Download Current Drugs for Antimalarial Chemoprophylaxis: A Review of

Current Drugs for Antimalarial Chemoprophylaxis:
A Review of Efficacy and Safety
Elaine C. Jong and Hans D. Nothdurft
The resurgence of malaria in areas where it had been
controlled previously and the concurrent emergence of
drug-resistant malaria strains contribute to the current
recommendations concerning malaria chemoprophylaxis. Chloroquine (e.g., Aralen), the former standard
for malaria prevention and treatment, is now effective only
in limited areas, and multidrug resistance has made
chemoprophylaxis with mefloquine (e.g., Lariam) less
effective in some regions. This has complicated the decision-making process with regard to selection of optimal
antimalarial drug regimens for international travelers.
Guidelines from the Centers for Disease Control and Prevention (CDC) provide recommendations for the use of
three currently available drugs for malaria prophylaxis in
chloroquine-resistant areas: mefloquine, doxycycline
(e.g., Vibramycin, Doryx), and atovaquone/proguanil
(e.g., Malarone). Guidelines from the World Health
Organization (WHO) include the three drugs above, and
in addition, consider proguanil (e.g., Paludrine) coadministered or in fixed-dose combination with chloroquine, and also primaquine among current choices for
malaria prophylaxis. This article presents a concise review
of current knowledge about use of these drug regimens
for prophylaxis against malaria.
Given the increase in international travel and the
spread of malaria into previously disease-free areas, growing numbers of travelers now face the risk of contracting
this disease.1 The number of cases of imported malaria has
been rising in the United States, Canada, and other developed countries since the 1970s. In 1997, over 1,500 cases
of imported malaria, including 6 fatalities, were reported
in the United States, whereas in Canada, 1,036 cases of
imported malaria were reported that year.2–5 Compounding
the problem of increased incidence of malaria,parasite resis-
tance to commonly used antimalarial drugs has also
emerged and is spreading rapidly.6 Resistance of Plasmodium falciparum to chloroquine, the most widely used antimalarial, is common in most endemic countries,7 and
multidrug resistance has evolved in certain areas.6
To prevent malaria, travelers to endemic areas are
advised to take appropriate antimalarial drugs and to use
personal protective measures to protect themselves from
mosquito bites.8,9 However, the spread of malaria and the
emergence of drug resistance have changed standard recommendations for chemoprophylaxis over the last decade,
leading to confusion among both travelers and their
health care providers.10–12 Surveys have shown that physicians often prescribe chemoprophylaxis that is inappropriate for regions in which drug sensitivity and malaria
risk patterns have changed over time.2,3,12–14 In addition,
many travelers, unaware of their risk or concerned about
potential side effects, commonly ignore drug prophylaxis
or do not comply with the prescribed regimens.6,8–16
These observations underscore the need for up-todate pretravel health advice. In light of the availability of
drugs for malaria prophylaxis that are both safe and
effective, physicians need to improve their knowledge of
these drugs—including their safety and their usefulness
in endemic regions with potential resistance. Importantly, physicians must be able to effectively communicate this information to their traveling patients,
emphasizing the critical importance of both complying
with chemoprophylaxis as prescribed and employing
other personal protective measures.8,9
Chemoprophylactic Drug Use
The primary consideration today in selecting a
therapeutic agent to prevent malaria is the risk of exposure to chloroquine-resistant or multidrug-resistant P. falciparum in the traveler’s itinerary. In previous years, when
most Plasmodium strains were predictably sensitive,
chloroquine was the drug of choice to both prevent and
treat malaria. Because of its safety, availability, and low
cost, the drug gained widespread use throughout the
world, becoming perhaps the second or third most
widely consumed drug.17 Chloroquine continues to be
widely used in developing countries despite the presence of chloroquine-resistant strains, a practice promoting drug pressure that selects for further resistance.1
Elaine C. Jong, MD: Department of Medicine, University of
Washington, Seattle, Washington; Hans D. Nothdurft, MD:
Department of Infectious Diseases and Tropical Medicine,
University of Munich, Munich, Germany.
The authors had no financial or other conflicts of interest to
disclose.
Reprint requests: E.C. Jong, Box 354410, University of
Washington, Seattle, WA 98195.
J Travel Med 2001; 8(Suppl 3):S48–S56.
S48
Jong and Nothdurft, Current Drugs for Antimalarial Chemoprophylaxis
In response to spreading chloroquine resistance,
other agents were introduced as alternative chemoprophylactic agents against malaria. Pyrimethaminesulfadoxine (e.g., Fansidar) and amodiaquine (e.g.,
Camoquine) were both marketed for this purpose but
proved to have an unacceptable risk of serious adverse
effects and are no longer recommended.12 In addition,
resistance to pyrimethamine-sulfadoxine has become
widespread in Southeast Asia and South America.18
Pyrimethamine-dapsone (e.g., Maloprim) was another
combination drug used in Asia and the South Pacific,
sometimes in combination with chloroquine, for prevention of chloroquine-resistant malaria. However, this
regimen did not gain widespread use among international travelers from Western countries; in part, because
access to pyrimethamine-dapsone was limited.18
In North America,currently recommended drugs for
malaria chemoprophylaxis in chloroquine-resistant areas
include mefloquine, doxycycline, and atovaquone/
proguanil. Both mefloquine and doxycycline are associated with some well-known side effects that may limit their
use in some patients,12,19,20 and resistance to mefloquine
has emerged in certain endemic areas.8,9,18 Atovaquone/
proguanil is a fixed-dose combination drug that has been
recently approved for both the prophylaxis and treatment of malaria, and is effective against malaria caused by
chloroquine-resistant or multidrug-resistant P.falciparum
strains.20, Although experience with the combination
product is limited, proguanil has a long history of safety.
Proguanil has been used alone and in combination with
chloroquine for malaria chemoprophylaxis for many years
following its development during World War II.21,22 The
rapid emergence of resistance to the drug limited its use
as a single agent, but the combination of chloroquine and
proguanil appears to be more effective than either drug
alone against chloroquine-resistant strains. Nonetheless,
this combination is significantly less effective than the other
drugs discussed here. Primaquine is another drug that was
developed as an antimalarial in the 1940s, and for decades,
the drug has been used predominantly for the prevention
and radical cure of relapsing forms of malaria, Plasmodium vivax and Plasmodium ovale. Over the past decade
however, several field studies have demonstrated primaquine’s utility as effective chemoprophylaxis against
chloroquine-resistant Plasmodium falciparum (CRPF), and
many experts now consider it one of the choices for prevention of CRPF among travelers.23,24
Compliance with Chemoprophylaxis
Poor compliance with chemoprophylaxis regimens
has been identified as an important risk factor for malaria
among travelers.25 One US study found that only 23%
of travelers to endemic areas had complied with rec-
S49
ommended chemoprophylaxis.10 A study of 547 Dutch
travelers (most taking chloroquine/proguanil) showed an
overall compliance rate of 60%, but this rate varied
depending on the destination (South America 45%,
West Africa 52%, Southeast Asia 53%, India 60%, East
Africa 78%).25 A study of 100 Spanish travelers showed
that 44% did not use any malaria chemoprophylaxis, 27%
defaulted from the recommended regimen, and 39%
employed self-treatment.5 Several case-control studies have
identified a 2- to 4-fold increased risk of malaria as a consequence of noncompliance with prescribed chemoprophylaxis.26
Age, reason for travel, and length of travel also correlate with compliance rates. Young people traveling
to “adventurous” destinations were the least likely to
comply with prophylaxis in the Dutch study.25 In
general, compliance tends to deteriorate with longer
terms of exposure or travel,26 although short-stay travelers also tend to not use or misuse chemoprophylaxis.3
Immigrants returning to visit friends or relatives in their
homelands rarely take chemoprophylaxis or use personal protection against mosquitoes. Lack of risk
awareness and limited access to pretravel health care
are probable factors contributing to the suboptimal use
of antimalarial measures among immigrant populations.3–5,11,15
Other factors that might influence compliance with
chemoprophylaxis include convenience of the prescribed
regimen (daily or weekly, duration of pretravel and posttravel medication), tolerability of side effects, and even
peer pressure.25–27 Among travelers, the potential for
serious toxicities is of great concern, and even minor side
effects sometimes cause travelers to discontinue their
chemoprophylaxis. This happens even though the potential morbidity from malaria is clearly worse than the
side effects of prophylaxis.15
Drugs for Malaria Chemoprophylaxis
Chloroquine Phosphate and Hydroxychloroquine Sulfate
Chloroquine remains the drug of choice for the
prevention and treatment of malaria due to sensitive P.
falciparum and P. vivax, as well as for infections with P.
ovale and Plasmodium malariae.8,9,28 However, because of
widespread resistance, its use against P. falciparum malaria
is limited.
Antimalarial actions. Chloroquine is a 4-aminoquinoline that inhibits heme polymerase, thus preventing the
parasite from converting heme, a toxic byproduct of
hemoglobin digestion, into nontoxic malarial pigment.
The erythrocytic (blood) phase of the parasite life cycle
is therefore interrupted but without affecting the hepatic
phase (Fig.).27,28
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Figure Plasmodium spp life cycle. When a malaria-infected
female Anopheles spp mosquito bites a human, it injects parasite sporozoites along with its saliva. The sporozoites migrate
rapidly to the liver, where they become either hypnozoites
(latent forms that may reemerge later) or tissue schizonts (in
which parasites actively reproduce). After 7–16 days, depending on the species, the schizonts rupture, releasing merozoites into the blood, where they invade red blood cells
(trophozoites). Here, the parasite multiplies, progressively
breaking down the red blood cell and inducing bouts of fever
and anemia in the infected individual. After 2–3 days, the red
blood cell ruptures, infecting other red blood cells, and the cycle
repeats itself.
Some infected red blood cells develop into gametocytes,
which are sexual forms. These are picked up by feeding mosquitoes, where they mature in the mosquito gut, and then are
passed on to other humans.
Most antimalarials are active against the blood stage of the
parasite. Atovaquone/proguanil, in contrast, is active against
both the blood and liver phases of the parasite.
Reproduced from Baird JK, Hoffman SL,27 with permission.
Drug resistance. Currently, chloroquine fails to cure P.
falciparum infections in most malaria endemic areas and
remains effective only in Haiti, the Dominican Republic, Central America, and parts of the Middle East. More
recently, resistance to chloroquine among P. vivax strains
has been identified in Southeast Asia, the South Pacific,
and South America.27–29
Pharmacology and metabolism. The drug is rapidly and
almost completely absorbed from the gastrointestinal
tract and localizes primarily in tissues (liver, spleen, kidneys, lung). It is metabolized by alkylation in the liver and
is excreted slowly by the kidneys, with a half-life of
3–7 days in normal healthy adults. Following therapeu-
J o u r n a l o f Tr a v e l M e d i c i n e , Vo l u m e 8 , S u p p l e m e n t 3
tic dosing, an effective blood concentration is usually
reached in minutes. Acidification of urine increases drug
excretion.28
Contraindications. The drug should be used with caution in alcoholics, in persons with hepatic disease, and
in persons taking hepatotoxic drugs. It is contraindicated
in persons with psoriasis, retinal or visual field changes,
and known hypersensitivity to the drug.8,9,28
Main drug interactions. Certain antacids and antidiarrheal
agents (kaolin, calcium carbonate, magnesium trisilicate)
should not be taken within 4 hours before or after
chloroquine, as they reduce its absorption. Chloroquine
may interfere with the antibody response to certain
rabies vaccines.28–31
Main adverse reactions. At therapeutic doses, the drug is
generally well tolerated,and side effects are rare.Minor side
effects include nausea and vomiting, headache, dizziness,
blurred vision, and itching (a nonallergic reaction that
occurs particularly in blacks). Chloroquine may worsen
symptoms of psoriasis. Taking the drug with meals may
reduce gastrointestinal symptoms. Retinal damage has
been associated with long-term therapy resulting in cumulative doses of 50–100 g of chloroquine base. Thus, baseline and twice-yearly visual examinations are prudent for
persons who have taken 300 mg chloroquine base weekly
for over 5 years,or 100 mg chloroquine base daily for over
3 years. One of the other antimalarial drug regimens
should be used if further chemoprophylaxis against malaria
is necessary.15,28,29
Special populations. Chloroquine has been shown to be
safe for pregnant women and infants.8,9,28
Overdosage. Chloroquine is very toxic in overdose,
leading to hypotension, cardiac arrhythmias, and convulsions. Treatment is supportive, as there is no specific
antidote.28,29
Dosing. Chloroquine phosphate compound or “salt” is
commonly available as 500 mg (300 mg chloroquine base)
and 250 mg (150 mg base) tablets. The adult regimen is
300 mg base (500 mg salt) orally, once weekly. For children, the dose based on body weight is 5 mg/kg base
(8.3 mg/kg salt) orally, once weekly, up to the maximum
adult dose of 300 mg base. Prophylaxis should start
1–2 weeks before travel and continue for 4 weeks after
departure from the malarious area.8,9,30,32
Hydrochloroquine sulfate is a chloroquine compound that is commonly available as 155 mg base (200 mg
salt) tablets. The adult dose is 310 mg base (400 mg salt
or 2 200 mg tablets) orally, once weekly. The pediatric dose is 5 mg/kg base (6.5 mg/kg salt) orally, once
weekly, up to the maximum adult dose of 310 mg base.8,9
The WHO lists an alternate chloroquine prophylaxis dosing schedule consisting of a total dose of 10 mg
of base/kg body weight, orally, per week, divided into 6
daily doses. The conventional adult dose used in this reg-
Jong and Nothdurft, Current Drugs for Antimalarial Chemoprophylaxis
imen is 100 mg base orally, once daily.29 As with the
weekly chloroquine regimen, prophylaxis should start
1–2 weeks before travel and continue for 4 weeks after
departure from the malarious area. Whereas the daily dosing regimen may be preferred by some travel health
advisors based on pharmacokinetic data, the daily chloroquine regimen should be used with caution in frequent
travelers and long-term travelers to endemic malaria
areas, as the cumulative dose of chloroquine base will reach
potentially toxic levels at a faster rate.
Proguanil
The combination of a weekly or daily regimen of
chloroquine prophylaxis as described above is sometimes combined with a daily regimen of proguanil
200 mg (adult dose) for chemoprophylaxis in areas where
P. falciparum resistance to chloroquine is assessed as moderate. Whereas the combination does not appear to be
as efficacious as mefloquine, doxycyline, or atovaquone/proguanil, it provides greater protection than
either drug alone, and is both accessible and affordable
in those areas where it is commonly recommended.
Some WHO experts recommend the chloroquine plus
proguanil regimen for large parts of the Arabian peninsula,Asia (except for Southeast Asia),Mauritania,Namibia,
and part of Colombia. The chloroquine plus proguanil
regimen has not been recommended by the CDC, and
this may be due in part to the fact that proguanil is not
licensed in the United States.8,9,21
Antimalarial actions. Proguanil acts on the primary tissue stages of P. falciparum, P. vivax, and P. ovale, although
it does not appear to affect hypnozoites. Its effect on P.
malariae is unknown.
Drug resistance. Drug resistance develops readily when
proguanil is used alone as a chemoprophylactic agent
against malaria. Currently, it is used in combination with
chloroquine or as a component of atovaquone/
proguanil.22
Pharmacology and metabolism. Proguanil appears to have
at least two mechanisms of action. Proguanil is metabolized in the liver to cycloguanil. Both proguanil and
cycloguanil are folate antagonists and inhibit malarial
dihydrofolate reductase. However, in combination with
atovaquone, proguanil, not cycloguanil, appears to be the
synergistic component against multi-drug resistant
malaria, suggesting a non-antifolate mechanism of action.
Proguanil and its principal metabolite cycloguanil reach
peak plasma concentrations within 4 hours of oral administration, and have an elimination half-life of approximately
16 hours.21,22
Contraindications. Proguanil should not be used in persons with hypersensitivity to sulfa drugs or pyrimethamine, or in infants in the first 2 months of life. Caution
S51
is also advised in persons with severe hepatic or renal dysfunction.21
Main drug interactions. Do not give concurrently with
other antifolate drugs,such as sulfa drugs or pyrimethamine.
Main adverse reactions. Mouth ulcers and hair loss have
been reported in association with use of proguanil at
chemoprophylactic doses.9,21
Special populations. The drug has a long history of
safety and is not contraindicated in pregnancy or infants
over 2 months of age.21
Dosing. Proguanil comes in tablets containing 100 mg
of proguanil hydrochloride (87 mg of proguanil base).
Proguanil is given at a daily dose of 3 mg/kg, yielding
the recommended adult dose of 200 mg (2 tablets) per
day. In some areas, a fixed dose combination of 100 mg
chloroquine (base) plus 200 mg of proguanil salt is marketed for adult use. When proguanil is used for chemoprophylaxis in combination with chloroquine, it should
be started 1 week prior to travel, taken every day during travel, and continued 4 weeks after travel in a malaria
endemic area.9,21
Mefloquine
Mefloquine is a highly efficacious drug (>90%)
against chloroquine-resistant P. falciparum malaria, and
because of growing chloroquine resistance and mefloquine’s widespread market availability since the 1980s,
this agent commonly has been used as an alternative to
chloroquine in prophylaxis against malaria in most parts
of the world. Concerns about potentially severe side
effects have been voiced in recent years, even though controlled trials have found the drug to be generally well tolerated, with only mild side effects.33–35
Antimalarial actions. Although its exact mechanism of
action remains unclear, mefloquine is thought to act by
competing with the parasite protein for heme binding,
thus resulting in a drug complex toxic to the parasite.28
Mefloquine is effective against P. falciparum, P. vivax, P. ovale,
and P. malariae, but it is generally only used against P. falciparum malaria since the other species remain mostly sensitive to chloroquine.8,9,32 In a broad review of prophylaxis
studies since 1982, mefloquine was found to have a protective efficacy of above 91% in nonimmune travelers to
areas of chloroquine-resistant P. falciparum (excluding
areas of clear multidrug resistance). A separate metaanalysis found a protective efficacy of 93–100%.26,33
Drug resistance. Resistance to mefloquine first emerged
in 1982 along Thailand’s borders with Cambodia and
Myanmar (Burma), with subsequent rare cases appearing in Africa and South America. Mefloquine-resistant
strains may be cross-resistant to halofantrine (e.g., Halfan)
and quinine.12,17,33,34
Pharmacology and metabolism. Mefloquine is a 4-quinoline methanol structurally related to quinine. After dos-
S52
J o u r n a l o f Tr a v e l M e d i c i n e , Vo l u m e 8 , S u p p l e m e n t 3
ing,the drug achieves peak plasma levels within 2–12 hours
and is extensively protein-bound. It is metabolized in the
liver, yielding a main metabolite that has no antimalarial
activity. The elimination half-life ranges from 13–24 days.
Food increases the bioavailability of mefloquine, so it is
recommended that the drug be given with meals.28,34
Contraindications. The drug should not be used in persons with a history of seizures or epilepsy, severe psychiatric disorders, cardiac conduction abnormalities, or
known allergy to the drug. However, individuals using
beta blockers or calcium channel blockers may use mefloquine if they have no underlying arrhythmia.8,9,33,34 The
drug is not recommended for travelers who perform tasks
requiring fine motor coordination and spatial manipulation (e.g., airline pilots and machine operators).8,9,33,34
Main drug interactions. Halofantrine should not be given
with or after mefloquine (e.g., presumptive treatment)
because of the risk of life-threatening arrhythmias.
Arrhythmias and convulsions may also occur if quinine
or chloroquine is given with mefloquine, but delaying
the dose of mefloquine by 12 hours after discontinuing
the other drug should avoid this effect. Also, mefloquine
should not be given to a person who has received malaria
treatment doses of mefloquine within the previous
4 weeks.31 Although older reports suggested that mefloquine might inactivate live typhoid vaccine, a recent
study found no significant effect.36
Main adverse reactions. At the recommended weekly
prophylactic dose, mefloquine is generally well tolerated.
Side effects are typically mild and self-limited and most
commonly include nausea, dizziness, headaches, difficulty
sleeping (insomnia), fatigue, and vivid dreams. Rare serious neurologic and psychiatric side effects have been
reported, commonly associated with treatment doses,
including severe depression with suicidal tendencies,
severe anxiety, acute psychosis, seizures, and delirium.8,9,33,34
Special populations. Mefloquine is safe for pregnant
women in their second or third trimester, but data on
its use in the first trimester are limited. The drug is
secreted in small amounts in breast milk, but the effects
on breast-fed infants are unknown.8,9,33,34
Dosing. Mefloquine has a weekly dosing schedule when
used for malaria prophylaxis. Mefloquine should be
started 1–2 weeks prior to departure, continued weekly
during travel, and taken for 4 weeks after leaving the
malaria endemic area.8,9,32 Although the drug does not
reach steady state blood levels until week 6 or 7 on
weekly dosing, this does not appear to significantly influence efficacy. The drug has been used safely for long-term
prophylaxis for at least 2 years.33,34,37 Therapeutic levels
may be reached rapidly by using a loading dose of one
tablet daily for 3 days.38
In the United States, mefloquine is formulated as a
tablet containing 250 mg of the mefloquine hydrochlo-
ride salt, equivalent to 228 mg mefloquine base. Dosing
is calculated using the mefloquine hydrochloride salt, with
the adult dose 250 mg (one tablet) orally, once weekly.
Children are dosed as follows: less than 15 kg, 5 mg salt/kg
body weight; 15–19 kg, 1⁄4 tablet; 20–30 kg, 1⁄2 tablet; 31–45
kg, 3⁄4 tablet; more than 45 kg, 1 tablet; all given orally,
once weekly.8,32,34
Outside the United States, mefloquine tablets contain 274 mg of mefloquine hydrochloride, which is
equivalent to 250 mg mefloquine base. Mefloquine is used
for chemoprophylaxis for children at a dose of 5 mg/kg
base weekly, which gives an adult dose of 250 mg base
(one tablet) orally, once weekly. Mefloquine is not recommended for infants weighing less than 5 kg. The
dose is adjusted by body weight for children up to 50
kg, over which the adult dose is given.9,32,34
Doxycycline
Doxycycline provides effective antimalarial prophylaxis in areas with high levels of transmission of
mefloquine-resistant or multidrug-resistant P. falciparum,
although it is not regarded as adequate prophylaxis for
P. vivax.8,9,39
Antimalarial actions. Doxycycline attacks the parasite
by interfering with ribosomal activity during the blood
phase of the life cycle. Although evidence hints that it
may also affect the liver phase, proof of causal prophylaxis has yet to be demonstrated.39,40
In recent trials using the currently recommended
dosage (100 mg/day adult dose), doxycycline has shown
protective efficacy ranging from 92–100% in nonimmune
and semi-immune adults living in endemic areas. In
areas of chloroquine resistance, it was equivalent to
mefloquine and atovaquone/proguanil and superior to
chloroquine/proguanil.30
Drug resistance. Resistance has not been reported among
Plasmodium spp, although bacterial resistance occurs.39
Pharmacology and metabolism. The drug is almost completely absorbed from the gastrointestinal tract and is
highly bound by plasma proteins (93%). It is excreted by
the kidneys and has a half-life of 18 hours, allowing for
once-daily dosing.39
Contraindications. Doxycycline should not be used by
pregnant or lactating women or by children younger than
8 years because of its deleterious effects on bone and tooth
development. Also, it should not be used by persons
with known sensitivity to the drug.8,9,39
Main drug interactions. Antacids containing aluminum,
calcium, or magnesium and iron-containing preparations may impair absorption of doxycycline. Doxycycline
may render oral contraceptives less effective. Also since
anticonvulsants such as phenytoin, barbituates, and carbamazepine induce hepatic microsomal enzyme activity,
Jong and Nothdurft, Current Drugs for Antimalarial Chemoprophylaxis
doxycycline levels and half life may be reduced. A dosage
adjustment of the latter may be required.31,39
Main adverse reactions. Side effects include photosensitivity that can result in an exaggerated sunburn reaction, nausea, esophagitis, and vaginal candidiasis. Users
should be advised to avoid midday sun exposure and use
a sunscreen preparation that contains an ultraviolet A
(UVA) blocker since the phototoxicity associated with
doxycycline is UVA induced. Women using doxycycline
for malaria chemoprophylaxis should obtain an over-thecounter or prescription antifungal drug to carry in their
travel medical kit to treat vaginal candidiasis should it
develop.15,39
Special populations. Doxycycline is contraindicated in
pregnant and lactating women and in children younger
than 8 years.8,9,39
Dosing. Adults: 100 mg orally, once daily. Children older
than 8 years: 2 mg/kg body weight orally, once daily, up
to 100 mg/day. Prophylaxis should begin 1–2 days before
entering the malarious area and be continued daily for
4 weeks after departure.8,9,32,39 The drug may be taken with
a meal to minimize gastrointestinal upset,and users should
not lie down for 1 hour after taking the drug to prevent
its reflux into the esophagus. The tablet should be swallowed with a full glass of water to ensure that it does not
get stuck in the esophagus,leading to esophageal ulceration.
Atovaquone/Proguanil
A fixed-dose combination of atovaquone and
proguanil was developed in the 1990s for both the prophylaxis and treatment of malaria.41 The combination has
been shown to be highly effective against malaria due to
chloroquine-resistant and multidrug-resistant P. falciparum strains.42–48 Because of its short pre-exposure and
postexposure dosing regimens, the drug is ideal for shortterm travelers.
Antimalarial actions. Atovaquone/proguanil achieves its
antimalarial effects by interfering with two pathways of
pyrimidine biosynthesis in the parasite. Atovaquone
selectively inhibits mitochondrial electron transport,
diminishing pyrimidine synthesis and preventing parasite replication. Proguanil (and its main active metabolite, cycloguanil) inhibits dihydrofolate reductase, leading
to depletion of pyrimidine stores and ultimately blocking parasite reproduction. Research evidence to date
suggests an additional mechanism for atovaquone/
proguanil synergy independent of proguanil’s antifolate
activity, but the molecular basis for this phenomenon is
incompletely understood.41
The drug combination has activity against both the
erythrocytic (blood) and exoerythrocytic (liver) stages of
Plasmodium SPP (see Fig.). The activity against liver-stage
S53
parasites (causal prophylaxis) allows atovaquone/proguanil
to be effective with short pre-exposure and postexposure dosing schedules.43,44
In multiple trials, atovaquone/proguanil has shown
high rates of protective efficacy between 98–100% in
semi-immune residents of malaria-endemic areas, including areas with a high prevalence of chloroquine-resistant
malaria.42,44,45
In an experimental challenge with P. falciparum in a
small number of humans, atovaquone and proguanil
were separately shown to have causal prophylactic activity against liver-stage parasites. However, atovaquone/
proguanil appears to lack activity against the latent liverstage of P. vivax, and thus relapse may occur unless additional treatment with primaquine is given.48
Drug resistance. Currently, there are no reports of resistance to atovaquone/proguanil, although resistance to
either component drug alone can be selected in vivo and
in vitro.
Pharmacology and metabolism. Although atovaquone is
highly protein-bound (>99%), it does not displace other
protein-bound drugs, indicating that drug interactions are
unlikely to occur by displacement. Proguanil is 75%
protein-bound in plasma. Food or dietary fat enhances
the absorption of atovaquone. Atovaquone is eliminated
by the liver and excreted unchanged in stool, with an
elimination half-life of 2–3 days in adults. Proguanil is
metabolized primarily to cycloguanil in the liver (via
cytochrome CYP2C19) and is eliminated by hepatic biotransformation and renal excretion. The mean elimination half-life of proguanil is 12–21 hours.49
Contraindications. The drug should not be used by
pregnant women, by women breast-feeding infants who
weigh less than 11 kg, or by infants less than 11 kg. It
also is contraindicated in persons with severe renal
impairment (creatinine clearance < 30 mL/min) or with
known hypersensitivity to either component drug.41
Main drug interactions. Concomitant treatment with
tetracycline is associated with a 40% reduction in the
plasma concentrations of atovaquone. Concomitant use
of the antiemetic metoclopramide may result in decreased
bioavailability of atovaquone. Concomitant use of
rifampin or rifabutin also results in reduced atovaquone
levels. The proguanil component of atovaquone/proguanil
appears to interfere with the immune response to oral
typhoid vaccine.41 An interval of 10 days after completion of the oral typhoid vaccine series is recommended
before beginning atovaquone/proguanil prophylaxis.36
Main adverse reactions. Side effects of atovaquone/
proguanil tend to be rare and may include abdominal pain,
nausea, vomiting, and headache.41,43 Two separate studies showed the combination of atovaquone/proguanil to
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J o u r n a l o f Tr a v e l M e d i c i n e , Vo l u m e 8 , S u p p l e m e n t 3
be better tolerated than either mefloquine or chloroquine/proguanil.46,47
Special populations. The drug is contraindicated in
pregnant women, in women breast-feeding infants less
than 11 kg, and in infants less than 11 kg.41
Overdosage. There have been no reports of overdose
with atovaquone/proguanil. Overdoses with atovaquone
and proguanil separately have occurred without fatality.
Dosing. The adult dose for malaria prophylaxis is 250
mg atovaquone/100 mg proguanil (1 adult tablet) orally,
once daily. The pediatric tablet contains one-fourth the
dose of the adult formulation: 62.5 mg atovaquone/25 mg
proguanil, and is dosed based on body weight: 11–20 kg,
62.5/25 mg (1 pediatric tablet); 21–30 kg, 125/50 mg
(2 pediatric tablets); 31–40 kg, 187.5/75 mg (3 pediatric
tablets); over 40 kg, 250/100 mg (1 adult tablet); all once
daily. Prophylaxis should start 1–2 days before travel and
continue for 1 week after departure from the malarious
area.8,9,41,43 To enhance absorption, the drug should be
taken with food or milk.41
demonstration of emerging primaquine resistance has not
yet been conclusive because varying degrees of chloroquine resistance among the malaria strains involved have
confounding effects on interpretation of the data.24
Pharmacology and metabolism. Primaquine is metabolized in the liver, and a small amount is excreted
unchanged in the urine. Peak plasma levels occur in
1–3 hours, and the plasma half-life is about 5 hours. One
of the major metabolic pathways leads to the formation of 5-hydroxyprimaquine and 5-hydroxy-demethylprimaquine. Both of these metabolites have antimalarial
activity, and cause methemaglobin formation.23
Contraindications. Primaquine is contraindicated in
glucose-6-phoshate dehydrogenase (G6PD) deficient
individuals. Individuals should have G6PD blood testing before taking this drug, as the drug can cause acute
intravascular hemolysis in persons with G6PD deficiency.
Main drug interactions. Do not use primaquine if the
individual is on any other drug that may induce hematologic disorders.
Main adverse reactions. Primaquine may cause doserelated symptoms of anorexia, nausea, vomiting, abdominal pain and cramps. These symptoms are rare with the
daily dose of 0.25 mg/kg base (15 mg base daily adult
dose), but may be seen with the daily dose of 0.50 mg/kg
base (30 mg base daily adult dose) that is recommended
when the drug is used for prophylaxis against chloroquineresistant or multidrug-resistant P. falciparum.23 Gastrointestinal side effects can be reduced by taking the drug
with food.
Special populations. Primaquine should not be used in
pregnant women, or in children less than 4 years old
because of the risk of hemolysis. The drug is also contraindicated in individuals with active rheumatoid arthritis and lupus erythematosus and other conditions that may
predispose to granulocytopenia.8,9,23
Dosing. Primaquine phosphate tablets contain 5.0 mg,
7.5 mg, or 15.0 mg of primaquine base. Tablets containing
15 mg base are equivalent to 26.3 mg primaquine phosphate salt. The primaquine prophylaxis regimen for
adults is 30 mg base (2 26.3 mg tablets salt) orally, once
daily, beginning 1 day before travel, continuing every day
during travel, and for 7 days following travel in a malaria
endemic area. Pediatric dosing for prophylaxis is based
on 0.5 mg base/kg body weight in children 4 years of
age or older.8,9,23
Primaquine
Antimalarial actions. Primaquine has activity against all
stages of the malaria parasite. Primaquine is the only currently available antimalarial drug that is highly efficacious
in eradicating the hepatic hypnozoite stage, and thus
can prevent relapsing malaria due to P. vivax and P. ovale.
(see Fig.) It has a long history of being used to prevent
relapse following chloroquine treatment of such infections. More recently, there has been renewed interest in
primaquine as a prophylactic drug. Several clinical studies showed that primaquine used as prophylaxis was 85
to 95% protective against P. falciparum and P. vivax when
used at a dose of 30 mg/day (base).50–52 Primaquine has
causal prophylactic activity, killing liver-stage schizonts
and preventing the release of merozoites from the liver
that invade the red blood cells during a primary infection (see Fig.). When used as a causal prophylactic drug,
primaquine needs to be taken only during and for a brief
period after exposure to infective mosquitoes, contributing to a short pre- and post-travel prophylaxis regimen. Primaquine is a blood schizonticide, capable of
killing the asexual parasite stages after invasion of red blood
cells, and also is gametocytocidal, capable of killing the
sexual stage gametocytes (see Fig.)23,24
The mechanisms of action are poorly understood,
but the 8-aminoquinolines are thought to act on plasmodial mitochondria through the generation of toxic
metabolites and by causing oxidative stress.24
Drug resistance. Clinical resistance to primaquine has
not been documented, although there are reports of
relapse of P.vivax following primaquine treatment. These
reports have usually involved P. vivax strains from Southeast Asia, Somalia, and the tropical Pacific region. The
Conclusion
Drug prophylaxis combined with personal protective measures against mosquito bites are important safeguards for persons traveling to malaria-endemic regions.
Whereas chloroquine remains the drug of choice for preventing malaria in chloroquine-sensitive regions, trav-
Jong and Nothdurft, Current Drugs for Antimalarial Chemoprophylaxis
elers must rely on other drugs for prophylaxis against
malaria in the rest of the world where malaria is endemic
and where chloroquine-resistant strains have emerged.
Mefloquine, doxycycline, and atovaquone/proguanil are
highly efficacious drugs for preventing malaria due to
chloroquine-resistant P. falciparum and are recommended
by the CDC and WHO for travelers to areas of risk. The
combination of chloroquine plus proguanil, and primaquine are two additional regimens for malaria chemoprophylaxis that are recommended by WHO malaria
consultants. Although several other antimalarial drugs and
drug combinations are being investigated in ongoing clinical trials for prevention and treatment of chloroquineresistant and multidrug-resistant malaria, these agents
are not currently recommended for chemoprophylaxis
in travelers.
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