Current Treatment Options in Infectious Diseases

, Volume 6, Issue 1, pp 47–57

Prevention of Malaria in Travelers: Bite Avoidance and Chemoprophylactic Measures

Authors

  • Robyn E. Elphinstone
    • MaRS Centre, Toronto Medical Discovery TowerUniversity Health Network-Toronto General Hospital, University of Toronto
  • Sarah J. Higgins
    • MaRS Centre, Toronto Medical Discovery TowerUniversity Health Network-Toronto General Hospital, University of Toronto
    • MaRS Centre, Toronto Medical Discovery TowerUniversity Health Network-Toronto General Hospital, University of Toronto
Travel Medicine (MP Stevens, Section editor)

DOI: 10.1007/s40506-013-0005-x

Cite this article as:
Elphinstone, R.E., Higgins, S.J. & Kain, K.C. Curr Treat Options Infect Dis (2014) 6: 47. doi:10.1007/s40506-013-0005-x
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Abstract

Prevention and management of malaria in travelers is dependent on awareness of risk, bite avoidance, chemoprophylaxis and early diagnosis. Prophylactic recommendations should be made based on details of travel itinerary and medical history. Travelers should be advised to use appropriate measures for avoiding mosquito bites, including insect repellent, insecticide-treated bed nets, and appropriate behavior modification. In areas of chloroquine sensitivity, chloroquine is usually the preferred chemoprophylactic agent. In areas of chloroquine resistance, atovaquone-proguanil, mefloquine or doxycycline may be used. Atovaquone-proguanil is highly effective in preventing Plasmodium falciparum malaria, is well-tolerated, and is active against both liver and blood stages, which decreases the length of time required for post-travel prophylaxis. Alternative agents include doxycycline and mefloquine. Doxycycline is also well-tolerated and is a less expensive alternative to atovaquone-proguanil, but must be taken for 4 weeks after leaving the malaria-endemic region. Mefloquine can also be considered, particularly in those who have previously demonstrated tolerance. Mefloquine is associated with increased risk of neuropsychiatric adverse events and is often started ∼ 3 weeks prior to departure to help determine tolerability. In areas of high P. vivax or P. ovale presence, the use of terminal primaquine prophylaxis can be considered to prevent relapses post-travel. As with all drug regimens, the risks and benefits of use must be weighed in each individual traveler. None of these agents are 100 % effective, and travelers should be informed to seek urgent medical attention if fever develops during or after travel, regardless of the agent used.

Keywords

MalariaTravelersProphylaxisBite avoidanceMefloquineChloroquineAtovaquone-proguanilPrimaquineDoxycyclineTafenoquine

Introduction

Malaria remains a leading global health challenge, with an estimated 219 million clinical malaria cases [1] and 1.24 million deaths attributed to Plasmodium falciparum infection reported annually [2]. Malaria remains endemic in 104 countries, primarily located in Africa and Asia [1]. Rates of international travel to malaria-endemic regions have increased drastically, with 233.6 million travelers visiting Asia and the Pacific, and 52.4 million travelers visiting Africa in 2012 [3]. Falciparum malaria remains a leading cause of acute and potentially life-threatening illness among Western travelers [4••]. With increased international travel and continued endemicity of malaria around the world, the number of travelers exposed to malaria is rising, and travelers need to be informed of effective measures to protect themselves from this potentially life-threatening disease.

There are significant risks associated with Plasmodium infection, especially with P. falciparum and Plasmodium vivax infection. Although the majority of infected individuals develop uncomplicated malaria and can be effectively managed with prompt diagnosis and treatment with appropriate anti-malarials, a subset may progress to severe disease. Severe malaria can manifest in a variety of forms, including cerebral malaria (malaria with coma and without other identifiable cause), severe malarial anemia, respiratory distress, metabolic acidosis and multi-organ failure. Life threatening infections can develop within 24 h of disease onset and, despite the use of first-line anti-malarials, fatality rates for severe malaria complications, such as cerebral malaria, remain high, at 15–30 % [5, 6]. Due to the risk of severe morbidity and mortality associated with malaria, prevention is a priority strategy for disease management. This review will emphasize two of the key principles for malaria prevention in travelers: bite avoidance and chemoprophylaxis, based on guidelines outlined by the World Health Organization (WHO) ‘ABCD’ approach. It is important to note that malaria prevention measures do not provide complete protection and early diagnosis is important for disease management. Physicians should inform patients of the importance of seeking prompt medical attention if they develop fever after entering a malaria-endemic area. Prophylaxis measures themselves are not without risk; therefore, in order to determine an appropriate course of action, it is important to weigh the relative risk of exposure and development of severe disease with the risk of adverse events (AEs) due to chemoprophylaxis.

Awareness of Risk: Considerations for Prophylaxis

The risk of a traveler contracting malaria is highly dependent on their behavior and geographical destination. Knowledge of individual risk factors is critical for malaria prevention. During the patient consult, malaria risk assessment should be based on a thorough evaluation of a detailed travel itinerary. Factors of importance include: destination (including rural vs. urban, altitude, season), malaria epidemiology, health status (e.g., comorbidities, age, pregnancy, and current medications), drug resistance, and behavior of the traveler (including purpose of travel, and adherence). Key considerations for risk assessment have been previously reviewed [7].

Areas considered to carry a high-risk of contracting malaria for travelers include Sub-Saharan Africa (80–90 % of reported cases in Western travelers), followed by Oceania, with a lower risk in South-Central/Southeast Asia [4••, 8••, 9••]. Travel healthcare providers should refer to current surveillance data (GeoSentinel Surveillance Network) and country databases (CDC, WHO, Health Canada) for estimates of country-specific intensity of malaria transmission and travel risks. The importance of prevention measures is highlighted in specific risk populations such as VFR (Visiting Friends and Relatives) travelers, who account for the majority of cases of imported malaria in Western countries [4••, 8••]. Increased frequency has been attributed to the fact that only 33 % of VFRs sought pre-travel consultation [4••] and VFRs tend to travel for longer durations, which is associated with increased risk of non-adherence to prophylaxis and/or exposure (visits ≥ 6 months) [10].

While assessing individual risk, it is important that travelers are informed of the risks associated with failure to adhere to recommended preventative measures. In a recent report, 6.3 % of travelers presenting to GeoSentinal clinics with malaria developed complications and 0.4 % of Western travelers with falciparum malaria died [4••]. Malaria infection in pregnant women is more severe and is associated with adverse pregnancy outcomes, including prematurity, abortion, and stillbirth [11].

Prophylaxis

Non-pharmacological Strategies: Mosquito Bite Avoidance

It is recommended that all travelers going to malaria-endemic regions take measures to prevent mosquito bites, particularly from dusk to dawn, regardless of the level of malaria transmission in the region. Travelers may do so by making use of appropriate insect repellants, bed nets, clothing, and sleeping arrangements.
  • The peak malaria transmission time occurs between dusk and dawn, due to the natural feeding habits of Anopheles mosquitoes. As such, outdoor activities should be limited during these times to reduce potential exposure. While indoors, travelers should reside in rooms with well-screened doors and windows.

  • When spending time outdoors or while residing in poorly protected dwellings, it is recommended to wear clothing that covers exposed skin (long sleeves, pants, hats, socks) and to apply insect repellent to exposed skin, in order to render the user less attractive to feeding and discourage mosquito bites. Repellents containing N,N-diethyl-3-methyl-benzamide (DEET) as the activate ingredient are considered highly effective at reducing the risk of arthropod bites [12, 13] (Class A-II). As such, topical application of DEET-based repellants (≥20 %) is recommended for both adults and children traveling to regions with malaria for longer-lasting protection (> 5 hours). Lower DEET formulations (<20 %) can be used for shorter durations of exposure (1–3 hours of protection). DEET-based repellants (formulations up to 30 %) are considered safe in children older than 2 months of age [14, 15]. Post-marketing surveillance from 1995–2001 in the USA found that the risk of serious neurological event following the use of topically-applied DEET repellant is low [16].

  • Picaridin-based repellants (KBR 3023; Bayrepel; 19 % preparation) provide equivalent efficacy and are recommended as an acceptable alternative to long-lasting DEET-based formulations for prevention against bites from malaria-transmitting mosquitoes [17, 18] (Class B-III).

  • Bed nets that are treated or impregnated with long-lasting insecticides are used worldwide for effective malaria control [19] and may provide additional protection for travelers in areas with a high rate of malaria transmission [20] (Class A-I). Systematic reviews of RCTs in malaria-endemic regions found that nets sprayed or impregnated with insecticides, such as permethrin, a synthetic pyrethroid insecticide, were associated with lower rates of malaria episodes compared to subjects with untreated or absent nets [19, 22]. The main AEs associated with permethrin-treated bed nets are skin irritation, itching and eye irritation [22]. Insecticide-treated nets are a relatively inexpensive and well-tolerated preventative measure for malaria but are often underutilized by travelers.

Pregnancy considerations.

A randomized placebo-controlled trial conducted in Thailand found no significant risk, in terms of survival, growth or neurological development, in children born to mothers who applied DEET-based mosquito repellent (20 % solution, 1.7 g DEET/day) during the second and third trimester to prevent malaria transmission [23] (Class B-I); the subjects were assessed at birth and 1 year of age. It is noted that this study did not assess safety during the first trimester of pregnancy, when the fetus is most vulnerable to adverse developmental effects, and thus further studies are required.

  • Permethrin-treated bed nets are considered safe for pregnant women and children [20].

Pharmacologic Treatment

There are two types of chemoprophylactic agents for the prevention of malaria: suppressive and causal. The majority of agents are suppressive and target the blood stages of malaria [24]. This has important implications for the duration of use required for these drugs after departing malaria-endemic regions. Agents in the other category are causal in effect and target both the liver and blood stages of malaria [24]. Currently, there are only two causal agents in use for the prevention of malaria and only one drug that can kill the dormant hypnozoites of P. vivax and P. ovale. A summary of key considerations for the following chemoprophylactic agents is presented in Table 1.
Table 1

Key considerations for chemoprophylactic antimalarial drugs

Drug

Standard adult dose

Contraindications*

Pregnancy considerations

Pediatric considerations

AWP# (total cost - 28 day trip&)% [90]

Chloroquine (CQ)

300 mg base/week at least 1 week prior to exposure and continued 4 weeks after travel

Patients with known sensitivities to CQ or related compounds, epilepsy

Recommended for use in CQ-sensitive areas. FDA category C

Recommended with food or syrup, 5 mg base/kg/week, not exceeding adult dose (300 mg)

$4.03/unit

($36.27)

Mefloquine

250 mg salt/week in USA (elsewhere 250 mg base/week), at least 1 week prior to exposure and continued 4 weeks after travel

Patients with known neuropsychiatric and neuropsychological issues (depression, anxiety, psychosis,schizophrenia, epilepsy, etc.)

Recommended for use in CQ-resistant areas. FDA Category B

At least 5 mg base/kg/week, taken with chocolate

$10.59/unit

($95.31)

Doxycycline

100 mg/daily, 1–2 days prior to travel and continued for 4 weeks after departure

Pregnancy, and children under 8 years old

Not recommended due to adverse events in fetus (tooth discoloration, inhibition of bone growth). FDA category D

Not recommended in children < 8 years old, due to permanent tooth discoloration, if alternatives are available.

$0.08/unit

($4.64)

Atovaquone-Proguanil

250 mg atovaquone/100 mg proguanil daily, 1–2 days prior to exposure and 7 days after departure

Severe renal disease

Not recommended for use during pregnancy due to limited evidence. FDA category C

62.5 mg atovaquone/25 mg proguanil daily based on weight

$7.15/unit

($264.55)

Primaquine

30 mg base/daily for 14 days

G6PD deficiency

Not recommended due to lack of evaluation

Recommended, 0.5 mg base/kg daily

$1.79/unit

($25.06)@

*The list of contraindications is not exhaustive, AWP Average Wholesale Price, #Lowest AWP available in the United States (USD) [90], &Relative costs for a 28-day travel period include pre- and post-travel requirements, %Total cost will depend on duration of travel, @Requires a test for G6PD, cost not included

Suppressive Chemoprophylaxis

Chloroquine

  • Chloroquine has been used continuously since its potent anti-malarial activity was recognized in the 1940s. Chloroquine is a suppressive agent that acts against intraerythrocytic parasites by inhibiting hemozoin formation [25]. Its use is now limited due to the widespread prevalence of chloroquine-resistant P. falciparum in most malaria-endemic regions. Chloroquine remains the drug of choice for areas with chloroquine-sensitive strains including Mexico, the Caribbean (Haiti and Dominican Republic) and parts of Central America, the Middle East and China [26]. Chloroquine-resistant P. vivax has been reported in Indonesia, Papua New Guinea, the Solomon Islands, Burma, Vanuatu, India, and Guyana [15]. It is recommended that travel healthcare advisors consult updated country-specific information [26] prior to prescribing chloroquine.

  • The standard adult dose of chloroquine for malaria chemoprophylaxis is 300 mg base weekly [15], starting 1–2 weeks prior to travel and continuing for 4 weeks after travel to malaria-endemic regions. Post-travel treatment requirements can lead to treatment non-compliance, especially in short-term travelers [27].

  • Chloroquine is contraindicated in patients with epilepsy or a history of psychosis, as it may exacerbate these conditions. Precautions should be taken in patients with a known history of liver disease, alcoholism, or concurrent administration of known hepatotoxic drugs. Chloroquine may exacerbate psoriasis and should be used with precaution in patients with this underlying condition. Concomitant use of chloroquine and mefloquine is not recommended, as co-administration may increase the risk of convulsions, electrocardiogram abnormalities and/or cardiac arrest [15]. Precautions should be used for travelers on long-term chloroquine therapy. Baseline examination and annual screening should be conducted and treatment should be discontinued if evidence of muscle weakness and ophthalmologic abnormalities (keratopathy and retinopathy) are observed. Travelers with glucose-6-phosphate dehydrogenase (G6PD) deficiencies should be monitored frequently for hemolytic anemia [15].

  • The standard chloroquine dose for malaria prophylaxis is well-tolerated, however, gastrointestinal upset is not uncommon (reported in >1 % of users). Administration with food can minimize GI symptoms. Other commonly reported AEs are listed in Table 2.
    Table 2

    Main adverse events and drug-drug interactions to consider for risk-benefit analysis of first-line malaria prophylaxis drugs

    Drug

    Main adverse events

    Drug-drug interactions

    Chloroquine (CQ)

    Gastrointestinal, headache, dizziness, blurred vision, insomnia and pruritis [21, 22, 28, 29]

    • Antacids, cimetidine and CYP2D6/CYP3A4 inhibitors: all affect CQ metabolism and absorption. Antacids should be given 4 h post-CQ intake. Cimetidine can be replaced with famotidine, nizatidine or ranitidine.

    • Cyclosporine, dapsone, MQ: plasma levels may be increased by CQ, leading to enhanced risk of AEs of dapsone (hemolytic reactions) and MQ (convulsions). Concomitant administration is not recommended

    Mefloquine (MQ)

    Neuropsychiatric events (e.g., depression, drowsiness, anxiety, strange dreams, dizziness, headache, visual impairments, seizures, psychosis, and vertigo), gastrointestinal, prolonged QTc intervals [36, 37, 40, 41]

    • Live typhoid vaccine: MQ can decrease effectiveness. Travelers should not start MQ until at least 3 days post vaccination.

    • Halofantrine, ketoconazole, quinine and its derivatives: MQ can prolong QTc intervals and increase cardiac events. Patients should avoid concomitant use.

    • Drugs that induce or inhibit CYP3A4 or P-glycoprotein: may affect metabolism and plasma levels of MQ and should be used with caution

    Doxycycline (DOX)

    Gastrointestinal upset, dyspepsia, photosensitivity and other skin reactions, headaches and dizziness, vaginitis [35, 41, 51••, 52]

    • Antacids, oral iron supplements, and anti-diarrheal medication containing bismuth subsalicylate, pectin or kaolin: interfere with absorption of DOX.

    • Anticoagualants, digoxin, barbiturates, carbamazapine, phenytoin, and penicillin: may affect the metabolism of DOX or have their metabolism altered by DOX.

    • Methoxyflurane: concomitant use should be avoided due to potentially lethal renal toxicity.

    • Drugs metabolized by CYP3A4: may have altered activity due to DOX inhibitory effects on CYP3A4

    Atovaquone-Proguanil

    Primarily, gastrointestinal upset, followed by headache, dizziness, malaise, skin rash, oral ulcers, sore throat, pruritis, upper respiratory infections and insomnia [57, 91]

    • Tetracycline, metoclopramide, rifampin, or rifabutin: decrease plasma concentration of atovaquone.

    • Inhibitors/inducers of CYP2C19: may alter the metabolism of proguanil

    Primaquine (PQ)

    Gastrointestinal upset, headache, dizziness, methemoglobinemia, fatigue, insomnia, and rash [70, 77]

    • Inhibitors or inducers of CYP2D6: may alter PQ metabolism.

    • Hemolytic-inducing drugs (i.e., antipyretics, analgesics, and sulfonamides): caution should be used due to increased hemolysis observed with PQ use

  • For travelers to chloroquine-resistant areas who have contraindications or intolerance to other first-line antimalarial drugs (e.g., mefloquine, atovaquone-proguanil or doxycycline), chloroquine plus proguanil combination therapy has been used as an alternative, although it has higher failure rates than the first-line drugs. The recommended adult dose of combination chloroquine–proguanil prophylaxis is 200 mg/daily proguanil and 300 mg base/weekly chloroquine, continued for 4 weeks after leaving a malarious region. Studies have not been able to conclusively show comparative efficacy relative to other first-line options [21, 22], and show an inferior tolerability profile compared to other antimalarials [21, 22, 28, 29]. Due to poor tolerability and lower efficacy versus other first-line agents, chloroquine–proguanil combination treatment is no longer recommended for malaria chemoprophylaxis.

Pregnancy considerations.

Chloroquine is recommended for pregnant and lactating women traveling to areas with chloroquine-sensitive P. falciparum [26, 30] and is an FDA Category C drug. When used at the recommended prophylaxis dose, its potential drug-related teratogenicity is low and any associated risk of drug exposure is outweighed by the significant risk of mortality and morbidity to both the mother and fetus associated with malaria. In studies conducted on children born to mothers taking therapeutic chloroquine for rheumatic disease (SLE, rheumatoid arthritis), no visual defects, adverse pregnancy outcomes, or congenital birth defects above the expected rate in a normal, unexposed population were associated with in utero chloroquine exposure at any stage of pregnancy [31, 32].

Pediatric considerations.

Chloroquine is recommended for pediatric travelers to areas with chloroquine sensitive strains. The recommended dose for infants and small children is 5 mg base/kg weekly. Overdose can be fatal. It is recommended to deliver the drug with food or syrup to improve palatability.

Mefloquine

  • Mefloquine has been used as a malaria chemoprophylactic agent since regulatory approval in 1989, and in some parts of the world, it is the only drug approved for this use [33]. The standard dose worldwide is 250 mg base/week, starting at least 1 week prior to travel and continuing for 4 weeks after exiting a malaria-endemic region. Weekly dosing requirements may contribute to higher rates of adherence with mefloquine [34]; however, decreased tolerability may increase rates of discontinuation and limit effectiveness [33]. Non-compliance due to poor drug tolerability may contribute to the overall higher rates, as efficacy has been shown to be 96–100 % with proper adherence to prophylaxis regimen [35, 36] (Class A-I).

  • Tolerability issues associated with mefloquine include neuropsychiatric AEs [36, 37], which are increased compared to other antimalarials [29, 33, 38], especially in women [29] (see Table 2). As such, mefloquine is often a less desirable choice for travelers [38, 39]. The FDA has added a black box to the label indicating a risk for permanent or prolonged neuropsychiatric side effects after the use and discontinuation of mefloquine. Mefloquine use is contraindicated in patients with a history of depression, anxiety, psychosis, schizophrenia and epilepsy. Mefloquine use is associated with changes in cardiac conduction, specifically QTc interval prolongation [40], and caution should be used in patients with cardiac disease. Gastrointestinal upset is frequently observed [36, 37, 41]. Most AEs are associated with the initial drug dose; therefore, early drug initiation (2–4 weeks prior to travel) is recommended to enable sufficient time to assess drug tolerability [42] and switch to doxycycline or atovaquone-proguanil, if necessary [43]. AEs tend to decrease with the duration of mefloquine exposure; long-term use appears to be well tolerated [44]. Three main drug interactions seen with mefloquine use are listed in Table 2.

  • Drug resistance to mefloquine is primarily an issue on the border regions of Thailand with Burma and Cambodia, with scattered reports elsewhere [45]. However, it is important to consult up-to-date resources due to the increasing development of resistance.

  • Mefloquine is a relatively inexpensive drug, but issues with tolerability limit its use. It remains an option for some travelers, particularly if they have previously tolerated it, and for pregnant women who cannot defer travel to high-risk chloroquine-resistant areas and have no contraindications to its use.

Pregnancy considerations.

When traveling to an endemic area with chloroquine resistance, mefloquine is considered an appropriate option for chemoprophylaxis [46], and is classified as an FDA Category B drug. Women taking mefloquine, particularly prior to conception and during the first trimester, have rates of fetal abnormalities similar to that of the background population [47••] (Class B-III). However, the ability of this study to adequately exclude a risk of birth defects has been questioned based on insufficient sample size, and minimal prospective reporting [48].

Pediatric considerations.

Mefloquine-associated AEs in children are similar to those reported in adults, including gastrointestinal upset, hallucinations, rash, and anorexia [49]. It is recommended that children receive a dose of at least 5 mg base/kg/weekly in order to achieve adequate plasma levels [50••]. Mefloquine can be given with chocolate or other sweet foods to disguise its bitter taste [50••].

Doxycycline

  • Doxycycline, an antibiotic, was approved for use as a malarial chemoprophylactic agent by the FDA in 1994 [51••]. Doxycycline requires daily dosing of 100 mg, beginning 1 or 2 days prior to travel and continuing for 4 weeks after leaving the malaria-endemic area. Doxycycline is 92–100 % effective for malaria prevention [35, 41, 52] (Class A-I). However, the frequent dosing that is required to maintain adequate drug plasma levels due to the short half-life of doxycycline tends to increase the chance of non-compliance [41], and thus susceptibility to malaria increases due to missed doses [53]. The FDA has approved doxycycline for malaria prophylaxis for periods of less than 4 months; however, there is limited evidence suggesting that doxycycline for longer periods is well-tolerated [42, 51••].

  • Overall, the use of doxycycline as a prophylactic agent is well-tolerated [52]; however, one study of non-immune troops in Afghanistan indicated an increase in the number of mild AEs reported with doxycycline use [41]. More severe AEs include esophagitis and esophageal ulcers [51••]. It is recommended that doxycycline be taken with food and lots of fluids in an upright position, and never just before sleep, to improve tolerability and decrease the likelihood of esophagitis [35]. Candidal vaginitis is another concern associated with the use of doxycycline [52] and users should carry a self-treatment course in case this occurs. There is some evidence from a survey questionnaire with a limited number of responders that suggests increased development of irritable bowel syndrome in doxycycline users [54]. However, evidence of an increased risk of Clostridium difficile is lacking, despite extensive prescriptions of the antibiotic [55].

  • The list of drug interactions with doxycycline is long, and therefore, it is important to consult the appropriate resources prior to prescribing this medication. Several common drug interactions for consideration are listed in Table 2.

Pregnancy and pediatric considerations.

Doxycycline is currently an FDA Category D drug and is contraindicated for use during pregnancy due to AEs. Doxycycline crosses the placenta, is present in breast milk, and may be associated with AEs to the fetus, including permanent tooth discoloration and bone hypoplasia. Similar events can occur in infants and children under the age of 8 years, when bone calcification and development occurs [51••]. Some evidence suggests that, unlike other tetracyclines, doxycycline does not cause tooth discoloration due to its limited calcium binding [56] (Class B-I). However, doxycycline is currently not recommended in children < 8 years old, if alternatives are available. For children over the age of 8, doxycycline at a dose of 2.2 mg/kg daily can be used [51••].

Causal Chemoprophylaxis

Atovaquone-Proguanil (AP)

  • The FDA approved AP in 2000. The standard recommended dose for malaria prophylaxis is 250 mg atovaquone and 100 mg proguanil per day (combined tablet), starting at least 1 day prior to travel and continuing for 7 days after leaving the endemic area.

  • Travelers are 2.6 times more likely to complete the full course of AP prophylaxis than those taking doxycycline, presumably due to the shorter duration of post-exposure treatment required after leaving an endemic area [38]. However, daily dosing may decrease overall adherence compared to the use of weekly mefloquine [34]. Improved adherence may occur if the interval between doses could be extended. In a small study, 100 % protection was achieved with a single dose of AP (500/200 mg) 7 days before sporozoite challenge in a small group of volunteers (n = 6), suggesting that prolonged dosing intervals may be possible [57] (Class B-I). This is likely to improve adherence; however, further studies are required.

  • AP is preferred by travelers [33]; it has rates of AEs similar to that of patients receiving placebo [58] (Class A-I), the best comparative tolerability profile [29, 33, 38], and the lowest rate of discontinuation [29, 33]. Common AEs associated with AP are listed in Table 2. It is important to note that the use of AP has been associated with rare, but serious dermatological AEs, including Stevens-Johnson Syndrome [59] and erythema multiforme [60]. AP is contraindicated in patients with severe renal disease [61] due to the association of pancytopaenia in patients with severe renal disease who are treated with proguanil. Amet et al. have published a review of the recommendations for malaria chemoprophylaxis in patients with renal failure [62•].

  • There are currently no countries listed with AP resistance [45]. However, there is evidence that naturally occurring mutations in the pf-cytb gene provide resistance to AP and have been associated with recrudescence [63, 64].

  • AP appears to be the most effective and preferred regimen for short-term travelers; however, there are adherence issues associated with daily dosing requirements and it is more expensive than the other regimens, which in turn limits its long-term use.

Pregnancy considerations.

AP is not recommended during pregnancy due to limited data (FDA category C drug). A Danish-based registry showed no significant association between AP exposure during the first trimester of pregnancy and birth defects (1.3 % in exposed vs. 2.5 % in unexposed) [65]; however, the number of exposed subjects reported in the registry is limited and further studies are warranted. The use of AP has been shown to be well-tolerated in the treatment of malaria during the second and third trimesters, with no significant AEs in mother or child [6668] (Class B-I).

Pediatric considerations.

The pediatric dose is 62.5 mg atovaquone and 25 mg proguanil daily, starting 1–2 days prior to and continuing for 7 days after departure [69]. AEs in children reflect those seen in adults, primarily gastrointestinal upset [69].

Primaquine

  • Primaquine was approved by the FDA in 1952 and is currently the only drug that eliminates hypnozoites. Primaquine is approved for use as “Presumptive Relapse Therapy” in travelers with prolonged or intense exposure to P. vivax or P. ovale, and as a “radical cure” in patients with confirmed infections [70]. The recommended dose is 30 mg base/daily (0.5 mg base/kg) for 14 days, and is usually done concomitantly with the last two weeks of a blood schizonticide [70]. Strain-specific increased risk of relapse was associated with lower primaquine doses (15 mg base/daily) previously recommended for relapse prevention [7173]. Rates of relapses for individuals taking 30 mg base/day for 14 days range from 0–30 % [7375]. Travelers may have altered primaquine activity due to the wide range of CYP2D6 gene polymorphisms [76].

  • A shorter duration of treatment may improve drug adherence [77]. To achieve efficacy with a shorter dose regimen, administration of a higher cumulative dose may be required. A recent study found that an increased dose (60 mg base/day for 7 days) was relatively safe in a cohort of Australian soldiers [77]. Methemoglobinuria was not measured in patients, but peripheral cyanosis, a surrogate marker for methemoglobin, was observed in 5 % of participants [77].

  • Primaquine is not approved as a primary prophylaxis agent; however, there is evidence to suggest that it may have comparative efficacy to other first-line antimalarial drugs. In travelers to Ethiopia taking 15 mg base of primaquine daily, starting 1 day prior to travel and continued 1–2 days after leaving the endemic area, the incidence of P. vivax was 5.7 % compared to 50–53 % for the groups who received mefloquine, doxycycline or chloroquine [78]. Primaquine given daily (30 mg base) had a 93 % efficacy against both P. vivax and P. falciparum in Papua, and was well-tolerated during the five months in which it was given [79]. Similarly in Indonesia, primaquine (0.5 mg base/kg) given daily for 1 year resulted in 100 % efficacy [80] (Class A-1).

  • Primaquine is contraindicated in G6PD-deficient individuals due to extensive hemolysis. Primaquine should not be prescribed to anyone whose G6PD status is unknown, including infants and unborn fetuses. In patients with mild to moderate G6PD deficiency, the WHO recommends 0.75 mg base/kg/weekly for 8 weeks [81], as it is suggested that prolonging the cumulative dose over a longer time period can limit AEs [75]. The regimen has been shown to be well-tolerated and effective at preventing relapses, with 0 % relapses using primaquine vs. 28 % in patients taking chloroquine alone in an Iranian study [82], and 5.1 % with primaquine vs. 31 % in patients receiving placebo in an RCT in Pakistan [75] (Class A-I). These studies suggest that prolonging the dosing schedule is effective at preventing relapses and that, due to the limited AEs associated with its use, it may provide a viable option for a radical cure in G6PD deficient patients. However, studies examining tolerability in G6PD deficient-individuals are required.

  • Primaquine is well-tolerated and associated with limited AEs (see Table 2), [70, 72, 73, 75, 7779] but higher doses have been reported to increase AEs [77]. It is recommended that primaquine be taken with food to limit gastrointestinal upset [78].

Pregnancy considerations.

Primaquine is contraindicated during pregnancy since the G6PD status of the fetus is unknown.

Pediatric considerations.

There is limited data on the use of primaquine in children; however, as long as the child is not G6PD-deficient, primaquine may be used [70]. The recommended dose in children is 0.5 mg base/kg daily [70].

Emerging Therapies

An ideal agent for malaria chemoprophylaxis should: (i) provide protection against all human disease-causing Plasmodium species and all stages during the parasite lifecycle (e.g., liver, blood and transmission stage), (ii) have a good safety and tolerability profile, and (iii) have a long plasma half-life to allow for a short or infrequent dosing regimen to improve adherence in travelers. Due to the prevalence of P. vivax, novel therapies should have activity against dormant hypnozoites, to reduce the risk of relapse in returned travelers.

Tafenoquine

  • Tafenoquine, a synthetic analog of primaquine, is a potential new 8-aminoquinoline drug for malaria prophylaxis being developed by the Walter Reed Army Institute for Research, GlaxoSmithKline, and Medicines for Malaria Venture. Tafenoquine may provide an advantage over other first-line therapies due to its activity against blood, latent liver (hypnozoites) and transmission stages of malaria parasites. Tafenoquine has a long plasma half-life (2–3 weeks) that could accommodate infrequent dosing regimens and improve drug adherence. Post-travel doses are not required [37].

  • Tafenoquine is not currently indicated for prevention of malaria; however, it has been shown to be effective against both P. vivax, and P. falciparum [8387]. Based on recent clinical trials, the prophylactic dose regimen for Tafenoquine is a 3-day loading dose (200 mg base/daily) plus 200 mg base weekly. Tafenoquine is also being investigated as a radical cure for P. vivax, with promising results [88].

  • Tafenoquine is generally well-tolerated; however, the risk of asymptomatic methemoglobinemia and hemolytic anemia in G6PD-deficient individuals is a limitation [89]. Benign and reversible corneal changes (vortex keratopathy) were observed in a large percentage of participants (∼93 %) in a Phase III trial to assess the safety and tolerability of tafenoquine in a non-immune population [37]. Mild to moderate gastrointestinal upset has been reported with tafenoquine prophylaxis [37, 83], but can be minimized if taken with food [86].

  • Studies-to-date suggest that Tafenoquine may represent a promising new agent for the prevention of malaria in non-immune travelers. However, further efficacy studies are required.

Conclusion

To reduce the risk of malaria contraction, there are numerous factors that must be considered prior to travel to endemic areas. The pre-travel consultation offers the physician the opportunity to inform the traveler of the associated risks of developing malaria, and to provide them with appropriate measures for prevention and what to do if they develop fever during or after travel. Each individual should be assessed for the risks and benefits of various preventative measures. All individuals should receive recommendations for appropriate bite avoidance measures. Chemoprophylactic agents should be recommended for certain travelers based on travel itinerary, medical history, individual risk assessment and drug characteristics. When patients are adequately informed, and adhere to appropriate malaria prevention measures, the risks of developing malaria or malaria-related complications are low.

Compliance with Ethics Guidelines

Conflict of Interest

Robyn E. Elphinstone, Sarah J. Higgins, and Kevin C. Kain declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

K.C. Kain is an author on studies, referred to in this article, involving human subjects. All studies received IRB approval, and informed consent was obtained. This article does not contain any studies with human or animal subjects performed by R.E. Elphinstone or S.J. Higgins.

Copyright information

© Springer Science + Business Media New York 2013