CLINICAL REVIEW CLINICIAN’S CORNER

Treatment of Malaria in the United States

A Systematic Review
Kevin S. Griffith, MD, MPH Context Many US clinicians and laboratory personnel are unfamiliar with the diag-
Linda S. Lewis, DVM, MPVM nosis and treatment of malaria.
Sonja Mali, MPH Objectives To examine the evidence base for management of uncomplicated and
severe malaria and to provide clinicians with practical recommendations for the diag-
Monica E. Parise, MD
nosis and treatment of malaria in the United States.

E
VEN THOUGH ENDEMIC MALARIA
has been eliminated from the
United States, it remains a lead-
ing infectious disease world-
wide. As a consequence, every year in
the United States an average 1200 cases
of malaria are reported, almost all im-
ported, resulting in up to 13 deaths per
year.1 The unfamiliarity of US clini-
cians and laboratory personnel with ma-
laria and drug resistance patterns has
contributed to delays in diagnosis and
treatment, at times with adverse out-
comes.2
To address this problem, we pro-
vide clinicians with practical recom-
mendations for the diagnosis and treat-
ment of malaria in the United States,
based on published evidence; the Cen-
ters for Disease Control and Preven-
tion (CDC) experience in assisting US
clinicians; and the available drugs and
diagnostic modalities used in this
country.
Evidence Acquisition Systematic MEDLINE search from 1966 to 2006 using the
search term malaria (with the subheadings congenital, diagnosis, drug therapy, epi-
demiology, and therapy). Additional references were obtained from searching the bib-
liographies of pertinent articles and by reviewing articles suggested by experts in the
treatment of malaria in North America.
Evidence Synthesis Important measures to reduce morbidity and mortality from
malaria in the United States include the following: obtaining a travel history, consid-
ering malaria in the differential diagnosis of fever based on the travel history, and
prompt and accurate diagnosis and treatment. Chloroquine remains the treatment
of choice for Plasmodium falciparum acquired in areas without chloroquine-
resistant strains. In areas with chloroquine resistance, a combination of atovaquone
and proguanil or quinine plus tetracycline or doxycycline or clindamycin are the best
treatment options. Chloroquine remains the treatment of choice for all other
malaria species, with the exception of P vivax acquired in Indonesia or Papua New
Guinea, in which case atovaquone-proguanil is best, with mefloquine or quinine
plus tetracycline or doxycycline as alternatives. Quinidine is currently the recom-
mended treatment for severe malaria in the United States because the artemisinins
are not yet available. Severe malaria occurs when a patient with asexual malaria
parasitemia, and no other confirmed cause of symptoms, has 1 or more designated
clinical or laboratory findings. The only adjunctive measure recommended in severe
malaria is exchange transfusion.
Conclusions Malaria remains a diagnostic and treatment challenge for US clinicians
as increasing numbers of persons travel to and emigrate from malarious areas. A strong
evidence base exists to help clinicians rapidly initiate appropriate therapy and mini-
mize the major mortality and morbidity burdens caused by this disease.
JAMA. 2007;297:2264-2277 www.jama.com

METHODS
We performed a systematic MEDLINE
search from 1966 to 2006 using the
search term malaria (with the subhead-
ings congenital, diagnosis, drug therapy,
epidemiology, and therapy). This search
was conducted on August 1, 2006, and
resulted in 5588 potentially relevant ar-
ticles. We reviewed titles and/or ab-
stracts of all articles to determine rel-
CME available online at
www.jama.com
evance to this article, hand searched
bibliographies of pertinent articles, and
reviewed articles suggested by experts
in the treatment of malaria in North
Author Affiliations: Malaria Branch, Division of Parasitic
Diseases, National Center for Zoonotic, Vector-Borne and
Enteric Diseases, Coordinating Center for Infectious Dis-
eases, Centers for Disease Control and Prevention, At-
lanta, Ga (Drs Griffith and Parise and Ms Mali); and Butte
County Department of Public Health, Oroville, Calif (Dr
Lewis).DrGriffithisnowwiththeBacterialDiseasesBranch,
DivisionofVector-BorneInfectiousDiseases,NationalCen-
ter for Zoonotic, Vector-Borne and Enteric Diseases, Co-
ordinating Center for Infectious Diseases, Centers for Dis-
ease Control and Prevention. Dr Parise is now with the
Parasitic Diseases Branch, Division of Parasitic Diseases,
America. Recommendations are based
on randomized controlled trials, ob-
servational studies, and consensus ex-
pert opinion.
National Center for Zoonotic, Vector-Borne and Enteric
Diseases, Centers for Disease Control and Prevention.
Corresponding Author: Monica E. Parise, MD, Para-
sitic Diseases Branch, Division of Parasitic Diseases, Na-
tional Center for Zoonotic, Vector-Borne and Enteric
Diseases, Centers for Disease Control and Preven-
tion, 4770 Buford Hwy NE MS F22, Atlanta, GA 30341
(MParise@cdc.gov).
Clinical Review Section Editor: Michael S. Lauer, MD.
We encourage authors to submit papers for consid-
eration as a Clinical Review. Please contact Michael
S. Lauer, MD, at lauerm@ccf.org.

2264 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted) ©2007 American Medical Association. All rights reserved.
 TREATMENT OF MALARIA IN THE UNITED STATES

BIOLOGICAL AND
EPIDEMIOLOGIC
CONSIDERATIONS
In the Plasmodium life cycle (FIGURE 1),
the asexual blood stages (rings, tropho-
zoites, schizonts) are responsible for the
symptoms of malaria, and thus are the
main target of chemotherapy. The
sexual blood stages (gametocytes) do
not cause any known pathology and
thus are not a primary target of treat-
ment. Dormant liver stage parasites
(hypnozoites) of Plasmodium vivax and
Plasmodium ovale may reactivate weeks
or months after the initial infection, pro-
ducing relapses.
Of the 4 Plasmodium species that in-
fect humans, Plasmodium falciparum is
the one with potential to rapidly progress
to severe illness or death. It predomi-
nates in sub-Saharan Africa, Hispani-
ola, and Papua New Guinea. Among the
other species, P vivax is the most com-
mon3 and predominates in South Asia,
Eastern Europe and Northern Asia, and
Central and most of South America.4
Plasmodium ovale occurs mostly in West
Africa and is occasionally encountered
in Southeast Asia and Papua New
Guinea. Plasmodium malariae occurs at
low frequency in a patchy distribution
worldwide. Plasmodium falciparum ac-
counts for slightly more than 50% and
P vivax approximately 25% of reported
cases in the United States.1,2
Chloroquine-resistant strains of P fal-
ciparum occur in all endemic areas ex-
cept Central America west of the Panama
Canal, Mexico, Hispaniola, and parts of

Figure 1. Plasmodium Life Cycle

Mosquito Stages Human Liver Stages Human Blood Stages

Exo-Erythrocytic
Schizont
Mosquito Injects
Sporozoites

Erythrocyte
Immature
Ruptured Merozoites Trophozoite
Exo-Erythrocytic (Ring Stage)
Sporozoites Infected
Schizont
Migrate to Hepatocyte
Salivary Glands
Ruptured
Schizont
Ruptured
Oocyst
A S E X U A L S TA G E S

Hypnozoite Hypnozoites
(Dormant Stage; Can Reactivate,
P vivax, P ovale) Causing Relapses
Oocyst
in Midgut
Mature
Trophozoite
Schizont

Ookinete
(Motile Zygote)
Amplification
of Infection

Zygote
S E X U A L S TA G E

Gametes Gametocytes

Mosquito Ingests
Gametocytes

The morphology of Plasmodium life cycle stages varies between species. Those shown in the illustration are Plasmodium falciparum, except for the hypnozoite, which
occurs only in Plasmodium vivax and Plasmodium ovale. In P falciparum, the mature asexual stages (eg, schizonts) are sequestered in the microvasculature of vital
organs due to cytoadherence of infected erythrocytes to the capillary endothelium and are rarely seen circulating in the peripheral blood. (Blood film photomicrograph
insets: Giemsa stain; source: Division of Parasitic Diseases/Centers for Disease Control and Prevention).

©2007 American Medical Association. All rights reserved. (Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2265
TREATMENT OF MALARIA IN THE UNITED STATES
Box. Manifestations
of Severe Malaria*
Prostration
Impaired consciousness/coma
Respiratory distress (acidotic
breathing)
Multiple convulsions
Circulatory shock
Pulmonary edema
Acute respiratory distress syndrome
Abnormal bleeding
Jaundice
Severe anemia
Acute renal failure
Disseminated intravascular
coagulation
Acidosis
Hemoglobinuria
Parasitemia ⬎5%
*Sources: WHO Management of Severe Ma-
laria (2000)21 and WHO Guidelines for the
Treatment of Malaria (2006).22
China and the Middle East, and multi-
drug-resistant strains occur in South-
east Asia, South America, and sub-
Saharan Africa. Due to increasing
resistance of P falciparum to the drug
combination of sulfadoxine and pyri-
methamine, the CDC no longer recom-
mends sulfadoxine-pyrimethamine for
treatment of malaria in the United States
or as standby treatment for US travel-
ers. A high prevalence of chloroquine-
resistant P vivax (CRPV) is found in
Papua New Guinea and Indonesia. Baird
and Hoffman have written an excellent
review on CRPV (which details well its
geographic distribution).5 There is evi-
dence for rates up to 25% in a few sites
in Burma,6 Malaysia,7 Vietnam,8 India,9
and Turkey.10,11
RECOGNITION
AND DIAGNOSIS
Consideration of malaria based on travel
history is the key to diagnosis. Any pa-
tient who has been in an endemic area
in the year preceding the onset of ma-
larial symptoms should be evaluated for
2266 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted)
the disease. The typical incubation pe-
riod usually varies between 9 and 18 days
for P falciparum, P vivax, and P ovale12;
it is longer (18-40 days) for P malariae
and may be as short as 7 days for P fal-
ciparum.13 However, symptoms may oc-
cur weeks or even months after expo-
sure as a result of inadequate prophylaxis
or treatment, immune response, or re-
lapses. Some temperate strains of P vivax,
such as the North Indian and North Ko-
rean strains, can exhibit delayed pri-
mary attacks, occurring 12 to 18 months
after an infected mosquito bite.14 Of cases
reported in the United States from 1995
to 2004, 98% (n=3626) of patients with
P falciparum malaria experienced their
first symptoms within the first 3 months
of arrival in the United States, and 57%
(n = 1743) and 96% (n = 2906) of pa-
tients with non-falciparum malaria had
symptom onset within the first 3 and 12
months, respectively. During this same
time period, 85% of patients with im-
ported P falciparum malaria acquired
their infection in Africa.
Absence of a travel history does not
rule out malaria. Patients may provide
an inaccurate history or may have been
infected in the United States through
other rarely occurring mechanisms such
as transfusion, congenital transmis-
sion, or local mosquito-borne trans-
mission.1
The initial presentation of malaria
is nonspecific and similar to that of
many other febrile illnesses. Fever is
the most commonly reported symp-
tom, being present in 78% to 100% of
case patients,2,15-18 but fever periodic-
ity is often not seen.15,19,20 Patients
may experience a wide spectrum of
other symptoms including chills,
headache, malaise, nausea, vomiting,
diarrhea, abdominal pain, myalgias,
back pain, weakness, dizziness, confu-
sion, cough, and/or coma. Spleno-
megaly is a frequent physical finding
(24%-40% of case patients). 15,16,18
Severe malaria is characterized by 1 or
more of the signs or symptoms shown
in the BOX. Severe malaria is almost in-
variably caused by P falciparum, with
rare reports of severe malaria caused by
P vivax.2,23-30
©2007 American Medical Association. All rights reserved.
Diagnostic confirmation is ob-
tained by microscopic demonstration
of malaria parasites on Giemsa-
stained thick and thin blood films,
which should be examined as soon as
possible but within 12 hours of the pre-
sentation of any patient with sus-
pected malaria. Institutions unfamil-
iar with malaria diagnosis should not
delay microscopic diagnosis (eg, by
sending the films out to a laboratory
that cannot provide same-day re-
sults), but should promptly refer the pa-
tient to a more experienced institu-
tion or consult with more experienced
personnel at other institutions, their
state department of health, or submit
digital images captured from stained
films directly to the CDC’s telediagno-
sis service (dpdx@cdc.gov, or through
the CDC Malaria Hotline or CDC Emer-
gency Operations Center [Malaria Hot-
line 770-488-7788 Monday-Friday, 8
AM to 4:30 PM. Off-hours, weekends,
and federal holidays, CDC clinicians
can be reached by calling the CDC
Emergency Operations Center at 770-
488-7100 and asking for the malaria cli-
nician on-call to be paged]).
The parasite density (ie, percentage
of infected erythrocytes on a thin film)
should be quantified as 1 measure of the
severity of the disease and its response
to treatment, which should be closely
monitored. If the initial film is nega-
tive and the patient is suspected of hav-
ing malaria, blood films should be re-
peated at 12- to 24-hour intervals for
48 to 72 hours. If the diagnosis is clini-
cally suspected and proficient labora-
tory diagnosis is impossible, empirical
treatment for P falciparum malaria, as
discussed below, should be initiated,
pending referral of the patient and/or
specimen. It is important that a differ-
ential identification of Babesia sp
(which may be morphologically simi-
lar to P falciparum) be made during mi-
croscopic examination. Although non-
specific, thrombocytopenia, a low white
blood cell count, and signs of hemoly-
sis, such as an elevated bilirubin level,
found during general laboratory test-
ing are possible clues to the presence
of malaria.

In addition to microscopy, polymer-
ase chain reaction and rapid immuno-
chromatographic diagnostic tests31 are
alternate diagnostic tools that are not
routinely available. Rapid immuno-
chromatographic diagnostic tests are
not yet licensed for use in the United
States. Serological tests document past
exposure and are thus of limited use in
acute case management.
CLINICAL SITUATIONS AND
RECOMMENDED TREATMENT
General
To manage malaria successfully, treat-
ing physicians should seek the answer
to the following 5 questions: (1) What
is the species? (2) What is the density
of parasitemia? (3) What is the drug-
resistant pattern where the infection
was acquired? (4) Are there signs of se-
vere malaria? and (5) Can the patient
tolerate oral medication?
Patients with malaria should be
treated immediately because P falcipa-
rum infections can rapidly progress to
severe illness or death in as little as 1
to 2 days.32 Immunity wanes in the
absence of continued antigen expo-
sure and thus semi-immune persons
who have left an endemic area for an
extended period of time and then
return are susceptible to severe disease
and death. If the species cannot be
identified, the patient should be
treated as if infected with P falciparum
until the infecting species can be iden-
tified. The patient’s travel history pro-
vides useful clues for selecting an
effective antimalarial drug, in terms of
risk of drug resistance. Because base
and salt conversions for antimalarial
drugs are a source of confusion and
can result in treatment errors,33 where
pertinent, the base equivalency is fol-
lowed by the salt equivalency in
parentheses (TABLE).
There has been some controversy
about the need for initial hospital ad-
mission for all patients with P falcipa-
rum malaria, and some authors have
tried to define triage criteria for which
patients need to be admitted vs those
who can be followed as outpatients.34
However, since these patients can de-
©2007 American Medical Association. All rights reserved.
TREATMENT OF MALARIA IN THE UNITED STATES
teriorate rapidly and progress to
death within 1 to 2 days,32 and many
centers do not have the expertise to ad-
equately triage (eg, to accurately quan-
tify the parasite density), the CDC ad-
vises that patients infected with P
falciparum or an unidentified Plasmo-
dium species should be initially admit-
ted to ensure that the medication is tol-
erated and the patient is improving
clinically and parasitologically. Blood
films should be repeated to ensure clear-
ance of P falciparum parasitemia. Pa-
tients who are not responding clini-
cally (with defervescence within 72
hours) need follow-up malaria blood
films and may also require a search for
other causes of fever. Of note, game-
tocytes may be less susceptible to many
antimalarial drugs than are asexual
parasites, and their persistence in the
blood in the absence of asexual para-
sites does not indicate drug resis-
tance.
Uncomplicated Falciparum Malaria
For P falciparum malaria acquired in a
limited number of areas (FIGURE 2),4
chloroquine (with hydroxychloro-
quine as a second-line alternative) re-
mains the treatment of choice (Table).
Chloroquine-resistant P falciparum
strains are found in all other malari-
ous areas, where 3 treatment options
are currently recommended: (1) oral
quinine plus either tetracycline, doxy-
cycline, or clindamycin; (2) atova-
quone-proguanil; or (3) mefloquine.
The first 2 options are preferred due to
a higher rate of moderate to severe neu-
ropsychiatric reactions seen when mef-
loquine is used at treatment doses35-50
compared with persons taking the drug
for prophylaxis. The incidence rate for
moderate or severe neuropsychiatric ad-
verse reactions at mefloquine treat-
ment doses has been estimated to be 1
in 215 to 1 in 1754 treatments.39,50 None
of the reported neuropsychiatric ad-
verse reactions were lethal and most re-
solved spontaneously.* Atovaquone-
proguanil was better tolerated than the
combination of quinine and tetracy-
*References 35, 37, 39, 41, 42, 46, 47, 50, 51.
(Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2267
cline in one trial that directly com-
pared the 2 regimens.52
Quinine has a rapid onset of action
and, in combination with either tetracy-
cline, doxycycline, or clindamycin, has
been shown to be a very efficacious treat-
ment option for P falciparum infections
acquired in regions with chloroquine-
resistant strains.52-73 For P falciparum in-
fections acquired in Southeast Asia, a
7-day course of both quinine and the ac-
companying antibiotic is recom-
mended54,59,60,63,64,69,70,73; for infections ac-
quired outside Southeast Asia, a 3-day
course of quinine and a 7-day course of
the accompanying antibiotic is recom-
mended.52,53,66 The quinine and antibi-
otic should be started at the same time
or should at least overlap by 2 days. Al-
though published treatment trials mainly
used quinine in combination with tet-
racycline, doxycycline has excellent an-
timalarial efficacy in chemoprophy-
laxis trials and is considered an equally
efficacious substitute.74-85 Tetracycline or
doxycycline is generally preferred to clin-
damycin as the accompanying antibi-
otic because of more extensive efficacy
data and field experience. The quinine
and clindamycin regimen also has been
shown to be efficacious against P falci-
parum infections acquired in areas with
chloroquine resistance† and is useful in
treatment of pregnant women and
children younger than 8 years in whom
tetracyclines and doxycycline are
contraindicated.
Quinine is commercially available in
the United States only as an oral medi-
cation. Cinchonism (a complex of symp-
toms including nausea, vomiting, head-
ache, tinnitus, deafness, dizziness, and
visual disturbances) is common with qui-
nine or quinidine (the isomer of qui-
nine) use. For example, tinnitus was re-
ported in 13% to 94% of patients taking
quinine in clinical trials,52,60,65,68,69,88 and
the syndrome of cinchonism was re-
ported in 94% of patients in another
trial.63 Quinine binding to plasma pro-
teins, principally to ␣-1-glycoprotein, is
increased in malaria.89,90 This explains
why plasma quinine levels that have been
†References 55, 58, 61, 62, 65-69, 72, 86, 87.
TREATMENT OF MALARIA IN THE UNITED STATES

Table. Antimalarial Drugs Available in the United States Recommended for Use in the Treatment of Malaria
Potential Adverse
Drug Indication Adult Dosage Pediatric Dosage* Effects Comments
Atovaquone- Plasmodium Adult tablet = 250 mg Pediatric tablet = 62.5 mg Abdominal pain, Not indicated for use in pregnant
proguanil falciparum from atovaquone/100 mg atovaquone/25 mg nausea, vomiting, women due to limited data
(oral) chloroquine- proguanil proguanil) diarrhea, Contraindicated if hypersensitivity to
resistant areas 4 Adult tablets orally per 5-8 kg: 2 pediatric tablets headache, rash, atovaquone or proguanil; severe
day ⫻ 3 d orally per day ⫻ 3 d mild reversible renal impairment (creatinine
⬎8-10 kg: 3 pediatric tablets elevations in liver clearance ⬍30 mL/min)
orally per day ⫻ 3 d aminotransferase Should be taken with food to increase
⬎10-20 kg: 1 adult tablet levels absorption of atovaquone
orally per day ⫻ 3 d
⬎20-30 kg: 2 adult tablets
orally per day ⫻ 3 d
⬎30-40 kg: 3 adult tablets
orally per day ⫻ 3 d
⬎40 kg: 4 adult tablets orally
per day ⫻ 3 d
Chloroquine P falciparum from 600-mg base (= 1000 mg 10-mg base/kg orally Nausea, vomiting, Safe in children and pregnant women
phosphate chloroquine- salt) orally immediately, immediately, followed by rash, headache, Give for chemoprophylaxis (500 mg
sensitive areas followed by 300-mg 5-mg base/kg orally at 6, dizziness, urticaria, salt orally every week) in pregnant
P vivax from base (= 500 mg salt) 24, and 48 h abdominal pain, women with chloroquine-sensitive
chloroquine- orally at 6, 24, and 48 h Total dose: 25-mg base/kg pruritus P vivax
sensitive areas Total dose: 1500-mg base Contraindicated if retinal or visual field
All P ovale; all (= 2500 mg salt) change; hypersensitivity to
P malariae 4-aminoquinolines
Use with caution in those with
impaired liver function since the
drug is concentrated in the liver
Clindamycin P falciparum from Oral: 20-mg base/kg/d Oral: 20-mg base/kg/d orally Diarrhea, nausea, rash Always use in combination with
(oral or IV) chloroquine- orally divided 3 times divided 3 times daily ⫻ 7 d quinine-quinidine
resistant areas daily ⫻ 7 d IV: 10-mg base/kg loading Safe in children and pregnant women
P vivax from IV: 10-mg base/kg loading dose IV followed by 5-mg
chloroquine- dose IV followed by base/kg IV every 8 h;
resistant areas 5-mg base/kg IV every 8 switch to oral clindamycin
(in combination with h; switch to oral (oral dose as above) as
quinine-quinidine) clindamycin (oral dose as soon as patient can take
above) as soon as oral medication; treatment
patient can take oral course = 7 d
medication; treatment
course = 7 d
Doxycycline P falciparum from Oral: 100 mg orally twice Oral: 2.2 mg/kg orally every Nausea, vomiting, Always use in combination with
(oral or IV) chloroquine- daily ⫻ 7 d 12 h ⫻ 7 d diarrhea, abdominal quinine-quinidine
resistant areas IV: 100 mg IV every 12 h IV: IV only if patient is not able pain, dizziness, Contraindicated in children ⬍8 y,
P vivax from and then switch to oral to take oral medication; for photosensitivity, pregnant women, and persons with
chloroquine- doxycycline (as above) children ⬍45 kg, give 2.2 headache, known hypersensitivity to
resistant areas (in as soon as patient can mg/kg IV every 12 h and esophagitis, tetracyclines
combination with take oral medication; then switch to oral odynophagia While food, milk, and divalent and
quinine-quinidine) treatment course = 7 d doxycycline (dose as Rarely hepatotoxicity, trivalent cations decrease the
above) as soon as patient pancreatitis, and absorption of tetracycline,
can take oral medication; benign intracranial doxycycline can be taken with food,
for children ⱖ45 kg, hypertension seen including milk products, which
use same dosing with tetracycline helps to decrease gastrointestinal
as for adults; treatment class of drugs disturbances
course = 7 d To prevent esophagitis, the
tetracyclines should be taken with
large amounts of fluids, and
patients should not lie down for 1 h
after taking the drugs
Concurrent treatment with
barbiturates, carbamazepine, or
phenytoin may cause a reduction in
serum concentrations of
doxycycline
Hydroxychlo- Second-line alternative 620-mg base (= 800 mg 10-mg base/kg orally Nausea, vomiting, Safe in children and pregnant
roquine for treatment of: salt) orally immediately, immediately, followed by rash, headache, women
(oral) P falciparum from followed by 310-mg 5-mg base/kg orally at 6, dizziness, urticaria, Give for chemoprophylaxis (310-mg
chloroquine- base (= 400 mg salt) 24, and 48 h abdominal pain, base orally every week) in pregnant
sensitive areas orally at 6, 24, and 48 h Total dose: 25-mg base/kg pruritus† women with chloroquine-sensitive
P vivax from Total dose: 1550-mg base P vivax
chloroquine- (= 2000 mg salt) Contraindicated if retinal or visual field
sensitive areas change; hypersensitivity to
All P ovale; all 4-aminoquinolines
P malariae Use with caution in those with
impaired liver function
(continued)

2268 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted) ©2007 American Medical Association. All rights reserved.
 TREATMENT OF MALARIA IN THE UNITED STATES

Table. Antimalarial Drugs Available in the United States Recommended for Use in the Treatment of Malaria (cont)
Drug Indication Adult Dosage Pediatric Dosage* Potential Adverse Effects Comments
Mefloquine‡ P falciparum from 684-mg base (= 750 mg salt) orally 13.7-mg base/kg Gastrointestinal complaints Contraindicated if hypersensitive to
chloroquine- as initial dose, followed by (= 15 mg salt/kg) (nausea, vomiting, diarrhea, the drug or to related
resistant areas, 456-mg base (= 500 mg salt) orally as initial abdominal pain), mild compounds; cardiac conduction
except orally given 6-12 h after dose, followed by neuropsychiatric complaints abnormalities; psychiatric
Thailand- initial dose 9.1-mg base/kg (dizziness, headache, disorders; and seizure disorders
Burmese and Total dose = 1250 mg salt (= 10 mg salt/kg) somnolence, sleep disorders), Do not administer if patient has
Thailand- orally given 6-12 h myalgia, mild skin rash, and received related drugs
Cambodian after initial dose fatigue; moderate to severe (chloroquine, quinine, quinidine)
border regions Total dose = 25 mg neuropsychiatric reactions, less than 12 h ago
P vivax from salt/kg electrocardiographic changes, May be used for chemoprophylaxis
chloroquine- including sinus arrhythmia, (250 mg salt orally every week) in
resistant areas sinus bradycardia, first degree pregnant women with
atrioventricular block, chloroquine-resistant P vivax
prolongation of QTc interval,
and abnormal T waves
Primaquine Radical cure of 30-mg base orally per day ⫻ 14 d 0.5-mg base/kg Gastrointestinal disturbances, Must screen for G6PD deficiency
phosphate P vivax and orally per day ⫻ methemoglobinemia prior to use
P ovale (to 14 d (self-limited), hemolysis in Contraindicated in persons with
eliminate persons with G6PD deficiency G6PD deficiency; pregnant
hypnozoites) women
Should be taken with food to
minimize gastrointestinal
adverse effects
Quinine sulfate P falciparum from 542-mg base (= 650 mg salt)§ 8.3-mg base/kg Cinchonism,㛳 sinus arrhythmia, Combine with tetracycline,
(oral) chloroquine- orally 3 times daily ⫻ 3 d (= 10 mg salt/kg) junctional rhythms, doxycycline, or clindamycin,
resistant areas (infections acquired outside orally 3 times daily atrioventricular block, except for P vivax infections in
P vivax from Southeast Asia) to 7 d ⫻ 3 d (infections prolonged QT interval, children ⬍8 y or pregnant women
chloroquine- (infections acquired in acquired outside ventricular tachycardia, Contraindicated in hypersensitivity
resistant areas Southeast Asia) Southeast Asia) to ventricular fibrillation (these including history of blackwater
7 d (infections are rare and more commonly fever, thrombocytopenic purpura,
acquired in seen with quinidine), or thrombocytopenia associated
Southeast Asia) hypoglycemia with quinine or quinidine use;
many cardiac conduction defects
and arrhythmias¶; myasthenia
gravis; optic neuritis
Quinidine Severe malaria 6.25-mg base/kg (= 10 mg salt/kg) Same as adult Cinchonism, tachycardia, Combine with tetracycline,
gluconate (all species, loading dose IV over 1-2 h, then prolongation QRS and QTc doxycycline, or clindamycin
(IV) independently of 0.0125-mg base/kg/min (= 0.02 intervals, flattening of T-wave Contraindicated in hypersensitivity;
chloroquine mg salt/kg/min) continuous (effects are often transient) history of blackwater fever
resistance) infusion for at least 24 h Ventricular arrhythmias, including history of blackwater
Patient unable to Alternative regimen: 15-mg base/kg hypotension, hypoglycemia fever, thrombocytopenic purpura
take oral (= 24 mg salt/kg) loading dose IV or thrombocytopenia associated
medication infused over 4 h, followed by with quinine or quinidine use;
Parasitemia ⬎10% 7.5-mg base/kg (= 12 mg many cardiac conduction defects
salt/kg) infused over 4 h every and arrhythmias#; myasthenia
8 h, starting 8 h after the loading gravis; optic neuritis
dose (see package insert); once
parasite density ⬍1% and
patient can take oral medication,
complete treatment with oral
quinine, dose as above
Quinidine-quinine course = 7 d in
Southeast Asia (3 d in Africa or
South America)
Tetracycline P falciparum from Oral: 250 mg orally 4 times daily ⫻ 25 mg/kg/d orally See doxycycline See doxycycline
(oral or IV) chloroquine- 7d divided 4 times
resistant areas IV: dosage same as for oral daily ⫻ 7 d
P vivax from IV: dosage same as
chloroquine- for oral
resistant areas
(in combination
with quinine-
quinidine)
Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; IV, intravenous.
*Pediatric dosage should never exceed adult dosage.
†Extrapolated from chloroquine literature.
‡Mefloquine should not be used to treat P falciparum infections acquired in the following areas: borders of Thailand with Burma (Myanmar) and Cambodia, western provinces of Cam-
bodia, eastern states of Burma (Myanmar), border between Burma and China, Laos along borders of Laos and Burma (and adjacent parts of Thailand-Cambodia border), and southern
Vietnam due to resistant strains.
§Quinine sulfate capsule manufactured in the United States is in a 324-mg dose; therefore, 2 capsules should be sufficient for adult dosing.
㛳Nausea, vomiting, headache, tinnitus, deafness, dizziness, and visual disturbances.
¶Refer to quinine sulfate, package insert (Mutual Pharmaceutical Inc, Philadelphia, Pa, August 2005).
#Refer to quinidine gluconate, package insert (Eli Lilly Co, Indianapolis, Ind, February 2002).

©2007 American Medical Association. All rights reserved. (Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2269
TREATMENT OF MALARIA IN THE UNITED STATES

Figure 2. Malaria Treatment Algorithm

History of Travel to Malaria-Endemic

Area or Clinical Suspicion of Malaria

Perform Thick and Thin Blood

Films and Read in <12 h

No Blood Film Yes

Positive?

Repeat Blood Films Every

12 to 24 h for 48 to 72 h

No Blood Film Yes

Positive? Calculate Parasite Density

Consider Alternate Diagnosis Evaluate Clinical Status

and Disease Severity

Uncomplicated Malaria Severe Malaria

and/or
Patient Unable to Take Oral Medication
Determine Infecting Species
Using Blood Film

Non-Falciparum Species Plasmodium falciparum or Species

Not Yet Identified∗ Regardless of Infecting
Species or Geographic
Region of Acquisition

Plasmodium malariae Plasmodium ovale or P vivax Acquired in Acquired in Chloroquine- Acquired in Chloroquine-
Plasmodium vivax Papua New Guinea Sensitive Area† Resistant Area‡
Acquired Outside or Indonesia
Papua New Guinea
or Indonesia

Chloroquine Chloroquine Atovaquone-Proguanil Chloroquine Oral Quinine Plus Intravenous Quinidine Plus
(Second-Line (Second-Line Alternatives: (Second-Line Tetracycline,§ or Tetracycline,§
Treatment: Treatment: Quinine Plus Treatment: Doxycycline,§ or Doxycycline,§ or Clindamycin
Hydroxychloroquine)|| Hydroxychloroquine)|| Tetracycline,§ or Hydroxychloroquine)|| Clindamycin
Doxycycline,§ or Admit to Intensive Care Unit
or Atovaquone-Proguanil Monitor Cardiac Function
Mefloquine or Continuously and Monitor
Mefloquine If Above Blood Pressure Frequently
Not Available Monitor Parasitemia, Glucose,
Hemoglobin, and Electrolytes
Periodically
Primaquine If Not G6PD Deficient Admit to Hospital Prevent and Treat
Complications
If G6PD Deficient, Counsel About Monitor Symptoms Daily
Possibility of Recurrence Consider Exchange Transfusion
Repeat Blood Films Daily Until If Parasite Density >10%
Negative or If Discharged Prior to or If Patient Has Altered
a Negative Film, at Day 7 Mental Status, Nonvolume
Overload Pulmonary Edema,
or Renal Complications

Switch to Oral Antimalarial

Repeat Blood Films If Symptoms Recur
Medication When Possible

*If species not yet identified is subsequently diagnosed as a non-falciparum infection, then complete treatment as per the identified species recommendations. G6PD
indicates glucose-6-phosphate dehydrogenase. †Central America west of the Panama Canal, Mexico, Hispaniola, parts of China, and the Middle East. ‡All malaria-
endemic countries except those listed in second footnote. §Contraindicated in pregnant women and children younger than 8 years of age. 㛳Drug options for chloroquine-
resistant P falciparum may also be used if chloroquine or hydroxychloroquine cannot be used.

2270 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted) ©2007 American Medical Association. All rights reserved.

associated with blindness and deafness
after self-poisoning, and which are
common during the treatment of malaria,
extremely rarely cause such adverse
effects in patients with malaria.91,92 Life-
threatening toxicity is rare and the symp-
toms of cinchonism are rarely sufficient
to warrant discontinuing quinine or
quinidine treatment.93
The tetracyclines (tetracycline and
doxycycline) and clindamycin should
always be used in combination with a
faster-acting antimalarial drug such as
quinine and never as monotherapy.
Atovaquone-proguanil has reported
cure rates of 94% to 100% for P falcipa-
rum infections acquired in Southeast
Asia, Africa, and South America.52,94-109
To date, there have been 12 published
cases of atovaquone-proguanil failure for
the treatment of P falciparum malaria
(from East, West, and Central Africa),
7 of which have had isolates with ge-
netically confirmed markers of resis-
tance (ie, mutations in the cytochrome
b gene),110-117 and thus, clinicians should
remain aware of the rare possibility of
atovaquone-proguanil treatment failures.
Mefloquine should not be used to
treat P falciparum infections acquired on
the borders of Thailand with Burma
(Myanmar) and Cambodia, in the west-
ern provinces of Cambodia, in the east-
ern states of Burma (Myanmar), on the
border between Burma and China, in
Laos along the borders of Laos and
Burma and the adjacent parts of the
Thailand Cambodia border, as well as
in southern Vietnam, because of re-
ports of a high prevalence of mefloquine-
resistant P falciparum in these areas.118
Although mefloquine is contraindi-
cated for chemoprophylactic use in per-
sons with active or recent history of de-
pression, generalized anxiety disorder,
psychosis, or other major psychiatric dis-
order, or in persons with a history of sei-
zures, it can be used for treatment in per-
sons with these conditions if the benefits
are judged to outweigh the risks.119 If re-
lated compounds (chloroquine, qui-
nine, or quinidine) have been given for
chemoprophylaxis or initial treatment,
mefloquine administration should be de-
layed at least 12 hours after the last dose
©2007 American Medical Association. All rights reserved.
TREATMENT OF MALARIA IN THE UNITED STATES
of the related compound to minimize the
risk of adverse events such as electro-
cardiographic abnormalities.119,120
Antimalarial drugs that are not rec-
ommended, even though they may be
available in other countries, include sul-
fadoxine-pyrimethamine, amodia-
quine, and halofantrine because of re-
sistance and/or toxicity problems.
Uncomplicated Non-Falciparum
Malaria
Chloroquine remains the treatment of
choice for all P malariae and P ovale in-
fections and for P vivax infections ac-
quired outside Papua New Guinea and
Indonesia; hydroxychloroquine is a
second-line alternative. Currently, there
are limited data on optimal treatment op-
tions for P vivax infections acquired in
areas with highly prevalent chloroquine
resistance (Papua New Guinea and In-
donesia). The best option may be
atovaquone-proguanil, with mefloquine
or quinine plus tetracycline or doxycy-
cline as alternatives. Both quinine (3
days) and either tetracycline or doxycy-
cline (7 days)121-128 and mefloquine129-135
have been historically used successfully
in case reports or small case series. More
recently, both atovaquone-proguanil, in
a relatively small study,99 and mefloquine
(at 15 mg/kg)136 have effectively treated
P vivax malaria in Indonesia, where high
rates of CRPV exist. Of note, although
initial studies of atovaquone-proguanil
showed high (68%) rates of recurrent
parasitemiabefore28daysoffollow-up101
(some of which may have been relapses),
subsequent (albeit small) studies have
demonstrated excellent efficacy (⬎95%)
of atovaquone-proguanil against P vivax
malaria.99,137 Data are too limited to rec-
ommend quinine-clindamycin69 for first-
line treatment of P vivax, including
CRPV, infections. Baird and colleagues
demonstrated 85% efficacy of chloro-
quine and high-dose (2.5 mg/kg base
over 3 days) primaquine for treatment
of CRPV.138 The CDC has not recom-
mended this regimen due to relative in-
experience with high-dose primaquine
and suboptimal efficacy.
Infections with P vivax and P ovale
should be treated with primaquine to
(Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2271
prevent potential relapses. To achieve
more reliable eradication of hypnozo-
ites, the CDC now recommends a regi-
men of 0.5 mg/kg to a maximum of 30
mg of primaquine base daily for 14 days.
The most common severe adverse effect
associated with primaquine is intravas-
cular hemolysis in persons with glucose-
6-phosphate dehydrogenase (G6PD) de-
ficiency, a contraindication to the use of
this drug. Patients must be screened for
G6PD prior to use of primaquine. Pri-
maquine treatment should, if possible,
overlap with the blood schizonticidal
treatment.138-140
Patients who are not able to take pri-
maquine should be counseled on the pos-
sibility of having a relapsing infection (es-
timated to be approximately 20% [range,
5%-80%])5 and the need to seek treat-
ment if similar symptoms recur. An-
other potential option for patients un-
able to take primaquine who are
experiencing frequent relapses is chlo-
roquine (or mefloquine, in the case of
CRPV) prophylaxis for the period of time
that relapses are most likely to occur (ie,
a few years). Although atovaquone-
proguanil has “causal prophylactic ac-
tivity” (ie, the ability to prevent blood
stage infection by killing developing liver
stage parasites), it does not appear to
eradicate hypnozoites101,102 and may not
prevent the establishment of hypnozo-
ites.141,142 Thus, patients with P vivax or
P ovale malaria who have been treated
with atovaquone-proguanil also need pri-
maquine. Although a modified regimen
of 45 mg (base) of primaquine weekly
for 8 weeks has been suggested as an al-
ternative for patients with mild G6PD de-
ficiency,143,144 the data on both safety and
efficacy of such a regimen are very lim-
ited. Primaquine for “radical cure” (ie,
primaquine used in conjunction with an
effective blood schizonticide for the treat-
ment of a patient with P vivax or P ovale
malaria) in a known G6PD-deficient in-
dividual should be used only after a care-
ful risk/benefit assessment and under
strict medical supervision.140
Severe Malaria
The single most important step in the
management of severe malaria is im-
TREATMENT OF MALARIA IN THE UNITED STATES
mediate initiation of appropriate par-
enteral treatment. In the United States,
the only parenteral drug currently avail-
able is quinidine gluconate. Blood films
should be examined every 12 hours un-
til negative for malaria parasites.91 Para-
site density typically decreases by 90%
over the first 48 hours with quinine or
quinidine therapy.145-149 If parasitemia
has not decreased as expected, poten-
tial causes of the problem should be in-
vestigated (eg, by checking the quini-
dine level). Quinidine levels should be
maintained in the range of 3 to 8
mg/L.91,150
Quinidine is more cardiotoxic than
quinine and should be administered in
an intensive care unit with continu-
ous electrocardiographic and frequent
blood pressure monitoring.145 Quini-
dine-related cardiovascular adverse ef-
fects are potentially serious and may be
more frequent if the drug is adminis-
tered rapidly.151 The risk of cardiotox-
icity is increased with bradycardia, hy-
pokalemia, and hypomagnesemia152 and
if the patient has received other drugs
that may prolong the QTc interval (eg,
quinine, mefloquine, or macrolide
antibiotics).
Because newer antiarrhythmic agents
have displaced quinidine gluconate,
quinidine is often not stocked in many
hospitals.152-154 Hospital drug services
should maintain or add quinidine glu-
conate to their formularies. If they do
not stock the drug, they must be able
to immediately locate a nearby source.
Otherwise, the hospital should con-
tact their local or regional distributor
to request the drug or contact the Eli
Lilly Co directly (telephone: 1-800-
821-0538).152 Assistance from the com-
pany to arrange a rapid shipment of the
drug is available between the hours of
6 AM and 6 PM. If further assistance is
needed in managing patients with ma-
laria, health care professionals can con-
tact the CDC Malaria Hotline.
Because most deaths from severe ma-
laria occur within the first 24 to 48
hours of treatment, an initial loading
dose of quinidine is recommended to
achieve therapeutic levels as rapidly as
possible145,155,156 unless the patient has
2272 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted)
received more than 40 mg/kg quinine
in the previous 2 days or has received
mefloquine in the previous 12 hours (in
which case the loading dose is not given
but a continuous quinidine infusion is
still administered).93 The quinidine in-
fusion should be temporarily slowed or
stopped if the QT interval increases to
greater than 0.6 seconds, the QRS com-
plex increases greater than 50%, the
QTc interval is prolonged by more than
25% of the baseline value, or if hypo-
tension unresponsive to fluid chal-
lenge develops.150,155 If significant elec-
trocardiographic changes persist or
malignant arrhythmias develop, phy-
sicians should treat the arrhythmias and
consider expert consultation through
the CDC Malaria Hotline or other tropi-
cal medicine experts. Options in such
severe situations may include admin-
istration of alternative antimalarial
drugs via nasogastric tube along with
exchange transfusion. Quinidine con-
tinuous infusion should be continued
during exchange transfusion.
Initial (including loading) doses of
parenteral quinine or quinidine need
not be reduced in persons with renal
failure. The pharmacokinetic proper-
ties of the cinchona alkaloids are al-
tered in malaria, with a contraction in
the volume of distribution that is pro-
portional to the severity of malarial ill-
ness.91,157 If renal failure persists or the
patient’s clinical condition does not im-
prove, the maintenance dosage should
be reduced by one third to one half on
the third treatment day.91
The artemisinin derivatives clear
parasites very rapidly, are now a key
component of malaria treatment world-
wide, and have been shown to reduce
mortality in severe malaria compared
with parenteral quinine.158 These drugs
are not yet available in the United States,
but the CDC hopes to make intrave-
nous artesunate available under an In-
vestigational New Drug protocol in
2007.
Exchange transfusion has been used
in the treatment of severe malaria since
1974 with apparent benefit,145,159,160 po-
tentially due to rapid reduction of para-
sitemia by direct parasite removal, re-
©2007 American Medical Association. All rights reserved.
duction of toxic byproducts, and/or
improved rheology with transfused
cells.161,162 The technical aspects of ex-
change transfusion have been dis-
cussed in an excellent review by Pow-
ell and Grima.162 However, exchange
transfusion and its indications will re-
main controversial until a carefully con-
trolled, adequately powered compara-
tive study is conducted, an unlikely
probability.163,164 In the decision to use
exchange transfusion, the potential risks
of exchange transfusion, including fluid
overload, febrile and allergic reac-
tions, metabolic disturbances, red blood
cell alloantibody sensitization, trans-
missible infection, cerebral hemor-
rhage, and line sepsis, must be weighed
against potential benefits.163 The CDC
recommends that exchange transfu-
sion be strongly considered for per-
sons with a parasitemia higher than 10%
or if complications such as cerebral ma-
laria, nonvolume overload pulmonary
edema, or renal compromise exist.150
Various adjunctive treatments ap-
pear in the literature that are either un-
proven or are harmful in the treat-
ment of severe malaria and are not
currently recommended. They in-
clude phenobarbital for prophylaxis of
seizures165-167; dexamethasone for treat-
ment of cerebral malaria156,168,169; hep-
arin for treatment of thrombocytope-
nia and/or fibrinogenemia170-176; iron
chelators that aim to reduce parasite
clearance time125,177,178; pentoxifylline for
inhibition of tumor necrosis factor syn-
thesis179; and dichloroacetate for treat-
ment of metabolic acidosis.180
Potential complications of severe
malaria181 should be recognized and
treated. Hypoglycemia may be masked
by the manifestations of cerebral
malaria, and thus frequent plasma glu-
cose determination is essential. Severe
and recurrent hypoglycemia may be
caused by hyperinsulinemia induced
by quinine or quinidine or by endo-
toxin or by parasite consumption.182,183
Hyperpyrexia can be treated with ace-
tominophen; nonsteroidal anti-
inflammatory drugs are not recom-
mended, given the frequency of
thrombocytopenia and coagulation

abnormalities. Pulmonary edema may
be due to either fluid overload or adult
respiratory distress syndrome and can
be minimized by keeping patients
euvolemic. Acute renal failure is gen-
erally oliguric. With dialysis, renal
function can be expected to return
after a median of 4 days, although
some patients may require dialysis for
2 to 3 weeks.184 Thrombocytopenia is
common in severe malaria. Laboratory
evidence of activated coagulation is
more common than is disseminated
intravascular coagulation with bleed-
ing.181,185,186 Hyponatremia,187 hypocal-
cemia, hypophosphatemia and hyper-
phosphatemia, and hypomagnesemia
and hypermagnesemia188 have all been
reported in patients with P falciparum
malaria.181
In patients with suspected cerebral
malaria, a lumbar puncture should be
performed to rule out bacterial menin-
gitis,157 and magnetic resonance imaging
or computed tomographic scans should
be performed to rule out intracerebral
bleeding, cerebral edema, and cerebral/
medullary herniation. Most survivors
with cerebral malaria regain conscious-
ness within 2 to 3 days, although it may
occasionally take more than a week.189
Induced Malaria
Because malaria acquired through
bloodborne transmission (eg, blood
transfusion or organ transplantation)
has no exoerythrocytic stage, prima-
quine treatment is not needed in in-
duced P vivax or P ovale infections.
Self-treatment
The CDC recommends the use of ma-
laria prophylaxis, rather than self-
treatment, for travelers to malarious
areas. However, travelers who elect not
to take prophylaxis, who do not choose
an optimal drug regimen (eg, chloro-
quine for travel to an area with chloro-
quine-resistant P falciparum malaria), or
those who require a less than optimal
drug regimen are at greater risk for ac-
quiring malaria and needing prompt
treatment. Travelers who are taking ef-
fective prophylaxis but who will be in
very remote areas may decide, in con-
©2007 American Medical Association. All rights reserved.
TREATMENT OF MALARIA IN THE UNITED STATES
sultation with their clinician, to take
along a dose of antimalarial medica-
tion for self-treatment. The only drug
recommended for self-treatment for US
travelers is atovaquone-proguanil. It
should not be used in patients on atova-
quone-proguanil prophylaxis because of
the risk of breakthrough parasitemia due
to a resistant organism in those pa-
tients. In such cases, specialized tropi-
cal medicine consultation should be
sought. Quinine-doxycycline is a sub-
optimal alternative due to potential ad-
verse drug reactions and the complex-
ity of the regimen. Travelers should be
advised that self-treatment of a pos-
sible malaria infection is only a tempo-
rary measure and that prompt medical
evaluation is imperative.4
Malaria in Children
Tetracycline and doxycycline have a
relative contraindication for use in in-
fants and children younger than 8 years
of age due to reports of drug deposi-
tion in calcifying areas of bones and
teeth that result in permanent tooth
staining, enamel hypoplasia, and de-
creased linear skeletal growth rate190,191;
clindamycin in combination with qui-
nine should be used instead. While the
US package insert recommends meflo-
quine for use in children older than 6
months of age,119 the drug is generally
well tolerated in children weighing
more than 5 kg,192-195 with vomiting as
the principal adverse effect.192-196 Al-
though few studies document the safety
and tolerability of primaquine in chil-
dren, the drug has been used for more
than 50 years with no apparent safety
problems. There is no evidence to sug-
gest that the drug cannot be used in
children of any age who do not have
G6PD deficiency.140 Neither the Ameri-
can Academy of Pediatrics nor US4 or
Canadian197 public health authorities list
a lower age limit for primaquine use.
Malaria in Pregnant Women
Malaria infection in pregnant women
is associated with high risks of both ma-
ternal and perinatal morbidity and mor-
tality, including spontaneous abor-
tion, stillbirth, premature delivery, low
(Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2273
birth weight, congenital infection,
and/or neonatal death. For uncompli-
cated P falciparum infections acquired
in regions with chloroquine-resistant
strains, quinine plus clindamycin has
been shown to be safe and efficacious
and is recommended.65 Concerns that
quinine may cause fetal toxicity or in-
duce labor when given late in preg-
nancy have not been substantiated at
the doses used for treatment of ma-
laria.198 An important adverse effect of
quinine in pregnant patients is hyper-
insulinemia, which can precipitate or
worsen hypoglycemia.198 Late in preg-
nancy, quinine is distributed to the fe-
tus, raising concerns about quinine trig-
gering insulin release and resulting in
fetal hypoglycemia.182 However, the
risks of untreated falciparum malaria
during pregnancy outweigh the poten-
tial risk of adverse drug effects from qui-
nine or quinidine.
Atovaquone-proguanil or meflo-
quine are not currently recommended for
treatment in pregnancy and should only
be used if quinine plus clindamycin or
quinine monotherapy is not available or
is not being tolerated. Tetracycline and
doxycycline are contraindicated. Al-
though 2 recent studies of the atova-
quone-proguanil and artesunate combi-
nation treatment for P falciparum
infections in pregnant women showed
the regimen to be well-tolerated with no
evidence of toxicity to the mother or fe-
tus,199,200 further study is needed before
atovaquone-proguanil can be recom-
mended for use during pregnancy.
Because primaquine can potentially
cause hemolytic disease in a G6PD-
deficient fetus, primaquine is contra-
indicated in pregnancy. Pregnant
women treated for P ovale and P vivax
infections should also receive chemo-
prophylaxis until delivery. The pro-
phylaxis regimen should consist of
either chloroquine, 300-mg base (=500
mg salt) orally once per week; or, for
P vivax infections acquired in areas with
chloroquine-resistant strains, meflo-
quine 228-mg base (= 250 mg salt)
orally once per week. While meflo-
quine is not recommended for malaria
treatment during pregnancy,201 sev-
TREATMENT OF MALARIA IN THE UNITED STATES
eral studies support its safety as che-
moprophylaxis during pregnancy.202-206
After delivery, women should be treated
with primaquine as recommended for
nonpregnant adult patients.
Congenital Malaria
There are approximately 2 cases of con-
genital malaria reported in the United
States annually. Infants typically pre-
sent at 1 to 2 months of age with fever,
anemia, failure to thrive, and spleno-
megaly. As with induced malaria, there
is no exoerythrocytic phase and thus no
need for primaquine treatment in P
vivax or P ovale congenital infections.
For mothers who are parasitemic either
during pregnancy or at delivery, clini-
cians should judge management of the
infant in each case individually, factor-
ing in such issues as reliability of fol-
low-up and access to medical care. In
some cases it may be appropriate to sim-
ply educate the mother about the risk
of congenital malaria and instruct her
to seek medical care if the baby devel-
ops symptoms of malaria. In others, pre-
sumptive treatment of the newborn may
be warranted.
Clinical Assistance and Reporting
The CDC posts current treatment rec-
ommendations on its Web site at www
.cdc.gov/malaria and has clinicians on
call 24 hours to provide advice to cli-
nicians on the diagnosis and treat-
ment of malaria.
Malaria is a nationally notifiable dis-
ease and all cases should be reported
to the appropriate state health depart-
ment. Case reporting is critical to moni-
tor trends in disease acquisition and to
provide recommendations for malaria
chemoprophylaxis and treatment.2,207-209
CONCLUSIONS
Malaria will remain a diagnostic and
treatment challenge for US clinicians as
increasing numbers of persons travel to
and emigrate from malarious areas. In
a review of all malaria deaths in the US
from 1963-2001, failure to diagnose ma-
laria on initial presentation, promptly
initiate treatment after diagnosis, and/or
prescribe an appropriate antimalarial
2274 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted)
drug, were substantial contributing fac-
tors in malaria deaths.2 Clinicians must
remain alert to the possibility of this dis-
ease and take immediate measures to-
ward prompt accurate diagnosis and
treatment.
Author Contributions: Drs Griffith, Lewis, and Parise
had full access to all of the data in the study and take
responsibility for the integrity of the data and the ac-
curacy of the data analysis.
Study concept and design: Griffith, Lewis, Parise.
Acquisition of data: Griffith, Lewis, Mali, Parise.
Analysis and interpretation of data: Griffith, Lewis,
Parise.
Drafting of the manuscript: Griffith, Lewis, Parise.
Critical revision of the manuscript for important in-
tellectual content: Griffith, Lewis, Mali, Parise.
Administrative, technical, or material support: Griffith,
Lewis, Mali.
Study supervision: Parise.
Financial Disclosures: None reported.
Disclaimer: The findings and conclusions in this re-
port are those of the authors and do not necessarily
represent the views of the Centers for Disease Con-
trol and Prevention.
Acknowledgment: We thank Phuc Nguyen-Dinh, MD,
MPH, Malaria Branch, Division of Parasitic Diseases,
Centers for Disease Control and Prevention (retired
in February 2007), for his thorough review and criti-
cal comments on the manuscript. He did not receive
any compensation for his contribution.
REFERENCES
1. Skarbinski J, James EM, Causer LM, et al. Malaria
surveillance–United States, 2004. MMWR Surveill
Summ. 2006;55:23-37.
2. Newman RD, Parise ME, Barber AM, Steketee RW.
Malaria-related deaths among U.S. travelers,
1963-2001. Ann Intern Med. 2004;141:547-555.
3. Mendis K, Sina BJ, Marchesini P, Carter R. The ne-
glected burden of Plasmodium vivax malaria. Am J Trop
Med Hyg. 2001;64(1-2 suppl):97-106.
4. Health Information for International Travel
2005-2006. Atlanta, Ga: Elsevier Inc; 2005.
5. Baird JK, Hoffman SL. Primaquine therapy for
malaria. Clin Infect Dis. 2004;39:1336-1345.
6. Marlar T, Myat Phone K, Aye Yu S, Khaing Khaing
G, Ma S, Myint O. Development of resistance to chlo-
roquine by Plasmodium vivax in Myanmar. Trans R
Soc Trop Med Hyg. 1995;89:307-308.
7. Jamaiah I, Anuar AK, Najib NA, Zurainee MN. Im-
ported malaria: a retrospective study in University Hos-
pital, Kuala Lumpur, a ten-year experience. Med J
Malaysia. 1998;53:6-9.
8. Phan GT, De Vries PJ, Tran BQ, et al. Artemisinin
or chloroquine for blood stage Plasmodium vivax ma-
laria in Vietnam. Trop Med Int Health. 2002;7:858-864.
9. Singh RK. Emergence of chloroquine-resistant vivax
malaria in south Bihar (India). Trans R Soc Trop Med
Hyg. 2000;94:327.
10. Kurcer MA, Simsek Z, Kurcer Z. The decreasing
efficacy of chloroquine in the treatment of Plasmo-
dium vivax malaria, in Sanliurfa, south-eastern Turkey.
Ann Trop Med Parasitol. 2006;100:109-113.
11. Kurcer MA, Simsek Z, Zeyrek FY, et al. Efficacy
of chloroquine in the treatment of Plasmodium vivax
malaria in Turkey. Ann Trop Med Parasitol. 2004;98:
447-451.
12. Sinden REG. The malaria parasites. In: Warrell DA,
Gilles HM, eds. Essential Malariology. 4th ed. Lon-
don, England: Arnold; 2002:26, 30.
13. Molineaux L. The epidemiology of human ma-
laria as an explanation of its distribution, including some
implications for its control. In: Wernsdorfer WH, ed.
©2007 American Medical Association. All rights reserved.
Malaria, Principles and Practice of Malariology, Vol-
ume 2. Edinburgh, Scotland: Churchill Livingstone;
1988:927.
14. Garnham P. Malaria parasites of man: life-cycles
and morphology. In: Wernsdorfer WH, McGregor I,
eds. Malaria: Principles and Practice of Malariology,
Volume 1. London, England: Churchill Livingstone;
1988:69.
15. Dorsey G, Gandhi M, Oyugi JH, Rosenthal PJ. Dif-
ficulties in the prevention, diagnosis, and treatment
of imported malaria. Arch Intern Med. 2000;160:2505-
2510.
16. Moore TA, Tomayko JF Jr, Wierman AM, Ren-
simer ER, White AC Jr. Imported malaria in the 1990s:
a report of 59 cases from Houston, Tex. Arch Fam Med.
1994;3:130-136.
17. Singh K, Wester WC, Trenholme GM. Problems
in the therapy for imported malaria in the United States.
Arch Intern Med. 2003;163:2027-2030.
18. Svenson JE, MacLean JD, Gyorkos TW, Key-
stone J. Imported malaria: clinical presentation and ex-
amination of symptomatic travelers. Arch Intern Med.
1995;155:861-868.
19. Lynk A, Gold R. Review of 40 children with
imported malaria. Pediatr Infect Dis J. 1989;8:745-
750.
20. McCaslin RI, Pikis A, Rodriguez WJ. Pediatric Plas-
modium falciparium malaria: a ten-year experience
from Washington, DC. Pediatr Infect Dis J. 1994;13:
709-715.
21. World Health Organization. WHO Guidelines for
the Treatment of Malaria. Geneva, Switzerland: WHO
Press; 2000.
22. World Health Organization. WHO Guidelines for
the Treatment of Malaria. Geneva, Switzerland: WHO
Press; 2006.
23. Beg MA, Khan R, Baig SM, Gulzar Z, Hussain R,
Smego RA Jr. Cerebral involvement in benign tertian
malaria. Am J Trop Med Hyg. 2002;67:230-232.
24. Curlin ME, Barat LM, Walsh DK, Granger DL. Non-
cardiogenic pulmonary edema during vivax malaria.
Clin Infect Dis. 1999;28:1166-1167.
25. Islam N, Qamruddin K. Unusual complications in
benign tertian malaria. Trop Geogr Med. 1995;47:141-
143.
26. Kochar DK, Saxena V, Singh N, Kochar SK, Ku-
mar SV, Das A. Plasmodium vivax malaria. Emerg In-
fect Dis. 2005;11:132-134.
27. Muhlberger N, Jelinek T, Gascon J, et al. Epide-
miology and clinical features of vivax malaria im-
ported to Europe: sentinel surveillance data from
TropNetEurop. Malar J. 2004;3:5.
28. Sachdev HS, Mohan M. Vivax cerebral malaria.
J Trop Pediatr. 1985;31:213-215.
29. Tanios MA, Kogelman L, McGovern B, Hassoun
PM. Acute respiratory distress syndrome complicat-
ing Plasmodium vivax malaria. Crit Care Med. 2001;
29:665-667.
30. Zingman BS, Viner BL. Splenic complications in
malaria: case report and review. Clin Infect Dis. 1993;
16:223-232.
31. Moody A. Rapid diagnostic tests for malaria
parasites. Clin Microbiol Rev. 2002;15:66-78.
32. Greenwood BM, Bradley AK, Greenwood AM,
et al. Mortality and morbidity from malaria among chil-
dren in a rural area of The Gambia, West Africa. Trans
R Soc Trop Med Hyg. 1987;81:478-486.
33. Kain KC, Gadd E, Gushulak B, McCarthy A,
MacPherson D. Errors in treatment recommenda-
tions for severe malaria. Committee to Advise on Tropi-
cal Medicine and Travel (CATMAT). Lancet. 1996;348:
621-622.
34. D’Acremont V, Landry P, Mueller I, Pecoud A, Gen-
ton B. Clinical and laboratory predictors of imported
malaria in an outpatient setting: an aid to medical de-
cision making in returning travelers with fever. Am J
Trop Med Hyg. 2002;66:481-486.
35. Caillon E, Schmitt L, Moron P. Acute depressive

symptoms after mefloquine treatment. Am J Psychiatry.
1992;149:712.
36. Ekue JM, Simooya OO, Sheth UK, Wernsdorfer
WH, Njelesani EK. A double-blind clinical trial of a com-
bination of mefloquine, sulfadoxine and pyrimeth-
amine in symptomatic falciparum malaria. Bull World
Health Organ. 1985;63:339-343.
37. Harinasuta T, Bunnag D, Wernsdorfer WH. A phase
II clinical trial of mefloquine in patients with chloro-
quine-resistant falciparum malaria in Thailand. Bull
World Health Organ. 1983;61:299-305.
38. Hennequin C, Bouree P, Bazin N, Bisaro F, Feline
A. Severe psychiatric side effects observed during pro-
phylaxis and treatment with mefloquine. Arch Intern
Med. 1994;154:2360-2362.
39. Luxemburger C, Nosten F, ter Kuiile F, Fre-
jacques L, Chongsuphajaisiddhi T, White NJ. Meflo-
quine for multidrug-resistant malaria. Lancet. 1991;338:
1268.
40. Marsepoil T, Petithory J, Faucher JM, Ho P, Vi-
riot E, Benaiche F. Encephalopathy and memory dis-
orders during treatments with mefloquine [article in
French]. Rev Med Interne. 1993;14:788-791.
41. Patchen LC, Campbell CC, Williams SB. Neuro-
logic reactions after a therapeutic dose of mefloquine.
N Engl J Med. 1989;321:1415-1416.
42. Phillips-Howard PA, ter Kuile FO. CNS adverse
events associated with antimalarial agents: fact or
fiction? Drug Saf. 1995;12:370-383.
43. Price R, van Vugt M, Phaipun L, et al. Adverse
effects in patients with acute falciparum malaria treated
with artemisinin derivatives. Am J Trop Med Hyg. 1999;
60:547-555.
44. Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wie-
dermann G, Mikolasek A, Kollaritsch H. Unexpected
frequency, duration and spectrum of adverse events
after therapeutic dose of mefloquine in healthy adults.
Acta Trop. 2002;81:167-173.
45. Rouveix B, Bricaire F, Michon C, et al. Meflo-
quine and an acute brain syndrome. Ann Intern Med.
1989;110:577-578.
46. Sowunmi A. Acute psychosis after mefloquine: a
case report. East Afr Med J. 1994;71:818-819.
47. Sowunmi A, Adio RA, Oduola AM, Ogunda-
hunsi OA, Salako LA. Acute psychosis after meflo-
quine: report of six cases. Trop Geogr Med. 1995;47:
179-180.
48. Sowunmi A, Salako LA, Oduola AM, Walker O,
Akindele JA, Ogundahunsi OA. Neuropsychiatric side
effects of mefloquine in Africans. Trans R Soc Trop Med
Hyg. 1993;87:462-463.
49. Speich R, Haller A. Central anticholinergic syn-
drome with the antimalarial drug mefloquine. N Engl
J Med. 1994;331:57-58.
50. Weinke T, Trautmann M, Held T, et al. Neuro-
psychiatric side effects after the use of mefloquine. Am
J Trop Med Hyg. 1991;45:86-91.
51. Stuiver PC, Ligthelm RJ, Goud TJ. Acute psycho-
sis after mefloquine. Lancet. 1989;2:282.
52. de Alencar FE, Cerutti C Jr, Durlacher RR, et al.
Atovaquone and proguanil for the treatment
of malaria in Brazil. J Infect Dis. 1997;175:1544-
1547.
53. Barata LC, Boulos M, Dutra AP. Use of tetracy-
cline and quinine combination in the treatment of
Plasmodium falciparum malaria [article in Portuguese].
Rev Soc Bras Med Trop. 1986;19:135-137.
54. Bunnag D, Karbwang J, Na-Bangchang K, Thana-
vibul A, Chittamas S, Harinasuta T. Quinine-tetracycline
for multidrug resistant falciparum malaria. Southeast
Asian J Trop Med Public Health. 1996;27:15-18.
55. Clyde DF, Gilman RH, McCarthy VC. Antima-
larial effects of clindamycin in man. Am J Trop Med
Hyg. 1975;24:369-370.
56. Colwell EJ, Hickman RL, Kosakal S. Quinine-
tetracycline and quinine-bactrim treatment of acute
falciparum malaria in Thailand. Ann Trop Med Parasitol.
1973;67:125-132.
©2007 American Medical Association. All rights reserved.
TREATMENT OF MALARIA IN THE UNITED STATES
57. Colwell EJ, Hickman RL, Kosakal S. Tetracycline
treatment of chloroquine-resistant falciparum ma-
laria in Thailand. JAMA. 1972;220:684-686.
58. Hall AP, Doberstyn EB, Nanokorn A, Sonkom P.
Falciparum malaria semi-resistant to clindamycin.
Br Med J. 1975;2:12-14.
59. Karbwang J, Molunto P, Bunnag D, Harinasuta
T. Plasma quinine levels in patients with falciparum
malaria when given alone or in combination with tet-
racycline with or without primaquine. Southeast Asian
J Trop Med Public Health. 1991;22:72-76.
60. Karbwang J, Na-Bangchang K, Thanavibul A, Bun-
nag D, Chongsuphajaisiddhi T, Harinasuta T. Com-
parison of oral artesunate and quinine plus tetracy-
cline in acute uncomplicated falciparum malaria. Bull
World Health Organ. 1994;72:233-238.
61. Kremsner PG, Winkler S, Brandts C, Neifer S, Bi-
enzle U, Graninger W. Clindamycin in combination with
chloroquine or quinine is an effective therapy for un-
complicated Plasmodium falciparum malaria in chil-
dren from Gabon. J Infect Dis. 1994;169:467-470.
62. Kremsner PG, Zotter GM, Feldmeier H, Gran-
inger W, Rocha RM, Wiedermann G. A comparative
trial of three regimens for treating uncomplicated fal-
ciparum malaria in Acre, Brazil. J Infect Dis. 1988;158:
1368-1371.
63. Looareesuwan S, Vanijanonta S, Viravan C, et al.
Randomised trial of mefloquine-tetracycline and qui-
nine-tetracycline for acute uncomplicated falciparum
malaria. Acta Trop. 1994;57:47-53.
64. Looareesuwan S, Wilairatana P, Vanijanonta S,
Kyle D, Webster K. Efficacy of quinine-tetracycline for
acute uncomplicated falciparum malaria in Thailand.
Lancet. 1992;339:369.
65. McGready R, Cho T, Samuel , et al. Randomized
comparison of quinine-clindamycin versus artesunate
in the treatment of falciparum malaria in pregnancy.
Trans R Soc Trop Med Hyg. 2001;95:651-656.
66. Metzger W, Mordmuller B, Graninger W, Bi-
enzle U, Kremsner PG. High efficacy of short-term qui-
nine-antibiotic combinations for treating adult ma-
laria patients in an area in which malaria is
hyperendemic. Antimicrob Agents Chemother. 1995;
39:245-246.
67. Miller LH, Glew RH, Wyler DJ, et al. Evaluation
of clindamycin in combination with quinine against
multidrug-resistant strains of Plasmodium falciparum.
Am J Trop Med Hyg. 1974;23:565-569.
68. Parola P, Ranque S, Badiaga S, et al. Controlled
trial of 3-day quinine-clindamycin treatment versus
7-day quinine treatment for adult travelers with un-
complicated falciparum malaria imported from the
tropics. Antimicrob Agents Chemother. 2001;45:932-
935.
69. Pukrittayakamee S, Chantra A, Vanijanonta S, Cle-
mens R, Looareesuwan S, White NJ. Therapeutic re-
sponses to quinine and clindamycin in multidrug-
resistant falciparum malaria. Antimicrob Agents
Chemother. 2000;44:2395-2398.
70. Pukrittayakamee S, Chotivanich K, Chantra A, Cle-
mens R, Looareesuwan S, White NJ. Activities of ar-
tesunate and primaquine against asexual- and sexual-
stage parasites in falciparum malaria. Antimicrob Agents
Chemother. 2004;48:1329-1334.
71. Reacher M, Campbell CC, Freeman J, Doberstyn
EB, Brandling-Bennett AD. Drug therapy for Plasmo-
dium falciparum malaria resistant to pyrimethamine-
sulfadoxine (Fansidar): a study of alternate regimens
in Eastern Thailand, 1980. Lancet. 1981;2:1066-1069.
72. Vaillant M, Millet P, Luty A, et al. Therapeutic ef-
ficacy of clindamycin in combination with quinine for
treating uncomplicated malaria in a village dispen-
sary in Gabon. Trop Med Int Health. 1997;2:917-919.
73. Vanijanonta S, Chantra A, Phophak N, Chindan-
ond D, Clemens R, Pukrittayakamee S. Therapeutic
effects of chloroquine in combination with quinine in
uncomplicated falciparum malaria. Ann Trop Med
Parasitol. 1996;90:269-275.
(Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2275
74. Andersen SL, Oloo AJ, Gordon DM, et al. Suc-
cessful double-blinded, randomized, placebo-
controlled field trial of azithromycin and doxycycline
as prophylaxis for malaria in western Kenya. Clin In-
fect Dis. 1998;26:146-150.
75. Baudon D, Martet G, Pascal B, Bernard J, Keund-
jian A, Laroche R. Efficacy of daily antimalarial che-
moprophylaxis in tropical Africa using either doxycy-
cline or chloroquine-proguanil: a study conducted in
1996 in the French Army. Trans R Soc Trop Med Hyg.
1999;93:302-303.
76. Karwacki JJ, Shanks GD, Kummalue T, Watana-
sook C. Primaquine induced hemolysis in a Thai soldier.
Southeast Asian J Trop Med Public Health. 1989;20:
555-556.
77. Ohrt C, Richie TL, Widjaja H, et al. Mefloquine
compared with doxycycline for the prophylaxis of ma-
laria in Indonesian soldiers: a randomized, double-
blind, placebo-controlled trial. Ann Intern Med. 1997;
126:963-972.
78. Pang L, Limsomwong N, Singharaj P. Prophylac-
tic treatment of vivax and falciparum malaria with low-
dose doxycycline. J Infect Dis. 1988;158:1124-1127.
79. Pang LW, Limsomwong N, Boudreau EF, Singharaj
P. Doxycycline prophylaxis for falciparum malaria.
Lancet. 1987;1:1161-1164.
80. Rieckmann KH, Yeo AE, Davis DR, Hutton DC,
Wheatley PF, Simpson R. Recent military experience
with malaria chemoprophylaxis. Med J Aust. 1993;158:
446-449.
81. Sanchez JL, DeFraites RF, Sharp TW, Hanson RK.
Mefloquine or doxycycline prophylaxis in US troops
in Somalia. Lancet. 1993;341:1021-1022.
82. Shamiss A, Atar E, Zohar L, Cain Y. Mefloquine
versus doxycycline for malaria prophylaxis in inter-
mittent exposure of Israeli Air Force aircrew in Rwanda.
Aviat Space Environ Med. 1996;67:872-873.
83. Shanks GD, Barnett A, Edstein MD, Rieckmann
KH. Effectiveness of doxycycline combined with pri-
maquine for malaria prophylaxis. Med J Aust. 1995;
162:306-307, 309-310.
84. Shanks GD, Roessler P, Edstein MD, Rieckmann
KH. Doxycycline for malaria prophylaxis in Austra-
lian soldiers deployed to United Nations missions in
Somalia and Cambodia. Mil Med. 1995;160:443-445.
85. Taylor WR, Richie TL, Fryauff DJ, et al. Malaria
prophylaxis using azithromycin: a double-blind, pla-
cebo-controlled trial in Irian Jaya, Indonesia. Clin In-
fect Dis. 1999;28:74-81.
86. Adehossi E, Parola P, Foucault C, et al. Three-
day quinine-clindamycin treatment of uncompli-
cated falciparum malaria imported from the tropics.
Antimicrob Agents Chemother. 2003;47:1173.
87. Ramharter M, Oyakhirome S, Klouwenberg PK,
et al. Artesunate-clindamycin versus quinine-
clindamycin in the treatment of Plasmodium falcipa-
rum malaria: a randomized controlled trial. Clin In-
fect Dis. 2005;40:1777-1784.
88. Duarte EC, Fontes CJ, Gyorkos TW, Abraham-
owicz M. Randomized controlled trial of artesunate
plus tetracycline versus standard treatment (quinine
plus tetracycline) for uncomplicated Plasmodium fal-
ciparum malaria in Brazil. Am J Trop Med Hyg. 1996;
54:197-202.
89. Silamut K, Molunto P, Ho M, Davis TM, White
NJ. Alpha 1-acid glycoprotein (orosomucoid) and
plasma protein binding of quinine in falciparum malaria.
Br J Clin Pharmacol. 1991;32:311-315.
90. Winstanley P, Newton C, Watkins W, et al. To-
wards optimal regimens of parenteral quinine for young
African children with cerebral malaria: the impor-
tance of unbound quinine concentration. Trans R Soc
Trop Med Hyg. 1993;87:201-206.
91. White NJ. The treatment of malaria. N Engl J Med.
1996;335:800-806.
92. Di Perri G, Allegranzi B, Bonora S. Quinine-
induced blindness reversed by an increase in alpha1-
acid glycoprotein level. Ann Intern Med. 2002;136:339.
TREATMENT OF MALARIA IN THE UNITED STATES
93. Severe falciparum malaria: World Health Orga-
nization, Communicable Diseases Cluster. Trans R Soc
Trop Med Hyg. 2000;94(suppl 1):S1-S90.
94. Anabwani G, Canfield CJ, Hutchinson DB. Com-
bination atovaquone and proguanil hydrochloride vs.
halofantrine for treatment of acute Plasmodium fal-
ciparum malaria in children. Pediatr Infect Dis J. 1999;
18:456-461.
95. Blanchard TJ, Mabey DC, Hunt-Cooke A, et al.
Multiresistant falciparum malaria cured using atova-
quone and proguanil. Trans R Soc Trop Med Hyg. 1994;
88:693.
96. Bouchaud O, Monlun E, Muanza K, et al. Atova-
quone plus proguanil versus halofantrine for the treat-
ment of imported acute uncomplicated Plasmodium
falciparum malaria in non-immune adults: a random-
ized comparative trial. Am J Trop Med Hyg. 2000;63:
274-279.
97. Bustos DG, Canfield CJ, Canete-Miguel E, Hutchin-
son DB. Atovaquone-proguanil compared with chlo-
roquine and chloroquine-sulfadoxine-pyrimeth-
amine for treatment of acute Plasmodium falciparum
malaria in the Philippines. J Infect Dis. 1999;179:1587-
1590.
98. Giao PT, De Vries PJ, Hung LQ, Binh TQ, Nam
NV, Kager PA. Atovaquone-proguanil for recrudes-
cent Plasmodium falciparum in Vietnam. Ann Trop Med
Parasitol. 2003;97:575-580.
99. Lacy MD, Maguire JD, Barcus MJ, et al. Atova-
quone/proguanil therapy for Plasmodium falciparum
and Plasmodium vivax malaria in Indonesians who lack
clinical immunity. Clin Infect Dis. 2002;35:e92-e95.
100. Llanos-Cuentas A, Campos P, Clendenes M, Can-
field CJ, Hutchinson DB. Atovaquone and proguani
hydrochloride compared with chloroquine or pyri-
methamine/sulfodaxine for treatment of acute Plas-
modium falciparum malaria in Peru. Braz J Infect Dis.
2001;5:67-72.
101. Looareesuwan S, Viravan C, Webster HK, Kyle
DE, Hutchinson DB, Canfield CJ. Clinical studies of
atovaquone, alone or in combination with other an-
timalarial drugs, for treatment of acute uncompli-
cated malaria in Thailand. Am J Trop Med Hyg. 1996;
54:62-66.
102. Looareesuwan S, Wilairatana P, Chalermarut K,
Rattanapong Y, Canfield CJ, Hutchinson DB. Efficacy
and safety of atovaquone/proguanil compared with
mefloquine for treatment of acute Plasmodium falci-
parum malaria in Thailand. Am J Trop Med Hyg. 1999;
60:526-532.
103. Malvy D, Djossou F, Vatan R, et al. Experience
with the combination atovaquone-proguanil in the
treatment of uncomplicated Plasmodium falciparum
malaria—report of 112 cases [article in French]. Med
Trop (Mars). 2002;62:229-231.
104. Mulenga M, Sukwa TY, Canfield CJ, Hutchin-
son DB. Atovaquone and proguanil versus pyrimeth-
amine/sulfadoxine for the treatment of acute falci-
parum malaria in Zambia. Clin Ther. 1999;21:841-852.
105. Radloff PD, Philipps J, Nkeyi M, Hutchinson D,
Kremsner PG. Atovaquone and proguanil for Plasmo-
dium falciparum malaria. Lancet. 1996;347:1511-1514.
106. Sabchareon A, Attanath P, Phanuaksook P, et al.
Efficacy and pharmacokinetics of atovaquone and pro-
guanil in children with multidrug-resistant Plasmo-
dium falciparum malaria. Trans R Soc Trop Med Hyg.
1998;92:201-206.
107. Thybo S, Gjorup I, Ronn AM, Meyrowitsch D,
Bygberg IC. Atovaquone-proguanil (malarone): an ef-
fective treatment for uncomplicated Plasmodium fal-
ciparum malaria in travelers from Denmark. J Travel
Med. 2004;11:220-223.
108. Uchiyama H, Okamoto A, Sato K, et al. Quinine-
resistant severe falciparum malaria effectively treated
with atovaquone and proguanil hydrochloride com-
bination therapy. Intern Med. 2004;43:624-627.
109. van Vugt M, Leonardi E, Phaipun L, et al. Treat-
ment of uncomplicated multidrug-resistant falcipa-
2276 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted)
rum malaria with artesunate-atovaquone-proguanil.
Clin Infect Dis. 2002;35:1498-1504.
110. David KP, Alifrangis M, Salanti A, Vestergaard
LS, Ronn A, Bygbjerg IB. Atovaquone/proguanil re-
sistance in Africa: a case report. Scand J Infect Dis.
2003;35:897-898.
111. Farnert A, Lindberg J, Gil P, et al. Evidence of
Plasmodium falciparum malaria resistant to atova-
quone and proguanil hydrochloride: case reports. BMJ.
2003;326:628-629.
112. Fivelman QL, Butcher GA, Adagu IS, Warhurst
DC, Pasvol G. Malarone treatment failure and in vitro
confirmation of resistance of Plasmodium falciparum
isolate from Lagos, Nigeria. Malar J. 2002;1:1.
113. Schwartz E, Bujanover S, Kain KC. Genetic con-
firmation of atovaquone-proguanil-resistant Plasmo-
dium falciparum malaria acquired by a nonimmune
traveler to East Africa. Clin Infect Dis. 2003;37:450-
451.
114. Wichmann O, Muehlen M, Gruss H, Mocken-
haupt FP, Suttorp N, Jelinek T. Malarone treatment
failure not associated with previously described mu-
tations in the cytochrome b gene. Malar J. 2004;3:14.
115. Kuhn S, Gill MJ, Kain KC. Emergence of atova-
quone-proguanil resistance during treatment of Plas-
modium falciparum malaria acquired by a non-
immune north American traveller to west Africa. Am
J Trop Med Hyg. 2005;72:407-409.
116. Schwobel B, Alifrangis M, Salanti A, Jelinek T.
Different mutation patterns of atovaquone resis-
tance to Plasmodium falciparum in vitro and in vivo:
rapid detection of codon 268 polymorphisms in the
cytochrome b as potential in vivo resistance marker.
Malar J. 2003;2:5.
117. Boggild AK, Parise ME, et al. Atovaquone-
proguanil: report from a CDC expert meeting on ma-
laria chemoprophylaxis (II). Am J Trop Med Hyg. 2007:
208-223 76.
118. Health Information for International Travel
2007-2008. Atlanta, Ga: Elsevier; 2007.
119. Product information: Larium brand of meflo-
quine hydrochloride tablets. Bas, Switzerland: Hoff-
man-La Roche; 2002.
120. Hall AP, Doberstyn EB, Karnchanachetanee C,
et al. Sequential treatment with quinine and meflo-
quine or quinine and pyrimethamine-sulfadoxine for
falciparum malaria. Br Med J. 1977;1:1626-1628.
121. Baird JK, Sustriayu Nalim MF, Basri H, et al. Sur-
vey of resistance to chloroquine by Plasmodium vivax
in Indonesia. Trans R Soc Trop Med Hyg. 1996;90:409-
411.
122. Baird JK, Wiady I, Fryauff DJ, et al. In vivo re-
sistance to chloroquine by Plasmodium vivax and Plas-
modium falciparum at Nabire, Irian Jaya, Indonesia.
Am J Trop Med Hyg. 1997;56:627-631.
123. Fryauff DJ, Tuti S, Mardi A, et al. Chloroquine-
resistant Plasmodium vivax in transmigration settle-
ments of West Kalimantan, Indonesia. Am J Trop Med
Hyg. 1998;59:513-518.
124. Murphy GS, Basri H, Purnomo HB, et al. Vivax
malaria resistant to treatment and prophylaxis with
chloroquine. Lancet. 1993;341:96-100.
125. Rieckmann KH, Davis DR, Hutton DC. Plasmo-
dium vivax resistance to chloroquine? Lancet. 1989;2:
1183-1184.
126. Schuurkamp GJ, Spicer PE, Kereu RK, Bulungol
PK, Rieckmann KH. Chloroquine-resistant Plasmo-
dium vivax in Papua New Guinea. Trans R Soc Trop
Med Hyg. 1992;86:121-122.
127. Sumawinata IW, Subianto B, Leksana B, et al.
Very high risk of therapeutic failure with chloroquine
for uncomplicated Plasmodium falciparum and P. vivax
malaria in Indonesian Papua. Am J Trop Med Hyg.
2003;68:416-420.
128. Whitby M, Wood G, Veenendaal JR, Rieck-
mann K. Chloroquine-resistant Plasmodium vivax.
Lancet. 1989;2:1395.
129. Alcantara AK, Uylangco CV, Sangalang RP, Cross
©2007 American Medical Association. All rights reserved.
JH. A comparative clinical study of mefloquine and chlo-
roquine in the treatment of vivax malaria. Southeast
Asian J Trop Med Public Health. 1985;16:534-538.
130. Collignon P. Chloroquine resistance in Plasmo-
dium vivax. J Infect Dis. 1991;164:222-223.
131. Dixon KE, Pitaktong U, Phintuyothin P. A clini-
cal trial of mefloquine in the treatment of Plasmo-
dium vivax malaria. Am J Trop Med Hyg. 1985;34:435-
437.
132. Hanna J. Chloroquine-resistant Plasmodium vivax:
how common? Med J Aust. 1993;158:502-503.
133. Harinasuta T, Bunnag D, Lasserre R, Leimer R,
Vinijanont S. Trials of mefloquine in vivax and of mef-
loquine plus “fansidar” in falciparum malaria. Lancet.
1985;1:885-888.
134. Pukrittayakamee S, Chantra A, Simpson JA, et al.
Therapeutic responses to different antimalarial drugs
in vivax malaria. Antimicrob Agents Chemother. 2000;
44:1680-1685.
135. Schwartz IK, Lackritz EM, Patchen LC. Chloro-
quine-resistant Plasmodium vivax from Indonesia.
N Engl J Med. 1991;324:927.
136. Maguire JD, Krisin, Marwoto H, Richie TL, Fry-
auff DJ, Baird JK. Mefloquine is highly efficacious
against chloroquine-resistant Plasmodium vivax ma-
laria and Plasmodium falciparum malaria in Papua,
Indonesia. Clin Infect Dis. 2006;42:1067-1072.
137. Looareesuwan S, Wilairatana P, Glanarongran
R, et al. Atovaquone and proguanil hydrochloride fol-
lowed by primaquine for treatment of Plasmodium
vivax malaria in Thailand. Trans R Soc Trop Med Hyg.
1999;93:637-640.
138. Baird JK, Basri H, Subianto B, et al. Treatment
of chloroquine-resistant Plasmodium vivax with chlo-
roquine and primaquine or halofantrine. J Infect Dis.
1995;171:1678-1682.
139. Glucose-6-phosphate dehydrogenase deficiency.
Bull World Health Organ. 1989;67:601-611.
140. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET,
Magill AJ. Primaquine: report from CDC expert meet-
ing on malaria chemoprophylaxis I. Am J Trop Med
Hyg. 2006;75:402-415.
141. Povinelli L, Monson TA, Fox BC, Parise ME, Mor-
risey JM, Vaidya AB. Plasmodium vivax malaria in spite
of atovaquone/proguanil (malarone) prophylaxis.
J Travel Med. 2003;10:353-355.
142. Jimenez BC, Navarro M, Huerga H, Lopez-
Roman E, Mendoza A, Lopez-Velez R. Tertian ma-
laria (Plasmodium vivax and Plasmodium ovale) in two
travelers despite atovaquone-proguanil prophylaxis.
J Travel Med. 2006;13:373-375.
143. Alving AS, Johnson CF, Tarlov AR, Brewer GJ,
Kellermeyer RW, Carson PE. Mitigation of the hae-
molytic effect of primaquine and enhancement of its
action against exoerythrocytic forms of the Chesson
strain of Plasmodium vivax by intermittent regimens
of drug administration: a preliminary report. Bull World
Health Organ. 1960;22:621-631.
144. Myat-Phone K, Myint O, Myint L, Thaw Z, Kyin
Hla A, Nwe Nwe Y. Emergence of chloroquine-
resistant Plasmodium vivax in Myanmar (Burma). Trans
R Soc Trop Med Hyg. 1993;87:687.
145. Miller KD, Greenberg AE, Campbell CC. Treat-
ment of severe malaria in the United States with a con-
tinuous infusion of quinidine gluconate and ex-
change transfusion. N Engl J Med. 1989;321:65-70.
146. Phillips RE, Warrell DA, White NJ, Looareesu-
wan S, Karbwang J. Intravenous quinidine for the treat-
ment of severe falciparum malaria: clinical and phar-
macokinetic studies. N Engl J Med. 1985;312:
1273-1278.
147. van Hensbroek MB, Onyiorah E, Jaffar S, et al.
A trial of artemether or quinine in children with cere-
bral malaria. N Engl J Med. 1996;335:69-75.
148. Newton PN, Angus BJ, Chierakul W, et al. Ran-
domized comparison of artesunate and quinine in the
treatment of severe falciparum malaria. Clin Infect Dis.
2003;37:7-16.

149. Molyneux ME, Taylor TE, Thomas CG, Mansor
S, Wirima JJ. Efficacy of quinine for falciparum ma-
laria according to previous chloroquine exposure.
Lancet. 1991;337:1379-1380.
150. Zucker JR, Campbell CC. Malaria: principles of
prevention and treatment. Infect Dis Clin North Am.
1993;7:547-567.
151. White NJ, Looareesuwan S, Warrell DA, Chong-
suphajaisiddhi T, Bunnag D, Harinasuta T. Quinidine
in falciparum malaria. Lancet. 1981;2:1069-1071.
152. Availability and use of parenteral quinidine glu-
conate for severe or complicated malaria. MMWR
Morb Mortal Wkly Rep. 2000;49:1138-1140.
153. Humar A, Sharma S, Zoutman D, Kain KC. Fa-
tal falciparum malaria in Canadian travellers. CMAJ.
1997;156:1165-1167.
154. Rosenthal PJ, Peterson C, Geertsma FR, Kohl S.
Availability of intravenous quinidine for falciparum
malaria. N Engl J Med. 1996;335:138.
155. Murphy S, English M, Waruiru C, et al. An open
randomized trial of artemether versus quinine in the
treatment of cerebral malaria in African children. Trans
R Soc Trop Med Hyg. 1996;90:298-301.
156. Warrell DA, Looareesuwan S, Warrell MJ, et al.
Dexamethasone proves deleterious in cerebral ma-
laria: a double-blind trial in 100 comatose patients.
N Engl J Med. 1982;306:313-319.
157. White NJ, Warrell DA. Managing cerebral malaria.
Br Med J (Clin Res Ed). 1982;285:439-440.
158. Dondorp A, Nosten F, Stepniewska K, Day N,
White N. Artesunate versus quinine for treatment of
severe falciparum malaria: a randomised trial. Lancet.
2005;366:717-725.
159. Hoontrakoon S, Suputtamongkol Y. Exchange
transfusion as an adjunct to the treatment of severe
falciparum malaria. Trop Med Int Health. 1998;3:156-
161.
160. Looareesuwan S, Phillips RE, Karbwang J, White
NJ, Flegg PJ, Warrell DA. Plasmodium falciparum hy-
perparasitaemia: use of exchange transfusion in seven
patients and a review of the literature. Q J Med. 1990;
75:471-481.
161. Burchard GD, Kroger J, Knobloch J, et al. Ex-
change blood transfusion in severe falciparum ma-
laria: retrospective evaluation of 61 patients treated
with, compared to 63 patients treated without, ex-
change transfusion. Trop Med Int Health. 1997;2:733-
740.
162. Powell VI, Grima K. Exchange transfusion for ma-
laria and Babesia infection. Transfus Med Rev. 2002;
16:239-250.
163. Pasvol G, Jacobs M. What is the future of ex-
change transfusion for falciparum malaria? J Infect.
1999;39:183-184.
164. Riddle MS, Jackson JL, Sanders JW, Blazes DL.
Exchange transfusion as an adjunct therapy in severe
Plasmodium falciparum malaria: a meta-analysis. Clin
Infect Dis. 2002;34:1192-1198.
165. Crawley J, Waruiru C, Mithwani S, et al. Effect
of phenobarbital on seizure frequency and mortality
in childhood cerebral malaria: a randomised, con-
trolled intervention study. Lancet. 2000;355:701-706.
166. Kochar D, Kumawat B, Bajiya HN, Chauhan S, Ko-
char SK, Agarwal RP. Prophylactic role of single dose
phenobarbitone in preventing convulsions in cerebral
malaria. J Assoc Physicians India. 1997;45:123-124.
167. White NJ, Looareesuwan S, Phillips RE, Chan-
thavanich P, Warrell DA. Single dose phenobarbi-
tone prevents convulsions in cerebral malaria. Lancet.
1988;2:64-66.
168. Hoffman SL, Rustama D, Punjabi NH, et al. High-
dose dexamethasone in quinine-treated patients with
cerebral malaria: a double-blind, placebo-controlled
trial. J Infect Dis. 1988;158:325-331.
169. Prasad K, Garner P. Steroids for treating cere-
bral malaria. Cochrane Database Syst Rev. 2000;(2):
CD000972.
©2007 American Medical Association. All rights reserved.
TREATMENT OF MALARIA IN THE UNITED STATES
170. Borochovitz D, Crosley AL, Metz J. Dissemi-
nated intravascular coagulation with fatal haemor-
rhage in cerebral malaria. Br Med J. 1970;2:710.
171. Hemmer CJ. Neither heparin nor acetylsalicylic
acid influence the clinical course in human Plasmo-
dium falciparum malaria: a prospective randomized
study. Am J Trop Med Hyg. 1991;45:608-612.
172. Munir M, Tjandra H, Rampengan TH, Mustad-
jab I, Wulur FH. Heparin in the treatment of cerebral
malaria. Paediatr Indones. 1980;20:47-50.
173. Punyagupta S, Srichaikul T, Akarawong K. The
use of heparin in fatal pulmonary edema due to acute
falciparum malaria. J Med Assoc Thai. 1972;55:121-
131.
174. Punyagupta S, Srichaikul T, Nitiyanant P, Petch-
clai B. Acute pulmonary insufficiency in falciparum ma-
laria: summary of 12 cases with evidence of dissemi-
nated intravascular coagulation. Am J Trop Med Hyg.
1974;23:551-559.
175. Rampengan TH. Cerebral malaria in children:
comparative study between heparin, dexametha-
sone and placebo. Paediatr Indones. 1991;31:59-66.
176. Reid HA. Letter: Adjuvant treatment of severe
falciparum malaria, intravascular coagulation, and
heparin. Lancet. 1975;1:167-168.
177. Thuma PE, Mabeza GF, Biemba G, et al. Effect
of iron chelation therapy on mortality in Zambian chil-
dren with cerebral malaria. Trans R Soc Trop Med Hyg.
1998;92:214-218.
178. Thuma PE, Olivieri NF, Mabeza GF, et al. As-
sessment of the effect of the oral iron chelator deferi-
prone on asymptomatic Plasmodium falciparum para-
sitemia in humans. Am J Trop Med Hyg. 1998;58:358-
364.
179. Looareesuwan S, Wilairatana P, Vannaphan S,
et al. Pentoxifylline as an ancillary treatment for se-
vere falciparum malaria in Thailand. Am J Trop Med
Hyg. 1998;58:348-353.
180. Agbenyega T, Planche T, Bedu-Addo G, et al.
Population kinetics, efficacy, and safety of dichloro-
acetate for lactic acidosis due to severe malaria in
children. J Clin Pharmacol. 2003;43:386-396.
181. Parise M, Lewis LS. Severe malaria: North Ameri-
can perspective. In: Feldman CSG, ed. Tropical and
Parasitic Infections in the ICU. New York, NY: Springer
Science⫹Business Media Inc; 2005:17-37.
182. Phillips RE, Looareesuwan S, White NJ, et al. Hy-
poglycaemia and antimalarial drugs: quinidine and re-
lease of insulin. Br Med J (Clin Res Ed). 1986;292:1319-
1321.
183. White NJ, Warrell DA, Chanthavanich P, et al.
Severe hypoglycemia and hyperinsulinemia in falci-
parum malaria. N Engl J Med. 1983;309:61-66.
184. White N. Controversies in the management of
severe falciparum malaria. In: Pasvol G, ed. Balliere’s
Clinical Infectious Diseases: Malaria [Volume 2]. Lon-
don, England: Baillière Tindall; 1995:309-330.
185. Butler T, Tong MJ, Fletcher JR, Dostalek RJ, Rob-
bins TO. Blood coagulation studies in Plasmodium fal-
ciparum malaria. Am J Med Sci. 1973;265:63-67.
186. Phillips RE, Looareesuwan S, Warrell DA, et al.
The importance of anaemia in cerebral and uncom-
plicated falciparum malaria: role of complications, dys-
erythropoiesis and iron sequestration. Q J Med. 1986;
58:305-323.
187. Marino P. The ICU Book. 2nd ed. Baltimore, Md:
Williams & Wilkins; 1998.
188. Davis TM, Pukrittayakamee S, Woodhead JS, Hol-
loway P, Chaivisuth B, White NJ. Calcium and phos-
phate metabolism in acute falciparum malaria. Clin Sci
(Lond). 1991;81:297-304.
189. Newton CR, Hien TT, White N. Cerebral malaria.
J Neurol Neurosurg Psychiatry. 2000;69:433-441.
190. U.D.E. Group, ed. USP DI Drug Information for
the Healthcare Provider. 23rd ed. Taunton, Mass: Mi-
cromedex Inc; 2003.
191. Conchie JM, Munroe JD, Anderson DO. The in-
(Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2277
cidence of staining of permanent teeth by the
tetracyclines. Can Med Assoc J. 1970;203:351-356.
192. Dubos F, Delattre P, Demar M, Carme B, Gen-
drel D. Safety of mefloquine in infants with acute fal-
ciparum malaria. Pediatr Infect Dis J. 2004;23:679-681.
193. Luxemburger C, Price RN, Nosten F, Ter Kuile
FO, Chongsuphajaisiddhi T, White NJ. Mefloquine in
infants and young children. Ann Trop Paediatr. 1996;
16:281-286.
194. Sowunmi A, Oduola AM. Open comparison of
mefloquine, mefloquine/sulfadoxine/pyrimeth-
amine and chloroquine in acute uncomplicated falci-
parum malaria in children. Trans R Soc Trop Med Hyg.
1995;89:303-305.
195. ter Kuile FO, Nosten F, Luxemburger C, et al.
Mefloquine treatment of acute falciparum malaria: a
prospective study of non-serious adverse effects in
3673 patients. Bull World Health Organ. 1995;73:631-
642.
196. ter Kuile FO, Nosten F, Thieren M, et al. High-
dose mefloquine in the treatment of multidrug-
resistant falciparum malaria. J Infect Dis. 1992;166:
1393-1400.
197. Canadian recommendations for the prevention
and treatment of malaria among international trav-
ellers. Committee to Advise on Tropical Medicine and
Travel CATMAT), Laboratory for Disease Control. Can
Commun Dis Rep. 2000;26(suppl 2):i-vi, 1-42.
198. Looareesuwan S, Phillips RE, White NJ, et al. Qui-
nine and severe falciparum malaria in late pregnancy.
Lancet. 1985;2:4-8.
199. McGready R, Keo NK, Villegas L, White NJ, Looa-
reesuwan S, Nosten F. Artesunate-atovaquone-
proguanil rescue treatment of multidrug-resistant
Plasmodium falciparum malaria in pregnancy: a pre-
liminary report. Trans R Soc Trop Med Hyg. 2003;97:
592-594.
200. McGready R, Stepniewska K, Edstein MD, et al.
The pharmacokinetics of atovaquone and proguanil
in pregnant women with acute falciparum malaria. Eur
J Clin Pharmacol. 2003;59:545-552.
201. Nosten F, Vincenti M, Simpson J, et al. The ef-
fects of mefloquine treatment in pregnancy. Clin In-
fect Dis. 1999;28:808-815.
202. Nosten F, Karbwang J, White NJ, et al. Meflo-
quine antimalarial prophylaxis in pregnancy: dose find-
ing and pharmacokinetic study. Br J Clin Pharmacol.
1990;30:79-85.
203. Nosten F, ter Kuile F, Maelankiri L, et al. Mef-
loquine prophylaxis prevents malaria during preg-
nancy: a double-blind, placebo-controlled study. J In-
fect Dis. 1994;169:595-603.
204. Phillips-Howard PA, Steffen R, Kerr L, et al. Safety
of mefloquine and other antimalarial agents in the first
trimester of pregnancy. J Travel Med. 1998;5:121-126.
205. Steketee RW, Wirima JJ, Slutsker L, Khoro-
mana CO, Heymann DL, Breman JG. Malaria treat-
ment and prevention in pregnancy: indications for use
and adverse events associated with use of chloro-
quine or mefloquine. Am J Trop Med Hyg. 1996;55
(suppl):50-56.
206. Vanhauwere B, Maradit H, Kerr L. Post-marketing
surveillance of prophylactic mefloquine (Lariam)
use in pregnancy. Am J Trop Med Hyg. 1998;58:
17-21.
207. Lackritz EM, Lobel HO, Howell BJ, Bloland P,
Campbell CC. Imported Plasmodium falciparum ma-
laria in American travelers to Africa: implications for
prevention strategies. JAMA. 1991;265:383-385.
208. Lobel HO, Campbell CC, Schwartz IK, Roberts
JM. Recent trends in the importation of malaria caused
by Plasmodium falciparum into the United States from
Africa. J Infect Dis. 1985;152:613-617.
209. Nahlen BL, Lobel HO, Cannon SE, Campbell CC.
Reassessment of blood donor selection criteria for
United States travelers to malarious areas. Transfusion.
1991;31:798-804.