MANAGEMENT

Approach
Malaria should always be managed in conjunction with an infectious diseases specialist.
Local guidelines will usually have contact details for advice. Most guidelines are similar,
but they will vary to some degree depending on whether drugs are licensed or available.
The following section is based on guidelines from the US Centers for Disease Control
and Prevention (CDC) and the World Health Organization (WHO). [53] [69]
Overview of management
Treatment will depend on the infecting species, the appearance of the blood smear (%
parasitaemia, presence of pre-schizonts or schizonts), and the clinical status of the
patient. Consideration should be given to the likely susceptibility of the parasite to the
treatment used, based on known epidemiology relating to the geographical area where
the infection was acquired. Specific treatment for malaria should not be given until malaria
infection has been confirmed, except in exceptional circumstances. Consequently, the
goal of therapy is to eradicate infection; to reduce the risk of complications by reducing
the parasite load as quickly as possible; and to avoid selecting resistance by using
multiple agents.

Artemisinin derivatives such as artesunate and artemether are extracts of the qinghao
plant ( Artemisia annua ). They have a rapid-onset therapeutic effect by clearing parasites
from the blood, and are currently the most effective antimalarial drugs known. In order to
prevent late recrudescences and emergence of resistance, they must be used in
combination with another drug; [70] oral monotherapy is not
recommended. [71] Artemisinin-based combination therapy (ACT) also reduces
gametocyte carriage and thereby lowers the risk of transmission, which is important in
endemic regions. [72] There is evidence to suggest that they are safe and effective for
uncomplicated malaria in endemic areas and in non-immune travellers. [73] [74] There is
also strong evidence to support the use of intravenous artesunate over intravenous
quinine for severe malaria. [53] However, in many countries these drugs are not available
or licensed (e.g., in the US, intravenous artesunate is available from the CDC malaria
hotline only). There have been reports of severe, often delayed, haemolysis in returning
travellers treated with artemisinins. [75] [76] [77] Based on this finding, European centres
have suggested monitoring haemoglobin levels for 4 weeks in patients treated with
intravenous artesunate. [78]

Plasmodium falciparum malaria is potentially fatal if not treated promptly, as life-

threatening complications can develop quickly in patients who initially appear well, and
even short delays increase morbidity and mortality. [32]This is especially the case in
certain risk groups including non-immune travellers, pregnant women, children, and older
adults. [12] [33] [34] Most authorities recommend that travellers with P falciparum malaria
should be hospitalised for treatment. Several observational studies conducted in centres
with a special interest suggested that falciparum malaria can be managed on an
outpatient basis, though specific criteria for safe outpatient management in a non-expert
setting are unclear. [79] [80] [81] [82] Where outpatient management is planned, daily
review with slide microscopy has been suggested. [78]

Patients with uncomplicated malaria can be treated effectively with oral antimalarial
therapy, but parenteral therapy is recommended if signs of severe malaria are present,
or if the patient is unable to tolerate oral therapy. Supportive care is an important aspect
of therapy, and a period on an intensive care unit is often necessary in cases of severe
malaria.

Non-falciparum malaria, caused by Plasmodium vivax , P ovale , P malariae , or P

knowlesi , is rarely life-threatening and can usually be managed on an outpatient basis
unless comorbidities are present. In infection with P vivax or P ovale , glucose-6-
phosphate dehydrogenase (G6PD) levels should be checked, as primaquine therapy will
be necessary to eradicate hypnozoite forms, and haemolysis may occur in patients who
are deficient in G6PD.

If the species cannot be identified, the patient should be treated as for P

falciparum infection. [69]

General approach to management of severe malaria

Severe malaria is almost always caused by falciparum infection. Patients are classified
as having severe malaria if they have one or more of the following. [53]

Clinical features

 Impaired consciousness (i.e., Glasgow coma score <11 in adults or Blantyre coma
score <3 in children)
 Prostration (i.e., generalised weakness so that the patient is unable to walk or sit
up without assistance)
 Multiple convulsions (more than 2 episodes in 24 hours)
 Deep breathing, respiratory distress (acidotic breathing)
 Circulatory collapse or shock - systolic blood pressure <80 mmHg in adults and
<70 mmHg in children (decompensated shock); capillary refill ≥3 seconds or
temperature gradient on leg (mid-to-proximal limb) without hypotension
(compensated shock)
 Clinical signs of jaundice
 Significant bleeding (e.g., recurrent or prolonged bleeding from gums, nose, or
venepuncture sites; haematemesis; melaena)
 Pulmonary oedema (radiological finding, or oxygen saturation <92% on room air
with a respiratory rate >30 breaths/minute often with chest indrawing and
crepitations on auscultation)

Laboratory findings

 Hypoglycaemia (blood glucose <40 mg/dL [<2.2 mmol/L])

 Metabolic acidosis (plasma bicarbonate <15 mEq/L [<15 mmol/L])
  Severe malarial anaemia (children <12 years of age: Hb ≤5 g/dL or haematocrit
of ≤15%; adults: Hb <7 g/dL or haematocrit of <20%) with a parasite count
>10,000/microlitre
 Serum bilirubin >3 mg/dL [>50 micromol/L] with a parasite count
>100,000/microlitre
 Hyperparasitaemia (>10%)
 Renal impairment (serum creatinine >3 mg/dL [265 micromol/L]).

In non-immune patients (e.g., travellers) and people in low-transmission settings,

parasitaemia >2% is associated with increased risk of severe disease. [53]

Patients with severe disease should be treated aggressively with parenteral antimalarial
therapy and transferred to the intensive care unit for intensive monitoring and
support. [31] Parenteral therapy precludes poor absorption and reduces the parasite load
as quickly as possible. Exchange transfusion for very high parasitaemia is controversial
and is not generally recommended. Delays in antimalarial therapy may increase morbidity
and mortality. [32] Specific regimens are detailed below.

Supportive therapy is vital and is aimed at correcting the above-mentioned complications.

This includes careful fluid management, often with renal support; airway protection;
control of seizures; and transfusion of blood products. Hypoglycaemia may be worsened
by quinine-induced hyperinsulinaemia, so should be monitored closely.

Uncomplicated P falciparum infection: non-pregnant

Chloroquine resistance is widespread in most regions of the world. Therefore, one of the
following oral regimens supported by the CDC or the WHO is recommended: [53] [69]

 artemisinin-based combination therapy (ACT) for 3 days; availability varies, but

the following regimens are recommended:
o artemether/lumefantrine
o dihydroartemisinin (also known as artenimol) plus piperaquine
o artesunate plus mefloquine
o artesunate plus amodiaquine
o artesunate plus sulfadoxine/pyrimethamine
 quinine (for 3 to 7 days, depending on location) plus 1 of the following: doxycycline
or tetracycline or clindamycin (for 7 days)
 atovaquone/proguanil (for 3 days)
 mefloquine (for 2 doses).
All regimens, except mefloquine-based regimens, are recommended equally. Mefloquine-
based regimens should be used only if the other options are not available due to an
increased rate of adverse effects and concerns about longer-lasting or permanent
neuropsychiatrical complications. [83]

Despite the WHO recommending the ACT options above equally, there is some evidence
from African studies that dihydroartemisinin plus piperaquine reduces the overall rates of
treatment failure when compared with artemether/lumefantrine, although failure rates in
general are low (i.e., <5%). [84] [ ] Also, a retrospective comparative analysis in Sweden
found a high rate of symptomatic late treatment failures with artemether/lumefantrine in
non-immune adults, particularly men. The efficacy of this drug was found to be 94.7%,
compared to 99.5% for other oral regimens in this study. [85] Resistance to
dihydroartemisinin plus piperaquine has been reported in Cambodia. [86]

There have been no reports of clinically significant chloroquine resistance in infections

acquired in parts of Central America (west of Panama Canal), Haiti and the Dominican
Republic, and some parts of the Middle East. Infections acquired in these regions may be
assumed to be chloroquine-sensitive and treated with chloroquine (preferred) or
hydroxychloroquine (for a total of 3 doses). This approach is not endorsed in the UK,
where chloroquine is not recommended for the treatment of P falciparum .

In low-transmission areas, the WHO recommend giving a single dose of primaquine with
ACT to to reduce transmission, except in pregnant women, infants aged <6 months, and
women breastfeeding infants aged <6 months. Testing for G6PD deficiency is not
required in these patients. [53] This regimen is thought to rapidly reduce the infectivity
and number of gametocytes available to mosquitoes, and at a population level is a useful
component of pre-elimination or elimination programmes. One study found that a single
dose of primaquine, when used as a gametocytocide, was unlikely to cause serious
toxicity, even in patients with G6PD deficiency.[87] A Cochrane review found that a single
low dose of primaquine (added to ACT) is as effective as higher doses and reduces the
infectiousness of people to mosquitoes at days 3-4 and 8. [ ] There was no evidence of
increased haemolysis at this dose; however, it should be noted that very few patients with
G6PD deficiency were included in the trials. It is unclear whether this would reduce
malaria transmission in communities. [88]

Complicated P falciparum infection: non-pregnant

Severe malaria is a medical emergency. Admission to an intensive care unit should be
considered. Patients with hyperparasitaemia, jaundice, anaemia, and renal impairment
do not necessarily require intensive care; however, such features are often associated
with other complications. Some patients may be able to be managed on an experienced
ward or high care unit. The decision to admit to intensive care should be discussed with
an infectious diseases specialist.

Recommended regimen for severe falciparum infection

 Parenteral artesunate should be given until the patient is able to take oral
treatment (but for at least 24 hours) and parasitaemia has fallen to <1% (usually a
minimum of 3 doses is suggested), followed by 1 of the following oral regimens: a
full course of locally available ACT; atovaquone/proguanil; doxycycline or
clindamycin, with or without quinine; or mefloquine. [53] [69]
 In the US, artesunate is available through the CDC malaria hotline only. If
obtaining the drug delays starting treatment by more than 6 hours, intravenous
quinine (if available) or quinidine should be started in the interim.[69]
Alternative regimens if preferred regimen unavailable

 The CDC recommends intravenous quinine (if available) or quinidine plus 1 of the
following: intravenous doxycycline or clindamycin. Quinine is the preferred option
as it is considered less toxic than quinidine. [53]Intravenous quinine or quinidine
should be continued until parasitaemia is <1% and the patient can tolerate oral
therapy. The patient can then be switched to oral quinine therapy. The patient
should also be switched to oral doxycycline or clindamycin as soon as they can
tolerate oral therapy. [69]
 The WHO recommends intramuscular artemether in preference to quinine if
parenteral artesunate is not available. [53] In areas where parenteral artesunate
is not available, a single dose of rectal artesunate may be administered to children
<6 years of age for pre-referral treatment. [89]

Patients taking parenteral quinidine or quinine should receive a loading dose unless they
have already received quinidine, quinine, or mefloquine in the preceding 12 hours. In
addition, they should be monitored for hypoglycaemia, hypotension, and ECG changes
(widening of QRS complex and prolongation of QTc interval).

In low-transmission areas, the WHO recommend giving a single dose of primaquine with
ACT to to reduce transmission, except in pregnant women, infants aged <6 months, and
women breastfeeding infants aged <6 months. [53] A Cochrane review found that a single
low dose of primaquine (added to ACT) is as effective as higher doses and reduces the
infectiousness of people to mosquitoes at days 3-4 and 8. [ ] There was no evidence of
increased haemolysis at this dose; however, it should be noted that very few patients with
G6PD deficiency were included in the trials. It is unclear whether this would reduce
malaria transmission in communities. [88]

Non-falciparum infection: non-pregnant

The majority of non-falciparum infections are uncomplicated. P malariae , P vivax , P
ovale , or P knowlesiinfection should be treated with oral chloroquine (preferred) or oral
hydroxychloroquine for a total of 3 doses. P knowlesi , which is found in parts of Southeast
Asia, replicates every 24 hours; therefore, rapid diagnosis and prompt treatment of
infection is essential. [90]

Treatment (or prophylactic) failure with chloroquine for P vivax malaria has been
observed in at least 24 countries, particularly in Indonesia and Papua New
Guinea. [91] Patients who do not respond to standard treatment with chloroquine should
use one of the following alternative oral regimens: [53] [69]

 ACT (except artesunate plus sulfadoxine/pyrimethamine)

 quinine plus 1 of the following: doxycycline or tetracycline (for 7 days)
 atovaquone/proguanil (for 3 days).
P vivax and P ovale treatment regimens should be followed by oral primaquine for 14
days to eliminate the hypnozoite stages that are dormant within the liver. The
hypnozoiticidal activity of primaquine is predominantly a function of the total dose
administered. The WHO recognises that a higher dose is needed in Southeast Asia,
where there is a higher rate of relapse than in other areas, and this is also reflected in the
CDC recommendations. [92] Regimens shorter than 14 days have been associated with
an increased rate of relapse.[93] Once-weekly dosing may be as effective as a 14-day
treatment course and may be better tolerated; however, there is currently insufficient
evidence to recommend this regimen.

Primaquine may cause haemolytic anaemia in patients with G6PD deficiency; therefore,
patients must be screened, if possible, prior to starting therapy. There are over 180
different genetic G6PD variants that are found commonly in tropical areas, with gene
frequencies ranging between 3% and 30%. [87] The extent of haemolysis depends on the
degree of G6PD deficiency, as well as the dose and duration of exposure. Two of the
most prevalent G6PD variants are the Mediterranean variant (found in Europe, west and
central Asia, and north India) that is associated with the most profound deficiencies, and
the African A-variant (found in Sub-Saharan Africa and in African-Americans) associated
with the mildest. [87] Radical cure regimens (once-weekly dosing) have been used in
those with P vivax malaria and mild G6PD variants. As haemolysis is self-limiting,
reticulocytosis following each dose compensates for haemolysis and the progressively
younger red-cell population becomes increasingly resistant to the drug’s haemolytic
effects. The WHO recommends the following options: [94]

 Patients with confirmed G6PD deficiency: consider a higher dose once weekly for
8 weeks with close monitoring for haemolysis.
 Patients with unknown G6PD status and testing not available: assess risks and
benefits of adding primaquine before prescribing.
Primaquine should not be used in pregnancy in case there is undetected G6PD deficiency
in the fetus, which can result in haemolysis. [95]

Overview of management in pregnancy

Treatment of malaria in pregnancy must be managed together with an infectious diseases
specialist.

Malaria in pregnancy is associated with increased infant and maternal morbidity and
mortality. Pregnant woman are at increased risk for severe malaria, anaemia, and
death. P falciparum -infected red cells sequester in the placenta, disrupting the nutritional
exchange between mother and fetus. Adverse effects on fetal outcome include increased
risk of abortion, stillbirth, and low birth weight. [57] [96]

There is insufficient information on the safety, efficacy, and pharmacokinetics of most

antimalarial agents in pregnancy, particularly use during the first trimester. Drugs that are
considered safe to use in pregnancy include ACT, quinine (or quinidine), clindamycin,
chloroquine, and hydroxychloroquine. [53] Primaquine should be avoided due to risk of
hemolysis as a result of undetected G6PD deficiency in the
fetus. [97]Atovaquone/proguanil is not recommended for use, due to a lack of safety data
in pregnancy. Tetracyclines are also not recommended in pregnancy. Mefloquine may be
used in second and third trimesters. [53]

Choice of regimen depends on the trimester of pregnancy, causative organism, and

whether the infection is complicated or uncomplicated.

Uncomplicated P falciparum infection: pregnant

First trimester:

 Quinine plus clindamycin is recommended for 7 days. [53] Observational data for
quinine exposure during the first trimester of pregnancy suggests a greater than
two-fold increase in stillbirth, miscarriage, and pre-term delivery when compared
with artemether/lumefantrine. These data will very likely prompt a review of the role
of quinine as a first-line drug in early pregnancy in the future.
 ACT may also be considered as an alternative option if quinine plus clindamycin
is not available or if treatment fails. In the absence of adequate safety data on the
artemisinin-derivatives in the first trimester, guideline developers are unable to
make recommendations regarding its use. However, safety assessments from
published prospective data on more than 700 women exposed to ACT in the first
trimester of pregnancy have not indicated any adverse effects of artemisinin-
derivatives on pregnancy or on the health of the fetus or neonate. [53]

Second and third trimesters:

 Current evidence suggests that ACT should be used to treat uncomplicated

falciparum malaria in the second and third trimesters of
pregnancy. [53] [98] Experience with artemisinin-derivatives in the second and
third trimesters is increasingly reassuring, with no adverse effects reported in
mothers or babies. [99] [100] [101] [102]In particular, dihydroartemisinin plus
piperaquine and artemether/lumefantrine have better safety and side effect profiles
compared to other ACTs. Dihydroartemisinin plus piperaquine has also been used
in trial settings as intermittent preventative treatment in pregnant woman in line
with WHO policy for high-transmission settings with excellent efficacy and safety
profiles.
 The most effective dosing of ACT combinations in pregnancy remains uncertain.
Lower total drug concentrations of ACT are achieved when compared with non-
pregnant women and lower efficacy has been reported in some settings when
compared with intravenous artesunate. [96] Increased volume of distribution and
other physiological changes that occur in pregnancy alter drug metabolism, thus
prospective pharmacokinetic studies are needed to improve treatment. This is
particularly important in areas with emerging artemisinin resistance, where sub-
therapeutic levels will further promote resistance and lead to treatment failures.
 Oral quinine plus clindamycin is a recommended alternative when ACT cannot be
given. Blood glucose levels should be monitored regularly due to associated
recurrent hypoglycaemia with quinine therapy. [53]
  Mefloquine is considered safe for the treatment of malaria during the second and
third trimesters and may be given with or without an artemisinin
derivative. [53] Mefloquine-based regimens should be used only if the other
options are not available due to an increased rates of adverse effects and concerns
about longer-lasting or permanent neuropsychiatrical complications. [69] [83]

Complicated P falciparum infection: pregnant

Severe malaria should be initially treated aggressively with parenteral therapy. Artesunate
is the treatment of choice for severe malaria in all trimesters of pregnancy. [53] A suitable
oral follow-on regimen can then be used.

Intravenous quinidine (intravenous quinine can also be used instead of quinidine;

however, it is not available in the US) plus intravenous clindamycin is an alternative
option. Intravenous quinidine should be continued until parasitaemia is <1% and the
patient can tolerate oral therapy. [69] Patients should receive a loading dose unless they
have already received quinidine, quinine, or mefloquine in the preceding 12
hours. [69] Blood glucose levels should be monitored regularly due to associated
recurrent hypoglycaemia with quinine therapy.

The WHO recommends intramuscular artemether (in preference to quinine) if parenteral

artesunate is not available. [53]

Non-falciparum infection: pregnant

The majority of non-falciparum infections are uncomplicated.

Chloroquine (or hydroxychloroquine as an alternative option) is recommended in all

chloroquine-susceptible infections in all trimesters. [53] [69] ACT is the treatment of
choice after the first trimester for either chloroquine-susceptible or chloroquine-resistant
infections. [53] Chloroquine-resistant P vivax malaria should be treated with quinine in
the first trimester. [53] Other options for chloroquine-resistant infections include quinine
plus clindamycin, or mefloquine. [69]

Patients with P vivax or P ovale infection should be maintained on chloroquine

prophylaxis once weekly until after delivery. [53]

Recurrent falciparum malaria

Recurrence of P falciparum malaria can occur from either treatment failure or re-infection.
Treatment failure may be due to drug resistance or inadequate treatment exposure (e.g.,
vomiting dose, suboptimal dose, poor adherence). Treatment failure should be confirmed
parasitologically, with microscopy or LDH-based RDTs, if possible. Recurrence of fever
and parasitaemia within 28 days of treatment is usually due to treatment failure, and an
alternative ACT that is known to be effective in the region is recommended. Recurrence
after 28 days may be due to either treatment failure or new infection, and a first-line ACT
is recommended. However, re-use of mefloquine within 60 days of the first treatment is
associated with an increased risk of neuropsychiatric events, and a regimen that does not
contain mefloquine should be used. [53] Re-treatment with the same ACT showed similar
efficacy to an alternative ACT or quinine plus clindamycin in a phase III randomised
controlled trial. [103]

A specialist should be consulted for guidance on treating these patients.

Artemisinin resistance
Clinical artemisinin resistance is defined as delayed parasite clearance following
treatment with an ACT. While this partial/relative resistance does not necessarily lead to
treatment failure (provided the partner drug is effective), it can lead to the development
of total resistance or slow parasite clearance. PfKelch13 (K13), a molecular marker for
artemisinin resistance, has been identified, and data collection on the geographical
distribution of this marker is helping to improve global surveillance of artemisinin
resistance. Despite this, ACT is still considered the most effective treatment for
uncomplicated falciparum malaria. [104]

A drug-resistant strain of P falciparum was reported in Vietnam in late 2017. [105] The
strain has been found to be resistant to dihydroartemisinin plus piperaquine, and was first
identified in Cambodia in 2008. It has since spread to northeastern Thailand, southern
Laos, and now southern Vietnam. This strain is highly responsive to artesunate plus
mefloquine.

Emerging treatments
RTS,S/AS01 malaria vaccine
A Plasmodium falciparum vaccine has been evolving over the past decade and has
reached a clinically useful product evaluated in a phase 3 study. [107] The vaccine is
intended for use in high-risk endemic regions, for the active immunisation of children aged
6 weeks to 17 months. The RTS,S/AS01 malaria vaccine is a P
falciparumcircumsporozoite protein fused with a complex adjuvant system, which is
immunogenic in infants and children. The vaccine requires the administration of four
doses: the first three are given at monthly intervals, and the fourth is given 18 months
after the third dose. During the 4-year study period, in children aged 5–17 months who
received the vaccine, efficacy was 39% (against clinical malaria) and 31.5% (against
severe malaria). Vaccine efficacy against all-cause hospitalization was 14.9%. This level
of protection would provide a significant reduction in morbidity and mortality if rolled out
across malaria-endemic regions. The vaccine has received endorsement from the
European Medicines Agency under Article 58, indicating that, in their assessment, the
quality of the vaccine, and the risk-benefit profile is favourable from a regulatory
perspective. The extent to which the protection demonstrated in the phase 3 trial can be
replicated in the context of the routine health system, particularly given the four-dose
vaccination schedule, is uncertain. The World Health Organization (WHO) is now actively
working towards pilot implementation schemes. Ghana, Malawi, and Kenya will take part
in a pilot scheme which will make the vaccine available in selected areas in 2018. [108]
Plasmodium falciparum sporozoite (PfSPZ) vaccine
PfSPZ is a whole malaria sporozoite vaccine that has been reported to be well tolerated,
safe, and effective in early-stage trials. [109] [110] It has received Fast Track designation
from the US Food and Drug Administration (FDA).

DSM265
A novel antimalarial drug that inhibits parasite dihydroorotate dehydrogenase (DHODH),
which is essential for pyrimidine biosynthesis. It is highly selective
for Plasmodium DHODH, and shows in vitro activity against liver and blood stages of P
falciparum . A randomised, double blind, phase I trial found that a single dose of DSM625
was well tolerated and effective for chemoprophylaxis. [111] Another phase Ia/Ib
randomised study found that while DSM625 was safe and cleared parasites, clearance
was faster when administered with mefloquine. [112]Further trials are needed.

Tafenoquine
Tafenoquine, a primaquine analogue, is an 8-aminoquinoline drug effective against all
stages of P falciparum andP vivax . In one study, administration with chloroquine
significantly reduced the rate of relapse compared with chloroquine alone, without an
increase in adverse effects. [113] [ ] Tafenoquine has a long half-life (i.e., 2-3 weeks),
and is therefore given as a single dose. This may improve patient compliance and the
rate of radical cure when compared with a 14-day course of primaquine; however, it
belongs to the same drug class as primaquine and therefore shares the same adverse
effects associated with it (e.g., gastrointestinal adverse effects, haemolysis in patients
with glucose-6-phosphate dehydrogenase deficiency). [114] As tafenoquine is effective
against multiple species, it may become very useful in areas of the world such as Papua
New Guinea and Southeast and eastern Asia in the future. Currently, its role in
chemoprophylaxis is yet to be established; however, it may become an important drug in
the treatment of malaria once more is known about its safety profile. The US Food and
Drug Administration has granted breakthrough therapy designation to the drug, although
it is not currently licensed anywhere in the world.

Atovaquone/proguanil (weekly dosing for prophylaxis)

Human phase 1 studies suggest that weekly dosing of atovaquone/proguanil may be
effective in the prevention of P falciparum infection in travellers. [115] Clinical studies
indicate that stopping atovaquone/proguanil prophylaxis upon return from endemic areas,
instead of continuing therapy for 7 days after leaving such areas, may be adequate in
preventing disease. [116] If phase 3 trials support these findings, this could have
significant benefits in terms of compliance and cost.

Primary prevention
Provision of targeted and appropriately delivered preventive messages and services for
travellers should be a priority. [29] Anopheles mosquitoes bite in the evening and at night.
Therefore, people should be advised to protect themselves from infection by avoiding
outdoor activity after sunset, using insect repellents, wearing long-sleeved shirts and
trousers, and using insecticide-treated bed nets. A Cochrane review found insufficient
evidence to conclude whether topical or spatial repellents prevent malaria in malaria-
endemic regions. There is some evidence that insecticide-treated clothing may reduce
the risk of malaria by 50% in the absence of long-lasting insecticide-treated nets;
however, the findings relate to studies involving refugees, so it is not known whether the
results apply to the general population. [37] [ ]

Non-immune individuals travelling to endemic areas should take antimalarial

chemoprophylaxis. CDC: malaria - choosing a drug to prevent malaria Plasmodium
falciparum chloroquine resistance is an increasing problem and affects all areas except
Central America west of the Panama Canal, Haiti, the Dominican Republic, and parts of
the Middle East.

People travelling to P falciparum chloroquine-sensitive areas can be given chloroquine or

hydroxychloroquine, to be taken 1 week prior to travel, weekly (same day each week)
during travel, and for 4 weeks after leaving the endemic area.

People travelling to P falciparum chloroquine-resistant areas should be prescribed one of

the following chemoprophylactic regimens:

 atovaquone/proguanil: to be taken 1 to 2 days prior to travel, daily during travel,

and for 7 days after leaving the endemic area
 doxycycline: to be taken 1 to 2 days prior to travel, daily during travel, and for 4
weeks after leaving the endemic area
 mefloquine: to be taken 2 to 3 weeks prior to travel, weekly during travel, and for
4 weeks after leaving the endemic area.

P falciparum mefloquine resistance occurs along the borders of Thailand with Myanmar
(formerly Burma) and Cambodia; the western provinces of Cambodia; the eastern states
of Myanmar and, recently, the border between Myanmar and China; the borders of Laos
and Myanmar; the adjacent parts of the Thailand-Cambodia border; and southern
Vietnam. Those travelling to P falciparum mefloquine-resistant areas may be prescribed
atovaquone/proguanil or doxycycline. Sporadic reports of P falciparum resistant to
atovaquone/proguanil have emerged from Africa, but resistance is currently
rare. [38] [39] [40]

A Cochrane review found that mefloquine is highly effective at reducing the risk of malaria,
although evidence did not come from short-term international travellers. Serious adverse
effects were not reported more frequently with mefloquine compared to
atovaquone/proguanil or doxycycline. However, patients were more likely to stop taking
mefloquine due to adverse effects compared to those taking atovaquone/proguanil, and
equally likely to stop taking mefloquine compared to those taking doxycycline.
Neurological adverse effects such as insomnia, anxiety, depression, and abnormal
dreams occurred more frequently with mefloquine. [41]

Travellers going to P ovale -endemic areas should be warned of potential symptoms and
signs of malaria. Only those people who have prolonged exposure in high-transmission
regions (e.g., western Pacific) should be advised to take post-exposure prophylaxis with
primaquine (administered for 14 days after leaving the endemic area). Travellers to low-
risk P vivax areas can travel without chemoprophylaxis. However, travellers to high-risk P
vivax areas (e.g., Papua New Guinea, Solomon islands) require both pre- and post-
exposure prophylaxis with primaquine. [42] P knowlesi is found in parts of Southeast
Asia, and chemoprophylaxis for this region is the same as for P vivax areas.

There is increasing evidence for the safety of chemoprophylaxis administered in all stages
of pregnancy based on studies of patients who live in endemic areas. [43] There is good
evidence for clinically important benefits on anaemia and parasitaemia in the mother, and
on birth weight in infants, with a range of prophylaxis regimens from studies in endemic
areas. [ ]

The safety of mefloquine in pregnant women is based on case series and limited
pregnancy outcome data, but it shows a similar safety profile to that seen in endemic
population studies. One Cochrane review of over 8000 pregnant women found that
mefloquine is effective and safe in regards to adverse pregnancy outcomes (including low
birth weight, prematurity, abortions, stillbirths, and congenital malformations) compared
to prophylaxis with sulfadoxine/pyrimethamine (in HIV-uninfected women) or
trimethoprim/sulfamethoxazole (in HIV-infected women), both of which are used for
prevention in endemic areas such as Africa. However, mefloquine is associated with an
increased risk of adverse effects such as dizziness, vomiting, and fatigue. [44][ ]

In areas with documented mefloquine resistance, there are no current safe and effective
chemoprophylactic agents for pregnant woman, as these areas are considered multi-drug
resistant. In such circumstances, pregnant woman are advised not to travel. Doxycycline
is considered to be contraindicated in pregnant women by most authorities (although, it
can possibly be used as a prophylactic agent during the first 15 weeks of pregnancy if
other options are unsuitable). Atovaquone/proguanil is also not recommended in
pregnancy, although data on the individual components are reassuring. [45]

Secondary prevention
Most countries require reporting of malaria so that epidemiological data can be collected.
In the US, healthcare providers should report all cases of laboratory-confirmed malaria
occurring in the US and its territories to their local or state health department.

Malaria is not contagious in non-endemic areas, due to the lack of an appropriate

mosquito vector. Prophylaxis of close contacts is unnecessary. It should be borne in mind,
however, that family members may have travelled with the patient and had the same
exposures and may also be developing malaria. Advice should be given to these people
to seek medical attention if they develop symptoms.

Appropriate advice regarding future antimalarial prophylaxis should be given to the patient
to prevent further episodes. Patients' attitudes about antimalarial prophylaxis will vary
depending on their prior experiences and duration of stay in endemic regions.