Prevention of malaria infection in travelers

INTRODUCTION — 

Malaria is an important cause of fever and serious illness in returned travelers [1,2]. The risk of malaria transmission depends on a variety of factors, including the geographic region visited and the type of traveler.

Prevention efforts should be aimed at all forms of malaria. Plasmodium species that cause human malaria include P. falciparum, P. vivax, P. ovale species, P. malariae, and P. knowlesi. P. falciparum is most frequently diagnosed in returning travelers and is most likely to result in severe disease and death [1,2]; however, all malaria species can cause severe disease and death [1-4].

P. falciparum accounts for 97 percent of cases worldwide and is typically chloroquine resistant (figure 1) [5,6]. P. vivax accounts for 3 percent of malaria cases worldwide, with approximately 75 percent of cases in Central and South America, and nearly half of the cases in Southeast Asia (figure 2) [5,7,8]. P. ovale species are rare; they are endemic primarily in Africa but can be found in other regions [9,10]. (See "Malaria: Epidemiology, prevention, and elimination", section on 'Epidemiology'.)

Issues related to risk assessment, counseling, mosquito bite prevention, and antimalarial chemoprophylaxis for prevention of malaria in travelers will be reviewed here. The clinical manifestations, diagnosis, and treatment of malaria are discussed separately. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Laboratory tools for diagnosis of malaria" and "Treatment of severe malaria" and "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)

The findings and conclusions in this topic are those of the contributors and do not necessarily represent the official position of the United States Centers for Disease Control and Prevention (CDC).

EPIDEMIOLOGY OF MALARIA AMONG TRAVELERS — 

Among nearly 10,000 nonmigrant travelers with fever seen at a GeoSentinel clinic between 2012 and 2021, malaria was the most common etiologic diagnosis, found in 21 percent of cases with fever [1]. In 2019, the United States Centers for Disease Control and Prevention (CDC) received reports of 2048 confirmed malaria cases in the United States; Africa was the primary region of acquisition [11]. P. falciparum accounted for 85.5 percent of cases; P. ovale spp, P. malariae, and P. knowlesi accounted for <10 percent of cases.

Most travelers who develop malaria do so because they do not take or adhere to an effective chemoprophylactic drug regimen [12-15]. In addition, many travelers frequently fail to use personal protection measures for mosquito bite prevention.

ASSESSING RISK — 

Risk assessment consists of reviewing the travel itinerary, type of traveler, and their medical history to determine whether chemoprophylaxis is indicated.

Review travel plans — Review of travel plans should include detailed understanding of destinations/geography, as well as other aspects of trip plans:

●Geography – The risk of malaria transmission depends upon the geographic region; variability exists within countries.

Geographic risk assessment for malaria requires a detailed review of the planned itinerary to identify malaria-endemic destinations. Country-specific information, together with the most recent guidelines and advisories, is available in the United States Centers for Disease Control and Prevention (CDC) publication "Health Information for the International Travel" (also known as the Yellow Book), which may be accessed online [16,17]. The World Health Organization provides useful online information, including maps and malaria data [18].

●Trip plans – In addition to geography, other important trip considerations include:

•Season – Risk is lower in dry season and higher in rainy season.

•Elevation – Risk is lower at >2000 to 2300 meters above sea level.

•Type of accommodation – Risk is increased with tenting or open-air accommodations; the risk is lower with screened or air-conditioned accommodations.

•Daytime versus nighttime outdoor exposure – Anopheles mosquitoes generally bite between dusk and dawn; increased risk is associated with time spent outdoors during these times.

•Duration and intensity of exposure – Risk increases with longer duration of travel or more intense mosquito exposure.

Review type of traveler and medical history — The traveler's medical history should be reviewed carefully when considering malaria risk and chemoprophylaxis use. (See "Travel advice", section on 'Review medical history and travel plans'.)

Important considerations include pregnancy, kidney function, history of neurologic and psychiatric disorders, arrhythmia, and glucose-6-phosphate dehydrogenase (G6PD) status. In addition, current medications and prior history of allergy or other drug intolerance should be reviewed.

Important risk groups include:

●Visiting Friends and Relatives (VFR) travelers – Travelers born in malaria-endemic regions (where they develop some immunity) who relocate outside the endemic area but subsequently return to visit friends and relatives are at high risk for malaria infection [19-21]. For these individuals, immunity wanes outside endemic areas, given the lack of ongoing exposure [22]; however, these travelers may not appreciate their increased risk for malaria infection and may be unaware that prophylaxis is warranted [19,23]. Among cases of imported malaria in 2019 among United States residents for whom the reason for travel was known, 79 percent occurred in VFRs [11,12].

●Pregnant travelers – Pregnant travelers should be advised to defer travel until after delivery whenever feasible. Malaria can be a life-threatening infection for both mother and fetus [24]. Risk of stillbirth, spontaneous abortion, and other adverse pregnancy outcomes is increased in the setting of malaria. (See 'Pregnant travelers' below.)

●Military personnel – Military personnel may have inadequate protection from mosquito bites given prolonged periods of night-time exposure to biting Anopheles mosquitoes with accommodations that have inadequate screens or bednets [25].

●Individuals with HIV infection – Travelers with human immunodeficiency virus (HIV) infection warrant the same approach to prevention of malaria as HIV-uninfected travelers. Potential drug interactions should be considered. (See 'Drug interactions' below.)

TRAVELER COUNSELING

●Understanding malaria risk – Travelers to endemic areas should understand that their planned itinerary puts them at risk for malaria, a serious infection that can be fatal after just several days of illness [26]. Pregnancy confers increased risk.

●Available preventive tools – Available prevention tools should be discussed in detail. These include:

•Mosquito bite prevention – Mosquito prevention measures should always be used. (See 'Mosquito bite prevention' below.)

•Antimalarial chemoprophylaxis – Chemoprophylaxis should be used in specific areas, depending on risk. (See 'Review travel plans' above.)

Chemoprophylaxis should be started prior to travel, continued regularly during exposure, and for a period of time following departure from the endemic area (table 1 and table 2) [27]. (See 'Chemoprophylaxis' below.)

Chemoprophylaxis agents vary with respect to cost, adverse effects, dosing schedule, and availability; these items should be reviewed carefully to facilitate adherence [28].

The drugs used for antimalarial prophylaxis are generally well tolerated. Side effects can occur, however. If there are concerns about tolerating a particular medication, a drug trial can be considered prior to departure. Minor side effects usually do not require stopping the drug. Clinicians should determine if symptoms are related to the medication and make a change if needed [17].

●Recognizing malaria symptoms – Symptoms of malaria may include fever, headache, myalgia, cough, nausea, abdominal pain, vomiting, and diarrhea. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)

Travelers should understand that no chemoprophylaxis regimen guarantees complete protection and that fever during or after travel is a medical emergency requiring urgent medical attention.

●Seeking medical attention – Travelers who develop fever during or after travel (even if they took chemoprophylaxis) should seek expert advice concerning malaria diagnosis and treatment without delay [29,30].

For patients who develop malaria during travel, an alternative antimalarial class should be used to treat infection, if available. The chemoprophylactic regimen should be continued, unless there are significant drug-drug interactions.

In addition, travelers should be counseled that their travel history is an important clue to bring to the attention of the health care provider during the year following exposure [30].

Factors influencing delayed presentation of malaria include:

•Infection with relapsing species (P. vivax and P. ovale spp) may present months following exposure despite chemoprophylaxis, since most chemoprophylactic agents (except primaquine and tafenoquine) do not eradicate the dormant hypnozoites of these species [30]. (See "Antimalarial drugs: An overview", section on 'Life cycle drug targets'.)

•In semi-immune individuals born in endemic areas, P. falciparum may present years after their last exposure [31]. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children", section on 'Incubation period'.)

TOOLS FOR PREVENTION — 

Mosquito bite prevention measures should always be used. Chemoprophylaxis should be used in specific areas, depending on risk. (See 'Review travel plans' above.)

Mosquito bite prevention — Travelers to endemic areas should receive guidance on methods to prevent mosquito bites; such measures also help reduce bites from sandflies and ticks. These include [32-35]:

●Avoiding outdoor exposure between dusk and dawn (feeding intervals for Anopheles mosquitoes responsible for malaria transmission).

●Staying in well-screened or air-conditioned accommodations.

●Sleeping within bed nets treated with insecticide; this is generally necessary only in areas with very high intensity transmission (not on usual tourist itineraries). (See "Malaria: Epidemiology, prevention, and elimination", section on 'Insecticide-treated nets (ITNs)'.)

●Wearing clothing that reduces the amount of exposed skin. In addition, clothing may be treated with permethrin or other residual insecticides [32,36-39].

●Wearing insect repellent. (See "Prevention of arthropod bites: Repellents and other measures".)

Chemoprophylaxis

Indications and antimalarial agents — Individual itineraries should be reviewed together with the most recent guidelines and advisories to determine the appropriate approach to chemoprophylaxis.

●Indications

•Primary prophylaxis – For travelers at risk for malaria infection in the context of travel to destinations with malaria transmission, we recommend chemoprophylaxis. (See 'Primary prophylaxis' below.).

For travelers to destinations where malaria cases occur only sporadically and risk to travelers is very low, mosquito-avoidance measures should be used; no chemoprophylaxis is needed.

Various expert bodies have developed guidance on regions where travelers should take malaria chemoprophylaxis [40]. There is generally consensus in high-transmission areas; however, recommendations may differ in lower-transmission areas due to differences in approaches, evidence interpretation, and risk tolerance [40]. Information regarding malaria transmission areas, drug resistance, malaria species, and recommended chemoprophylaxis options is available on the United States Centers for Disease Control and Prevention (CDC) website [16].

Use of chemoprophylaxis in travelers is supported by a meta-analysis including 12 randomized trials comparing mefloquine with placebo among more than 1900 individuals in endemic areas [41]. Fewer cases of malaria were observed among those who received mefloquine compared with placebo (17 versus 153 events; risk ratio [RR] 0.09; 95% CI 0.04-0.19). These findings may overestimate the benefit of mefloquine among short-term travelers, given lower risk of malaria infection with shorter duration of exposure.

•Preventing relapse – For long-term travelers (>6 months) to regions where there is transmission of P. vivax or P. ovale spp (even if P. falciparum is the predominant endemic species) who receive primary prophylaxis with an agent that does not have activity against hypnozoites (these include atovaquone-proguanil, doxycycline, mefloquine, or chloroquine), we suggest administration of presumptive antirelapse therapy. (See 'Preventing relapse' below.)

●Antimalarial agents – Chemoprophylaxis options for malaria include atovaquone–proguanil, doxycycline, mefloquine, chloroquine, primaquine, and tafenoquine. Dosing is outlined in the tables (table 1 and table 2). Drug mechanisms are shown in the figure (figure 3).

For patients traveling to multiple destinations with variable patterns of malaria risk, it may be simplest to select a single agent that will be effective for the entire duration of exposure.

Antimalarial therapy should be started prior to travel, continued regularly during exposure, and for a period of time following departure from the endemic area.

In general, most chemoprophylaxis regimens are designed to prevent primary attacks of malaria. Primaquine and tafenoquine can prevent relapses of malaria caused by P. vivax and P. ovale spp. (See 'Preventing relapse' below.)

•Prescription supply – A prescription for the full supply of medication should be written and filled prior to departure; the sale of counterfeit and poor-quality antimalarials is an increasing problem in Asia and Africa [42].

•Maximum duration – It is appropriate to administer antimalarial drugs for as long as needed for the prevention of malaria infection; there is no evidence of toxicity after prolonged use. Evidence supports long-term use of atovaquone-proguanil, doxycycline, mefloquine, and chloroquine for up to two years [43,44]. Tafenoquine is approved for prophylaxis for up to six months, with limited safety data for use up to one year [45,46]. For those staying in a malaria-endemic country for >6 months, it will be important to identify local health resources for timely diagnosis and treatment of malaria.

Primary prophylaxis

Approach to drug selection — Drug selection should be guided by the travel itinerary and the traveler's medical history. (See 'Assessing risk' above.)

Additional considerations for drug selection include contraindications, potential adverse effects (table 1 and table 2), drug interactions (see 'Drug interactions' below), dosing schedule (daily versus weekly), availability, and cost.

●Options for malaria species in most areas – Chloroquine-resistant P. falciparum is widespread in endemic areas of Africa, Asia, Oceania, and South America.

•Preferred chemoprophylaxis regimen – For most short-term travelers, we suggest atovaquone-proguanil (administered daily) given greater tolerability. However, for those with contraindications (eg, severe kidney impairment), other options, such as doxycycline, mefloquine, and tafenoquine, are equally effective.

•Other chemoprophylaxis options

-Doxycycline – Doxycycline (administered daily) is a reasonable alternative to atovaquone-proguanil if tolerated; adverse effects include gastrointestinal discomfort and photosensitivity.

-Mefloquine – In regions with mefloquine-resistant P. falciparum, mefloquine should not be used for prophylaxis. P. falciparum strains resistant to chloroquine and mefloquine are present in Southeast Asia on the borders of Thailand with Burma (Myanmar) and Cambodia, in the western provinces of Cambodia, in the eastern states of Burma on the border between Burma and China, along the borders of Burma and Laos, and in southern Vietnam.

Outside of these regions, mefloquine (administered weekly) is a reasonable alternative to atovaquone-proguanil in the absence of contraindications (these include patients with neurologic and psychiatric disorders as well as those with arrhythmia).

Some long-term travelers may prefer mefloquine (in the absence of contraindications), given weekly administration and lower cost.

-Tafenoquine – Tafenoquine (administered weekly following loading dose) is a reasonable alternative to atovaquone-proguanil in patients ≥18 years of age with no history of psychosis; a quantitative glucose-6-phosphate dehydrogenase (G6PD) test must be done to rule out G6PD deficiency prior to administration. (See "Antimalarial drugs: An overview", section on 'Tafenoquine'.)

●Additional options for areas with exclusively chloroquine-sensitive malaria – Chloroquine-sensitive P. falciparum exists in Haiti, the Caribbean, and in Central America west and north of the Panama Canal. For these regions, in addition to the drugs outlined above, additional options include chloroquine or hydroxychloroquine.

●Additional options for areas with exclusively (>90 percent) P. vivax – P. vivax is the predominant species (>90 percent) in Mexico, parts of Central America, Cambodia, North Korea, and South Korea. For these regions, in addition to the drugs outlined above, primaquine is an additional option. A quantitative G6PD test must be done to rule out G6PD deficiency prior to administration of primaquine.

For travelers at risk for relapse (see 'Preventing relapse' below) who use primaquine for primary prophylaxis, no additional treatment for relapse prevention is required.

Available drugs — Antimalarial regimens and dosing are summarized in the tables (table 1 and table 2).

Atovaquone-proguanil

●Activity – Atovaquone acts synergistically with proguanil against P. falciparum and the other malaria species [47]. Atovaquone-proguanil targets the active liver tissue schizonts as well as the asexual blood stages of the parasite. Atovaquone-proguanil does not prevent hypnozoite formation by P. vivax or P. ovale spp. (See 'Preventing relapse' below.)

●Efficacy – The efficacy of atovaquone-proguanil for malaria prevention is comparable to that of mefloquine.

In a randomized trial including 976 travelers treated with atovaquone-proguanil or mefloquine, efficacy for malaria prevention was comparable; there were no cases of confirmed malaria in either group [48]. Those who received atovaquone-proguanil had fewer treatment-related neuropsychiatric adverse effects (14 versus 29 percent), fewer adverse effects of moderate or severe intensity (10 versus 19 percent), and fewer adverse effects that caused prophylaxis to be discontinued (1.2 versus 5.0 percent).

●Administration – Dosing is summarized in the tables (table 1 and table 2). Atovaquone-proguanil is administered daily with food beginning one to two days prior to exposure, during exposure, and for one week following exposure [49-51]. Shorter courses are not recommended [52].

●Adverse effects – The drug is well tolerated, with excellent profiles of safety and efficacy [47,48,53-60]. Adverse effects may include gastrointestinal upset, insomnia, headache, rash, and mouth ulcers [53,61]. In general, atovaquone-proguanil is associated with fewer side effects than mefloquine [60].

●Contraindications – Atovaquone-proguanil is contraindicated in patients with creatinine clearance <30 mL per minute, and it is not recommended for use in pregnant women, infants weighing <5 kg, or women breastfeeding infants weighing <5 kg due to insufficient safety data.

Doxycycline

●Activity – Doxycycline has activity against chloroquine-sensitive and chloroquine-resistant P. falciparum, as well as the other malaria species that cause human malaria [62-64]. Doxycycline targets the asexual blood stages of the parasite. Doxycycline does not prevent hypnozoite formation by P. vivax or P. ovale spp. (See 'Preventing relapse' below.)

Doxycycline provides some protection against infection with some rickettsial infections (eg, scrub typhus) and Leptospira spp [65,66].

●Efficacy – Comparative trials have demonstrated equivalent efficacy of doxycycline with mefloquine (eg, 93 to 99 percent) for malaria prevention [67,68].

●Administration – Dosing is summarized in the tables (table 1 and table 2). Doxycycline is administered daily beginning one to two days prior to exposure, daily during exposure, and daily for four weeks following exposure [64]. Noncompliance (even for a few days) with this daily regimen is an important reason for doxycycline prophylaxis failure [69].

●Adverse effects – Doxycycline is usually well tolerated but has been associated with gastrointestinal upset; less commonly, ultraviolet photosensitivity, Candida vaginitis, and rare cases of esophageal ulceration may also occur [70-72]. The drug should be taken with fluids and food; it should not be administered immediately before lying down. Doxycycline may cause sun sensitization; sunscreen should be applied liberally (before insect repellent). It is advisable to offer women antifungal self-treatment for management of Candida vaginitis (eg, fluconazole).

●Contraindications – Doxycycline is contraindicated in pregnant and breastfeeding women and for malaria prophylaxis in children <8 years of age.

Mefloquine

●Activity – Mefloquine is effective for prevention of malaria due to chloroquine-sensitive and chloroquine-resistant P. falciparum, as well as the other malaria species [41]. Mefloquine targets the asexual blood stages of the parasite. Mefloquine does not prevent hypnozoite formation by P. vivax or P. ovale spp. (See 'Preventing relapse' below.)

Mefloquine is not effective for prevention of malaria due to mefloquine-resistant P. falciparum, which is present in Southeast Asia on the borders of Thailand with Burma (Myanmar) and Cambodia, in the western provinces of Cambodia, in the eastern states of Burma on the border between Burma and China, along the borders of Burma and Laos, and in southern Vietnam [62]. (See 'Review travel plans' above.)

●Efficacy – The effectiveness of mefloquine for malaria prophylaxis is >90 percent. Data regarding mefloquine efficacy are discussed above [41]. (See 'Indications and antimalarial agents' above.)

●Administration – Dosing is summarized in the tables (table 1 and table 2). Mefloquine is administered weekly beginning at least two weeks prior to exposure, during exposure, and for four weeks following exposure.

For pregnant women who cannot avoid travel to areas with chloroquine-resistant P. falciparum, mefloquine may be safely administered during all trimesters [73,74]. (See 'Pregnant travelers' below.)

●Adverse effects – Some travelers experience adverse effects from mefloquine; most are mild, self-limited, and do not require discontinuation of the drug. The most frequent adverse effects are gastrointestinal upset, lightheadedness, headache, difficulty concentrating, mood swings, and strange dreams [28].

About 5 percent of travelers experience disabling neuropsychiatric adverse effects requiring discontinuation of the drug. These include anxiety, depression, nightmares, paranoid ideation, and dizziness. About 1 in 10,000 travelers experience severe neuropsychiatric reactions such as seizures and psychosis. Adverse effects appear to be more common among women and less frequent among children [75].

Most adverse effects requiring mefloquine discontinuation occur within the first three doses. Therefore, some favor starting mefloquine four weeks prior to travel to determine drug tolerance.

●Contraindications – Contraindications to mefloquine include known hypersensitivity to the drug, a history of seizures or major psychiatric disorder, and a recent history of depression or anxiety. Development of psychiatric symptoms (such as depression, anxiety, restlessness, or confusion) while taking mefloquine should be viewed as a possible prelude to other events; in such circumstances, it is advisable to stop the drug immediately and switch to a different prophylaxis agent. Mefloquine has also been associated with sinus bradycardia and QT interval prolongation; therefore, it should be used with caution in patients with cardiac conduction disorders or those taking antiarrhythmic medications.

Chloroquine

●Activity – Chloroquine is effective for prevention of malaria for travelers to malarious areas without chloroquine resistance (Haiti, the Caribbean, and in Central America west and north of the Panama Canal). Chloroquine has activity against all plasmodial species causing human malaria with the exception of chloroquine-resistant P. falciparum strains (in most of the world) and uncommon strains of chloroquine-resistant P. vivax in Oceania and Asia. (See 'Review travel plans' above.)

Chloroquine targets the asexual blood stages of the parasite. Chloroquine does not prevent hypnozoite formation by P. vivax or P. ovale. (See 'Preventing relapse' below.)

●Administration – Dosing is summarized in the tables (table 1 and table 2). Formulations include chloroquine phosphate and hydroxychloroquine (table 1) [62]. Chloroquine is administered once weekly starting one week prior to exposure, once weekly while in the malaria-endemic area, and then once weekly for four weeks following exposure.

●Adverse effects – Apart from its bitter taste, chloroquine is usually well tolerated. Minor side effects include gastrointestinal disturbances, dizziness, blurred vision, and headache; gastrointestinal problems may be alleviated by taking the drug with food. It has been associated with flares of psoriasis and pruritus, although serious side effects are rare [76]. The mechanism of pruritus is not entirely clear, but it appears to be a side effect of the medicine, not an allergic reaction. Retinal injury, which can occur when high doses of chloroquine are used to treat rheumatoid arthritis, does not occur with the weekly doses used for malaria prevention [77]. Chloroquine is safe for use in pregnancy and while breastfeeding.

Primaquine

●Activity – Primaquine is an option for primary prophylaxis for travelers to areas where the principal endemic species (>90 percent) is P. vivax (such as Mexico, parts of Central America, Cambodia, North Korea, and South Korea).

In addition, primaquine is useful for preventing relapses from the hypnozoite forms of P. vivax and P. ovale spp.

Primaquine has schizonticidal activity against the tissue stages of all species and the blood stages of the non-falciparum species, but lacks sufficient blood schizonticidal activity against P. falciparum, so it should not be used as primary prophylaxis in areas with P. falciparum.

●Efficacy – The efficacy of primaquine for protection against P. vivax infection is 85 to 92 percent [78-83].

●Administration – A G6PD level must be obtained prior to administration of this drug, and patients should receive primaquine only if G6PD deficiency has been excluded.

Dosing is outlined in the tables (table 1 and table 2). For primary prophylaxis, primaquine is administered daily beginning one to two days prior to exposure, once daily during exposure, and daily for seven days following exposure [80].

For prevention of relapse, the approach to administration of primaquine is discussed below. (See 'Preventing relapse' below.)

●Adverse effects – Primaquine can cause hemolytic anemia in those with G6PD deficiency. Primaquine may also cause gastrointestinal upset that can be minimized if taken with food.

●Contraindications – Primaquine can cause severe hemolytic anemia in those with G6PD deficiency and is contraindicated in anyone with G6PD deficiency or who has not been tested for G6PD deficiency. Primaquine is contraindicated in pregnancy and women breastfeeding infants with unknown G6PD status.

Tafenoquine

●Activity – Tafenoquine is an 8-aminoquinoline drug related to primaquine. Tafenoquine is effective for primary prophylaxis of malaria due to chloroquine-sensitive and chloroquine-resistant P. falciparum, as well as the other malaria species.

Tafenoquine is active against all stages of Plasmodium species, including hypnozoites of P. vivax (and by extrapolation, P. ovale spp).

●Efficacy – The efficacy of tafenoquine for malaria prevention is comparable to that of mefloquine (>90 percent) [46,84,85]. In a systematic review and meta-analysis including 2495 participants in nine randomized trials, prophylaxis with tafenoquine was associated with reduction of malaria infection compared with placebo (RR 0.22; 95% CI 0.07-0.73) [46].

●Administration – Tafenoquine has been approved by the US Food and Drug Administration for prevention of infection due to all species of malaria in individuals ≥18 years of age [86].

A quantitative G6PD test must be done to rule out G6PD deficiency prior to the first administration of the drug. Note that qualitative G6PD testing can miss those with moderate deficiency and is not sufficient to establish normal G6PD activity.

Dosing is outlined in the tables (table 1 and table 2). Tafenoquine is administered daily beginning three days prior to exposure, weekly during exposure (starting seven days after last loading dose), and once in the week following exposure [87]. Use for prophylaxis is limited to a six-month duration.

●Adverse effects – Tafenoquine should be taken with food to prevent gastrointestinal upset. The most common side effects include dizziness, nausea, vomiting, headache, and nonclinically significant decreases in hemoglobin. Vortex keratopathy not affecting visual acuity is also associated with the use of tafenoquine, and in studies of use up to six months, has been observed to be reversible upon discontinuation of the medication [46,88].

●Contraindications – Tafenoquine can cause severe hemolytic anemia in those with G6PD deficiency and is contraindicated in anyone with G6PD deficiency or who has not been tested for G6PD deficiency. Tafenoquine is contraindicated in pregnancy since the G6PD status of the fetus is unknown. Tafenoquine should not be used in women breastfeeding infants with unknown or deficient G6PD levels.

Use of tafenoquine is not recommended in patients with a history of psychiatric disorders [86,89].

Drug interactions — Prior to prescribing antimalarial medication, the traveler's medication history should be reviewed in detail with consideration for potential drug-drug interactions; this may be done using the drug interactions program included in UpToDate. Some relatively common drugs with important interactions include:

●Warfarin – Atovaquone-proguanil and doxycycline may diminish metabolism of warfarin. Coagulation parameters should be monitored closely if these drugs are used together, and the warfarin dosing may need to be reduced [90].

●Antiarrhythmic agents – These drugs should be used with caution in the setting of mefloquine administration, which has been associated with sinus bradycardia and QT interval prolongation.

●Immunosuppressive medications – Chloroquine may increase cyclosporine levels, and both doxycycline and mefloquine may increase levels of cyclosporine and tacrolimus [91]. Atovaquone-proguanil does not have known interactions with these medications.

●Antiretroviral agents – Drug-drug interactions are common with some antiretroviral agents. Information about these interactions should be reviewed prior to prescribing antimalarial medications [92].

Special populations

Pregnant travelers

●Malaria risk – Malaria can be a life-threatening infection for both mother and fetus [24,93]. Pregnant women should be advised to defer travel until after delivery whenever feasible. Risk of stillbirth, spontaneous abortion, and other adverse pregnancy outcomes is increased in the setting of malaria. (See "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome".)

●Chemoprophylaxis – For pregnant travelers who cannot defer travel, mosquito avoidance measures should be used in conjunction with primary chemoprophylaxis as outlined below.

•Drug selection – Dosing is outlined in the table (table 1).

-For pregnant travelers to most areas, we favor mefloquine for chemoprophylaxis [94-96].

-For pregnant travelers to areas with exclusively chloroquine-sensitive P. falciparum malaria, we favor chloroquine over mefloquine given greater tolerability [62,97].

-Issues related to relapse prevention during pregnancy are discussed separately. (See "Malaria in pregnancy: Prevention and treatment", section on 'Antirelapse therapy'.)

•Drug safety in pregnancy – Mefloquine may be safely administered during all trimesters [74,94,98,99].

Atovaquone-proguanil is not recommended for use during pregnancy because of limited availability of data on its safety and because other options are available. If other antimalarial drug options are not feasible, however, clinicians and patients should discuss the risks and benefits of using atovaquone-proguanil [100,101].

There is some concern that doxycycline administered during pregnancy has potential adverse effects to the fetus including dysplasia, inhibition of bone growth, and dental discoloration. Its use in pregnancy is allowed in some countries up to the first 15 weeks in pregnancy; in others its use is contraindicated in pregnancy.

Neither primaquine nor tafenoquine should be administered during pregnancy given the possibility of fetal G6PD deficiency.

Children — For children ≥5 kg traveling to most areas, atovaquone-proguanil (administered daily) may be preferred over the other agents given greater tolerability [54]. Doxycycline is an alternative for children ≥8 years of age. Mefloquine is an alternative for infants and children of all weights.

For children traveling to areas with exclusively chloroquine-sensitive P. falciparum malaria, chloroquine may be used in infants and children of all weights

Dosing is summarized in the table (table 2). Antimalarial prophylaxis medications are only available in pill form; for children unable to swallow pills, the pills should be crushed and mixed with food or drink.

Preventing relapse

●Rationale – Late-onset or relapsed disease due to reactivation of hypnozoites (a quiescent liver stage) (figure 3) can occur up to many months after initial infection with P. vivax or P. ovale spp. 

Travelers who receive primary prophylaxis with an agent that does not have activity against hypnozoites (these include atovaquone-proguanil, doxycycline, mefloquine, or chloroquine) may be at risk for relapse [28,102].

Presumptive antirelapse therapy (PART; also termed terminal prophylaxis) refers to administration of primaquine to eliminate any hypnozoites and prevent relapsing malaria.

Issues related to risk of relapse and efficacy for antirelapse treatment are discussed in further detail separately. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae", section on 'Relapse'.)

●Indications

•Which travelers? – PART is indicated for travelers with prolonged exposure (>6 months) or intense mosquito exposure in regions where there is P. vivax or P. ovale spp, in the absence of G6PD deficiency [17].

PART is not needed for travelers who receive primary prophylaxis with an agent that has activity against dormant hypnozoites (these include tafenoquine and primaquine).

•Which destinations? – Information regarding geographic regions with P. vivax or P. ovale spp is available by country on the CDC website.

There is variability in the frequency of relapse and the duration of latency between geographic zones [103,104]:

-The zone comprising Southeast Asia, Papua New Guinea, and Melanesia has the highest predicted incidence of relapse (800 to 1200 per 100,000 person days) and the fastest mean time to relapse (approximately 45 days).

-The zone comprising Northern Asia and Europe has the lowest incidence of relapse (130 per 100,000 person-days) and the longest mean time to relapse (approximately 10 months), but relapse may occur several years after exposure.

PART could be considered for travelers to highly endemic P. vivax areas in the Pacific Islands (Papua New Guinea, Vanuatu, and Solomon Islands or the Horn of Africa), even for trips <6 months [105].

●Approach – Following departure from an endemic area, primaquine is administered for 14 days after leaving a malaria-endemic area, concurrently with the primary prophylaxis regimen [17]; dosing is summarized in the tables (table 1 and table 2).

A quantitative G6PD test must be done to rule out G6PD deficiency prior to the first administration of primaquine. Patients with G6PD deficiency should forgo PART. (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

•If atovaquone-proguanil is used for primary prophylaxis, travelers can take primaquine during the final seven days of atovaquone-proguanil, and then for an additional seven days.

•If chloroquine, doxycycline, or mefloquine is used for primary prophylaxis, travelers can take primaquine during the last two weeks of postexposure prophylaxis.

•If concurrent administration of primary and PART is not feasible, instruct travelers to take primaquine after completing their primary prophylaxis medication.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria" and "Society guideline links: Travel medicine".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Vaccines for travel (The Basics)" and "Patient education: Malaria (The Basics)")

●Beyond the Basics topic (see "Patient education: General travel advice (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Assessing risk – Risk assessment consists of reviewing the travel itinerary to determine whether chemoprophylaxis is indicated. The traveler's medical history should be considered in guiding choice of chemoprophylaxis. Country-specific information is available in the United States Centers for Disease Control and Prevention (CDC) website, together with the most recent guidelines and advisories. (See 'Assessing risk' above.)

●Traveler counseling – Travelers should be counseled that their itinerary puts them at risk for malaria, a serious infection that can be fatal. They should be educated on recognizing malaria symptoms; those who develop fever during or after travel (even if they took chemoprophylaxis) should seek expert advice concerning malaria diagnosis and treatment.

●Mosquito bite prevention – All travelers should be counseled on mosquito bite prevention. Methods include avoiding outdoor exposure between dusk and dawn, staying in screened or air-conditioned accommodations, wearing protective clothing, and using insect repellant. (See 'Mosquito bite prevention' above.)

●Primary prophylaxis – For travelers at risk for malaria infection in the context of travel to destinations with malaria transmission, we recommend chemoprophylaxis (Grade 1B). Drug dosing is summarized in the tables (table 1 and table 2). (See 'Indications and antimalarial agents' above.)

•Nonpregnant adults – Considerations for drug selection include risk of exposure to drug-resistant malaria, contraindications, potential adverse effects, drug interactions, dosing schedule (daily versus weekly), availability, and cost.

For most short-term travelers, we suggest atovaquone given its greater tolerability and fewer side effects (Grade 2C). However, for those with contraindications (eg, severe kidney impairment), other options, such as doxycycline, mefloquine, and tafenoquine, are equally effective. (See 'Approach to drug selection' above.)

•Pregnant travelers – Pregnant travelers should be advised to defer travel until after delivery whenever feasible. For pregnant travelers to most areas, we favor mefloquine for chemoprophylaxis; for those traveling to areas with exclusively chloroquine-sensitive Plasmodium falciparum malaria, we favor chloroquine over mefloquine given greater tolerability. (See 'Pregnant travelers' above.)

●Preventing relapse (see 'Preventing relapse' above)

•Late-onset or relapsed disease due to reactivation of hypnozoites (a quiescent liver stage) (figure 3) can occur up to many months after initial infection with Plasmodium vivax or Plasmodium ovale spp. 

•For long-term travelers (>6 months) to regions where there is transmission of P. vivax or P. ovale spp (even if P. falciparum is the predominant endemic species) who receive primary prophylaxis with an agent that does not have activity against hypnozoites (these include atovaquone-proguanil, doxycycline, mefloquine, or chloroquine), we suggest administration of presumptive antirelapse therapy (Grade 2C).

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Ellen O Boundy, ScD, MS, RN, who contributed to an earlier version of this topic review.