Drug Resistance

The development of drug resistance has emerged as one of greatest threats to malaria

control.

1,2 Resistance to antimalarial drugs has been confirmed for two malaria

species, P. falciparum and P. vivax, while the development of drug resistance is

currently unknown for P. malariae or P. ovale. Of note, there have been two cases of

chloroquine-resistant P. malariae reported from Indonesia, though the clinical

significance remains undefined.

6

Chloroquine-resistant P. falciparum (CRPf) has become widespread and is now

found throughout most malaria-endemic areas, including all of sub-Saharan Africa,

South America, the Indian subcontinent, Southeast Asia, and Oceania. Presently,

CRPf, is not found in Mexico, the Caribbean, Central America, Argentina, and parts

of the Middle East.

7 P. falciparum resistance has also developed to nearly all of the

other currently available antimalarial agents, such as sulfadoxine/pyrimethamine,

mefloquine, halofantrine, and quinine, along with the emergence of resistance to

artemisinin derivatives in parts of Southeast Asia. In some parts of the world, the

impact of multidrug-resistant malaria can be extensive.

Chloroquine-resistant P. vivax has also emerged as a global public health concern.

First identified in 1989 among Australians living in or traveling to Papua New

Guinea, chloroquine-resistant P. vivax has now been identified also in Southeast

Asia, on the Indian subcontinent, and in South America. Since these areas are also

co-endemic for CRPf, this has had minimal impact on chemoprophylactic

recommendations because the antimalarial choice for these areas is not chloroquine.

3

There are several online resources available to retrieve updated malaria

information and country-specific risks from several sources, including the Centers for

Disease Control and Prevention (CDC) and WHO.

1,3

Acute Malaria

SIGNS AND SYMPTOMS

CASE 81-1

QUESTION 1: M.T., a 27-year-old male college student, presents to the emergency department (ED) with

complaints of malaise, myalgia, headache, and fever of 5 days’ duration. A native of Ghana, West Africa, he

recently visited his parents who live in a remote area of Ghana, and he returned home to the United States 4

weeks ago. Two days prior to admission to the ED, he had an abrupt onset of coldness and chills, followed 1

hour later by a high fever, sweating, headache, nausea, and vomiting. The episode of chills and fever lasted

about 24 hours, after which he became asymptomatic. On the afternoon of admission, he had another bout of

chills that preceded a fever of 40°C.

When interviewed for his medical and travel history, he mentioned that he did not take malaria prophylaxis

because he thought that he was protected since he was born and raised in Ghana and then as a teenager moved

to the United States to live with relatives and to attend school. He also did not use mosquito-avoidance

measures during his recent trip to Ghana.

Physical examination reveals a slender black man who is acutely ill and complaining of severe abdominal

pain. Abdominal examination reveals a soft, tender spleen that is slightly enlarged. Blood pressure (BP) is

110/70 mm Hg; pulse, 120 beats/minute; respiration rate, 32 breaths/minute with crackles on pulmonary

auscultation; and temperature, 40°C. Laboratory findings include the following:

Hemoglobin (Hgb), 11 g/dL

Hematocrit (Hct), 34%

White blood cell (WBC) count, 5,300 cells/μL with 76% neutrophils (normal, 45%–65%), 23% lymphocytes

(normal, 15%–35%), and 1% monocytes. Platelets 26,000/microliter

Creatinine 1.5 mg/dL

CRP 228.9 mg/dL

Bilirubin, 1.0 mg/dL

Urinalysis reveals trace amounts of albumin and the presence of urobilinogen. Thick and thin films of M.T.’s

blood are prepared and a parasitemia of 20% is reported. A Giemsa stain of the thin film demonstrates P.

falciparum gametocytes.

Describe how M.T.’s presentation is consistent with P. falciparum malaria and explain his risk factors.

M.T. recently visited Ghana, West Africa, where P. falciparum is endemic. The

incubation period ranges between 1 week and 3 months, though it may occur later in

rare cases.

8,9 Early symptoms of malaria are nonspecific with fever presenting in

most patients and is often accompanied by rigors, as in M.T.’s presentation.

Approximately two-thirds of infected persons usually experience symptoms such as

headache, muscle aches and pains, and malaise, while about one-third of patients

experiencing dry cough in the absence of other respiratory symptoms, diarrhea, and

other gastrointestinal (GI) symptoms.

6 M.T.’s presentation is consistent with the

majority of malaria-infected travelers because approximately 90% of them do not

become symptomatic until they return home.

10–12 Given the nonspecific

symptomatology with malaria, it is important that a good travel history is obtained as

part of the evaluation. M.T.’s history of travel to an endemic area, the cyclical

paroxysmal episodes of chills and fever, the presence of thrombocytopenia,

abdominal pain, splenomegaly, and the identification of P. falciparum gametocytes in

M.T.’s blood confirm the diagnosis of malaria.

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p. 1696

Because M.T. grew up in Ghana in his early years but has been living for over a

decade in the United States (a non-endemic country), he is considered to be in a highrisk group known as “travelers visiting friends and relatives” or VFR travelers.

13

When he returned to Ghana, an endemic country, to visit his parents, his loss of

immunity over a period of time, placed him in a high-risk group for malaria.

Unfortunately, M.T. neglected to take malaria chemoprophylaxis because he thought

his risk was low. Healthcare providers should raise awareness of the importance for

malaria prophylaxis as well as other prevention strategies for VFR travelers.

TREATMENT

CASE 81-1, QUESTION 2: How should P. falciparum malaria in M.T. be treated?

Unfortunately, M.T. has acquired falciparum malaria, the most severe form of

malaria with the highest mortality rate. Thus, M.T.’s treatment is a medical

emergency, requiring immediate attention as mortality correlates with diagnostic and

therapeutic delay.

8 M.T. would be classified as having a severe case of malaria with

complications, which could result in organ damage, including cerebral malaria. This

is a particular feature of P. falciparum which unlike the other forms causes red blood

cell adhesion to blood vessel walls causing local damage and ischemia to end

organs. His clinical symptoms along with the results of 20% parasitemia support a

severe case of falciparum malaria.

Specific treatment guidelines for treatment of malaria in the United States are

provided by the Centers for Disease Control and Prevention (CDC)

14 at

http://www.cdc.gov/malaria/diagnosis_treatment/treatment.html and by the

World Health Organization

15 available at

http://www.who.int/malaria/publications/atoz/9789241549127/en/.

Because M.T.’s condition is critical, he should be admitted to an acute care unit

and started on intravenous (IV) artesunate for at least 24 hours. According to WHO

guidelines for severe malaria, intravenous or intramuscular artesunate is the drug of

choice for treatment of severe malaria because it has demonstrated a greater

reduction in mortality compared with parenteral quinine.

15 Many

hospitals/institutions no longer stock intravenous quinidine gluconate for treatment of

malaria and if used the drug requires careful cardiac monitoring. Parenteral

artesunate can be obtained from the CDC (Malaria Hotline: 770-488-7788 or tollfree 855-856-4713 or after hours at 770-488-7100 for malaria clinician on call) as

an investigational drug (IND). If parenteral artesunate is not available, an alternative

agent would be the use of intramuscular artemether, which is preferred over the use

of quinine for treatment of adults and children with malaria.

Once M.T. has received at least 24 hours of parenteral therapy and is able to

tolerate oral therapy, he would complete 3 days of therapy with an artemisinin-based

combination therapy (ACT), such as artemether–lumefantrine (Coartem). The

artemisinin component is effective at rapidly clearing parasites from the blood. If an

ACT is unavailable, other options can be used: artesunate + clindamycin, artesunate

+ doxycycline, quinine + clindamycin, or quinine + doxycycline, though tolerability

and side effects of quinine are problematic. The risk of death is greatest within the

first 24 hour, requiring careful monitoring for management of complications as well

as supportive care.

Managing Other Plasmodium Species

CASE 81-1, QUESTION 3: How would M.T.’s treatment of malaria differ if it had been a different

Plasmodium species?

If M.T. had been infected with one of the other species of Plasmodium (P. vivax,

P. ovale, or P. malariae) treatment with an ACT for 3 days would be considered

first-line treatment for all species.

15 This approach will provide sufficient efficacy

for malaria treatment, promote good medication adherence, and minimize the risk of

drug resistance. There are five ACTs recommended for the treatment of

uncomplicated malaria:

artemether + lumefantrine

artesunate + amodiaquine

artesunate + mefloquine

artesunate + SP (sulfadoxine-pyrimethamine)

dihyroartemisinin + piperaquine

It is important to check for chloroquine-resistant regions such as chloroquineresistant P. vivax, which has been documented in Papua New Guinea and Indonesia,

Brazil, Columbia, Ethiopia, Guatemala, Guyana, India, Myanmar, Peru, the Republic

of Korea, Solomon Islands, Thailand, and Turkey.

8,16

Patients with P. ovale and P. vivax should also be given primaquine to prevent

relapses from the latent exoerythrocytic stages in the liver.

2 Before primaquine is

used in any patient, glucose-6-phosphate dehydrogenase (G6PD) deficiency must be

ruled out by laboratory testing because it can cause hemolysis that can be fatal in

G6PD-deficient individuals.

PREVENTION OF MALARIA

CASE 81-1, QUESTION 4: What malaria chemoprophylaxis recommendation would have been options for

M.T. prior to his travel to visit his parents in Ghana? Provide guidance to M.T. regarding antimalarial options,

adverse effects, counseling parameters, and mosquito-avoidance measures.

Travelers to malaria-endemic areas, such as M.T., should receive malaria

prophylaxis and should follow mosquito-avoidance measures.

7 The goal of malaria

prevention is to prevent malaria caused not only by P. falciparum but also by all

species. It is important to assess an individual’s level of risk, which includes the

destination country, the detailed itinerary, including specific activities (e.g., backpacking in the wilderness), types of accommodations, and style of travel. Pregnancy,

lactation, and other conditions, HIV disease, other immunocompromised diseases, as

well as drug resistance at the destination will impact the risk assessment.

Because M.T. is a first-generation immigrant living in a non-endemic country and

was returning to Ghana, his country of origin, as a VFR traveler he was considered at

high risk for contracting malaria. Recommendations for drugs used for malaria

prophylaxis are provided by the CDC

17 at

https://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseases-related-totravel/malaria#3-10-chlor

Given M.T.’s travel destination to Ghana with P. falciparum estimates at 90%,

appropriate options for malaria prophylaxis are atovaquone–proguanil, doxycycline,

or mefloquine. It is important that M.T. understands the differences in the agents,

including proper administration, their adverse effect profile, and potential drug

interactions. Table 81-1 provides a summary of the various agents for malaria

prophylaxis and highlights adverse effects, contraindications, precautions, and

potential drug interactions.

5,7,18 The importance of beginning chemoprophylaxis prior

to travel should be emphasized. While medications for malaria prophylaxis may be

available at the destination location, travelers are strongly discouraged from

obtaining chemoprophylaxis medications while abroad because the quality of these

products are not known. These products may be counterfeit or may have been

manufactured using substandard manufacturing practices or may contain

contaminants.

19,20

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p. 1697

Table 81-1

Antimalarial Drugs Used for Malaria Prophylaxis

Drug Usage Adverse Effects

Contraindications

and Precautions Drug Interactions

Atovaquone–

proguanil (fixed drug

combination)

Prophylaxis in all

areas

Begin 1–2 days

before travel to

malarious areas

Take daily (same

time each day) while

in malarious area and

for 7 days after

leaving such areas

Take with food or a

milky drink

In the United States

and European Union,

a pediatric

formulation is

available (quarter

strength = 62.5 mg

atovaquone and 25

mg proguanil). CDC

sanctions

atovaquone/proguanil

for infants >5 kg.

WHO allows use in

infants weighing >11

kg

Nausea, vomiting,

abdominal pain,

increased

transaminase,

seizures, and rash

Contraindicated in

severe renal

impairment

(creatinine clearance

<30 mL/minute)

Not recommended in

pregnancy or

breastfeeding (use

only during

pregnancy if

potential benefits of

therapy outweigh

potential risk to

infant)

Tetracycline,

rifampin, and

rifabutin significantly

decrease

atovaquone level

(avoid concurrent

use)

May interact with

antiretroviral

protease inhibitors

ritonavir, darunavir,

atazanavir, indinavir,

and lopinavir, in

addition to the nonnucleoside reverse

transcriptase

inhibitors

nevirapine,

etravirine, and

efavirenz; monitor

when used

Metoclopramide:

may reduce

bioavailability of

atovaquone; avoid

use of this agent as

Partial doses may

need to be prepared

by a pharmacist and

dispensed in capsules

an antiemetic to

treat vomiting that

may occur with

atovaquone at

treatment doses

Avoid use with

cimetidine and

fluvoxamine because

of interference with

proguanil’s

metabolism

Chloroquine

phosphate

Prophylaxis only in

areas with

chloroquine-sensitive

malaria

Begin 1–2 weeks

before travel to

malarious areas.

Take weekly (same

day of the week)

while in malarious

area and for 4 weeks

after leaving such

areas

Chloroquine sulfate

(Nivaquine) is not

available in the

United States and

Canada, but it is

available in most

malaria-endemic

countries in both

tablet and syrup

forms

May exacerbate

psoriasis; pruritus in

black-skinned

individuals, nausea,

headache, skin

eruptions, reversible

corneal opacity, nail

and mucous

membrane

discoloration, nerve

deafness,

photophobia,

myopathy,

retinopathy with

daily use, blood

dyscrasias,

psychosis, seizures,

and alopecia

Contraindications:

Persons

hypersensitive to 4-

aminoquinoline

compounds and in

G6PD-deficient

individuals

(hemolysis is rare

when given at

prophylactic and

therapeutic doses)

Preexisting

retinopathy, diseases

of the central

nervous system,

myasthenia gravis,

disorders of the

blood-producing

organs, a history of

epilepsy or psychosis

Dosage reduction

may be required:

hepatic function

impairments

May increase risk of

prolonged QTc

interval when given

with other QTprolonging agents

(e.g., sotalol,

amiodarone, and

lumefantrine);

antiretroviral

rilpivirine prolongs

QTc; avoid

combination of

chloroquine with any

of these agents

Chloroquine inhibits

CYP2D6 and when

used concomitantly

with substrates of

this enzyme (e.g.,

metoprolol,

propranolol,

fluoxetine,

paroxetine, and

flecainide); increase

monitoring for side

effects

Chloroquine

absorption may be

reduced by antacids

or kaolin; space

apart by ≥4 hours

Avoid concomitant

use of cimetidine

and chloroquine as

cimetidine can inhibit

chloroquine’s

metabolism; avoid

concurrent use of

CYP3A4 inhibitors

such as ritonavir,

ketoconazole, and

erythromycin as they

may increase

chloroquine levels

Chloroquine may

increase digoxin

levels, requiring

careful monitoring

Use with caution

with calcineurin

inhibitors as their

levels may be

increased by

chloroquine

Chloroquine inhibits

bioavailability of

ampicillin; space

apart doses by 2

hours.

Chloroquine may

decrease the

bioavailability of

ciprofloxacin and

methotrexate

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p. 1698

Doxycycline Prophylaxis in all

areas

Begin 1–2 days

before travel to

malarious areas

Take daily at the

same time each day

while in the

malarious area and

for 4 weeks after

leaving such areas

GI upset (nausea,

vomiting, abdominal

pain, and diarrhea

(less frequent than

with other

tetracycline agents);

esophageal

ulceration; vaginal

candidiasis,

photosensitivity,

allergic reactions,

blood dyscrasias,

azotemia in renal

diseases, and

hepatitis

Contraindicated in

children aged <8

years and in

pregnant women

Breastfeeding:

excreted into breast

milk; may cause

permanent

discoloration of

teeth, damage to

tooth enamel,

impairment of

skeletal growth, and

photosensitivity in

breastfed infants

Phenytoin,

carbamazepine, and

barbiturates may

decrease

doxycycline’s halflife

Anticoagulants: may

require reduction in

anticoagulant dose

while taking

doxycycline; close

monitoring of

prothrombin time

Absorption may be

impaired by

concomitant

ingestion of bismuth

subsalicylate,

preparations

containing iron,

calcium, magnesium,

or aluminum; avoid

taking these

preparations within 3

hours of taking

doxycycline

Doxycycline may

interfere with

bactericidal activity

of penicillin; avoid

use of both drugs

together

Hydroxy-chloroquine

sulfate

An alternative to

chloroquine for

prophylaxis only in

areas with

chloroquine-sensitive

malaria

Mefloquine Prophylaxis in areas

with mefloquinesensitive malaria

Begin ≥2 weeks

prior to travel to

malarious areas

Take weekly on the

same day of the

week while in the

malarious area and

for 4 weeks after

leaving such areas

Travelers should

receive a copy of the

FDA Medication

Guide when

receiving a

prescription for

mefloquine

Dizziness, diarrhea,

nausea, vivid

dreams, nightmares,

irritability, mood

alterations,

headache, insomnia,

anxiety, seizures, and

psychosis

Contraindicated in

persons allergic to

mefloquine or

related compounds

(quinine, quinidine)

and in persons with

active depression, a

recent history of

depression,

generalized anxiety

disorder, psychosis,

schizophrenia, other

major psychiatric

disorders, or seizures

Caution: in persons

with psychiatric

disturbances or a

previous history of

depression

Not recommended

for persons with

cardiac conduction

abnormalities Use

with caution or avoid

in individuals taking

antiarrhythmic or βblocking agents,

calcium channel

blockers,

antihistamines, H1-

blocking agents,

tricyclic

antidepressants, or

phenothiazines

Use in second and

third trimesters in

pregnancy for

women who cannot

defer travel to highrisk areas is

sanctioned by

manufacturer, CDC,

and WHO

Breastfeeding:small

May interact with

antimalarial drugs

that alter cardiac

conduction;

increased toxicities

with lumefantrine

(available in United

States in fixed

combination to treat

uncomplicated P.

falciparum malaria);

avoid or use with

caution because of

potentially causing

fatal prolongation of

the QTc interval

May lower plasma

concentrations of

anticonvulsant

agents, such as

valproic acid,

carbamazepine,

phenobarbital, and

phenytoin; avoid

concurrent use

May increase levels

of calcineurin

inhibitors and mTOR

inhibitors

(tacrolimus,

cyclosporine A, and

sirolimus)

Potent CYP3A4

inhibitors (e.g.,

clarithromycin,

erythromycin,

ketoconazole,

voriconazole, and

itraconazole,

ritonavir, lopinavir,

darunavir,

atazanavir, and

cobicistat) may

increase the levels

amounts secreted in

breast milk; effect

on breastfed infants

is unknown

of mefloquine,

increasing the risk of

QT prolongation

CYP3A4 inducers

(e.g., efavirenz,

nevirapine,

etravirine, rifampin,

and rifabutin) may

reduce plasma

concentrations of

mefloquine and

concurrent use

should be avoided

Avoid concurrent

use with agents

boceprevir and

telaprevir (drugs

used to treat

hepatitis C)

p. 1698

p. 1699

Primaquine Prophylaxis for

short-duration travel

to areas with

principally P. vivax

Used for

presumptive

antirelapse therapy

(terminal

prophylaxis) to

decrease the risk for

relapses of P. vivax

and P. ovale

Start therapy 1–2

days before travel to

malarious areas

Take daily at the

same time each day

while in the

malarious area and

for 7 days after

leaving such area

A documented

normal G6PD level

should be obtained

prior to starting

primaquine therapy

GI upset; hemolysis

in G6PD deficiency,

methemo-globinemia

Contraindicated in

individuals with

G6PD deficiency

(G6PD levelshould

be obtained prior to

starting primaquine

therapy as G6PD

deficiency must be

ruled out by

laboratory testing).

Contraindicated

during pregnancy

and lactation (unless

the infant being

breastfed has a

documented normal

G6PD level)

Sources:Arguin PM, Tan KR. Malaria. In: Centers for Disease Control and Prevention. CDC Health Information

for International Travel 2016. New York, NY: Oxford University Press; 2016:242–255; Youngster I, Barnett ED.

Interactions among travel vaccine & drugs. In: Centers for Disease Control and Prevention. CDC Health

Information for International Travel 2016. New York, NY: Oxford University Press; 2016:54–57; Schlagenhauf P,

Kain KC. Malaria prophylaxis. In: Keystone JS et al, eds. Travel Medicine. 3rd ed. Philadelphia, PA: Saunders

Elsevier; 2013:146–147.

M.T. should be counseled regarding mosquito-avoidance measures, not only for

malaria but also for protection against Aedes mosquitos (transitions of dengue,

chikungunya, and the Zika viruses). Because malaria transmission occurs primarily

between dusk and dawn, contact with mosquitos can be reduced by remaining in

well-screened areas, using mosquito bed-nets (preferable insecticide-treated nets),

using insecticide sprays, wearing clothes that cover most of the body, and treating

clothing with permethrin. Table 81-2 summarizes strategies to optimize protection

against mosquitos and items that travelers can include in a travel kit for malaria

prevention.

21,22

In addition to mosquito-avoidance measures, it is important to

emphasize to travelers, such as M.T., to inspect themselves and their clothing for

ticks during outdoor activity and at the end of the day (see Chapter 82, Tick-Borne

Diseases for further information).

STANDBY EMERGENCY TREATMENT

Given the risk of complications and deaths because of the delay initiating treatment of

malaria, the concept of standby emergency treatment (SBET) was introduced in the

late 1980s and then updated to provide travelers with a treatment dose of an

appropriate antimalarial drug to be carried and taken in case of a febrile illness,

when prompt medical attention is unavailable within 24 hours following the onset of

symptoms.

23–25 The major issue with SBET is the difficulty for travelers to make a

self-diagnosis of malaria based on clinical symptoms. For those situations in which

the traveler does not have access to medical care and develops a febrile illness with

symptoms consistent with malaria, a supply of medications could be administered

presumptively until medical evaluation is available.

CASE 81-1, QUESTION 5: Would M.T. have been a candidate for SBET prior to his trip to Ghana?

In the United States, two malaria treatment regimens are available that could be

prescribed for self-treatment: atovaquone–proguanil and artemether–lumefantrine.

Because M.T. was traveling to a remote region in Ghana, discussing this option with

a travel health provider would have been important in preparation for his trip. M.T.

is a good candidate for SBET and could have taken a reasonable supply of a fullcourse of an approved malaria treatment regimen with him on his trip. It is important

to note that the use of the same or related drugs that are taken for prophylaxis are not

recommended to treat malaria. Thus, if M.T. was taking a reliable supply of

atovaquone–proguanil as SBET, then atovaquone–proguanil would not be selected

for malaria prophylaxis. Either mefloquine or doxycycline would be acceptable

choices for malaria prophylaxis.

The introduction of rapid diagnostic tests (RDTs), which are based on the

immunochromatographic detection of plasmodial proteins, has become an important

component of the current global malaria control strategies, alongside ACTs for

falciparium malaria across most areas of endemicity. The use of RDTs is being

evaluated as a tool for self-use by travelers to determine if it will help them decide

whether or not to use SBET.

23 Future directives will continue to evaluate the

feasibility and utility of RDTs in providing guidance to travelers on whether to

initiate SBET.

CASE 81-2

QUESTION 1: J.P., a 35-year-old male who owns a small business in the United States, is planning to visit his

seriously ill grandmother who lives in eastern region of Indonesia. J.P. immigrated to the United States when he

was 20 years old, and he has not previously had a chance to go back to Indonesia. Given his concern for his

grandmother’s health, his wife, R.T., who is 24 weeks pregnant, wants to join him and also bring their 6-yearold daughter. R.T. is also from Indonesia and moved to the United States 8 years ago. Assess the malaria risks

of each member of the family.

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p. 1700

Table 81-2

Mosquito Protection Measures

Protective Measures Comments

Clothing Wear a long-sleeved shirt, long

pants, and socks

Treat clothing with permethrin

24–48 hours prior to travel to

allow them to dry or purchase

pretreated clothing

Permethrin-treated clothing will retain repellant activity

through multiple washes

Repellants used on skin can also be applied to clothing

and must be reapplied after laundering

Clothing treated with other repellent products (e.g.,

DEET) provides protection from biting arthropods but

will not last through washing and will require more

frequent reapplications

Insecticides Permethrin: highly effective

insecticide–acaricide and

repellent

Repellents for use on

skin and clothing

Apply lotion, liquid, or spray

repellent to exposed skin

Ensure adequate protection

during times of the day when

mosquitos are most active

(malaria vector mosquitos bite

mainly from dusk to dawn)

Reapply repellants as protection

wanes and mosquitos start to

bite

Purchase repellents before

traveling

Repellents may be used with sunscreen. General

recommendation: use separate products, applying

sunscreen first and then applying the repellent.

Combination sunscreen and repellent products are not

recommended, because sunscreen may need to be

reapplied more frequently and in larger amounts than

repellents

Travelers may need to reapply sunscreen more often

as limited data show a one-third decrease in the sun

protection factor of sunscreens when DEET-containing

insect repellents are used after a sunscreen is applied

DEET (chemical name: N,Ndiethyl-m-toluamide or N,Ndiethyl-3-methyl-benzamide)

DEET formulations worldwide:

concentrations range from 5%

Gold standard of insect repellents for several decades

In the United States registered for use by the general

public since 1957

Can be applied to skin, clothing, mesh insect nets or

shelters, window screens, tents, or sleeping bags

to 100%.

For most activities, 10%–35%

DEET will usually provide

adequate protection

Picaridin (KBR 3-23 [Bayrepel]

and Picaridin outside of the

United States; chemical name:

21-(2-hydroxyethylo)-1-

piperidinecarboxylic acid 1-

methylpropyl ester)

Oil of lemon eucalyptus (OLE)

or PMD (chemical name: paramenthane-3,8-diol). The

synthesized version of OLE.

Note that EPA-registered repellent products contain

the active ingredient OLE (or PMD). “Pure” oil of

lemon eucalyptus (essential oil is not formulated as a

repellent) and not recommended because it has not

undergone validated safety and efficacy testing and is

not registered with the EPA as an insect repellent.

IR3535 (chemical name: 3-[Nbutyl-N-acetyl]-aminopropionic

acid, ethyl ester).

EPA, Environmental Protection Agency.

Source: Fradin MS. Insect protection. In: Keystone JS et al, eds. Travel Medicine. 3rd ed. Philadelphia, PA:

Saunders Elsevier; 2013:51–61; Nasci RS et al. Protection against mosquitoes, ticks, & other arthropods. In:

Centers for Disease Control and Prevention. CDC Health Information for International Travel 2016. New York,

NY: Oxford University Press; 2016:94–99; Schlagenhauf P, Kain KC. Malaria prophylaxis. In: Keystone JS et al,

eds. Travel Medicine. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2013:143–144.

Malaria prevention strategies for both short-term and long-term travelers consist

of a combination of mosquito-avoidance measures and chemoprophylaxis. It is

important to assess the individual risk of each traveler, including a detailed itinerary

of the specific cities, types of accommodations, and activities (e.g., backpackers,

adventure travelers).

Similar to the previous case of M.T., (Case 81-1) VFR travelers, such as J.P. and

R.T., are at high risk because they are first-generation immigrants living in nonendemic countries who are returning to their countries of origin. They may consider

themselves to be at no risk because they were raised in a malarious country

(Indonesia) and consider themselves immune. They should be advised that any

acquired immunity is lost quickly and they are considered to have the same risk as

nonimmune travelers. Because R.T. is pregnant, she should be advised that malaria

infection in pregnant women can be more severe with increased risk for adverse

pregnancy outcomes than in nonpregnant women. In particular, falciparum malaria

acquired during pregnancy has been associated with an increased risk of miscarriage

and still birth, intrauterine growth retardation, as well as other complications, and

maternal mortality.

7 She should be advised to avoid travel to eastern Indonesia

because it is an endemic region. Their 6-year-old daughter should also follow

preventive measures because infants, children, and adolescents of any age can

contract malaria and they are traveling to a malarious region.

CASE 81-2, QUESTION 2: J.P. and his wife R.T. have not finalized their decision if they will travel together

to visit J.P.’s grandmother, and bring their daughter. They want to learn more about resources available to them

and options for malaria prevention for this trip, so that they can weigh the risks and benefits of traveling to

Indonesia.

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In eastern Indonesia, including Papua New Guinea, chemoprophylaxis is

recommended for J.P. and his family that will protect them against CRPf infections.

The CDC Health Information for International Travel

26

(commonly referred to as the

Yellow Book) serves as a useful resource for both travelers and clinicians regarding

updated information on parasitic diseases and immunization requirements. In

addition, travelers such as J.P. and his wife and clinicians can select the type of

traveler on the program menu, which in their case they would select “traveling with

children,” “visiting friends or family,” and also the “pregnant women” categories,

which will provide them with additional relevant information for their special needs.

In addition the CDC Malaria Hotline, mentioned previously provides malaria

support. Other useful resources include the Morbidity and Mortality Weekly Reports

and the WHO.

Non-Falciparum Prophylaxis

It is important to note that nearly all P. falciparum is chloroquine resistant and P.

vivax and P. falciparum are the two most common encountered in travelers to eastern

Indonesia (refer to section that follows for prophylaxis for P. falciparum). There

have been reports confirming a high prevalence of chloroquine-resistant P. vivax in

Papua New Guinea or Indonesia.

14 Therefore, antovaquone–proguanil, doxycycline,

or mefloquine would be recommended as options for treatment, and mefloquine

would be the appropriate choice during pregnancy. In addition, infections with P.

vivax and P. ovale can relapse as a result of hypnozoites that remain dormant in the

liver. Therefore, a 14-day course of primaquine therapy is recommended with

appropriate screening for G6PD deficiency prior to treatment. Primaquine should be

avoided during pregnancy.

Prophylaxis for Plasmodium falciparum

There are three broadly equally effective prophylactics for most regions where there

is P. falciparum—atovaquone–proguanil, doxycycline, and mefloquine. Selection of

an antimalarial agent depends on individual factors, patient preference regarding the

regimen, the side effect profile, and contraindications (see Table 81-1).

Prophylaxis for P. falciparum can be achieved by taking the combination of

atovaquone and proguanil administered once daily 1 to 2 days before entering

malarious areas, continued for the duration of malaria exposure, and for 1 week after

return. Mefloquine should be taken beginning at least 1 week prior to entering

malarious areas, and continuing through 4 weeks after leaving the endemic area. A

third option is doxycycline beginning 1 day before entering malarious areas,

continued for the duration of the stay, and for 4 weeks after leaving the malarious

area.

In pregnant patients, such as R.T., traveling to CRPf areas, mefloquine is the only

medication recommended for malaria prophylaxis during pregnancy. Atovaquone–

proguanil is not recommended for use during pregnancy because data are still lacking

to fully evaluate its safety, and doxycycline is contraindicated. Given the prevalence

o f P. falciparum and P. vivax in eastern Indonesia, chloroquine would not be

recommended and mefloquine would be an appropriate option for R.T. who is in her

second trimester. As mentioned above, P. vivax resistance would also be a concern

for travel to eastern Indonesia, and mefloquine would provide appropriate coverage.

Given the risks of acquiring malaria during pregnancy, J.P. and R.T. should

reconsider their decision to travel together. With regard to their 6-year-old daughter,

mefloquine and atovaquone–proguanil are options as doxycycline is contraindicated

in children less than 8 years of age. Practical advice should be emphasized, including

physical barriers (e.g., clothes, mosquito nets), insect repellent, and minimizing the

stay in the endemic area also decrease the likelihood of transmission. Table 81-2

summarizes strategies to optimize protection against mosquitos and items that

travelers can be advised to include in a traveler kit for malaria prevention.

Considerations when selecting a drug for malaria prophylaxis are available by the

CDC

17 at http://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseasesrelated-to-travel/malaria.

MALARIA VACCINE

CASE 81-2, QUESTION 3: Could J.P. be vaccinated as an alternative to chemoprophylaxis?

Currently, no malaria vaccine is available because there have been numerous

challenges in the development of a vaccine, including the technical complexity of

developing a vaccine against a parasite and the lack of a traditional market.

27 As a

result of successful in vitro P. falciparum cultivation and advances in genetic

engineering and monoclonal antibody research, some progress has been made, but

this vaccine is years from approval. The malaria parasite undergoes many

transformations during its development, and each stage expresses a different

plasmodial genome that generates a large number of antigens. The development of a

malaria vaccine relies on the identification and characterization of these antigens and

the subsequent production of monoclonal antibodies. Presently there are over a dozen

vaccine candidates in clinical development that are being evaluated. A Malaria

Vaccine Technology Roadmap has been designed by leading global health

organizations that is focused on accelerating the development of a highly effective

malaria vaccine.

CASE 81-3

QUESTION 1: C.S., a 29-year-old female, comes to the community pharmacy with a prescription for

mefloquine that she obtained from a local travel medicine clinic. She explains that she will be traveling to subSaharan Africa for 6 weeks with a group of female friends, and she is concerned about experiencing adverse

effects to mefloquine while she is on her 1-month safari trip. She also wants your advice regarding malaria

prevention. She currently takes an oral contraceptive and also a multivitamin daily and has no known drug

allergies. Provide guidance to C.S. regarding mefloquine and advice on approaches to malaria prevention.

It is important to consider patient-specific factors in C.S. and drug-related factors.

Given her concerns, C.S. can be advised to start early with mefloquine prophylaxis

(2.5–3 weeks before her trip), which will be taken weekly on the same day.

7 This

will allow her to assess her tolerability to mefloquine as the majority of adverse

effects occur within the first three doses. If there are any tolerability issues that

occur, this will enable her to switch to another agent.

In terms of overall malaria prevention strategies, the importance of adherence to

malaria prophylaxis should be emphasized, because C.S. will begin mefloquine prior

to her trip and will continue therapy while she is in the malarious region, and for 4

weeks after leaving the area. Personal protection measures should be reviewed with

C.S., including habitat avoidance, the use of insect repellants, protective clothing,

and bed-nets (see Table 81-2).

21,22 For example, if C.S. selects a product containing

DEET (N,N-diethyl-m-toluamide or N,N-diethyl-3-methylbenzamide), she should be

counseled on using a sunscreen product separately (rather than a combination

product). Sunscreen may need to be reapplied more often and in larger amounts than

the insect repellent because limited data has shown a one-third decrease in the sun

protection factor of sunscreens when DEET-containing insect repellents are used

after a sunscreen is applied.

22

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