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

METHODS
evance to this article, hand searched America. Recommendations are based
We performed a systematic MEDLINE bibliographies of pertinent articles, and on randomized controlled trials, ob-
search from 1966 to 2006 using the reviewed articles suggested by experts servational studies, and consensus ex-
search term malaria (with the subhead- in the treatment of malaria in North pert opinion.
ings congenital, diagnosis, drug therapy,
epidemiology, and therapy). This search Author Affiliations: Malaria Branch, Division of Parasitic National Center for Zoonotic, Vector-Borne and Enteric
Diseases, National Center for Zoonotic, Vector-Borne and Diseases, Centers for Disease Control and Prevention.
was conducted on August 1, 2006, and Enteric Diseases, Coordinating Center for Infectious Dis- Corresponding Author: Monica E. Parise, MD, Para-
resulted in 5588 potentially relevant ar- eases, Centers for Disease Control and Prevention, At- sitic Diseases Branch, Division of Parasitic Diseases, Na-
ticles. We reviewed titles and/or ab- lanta, Ga (Drs Griffith and Parise and Ms Mali); and Butte tional Center for Zoonotic, Vector-Borne and Enteric
County Department of Public Health, Oroville, Calif (Dr Diseases, Centers for Disease Control and Preven-
stracts of all articles to determine rel- Lewis).DrGriffithisnowwiththeBacterialDiseasesBranch, tion, 4770 Buford Hwy NE MS F22, Atlanta, GA 30341
DivisionofVector-BorneInfectiousDiseases,NationalCen- (MParise@cdc.gov).
ter for Zoonotic, Vector-Borne and Enteric Diseases, Co- Clinical Review Section Editor: Michael S. Lauer, MD.
CME available online at ordinating Center for Infectious Diseases, Centers for Dis- We encourage authors to submit papers for consid-
www.jama.com ease Control and Prevention. Dr Parise is now with the eration as a Clinical Review. Please contact Michael
Parasitic Diseases Branch, Division of Parasitic Diseases, 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 Plasmodium ovale may reactivate weeks Plasmodium ovale occurs mostly in West
EPIDEMIOLOGIC or months after the initial infection, pro- Africa and is occasionally encountered
CONSIDERATIONS ducing relapses. in Southeast Asia and Papua New
In the Plasmodium life cycle (FIGURE 1), Of the 4 Plasmodium species that in- Guinea. Plasmodium malariae occurs at
the asexual blood stages (rings, tropho- fect humans, Plasmodium falciparum is low frequency in a patchy distribution
zoites, schizonts) are responsible for the the one with potential to rapidly progress worldwide. Plasmodium falciparum ac-
symptoms of malaria, and thus are the to severe illness or death. It predomi- counts for slightly more than 50% and
main target of chemotherapy. The nates in sub-Saharan Africa, Hispani- P vivax approximately 25% of reported
sexual blood stages (gametocytes) do ola, and Papua New Guinea. Among the cases in the United States.1,2
not cause any known pathology and other species, P vivax is the most com- Chloroquine-resistant strains of P fal-
thus are not a primary target of treat- mon3 and predominates in South Asia, ciparum occur in all endemic areas ex-
ment. Dormant liver stage parasites Eastern Europe and Northern Asia, and cept Central America west of the Panama
(hypnozoites) of Plasmodium vivax and Central and most of South America.4 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

the disease. The typical incubation pe- Diagnostic confirmation is ob-


Box. Manifestations riod usually varies between 9 and 18 days tained by microscopic demonstration
of Severe Malaria* for P falciparum, P vivax, and P ovale12; of malaria parasites on Giemsa-
Prostration it is longer (18-40 days) for P malariae stained thick and thin blood films,
and may be as short as 7 days for P fal- which should be examined as soon as
Impaired consciousness/coma
ciparum.13 However, symptoms may oc- possible but within 12 hours of the pre-
Respiratory distress (acidotic cur weeks or even months after expo- sentation of any patient with sus-
breathing)
sure as a result of inadequate prophylaxis pected malaria. Institutions unfamil-
Multiple convulsions or treatment, immune response, or re- iar with malaria diagnosis should not
Circulatory shock lapses. Some temperate strains of P vivax, delay microscopic diagnosis (eg, by
Pulmonary edema such as the North Indian and North Ko- sending the films out to a laboratory
Acute respiratory distress syndrome rean strains, can exhibit delayed pri- that cannot provide same-day re-
Abnormal bleeding
mary attacks, occurring 12 to 18 months sults), but should promptly refer the pa-
after an infected mosquito bite.14 Of cases tient to a more experienced institu-
Jaundice
reported in the United States from 1995 tion or consult with more experienced
Severe anemia to 2004, 98% (n=3626) of patients with personnel at other institutions, their
Acute renal failure P falciparum malaria experienced their state department of health, or submit
Disseminated intravascular first symptoms within the first 3 months digital images captured from stained
coagulation of arrival in the United States, and 57% films directly to the CDC’s telediagno-
Acidosis (n = 1743) and 96% (n = 2906) of pa- sis service (dpdx@cdc.gov, or through
Hemoglobinuria tients with non-falciparum malaria had the CDC Malaria Hotline or CDC Emer-
symptom onset within the first 3 and 12 gency Operations Center [Malaria Hot-
Parasitemia ⬎5%
months, respectively. During this same line 770-488-7788 Monday-Friday, 8
*Sources: WHO Management of Severe Ma- time period, 85% of patients with im- AM to 4:30 PM. Off-hours, weekends,
laria (2000)21 and WHO Guidelines for the ported P falciparum malaria acquired and federal holidays, CDC clinicians
Treatment of Malaria (2006).22
their infection in Africa. can be reached by calling the CDC
Absence of a travel history does not Emergency Operations Center at 770-
rule out malaria. Patients may provide 488-7100 and asking for the malaria cli-
China and the Middle East, and multi- an inaccurate history or may have been nician on-call to be paged]).
drug-resistant strains occur in South- infected in the United States through The parasite density (ie, percentage
east Asia, South America, and sub- other rarely occurring mechanisms such of infected erythrocytes on a thin film)
Saharan Africa. Due to increasing as transfusion, congenital transmis- should be quantified as 1 measure of the
resistance of P falciparum to the drug sion, or local mosquito-borne trans- severity of the disease and its response
combination of sulfadoxine and pyri- mission.1 to treatment, which should be closely
methamine, the CDC no longer recom- The initial presentation of malaria monitored. If the initial film is nega-
mends sulfadoxine-pyrimethamine for is nonspecific and similar to that of tive and the patient is suspected of hav-
treatment of malaria in the United States many other febrile illnesses. Fever is ing malaria, blood films should be re-
or as standby treatment for US travel- the most commonly reported symp- peated at 12- to 24-hour intervals for
ers. A high prevalence of chloroquine- tom, being present in 78% to 100% of 48 to 72 hours. If the diagnosis is clini-
resistant P vivax (CRPV) is found in case patients,2,15-18 but fever periodic- cally suspected and proficient labora-
Papua New Guinea and Indonesia. Baird ity is often not seen.15,19,20 Patients tory diagnosis is impossible, empirical
and Hoffman have written an excellent may experience a wide spectrum of treatment for P falciparum malaria, as
review on CRPV (which details well its other symptoms including chills, discussed below, should be initiated,
geographic distribution).5 There is evi- headache, malaise, nausea, vomiting, pending referral of the patient and/or
dence for rates up to 25% in a few sites diarrhea, abdominal pain, myalgias, specimen. It is important that a differ-
in Burma,6 Malaysia,7 Vietnam,8 India,9 back pain, weakness, dizziness, confu- ential identification of Babesia sp
and Turkey.10,11 sion, cough, and/or coma. Spleno- (which may be morphologically simi-
megaly is a frequent physical finding lar to P falciparum) be made during mi-
RECOGNITION (24%-40% of case patients). 15,16,18 croscopic examination. Although non-
AND DIAGNOSIS Severe malaria is characterized by 1 or specific, thrombocytopenia, a low white
Consideration of malaria based on travel more of the signs or symptoms shown blood cell count, and signs of hemoly-
history is the key to diagnosis. Any pa- in the BOX. Severe malaria is almost in- sis, such as an elevated bilirubin level,
tient who has been in an endemic area variably caused by P falciparum, with found during general laboratory test-
in the year preceding the onset of ma- rare reports of severe malaria caused by ing are possible clues to the presence
larial symptoms should be evaluated for P vivax.2,23-30 of malaria.
2266 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted) ©2007 American Medical Association. All rights reserved.
TREATMENT OF MALARIA IN THE UNITED STATES

In addition to microscopy, polymer- teriorate rapidly and progress to cline in one trial that directly com-
ase chain reaction and rapid immuno- death within 1 to 2 days,32 and many pared the 2 regimens.52
chromatographic diagnostic tests31 are centers do not have the expertise to ad- Quinine has a rapid onset of action
alternate diagnostic tools that are not equately triage (eg, to accurately quan- and, in combination with either tetracy-
routinely available. Rapid immuno- tify the parasite density), the CDC ad- cline, doxycycline, or clindamycin, has
chromatographic diagnostic tests are vises that patients infected with P been shown to be a very efficacious treat-
not yet licensed for use in the United falciparum or an unidentified Plasmo- ment option for P falciparum infections
States. Serological tests document past dium species should be initially admit- acquired in regions with chloroquine-
exposure and are thus of limited use in ted to ensure that the medication is tol- resistant strains.52-73 For P falciparum in-
acute case management. erated and the patient is improving fections acquired in Southeast Asia, a
clinically and parasitologically. Blood 7-day course of both quinine and the ac-
CLINICAL SITUATIONS AND films should be repeated to ensure clear- companying antibiotic is recom-
RECOMMENDED TREATMENT ance of P falciparum parasitemia. Pa- mended54,59,60,63,64,69,70,73; for infections ac-
General tients who are not responding clini- quired outside Southeast Asia, a 3-day
To manage malaria successfully, treat- cally (with defervescence within 72 course of quinine and a 7-day course of
ing physicians should seek the answer hours) need follow-up malaria blood the accompanying antibiotic is recom-
to the following 5 questions: (1) What films and may also require a search for mended.52,53,66 The quinine and antibi-
is the species? (2) What is the density other causes of fever. Of note, game- otic should be started at the same time
of parasitemia? (3) What is the drug- tocytes may be less susceptible to many or should at least overlap by 2 days. Al-
resistant pattern where the infection antimalarial drugs than are asexual though published treatment trials mainly
was acquired? (4) Are there signs of se- parasites, and their persistence in the used quinine in combination with tet-
vere malaria? and (5) Can the patient blood in the absence of asexual para- racycline, doxycycline has excellent an-
tolerate oral medication? sites does not indicate drug resis- timalarial efficacy in chemoprophy-
Patients with malaria should be tance. laxis trials and is considered an equally
treated immediately because P falcipa- efficacious substitute.74-85 Tetracycline or
rum infections can rapidly progress to Uncomplicated Falciparum Malaria doxycycline is generally preferred to clin-
severe illness or death in as little as 1 For P falciparum malaria acquired in a damycin as the accompanying antibi-
to 2 days.32 Immunity wanes in the limited number of areas (FIGURE 2),4 otic because of more extensive efficacy
absence of continued antigen expo- chloroquine (with hydroxychloro- data and field experience. The quinine
sure and thus semi-immune persons quine as a second-line alternative) re- and clindamycin regimen also has been
who have left an endemic area for an mains the treatment of choice (Table). shown to be efficacious against P falci-
extended period of time and then Chloroquine-resistant P falciparum parum infections acquired in areas with
return are susceptible to severe disease strains are found in all other malari- chloroquine resistance† and is useful in
and death. If the species cannot be ous areas, where 3 treatment options treatment of pregnant women and
identified, the patient should be are currently recommended: (1) oral children younger than 8 years in whom
treated as if infected with P falciparum quinine plus either tetracycline, doxy- tetracyclines and doxycycline are
until the infecting species can be iden- cycline, or clindamycin; (2) atova- contraindicated.
tified. The patient’s travel history pro- quone-proguanil; or (3) mefloquine. Quinine is commercially available in
vides useful clues for selecting an The first 2 options are preferred due to the United States only as an oral medi-
effective antimalarial drug, in terms of a higher rate of moderate to severe neu- cation. Cinchonism (a complex of symp-
risk of drug resistance. Because base ropsychiatric reactions seen when mef- toms including nausea, vomiting, head-
and salt conversions for antimalarial loquine is used at treatment doses35-50 ache, tinnitus, deafness, dizziness, and
drugs are a source of confusion and compared with persons taking the drug visual disturbances) is common with qui-
can result in treatment errors,33 where for prophylaxis. The incidence rate for nine or quinidine (the isomer of qui-
pertinent, the base equivalency is fol- moderate or severe neuropsychiatric ad- nine) use. For example, tinnitus was re-
lowed by the salt equivalency in verse reactions at mefloquine treat- ported in 13% to 94% of patients taking
parentheses (TABLE). ment doses has been estimated to be 1 quinine in clinical trials,52,60,65,68,69,88 and
There has been some controversy in 215 to 1 in 1754 treatments.39,50 None the syndrome of cinchonism was re-
about the need for initial hospital ad- of the reported neuropsychiatric ad- ported in 94% of patients in another
mission for all patients with P falcipa- verse reactions were lethal and most re- trial.63 Quinine binding to plasma pro-
rum malaria, and some authors have solved spontaneously.* Atovaquone- teins, principally to ␣-1-glycoprotein, is
tried to define triage criteria for which proguanil was better tolerated than the increased in malaria.89,90 This explains
patients need to be admitted vs those combination of quinine and tetracy- why plasma quinine levels that have been
who can be followed as outpatients.34
However, since these patients can de- *References 35, 37, 39, 41, 42, 46, 47, 50, 51. †References 55, 58, 61, 62, 65-69, 72, 86, 87.

©2007 American Medical Association. All rights reserved. (Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2267
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.
TREATMENT OF MALARIA IN THE UNITED STATES

associated with blindness and deafness of the related compound to minimize the prevent potential relapses. To achieve
after self-poisoning, and which are risk of adverse events such as electro- more reliable eradication of hypnozo-
common during the treatment of malaria, cardiographic abnormalities.119,120 ites, the CDC now recommends a regi-
extremely rarely cause such adverse Antimalarial drugs that are not rec- men of 0.5 mg/kg to a maximum of 30
effects in patients with malaria.91,92 Life- ommended, even though they may be mg of primaquine base daily for 14 days.
threatening toxicity is rare and the symp- available in other countries, include sul- The most common severe adverse effect
toms of cinchonism are rarely sufficient fadoxine-pyrimethamine, amodia- associated with primaquine is intravas-
to warrant discontinuing quinine or quine, and halofantrine because of re- cular hemolysis in persons with glucose-
quinidine treatment.93 sistance and/or toxicity problems. 6-phosphate dehydrogenase (G6PD) de-
The tetracyclines (tetracycline and ficiency, a contraindication to the use of
doxycycline) and clindamycin should Uncomplicated Non-Falciparum this drug. Patients must be screened for
always be used in combination with a Malaria G6PD prior to use of primaquine. Pri-
faster-acting antimalarial drug such as Chloroquine remains the treatment of maquine treatment should, if possible,
quinine and never as monotherapy. choice for all P malariae and P ovale in- overlap with the blood schizonticidal
Atovaquone-proguanil has reported fections and for P vivax infections ac- treatment.138-140
cure rates of 94% to 100% for P falcipa- quired outside Papua New Guinea and Patients who are not able to take pri-
rum infections acquired in Southeast Indonesia; hydroxychloroquine is a maquine should be counseled on the pos-
Asia, Africa, and South America.52,94-109 second-line alternative. Currently, there sibility of having a relapsing infection (es-
To date, there have been 12 published are limited data on optimal treatment op- timated to be approximately 20% [range,
cases of atovaquone-proguanil failure for tions for P vivax infections acquired in 5%-80%])5 and the need to seek treat-
the treatment of P falciparum malaria areas with highly prevalent chloroquine ment if similar symptoms recur. An-
(from East, West, and Central Africa), resistance (Papua New Guinea and In- other potential option for patients un-
7 of which have had isolates with ge- donesia). The best option may be able to take primaquine who are
netically confirmed markers of resis- atovaquone-proguanil, with mefloquine experiencing frequent relapses is chlo-
tance (ie, mutations in the cytochrome or quinine plus tetracycline or doxycy- roquine (or mefloquine, in the case of
b gene),110-117 and thus, clinicians should cline as alternatives. Both quinine (3 CRPV) prophylaxis for the period of time
remain aware of the rare possibility of days) and either tetracycline or doxycy- that relapses are most likely to occur (ie,
atovaquone-proguanil treatment failures. cline (7 days)121-128 and mefloquine129-135 a few years). Although atovaquone-
Mefloquine should not be used to have been historically used successfully proguanil has “causal prophylactic ac-
treat P falciparum infections acquired on in case reports or small case series. More tivity” (ie, the ability to prevent blood
the borders of Thailand with Burma recently, both atovaquone-proguanil, in stage infection by killing developing liver
(Myanmar) and Cambodia, in the west- a relatively small study,99 and mefloquine stage parasites), it does not appear to
ern provinces of Cambodia, in the east- (at 15 mg/kg)136 have effectively treated eradicate hypnozoites101,102 and may not
ern states of Burma (Myanmar), on the P vivax malaria in Indonesia, where high prevent the establishment of hypnozo-
border between Burma and China, in rates of CRPV exist. Of note, although ites.141,142 Thus, patients with P vivax or
Laos along the borders of Laos and initial studies of atovaquone-proguanil P ovale malaria who have been treated
Burma and the adjacent parts of the showed high (68%) rates of recurrent with atovaquone-proguanil also need pri-
Thailand Cambodia border, as well as parasitemiabefore28daysoffollow-up101 maquine. Although a modified regimen
in southern Vietnam, because of re- (some of which may have been relapses), of 45 mg (base) of primaquine weekly
ports of a high prevalence of mefloquine- subsequent (albeit small) studies have for 8 weeks has been suggested as an al-
resistant P falciparum in these areas.118 demonstrated excellent efficacy (⬎95%) ternative for patients with mild G6PD de-
Although mefloquine is contraindi- of atovaquone-proguanil against P vivax ficiency,143,144 the data on both safety and
cated for chemoprophylactic use in per- malaria.99,137 Data are too limited to rec- efficacy of such a regimen are very lim-
sons with active or recent history of de- ommend quinine-clindamycin69 for first- ited. Primaquine for “radical cure” (ie,
pression, generalized anxiety disorder, line treatment of P vivax, including primaquine used in conjunction with an
psychosis, or other major psychiatric dis- CRPV, infections. Baird and colleagues effective blood schizonticide for the treat-
order, or in persons with a history of sei- demonstrated 85% efficacy of chloro- ment of a patient with P vivax or P ovale
zures, it can be used for treatment in per- quine and high-dose (2.5 mg/kg base malaria) in a known G6PD-deficient in-
sons with these conditions if the benefits over 3 days) primaquine for treatment dividual should be used only after a care-
are judged to outweigh the risks.119 If re- of CRPV.138 The CDC has not recom- ful risk/benefit assessment and under
lated compounds (chloroquine, qui- mended this regimen due to relative in- strict medical supervision.140
nine, or quinidine) have been given for experience with high-dose primaquine
chemoprophylaxis or initial treatment, and suboptimal efficacy. Severe Malaria
mefloquine administration should be de- Infections with P vivax and P ovale The single most important step in the
layed at least 12 hours after the last dose should be treated with primaquine to management of severe malaria is im-
©2007 American Medical Association. All rights reserved. (Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2271
TREATMENT OF MALARIA IN THE UNITED STATES

mediate initiation of appropriate par- received more than 40 mg/kg quinine duction of toxic byproducts, and/or
enteral treatment. In the United States, in the previous 2 days or has received improved rheology with transfused
the only parenteral drug currently avail- mefloquine in the previous 12 hours (in cells.161,162 The technical aspects of ex-
able is quinidine gluconate. Blood films which case the loading dose is not given change transfusion have been dis-
should be examined every 12 hours un- but a continuous quinidine infusion is cussed in an excellent review by Pow-
til negative for malaria parasites.91 Para- still administered).93 The quinidine in- ell and Grima.162 However, exchange
site density typically decreases by 90% fusion should be temporarily slowed or transfusion and its indications will re-
over the first 48 hours with quinine or stopped if the QT interval increases to main controversial until a carefully con-
quinidine therapy.145-149 If parasitemia greater than 0.6 seconds, the QRS com- trolled, adequately powered compara-
has not decreased as expected, poten- plex increases greater than 50%, the tive study is conducted, an unlikely
tial causes of the problem should be in- QTc interval is prolonged by more than probability.163,164 In the decision to use
vestigated (eg, by checking the quini- 25% of the baseline value, or if hypo- exchange transfusion, the potential risks
dine level). Quinidine levels should be tension unresponsive to fluid chal- of exchange transfusion, including fluid
maintained in the range of 3 to 8 lenge develops.150,155 If significant elec- overload, febrile and allergic reac-
mg/L.91,150 trocardiographic changes persist or tions, metabolic disturbances, red blood
Quinidine is more cardiotoxic than malignant arrhythmias develop, phy- cell alloantibody sensitization, trans-
quinine and should be administered in sicians should treat the arrhythmias and missible infection, cerebral hemor-
an intensive care unit with continu- consider expert consultation through rhage, and line sepsis, must be weighed
ous electrocardiographic and frequent the CDC Malaria Hotline or other tropi- against potential benefits.163 The CDC
blood pressure monitoring.145 Quini- cal medicine experts. Options in such recommends that exchange transfu-
dine-related cardiovascular adverse ef- severe situations may include admin- sion be strongly considered for per-
fects are potentially serious and may be istration of alternative antimalarial sons with a parasitemia higher than 10%
more frequent if the drug is adminis- drugs via nasogastric tube along with or if complications such as cerebral ma-
tered rapidly.151 The risk of cardiotox- exchange transfusion. Quinidine con- laria, nonvolume overload pulmonary
icity is increased with bradycardia, hy- tinuous infusion should be continued edema, or renal compromise exist.150
pokalemia, and hypomagnesemia152 and during exchange transfusion. Various adjunctive treatments ap-
if the patient has received other drugs Initial (including loading) doses of pear in the literature that are either un-
that may prolong the QTc interval (eg, parenteral quinine or quinidine need proven or are harmful in the treat-
quinine, mefloquine, or macrolide not be reduced in persons with renal ment of severe malaria and are not
antibiotics). failure. The pharmacokinetic proper- currently recommended. They in-
Because newer antiarrhythmic agents ties of the cinchona alkaloids are al- clude phenobarbital for prophylaxis of
have displaced quinidine gluconate, tered in malaria, with a contraction in seizures165-167; dexamethasone for treat-
quinidine is often not stocked in many the volume of distribution that is pro- ment of cerebral malaria156,168,169; hep-
hospitals.152-154 Hospital drug services portional to the severity of malarial ill- arin for treatment of thrombocytope-
should maintain or add quinidine glu- ness.91,157 If renal failure persists or the nia and/or fibrinogenemia170-176; iron
conate to their formularies. If they do patient’s clinical condition does not im- chelators that aim to reduce parasite
not stock the drug, they must be able prove, the maintenance dosage should clearance time125,177,178; pentoxifylline for
to immediately locate a nearby source. be reduced by one third to one half on inhibition of tumor necrosis factor syn-
Otherwise, the hospital should con- the third treatment day.91 thesis179; and dichloroacetate for treat-
tact their local or regional distributor The artemisinin derivatives clear ment of metabolic acidosis.180
to request the drug or contact the Eli parasites very rapidly, are now a key Potential complications of severe
Lilly Co directly (telephone: 1-800- component of malaria treatment world- malaria181 should be recognized and
821-0538).152 Assistance from the com- wide, and have been shown to reduce treated. Hypoglycemia may be masked
pany to arrange a rapid shipment of the mortality in severe malaria compared by the manifestations of cerebral
drug is available between the hours of with parenteral quinine.158 These drugs malaria, and thus frequent plasma glu-
6 AM and 6 PM. If further assistance is are not yet available in the United States, cose determination is essential. Severe
needed in managing patients with ma- but the CDC hopes to make intrave- and recurrent hypoglycemia may be
laria, health care professionals can con- nous artesunate available under an In- caused by hyperinsulinemia induced
tact the CDC Malaria Hotline. vestigational New Drug protocol in by quinine or quinidine or by endo-
Because most deaths from severe ma- 2007. toxin or by parasite consumption.182,183
laria occur within the first 24 to 48 Exchange transfusion has been used Hyperpyrexia can be treated with ace-
hours of treatment, an initial loading in the treatment of severe malaria since tominophen; nonsteroidal anti-
dose of quinidine is recommended to 1974 with apparent benefit,145,159,160 po- inflammatory drugs are not recom-
achieve therapeutic levels as rapidly as tentially due to rapid reduction of para- mended, given the frequency of
possible145,155,156 unless the patient has sitemia by direct parasite removal, re- thrombocytopenia and coagulation
2272 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted) ©2007 American Medical Association. All rights reserved.
TREATMENT OF MALARIA IN THE UNITED STATES

abnormalities. Pulmonary edema may sultation with their clinician, to take birth weight, congenital infection,
be due to either fluid overload or adult along a dose of antimalarial medica- and/or neonatal death. For uncompli-
respiratory distress syndrome and can tion for self-treatment. The only drug cated P falciparum infections acquired
be minimized by keeping patients recommended for self-treatment for US in regions with chloroquine-resistant
euvolemic. Acute renal failure is gen- travelers is atovaquone-proguanil. It strains, quinine plus clindamycin has
erally oliguric. With dialysis, renal should not be used in patients on atova- been shown to be safe and efficacious
function can be expected to return quone-proguanil prophylaxis because of and is recommended.65 Concerns that
after a median of 4 days, although the risk of breakthrough parasitemia due quinine may cause fetal toxicity or in-
some patients may require dialysis for to a resistant organism in those pa- duce labor when given late in preg-
2 to 3 weeks.184 Thrombocytopenia is tients. In such cases, specialized tropi- nancy have not been substantiated at
common in severe malaria. Laboratory cal medicine consultation should be the doses used for treatment of ma-
evidence of activated coagulation is sought. Quinine-doxycycline is a sub- laria.198 An important adverse effect of
more common than is disseminated optimal alternative due to potential ad- quinine in pregnant patients is hyper-
intravascular coagulation with bleed- verse drug reactions and the complex- insulinemia, which can precipitate or
ing.181,185,186 Hyponatremia,187 hypocal- ity of the regimen. Travelers should be worsen hypoglycemia.198 Late in preg-
cemia, hypophosphatemia and hyper- advised that self-treatment of a pos- nancy, quinine is distributed to the fe-
phosphatemia, and hypomagnesemia sible malaria infection is only a tempo- tus, raising concerns about quinine trig-
and hypermagnesemia188 have all been rary measure and that prompt medical gering insulin release and resulting in
reported in patients with P falciparum evaluation is imperative.4 fetal hypoglycemia.182 However, the
malaria.181 risks of untreated falciparum malaria
In patients with suspected cerebral Malaria in Children during pregnancy outweigh the poten-
malaria, a lumbar puncture should be Tetracycline and doxycycline have a tial risk of adverse drug effects from qui-
performed to rule out bacterial menin- relative contraindication for use in in- nine or quinidine.
gitis,157 and magnetic resonance imaging fants and children younger than 8 years Atovaquone-proguanil or meflo-
or computed tomographic scans should of age due to reports of drug deposi- quine are not currently recommended for
be performed to rule out intracerebral tion in calcifying areas of bones and treatment in pregnancy and should only
bleeding, cerebral edema, and cerebral/ teeth that result in permanent tooth be used if quinine plus clindamycin or
medullary herniation. Most survivors staining, enamel hypoplasia, and de- quinine monotherapy is not available or
with cerebral malaria regain conscious- creased linear skeletal growth rate190,191; is not being tolerated. Tetracycline and
ness within 2 to 3 days, although it may clindamycin in combination with qui- doxycycline are contraindicated. Al-
occasionally take more than a week.189 nine should be used instead. While the though 2 recent studies of the atova-
US package insert recommends meflo- quone-proguanil and artesunate combi-
Induced Malaria quine for use in children older than 6 nation treatment for P falciparum
Because malaria acquired through months of age,119 the drug is generally infections in pregnant women showed
bloodborne transmission (eg, blood well tolerated in children weighing the regimen to be well-tolerated with no
transfusion or organ transplantation) more than 5 kg,192-195 with vomiting as evidence of toxicity to the mother or fe-
has no exoerythrocytic stage, prima- the principal adverse effect.192-196 Al- tus,199,200 further study is needed before
quine treatment is not needed in in- though few studies document the safety atovaquone-proguanil can be recom-
duced P vivax or P ovale infections. and tolerability of primaquine in chil- mended for use during pregnancy.
dren, the drug has been used for more Because primaquine can potentially
Self-treatment than 50 years with no apparent safety cause hemolytic disease in a G6PD-
The CDC recommends the use of ma- problems. There is no evidence to sug- deficient fetus, primaquine is contra-
laria prophylaxis, rather than self- gest that the drug cannot be used in indicated in pregnancy. Pregnant
treatment, for travelers to malarious children of any age who do not have women treated for P ovale and P vivax
areas. However, travelers who elect not G6PD deficiency.140 Neither the Ameri- infections should also receive chemo-
to take prophylaxis, who do not choose can Academy of Pediatrics nor US4 or prophylaxis until delivery. The pro-
an optimal drug regimen (eg, chloro- Canadian197 public health authorities list phylaxis regimen should consist of
quine for travel to an area with chloro- a lower age limit for primaquine use. either chloroquine, 300-mg base (=500
quine-resistant P falciparum malaria), or mg salt) orally once per week; or, for
those who require a less than optimal Malaria in Pregnant Women P vivax infections acquired in areas with
drug regimen are at greater risk for ac- Malaria infection in pregnant women chloroquine-resistant strains, meflo-
quiring malaria and needing prompt is associated with high risks of both ma- quine 228-mg base (= 250 mg salt)
treatment. Travelers who are taking ef- ternal and perinatal morbidity and mor- orally once per week. While meflo-
fective prophylaxis but who will be in tality, including spontaneous abor- quine is not recommended for malaria
very remote areas may decide, in con- tion, stillbirth, premature delivery, low treatment during pregnancy,201 sev-
©2007 American Medical Association. All rights reserved. (Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2273
TREATMENT OF MALARIA IN THE UNITED STATES

eral studies support its safety as che- drug, were substantial contributing fac- Malaria, Principles and Practice of Malariology, Vol-
ume 2. Edinburgh, Scotland: Churchill Livingstone;
moprophylaxis during pregnancy.202-206 tors in malaria deaths.2 Clinicians must 1988:927.
After delivery, women should be treated remain alert to the possibility of this dis- 14. Garnham P. Malaria parasites of man: life-cycles
and morphology. In: Wernsdorfer WH, McGregor I,
with primaquine as recommended for ease and take immediate measures to- eds. Malaria: Principles and Practice of Malariology,
nonpregnant adult patients. ward prompt accurate diagnosis and Volume 1. London, England: Churchill Livingstone;
treatment. 1988:69.
15. Dorsey G, Gandhi M, Oyugi JH, Rosenthal PJ. Dif-
Congenital Malaria ficulties in the prevention, diagnosis, and treatment
Author Contributions: Drs Griffith, Lewis, and Parise
There are approximately 2 cases of con- had full access to all of the data in the study and take of imported malaria. Arch Intern Med. 2000;160:2505-
responsibility for the integrity of the data and the ac- 2510.
genital malaria reported in the United curacy of the data analysis. 16. Moore TA, Tomayko JF Jr, Wierman AM, Ren-
States annually. Infants typically pre- Study concept and design: Griffith, Lewis, Parise. simer ER, White AC Jr. Imported malaria in the 1990s:
Acquisition of data: Griffith, Lewis, Mali, Parise. a report of 59 cases from Houston, Tex. Arch Fam Med.
sent at 1 to 2 months of age with fever, 1994;3:130-136.
Analysis and interpretation of data: Griffith, Lewis,
anemia, failure to thrive, and spleno- Parise. 17. Singh K, Wester WC, Trenholme GM. Problems
megaly. As with induced malaria, there Drafting of the manuscript: Griffith, Lewis, Parise. in the therapy for imported malaria in the United States.
Critical revision of the manuscript for important in- Arch Intern Med. 2003;163:2027-2030.
is no exoerythrocytic phase and thus no tellectual content: Griffith, Lewis, Mali, Parise. 18. Svenson JE, MacLean JD, Gyorkos TW, Key-
need for primaquine treatment in P Administrative, technical, or material support: Griffith, stone J. Imported malaria: clinical presentation and ex-
Lewis, Mali. amination of symptomatic travelers. Arch Intern Med.
vivax or P ovale congenital infections. Study supervision: Parise. 1995;155:861-868.
For mothers who are parasitemic either Financial Disclosures: None reported. 19. Lynk A, Gold R. Review of 40 children with
during pregnancy or at delivery, clini- Disclaimer: The findings and conclusions in this re- imported malaria. Pediatr Infect Dis J. 1989;8:745-
port are those of the authors and do not necessarily 750.
cians should judge management of the represent the views of the Centers for Disease Con- 20. McCaslin RI, Pikis A, Rodriguez WJ. Pediatric Plas-
infant in each case individually, factor- trol and Prevention. modium falciparium malaria: a ten-year experience
Acknowledgment: We thank Phuc Nguyen-Dinh, MD, from Washington, DC. Pediatr Infect Dis J. 1994;13:
ing in such issues as reliability of fol- MPH, Malaria Branch, Division of Parasitic Diseases, 709-715.
low-up and access to medical care. In Centers for Disease Control and Prevention (retired 21. World Health Organization. WHO Guidelines for
in February 2007), for his thorough review and criti- the Treatment of Malaria. Geneva, Switzerland: WHO
some cases it may be appropriate to sim- cal comments on the manuscript. He did not receive Press; 2000.
ply educate the mother about the risk any compensation for his contribution. 22. World Health Organization. WHO Guidelines for
of congenital malaria and instruct her the Treatment of Malaria. Geneva, Switzerland: WHO
Press; 2006.
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