MALARIA

ILOs

At the end of this session, the student will be able to:

▪ Recognize malaria as a potentially fatal vector borne disease with an epidemiological
significance.
▪ Understand life cycle of malaria in both vector and human.
▪ Grasp knowledge about the geographical distribution of different malaria species.
▪ Understand that life cycle of malaria varies according to etiological species.
▪ Consider malaria for any patient with fever, fatigue and hemolysis with history of
visiting an endemic area.
▪ Recognize the different stages of malaria presentation.
▪ Recognize malaria complications.
▪ Plan chemoprophylaxis according to areas of drug resistance.
▪ Interpret blood film and serological test results to establish diagnosis by the different
species of malaria.
▪ Develop treatment strategy based on malaria species as well as areas of drug resistance
and sensitivity.

INTRODUCTION

Malaria is an acute and chronic disease caused by obligate intracellular protozoa of

the genus Plasmodium. Historically, four species of malaria parasites were
considered capable of infecting humans: Plasmodium falciparum, Plasmodium
vivax, Plasmodium ovale and Plasmodium malariae; however, recently, a fifth –
Plasmodium knowlesi – has been recognized as a significant human pathogen.

The majority (56%) of malaria infections are in sub-Saharan Africa, followed by

Southeast Asia (27%), the Eastern Mediterranean (12%) and South America (3%)
[3]. The parasites are transmitted to humans by female Anopheles mosquitos. The
clinical presentation is highly variable but is generally characterized by an
undifferentiated febrile illness with headache, chills and rigors, anemia and
splenomegaly.

Plasmodium falciparum is the species most commonly associated with severe and
complicated disease.
Plasmodium vivax is the dominant species found outside of Africa; its distribution
(the Middle East, Asia, the Western Pacific and Central and South America)

P. ovale (primarily West Africa). Plasmodium malariae has a worldwide

distribution, generally in isolated pockets, and, to date, P. knowlesi is restricted to
South and Southeast Asia, primarily in areas harboring macaque monkeys.

In sub-Saharan Africa, nearly all of the malaria-associated morbidity and mortality

is caused by P. falciparum.

Individuals of all ages remain susceptible to infection, but immunity to severe

disease develops over time, the result of repeated exposure to bites from infected
anopheline mosquitoes.

EPIDEMIOLOGY
TRANSMISSION

The epidemiology of malaria is fundamentally determined by the dynamics and

intensity of parasite transmission. Vector abundance and longevity are major
contributors to transmission rates and these are strongly influenced by temperature,
rainfall and humidity.

Malaria transmission is also influenced by climate. The optimal conditions occur

when the temperature is between 20°C and 30°C and the mean relative humidity is
at least 60%. Sporogony does not occur at temperatures below 16°C or higher than
33°C. Water temperatures regulate the duration of the aquatic cycle of the
mosquito vector. A high relative humidity increases mosquito longevity and
therefore increases the probability that an infected mosquito will survive long
enough to become infective.

The proximity of human habitation to breeding sites directly influences vector-

human contact and, therefore, transmission. The stability of breeding sites is
influenced by water supply, soil and vegetation.

Irrigation schemes, dams and other man-made changes affecting land use can
radically alter stable patterns of malaria transmission.
ACQUIRED IMMUNITY

The incidence and prevalence of malaria illness is determined largely by acquired

immunity. The burden of disease and death is borne by non-immune individuals. In
areas of stable transmission (e.g. most of sub-Saharan Africa), young children are
the non-immune individuals at risk of life-threatening malaria. Older children and
adults are “semi-immune”; their malaria infections may be asymptomatic or they
may develop uncomplicated malaria illnesses.

Pre-patent period: the time from inoculation of sporozoites from mosquitoes until
asexual erythrocytic stage parasites are detected by microscopy in the bloodstream.
This measure can be influenced by the parasite detection technique (PCR > rapid
diagnostic tests > microscopy).

Incubation period: the time from inoculation of sporozoites from mosquitoes until
an individual develops clinical signs or symptoms of malaria – this is always
longer than the pre- patent period, but the time difference is determined by immune
status. Non-immune individuals develop symptoms with low parasitemias, so the
incubation period is shorter than in semi-immune individuals, who may be able to
tolerate significant parasitemias without becoming symptomatic.

Recurrence: repeat intra-erythrocytic infection causing malaria-associated

symptoms.

Relapse: a recurrent infection caused by a new brood of blood-stage parasites

emerging from hypnozoites in the liver (P. vivax, P. ovale).

Recrudescence: a recurrent infection caused by the growth of an undetectable

blood stage infection (generally the result of drug resistance, unusual
pharmacokinetics or an incomplete dose). It can also occur in
immunocompromised individuals, most famously with P. malariae.

Re-infection: a recurrent infection caused by new exposure to infective

mosquitoes, best differentiated from recrudescence by molecular methods.
INNATE IMMUNITY

On a population level, several genetic polymorphisms and mutations conferring

risk or protection have been identified; most involve mutations in the alpha or beta
chain of hemoglobin (hemoglobinopathies), such as sickle cell anemia and trait, the
thalassemias, hemoglobin C, red blood cell enzyme deficiencies, such as glucose 6
phosphate deficiency (G6PD), Individuals with sickle cell trait (HbAS) are less
likely to develop severe malaria once infected than are individuals who are
homozygous (HbAA).

NATURAL HISTORY, PATHOGENESIS AND PATHOLOGY

Malaria is usually transmitted during the bite of an infected female Anopheles
mosquito or, more rarely, through the direct inoculation of infected red blood cells
(i.e. congenital malaria, transfusion malaria and malaria from contaminated
needles).

LIFECYCLE

Infection begins when sporozoites in mosquito saliva enter the blood stream and,
within 30 minutes, have invaded hepatocytes.

The duration of the asexual replication phase inside the hepatocytes varies from
11–12 days in P. falciparum, P. vivax and P. ovale, to 35 days in P. malariae. The
nucleus undergoes repeated division, resulting in the formation of thousands of
uninucleate merozoites. the host is asymptomatic.

In P. falciparum and P. malariae infections, the liver tissue schizonts/ meronts

rupture at about the same time and none persists in the liver. In contrast, P. vivax
and P. ovale have two types of exoerythrocytic forms: a primary type develops and
ruptures within 6–9 days; the secondary type – the hypnozoite – may remain
dormant in the liver for weeks, months, or up to 5 years before developing, and
causing relapses of erythrocytic infection unless the patient is treated with
primaquine – a drug that targets this lifecycle stage.

Plasmodium falciparum and P. knowlesi are capable of invading erythrocytes of

any age, but P. vivax and P. ovale selectively invade reticulocytes. Serial cycles of
asexual replication take place in erythrocytes and, again, the duration varies with
the species, ranging from 24 hours in P. knowlesi to 48 hours in P. falciparum, P.
vivax and P. ovale, and 72 hours in P. malariae.

The youngest stages in the blood are small, rounded trophozoites, known as ring
forms. As they grow, they become more irregular and ameboid. During
development, the parasites consume hemoglobin leaving an iron-containing
compound known as hematin or hemozoin as the product of digestion; it is visible
in the cytoplasm of the parasite as dark granules. The schizont/meront stage begins
when the parasite undergoes nuclear division and culminates in segmentation to
form merozoites.

In response to a variety of stimuli, some parasites undergo gameto- cytogenesis.

When male and female gametes are ingested by a female anopheline taking a blood
meal from a human host, the sexual replication phase of the malaria parasite
ensues, starting in the mosquito mid-gut and ending in the salivary glands. The
erythrocytic lifecycle continues until it is abrogated by effective chemotherapy or
reined in by the host’s acquired immunity.

The life cycle of P. falciparum differs from the other four human malaria parasites
in one important respect: during the latter half of the intra-erythrocytic cycle,
mature falciparum-infected red blood cells (schizonts) effectively disappear from
the peripheral blood.

Mode of transmission

1. Bite of the female Anopheles mosquito. Sporozoites present in the salivary

gland are injected with the saliva into the skin of man. This is the main route
of infection.
2. Blood transfusion can transmit the infection. In this condition erythrocytic
stages are passed from infected blood to the recipient, initiating immediately
the erythrocyte cycle. The shared use of needles or syringes contaminated
with infected blood can also transmit malaria.
3. Congenital malaria has been reported in Africa.
CLINICAL FEATURES
Incubation period

• Parasitological incubation period (pre-patent period) is the minimum time

between the entry of the sporozoites and the first appearance of parasites in
the red blood cells. It varies from 6 to 20 days.

• Clinical incubation period is the interval between the entry of sporozoites

and the first clinical manifestation. This varies according to the species of
malaria from 8 to 24 days.

PRODROMAL SYMPTOMS

Some patients have vague prodromal symptoms, such as malaise, myalgia, low
back pain, headache, anorexia and mild fever, before parasitemia can be detected
by the usual microscopic techniques. These manifestations may persist for 2–3
days before an acute paroxysm begins. The incubation period, or time from
exposure to onset of symptoms, can be prolonged by partial immunity and/or by
chemoprophylaxis.

PERIODICITY

1. Plasmodium vivax:Causing benign tertian malaria.

2. Plasmodium ovale: Causing benign tertian malaria or ovale malaria.
3. Plasmodium malariae:Causing quartan malaria.
4. Plasmodium falciparum: Causing sub-tertian or malignant malaria.
5. Plasmodium knowlesi: Plasmodium species of monkeys is now recognized
as a significant pathogen of humans in South-East Asia.

UNCOMPLICATED MALARIA

Uncomplicated malaria illness is by far the most common clinical manifestation of

a malaria infection and fever, or history of fever, is the most common symptom.
There are no pathognomonic signs by which “uncomplicated malaria” can be
distinguished from common viral causes of fever. The presence of malaria
parasitemia increases the odds of a causal connection, especially in non-immune
individuals. In practical terms, symptomatic, parasitemic individuals who are alert
enough to take oral medications are considered to have “uncomplicated malaria”.

Common presenting signs are generalized constitutional symptoms including fever,

chills, dizziness, backache, myalgia, malaise and fatigue (frequently summarized
as “total body pain” by endemic-area adults). Gastrointestinal symptoms (i.e.
anorexia, nausea, vomiting, abdominal pain and diarrhea) can be prominent,
causing confusion with gastroenteritis. Patients may have nonproductive cough and
dyspnea, consistent with acute respiratory infections. Young children and semi-
immune adults may present with only fever and headache.

Malarial paroxysms
These occur due to rupture of erythrocytic schizonts. At first the malarial
paroxysms are irregular, then, they become regular and synchronized.
Malarial paroxysms are characterized by three stages:

• Cold stage: The patient shivers and his temperature rise sharply. This lasts
from half an hour to two hours.

• Hot stage: The patient is flushed, with a high temperature, dry skin and
congested conjunctiva. It lasts from four to six hours.

• Sweating stage: There is rapid drop of temperature and marked sweating.

It lasts from two to three hours.

The paroxysms are repeated every third day (tertian) in P. vivax and P. ovale
or every fourth day (quartan) in P. malariae. In P. falciparum, fever is more
or less continuous, daily (subtertian) or, every third day.

LABORATORY FINDINGS
Anemia, leukopenia and thrombocytopenia are usual.

The reticulocyte count is normal or depressed, despite the hemolysis, and becomes
elevated usually 5–7 days after the parasitemia has cleared.

Urinalysis reveals albuminuria and urobilinogen; increased conjugated bilirubin is

present in many patients.
Some patients are jaundiced and concomitant abnormalities in liver function tests
may cause diagnostic confusion with viral hepatitis. Serum alanine
aminotransferase (ALT) and aspartate transaminase (AST), are usually elevated.
Both the direct and the indirect bilirubin can be elevated.

Prothrombin times can be prolonged.

Malarial relapse and recrudescence

• Malarial relapse is the reappearance of the clinical manifestations after a
period of apparent cure with complete initial clearing of organisms from the
peripheral blood. It occurs due to activation of hypnozoites. Thus, they occur
only in P. vivax and P. ovale. Relapses occur weeks or months or even years
after the primary infection. The symptoms of a relapse start more abruptly
than in the primary infection as the infection is more synchronous.
Primaquine will eradicate hypnozoites in over 80% of patients but if it is not
given, relapse occurs in approximately half of those infected.

• Recrudescence is reappearance of malarial signs and symptoms in

patients whose blood stream infection has been previously at a low level
thus not initiating a malarial paroxysm. It can occur with the four species of
malaria. In P. malariae, they may recur even after too many years of
infection. It is attributed to incomplete treatment in P. falciparum and these
tend to arise 2-4 weeks following treatment.

COMPLICATED MALARIA
• Severe malaria

Death from acute P. vivax, P. ovale, and P. malariae infection is very rare.
On the contrary falciparum malaria is a potentially lethal infection. Severe
malaria occurs in P. falciparum due to blocking of the fine capillaries of
internal organs resulting in

• Cerebral malaria: Poor prognostic features on admission as deep coma,

convulsions, extensor posturing, hyperventilation, hypoglycemia,
hyperparasitemia, predominance of mature parasites on the peripheral blood
smear.
 • METABOLIC ACIDOSIS

Capillary blood pH <7.3, plasma bicarbonate <15 mmol/L or plasma lactate

concentrations >5 mmol/L are all associated with severe disease and with poor
outcomes. Acidosis, manifested clinically as abnormally deep breathing is a poor
prognostic feature in parasitemic children with or without neurologic compromise.

• SEVERE ANEMIA
• RESPIRATORY FAILURE

Respiratory failure associated with ARDS can develop rapidly; clinically it is

indistinguishable from the ARDS that develops as a result of septicemia, toxic
inhalants or other causes. Patients become hypoxemic and may require
mechanically-assisted ventilation. Aggressive management of malaria-associated
ARDS should be used wherever available.

• ALGID MALARIA

The majority of patients with severe malaria remain well perfused, but a small
proportion develop algid malaria – defined as low blood pressure, cold and
clammy extremities, hypoglycemia and acidosis. In most cases, this represents
septic shock and pathogens are cultured from the blood. The judicious
administration of antibiotics, fluids and inotropes is recommended for this small
group of patients. The sudden onset of hypotension in a patient with vivax malaria
should prompt consideration of splenic rupture or subcapsular bleeding.

• Hypoglycemia equal to or less than 40mg/dl

• Renal impairment
• Non cardiogenic pulmonary oedema

Black water fever: is the massive intravascular hemolysis releasing hemoglobin

directly into the blood vessels and into the urine (black urine). This condition is
associated with high mortality. Half of these deaths were caused by renal failure.
The most probable explanation for black water fever is an autoimmune reaction of
the body against the parasitic interaction, severe infections, or inorganic drug
reactions

• Other complications are bacterial superinfection and patient is predisposed

to Salmonella septicemia.
 • ACUTE RENAL FAILURE

Acute renal failure is another complication that is far more common among adults
than among children; it is also more common in patients with hemoglobinuria
(“blackwater fever”). Acute renal failure can also result from acute tubular necrosis
-a sequelae of reduced renal perfusion-. Anuria is a poor prognostic sign and
hemoperfusion, renal or peritoneal dialysis are often necessary. but, as in cerebral
malaria, renal abnormalities are reversible and patients appropriately supported
through the critical period often enjoy a full recovery.

• Quartan malarial nephropathy

Chronic or repeated infections with P. malariae may cause soluble immune

complex injury to renal glomeruli resulting in the nephrotic syndrome. The
pattern of renal involvement varies from asymptomatic proteinuria to full-
blown nephrotic syndrome. Oedema, ascites, or pleural effusions are the
usual presenting features. Quartan nephropathy usually does not respond to
treatment with either antimalarial agents or glucocorticoids and cytotoxic
drugs.

• POST-MALARIA NEUROLOGIC SYNDROME

▪ This is a rare transient neurologic syndrome, reported most commonly in

non-immune travelers after a successfully treated episode of severe
falciparum malaria.
▪ The onset is generally within 1–2 weeks of recovery, but can be as long as 2
months after.
▪ The clinical features range from confusion and tremors, to aphasia, seizures,
ataxia, psychosis and impaired consciousness.
▪ There may be a lymphocytic pleocytosis in the CSF; imaging studies may or
may not show nonspecific white matter changes.
▪ The symptoms are generally self-limiting; steroids have been used with good
results in some patients.

• TRANSFUSION MALARIA

Any of the five species of human malaria can be transmitted directly from an
infected blood donor, accidental infection by a contaminated needle, or from
infected intravenous drug users sharing needles. The incubation period following
infection is as short as a few days for P. falciparum, but can be up to 40 days or
longer for P. malariae.

Diagnosis
BLOOD FILMS

The gold standard of malaria diagnosis remains the blood film.

Parasites can be counted as a percentage of red cells on a thin film, or against white
blood cells on a thick film. Blood can be stained with Giemsa, Leishman, Field or
Wright’s stains.

The most important initial distinction is to determine whether malaria parasites are
present: for this, a thick film is most efficient. Species identification is best done
on thin films. The golden brown malaria pigment (hemozoin) in monocytes or
leukocytes suggests a current or recent malaria infection, even in the absence of a
patent parasitemia.

• Quantitative Buffy Coat Technique (QBC).

• Sternal puncture (Bone marrow biopsy).
• IHAT, IFAT or ELISA tests can be used, especially in cases of blood
donors, to prevent the spread of malaria by blood transfusion.
• Immunodiagnostic dipstick techniques (IDST) can be used for detecting
parasite antigens in the peripheral blood.
• Polymerase chain reaction (PCR) to detect the parasite DNA in blood.

TREATMENT OF MALARIA
Treatment of acute malaria attack

Once the diagnosis of malaria has been made, appropriate antimalarial treatment
must be initiated immediately. Treatment should be guided by the following four
main factors:

• Infecting Plasmodium species.

• Clinical status of the patient; patients diagnosed with malaria are generally
categorized as having either uncomplicated or severe malaria.
 • Expected drug susceptibility of the infecting parasite as determined by the
geographic area where the infection was acquired.
• Previous use of antimalarials, including those taken for malaria
chemoprophylaxis.

• The treatment regimen should not involve the drug or drug combination used
for prophylaxis.

Recommended treatment of uncomplicated malaria

Chloroquine sensitive malaria

For all chloroquine sensitive plasmodium species, chloroquine or

hydroxychloroquine.

Chloroquine resistant malaria

Treatment is intended for chloroquine resistant P.falciparum, chloroquine

resistant P.vivax and unidentified species.

• The first line of treatment is Atovaquone-proguanil or Artemether-

lumefantrine.
• The second line of treatment includes quinine sulfate in combination with
doxycycline, tetracycline, or clindamycin.
• Mefloquine is recommended only when drugs of the first and second line
cannot be used.

For pregnant patients, Artemether-lumefantrine should be avoided in the 1st

trimester while quinine in combination with tetracycline or doxycycline and
atovaquone – proguanil should be avoided in all trimesters.

For P.vivax or P.ovale, additional treatment with primaquine or tafenoquine is

considered to eradicate the hypnozoites.

Recommended treatment of severe malaria

Intravenous artesunate is the treatment of choice for severe malaria in children and
adults. However, intravenous quinine is also an effective alternative if artesunate is
not available. When the patient is well enough to take oral medication, treatment
should be completed with a full course of oral antimalarial drugs.
P. falciparum

WHO-recommended artemisinin-based combination therapy (ACT):

• Artemether + lumefantrine (AL) Given at 0, 8, 24, 36, 48 and 60 hours:

5–15 kg: 1 tablet

16–25 kg: 2 tablets
26–35 kg: 3 tablets
>35 kg: 4 tablets (adult dose)

• Artesunate + amodiaquine (AS + AQ)

4 mg/kg/day AS and 10 mg/kg/day AQ daily for 3 days
• Artesunate + mefloquine (AS + MQ)

4 mg/kg/day AS daily for 3 days. MQ can be taken as 15 mg/kg on day 1 and 10

mg/kg on day 2, or as 8.3 mg/kg/daily for 3 days

• Artesunate + sulfadoxine-pyrimethamine (AS + SP)

4 mg/kg AS daily for 3 days; 25 mg/1.25 mg/kg SP on Day 1
• Other options:
Chloroquine (if known to be chloroquine sensitive) Adults: 600 mg base
(=1000 mg salt) p.o., followed by 300 mg base (=500 mg salt) p.o. at 6, 24
and 24 hours

Children: 10 mg base/kg p.o., followed by 5 mg base/kg p.o. at 6, 24 and 48 hours

• Oral quinine sulfate plus doxycycline, tetracycline or clindamycin.

Chloroquine can cause significant pruritus in dark-skinned individuals.

Overdoses (>2 g) can be fatal; adrenaline and diazepam are antidotes.

Bitter taste
Frequent dosing needed because of a short half-life Cinchonism: tinnitus, nausea,
headaches, dizziness and disturbed vision.

Overdosing leads to cardiotoxicity, more so with quinidine.

Quinine sulfate: 542 mg base (= 650 mg salt) p.o. three times a day for 3 days (7
days for infections acquired in Southeast Asia).

Doxycycline: 100 mg p.o. twice a day for 7 days.

Tetracycline: 250 mg p.o. four times a day for 7 days.

Clindamycin: 20 mg base/kg/day, p.o., divided three times a day for 7 days.

Rapid IV or IM administration can precipitate hypoglycemia. Doxycycline and

tetracycline are not recommended during pregnancy or in children under the age of
8 years.

Clindamycin is recommended for these two groups. Doxycycline should be taken

with food to minimize the risk of esophageal erosions.

Both drugs may cause photosensitivity and disrupt normal flora enough to
precipitate vaginal yeast infections.

Atovaquone-proguanil
Adult tablet: 250 mg atovaquone, 100 mg proguanil.

Pediatric tablet: 62.5 mg atovaquone, 25 mg proguanil.

▪ 5–8 kg: two 25-mg pediatric tablets daily for 3 days.

▪ 9–10 kg: three 25-mg pediatric tablets daily for 3 days.
▪ 11–20 kg: one adult 100-mg tablet daily for 3 days.
▪ 21–30 kg: two adult 100-mg tablets daily for 3 days.
▪ 31–40 kg: three adult 100-mg tablets daily for 3 days.
▪ >40 kg: four adult 100-mg tablets daily for 3 days.

Mefloquine
Adults: 684 mg base (= 750 mg salt) p.o., followed by 456 mg base (= 500 mg salt)
p.o., 6–12 hours later.

Children: 13.7 mg base/kg (= 15 mg salt/kg) p.o., followed by 9.1 mg base/kg (=

10 mg salt/kg) p.o., 6–12 hours later.

Atovaquone targets an element of the parasite electron transport chain and is thus
well-tolerated by the host.
Proguanil interferes with folate metabolism and has been associated with aphthous
oral ulcers.

Side effects include vomiting, dizziness, and exacerbation of cardiac conduction

abnormalities.

Not recommended for individuals with a history of psychiatric disorders.

May disrupt sleep or cause vivid dreams.

Primaquine is contraindicated in individuals with G6PD deficiency and during

pregnancy.

Malaria infection as a result of blood transfusion or organ transplantation does not

require radical cure.

Primaquine is a gametocytocidal drug.

Relapse
Both P. vivax and P. ovale have a tendency to relapse after resolution of the
primary infection. Relapse, which results from maturation of persistent
hypnozoites in the liver, must be distinguished from recrudescence of the primary
infection because of incomplete treatment. P. falciparum is the usual cause of
recrudescent.

(but this can be as long as 10 weeks following mefloquine treatment). Relapses

occur weeks or months (or even years) after the primary infection.

Chemoprophylaxis
When prescribing antimalarial prophylaxis to travelers, it is important to
emphasize that no antimalarial is completely effective, and that a febrile illness
could still be malaria

It is essential that prophylaxis is taken regularly, and for most drugs continued for
4 weeks after leaving the transmission area. The need to take the drugs for a month
after leaving the transmission area is to ‘catch’ any parasites acquired shortly
before departure when they leave the liver. But drugs acting on the liver stages
(atovaquone-proguanil, primaquine) can be stopped immediately (many advocate
continuing for 1 week after exposure to ensure prevention).
This is a particular advantage for travelers visiting a malarious area for a short
time. It is prudent to begin prophylaxis 1 week before departing for a malarious
area so that tolerance to the drug regimen can be assessed, and therapeutic
concentrations are present on arrival. In some situations where the risks of
acquiring vivax malaria are high (such as in military personnel), a full 2-week
course of primaquine is given on leaving the endemic area. This is called ‘terminal
pro- phylaxis’ and aims to eradicate hypnozoites. In anglophone countries,
chloroquine is prescribed weekly, but in francophone countries it is given once
daily (this is theoretically preferable).

Mefloquine and pyrimethamine-dapsone are taken once a week and proguanil,

atovaquone-proguanil, primaquine and doxycycline daily. Amodiaquine, quinine,
sulphadoxine-pyrimethamine and the artemisinin drugs should not be used for
prophylaxis

Chemoprophylaxis Choices
The three most commonly prescribed medications for chemoprophylaxis are
atovaquone-proguanil, doxycycline, and mefloquine.
Atovaquone-proguanil: Atovaquone-proguanil targets both liver and blood
schizonts and is effective against chloroquine-resistant P. falciparum. Dosing
begins 1 to 2 days before the traveler enters the malarial zone, and one tablet is
taken at the same time each day until seven days after exiting the malarial zone.
The drug is well-tolerated; side effects include gastrointestinal upset, headaches,
and transaminitis. Atovaquone-proguanil is not indicated for pregnant women,
children under 5kg, or patients with creatinine clearance less than 30mL/min.
There is no evidence regarding the clinical impact of co-administering warfarin
and atovaquone-proguanil, but monitoring of the international normalized ratio
may be required.
Doxycycline: Doxycycline targets blood schizonts and is effective against
chloroquine-resistant P. falciparum. The medication is started 1 to 2 days before
travel and continued daily until four weeks after return. Side effects include GI
upset, pill esophagitis, and photosensitivity. Doxycycline is typically the most
inexpensive of the medications.
Mefloquine: Mefloquine targets blood schizonts and is effective against
chloroquine-resistant P. falciparum, though mefloquine resistance has emerged in
parts of Southeast Asia. Travelers begin the medication at least two weeks before
travel and take it weekly until four weeks after return. Neuropsychiatric adverse
effects include seizures and psychosis. Providers should avoid the drug in patients
with these histories as well as recent or active depression, schizophrenia, or
generalized anxiety disorder. Other adverse effects include vivid dreams,
gastrointestinal upset, and headaches. Many prescribers will start the medication 1
to 2 months before travel to assess for these adverse effects.
Primaquine: Primaquine targets liver hypnozoites and can be used as prophylaxis
in areas with only P. vivax. Travelers begin the medication two days before travel
and take it daily until seven days after return. Primaquine is more common as
presumptive anti-relapse therapy (PART), where it is taken daily upon returning
from a P. vivax or P. ovale endemic area in the final 14 days of post-travel
treatment. The exception is when atovaquone-proguanil was used for primary
prevention, in which case primaquine gets administered along with the final seven
days of the primary prevention drug and for an additional seven days. Providers
must test travelers for glucose-6-phosphate dehydrogenase (G6PD) deficiency
before prescribing the medication as it can cause fatal hemolytic anemia. Side
effects consist mostly of gastrointestinal upset. Prophylaxis with primaquine is
currently an off-label recommendation from the CDC.
Tafenoquine: Tafenoquine is active against hypnotize and erythrocytic forms
of Plasmodium species. It also has activity against pre-erythrocytic forms, which
prevents relapses of P. vivax. It is approved for prophylaxis for those over 16 years
old. Dosing is daily for three days before travel to an endemic area, then weekly
until seven days after return from travel. This drug also may cause life-threatening
hemolytic anemia in patients with G6PD deficiency, and testing is essential before
initiating the regimen. There are reports of psychiatric side effects, and use should
discontinue in cases of psychotic symptoms. Other side effects include GI upset,
headache, asymptomatic elevations in methemoglobin levels and epithelial
keratopathy. Because the medication has a half-life of 17 days, delayed
presentations of adverse reactions may occur.
Vaccines
Addressing challenges of long-term immunity and durable protection are all
currently underway. Though researchers have attempted to develop a vaccine for
decades, it has proven difficult due to the complicated lifecycle and antigenic
changes of the protozoa.
Special Populations
Pregnant travelers should generally be counseled to avoid travel to malaria-
endemic areas until after delivery as malaria increases the risk for prematurity,
spontaneous abortion, and stillbirth. Malaria may also be more severe in pregnant
patients. In situations where deferring travel is not possible, mefloquine,
chloroquine, and hydroxychloroquine are safe for pregnancy when accounting for
the usual contraindications and resistance patterns. Doxycycline is contraindicated
in pregnant women due to concerns for fetal dental discoloration and bone growth
inhibition. Atovaquone-proguanil has not been well-studied in pregnant women
and is generally not prescribed in this population. Primaquine should also not be
used in pregnant travelers due to concerns about fetal G6PD deficiency.
Breastfeeding: There is not enough antimalarial drug excreted in breastmilk to
provide chemoprophylaxis to infants. As mefloquine, chloroquine, and
hydroxychloroquine are safe for infants; they are also reasonable during
breastfeeding. Little data exists for doxycycline, but it is generally not
recommended for use in the breastfeeding mother. Atovaquone-proguanil also has
little safety data and is not recommended for prophylaxis in those breastfeeding
infants under 5 kg. Primaquine also has no available data; however, both the
mother and the infant require G6PD deficiency testing before prophylaxis with
primaquine. Tafenoquine is also not recommended due to a lack of data.
Children Atovaquone-proguanil is an option for children over 5 kg. Mefloquine,
chloroquine, and primaquine can be prescribed to children, taking into account the
usual contraindications and resistance patterns. Children under the age of 8 should
not receive doxycycline due to concerns of dental discoloration. Pediatric weight-
based doses should not exceed adult doses and may be tolerated best when mixed
with something sweet to overcome the bitter taste. The medication should also be
taken on a full stomach to reduce the risk of vomiting or other GI upset. Overdose
of antimalarials, especially chloroquine, can be fatal to children - childproof bottles
and regular safety measures are essential.