhibits parasite
mitochondrial electron transport. ATQ has similar
activity against both chloroquine-sensitive and
chloroquine-resistant P. falciparum isolates. However,
when ATQ is used as monotherapy, resistance
develops rapidly. ATQ displays in vitro antagonism
with artemisinin compounds and quinolines but
synergy with proguanil and tetracycline. Proguanil
displays its synergistic activity with ATQ even in
the context of documented proguanil resistance.
The fixed drug combination Malarone® (tablet:
250 mg ATQ and 100 mg proguanil) is licensed
in Canada for the treatment of uncomplicated
malaria, but it is not currently licensed for
chemoprophylaxis.
Compared with other standard antimalarial
regimens, the ATQ/proguanil combination has
demonstrated excellent safety and tolerance with
fewer reported adverse events than mefloquine
and quinine plus tetracycline. During treatment,
the most frequent adverse events are those associated with the gastrointestinal tract. Approximately
8% to 15% of adults and children will experience
nausea, vomiting, abdominal pain or diarrhea, and
in 5% to 10% there will be transient, asymptomatic
elevations in transaminases and amylase. Serious
adverse events associated with ATQ/proguanil are
rare. One episode of anaphylaxis has been attributed
to this combination. Three patients experienced
convulsions 2 to 5 days after initiation of therapy,
each with a history of seizure disorders. ATQ
has been associated with fever and rash in HIVinfected patients, requiring discontinuation of
therapy. It has been shown to be teratogenic in
rabbits but not in rat models (FDA category C
drug). Pregnancy and hypersensitivity to either
component are the only contraindications to
ATQ/proguanil.
26
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 ATQ and proguanil (dosed
once daily for 3 days) has exceeded 95%. As well,
published case reports have documented that this
combination drug successfully treated multidrugresistant malaria that had failed to respond to
other therapies. (AI – evidence-based medicine –
see Appendix II, page 34).
ATQ/proguanil combination therapy has also
been effective in pediatric populations at a dose
of 20 mg/kg/day of ATQ and 8 mg/kg/day of
proguanil for 3 days.
Three placebo-controlled studies have demonstrated
a greater than 95% efficacy of ATQ/proguanil as
a chemoprophylactic agent against P. falciparum
malaria in semi-immune adults and children at an
adult dose of 1 tablet per day. Mounting evidence
indicates that ATQ/proguanil is effective as a causal
(acting at the liver stage) as well as suppressive
(acting at the blood stage) prophylactic agent
and can therefore be discontinued 1 week after
departure from a malaria-endemic area. Additional
studies in non-immune adults and children are
required in order to satisfy regulatory agencies of
its safety and effectiveness as a chemoprophylactic
agent.
Recommendations
i.
ATQ combined with proguanil (Malarone®),
an effective and well-tolerated therapy, can
now be considered as first line therapy (with
attention to contraindications and precautions)
for uncomplicated multidrug-resistant
P. falciparum malaria. (A I – evidencebased medicine recommendations – see
Appendix II, page 34).
ii. There are insufficient data at present to
recommend its use for malaria caused by
other Plasmodium species (vivax, ovale, malariae).
(C – evidence-based medicine recommendations – see Appendix II, page 34).
iii. ATQ/ proguanil may be considered for the
treatment of falciparum malaria that fails
standard drug regimens (A I – evidence-based
medicine recommendations – see Appendix II,
page 34).
iv. At present ATQ/proguanil (Malarone®) is
not licensed for prophylaxis use in Canada;
however, there may be limited use for ATQ/
proguanil as a prophylactic agent (with attention
to contraindications and precautions) when
other recommended options are either inappropriate or contraindicated. (B I – evidencebased medicine recommendations – see
Appendix II, page 34).
b. Primaquine and Tafenoquine for the
Prevention of Malaria
Primaquine is an 8-aminoquinolone that has been
used for decades to prevent relapses of P. vivax and
P. ovale infections (radical cure) and as a gametocidal
agent to decrease the transmission of P. falciparum
in malaria-endemic areas. Because primaquine has
activity against both blood and tissue (liver) stages
of malaria, it can eliminate P. vivax and P. falciparum
infections that are developing in the liver (causal
prophylaxis) and prevent symptomatic or clinical
infection.
Recent randomized double blind, placebo-controlled
studies have examined the efficacy of primaquine
as a prophylactic agent in partially immune Kenyan
children and non-immune Indonesian and Colombian
men. 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 persons
who were not G6PD deficient.
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.
Primaquine is contraindicated in patients with
severe G6PD deficiency. 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/week; adult dose
45 mg base weekly for 6 weeks); however, this reduced dose is insufficient for chemoprophylactic
activity. When used at prophylactic doses (0.5 mg
base/kg/day) in children and men with normal
G6PD activity, mean methemoglobin rates (5.8%)
were below those associated with toxicity (>10%).
Collectively, these data indicate that primaquine
appears to be a safe and effective prophylactic
agent in semi-immune children and non-immune
adults. Theoretically, because primaquine is a causal
agent, individuals should be required to take it
only during periods of exposure and for 1 week
after departure from the malaria-endemic area.
This would avoid the requirement to complete
4 weeks of chemoprophylaxis following exposure
(a common reason for non-adherence with standard regimens) and may be particularly useful for
travellers with short exposures (2 to 7 days) in
high-risk areas such as sub-Saharan Africa and
New Guinea. Primaquine should be taken daily
starting 1 day before entering a malaria-endemic
area, continued while in the area and for 1 week
after departure.
Tafenoquine (WR 238605) 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. Phase 2 studies are ongoing
in semi- and non-immune people. In the future,
tafenoquine may provide another option for chemoprophylaxis in those without G6PD deficiency.
Recommendations
i.
Primaquine chemoprophylaxis is contraindicated in individuals with G6PD deficiency
and during pregnancy (E II – evidence-based
medicine recommendations – see appendix II,
page 34).
ii. 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 recommendations – see appendix II,
page 34).
27
c. Artemisinin Derivatives (Qinghaosu) for
the Treatment of Drug-Resistant Malaria
Artemisinin (qinghaosu) is a naturally occurring
sesquiterpene lactone peroxide structurally unrelated
to any known antimalarial. Qinghaosu, derived
from cultivated Artemisia annua, is available as the
parent compound artemisinin (oral, parenteral,
and suppository formulations) and as three semisynthetic derivatives: a water-soluble hemisuccinate
salt (artesunate) for parenteral or oral administration; and two oil-soluble compounds (artemether
and arteether) for intramuscular injection. All are
metabolized to a biologically active metabolite,
dihydroartemisinin. Artesunate is a prodrug for
dihydroartemisinin and as such is the most rapidly
active of the derivatives examined to date. All
compounds have their antiparasitic effects on the
younger ring-form parasites, thereby decreasing
the numbers of late parasite forms that can obstruct the host’s microvasculature.
All artemisinin preparations have been studied and
used only for treatment. They are recommended
for treatment use only and not for prophylaxis.
All compounds are at least as efficacious as quinine
in the treatment of severe and complicated malaria.
Qinghaosu and its derivatives lead to faster parasite (mean: 32% faster) and fever (mean: 17%
faster) clearance times 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 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 less than 5 days. Recent studies
have examined longer durations of therapy (7 days)
and combinations of qinghaosu derivatives and
mefloquine in order 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.
28
Artemisinin derivatives have been used by 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 toxicity. Neurologic 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 toxicity in humans have not been
performed. The safety of qinghaosu derivatives in
pregnancy has not been established. Because of
their short half-life artemisinin and its derivatives
should not be used for prophylaxis.
Artemisinin and its derivatives are now available
and increasingly used in Southeast Asia and Africa;
none is licensed in Canada. Combinations of
artesunate and mefloquine appear to be the most
active drug regimens for treatment of multidrugresistant falciparum malaria in Southeast Asia.
The quality of artemisinin derivatives available in
developing countries is 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). However,
at present, there are insufficient toxicity data
or evidence of clinical superiority over standard
therapy to routinely recommend these as firstline agents, particularly for P. falciparum infections acquired in Africa (A I – evidence-based
medicine recommendations – see Appendix II,
page 34).
ii. Artemisinin compounds should not be used for
chemoprophylaxis. (C III – evidence-based
medicine recommendations – see Appendix II,
page 34).
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 (A I – evidence-based
medicine recommendations – see Appendix II,
page 34).
Artemisinin derivatives are not currently
available in North America or Europe.
in Canada and has recently been withdrawn from
the market because of concerns about cardiotoxicity.
It remains widely available in the tropics, and
travellers should be made aware of the danger
of this drug. The World Health Organization has
reported cardiac deaths associated with the use of
halofantrine and no longer recommends its use.
UNTIL THERE IS A CLEARER UNDERSTANDING OF
THE FREQUENCY AND DETERMINANTS OF
HALOFANTRINE CARDIOTOXICITY,
ESTABLISHED ALTERNATIVES ARE PREFERRED
d. Azithromycin for the Prevention of
Malaria
Azithromycin (Zithromax®) is a macrolide antibiotic
that has been shown to have only limited effectiveness in the prevention of malaria (A II – evidencebased medicine recommendations – see Appendix
II, page 34). Studies performed to date are small
and suggest that azithromycin is less effective than
mefloquine or doxycycline. Azithromycin should
be considered for chemoprophylaxis only in highly
selected groups. It is considered to be safe in
pregnancy and in children, and is available in
suspension. However, in view of the serious consequences of malaria in pregnancy, utilization of this
suboptimal antimalarial would not routinely be
recommended. If used, azithromycin requires daily
dosing (adult dose of 1 tablet per day) starting the
day before exposure, continued during exposure
and for 4 weeks after departure from the malarial
region.
Recommendations
There is insufficient evidence to recommend
azithromycin as an alternative antimalarial except
in circumstances in which other, more effective
and safer medications are not available or are
contraindicated. (CI – evidence-based medicine
recommendations – see Appendix II, page 34).
e. Halofantrine for the Treatment of
Malaria
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
Recommendations
i.
Halofantrine should not be used for selfdirected therapy (D II – evidence-based
medicine recommendations – see Appendix II,
page 34).
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 –
evidence-based medicine recommendations
– see Appendix II, page 34).
iii. Travellers who inquire about halofantrine or
who are likely to encounter its use (e.g. West
Africa) should be informed of its potential
cardiotoxicity (C III – evidence-based medicine recommendations – see Appendix II,
page 34).
f. Pyronaridine for the Treatment of
Malaria
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. The drug has been shown to be very
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.
29
_______
APPENDIX I† _______
Malaria Risk by Geographic Areas in Countries with Endemic Malaria
Country
Afghanistan
Algeria
Angola
Argentina
Armenia
Azerbaijan
Bangladesh
Belize
Benin
Bhutan
Bolivia
Botswana
Brazil
Burkina Faso
Burma: see Myanmar
Burundi
Cambodia
Cameroon
Cape Verde
Central African Republic
Chad
China
Colombia
Comoros
Congo
Costa Rica
Côte d’Ivoire (formerly Ivory
Coast)
†
30
All
Very limited in Sahara region
All
Areas of risk within country
P vivax in rural areas near Bolivian and Paraguay borders
Risk limited to western borders areas: Masis, Ararat, and Artashat regions in Ararat district. No
risk in tourist areas.
Southern border areas and Khachmas region in north
All, except no risk in city of Dhaka
Rural areas including resort areas, off shore islands, and forest preserves, except no risk in central coastal Belize District
All
Rural areas, in districts bordering India
Rural areas < 2500 metres only, except no risk in Oruro Department and Province of Ingavi,
Los Andes, Omasuyos, Pacajes, Southern and Central Potosi Department.
Northern part of country (North of 21o South) from November to June
Risk in Acre and Rondonia states, territories of Amapa and Roraima, and in rural areas of
Amazonas, Maranhao, Mato Grosso, Para, and Tocantins. The outskirts of Manaus and Porto
Velho are risk areas. Note: No risk for travellers to coastal states from the horn to Uruguay border and Iguassu Falls.
All
Recommended Regimens
Mefloquine
None
Mefloquine
Chloroquine
Chloroquine
Chloroquine
Mefloquine
Chloroquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
All
All, except no risk in Phnom Penh and around Tonle Sap. Malaria risk exists in Angkor Wat.
Mefloquine
Mefloquine (doxycycline on
western borders)
All
Mefloquine
Limited risk exists on Sao Tiago Island from September to November
None
All
Mefloquine
All
Mefloquine
Chloroquine (mefloquine for
Rural areas only in Anhui, Fujian, Guangdong, Guangxi, Guizhou, Hainan, Hubei, Hunan,
Jiangsu, Jiangxi, Shandong, Shanghai, Sichuan, Xinjiang, Xizang, Yunnan and Zhejiang prov- Hainan Island and southern
inces/autonomous regions. Transmission occurs < 1500 metres from July to November north of provinces bordering Myanmar,
33o North, from May to December between 33o North and 25o N and throughout the year below Lao People's Democratic
25o North. Note: Travellers visiting cities and popular rural tourist routes are generally not at
Republic and Vietnam)
risk and require no prophylaxis.
In general, rural areas only, no risk in Bogota and vicinity
Mefloquine
All
Mefloquine
All
Mefloquine
Rural areas only (including tourist areas). No risk in central highlands. Limited risk in rural ar- Chloroquine
eas of Alajuela, Guanacaste, Limon, Heredia and Los Chiles provinces.
All
Mefloquine
Adapted from CDC Health Information for International Travel 1999-2000 and WHO International Travel
and Health 2000.
Country
Areas of risk within country
Democratic Republic of Congo All
Djibouti
All
Dominican Republic
All rural areas. Highest risk in areas bordering Haiti. Travellers visiting resort areas are generally not at risk and require no prophylaxis.
Ecuador
All provinces along eastern border and Pacific coast: Canar, Cotopasi, El Oro, Esmeraldas,
Guayas, Los Rios, Manabi, Morona-Santiago, Napo, Pastaza, Pinchincha, Sucumbios, Zamora,
Chinchipe. (No risk in Quito and vicinity, the central highland tourist areas or the Galapagos Islands.)
Egypt
Limited risk in El Faiyum area and part of Southern (upper) Egypt. (No risk in main tourist areas including cruises.)
El Salvador
Rural areas only
Equatorial Guinea
All
Eritrea
All, except no risk in Asmara and above 2,000 metres
Ethiopia
All, except no risk in Addis Ababa and above 2,000 metres
French Guiana
All
Gabon
All
Gambia
All
Ghana
All
Guatemala
Rural areas only, except no risk in central highlands above 1,500 metres
Guinea
All
Guinea-Bissau
All
Guyana
High risk in rural areas of all interior regions including Rupununi, North West Regions and
along Pomeroon River. The risk in Georgetown and New Amsterdam is low.
Haiti
All
Honduras
High risk of predominantly P. vivax in rural areas only
India
Indonesia
Iran, Islamic Republic of
Iraq
Ivory Coast: see Côte d’Ivoire
Kenya
Korea, Democratic People's
Republic of (North)
Korea, Republic of (South)
Lao People’s Democratic
Republic
Liberia
Libyan Arab Jamahiriya
Madagascar
Malawi
Malaysia
Mali
Mauritania
Mauritius
All areas below 2,000 metres including Delhi and Bombay, except no transmission in parts of
the states of Himachal Pradesh, Jammu, Kashmir, and Sikkim
In general, rural areas only, except high risk in all areas of Irian Jaya (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.
Limited risk in rural areas only (March to November) in the provinces of Sistan-Baluchestan,
Kermany and Hormozgan, the southern parts of Fars, Kohgiluyeh-Boyar, Lorestan and Chahar
Mahai-Bakhtiani and the north of Khuzestan.
All areas in northern region (May to November): Duhok, Erbil, Basrah, Tamim, Ninawa and
Sulaimaniya province.
Recommended Regimens
Mefloquine
Mefloquine
Chloroquine
Mefloquine
Chloroquine
Chloroquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Chloroquine
Mefloquine
Mefloquine
Mefloquine
Chloroquine
Chloroquine
Mefloquine
Mefloquine
Mefloquine
Chloroquine
All areas including game parks except low risk in city of Nairobi and above 2,500 metres
Mefloquine
None
Risk of P. vivax in and along demilitarized zone, areas not visited by travellers. Antimalarial
drugs are not recommended for tourists.
All areas, except no risk in city of Vientiane
None
All
Limited risk in two small foci in southwest of country from February to August
All, highest risk in coastal areas
All
Remote rural areas of peninsular Malaysia and Sarawak (NW Borneo), urban and coastal areas
are malaria free. All areas of Sabah (NE Borneo).
All
All areas, except no risk in the northern areas of Dakhlet-Nouadhibou and Tiris-Zemour. In
Inchiri and Adrar, risk from July to October.
Mefloquine
None
Mefloquine
Mefloquine
Mefloquine
Limited malaria risk from P. vivax exists in some southern areas.
Risk of P. vivax in rural areas only, except no risk in Rodrigues Island
Mefloquine
Mefloquine
Mefloquine
Chloroquine
31
Mayotte
Mexico
Country
Morocco
Mozambique
Myanmar (formerly Burma)
Namibia
Nepal
New Hebrides: see Vanuatu
Nicaragua
Niger
Nigeria
Oman
Pakistan
Panama
Papua New Guinea
Paraguay
Peru
Philippines
Rwanda
Sao Tome and Principe
Saudi Arabia
Senegal
Sierra Leone
Solomon Islands
Somalia
South Africa
Sri Lanka
Sudan
Suriname
Swaziland
Syrian Arab Republic
Tajikistan
Tanzania, United Republic of
Thailand
Togo
32
Areas of risk within country
Recommended Regimens
All
Mefloquine
Rural areas including rural resort areas of the following states: Campeche, Chiapas, Chihauhua, Chloroquine
Durango, Guerrero, Hidalgo, Jalisio, Michoacan, Nayarit, Oaxaca, Quintana Roo, Sinaloa,
Sonora and Veracrus.
None
Very limited risk of P. vivax in rural areas of some provinces
All
Rural areas. Note: Travellers to Yangon (Rangoon) and Mandalay are not at risk and need no
prophylaxis.
All areas of Ovamboland and Caprivi Strip
Rural areas in Terai District and hill districts below 1,200 metres. No risk in Kathmandu.
Mefloquine
Mefloquine (doxycyline for
Thai borders)
Mefloquine
Mefloquine
Rural areas and outskirts of Bluefields, Bonanza, Chinandega, Leon, Puerto Cabeza, Rosita and
Siuna
All
All
All
All areas below 2,000 metres including cities
Rural areas north and west of Canal
Rural areas south and east of Canal
No risk in the Canal Zone or in Panama City
All
Chloroquine
In general, only rural areas bordering Brazil. P. vivax predominates.
Rural areas only. 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) and no prophylaxis
needed.
Rural areas only, except no risk in Manila and province of Bohol, Catanduanes and Cebu.
Chloroquine resistance in rural areas of Luzon, Basilian, Mindoro, Palawan, Mindanao and
Sulu-Archipelago.
All
All
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
All
All
All
All
Rural areas (including game parks) in the northern, eastern and western low altitude areas of
the Transvaal and the Natal Coast north of 28o south.
All rural areas except no risk in Colombo, Kalutara, Nuwara Eliya.
All
Rural areas only, except no risk in Paramaribo district and coastal areas north of 5o North.
All lowland areas
Rural areas only (May to October) especially along northern border. No risk in districts of Damascus, Deir-es-zor and Sweida.
Risk predominantly in southern border areas (Khatlon region); risk in some central
(Dushanbe), western (Gorno-Badakhshan) and northern (Leninabad) areas. Chloroquine resistance suspected in some areas.
All
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, Pattaya, Phuket, Samui).
Mefloquine resistance reported from areas on borders with Myanmar and Cambodia.
All
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Chloroquine
Mefloquine
Mefloquine
Chloroquine
Chloroquine
Mefloquine for borders with
Brazil and Ecuador
Chloroquine
Mefloquine for chloroquineresistant areas.
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Chloroquine
Chloroquine
Mefloquine
Doxycycline for overnight exposure in rural areas on border with Myanmar and
Cambodia.
Mefloquine
Turkey
Country
Uganda
United Arab Emirates
Vanuatu (formerly New
Hebrides)
Venezuela
Viet Nam
Yemen
Zaire: see Democratic
Republic of Congo
Zambia
Zimbabwe
Areas of risk within country
Cukurova/Amikova areas and southeast Anatolia (April to October). No risk in main tourist areas in west and south-west.
All
Risk in foothills and valleys in the mountainous regions of northern Emirates. No risk in cities of
Dubai, Sharjah, Ajman, Umm al Qaiwain and Emirate of Abu Dhabi.
All, except no risk on Futuna Island.
Recommended Regimens
Chloroquine
Mefloquine
Chloroquine
Mefloquine
Rural areas only, in all border states and territories and the states of Barinas, Merida, and
Portugesa
Rural areas only, no risk in Red Delta and coastal plain north of Nha Trang.
All except no risk in Aden and airport areas.
Mefloquine
All
All except no risk in cities of Harare and Bulawayo.
Mefloquine
Mefloquine
Mefloquine
Mefloquine
Countries not listed are considered free of malaria.
33
_______
APPENDIX II _______
Strength and Quality of Evidence Summary Sheet*
Categories for the strength of each recommendation
CATEGORY
DEFINITION
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
GRADE
*
34
DEFINITION
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.
_______
APPENDIX III _______
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 (see section 2a, page 3, section 4, page 14, and Appendix I, page 30)
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. Pregnant women and adults taking
young children should question the necessity of the trip.
b) Anti-mosquito measures (see section 2b, page 3)
Travellers should be instructed on how to protect themselves against mosquito bites.
c) Chemoprophylaxis (see section 3, page 6)
Travellers should be:
1. advised to start chemoprophylaxis before travel, to use prophylaxis continuously while in malariaendemic areas and for 4 weeks after leaving such areas (except for Malarone® and primaquine,
which are taken for 1 week after leaving such areas).
2. questioned about drug allergies and other contraindications for drug use.
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.
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 (see section 7, page 21)
Travellers should be:
1. informed that symptoms of malaria may be mild, and that they should suspect malaria if they experience a fever or flu-like illness (unexplained fever).
2. informed that malaria may be fatal if treatment is delayed.
3. informed that 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
films should be brought home for review).
35
4. reminded that self treatment (if prescribed) should be taken only if prompt medical care is not
available within 24 hours and that medical advice should still be sought as soon as possible after
self-treatment (see section 6, page 19).
5. reminded to continue to take chemoprophylaxis in cases of suspected or proven malaria.
e) Special hosts (see section 4, page 14)
Pregnant women, young children and immunocompromised individuals require special attention
because of the potential effects of malaria illness and inability to use some drugs.
(Adapted from International Travel and Health, World Health Organization, Geneva, 1999).
36
_______
APPENDIX IV _______
Misconceptions about Malaria and Mefloquine
1. Myth: Malaria is not a serious infection for healthy people.
Fact:
Malaria is a major killer worldwide and is the principal life-threatening infectious disease that
Canadian travellers face when travelling to high-risk areas of the world. In recent years there
has been a dramatic increase in malaria cases in Canadian travellers, including several deaths.
2. Myth: All travellers to the developing world need malaria prophylaxis.
Fact:
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 protection measures, such
as treated mosquito nets and insect repellents, to avoid mosquito bites.
3. Myth: Pregnant women, babies and children should not receive malaria prophylaxis.
Fact:
On the contrary, pregnant women, babies and small children are at particular risk for 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.
4. Myth: Most people who take mefloquine have serious side effects.
Fact:
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 mefloquine. Over 11 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
(95-99%) have either no side effects or only mild and temporary ones. Occasionally, a traveller 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. Death from malaria, however, is not.
5. Myth: Drugs that are safer than mefloquine are available either in Canada or abroad.
Fact:
For high-risk regions of the world, mefloquine is the most effective drug to prevent malaria.
Alternatives typically offered to travellers to Africa (e.g. chloroquine, proguanil [Paludrine®],
amodiaquine, pyrimethamine [Daraprim®], pyrimethamine plus sulfadoxine [Fansidar®],
pyrimethamine plus dapsone [Maloprim®]) are significantly less effective and often more
toxic than mefloquine. Doxycycline is an effective alternative but may occasionally have troublesome side effects and must be taken each and every day in order to prevent malaria.
37
6. Myth: If I take prophylaxis, the malaria I get will be more resistant to treatment.
Fact:
The prevention of malaria in travellers using prophylactic drugs (including mefloquine) does
not promote the development of resistant malaria parasites. Appropriately used prophylaxis
can actually reduce resistance by lowering the burden of malaria disease.
7. Myth: There is only a limited period in which one can take prophylaxis safely.
Fact:
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. Many mild side effects decrease with
continued use of prophylaxis.
8. Myth: Some malaria cannot be treated.
Fact:
If identified early and treated appropriately, almost all malaria can be completely cured. However, even short delays in the diagnosis of malaria can make treatment more difficult and less
successful.
9. Myth: Once infected with malaria, you are infected for life.
Fact:
Appropriate treatment and follow-up can ensure complete cure of malaria.
10. Myth: Individuals born and raised in a malarial country are immune for life.
Fact:
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 malarious area.
Although avoidance of mosquito bites is important for protection (e.g. appropriate clothing,
screens and mosquito nets, repellents), anti-malarial 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.
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_______
Appendix V _______
Contact Information for Malaria Centres of Excellence
The following hospital centres across Canada have been identified as Centres of Excellence for Malaria.
Each Centre will have depositories of parenteral quinine for the treatment of severe malaria and can
provide expertise in the management of malaria infections.
To obtain parenteral quinine, please contact the listed pharmacy in your area. Please refer to Table 4
for dosing information.
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.
Program Coordinator
Name:
Dr. Kevin C. Kain
Piri Babos, Phamacist
Address:
The Toronto General Hospital
200 Elizabeth St. ENG-224
Toronto, Ontario
M5G 2C4
The Toronto General Hospital
Department of Pharmacy
200 Elizabeth St. ENG-260
Toronto, Ontario
M5G 2C4
Phone #:
(416) 340-3535
Tel: (416) 340-3462
Fax #:
(416) 595-5826
E-Mail:
Kevin.Kain@uhn.on.ca
Participants, by province
British Columbia
Name:
Dr. William Bowie
Dr. Fawziah Marra, Pharmacist
Address:
GF Strong Research Laboratory
Vancouver General Hospital
452D-2733 Heather Street
Vancouver, British Columbia
V5Z 3J5
Vancouver General Hospital
Department of Pharmacy
855 W 12th Ave
Vancouver, British Columbia
V5Z 1M9
Phone #:
(604) 875-4147
(604) 875-4077
Fax #:
(604) 875-4013
E-Mail:
bowie@interchange.ubc.ca
fawziah@interchange.ubc.ca
39
Alberta
Name:
Dr. Stan Houston
Amy Law, Pharmacist
Address:
Division of Infectious Diseases
University of Alberta Hospital
8440-112th Street
Edmonton, Alberta
T6G 2R7
University of Alberta Hospital Pharmacy
8440-112th Street
Edmonton, Alberta
T6G 2R7
Phone #:
(780) 407-8035
(780) 407-1586
Fax #:
(780) 407-6990
E-Mail:
shouston@gpu.srv.ualberta.ca
Name:
Dr. H. Dele Davies
Dominique Van Schijndel, Pharmacist
Address:
Division of Infectious Diseases
Alberta Children’s Hospital
1820 Richmond Road SW
Calgary, Alberta
T2T 5C7
Alberta Children’s Hospital Pharmacy
1820 Richmond Road SW
Calgary, Alberta
T2T 5C7
Phone #:
(403) 229-7211
(403) 229-7204
Fax #:
(403) 541-7508
E-Mail:
dele.davies@crha-health.ab.ca
Saskatchewan
Name:
Dr. Karen McClean
Janet Harding, Pharmacist
Address:
Division of Infectious Diseases
Royal University Hospital
103 Hospital Drive
Saskatoon, Saskatchewan
S7N 0W8
The Royal University Hospital Pharmacy
103 Hospital Drive
Saskatoon, Saskatchewan
S7N 0W8
Phone #:
(306) 655-1000
(306) 655-2264
Fax #:
(306) 975-0383
E-Mail:
karen.mcclean@usask.ca
Manitoba
Name:
Dr. Pierre Plourde
Anita Richard, Pharmacist
Address:
St-Boniface Hospital
Room C 5124
Winnipeg, Manitoba
R2H 2A6
St-Boniface General Hospital Pharmacy
409 Avenue Taché
Winnipeg, Manitoba
R2H 2A6
Phone #:
(204) 237-2927
(204) 237-2161
Fax #:
(204) 233-7125
E-Mail:
plourde@cc.umanitoba.ca
40
Ontario
Name:
Dr. Kevin C. Kain
Piri Babos, Phamacist
Address:
The Toronto General Hospital
200 Elizabeth St. ENG-224
Toronto, Ontario
M5G 2C4
The Toronto General Hospital
Department of Pharmacy
200 Elizabeth St. ENG-260
Toronto, Ontario
M5G 2C4
Phone #:
(416) 340-3535
Tel: (416) 340-3462
Fax #:
(416) 595-5826
E-Mail:
Kevin.Kain@uhn.on.ca
Name:
Dr. Anne E. McCarthy
Mike Tierney, Pharmacist
Address:
Division of Infectious Diseases
Assistant Professor
University of Ottawa
Ottawa Hospital (General Campus)
501 Smyth Road
Ottawa, Ontario K1H 8L6
Ottawa Hospital Pharmacy
501 Smyth Road
Ottawa, Ontario
K1H 8L6
Phone #:
(613) 737-8184
(613) 737-8342
Fax #:
(613) 737-8682
E-Mail:
amccarthy@ogh.on.ca
Name:
Dr. Doug MacPherson
Giti Sobhi, Pharmacist
Address:
St. Joseph’s Regional Laboratory
50 Charlton Avenue East
Hamilton, Ontario
L8N 4A6
McMaster University Pharmacy
1200 Main Street W
Hamilton, Ontario
L8S 4J9
Phone #:
(905) 522-1155 Ext. 4011
(905) 521-2100 Ext. 73447
Fax #:
(905) 521-6090
E-Mail:
dmacpher@fhs.csu.mcmaster.ca
sobhi@ihis.cmh.on.ca
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
Ste Foy, Québec
G1V 4G2
Phone #:
(418) 656- 4141 Ext. 7882
(418) 656- 4141 Ext. 7916
Fax #:
(418) 654-2147
E-Mail:
micro.pchul@chuq.ulaval.qc.ca
Quebec
luc.bergeron@chuq.qc.ca
41
Name:
Dr. Brian Ward
Denise Kalyvas, Pharmacist
Address:
The Montreal General Hospital
1650 Cedar Avenue
Room D7-153
Montreal, Québec
H3G 1A4
The Montreal General Hospital Pharmacy
1650 Cedar Avenue
Room C1-200
Montreal, Québec
H3G 1A4
Phone #:
(514) 921-6953
(514) 937-6011 ext. 4933
Fax #:
(514) 934-8347
E-Mail:
cybj@musica.mcgill.ca
Nova Scotia
Name:
Dr. David Haldane
Bonnie Salsman, Pharmacist
Address:
Microbiology Laboratory
Mackenzie Building
VG Site, QE II HSC
5788 University Ave,
Halifax, Nova Scotia
B1H 1V8
Pharmacy Department
VG Site, QE II HSC
1278 Tower Rd
Halifax, Nova Scotia
B3H 2Y9
Phone #:
(902) 473-6624
(902) 473-6575
Fax #:
(902) 473-4432
E-Mail:
plmdjh@qe2-hsc.ns.ca
Newfoundland
Name:
Dr. Chan Nguyen
Andrea Woodland, Pharmacist
Address:
Division of Infectious Diseases
General Hospital
The Health Care Corporation
300 Prince Philip Drive
St. John’s, Newfoundland
A1B 3V6
Dept of Pharmacy
Health Science Centre
300 Prince Philip Drive
St. John’s, Newfoundland
A1B 3V6
Phone #:
(709) 737- 5163 or 4215
(709) 737- 6455
Fax #:
(709) 737-4298
E-Mail:
cnguyen@morgan.ucs.mun.ca
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