**1. Introduction**

Malaria remains the most important parasitic disease in the world, causing approximately 250 million infections annually and one million deaths, mostly in African children. International travelers are at risk of developing malaria when visiting endemic regions, and account for an estimated 30,000 cases of malaria annually (World Health Organization, 2011). The parasite is transmitted by the female Anopheles mosquito and is caused by four protozoa of the *Plasmodium* genus *(P. falciparum, P. vivax, P. ovale* and *P. malaria)*. *P. falciparum* causes the most significant disease burden with the highest morbidity and mortality. In addition to mosquito control and avoidance measures, chemoprophylaxis remains a critical component for preventing malaria infection in nonimmune travelers.

Addressing malaria chemoprophylaxis for the international traveler can be challenging. In addition to patient-specific factors, the provider must consider a wide array of other variables, such as the predicted risk of malaria associated with the destination, type and duration of exposure during the trip as well, as the profile of the drug being prescribed. Seasonal, geographic, and climate are among the environmental variables that should be addressed to appreciate risk of malaria transmission. There can be upwards of a 200-fold difference in relative risk of contracting malaria depending on geographic variables for the international traveler, with sub-Saharan Africa conferring the greatest risk (Leder et al., 2004; Freedman, 2008). The traveler's accommodations, anticipated understanding and adherence to mosquito avoidance and control measures, chemoprophylaxis and access to appropriate medical care contribute to the risk of morbidity and mortality associated with malaria.

Patient-specific variables can also present challenges to the provider. Pregnant, nursing and pediatric travelers present unique considerations when determining the most appropriate chemoprophylactic regimen. Pregnant patients incur a much higher risk of mortality and morbidity from malaria than non-pregnant travelers, and require extensive counselling on the risks and benefits of proposed travel to areas at risk of transmission. Emerging parasite drug resistance patterns, side-effect profiles, both long and short term, contraindications and poor adherence are additional challenges that need to be considered when selecting an appropriate antimalarial chemoprophylactic agent. In addition, how to address chemoprophylaxis in long-term travelers, generally defined as travel greater than six-

Malaria Chemoprophylaxis for the International Traveler, Current Options and Future Possibilities 141

feeds at night, making the hours between dusk and dawn those that the traveler must be most vigilant for vector avoidance and mosquito control measures. Staying indoors, sleeping in screened-structures, and using mosquito nets during peak feeding times are all effective and relatively simple ways to reduce transmission of malaria. Other protective measures including clothing that minimizes exposed skin, eliminating mosquito breeding sites, and using appropriate repellents/insecticides on skin and clothing, should be

A systematic literature review concluded that environmental management programs were highly effective at reducing the morbidity and mortality associated with malaria, and if educated properly travelers can reduce their risk significantly through these personal and

Insecticides such as permethrin can be used as a spray to kill mosquitoes on contact, or can be used to impregnate clothes and mosquito nets for long-term protection. A 2003 randomized-controlled trial in sub-Saharan Africa showed a reduction in all-cause child mortality by 15-33% with the use of permethrin treated bed nets and curtains, and a 1995 study of permethrin impregnated uniforms in Columbian soldiers showed a decrease in incidence of malaria from 14% to 3% (Phillips-Howard & Nahlen et al., 2003; Soto & Medina et al., 1995), indicating mosquito avoidance and control measures can be highly effective in

Repellents prevent arthropod bites via alterations to sensorial organs. There are several different commercially available repellents including DEET (*N*,*N*-diethly-3-methylbenzamide), picaridin (2-(2-hydroxyethyl)-1-piperidinecarboxylic acid 1-methylpropyl ester), oil of lemon eucalyptus (*para*-menthane-3,8-diol), and IR3535 (3-[*N*-butyl-*N*-acetyl] aminopropionic acid, ethyl ester). The efficacy and duration of repellents vary considerably among products and species of mosquito (Zielinski-Gutierrez et al., 2012). Several studies have suggested DEET and picaridin to be the most efficacious and long lasting (Fradin & Day, 2002; Trigg, 1996; Govere et al., 2000; Badolo et al., 2004). Both DEET and picaridin demonstrate efficacy between five and seven hours after application, with variations in efficacy and duration of effectiveness related to repellent concentration, humidity, temperature, perspiration, exposure to water, and abrasion (Zielinski-Gutierrez et al., 2012). There seems to be a ceiling effect with DEET at concentrations above 50%, where higher

DEET, at concentrations up to 50%, can be used on children over two months of age. Children less than two months should be protected with a child carrier covered with a mosquito net. Beyond labeled precautions, the U.S. Environmental Protection Agency (EPA) and CDC do not recommend additional warnings for repellents in children > 2 months, pregnant or lactating women (Zielinski-Gutierrez et al., 2012). Like physical barriers, repellents and insecticides are only effective if used properly and consistently, thus ensuring the traveler is

Educating travelers on the clinical indications, as well as proper use and risks of chemoprophylaxis is an important part of pre-travel counseling. Patients should be told of the options available for the area they are traveling based on CDC recommendations, and when clinically indicated, an appropriate chemoprophylaxis should be chosen and

aware of proper use before departing is an essential part of pre-trip counseling.

discussed with the traveler as well (Chen et al., 2006; CDC, 2012).

environmental protective measures (Keiser et al., 2005).

preventing malaria transmission.

concentrations do not offer additional benefit.

**4. Chemoprophylaxis** 

months in duration, can be very difficult as consensus guidelines in this population are not available (Chen et al., 2006).

It has been over ten years since the U.S. Food and Drug Administration has approved an antimalarial chemoprophylactic drug. Lack of market incentive, increasing difficulty in the design and execution of clinical trials, as well as the changing ethical environment after Declaration of Helsinki 2000 have contributed to the lag in continued development for the malaria chemoprophylaxis indication (Dow et al., 2008).
