Version May 2024
INTRODUCTION — Malaria is an important cause of fever and serious illness in returned travelers [1,2]. Among nearly 7000 returned travelers with fever seen at a GeoSentinel clinic between 1997 and 2006, for example, malaria was the most common specific etiologic diagnosis, found in 21 percent of cases [1]. The relative risk of malaria is higher among returned travelers from sub-Saharan Africa than those from Asia or the Americas [3].
There were 2161 cases of malaria reported in 2017 to the United States Centers for Disease Control and Prevention (CDC) [3]. More than half of the reported cases are due to Plasmodium falciparum, which causes the most severe disease; patients with P. falciparum may progress to life-threatening illness within hours [4,5]. Since 2011, there has been an average of seven malaria deaths per year in the United States.
Prevention efforts should be aimed at all forms of malaria. In addition to P. falciparum, other Plasmodium species that cause human malaria include P. vivax, P. ovale, P. malariae, and P. knowlesi. While P. falciparum is most likely to result in severe disease, all malaria species can cause severe disease and death [6,7]. In general, most chemoprophylaxis regimens are designed to prevent primary attacks of malaria. Primaquine and tafenoquine can also prevent relapses of malaria caused by P. vivax and P. ovale. (See 'Drug mechanisms' below and 'Primaquine' below and 'Tafenoquine' below.)
Most travelers who develop malaria do so because they do not adhere to an effective chemoprophylactic drug regimen [8-10]. In addition, many travelers frequently fail to use personal protection measures for mosquito bite prevention.
Issues related to risk assessment, counseling, mosquito bite prevention, and antimalarial chemoprophylaxis for prevention of malaria 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 report are those of the authors and do not necessarily represent the official position of the CDC.
RISK ASSESSMENT — The risk of malaria transmission depends on a variety of factors including the geographic region visited and the type of traveler [11].
Destination — In addition to the geographic region visited, the risk of malaria transmission depends upon the type of accommodation (eg, open air, tented, air conditioned, or screened), the season (rainy versus dry), the elevation, and the duration of exposure.
Geographic risk assessment for malaria requires a detailed review of the planned itinerary together with the most recent United States Centers for Disease Control and Prevention (CDC) guidelines and advisories [12]. Listings of regions where malaria transmission occurs, the presence of antimalarial drug resistance, and recommended chemoprophylaxis for specific destination are available in the CDC publication "Health Information for International Travel" (also known as the Yellow Book), which may be accessed online [13]. The World Health Organization (WHO) provides useful online information including maps and malaria data [14].
An excellent summary of areas where malaria transmission occurs and prophylaxis by country is available on the CDC website.
Type of traveler — Important risk groups include travelers born in regions with endemic malaria who relocate outside the endemic area but subsequently return to visit friends and relatives (known as VFRs), pregnant patients, and military personnel.
VFR travelers are at greatest risk for malaria infection; this group includes individuals born in regions with endemic malaria who have emigrated outside these regions, as well as the subsequent generation of children born outside endemic areas [15-17]. VFRs pose unique challenges for malaria prevention since those with acquired immunity afforded some degree of protection against malaria while they resided in the endemic area, although such immunity wanes outside endemic regions [18]. In addition, such individuals may have difficulty seeking or accessing preventive services, may receive incorrect information regarding appropriate prophylaxis measures, and may not appreciate the risk or severity of infection once their immunity has waned [15]. Among patients for whom reason for travel was known, 70 percent of the severe cases of imported malaria in 2015 (including all five deaths) were in VFRs [3].
Pregnant travelers should be advised to defer travel until after delivery whenever feasible. (See 'Pregnant patients' below.)
Military personnel represent another important risk group; these individuals 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 [19].
Human immunodeficiency virus (HIV)-infected travelers warrant the same approach to prevention of malaria as HIV-uninfected travelers. Potential drug interactions should be considered. (See 'Drug interactions' below.)
TOOLS FOR PREVENTION
Counseling — Travelers to malarious 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 [20]. Prevention measures include avoiding mosquito bites and adhering to antimalarial chemoprophylaxis. However, travelers should also understand that no chemoprophylaxis regimen guarantees complete protection and that fever during or after travel is a medical emergency requiring urgent medical attention [21]. Other symptoms may include headache, myalgia, cough, nausea, abdominal pain, vomiting, and diarrhea. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)
Travelers should be counseled that their travel history is an important clue to bring to the attention of the health care provider in the case of illness during the first year following exposure [21]. Because most chemoprophylactic agents (with the exception of primaquine and tafenoquine) do not eradicate the dormant hypnozoites of P. vivax and P. ovale capable of causing relapsing malaria, infection with these species may present months following exposure in spite of full adherence to chemoprophylaxis [21]. (See 'Drug mechanisms' below and 'Primaquine' below and 'Tafenoquine' below.)
In semi-immune individuals born in endemic areas, P. falciparum may present years after their last period of exposure [22].
Travelers planning prolonged visits to endemic areas should continue prophylaxis throughout their stay and for the recommended period of time afterward. Local laboratories in developing regions may have high rates of false-positive malaria diagnoses; travelers who become ill should be advised to seek expert advice concerning malaria diagnosis and therapy [23-25]. In such cases, the chemoprophylactic regimen should be continued together with treatment offered locally, unless there are significant drug-drug interactions (such as mefloquine with halofantrine). If the initial evaluation demonstrates negative blood films, thick and thin blood films or rapid diagnostics should be repeated twice (12 to 24 hours apart).
Pregnant patients are an important risk group, as malaria can be a life-threatening infection for both mother and fetus [26]. Risk of stillbirth, spontaneous abortion, and other adverse pregnancy outcomes are increased in the setting of malaria; pregnant patients should be advised to defer travel until after delivery whenever feasible. (See 'Pregnant patients' below.)
Mosquito bite prevention — Travelers to malarious areas should receive instructions regarding methods to prevent bites from Anopheles mosquitoes; such measures also help reduce bites from sandflies, ticks, and other mosquito species. These include [27-29]:
●Avoiding outdoor exposure between dusk and dawn (when Anopheles mosquitoes feed)
●Wearing clothing that reduces the amount of exposed skin
●Wearing insect repellant
●Sleeping within bed nets treated with insecticide (eg, permethrin)
●Staying in well-screened or air-conditioned rooms
Insect repellents recommended by the United States Centers for Disease Control and Prevention for reducing the risk of malaria include N,N-diethyl-m-toluamide (DEET), picaridin, ethyl butylacetylaminopropionate (IR3535), and oil of lemon eucalyptus (OLE) [13,28]. (See "Prevention of arthropod and insect bites: Repellents and other measures".)
●DEET (30 to 50%) is generally protective for at least four hours, although lower percentage preparations provide a shorter duration of protection. When used as directed, this same concentration of DEET is safe for infants and children >2 months.
●Picaridin is a synthetic repellant. This agent (20% concentration) and DEET (35% concentration) have comparable efficacy for protection against malaria vectors up to eight hours after application [30].
●IR3535 (15% or higher) is protective for about eight hours.
●OLE in products registered with the Environmental Protection Agency is an effective repellant and can be used in children >3 years. "Pure" eucalyptus oil (essential oil) has not been tested for efficacy or safety.
In addition to applying insect repellants to the skin, fabric may be treated with permethrin or other residual insecticides [27,29,31,32]. Permethrin is a synthetic compound that causes nervous system toxicity to insects with low toxicity for humans [33]. It is available in outdoor supply stores as an aerosol clothing spray (eg, Permanone Repellent).
Clothing and bed netting treated with permethrin effectively repel mosquitoes for more than one week even with washing and field use [27,29]. Standard nets dipped in permethrin are effective for three washes, whereas newer formulations can withstand 20 washes. Long-lasting insecticide impregnated nets (LLINs) can remain effective as long as three years. Since use of such nets is very effective for reducing the risk of malaria, travelers to endemic areas with accommodations lacking screens or air conditioning (such as travelers visiting friends and relatives or backpackers) should sleep under insecticide-treated nets [29]. It is advisable to bring netting as local availability may be unpredictable.
Chemoprophylaxis — Individual itineraries should be reviewed together with the most recent guidelines and advisories to determine the appropriate approach to chemoprophylaxis (figure 1 and figure 2 and figure 3) [12,13].
Listings of regions where malaria transmission occurs, the presence of antimalarial drug resistance, and recommended chemoprophylaxis for specific destination are available in the United States Centers for Disease Control and Prevention (CDC) publication "Health Information for International Travel" (also known as the Yellow Book). Additional information is available on the CDC's malaria website [13]. The World Health Organization (WHO) provides useful online information including maps and malaria data [14].
Suggested approach — Selection of chemoprophylaxis must be tailored to individual itineraries and circumstances. For patients traveling to several destinations with different malaria transmission patterns, it may be simplest to select a single agent that will be effective for the entire duration of exposure.
●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.
●For travelers at risk of malaria infection in destinations where chloroquine-resistant P. falciparum malaria is present, mosquito avoidance measures should be used in conjunction with chemoprophylaxis. Options for chemoprophylaxis include atovaquone-proguanil, mefloquine, doxycycline, and tafenoquine; all four agents are highly efficacious for prevention of malaria. Comparative studies among travelers taking mefloquine or atovaquone-proguanil have demonstrated that fewer side effects are experienced among recipients of atovaquone-proguanil, although this agent is more costly [34]. Short-term travelers may prefer the shorter course of atovaquone-proguanil, whereas long-term travelers may prefer the convenience of weekly mefloquine. Doxycycline must be taken daily and may cause sun sensitization. Travelers must be tested for G6PD deficiency before using tafenoquine. (See 'Tafenoquine' below.)
●For travelers at risk of malaria infection in the very few destinations in the world where chloroquine-sensitive P. falciparum malaria is present, mosquito avoidance measures should be used in conjunction with chemoprophylaxis. Chloroquine may be used, although short-term travelers may prefer the shorter course of atovaquone-proguanil or tafenoquine. Mefloquine and doxycycline are also effective agents.
●For travelers at risk of malaria infection in destinations where P. falciparum strains resistant to chloroquine and mefloquine are present (such as in the malaria-endemic regions of Thailand bordering Myanmar [Burma] and Cambodia [eg, eastern provinces of Myanmar (Burma) and western provinces of Cambodia], China, Laos, and Vietnam), mosquito avoidance measures should be used in conjunction with chemoprophylaxis. Options include atovaquone-proguanil, doxycycline, or tafenoquine.
●For travelers at risk of malaria infection in destinations where the predominant species is P. vivax (such as the malaria-endemic parts of Mexico and Central America), mosquito avoidance measures should be used in conjunction with chemoprophylaxis. Primaquine or tafenoquine may be used in the absence of glucose-6-phosphate dehydrogenase (G6PD) deficiency; chloroquine is also effective. Short-term travelers may prefer the shorter course of atovaquone-proguanil or tafenoquine. Mefloquine and doxycycline are also effective agents [35].
It is appropriate to administer antimalarial drugs for as long as needed for prevention of malaria infection; there is no evidence of toxicity after prolonged use. Evidence supports long-term use of atovaquone-proguanil, chloroquine, doxycycline, and mefloquine for up to two years [36,37]. Beyond two years, data are more limited. For those staying in a malaria-endemic country for extended (>6 months) period of time, it will be important to identify local health resources for the timely diagnosis and treatment of malaria.
Antimalarial therapy 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) [38]. 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 [39,40]. Travelers should understand the importance of careful adherence to the chemoprophylaxis regimen, even though no chemoprophylaxis regimen guarantees complete protection. Individual agents are discussed in detail in the following section (table 1).
Drug regimens — Chemoprophylaxis agents vary with respect to cost, adverse effects, and dosing schedule [41]. Reviewing these items during the travel visit is important for facilitating adherence. Availability of the drugs, as well as recommendations for their use, may vary depending on the country of origin.
Atovaquone-proguanil — Atovaquone acts synergistically with proguanil against chloroquine-sensitive and chloroquine-resistant P. falciparum, as well as the other malaria species that cause human malaria [42]. The efficacy of atovaquone-proguanil is equivalent to that of mefloquine [43]. Atovaquone-proguanil does not prevent hypnozoite formation by P. vivax or P. ovale; in areas with high rates of infection due to these species, presumptive antirelapse therapy with primaquine or tafenoquine may be necessary to prevent relapse for persons who had been to those areas for extended periods of time. (See 'Drug mechanisms' below and 'Primaquine' below and 'Tafenoquine' below.)
Atovaquone-proguanil is administered daily with food beginning one to two days prior to exposure, during exposure, and for one week following exposure [44-46]. Shorter courses are not recommended [47]. Dosing is outlined in the tables (table 1 and table 2). The drug is well tolerated, with excellent profiles of safety and efficacy [34,42,43,48-54]. Adverse effects may include gastrointestinal upset, insomnia, headache, rash, and mouth ulcers [48,55].
Atovaquone-proguanil is contraindicated in patients with creatinine clearance <30 mL per minute, and it is not recommended for use in pregnant patients, infants weighing <5 kg, or women breastfeeding infants weighing <5 kg due to insufficient safety data.
Chloroquine — Chloroquine may be used for prophylaxis for individuals traveling to malarious areas without chloroquine resistance (figure 1 and figure 2 and figure 3) (see 'Drug resistance' below). Chloroquine has activity against all plasmodial species causing human malaria with the exception of chloroquine-resistant P. falciparum strains and uncommon strains of P. vivax in Oceania and Asia. In addition, chloroquine does not prevent the development of hypnozoites, the dormant forms of P. vivax or P. ovale malaria. Thus, for those with extended exposure to areas with high rates of infection due to these species, presumptive antirelapse therapy with primaquine or tafenoquine may be necessary to prevent relapse. (See 'Drug mechanisms' below and 'Primaquine' below and 'Tafenoquine' below.)
Formulations include chloroquine phosphate and hydroxychloroquine (table 1) [13]. 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. Dosing is outlined in the tables (table 1 and table 2).
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 [56]. 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 [57]. Chloroquine is safe for use in pregnancy and while breastfeeding.
Doxycycline — Doxycycline has activity against chloroquine-sensitive and chloroquine-resistant P. falciparum, as well as the other malaria species that cause human malaria [13,58-60]. Comparative trials have demonstrated equivalent efficacy of doxycycline with mefloquine (eg, 93 to 99 percent) [59,61-63]. Doxycycline can provide some protection against infection with some rickettsial infections (eg, scrub typhus) and Leptospira spp [64,65]. However, doxycycline does not prevent the development of the hypnozoites of P. vivax or P. ovale malaria. Thus, for those with extended exposure to areas with high rates of infection due to these species, presumptive antirelapse therapy with primaquine or tafenoquine may be necessary to prevent relapse. (See 'Drug mechanisms' below and 'Primaquine' below.)
Doxycycline is administered daily beginning one to two days prior to exposure, daily during exposure, and daily for four weeks following exposure. Dosing is outlined in the tables (table 1 and table 2). Noncompliance (even for a few days) with this daily regimen is an important reason for doxycycline prophylaxis failure [48,66].
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 [67-69]. The drug should be taken with fluids and food; it should not be administered immediately before lying down. Sunscreen should be applied liberally (before insect repellent) for the duration of prophylaxis. It is advisable to offer women antifungal self-treatment for management of Candida vaginitis (eg, fluconazole). Doxycycline is contraindicated in pregnant and breastfeeding women and for malaria prophylaxis in children <8 years of age.
Mefloquine — Mefloquine is effective for prevention of malaria due to chloroquine-sensitive and chloroquine-resistant P. falciparum, as well as the other malaria species that cause human malaria [70]. In a study of almost 140,000 travelers to East Africa, the prophylactic efficacy of mefloquine was 91 percent [71,72].
Mefloquine is not effective for prevention of malaria due to mefloquine-resistant P. falciparum, which is found along the Thailand-Cambodian border region and parts of China, Myanmar (Burma), Vietnam, and Laos [13] (see 'Drug resistance' below). In addition, mefloquine does not prevent the development of the hypnozoites of P. vivax or P. ovale malaria. For those with extended exposure to areas with high rates of infection due to these species, presumptive antirelapse therapy with primaquine or tafenoquine may be necessary to prevent relapse. (See 'Drug mechanisms' below and 'Primaquine' below and 'Tafenoquine' below.)
Mefloquine is administered weekly beginning at least two weeks prior to exposure, during exposure, and for four weeks following exposure. Dosing is outlined in the tables (table 1 and table 2). 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 [41]. 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 [73]. 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 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.
For pregnant patients who cannot avoid travel to areas with chloroquine-resistant P. falciparum, mefloquine may be safely administered during all trimesters [74]. (See 'Pregnant patients' below.)
Primaquine — Primaquine has activity against many stages of the malaria parasite including hypnozoites, tissue schizonts, gametocytes, and asexual blood stages of P. vivax (figure 4) [21,75] (see "Pathogenesis of malaria", section on 'Life cycle'). It is useful for preventing relapses from the hypnozoite forms of P. vivax and P. ovale; it also has activity against P. falciparum gametocytes [59]. The efficacy of primaquine for protection against P. falciparum and P. vivax is 74 to 95 percent and 85 to 92 percent, respectively [59,61,76-78]. Primaquine has poorer efficacy against P. falciparum and therefore should not be used as primary prophylaxis in areas with P. falciparum.
Primaquine may be used either as presumptive antirelapse therapy (PART; the term terminal prophylaxis has also been used in the literature) (see 'Relapse prevention' below) or as primary prophylaxis. Primaquine primary prophylaxis is appropriate for travelers to regions where the principal endemic species is P. vivax (such as Mexico and Central America) (figure 2). Primaquine is administered daily beginning one to two days prior to exposure, once daily during exposure, and daily for seven days following exposure. Dosing is outlined in the tables (table 1 and table 2) [76].
Primaquine can cause hemolytic anemia in those with G6PD deficiency. Therefore, a G6PD level must be determined prior to the first administration of this drug, and patients should receive primaquine only if G6PD deficiency has been excluded. Primaquine may also cause gastrointestinal upset that can be minimized if taken with food. Primaquine is contraindicated in pregnancy and women breastfeeding infants with unknown G6PD status.
Tafenoquine — Tafenoquine is an 8-aminoquinoline drug related to primaquine. It is active against all stages of Plasmodium species, including hypnozoites (dormant liver stage) of the P. vivax (and by extrapolation, P. ovale) parasite responsible for relapses of malaria. Its long half-life (approximately two weeks) allows for fewer doses than primaquine. In the single available comparative trial, it had similar prophylactic outcomes as mefloquine [79-81].
Tafenoquine was approved by the United States Food and Drug Administration in 2018 for prevention of infection due to all species of malaria in individuals ≥18 years of age, and for radical cure P. vivax infection in individuals ≥16 years of age. Use for prophylaxis is limited to six months duration.
When used for malaria prophylaxis, the regimen consists of 200 mg daily (two 100 mg tablets) by mouth beginning three days prior to exposure, weekly during exposure (starting seven days after last loading dose), and once in the week following exposure [82]. The dosing regimen may be appealing for those with shorter trips or seeking last-minute travel advice. Tafenoquine should be taken with food to prevent gastrointestinal upset.
Tafenoquine can cause severe hemolytic anemia in those with G6PD deficiency. Therefore, 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. 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. The most common side effects include dizziness, nausea, vomiting, headache, and nonclinically significant decreases in hemoglobin. Use of tafenoquine is not recommended in patients with a history of psychiatric disorders [83,84]. Vortex keratopathy not affecting visual acuity is also associated with use of tafenoquine and in studies of use up to six months has been observed to be reversible upon discontinuation of the medication.
Relapse prevention — Late-onset or relapsed disease due to reactivation of hypnozoites can occur up to many months after initial infection with P. vivax and P. ovale. Hypnozoites are a quiescent stage in the liver that exist only in the setting of P. vivax and P. ovale infection. Hepatic stages cause no fever symptoms, and one does not need to have had a primary clinical episode of malaria in order to have a relapse.
Use of primaquine for presumptive antirelapse therapy (PART) is appropriate for travelers to regions where there is substantial transmission of P. vivax or P. ovale, even if P. falciparum is the predominant endemic species [41,85]. If primaquine or tafenoquine is used for prophylaxis, there is no need for PART.
PART is especially appropriate for travelers with prolonged stays (eg, several months or more) where P. vivax or P. ovale are present [41]. In addition to taking an agent for prophylaxis with activity against blood-stage parasites prior to, during, and following exposure (such as atovaquone-proguanil, chloroquine, mefloquine, or doxycycline), primaquine is added for activity against liver hypnozoites, which can cause disease after completion of the primary chemoprophylaxis regimen (figure 4). If primaquine or tafenoquine is used for primary chemoprophylaxis, PART is not needed.
Following departure from an endemic area, primaquine may be administered for relapse prevention, as follows:
●Primaquine should be administered for 14 days together with the remainder of the primary prophylaxis regimen. If the primary prophylaxis regimen has already been completed, a course of primaquine is still beneficial for prevention of relapse (table 1 and table 2).
Issues related to relapse prevention are discussed in further detail separately. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae", section on 'Preventing relapse'.)
Special populations
Pregnant patients — Malaria can be a life-threatening infection for both mother and fetus [26,86]. Risk of stillbirth, spontaneous abortion, and other adverse pregnancy outcomes is increased in the setting of malaria, and pregnant patients should be advised to defer travel until after delivery whenever feasible. (See "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome".)
For pregnant patients who cannot defer travel to regions where chloroquine-sensitive malaria is present, mosquito avoidance measures should be used in conjunction with chemoprophylaxis with chloroquine [13,87]. Mefloquine is also acceptable.
For pregnant patients who cannot defer travel to regions where chloroquine-resistant malaria is present, mosquito avoidance measures should be used in conjunction with chemoprophylaxis using mefloquine [88-90].
Mefloquine may be safely administered during all trimesters [88,91,92]. Safety data on atovaquone-proguanil in pregnancy are limited, so this agent should be avoided in pregnancy. 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. Primaquine and tafenoquine should not be administered during pregnancy given the possibility of fetal G6PD deficiency.
Issues related to mosquito avoidance are discussed separately. (See "Prevention of arthropod and insect bites: Repellents and other measures".)
Children — All children traveling to malaria-endemic areas should take antimalarial prophylaxis. Chloroquine and mefloquine are options for use in infants and children of all ages and weights (table 2). Atovaquone-proguanil may be administered to individuals ≥5 kg; doxycycline may be administered to individuals ≥8 years (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.
Drug mechanisms — There are three major categories of drugs for prevention of malaria (figure 4):
●Tissue (hepatic) schizonticides – These drugs target the liver stages of the parasite, the active tissue schizonts. Atovaquone-proguanil and tafenoquine have proven activity against liver stages of P. falciparum.
●Hypnozoiticide – Hypnozoites are a quiescent stage in the liver that exist only in the setting of P. vivax and P. ovale infection. This liver stage does not cause clinical symptoms, but, with reactivation and release into the circulation, late-onset or relapsed disease can occur up to many months after initial infection. Primaquine and tafenoquine are active against the hypnozoites of P. vivax and P. ovale. (See 'Relapse prevention' above and 'Primaquine' above and 'Tafenoquine' above.)
●Blood schizonticides – This class of drugs targets the asexual blood stages of the parasite; it includes chloroquine, mefloquine, doxycycline, atovaquone-proguanil, tafenoquine, and to some degree, primaquine. Because the first three agents act on blood parasites following release from the initial maturation phase in the liver, these drugs must be continued for four weeks following exposure to eradicate parasites released from the liver.
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 and therefore should not be used to treat or prevent this illness. Since atovaquone-proguanil, primaquine, and tafenoquine act as both blood and tissue schizonticides, they interfere with development of actively replicating parasites in the liver and so can be discontinued one week (single post-trip dose for tafenoquine) after the end of exposure. On the basis of small human challenge studies, some experts recommend discontinuing these drugs three days after exposure [75,93]. However, cases of acute malaria have been reported after abbreviated courses of atovaquone-proguanil chemoprophylaxis. A larger study is needed to determine whether an abbreviated course is adequate.
Drug resistance — Antimalarial selection should include the considerations of regions with malarial drug resistance (figure 1 and figure 2 and figure 3) [94-97]. Individual itineraries should be reviewed together with the most recent guidelines and advisories [12,13].
Resistance of P. falciparum to chloroquine is widespread; regions with chloroquine-resistant and chloroquine-sensitive malaria are summarized below:
●Chloroquine-resistant P. falciparum is widespread in endemic areas of Africa, Asia, and Oceania.
●Chloroquine-sensitive P. falciparum exists in the Caribbean and in Central America west and north of the Panama Canal (figure 1 and figure 2 and figure 3) [13].
●P. falciparum strains resistant to chloroquine and mefloquine are rare but are prevalent in the regions of Thailand bordering Myanmar (Burma) and Cambodia (eg, eastern provinces of Myanmar and western provinces of Cambodia) and in parts of China, Laos, and Vietnam [13].
●Chloroquine-resistant P. vivax is widespread in Indonesian Papua and Papua New Guinea [13,98].
Drug interactions — Prior to prescribing antimalarial medication, the traveler's medication history should be reviewed in detail with consideration for potential drug-drug interactions. 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 [99].
●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 [100]. 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 [101].
Monoclonal antibodies — Issues related to monoclonal antibodies for malaria prevention are discussed further separately. (See "Malaria: Epidemiology, prevention, and control", section on 'Monoclonal antibodies'.)
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".)
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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
●General principles – Malaria is an important cause of fever and serious illness in returned travelers. Approximately 2000 cases of imported malaria are reported annually to the United States Centers for Disease Control and Prevention (CDC); more than half of these are due to Plasmodium falciparum. (See 'Introduction' above.)
●Risk assessment
•Destination – Risk assessment for malaria requires detailed review of the planned itinerary together with the most recent CDC guidelines and advisories. A summary of areas with malaria transmission and prophylaxis by country is available on the CDC website. (See 'Destination' above.)
•Type of traveler – High-risk groups also include travelers born in regions with endemic malaria who relocate outside the endemic area but subsequently return to visit friends and relatives, pregnant patients, and military personnel. (See 'Type of traveler' above.)
●Counseling – Travelers to malarious areas should be counseled regarding mosquito bite prevention and adherence to antimalarial chemoprophylaxis if indicated. However, travelers must also understand that no chemoprophylaxis regimen guarantees complete protection; fever during or after travel is a medical emergency requiring urgent medical attention. (See 'Counseling' above.)
●Mosquito bite prevention – Travelers should receive instructions regarding methods to prevent bites from Anopheles mosquitoes, including avoiding outdoor exposure between dusk and dawn, wearing clothing that reduces the amount of exposed skin, wearing insect repellant (eg, N,N-diethyl-meta-toluamide [DEET], picaridin, ethyl butylacetylaminopropionate [IR3535] or oil of lemon eucalyptus), staying in well-screened or air-conditioned rooms, and sleeping within bed nets treated with insecticide (eg, permethrin). (See 'Mosquito bite prevention' above.)
●Chemoprophylaxis – We recommend chemoprophylaxis for patients at risk of malaria infection because of travel to destinations with malaria transmission (Grade 1A). Because of variation in malaria transmission and antimalarial drug resistance, individual itineraries should be reviewed together with the most recent CDC guidelines and advisories (table 1 and table 2). (See 'Chemoprophylaxis' above and 'Suggested approach' above.)
●Relapse prevention – Late-onset or relapsed disease due to reactivation of Plasmodium vivax or Plasmodium ovale hypnozoites can occur up to many months after initial infection. Use of primaquine or tafenoquine for presumptive antirelapse therapy is appropriate for travelers to regions where there is substantial transmission of P. vivax or P. ovale, even if P. falciparum is the predominant endemic species. (See 'Relapse prevention' above.)
●Pregnant patients – Pregnant patients traveling to malarious areas are increased risk for life-threatening infection and adverse outcomes for both mother and fetus. Pregnant patients should be advised to defer travel to malarious areas until after delivery whenever feasible. Chemoprophylaxis in the setting of pregnancy is discussed above. (See 'Pregnant patients' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ellen O Boundy, ScD, MS, RN, who contributed to an earlier version of this topic review.
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