Nile university

Faculty of medicine (MBBS)

Fourth year

Clinical microbiology
Malaria (parasitology)

Supervised by:
Dr. Wafa Mohammed Hussein

Done by:

Ghufran Ahmed Mohamed 4th year

Introduction
Malaria has been a major disease of humankind for thousands of years. It is referred to in
numerous biblical passages and in the writings of Hippocrates. Although drugs are available
for treatment, malaria is still considered by many to be the most important infectious disease
of humans: there are approximately 200 million to 500 million new cases each year in the
world, and the disease is the direct cause of 1 million to 2.5 million deaths per year.

Malaria is caused by protozoa of the genus Plasmodium. Four species cause disease in
humans: P falciparum, P vivax, P ovale and P malariae. Other species of plasmodia infect
reptiles, birds and other mammals. Malaria is spread to humans by the bite of female
mosquitoes of the genus Anopheles.

Clinical Manifestations
The most characteristic symptom of malaria is fever. Other common symptoms include chills,
headache, myalgias, nausea, and vomiting. Diarrhea, abdominal pain, and cough are
occasionally seen. As the disease progresses, some patients may develop the classic malaria
paroxysm with bouts of illness alternating with symptom-free periods . The malaria paroxysm
comprises three successive stages. The first is a 15-to-60 minute cold stage characterized by
shivering and a feeling of cold. Next comes the 2-to-6 hour hot stage, in which there is fever,
sometimes reaching 41°C, flushed, dry skin, and often headache, nausea, and vomiting.
Finally, there is the 2-to-4 hour sweating stage during which the fever drops rapidly and the
patient sweats. In all types of malaria the periodic febrile response is caused by rupture of
mature schizonts. In P vivax and P ovale malaria, a brood of schizonts matures every 48 hr, so
the periodicity of fever is tertian (“tertian malaria”), whereas in P malariae disease, fever
occurs every 72 hours (“quartan malaria”). The fever in falciparum malaria may occur every 48
hr, but is usually irregular, showing no distinct periodicity. These classic fever patterns are
usually not seen early in the course of malaria, and therefore the absence of periodic,
synchronized fevers does not rule out a diagnosis of malaria.

Physical findings in malaria are nonspecific and offer little aid in diagnosis. In many cases
there may be no positive findings other than fever. Splenomegaly is common but may not be
apparent early in disease. Hepatomegaly, jaundice, hypotension and abdominal tenderness
may also be seen. Malaria does not cause lymphadenopathy and is not associated with a rash.

A variety of laboratory abnormalities may be seen in a case of uncomplicated malaria. These

include normochromic, normocytic anemia, thrombocytopenia, leukocytosis or leukopenia,
hypoglycemia, hyponatremia, elevated liver and renal function tests, proteinuria, and
laboratory evidence of disseminated intravascular coagulation (although clinically important
bleeding is rare). Eosinophilia is not seen. Patients with complicated malaria occasionally
show evidence of massive intravascular hemolysis with hemoglobinemia and hemoglobinuria.

If the diagnosis of malaria is missed or delayed, especially with P falciparum infection,

potentially fatal complicated malaria may develop. The most frequent and serious
complications of malaria are cerebral malaria and severe anemia. Cerebral malaria is defined
as any abnormality of mental status in a person with malaria and has a case fatality rate of 15
to 50 percent. Other complications include: hyperparasitemia (more than 3 to 5 percent of
the erythrocytes parasitized); severe hypoglycemia; lactic acidosis; prolonged hyperthermia;
shock; pulmonary, cardiac, hepatic, or renal dysfunction; seizures; spontaneous bleeding; or
high-output diarrhea or vomiting. These manifestations are associated with poor prognosis.
Persons at increased risk of severe disease from malaria include older persons, children,
pregnant women, nonimmune persons and those with underlying chronic illness. Other
complications of malaria infection include gram-negative sepsis, aspiration pneumonia and
splenic rupture.

Classification
Only four species of the protozoan genus Plasmodium usually infect humans: P falciparum, P
vivax, P malariae, and P ovale . P falciparum and P vivax account for the vast majority of
cases. P falciparum causes the most severe disease.

Structure and Life Cycle

Like many protozoa, plasmodia pass through a number of stages in the course of their two-
host life cycle. The stage infective for humans is the uninucleate, lancet-shaped sporozoite
(approximately 1 × 7 μm). Sporozoites are produced by sexual reproduction in the midgut of
vector anopheline mosquitoes and migrate to the salivary gland. When an infected Anopheles
mosquito bites a human, she may inject sporozoites along with saliva into small blood vessels
(Fig. 83-3). Sporozoites are thought to enter liver parenchymal cells within 30 minutes of
inoculation. In the liver cell, the parasite develops into a spherical, multinucleate liver-stage
schizont which contains 2,000 to 40,000 uninucleate merozoites. This process of enormous
amplification is called exoerythrocytic schizogony. This exoerythrocytic or liver phase of the
disease usually takes between 5 and 21 days, depending on the species of plasmodium.
However, in P vivax and P ovale infections, maturation of liver-stage schizonts may be
delayed for as long as 1 to 2 years. These quiescent liver-phase parasites are called
hypnozoites.

Regardless of the time required for development, the mature schizonts eventually rupture,
releasing thousands of uninucleate merozoites into the bloodstream. Each merozoite can
infect a red blood cell. Within the red cell, the merozoite develops to form either an
erythrocytic-stage (blood-stage) schizont (by the process of erythrocytic schizogony) or a
spherical or banana-shaped, uninucleate gametocyte. The mature erythrocytic-stage schizont
contains 8 to 36 merozoites, each 5 to 10 μm long, which are released into the blood when the
schizont ruptures. These merozoites proceed to infect another generation of erythrocytes.
The time required for erythrocytic schizogony-which determines the interval between the
release of successive generations of merozoites-varies with the species of plasmodium and is
responsible for the classic periodicity of fever in malaria.

The gametocyte, which is the sexual stage of the plasmodium, is infectious for mosquitoes
that ingest it while feeding. Within the mosquito, gametocytes develop into female and male
gametes (macrogametes and microgametes, respectively), which undergo fertilization and
then develop over 2 to 3 weeks into sporozoites that can infect humans. The delay between
infection of a mosquito and maturation of sporozoites means that female mosquitoes
mustlive a minimum of 2 to 3 weeks to be able to transmit malaria. This fact is important in
malaria control efforts.

Pathogenesis
Clinical illness is caused by the erythrocytic stage of the parasite. No disease is associated
with sporozoites, the developing liver stage of the parasite, the merozoites released from the
liver, or gametocytes.

The first symptoms and signs of malaria are associated with the rupture of erythrocytes when
erythrocytic-stage schizonts mature. This release of parasite material presumably triggers a
host immune response. The cytokines, reactive oxygen intermediates, and other cellular
products released during the immune response play a prominent role in pathogenesis, and
are probably responsible for the fever, chills, sweats, weakness, and other systemic
symptoms associated with malaria. In the case of falciparum malaria (the form that causes
most deaths), infected erythrocytes adhere to the endothelium of capillaries and
postcapillary venules, leading to obstruction of the microcirculation and local tissue anoxia.
In the brain this causes cerebral malaria ; in the kidneys it may cause acute tubular necrosis
and renal failure; and in the intestines it can cause ischemia and ulceration, leading to
gastrointestinal bleeding and to bacteremia secondary to the entry of intestinal bacteria into
the systemic circulation. The severity of malaria-associated anemia tends to be related to the
degree of parasitemia. The pathogenesis of this anemia appears to be multifactorial.
Hemolysis or phagocytosis of parasitized erythrocytes and ineffective erythropoiesis are the
most important factors, and phagocytosis of uninfected erythrocytes and an autoimmune
hemolytic anemia have also been implicated. Massive intravascular hemolysis leading to
hemoglobinuria and renal failure is referred to as blackwater fever. It was described more
frequently in the past than currently. Hemolysis may also occur after the use of certain
antimalarials (especially primaquine) in patients with glucose 6-phosphate dehydrogenase
deficiency.

Host Defenses
Susceptibility to malaria infection and disease is regulated by hereditary and acquired
factors. It now seems clear that the sickle cell trait (which is the cause of sickle-cell anemia)
developed as a balanced polymorphism to protect against serious P falciparum disease.
Although individuals with sickle cell anemia or the sickle cell trait are as easily infected with
malaria parasites as normal individuals, they rarely exhibit malaria disease because P
falciparum develops poorly in their erythrocytes. The virtual absence of P vivax infections in
many areas of Africa is explained by the fact that most blacks do not have Duffy blood-group
antigens, which apparently function as erythrocyte surface receptors for P vivax merozoites;
without the Duffy antigen, the parasites cannot invade. Malaria parasites do not develop well
in ovalocytes, and it has been suggested that ovalocytosis, which is quite common in some
malarious areas, such as New Guinea, may reduce the incidence of malaria. Some
investigators have suggested that glucose 6-phosphate dehydrogenase deficiency, as well as
a number of other hemoglobinopathies (including the thalassemias and hemoglobin E), also
protect against malaria infection, but the evidence for these associations is less compelling.

Acquired immunity can also protect against malaria infection and the development of malaria
disease. In malarious areas, both the prevalence and severity of malaria infections decrease
with age. However, in contrast to many viral infections, multiple infections with malaria do not
confer longlasting, sterile protective immunity. Virtually all adults in malarious areas suffer
repeated malaria infections. Individuals who are repeatedly exposed to malaria develop
antibodies against many sporozoite, liver-stage, blood-stage, and sexual-stage malaria
antigens. It is thought that antibodies acting against sporozoites, liver-stage and blood-stage
organisms are responsible for the decreased susceptibility to malaria infection and disease
seen in adults in malarious areas, and that antibodies against the sexual stages of plasmodia
may reduce malaria transmission. Additional work also suggests that the naturally acquired
immunity includes the release of cytokines that act against all stages of the parasite, and also
a cytotoxic T cell response directed at liver stages of the parasite.

Acquired antibody-mediated immunity is apparently transferred from mother to fetus across

the placenta. This passively transferred immunity is lost within 6 to 9 months, as is the
immunity in adults if they leave a malarious area and are no longer exposed to plasmodia.
Pregnant women, particularly primigravidas, are more susceptible to malaria infections and
serious disease.

Epidemiology
Malaria is transmitted primarily by the bite of infected anopheline mosquitoes. It can also be
transmitted by inoculation of infected blood and congenitally. Anophelines feed at night and
their breeding sites are primarily in rural areas. The greatest risk of malaria is therefore from
dusk to dawn in rural areas. In many malaria-endemic areas, there is little or no risk in urban
areas. However, urban transmission is common in some parts of the world, especially Africa.

Malaria was once transmitted in many parts of the world, for example, as far north as North
Dakota in the United States. Dueboth to environmental changes and to eradication
campaigns conducted in the years after World War II, endemic malaria transmission has been
eliminated from many areas, including the United States and Europe. The disease is still
widely transmitted in the tropics and subtropics. In these areas malaria transmission may be
endemic, occurring predictably every year, or it may be epidemic, occurring sporadically
when conditions are correct. Endemic transmission of malaria may be year-round or
seasonal. In some areas of Africa, 90 to 100 percent of children less than 5 years old have
malaria parasites circulating in their blood all the time. Because naturally acquired immunity
develops with increasing exposure, in endemic areas malaria disease is primarily found in
children. In epidemic areas, on the other hand, naturally acquired immunity falls off between
epidemics, and malaria therefore affects all age groups during epidemics.

Approximately 1,000 cases of malaria are reported each year in the United States in returning
travelers. Of the 1016 imported cases reported in 1991, the majority were acquired in Africa
(466 cases) and India (221 cases). P vivax accounted for 43% of the cases and P. falciparum
for 39%. The risk to travelers of acquiring P falciparum is greatest in Africa. This is because it
is the most prevalent species there, malaria transmission is much more intense there than in
other parts of the world, and there is significant risk in urban areas.

Anopheles mosquitoes capable of transmitting malaria are found in a number of areas of the
United States. Local transmission may therefore occur when these mosquitoes feed upon
malariainfected individuals, generally immigrants from malaria-endemic areas. Local
transmission has recently occurred in southern California, New Jersey, New York City, and
Houston, Texas. Malaria may also occur when infected mosquitoes are transported into non-
endemic areas, such as by airplanes or ships.

In the late 1950s and early 1960s, it was thought that malaria could be eradicated through
the widespread use of insecticides such as DDT and by treatment of cases with chloroquine.
Eradication is no longer thought possible, however, because of the development of drug
resistance by both the mosquito and the parasite, and because of deteriorating social and
economic conditions in many malaria-endemic countries. These changes have resulted in a
dramatic increase in the incidence of malaria in many parts of the world, and an increase in
malaria-related mortality in some of these areas.

Diagnosis
In the United States, many of the deaths from malaria are the result of delayed diagnosis and
treatment because the health care provider did not suspect malaria. The diagnosis of malaria
requires a high index of suspicion; malaria should be considered in any individual who has a
fever and has visited an endemic area for malaria, received a blood transfusion, or used
intravenous drugs. Although 95 percent of individuals infected with malaria develop their
primary illness within 6 weeks of exposure, somemay have primary attacks up to a year after
exposure, and relapses of malaria can occur up to 2–3 years after exposure. Therefore,
individuals having a febrile illness and a history of exposure in the last 2–3 years should be
evaluated for malaria.
Definitive diagnosis of malaria generally requires direct observation of malaria parasites in
Giemsa-stained thick and thin blood smears. Thick blood smears are more difficult to
interpret than thin blood smears but they are much more sensitive, as more blood is
examined. Thin blood smears, in which parasites are seen within erythrocytes, are used to
determine the species of the infecting parasite. The presence of diagnostic forms can vary
markedly with the stage of the life cycle, especially early in disease. In falciparum malaria,
most organisms are not present in the peripheral blood because they are sequestered in the
microvascular tissue of internal organs. If malaria is suspected, blood smears should be
examined every 6 to 12 hr for at least 2 days. New diagnostic methods include a rapid
antigen-capture dipstick test and a technique for detecting parasites with a fluorescent stain.
Both of these tests are fast, easy to perform and are highly sensitive and specific

Other diagnostic methods include assays to detect malaria antibodies and antigens, and
polymerase chain reaction/DNA and RNA probe techniques. These techniques are used
primarily in epidemiologic studies and immunization trials and rarely in the diagnosis of
individual patients.

Control
The principles of medical management of malaria reflect the fact that falciparum malaria can
progress rapidly to a life-threatening state and that complications can occur even after the
initiation of therapy. They are: (1) early recognition of infection due to P falciparum; (2) rapid
institution of appropriate therapy; (3) recognition and therapy of complications; and (4)
monitoring of clinical and parasitologic response to therapy.

Malaria therapy is complicated by the fact that parasites may be present in the blood and the
liver and that different drugs are required to eradicate each. Drugs which kill malaria
parasites in the blood are called blood-stage schizonticides and those that kill them in the
liver are called tissue schizonticides. A clinical cure refers to the elimination of parasites from
the blood, which will relieve the signs and symptoms of disease. A radical cure is the
eradication of all parasites from the body, both blood and liver. In cases of P falciparum and
P malariae, which do not have latent liver forms (hypnozoites), an effective dose of a blood
schizonticide to which the parasite is sensitive should lead to radical cure. In cases of P vivax
andPovale malaria, which do form hypnozoites, radical cure requires therapy with both a
blood schizonticide and a tissue schizonticide.

Recurrence of malaria infections after treatment is due either to recrudescence or to relapse.

Recrudescence occurs when the blood schizonticide does not eliminate all parasites from the
blood stream, either because the dose was inadequate or because the parasite is resistant to
the drug. Relapse occurs in P vivax and P ovale infections after the delayed development of
liver- stage parasites that have not been treated adequately with a tissue schizonticide.

Resistance of malaria parasites to antimalarials may be complete or relative; relative

resistance can be overcome by raising the dose of the antimalarial.
The choice of blood schizonticide depends upon the clinical condition of the patient,
infecting species and possibility of drug resistance. Parenteral therapy is reserved for
patients unable to take medications by mouth and for those with complicated malaria.

Chloroquine-resistant P falciparum is widespread and currently exists in all malarious areas

of the world except Mexico, Central America, the Caribbean and parts of the Middle East. P
falciparum resistant to multiple drugs is most prevalent in S.E. Asia but is also present in
Africa and Brazil. Chloroquine-resistant P vivax is prevalent on the island of New Guinea.
Primaquine-resistant P vivax is most prevalent in S.E. Asia and Oceania and is reported from
other areas. Drug resistance has not been reported for P ovale or P malariae.

If ever in doubt as to infecting species or presence of resistance, clinicians should assume the
infection to be chloroquine-resistant P falciparum. Such therapy will cover all malaria
species, although side effects may be more common.

The response to antimalarial therapy is monitored both clinically and by examining repeated
blood films. Blood smears should be continued daily in all malaria patients until parasites are
no longer detected. In severe or complicated malaria, parasitemia should be evaluated twice
daily. Parasitemia should decrease by 75% and clinical status improve within 48 hr after
initiating therapy. If not, drug resistance, inadequate drug levels or the presence of clinical
complications should be suspected.

Treatment of Specific Infections

Uncomplicated, chloroquine-sensitive infections

All patients with uncomplicated P malariae, P ovale,and P vivax and P falciparum from
chloroquine sensitive areas should be treated with oral chloroquine. The drug is highly
effective, well tolerated and inexpensive.

Uncomplicated, chloroquine-resistant P falciparum

Therapy of chloroquine-resistant P falciparum is complicated and depends primarily on area

of disease acquisition. Patients with uncomplicated disease acquired in areas of chloroquine
resistance can be treated with one of several regimens effective against chloroquine-resistant
parasites. In the United States, two regimens are used primarily: (1) mefloquine alone, or (2)
quinine, plus doxycycline or pyrimethamine/sulfadoxine (FansidarR). Other effective drugs
include halofantrine, artemisinin (qinghaosu) derivatives, and clindamycin. Halofantrine and
artemisinin are used widely overseas but are not currently available in the U.S.

Uncomplicated, chloroquine-resistant P vivax

Chloroquine-resistant P vivax is highly prevalent on the island of New Guinea (Papua New
Guinea and Irian Jaya, Indonesia) and may be present elsewhere. Recent studies in Indonesia
have shown halofantrine, and chloroquine plus primaquine to be highly effective against
these resistant strains. Although not specifically tested, the above regimens for chloroquine-
resistant P falciparum should also be effective.

Complicated infections

Severe or complicated malaria is a medical emergency. It is caused almost exclusively by P.

falciparum. Patients with complicated malaria (see Clinical Manifestations above) should be
treated with intravenous antimalarials and in an intensive care unit whenever possible. The
drugs of choice are intravenous quinidine or quinine (IV quinine no longer available in the
U.S.). Patients on these regimens must be observed closely for signs of hypotension or
myocardial conduction abnormalities. Therapeutic plasma levels are 5 to 15 μg/ml for quinine
and 5 to 10 μg/ml for quinidine. Oral quinine, plus doxycycline or FansidarR, is substituted as
soon as there is clinical improvement. If acquired in an area of chloroquine-sensitive
parasites, parenteral chloroquine may also be given. Artemisinin compounds show promise
for therapy of severe malaria because they decrease parasitemia faster than all other
antimalarials.

Any complicated P malariae, P vivax, or P ovale infection should be treated in the same way
as a complicated P falciparum infection, since mixed infections are common.

Radical cure of P vivax and P ovale infections

For infections due to P vivax or P ovale, primaquine should be given after therapy of the
blood-stage infection to eradicate hypnozoites of these species and prevent relapses. P vivax
with decreased sensitivity to primaquine is prevalent in SE Asia and Oceania, where up to
30% of cases relapse after the standard regimen of 15 mg/day primaquine base for 14 days,
and is reported from other areas. Resistance is usually relative and most initial failures
respond to 30 mg/day for 14 days. Primaquine should be used with caution in persons who
are G6PD deficient due to its potential to cause severe hemolysis.

Ancillary Therapy and Treatment of Complications

Supportive care and therapy of malaria complications may be as critical as choosing the
correct antimalarial. Clinicians should monitor patients for complications (see Clinical
Manifestations) and treat them as they occur.

Hyperthermia should be treated with cooling blankets and antipyretics. Proper fluid
management is essential to prevent renal failure or pulmonary edema. If oliguric renal failure
persists after fluid status is corrected, the patient is treated like other patients in the oliguric
stage of acute tubular necrosis. Pulmonary edema, which may present like the adult
respiratory distress syndrome (ARDS), is an uncommon but frequently fatal complication of
severe P falciparum infection. It is treated by careful fluid management and application of
the principles used in treating ARDS. Transfusion of erythrocytes may be necessary for
severe anemia. Seizures are frequent with cerebral malaria and should be treated with
standard anticonvulsants. Corticosteroids are of no benefit in the therapy of cerebral malaria.
Hyperparasitemia may be treated with exchange transfusion. Exchange transfusion is
generally reserved for individuals with more than 15 percent parasitemia or more than 5
percent parasitemia with cerebral malaria or other severe manifestation. Plasma glucose
levels should be monitored regularly and hypoglycemia treated if it occurs. Aspiration
pneumonia may occur when unconscious cerebral malaria patients suffer seizures and
vomiting. Aspiration is prevented by controlling seizures and by attention to general airway
management in the unconscious patient. Gram-negative bacteremia is a frequent
accompaniment of severe P falciparuminfection. Gram-negative organisms probably enter
the circulation in areas of the bowel wall that are ischemic as a result of microcirculatory
obstruction by parasitized erythrocytes. Any patient who is not responding to antimalarial
therapy as expected should be investigated for bacteremia. Hypotension and shock may
complicate severe malaria. If these occur, treatable causes should be considered, including
Gram-negative sepsis, gastrointestinal hemorrhage, hypovolemia, and splenic rupture.
Splenic rupture is seen infrequently but is one of the few fatal complications of vivax malaria.

Recent studies have found a strong association between sustained lactic acidosis and poor
outcome in severe malaria. Until further work defines the role of specific interventions (e.g.,
sodium dichloroacetate and sodium bicarbonate) in reversing lactic acidosis in severe
malaria, treatment must be aimed at the correction of defects in oxygenation and tissue
perfusion and metabolic abnormalities such as hypoglycemia.

Special Conditions

Malaria during pregnancy presents a unique problem. Pregnant women are at higher risk of
developing severe and fatal malaria. Hyperparasitemia, hypoglycemia and pulmonary edema
are more common in pregnant women with P falciparum infections. Pregnant women should
be treated promptly with appropriate doses of antimalarials. Quinine does not appear to
induce labor as was once thought. Pregnant women with chloroquine-sensitive P vivax
infections should be treated with chloroquine to eliminate the erythrocytic-stage infection
and then placed on weekly chloroquine to prevent relapse, as the safety of primaquine in
pregnancy is not known.

Prevention of Malaria

Individuals with little or no previous exposure who develop malaria may rapidly progress to
severe, often fatal disease. Most cases of malaria in Americans can be prevented by
chemoprophylaxis and by avoiding the mosquito vector.

The female Anopheles mosquito feeds from dusk until dawn. During these hours, individuals
should avoid contact with the mosquito by wearing protective clothing, using an insect
repellent containing N,N-diethyl-l-m-toluamide (DEET), staying in screened areas and
spraying these areas with pyrethrumcontaining insecticides, and by sleeping under
insecticide-impregnated bednets.
Travelers to endemic areas should be advised not only on avoiding the mosquito vector but
also on chemoprophylaxis. It must be emphasized that chemoprophylaxis is not one hundred
percent effective; regardless of prophylaxis, malaria must be considered in the differential
diagnosis of any febrile illness in an individual who has been in an area endemic for malaria
within the last 2–3 years.

Chemoprophylaxis is designed to kill the parasite after it has gained access to the body but
before it leads to the rupture of host RBCs, which causes the symptoms of malaria. Drugs
may accomplish this by attacking the parasite in either the liver or the blood. Causal
chemoprophylaxis refers to killing the parasite in the liver before it gains access to the blood.
Suppressive chemoprophylaxis is accomplished by drugs which attack asexual parasites in
the blood. Most antimalarial drugs attack parasites in the blood and are therefore
suppressive chemoprophylactics. Primaquine is the only antimalarial drug currently available
which reliably kills liver stage organisms.

The choice of a chemoprophylactic regimen depends on several factors: the health of the
individual (including factors such as pregnancy, age, and chronic illness); the risk and types of
malaria in the areas to be visited; and the presence of drug-resistant P falciparum.

Chloroquine is the recommended chemoprophylactic for those travelling to areas where

plasmodia are still chloroquine sensitive (Mexico, Central America, Haiti, the Dominican
Republic, and the Middle East). There are very few contraindications to chloroquine. Most
travellers, however, visit areas where there is chloroquine resistance and other drugs,
generally with greater toxicity, must be used. For most of these travelers, mefloquine is the
drug of choice and doxycycline is as acceptable alternative. Extensive mefloquine resistance
makes doxycycline the drug of choice for those visiting the borders of Thailand. Chloroquine
plus proguanil (proguanil is not available in the U.S.) is another possible regimen for
chloroquine-resistant areas, but this regimen is much less effective than mefloquine or
doxycycline. Recent work also suggests that primaquine, apparently acting against liver-stage
organisms, is as effective as mefloquine and doxycycline for chemoprophylaxis in areas of
chloroquine resistance.

Prophylaxis with chloroquine or mefloquine should begin 2 weeks before entering the
malarious area (to ensure tolerance to the drug and to provide adequate blood levels) and
should continue throughout the stay in the area and for 4 weeks after leaving. Doxycycline
should be started 1 to 2 days before travel to a malarious area and should be taken daily
during the stay in the area and for 4 weeks after leaving. Taking the drugs after leaving the
malarious area is referred to as terminal prophylaxis and is necessary to kill organisms which
emerge from the liver after the person returns home. When there has been a significant risk of
exposure to P vivax or P ovale, primaquine should be taken for 14 days after returning home
to eliminate remaining liver stage parasites. Primaquine may be taken any time during the 4
weeks in which the blood schizonticide is being taken.
References
1. Beadle C, Long GW, Weiss WR. et al. SL Diagnosis of malaria by detection of Plasmodium
falciparum HRP-2 antigen with a rapid dipstick antigen-capture assay. Lancet.
1994;343:564.[PubMed]
2. Bruce-Chwatt LJ: Essential Malariology, 3rd ed. Edward Arnold, Boston, 1993.
3. Centers for Disease Control: Health Information for International Travel 1993. HHS
Publication (CDC) 938280. Washington, DC, 1993 .
4. Good MF, Saul AJ,(eds.) Molecular Immunological Considerations in Malaria Vaccine
Development. Boca Raton, CRC Press: 1993 .
5. Hoffman SL. Diagnosis, Treatment and Prevention of Malaria. Med Clin North Am.
1992;76:1327.[PubMed]
6. Kozarsky PE, Lobel HO. Antimalarial agents: are we running out of options? Curr Opin
Infect Dis. 1994;7:701.
7. Mendis KN, Carter R. Clinical Disease and Pathogenesis in Malaria. Parasitol Today.
1995;11:2–15.[PubMed]
8. Tanner M, Teuscher T. Alonso PL. SPf66 - The first malaria vaccine. Parasitol Today.
1995;11:10.[PubMed]
9. Warrell DA, Molyneux, Beales PF, eds. Severe and Complicated Malaria. Trans R Soc Trop
Med Hyg 84 (Suppl 2):1-65, 1990 . [PubMed]