Protection of Travelers

Protection of Travelers David O. Freedman Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition, 323, 3559-3567.e2 Keywords altitude, dengue, immunizations, malaria, pregnancy, prophylaxis, rabies, travel medicine, traveler's diarrhea, yellow fever Short View Summary The pretravel office visit with an adult traveler to the developing world should follow a structured approach. Perform Risk Assessment Exact itinerary, including regions within each country to be visited, dates of travel to assess risk of seasonal diseases, age, past vaccination history, underlying illness(es), current medications, pregnancy status, allergies, purpose of trip, risk exposures—blood, body fluids, adventure or extensive outdoor exposures, urban versus rural travel, type of accommodations, level of aversion to risk, and financial limitations that may necessitate prioritization of interventions Administer Immunizations Routine vaccinations that are not up-to-date, including measles-mumps-rubella (MMR), tetanus-diphtheria–acellular pertussis (Tdap), pneumococcal, varicella, zoster Indicated routine travel vaccines, including hepatitis A, hepatitis B, typhoid, and influenza Indicated specialized vaccines, including yellow fever, rabies, polio, meningococcal, and, in certain countries, tick-borne encephalitis and cholera Provide Malaria Prevention (If Indicated) Several equally effective drugs of choice may be indicated, including atovaquone/proguanil, mefloquine, and doxycycline. Ascertain which is best suited to the individual patient and itinerary. Educate on personal protection against arthropods. Traveler's Diarrhea Recommend food and water precautions as well as hand hygiene. Prescribe and educate on standby therapy with a quinolone antibiotic or azithromycin, and advise on use of loperamide and oral hydration if needed. Teach Essential Preventive Behaviors Most travel-related health problems, including vaccine-preventable diseases, can be avoided through simple behaviors initiated by the traveler. Educate on appropriate strategies in the following categories (some topics are not applicable to all destinations): mosquito repellants, bloodborne and sexually transmitted diseases, safety and crime avoidance, injury prevention, swimming safety, rabies, skin/wound care, tuberculosis, packing for healthy travel, and obtaining health care abroad. Discuss Other Applicable Heath Issues Advise and prescribe for altitude illness, motion sickness, or jet lag. Discuss prevention of specific travel-related infections that are of some risk to the traveler and have a possible preventive strategy not included in the strategies given above. Discuss any minimal-risk conditions (e.g., hemorrhagic fevers) that are a frequent cause of patient anxiety. The pretravel management of the international traveler should be based on risk management principles. Prevention strategies and medical interventions need to be individualized according to both the itinerary and factors that are dependent on the traveler. A structured approach to patient interaction ( Table 323-1 ) is the most efficient way to cover the necessary educational and preventive interventions. Because many of these measures will be initiated only much later at the traveler's destination, clearly printed instructions in lay language are advisable. The worldwide epidemiology of travel-related diseases is constantly changing. A body of knowledge in travel medicine has been published, and online and print resources ( Table 323-2 ) should be consulted frequently12 to keep current. TABLE 323-1 Structured Approach to the Pretravel Office Visit with a Traveler to the Developing World Perform Risk Assessment The following must always be ascertained to determine appropriate preventive medical recommendations. Preprinted medical record forms may be used to record these. Exact itinerary, including regions within each country to be visited Dates of travel to assess risk of seasonal diseases Age Past vaccination history Underlying illness(es) Current medications Pregnancy status Allergies Purpose of trip Risk exposures—blood, body fluids, adventure or extensive outdoor exposures Urban versus rural travel Type of accommodations Level of aversion to risk Financial limitations that may necessitate prioritization of interventions Administer Immunizations Administer routine vaccinations that are not up-to-date. Administer indicated travel vaccines. Provide to patient legally mandated Vaccine Information Statements from the Centers for Disease Control and Prevention ( http://www.cdc.gov/vaccines/pubs/vis/ ). Provide printed checklist to patient, listing vaccines administered. Record in the clinic record vaccines administered, lot number, and date. Document vaccines offered to but declined by patient, as well as nonrecommended vaccines administered at the patient's request. Provide Malaria Prevention (if Indicated) Determine whether malaria risk exists for the destination country. If yes: Does the patient's itinerary within that country put him or her at risk? If yes: Recommend malaria chemoprophylaxis. Several equally effective drugs of choice may be indicated. Ascertain which is best suited to the individual patient and itinerary. Educate on personal protection against arthropods. Educate on Traveler's Diarrhea Recommend food and water precautions. Prescribe and educate on standby therapy with azithromycin and advise on use of loperamide and oral hydration if needed. Teach Essential Preventive Behaviors Most travel-related health problems, including vaccine-preventable diseases, can be avoided through simple behaviors initiated by the traveler. Educate on appropriate strategies in the following categories (some topics are not applicable to all destinations): bloodborne and sexually transmitted diseases, safety and crime avoidance, injury prevention, swimming safety, rabies, skin/wound care, tuberculosis, packing for healthy travel, obtaining health care abroad. Discuss Other Applicable Heath Issues Advise and prescribe for altitude illness, motion sickness, or jet lag. Discuss prevention of specific travel-related infections that are of some risk to the traveler and have a possible preventive strategy not included in the strategies above. Discuss any minimal-risk conditions (e.g., hemorrhagic fevers) that are a frequent cause of patient anxiety. View full size TABLE 323-2 In-depth Information Resources for Travel Medicine Authoritative Websites Updated Constantly with Epidemiologic and Outbreak Information Centers for Disease Control and Prevention (CDC) Travelers Health http://www.cdc.gov/travel World Health Organization (WHO) Travelers Health http://www.who.int/ith Public Health Agency of Canada. Committee to Advise on Tropical Medicine and Travel (CATMAT) http://www.phac-aspc.gc.ca/tmp-pmv/catmat-ccmtmv/index-eng.php WHO Disease Outbreak News http://www.who.int/csr/don/en/ WHO Weekly Epidemiological Record http://www.who.int/wer CDC Morbidity and Mortality Weekly Report http://www.cdc.gov/mmwr WHO Disease by Disease Health Topics http://www.who.int/health_topics/en/ In-depth References on Specialized Topics Centers for Disease Control and Prevention. Health Information for International Travel 2014. (The “CDC Yellow Book”). U.S. Public Health Service. Atlanta. Full text and hard copy order information available at http://wwwnc.cdc.gov/travel/page/yellowbook-2014-home.htm World Health Organization. International Travel and Health 2012 (WHO “Green” Book). Published annually. Available from authorized WHO book agents. Full text online at http://www.who.int/ith Keystone JS, Freedman DO, Kozarsky P, et al, eds. Travel Medicine. 3rd ed. Philadelphia: Saunders; 2013. (ISBN: 978-1455710768) Plotkin SA, Orenstein WA, Offit P. Vaccines. 6th ed. Philadelphia: Saunders; 2012. (ISBN:978-1455700905) Auerbach PS. Wilderness Medicine. 6th ed. St Louis: Mosby; 2011. (ISBN 978-1437716788) View full size Epidemiology of Travel-Related Illness Globally, approximately 100 million people travel from industrialized to developing countries each year. Of note, travel to Africa, which presents a particularly high risk for a number of infectious diseases, is undertaken each year by many fewer (800,000) U.S. residents than European residents. Several recent analyses have provided much needed new data on the profiles of travel-related illness determined by destination of travel. 345Depending on destination, 22% to 64% of travelers report some illness; most of these problems are mild, self-limited illnesses, such as diarrhea, respiratory infections, and skin disorders. 3 Rates are significantly higher in summer. Approximately 8% of travelers consult a physician either during or after a trip, but less than 1% require hospitalization. Infectious diseases account for up to 10% of morbidity during travel but only 1% of deaths, with mala ria the most common disease. Causes of death vary according to the population studied. At destinations that attract seniors, cardiovascular events predominate, whereas in developing countries, motor vehicle accidents and drowning prevail. Immunization The choice of vaccines for an individual traveler is based on risk of exposure to vaccine-preventable diseases on the chosen itinerary; the severity of disease, if acquired; and any risks presented by the vaccine itself. Travelers differ in their tolerance of risk. Requests for immunization against diseases that are actually of negligible risk to the traveler, but have the potential for poor outcome if acquired, are often difficult for the physician to refuse because sporadic travel-related cases do occur each year. For the vaccine-preventable diseases, the monthly incidence for nonimmune travelers to developing countries is most significant for symptomatic hepatitis A (HA), at 0.03% per month overall, and is still considerable for perceived low-risk destinations such as Mexico. 6 The risk of symptomatic hepatitis B (HB) is most significant for long-stay travelers and expatriates, at 0.25% per month. Enteric fever (typhoid and paratyphoid) has a risk of 0.03% per month on the Indian subcontinent and is 10 times lower in Africa and parts of Latin America. 57 Risk of yellow fever (YF) may be as high as 0.1% per month of travel to an area with current epidemic transmission, but the risk varies greatly between destinations encompassed by the endemic area map. 8 The risk of meningococcal meningitis, rabies, cholera, polio, measles, varicella, and Japanese encephalitis in travelers is not known but is thought to be small (<0.0001%) even for travel to highly endemic areas. Table 323-3 provides data on dosing, administration, need for boosters, and possible accelerated regimens for vaccines administered in the travel medicine setting. Details on vaccine composition, mechanism of action, use for routine adult and childhood primary vaccination, and adverse reactions can be found in Chapter 321 . The following discussion focuses on indications for each vaccine in the context of travel. TABLE 323-3 Travel-Related Vaccines of Adults DISEASE VACCINE PRIMARY COURSE ROUTE FURTHER BOOSTERS Vaccines to Consider for All Destinations Hepatitis A Killed virus 0, 6-18 mo a IM None Hepatitis B Recombinant viral antigen 0, 1, 6 mo IM None A: 0, 1, 2, and 12 mo IM None A: 0, 1, 3 wk and 12 mo b IM Hepatitis A/B Combination of monovalent preparations 0, 1, 6 mo IM None A: 0, 1, 3 wk and 12 mo IM None Typhoid Capsular Vi polysaccharide Single dose IM 2-3 yr Live-attenuated Ty21a bacteria 0, 2, 4, 6 days Oral 5 yr Influenza Inactivated viral Single dose IM Annual Live-attenuated virus Single dose Nasal Annual Varicella Live-attenuated virus 0, 4-8 wk SC None Vaccines for Selected Destinations Yellow fever Live-attenuated 17D virus Single dose SC Lifetime protection c Meningococcus Quadrivalent conjugated polysaccharide (A, C, Y, W135) Single dose IM 5 yr Rabies Inactivated cell culture viral 0, 7, 21-28 days IM d None routinely but two doses after each exposure Japanese encephalitis (Vero cell) Inactivated viral 0, 28 days IM 1 yr if at continued risk. No data on subsequent doses Polio e Inactivated viral Single dose if adequate childhood series SC; IM acceptable None Cholera Killed bacteria + recombinant B toxin subunit f , g 0, 1 wk Oral 2 yr for cholera; 3 mo for ETEC Tick-borne encephalitis h Inactivated viral 0, 1-3 mo, 9-12 mo IM 3 yr View full size A, accelerated regimen to be used for imminent departures; ETEC, enterotoxigenic E. coli; IM, intramuscular; SC, subcutaneous. a Second dose may be delayed up to 8 years without diminished efficacy. b Regimen not approved by the U.S. Food and Drug Administration for monovalent hepatitis B vaccine but approved for combination hepatitis A/B vaccine containing the same quantity of hepatitis B antigen. c Until 2016, some countries that have mandatory entry requirements may require vaccination every 10 years. d Intradermal rabies preexposure vaccine is no longer produced, and the intramuscular 1.0-mL vials are not licensed for intradermal use in a 0.1-mL dose. e Oral polio vaccine is no longer produced in the United States. f Not available in the United States but available in Canada and most European countries. No cholera vaccine of any kind is currently available in the United States. g Also licensed in some countries for traveler's diarrhea because of enterotoxigenic Escherichia coli. h Not available in United States but available in endemic areas and in Canada and the United Kingdom by special release. Update of Routine Immunizations Because of the increased prevalence of many infections in the developing world, routine adult immunizations need to be current. 9 If no adult doses of tetanus-diphtheria–acellular pertussis (Tdap) have ever been given, a dose of Tdap should be given regardless of the time elapsed since the last tetanus/diphtheria vaccination, but travelers to remote areas where tetanus toxoid (indicated in cases of dirty trauma) will be inaccessible, should get boosters at 5-year intervals. Persons born in the United States before 1957 or born anytime in the developing world are considered immune to measles. Other adult travelers should have received at least two doses of live measles-containing vaccine during their life, unless a history of measles infection can be documented. Although persons born before 1957 in the United States are presumed to be immune, one dose of measles-mumps-rubella (MMR) or one dose each of single-antigen mumps vaccine and single-antigen measles vaccine should be considered for such persons without other evidence of immunity and who are traveling for purposes of health care or humanitarian work that has the potential to put them in close contact with persons who are ill. All individuals older than 6 months should receive the influenza vaccine each fall or winter. Unvaccinated persons who have the accepted routine indications for the pneumococcal vaccine (see Chapter 321 ) should receive this during the pretravel consultation. Varicella is primarily a disease of adolescents and young adults in tropical, nonindustrialized countries. Two doses of varicella vaccine, spaced by at least 4 weeks, should be considered for adult travelers without evidence of varicella immunity. Adults born before 1980 in the United States are considered immune. Vaccines to Consider for All Destinations in the Developing World Hepatitis A HA vaccine is indicated for every nonimmune traveler to countries or areas with moderate-to-high risk of infection ( Fig. 323-1 ), which includes essentially everyone traveling outside the United States, Canada, Japan, Australia, New Zealand, Scandinavian countries, and developed countries in Europe. A single dose of hepatitis A vaccine given any time before travel provides adequate protection. The Centers for Disease Control and Prevention (CDC) recommends ancillary concomitant immune globulin for travelers older than 40 years who are planning to depart in 2 weeks or less, 9 but this recommendation has not been widely adopted in practice. Individuals born in the developing world are generally immune to HA. Persons with a history of hepatitis or who previously lived in an endemic country for a prolonged period may benefit from prevaccination serum antibody testing. Open full size image FIGURE 323-1 Worldwide distribution of important travel-related diseases. *Yellow Fever (YF) vaccination is generally not recommended in areas where there is low-potential YF virus exposure. However, vaccination might be considered for a small subset of travelers to these areas who are at increased risk for exposure to YF virus because of prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites. Consideration for vaccination of any traveler must take into account the traveler's risk of being infected with YF virus, country entry requirements, and individual risk factors for serious vaccine-associated adverse events (e.g., age, immune status). (From World Health Organization. International Travel and Health. Available at http://www.who.int/ith .) Hepatitis B Travelers born in the United States after 1992 already have received a HB vaccine series. Pretravel HB vaccination is indicated for all nonvaccinated travelers with standard indications, such as health care workers and all longer-stay travelers who will be visiting or residing in high- or moderate-risk areas (see Fig. 323-1 ). Transmission via routes such as sexual contact, blood transfusions, contaminated medical equipment, body piercing, tattooing, acupuncture, and sharing of cooking and bathroom facilities is difficult to control or predict in the context of travel. Vaccination is usually advocated for short-term travelers, especially younger travelers and those anticipating close contact with local populations, even if they have no specific risk factors. Adventure travelers (accident prone), backpackers, and those with underlying medical conditions are more likely to require contact with the medical system. Business and other regular travelers who fly internationally on multiple but short trips have a cumulative risk that increases with time, and such individuals should receive the HB vaccine. Accelerated and hyperaccelerated schedules (see Table 323-3 ) are used widely in practice and are approved in many countries. These are helpful in administering all three primary doses necessary for high assurance of protection in the frequent circumstance in which the traveler is leaving in a very short time and is at risk of HB exposure. 10 Combination Hepatitis A and Hepatitis B Vaccine The combined HA and HB vaccine provides convenience for travelers, with an overlap of indications for use of the individual vaccines. The accelerated 3-week schedule (see Table 323-3 ) was licensed in the United States in 2007. 11 Typhoid Typhoid vaccine is indicated for all travelers to the Indian subcontinent and considered for those traveling to other endemic areas under all but the most deluxe and protected of conditions. Risk increases with trip duration, lodging and/or eating with local residents, and extent of travel off the usual tourist itineraries. In risk areas, food and water precautions should still be followed rigorously because typhoid vaccines are only from 53% to 72% protective, 12 and a large oral inoculum may overwhelm even an optimal antibody response. The recent increase in quinolone-resistant Salmonella Typhi in Asia has decreased the threshold for typhoid vaccination because infection, once acquired, may require inpatient parenteral therapy with ceftriaxone or a carbapenem, 13although evidence for high-dose oral azithromycin efficacy is accumulating. Current typhoid vaccines do not protect against Salmonella Paratyphi , which is emerging in many areas. 13 Adherence to the oral vaccine regimen may be as low as 70%. 14 Influenza Influenza is transmitted year-round in the tropics. Increasing data show that influenza may be the most common vaccine-preventable illness in travelers. 151617 An increased risk of influenza has been reported among cruise ship passengers. 18 All travelers to destinations with current influenza virus circulation, not just those with the usual risk factors, should strongly consider influenza vaccination. 19 No proven benefit has been demonstrated to revaccinating persons before summer travel who were already vaccinated the previous fall. In China and Southeast Asia, avoiding poultry markets and farms may decrease risk of avian influenzas such as H7N9. Vaccines to Consider Only for Certain Destinations Yellow Fever The primary indication for YF vaccination is to prevent infection in individuals at risk. However, YF is currently the only vaccine that falls under the International Health Regulations that may necessitate vaccination purely for regulatory reasons. 20 Neither YF vaccine nor any other vaccine is currently required for readmission to the United States. In general, all healthy adult travelers to areas with a risk of yellow fever transmission (see Fig. 323-1 ) should be vaccinated. This endemic area may be restricted to only a portion of a country. Because of rare but serious vaccine-associated adverse side effects (see Chapter 321 ), persons who are not at any risk of exposure should not be vaccinated. 21 Urban YF rarely occurs in South America, but a number of urban areas are considered to have potential risk. Short-term travel that is restricted to very large urban areas in the endemic zone of South America carries negligible, if any, risk, but the situation may change rapidly. It is prudent to vaccinate persons who have anything less than a definite, fixed itinerary and who will travel anywhere close to regions with risk of transmission. A number of African countries (Angola, Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Congo, Côte d'Ivoire, Democratic Republic of Congo, Gabon, Ghana, Guinea-Bissau, Liberia, Mali, Niger, Rwanda, São Tomé, Sierra Leone, Togo) and one in South America (French Guiana) require proof of YF vaccination from all arriving travelers. Other countries, both within and outside the risk zone, have submitted more complex requirements to the World Health Organization (WHO). They may require an official vaccination certificate only for individuals arriving directly from or via a country in the YF endemic zone, but not from arriving travelers from other countries. Such transits may include even an airplane connection in an affected country. These YF-free countries usually have the conditions and vectors to initiate a YF transmission cycle, and the purpose of the vaccine requirement is to prevent entry of viremic travelers. Current country-by-country YF entry requirements are available at www.who.int/ith/chapters/en/index.html . The requirement often applies even if the arriving traveler has not visited an area within a country of departure that is endemic for YF. A special permit, obtainable in the United States from state health departments, is required to legally stamp an international certificate of vaccination as from an authorized YF vaccine center. The International Health Regulations enable clinicians who decide that YF vaccine is contraindicated on medical grounds to provide the traveler with a letter stating the reasons for that opinion, which can be presented to immigration authorities upon arrival at the destination. Acceptance of such “waiver letters” is at the complete discretion of the destination country. 20 On arrival, the receiving country may also quarantine the traveler for up to 6 days or request that the traveler be placed under surveillance. No specific format exists for written documentation of medical contraindication. Letters of waiver are most appropriate for individuals needing a certificate purely for regulatory reasons. Waiver letters should be given with great reluctance for those with medical contraindications to vaccination (see Chapter 321 ) who plan to visit an endemic area. The variable risk within the endemic regions of the world needs to be considered (in consultation with an expert, if necessary), and cancellation of travel should be recommended strongly if the risk is more than negligible. A YF certificate becomes valid for entry 10 days after it is stamped and dated. Although officially valid for 10 years, the true duration of immunity from YF vaccination is probably much longer and may exceed 30 years. Beginning in 2016, WHO has mandated that a yellow fever vaccination certificate is good for indicating lifetime immunity. A few countries may enforce YF regulations on individuals who have been in endemic areas as much as 30 days previously, even though the International Health Regulations recognize only up to a 6-day requirement. Meningococcus Meningococcal vaccine is recommended for travelers to Africa's sub-Saharan “meningitis belt” (see Fig. 323-1 ) during the dry season, from December through June, especially if prolonged contact with the local populace is likely. Out-of-season epidemics have occurred in Ethiopia, Somalia, and Tanzania, indicating possible changes in epidemiologic trends perhaps resulting from climate changes. 2223 Muslims undertaking Hajj and Umrah pilgrimages in Saudi Arabia are at a higher risk of meningococcal disease, and proof of vaccination with quadrivalent vaccine within the past 3 years is required to obtain pilgrimage visas. 24 Rabies A preexposure rabies series is indicated for long-stay travel to endemic areas of Latin America, Asia, or Africa (see Fig. 323-1 ), where the rabies threat is constant and where access to adequate postexposure rabies immune globulin and vaccine is likely to be limited. Countries with the highest risk of rabies include the Indian subcontinent, Thailand, Vietnam, and most sub-Saharan African countries. For short-term travel, risk groups for whom immunization should be considered include adventure travelers, bikers, hikers, cave explorers, or business travelers who travel for short but frequent trips and plan to go running outdoors on these trips. Regardless of vaccination status, travelers should be instructed to cleanse well with soapy water any bite or animal scratch involving broken skin immediately and to seek postexposure treatment for rabies (see Chapter 165 ). Japanese Encephalitis Japanese encephalitis (JE) is endemic to many rural farming areas of Southeast Asia and the Indian subcontinent (see Fig. 323-1 ). Sporadic cases with severe sequelae continue to occur in travelers. 25 In temperate regions, the transmission season is from April through November. In tropical or subtropical regions of Oceania and Southeast Asia, transmission may occur year-round. Vaccination is recommended for (1) long-stay travel to an endemic rural area; (2) expatriation to anywhere in an endemic country; (3) short-term travel to endemic rural areas with extensive unprotected outdoor exposure, such as with adventure travel; or (4) short-term travel in the face of a current local epidemic. 2627 Dengue, Chikungunya, and Zika Virus Large areas of the world, including the Caribbean, are endemic for these mosquito-borne infections, which cause fever, rash, headache, conjunctivitis, and myalgias (see Chapters 153 and 155 ). Chikungunya can cause severe arthralgia that persists for months. Zika virus can also cause arthralgia and has been associated with Guillain-Barré syndrome and perhaps microcephaly in the fetuses of infected women. Sexual transmission of Zika virus from infected males to pregnant females may have occurred. The period of risk for sexual transmission, if it exists, is as yet unknown. There are no commercially available vaccines or treatment for any of these three viral diseases. Clothing and mosquito repellants (see later) may decrease exposure to the urban, day-biting mosquitoes that can transmit all three diseases. Polio Because of eradication efforts, poliomyelitis remains in only a few countries, but complete control remains elusive (see Fig. 323-1 ). Adults traveling to countries that are currently polio endemic (updated information atwww.polioeradication.org ) and who have previously completed a primary vaccine series should receive a one-time single dose of inactivated polio vaccine as a booster if the last dose or booster dose was administered at least 10 years previously. Cholera Cholera vaccination is no longer required by any country, and the risk to typical travelers is insignificant. 28However, medical and aid workers staying for short periods in disaster areas or refugee camps may consider cholera vaccine. A highly effective oral, killed, whole-cell–B subunit vaccine 28 is available widely outside the United States. This vaccine also has about 50% efficacy against enterotoxigenic Escherichia coli and a 7% to 23% efficacy against all traveler's diarrhea (TD) and has this indication in some countries (see Fig. 323-1 ). Tick-Borne Encephalitis Tick-borne encephalitis (TBE) is an emerging, important, and serious flavivirus central nervous system infection in endemic areas. Distribution is highly focal in a range that extends in a swath from Germany through Scandinavia and the Baltic to Siberia and Vladivostok in the East. Risk to travelers is low unless extensive outdoor activities are planned in forested regions in endemic areas. 29 Immunization against TBE is recommended for adventure travel, extensive outdoor exposure, or camping in the forests of the endemic countries between April and October. Tick precautions are also recommended. The vaccine is available in most endemic countries and by special release in Canada and the United Kingdom. 30 Spacing and Interactions of Travel-Related Vaccines All currently indicated immunizations can and should be given at the same time and in any combination. If two live viral antigens are not administered on the same day, they must be spaced by a month. However, YF vaccine can be given at any interval with respect to single-antigen measles vaccine. Live oral vaccines (typhoid, polio) can be administered at any interval with respect to any live virus vaccine. Minimum intervals between vaccine doses must be respected, although 4 or fewer days before the next interval are acceptable. 31 Regimens that involve 1-week intervals (rabies, JE, accelerated hepatitis) are exceptions. There is not a maximal interval between doses of a primary vaccine series; interrupted series, except oral typhoid and rabies, need not be restarted but can be resumed beginning with the dose that is overdue. Anaphylactic egg allergy precludes administration of YF, influenza, and MMR vaccines. No current vaccine contains penicillin. Baseline purified protein derivative skin tests, often done in the pretravel setting, can be given on the day that live virus vaccines are administered or else must be done more than 4 weeks later. Antibacterial drugs should not be given within 24 hours of a dose of live oral typhoid or oral cholera vaccine. Malaria Chemoprophylaxis An average of 1500 imported cases of malaria is reported annually in the United States. Estimates of risk in travelers not taking chemoprophylaxis vary widely by destination but range from 3.4% per month in West Africa to one tenth that on the Indian subcontinent and a further 10-fold reduction in South America. 532 The majority of cases of imported malaria in the United States and Europe occur in noncitizen immigrants visiting friends and relatives abroad. 33 Malaria chemoprophylactic drugs are underused by these ethnic minority travelers. Eighty percent of all imported falciparum malaria originates in Africa. Risk of travelers' malaria may not be the same as the risk for those in local populations. Travelers often operate in a more protected environment. Transmission, and in particular high transmission, is quite focal even within the shaded areas in Figure 323-2 . In addition to the precise locations within the country or countries to be visited, the risk of travelers' malaria depends on the length of the trip, the season, whether the traveler adheres to precautions concerning mosquitoes, and whether the traveler spends the evening and nighttime hours where significant exposure to the vector may occur. Restriction of nighttime activities to air-conditioned hotels or other locations where there are few mosquitoes reduces the risk. With the exception of sub-Saharan Africa and certain cities in India, travel restricted to capital cities and other urban areas (as is typical of business travel) is associated with no risk or an insignificant risk of contracting malaria, despite the risk in areas nearby. The lifetime range of flight of an Anopheles mosquito is 1 km. Daytime side trips to malarial areas present no risk. At the same time, exposure to mosquitoes for even a few hours in an area with a high risk of transmission may result in infection. The decision regarding whether to prescribe chemoprophylaxis should also take into account the possibility of deviation from the preset itinerary brought to the pretravel consultation, as well as the traveler's personal tolerance for what may be an epidemiologically insignificant level of risk for the specific trip. Open full size image FIGURE 323-2 Malaria-endemic areas. Shading indicates areas where malaria is endemic, and stippling indicates drug sensitivity patterns that affect choice of prophylactic agent. (From Freedman DO. Clinical practice. Malaria prevention in short-term travelers. N Engl J Med. 2008;359:603-612.) Resources describing current country-specific malaria microepidemiology should be accessible immediately to those prescribing malaria prophylaxis (see Table 323-1 ). Dosing and pharmaceutical properties of antimalarial drugs are described in Chapters 40 and 276 . Drug resistance patterns that affect the choice of an antimalarial drug for chemoprophylaxis are shown in Figure 323-2 . In the limited number of countries where it is still effective, chloroquine, 500 mg salt (300 mg base) per week beginning the week before the first exposure to malaria and continuing for 4 weeks after the last exposure, is still the drug of choice; however, atovaquone/proguanil may still be used by short-stay travelers who prefer the shorter duration of that regimen. For all other areas of the world, three drugs are equally effective, and the choice depends on both traveler and itinerary factors. Atovaquone/proguanil (250/100 mg) is a well-tolerated, once-a-day drug that should be started 1 day before arrival in the malarial area (may not coincide with first overseas destination) and continued for 7 days after the last exposure. The short period of postexposure use makes it convenient for the many travelers on typical 1- to 3-week itineraries. High cost and daily dosing make it difficult to use for extended periods. Weekly mefloquine (250 mg) is given 2 and, preferably, 3 weeks before the first exposure to malaria and continued for 4 weeks thereafter. Weekly dosing and a long track record of efficacy make this drug the most effective for long-stay travelers. If contraindications to mefloquine exist for long-stay travelers, daily doxycycline (100 mg) beginning 1 day before exposure can be used; unlike atovaquone/proguanil, it must be continued for 4 weeks after exposure. Generic doxycycline is the cheapest of the antimalarials, so it is attractive to both short- and long-stay budget travelers. For travelers to chloroquine-sensitive areas who are unable to tolerate chloroquine, any of the three latter drugs are effective. Approximately 5% of individuals who take either mefloquine or doxycycline discontinue therapy because of side effects. 34 Chemoprophylaxis may be started well before departure (3 to 4 weeks for mefloquine) in those concerned about possible intolerance to any drug. Mefloquine has been associated with neuropsychiatric side effects 35 in some and should not be prescribed for persons with active depression or a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorder. It should be used with caution in patients with a previous history of depression. If prodromal psychiatric symptoms occur during use, the drug should be discontinued and an alternative medication substituted. Doxycycline is an esophageal and gastric irritant. It needs to be taken with a full glass of water on a full stomach, and the user should not go to sleep or lie down for 30 minutes after ingestion. Female travelers may get vaginal candidiasis and should carry self-therapy for candidiasis when prescribed doxycycline. The rare traveler intolerant of all of the three drugs may consider daily primaquine after consultation with a malaria expert and after glucose-6-phosphate dehydrogenase (G6PD) testing. Travelers should be reminded in writing to continue antimalarial drugs for the appropriate period after the last possible exposure, that malaria can still occur despite chemoprophylaxis, and that a malaria smear or malaria rapid diagnostic test is mandatory for any febrile illness occurring within 3 months after travel. Unless primaquine itself is used for primary prophylaxis during the trip, none of the primary prophylactic drugs discussed earlier is effective against the dormant hepatic hypnozoites of Plasmodium vivax or Plasmodium ovale, which may cause delayed relapses of malaria. Presumptive antirelapse therapy refers to a regimen at the end of the exposure period, to kill residual hypnozoites of these two species. Per CDC guidelines, primaquine, 30 mg base per day for 14 days, after checking G6PD levels, is indicated only for those with prolonged and extensive exposure to P. vivax or P. ovale. This effectively excludes most short-term travelers. Malaria chemoprophylaxis recommendations are likely to change periodically. Physicians may check the CDC or WHO travel websites (see Table 323-2 ). In destinations with mainly P. vivax, the CDC now recommends that primaquine can be considered as one of the first-line choices for primary malaria prophylaxis because it has the added benefit of eliminating dormant hypnozoites and preventing later relapses with the use of a single-drug regimen. Primaquine should not be used for primary prophylaxis in Africa, where high-intensity transmission with Plasmodium falciparumpredominates. Chloroquine-resistant P. vivax occurs only in areas in which the other drugs are already indicated for prophylaxis because of the concomitant presence of resistant P. falciparum. For stays in areas with very low transmission rates of malaria, some physicians, notably in Europe, may advise that only a standby drug be carried, which should be taken in the event that symptoms suggestive of malaria occur and there is no access to a physician or facility that can perform a competent malaria smear within 6 to 12 hours. This strategy is especially attractive for long-stay travelers. In areas with chloroquine-resistant P. falciparum, atovaquone/proguanil, four 250/100 tablets orally as a single daily dose for 3 consecutive days, or artemether/lumefantrine, four 20/120 mg tablets twice a day for 3 consecutive days, are recommended. In areas without chloroquine-resistant P. falciparum, chloroquine is the drug of choice. Prevention of malaria in travelers residing in malarial areas for 6 months or more presents complex problems that have been reviewed elsewhere.