Current Diagnosis & Treatment in Infectious Diseases

Section VIII - Miscellaneous Infections

89. Infections in Travelers

DeVon C. Hale MD

Caroline Milne MD

Essentials of Diagnosis

  • Fever
  • Weight loss
  • Diarrhea
  • Myalgia
  • Headache
  • Skin rash

General Considerations

International travel has become a normal part of life. Physicians who are knowledgeable regarding common infections encountered in international travel and ways to prevent infection can provide a great service to their patients.

Most travelers will not encounter “tropical disease”; a study of > 10,000 Swiss travelers to developing countries in the early 1980s revealed that the most commonly encountered illness was diarrhea. No persons were infected with cholera or typhoid. The risk of acquisition of disease depends on where one is traveling and the travel conditions. Standards of sanitation and native immunization rates vary, especially in developing countries. In most developed countries, risk of disease is no greater than in the United States. This chapter focuses on pretravel evaluation of the international traveler, including vaccination recommendations and advice to help in prevention of disease. We also discuss post-travel evaluation, with special attention paid to travelers' diarrhea, typhoid fever, and malaria.

PRETRAVEL EVALUATION

It is essential that physicians evaluating international travelers have accurate and current advice. Information for the practitioner can be found in Health Information for the International Traveler from the Centers for Disease Control and Prevention (CDC) and International Travel and Health Vaccination Requirements and Health Advice from the World Health Organization (WHO). Both titles are available, or on the CDC (http://www.cdc.gov/) or WHO (http://www.who.int/) web site, respectively. Information about current outbreaks of disease (only yellow fever and cholera) can be found in the CDC's Summary of Health Information for International Travel, which is published biweekly.

The patient's initial pretravel visit should occur at least 6 weeks before departure. At that time, a pertinent medical history should be taken and physical examination performed. The patient's itinerary and travel conditions should also be elicited.

Travel advice should begin with general-safety advice; an estimated 0.5% of travelers will suffer some sort of accident. Motor vehicle accidents are responsible for 25% of all mortality abroad. The traveler should also be aware of where to obtain medical attention. If medical attention is needed abroad, the traveler can contact the American Embassy for names of physicians and hospitals. The primary physician's name and phone number should be carried on the traveler.

Preparation is the key to disease prevention. Travelers should carry a medical kit with necessary supplies and medications for self-treatment when able. Travelers on medications for chronic illnesses need a sufficient supply. Other important medications include commonly used pain relievers such as acetaminophen and aspirin, antihistamines for allergies, decongestants and cough suppressants, antacids, antidiarrheal agents, and laxatives. Topical antibiotics and anti-itch lotions could also be carried. Antibiotics to be used for treatment of specific illness, especially if the traveler will be in remote areas away from medical attention, may be considered. First-aid supplies such as bandages, gauze, tape, syringes, needles, scissors, and tweezers should be included in the medical kit. Other materials such as antimalarial agents, insect repellent, and water purification tablets should be carried when applicable (Table 89-1).

Travelers' diarrhea is the most common illness suffered abroad. This illness is most often acquired through contaminated food or water. Because of varying sanitation practices abroad, it is important that the traveler be aware of risk of diseases spread through food and water (Table 89-2). In general, tap water in developing countries is considered unsafe to drink. This includes ice cubes and other nonbottled drinks that may have been prepared by using nonpurified tap water. Boiling is the most effective method of making local water safe from biological hazards. For short trips many travelers rely on carbonated water and reputable brands of bottled water. Water purification pumps are available at most outdoor supply stores. Chemical methods of water purification are listed in Table 89-2. Both were found to be equally effective. Very cold water (< 4°C) may need to be warmed to room temperature or have prolonged exposure to the purification agent for improved effectiveness. Food should be selected by using common sense. In general, raw and undercooked foods are more likely to be contaminated. Salads and raw fruits and vegetables are more likely to carry diarrhea-producing organisms. It is safest to choose well-cooked, hot foods. Food available from street vendors in developing countries has been associated with an increased risk of disease.

Table 89-1. Traveler's medical supply kit.

First aid supplies

Medications

Bandages
Gauze
Tape
Syringes
Needles
Scissors
Tweezers

Pain relievers (acetaminophen, ibuprofen)
Cough suppressants
Decongestants
Antihistimines
Antacids
Antidiarrheal agents
Topical antibiotics
Anti-itch lotions (calamine)
Sunscreen

Incidences of diseases carried by mosquitoes and other arthropod vectors can also be decreased by taking preventive measures. (Table 89-3). Anophelesmosquitoes (the vector for malaria) bite between dusk and dawn. Avoidance of outdoor activities during this time is best if possible. Clothing should cover as much skin as possible, and sandals should be avoided. DEET (N, N-dimethyl-meta-toluamide)-containing insect repellents are recommended. The CDC recommends solutions containing < 35% DEET for adults and 6–10% DEET-containing solutions for children. Bed nets should be used when windows will be open. For extra protection, clothing and bed nets can be treated with permethrin solutions.

Routine Immunization Recommendations

The CDC Advisory Committee on Immunization Practices meets periodically to make vaccine recommendations based on scientific evidence of benefit versus risk to achieve protection against communicable disease. Routine vaccinations against diphtheria, tetanus, pertussis, measles, mumps, rubella, poliomyelitis, and Haemophilus influenzae infections are commonly administered during childhood in the United States. All international travelers should be current on these routine vaccinations. Immunization rates may be much lower in developing countries, and these diseases, which have low incidences in the United States, are more prevalent in these areas. Table 89-4 gives childhood dosing schedules, and Table 89-5 gives the pregnancy dosing schedules.

Table 89-2. Safe water and water purification techniques.

Boil water—bring water to a boil
Use carbonated or bottled water
Use purchased water filters
Drink alcohol-containing beverages
Use chemical water purification methods
   Iodine, 2% tincture (10 drops/liter of water for 30 min)
   Chlorine bleach (4 drops/liter of water for 30 min)

Table 89-3. Insect precautions.

Clothing should be worn to cover as much skin as possible
Screens should be placed on open windows
Mosquito bed nets should be used when windows will be open
DEET–containing insect sprays should be used
Clothing and bed nets can be rinsed in permethrin solutions

  • Diphtheria, Tetanus, and Pertussis.Diphtheria and tetanus remain health problems throughout the world. The diseases occur almost exclusively in unimmunized or inadequately immunized populations. The primary vaccination series consists of three doses of tetanus-diphtheria toxoid. Doses 1 and 2 are given 4–8 weeks apart. The third dose is given 6–12 months after the second. Although most adult travelers will have received their primary immunizations against these diseases as children, a booster is recommended every 10 years after completion of the primary series. See Chapter 56 for a detailed description of the clinical presentation of these diseases.

Pertussis is quite common in inadequately immunized countries, especially in western areas of the former Soviet Union. Vaccination against this disease is recommended for all travelers under age 7 years who have not received primary immunization against pertussis. Pertussis vaccination is not recommended for people over age 7 owing to greater perceived risk than benefit. See Chapter 56 for a detailed description of the clinical presentation of pertussis.

  • Measles.Measles is often a serious disease, especially in adults, because it can be complicated with bronchopneumonia. Vaccination is recommended for all persons born after 1957. Those born before 1957 are considered naturally immune because measles was endemic throughout the world. A 2-dose subcutaneous vaccine is expected to induce immunity. A single adult booster is recommended. See Chapter 34 for a detailed description of the clinical presentation of measles.
  • Mumps.Mumps vaccination is commonly completed with combination measles and rubella vaccines (MMR). The combined vaccination is a 2-dose schedule. Vaccination is recommended for all persons born after 1957, because adults born before 1957 are considered naturally immune. See Chapter 35 for a detailed description of the clinical presentation of mumps.
 

Table 89-4. Recommended childhood immunization schedule United States, January–December, 2001. Vaccines1are listed under routinely recommended ages. Bars indicate range of recommended ages for immunization. Any dose not given at the recommended age should be given as a “catch-up” immunization at any subsequent visit when indicated and feasible. Ovals indicate vaccines to be given if previously recommended doses were missed or given earlier than the recommended minimum age.

Table 89-5. Vaccination during pregnancy.

Disease Vaccination

Vaccine Type

Indications for Vaccination During Pregnancy

Live virus vaccine

Measles

Live-attenuated

Contraindicated

Mumps

Rubella

Yellow fever

Live-attenuated

Contraindicated except if exposure to yellow fever virus is unavoidable

Poliomyelitis

Trivalent live-attenuated (oral polio vaccine)

Persons at substantial risk of exposure to polio

Inactivated virus vaccines

 

Hepatitis A

Killed Virus

Data on safety in pregnancy are not available. Should weigh the theoretical risk of vaccination against the risk of disease

Hepatitis B

Recominant produced, purified hepatitis B surface antigen

Pregnancy is not a contraindication

Influenza

   Inactivated type A and type B virus vaccines

Usually recommended only for patients with serious underlying disease. Consult health authorities for current recommendations

Japanese Encephalitis

Killed virus

Should reflect actual risks of disease and probable benefits of vaccine

Poliomyelitis

Killed virus (inactivated poilio vaccine)

Oral polio vaccine preferred when immediate protection of pregnant females is needed; however, inactivated polio vaccine is alternative if complete vaccination series can be administered before exposure

Rabies

Killed virus
Rabies immunoglobulin

Substantial risk of exposure

Live bacterial vaccines

 

Typhoid (Ty21a)

Live bacterial

Should reflect actual risks of disease and probable benefits of vaccine

Inactivated bacterial vaccines

Cholera Typhoid

Killed bacterial

Should reflect actual risks of disease and probable benefits of vaccine

Plague

Killed bacterial

Selective vaccinatin of exposed persons

Meningococcal

Polysaccharide

Only in unusual outbreak situations

Pneumococcal

Polysaccharide

Only for high–risk persons

Haemophilus b conjugate

Polysaccharide–protein

Only for high–risk persons

Toxoids

Tetanus–diphtheria

Combined tetanus–diphtheria toxoids, adult formulation

Lack of primary series, or no booster within past 10 years

Immune globulins, pooled or hyperimmune

Immune globulin or specific globulin preparations

Exposure or anticipated unavoidable exposure to measles, hepatitis A, hepatitis B, rabies, or tetanus

  • Rubella.The rubella virus is associated with some morbidity in adults. In pregnant women, there is a high rate of fetal death and deformation. A single dose of rubella virus vaccine is recommended for all people. This vaccination is commonly given in the two-dose MMR combination series. See Chapter 36 for a detailed description of the clinical presentation of rubella.
  • Poliomyelitis.Poliomyelitis remains endemic and epidemic in some parts of the world. The WHO has made a goal for complete eradication. A primary series of oral polio virus vaccine, which includes three doses, or enhanced-potency inactivated polio virus vaccine should be completed before travel. For travelers to developing countries, who have completed a primary series, a single adult booster dose of oral polio vaccine OR inactivated polio vaccine is recommended. Inactivated polio vaccine is recommended to previously unvaccinated adults and immunocompromised hosts owing to the higher risk of vaccine-associated disease in these groups. See Tables 89-6 and 89-7 for dosing information. See Chapter 27 for a detailed description of the clinical presentation of this disease.
  • Haemophilus influenzae type b.H influenzae type b causes severe childhood disease including meningitis and pneumonia. Vaccination is recommended for all children under age 5 years, regardless of travel plans. An unvaccinated child 15–59 months old needs only a single dose. The vaccine is not recommended for children over age 5. See Table 89-8 for complete dosing schedules. See Chapter 56 for a detailed description of the clinical presentation of this disease.

Table 89-6. Oral poliovirus vaccine.

Doses

Number of Doses

Comments

Primary series

3

Give doses 1, 2 and 3 6–8 wk apart, customarily at 2, 4, and 6 mo of age (For adults see text)

Supplementary

1

Give dose 4 to children 4–6 years of age

Additional

1

Give a dose, once, to persons traveling to developing countries

Other Recommended Vaccinations

  • Hepatitis B.Hepatitis B infection is associated with a high degree of morbidity and mortality (see also Chapter 39). It is most often spread via contact with bodily secretions such as blood or by intimate sexual contact. It can cause a fulminant acute hepatitis, a chronic hepatitis, or both, which may lead to increased risk of cirrhosis, hepatocellular carcinoma, and death. In most of the developed world, hepatitis B surface antigen prevalence is low—< 1% of the general population. In Africa, Southeast Asia, the Middle East (except Israel), the Pacific Islands, and certain parts of the Caribbean (Haiti and the Dominican Republic), the prevalence of disease carrier status is as high as 8%, regardless of socioeconomic status. Universal precautions are usually not taken in developing countries, and sterilization techniques may not be adequate; therefore, patient risk of acquisition of disease from medical care is much higher than in the United States. Although a hepatitis B viral vaccination series is now recommended for all health care providers and infants in the United States, many travelers may not be immunized before travel.

Previously unvaccinated persons who will provide health care, who are at risk of having to receive health care, or who might have any exposure to blood or other body secretions abroad are encouraged to receive the vaccination series. Travelers who plan on residing in a given endemic area for > 6 months should also receive the vaccine.

Primary vaccination consists of three intramuscular (i.m.) doses of recombinant DNA vaccine. After the initial vaccination, doses are scheduled at 1 month and 6 months. Table 89-9 gives the dosing schedule. Protection is increased with each dose of the vaccine; thus travelers who cannot complete the 6-month series before travel may still receive benefit from initiating the series. An alternative accelerated schedule is also available, with dose scheduling at 0, 1, and 2 months, followed by a booster at 12 months.

  • Hepatitis A.Hepatitis A virus is transmitted via ingestion of contaminated food or water. It is highly endemic in most of the developing world and in some areas of the developed world (see also Chapter 39). Risk of acquisition can be decreased by following the recommended food and water practices discussed earlier in this chapter. Hepatitis A vaccine or immunoglobulin protection is recommended for all travelers to areas with intermediate or high endemic rates. This includes all developing countries, eastern Europe, and Russia. For some travelers, screening for hepatitis A virus antibodies may be beneficial before primary immunization. This is indicated in travelers > 40 years old or those born in endemic areas.

Protection from disease can be obtained via two methods, inactivated vaccine or immunoglobulin. Two inactivated hepatitis A vaccines, HAVRIX and VAQTA, are currently approved for use in the United States. The vaccine is administered i.m. in a two- to three-dose series. See Tables 89-10 and 89-11 for recommended dose and schedules.

An alternative protection against hepatitis A virus is immunoglobulin. A single intramuscular dose (0.02 mL/kg) offers protection against hepatitis A virus for ≤ 3 months. Protection can be provided for ≤ 5 months with a larger dose (0.06 mL/kg) but must be repeated if protection is required for longer than that time. At present, hepatitis A vaccine is not approved for use in pregnancy or children < 2 years old; therefore, immunoglobulin is currently the prevention of choice in these groups. See Table 89-12 for dosing recommendations.

Table 89-7. Inactivated poliovirus vaccine

Doses

Number of Doses

Dose Volume

Comments

Primary series

3

As indicated by manufacturer

Give doses 1 and 2 4–8 wk apart; give dose 3 6–12 mo after dose 2

Booster

1

 

Give dose 4 to children 4–6 years of age

Additional

1

 

Give a dose, once, to persons traveling to developing countries

Rarely Indicated Vaccinations

  • Rabies.Rabies virus causes disease of the central nervous system (CNS), manifested as encephalitis (see also Chapter 43). It is transmitted by infected secretions of mammal hosts. Almost all exposures are secondary to animal bites; however, there are rare reported cases of nonbite infection. Rabies infection is a significant cause of morbidity and mortality throughout the world. It is estimated to cause ≤ 50,000 deaths each year. Endemic areas of the world include Mexico, parts of South America, India, Nepal, Sri Lanka, Thailand, and Vietnam.

Table 89-8. Recommended Haemophilus influenzae type b routine vaccination schedule by age.

Vaccine

2 months

4 months

6 months

12 months

15 months

HbOC

Dose 1

Dose 2

Dose 3

Booster

PRP-OMP

Dose 1

Dose 2

Booster

PRP-D1

Single dose

1PRP-D is recommended only for children ≥ 15 months of age.

Travelers to rabies-endemic regions, especially those who will have known exposure to animals, should consider preexposure prophlaxis. Preexposure vaccine does not eliminate the need for postexposure treatment; however, it does eliminate the need for immune serum globulin and decreases the number of vaccine booster doses needed.

There are three preexposure vaccinations available: human diploid cell rabies vaccine, rabies vaccine adsorbed, and chicken embryo rabies vaccine. They are given in 1.0-mL doses, i.m., on days 0, 7, and 28. Human diploid cell rabies vaccine can be given via the intradermal route, but this route is not recommended if any drugs interfering with immune response are used simultaneously. Rabies vaccines being used in other countries may contain neural-tissue–derived Semple vaccines or suckling mouse-brain products, which are considered less effective and have more associated side effects.

Postexposure vaccine should be given immediately after exposure. All wounds should be thoroughly cleaned with soap and water. For those not previously immunized, postexposure vaccination consists of five doses of human diploid cell rabies vaccine, rabies vaccine adsorbed, or chicken embryo rabies vaccine, each 1.0 mL i.m., on days 0, 3, 7, 14, and 28. In addition, rabies immune globulin, 20 IU/kg of body weight, is given one-half i.m. and one-half infiltrated into the wound site, on day 0. It can be given ≤ 7 days after exposure if unavoidable. For those previously immunized, two doses of human diploid cell rabies vaccine or rabies vaccine adsorbed (1.0 mL i.m. on days 0 and 3) are administered. Immune serum globulin should not be used.

  • Japanese Encephalitis.Japanese encephalitis virus infection affects the CNS (see also Chapter 7). The illness may present as a febrile headache, meningitis, or encephalitis. Transmission occurs from the bite of the mosquito Culex tritaeniorhynchus, which is the major vector species. Risk of acquiring Japanese encephalitis virus is low and of exhibiting clinical manifestations of disease is lower; only 1:300 seroconverters develop encephalitis.

Risk increases with outdoor exposure to mosquitoes during transmission season and with travel to rural areas of endemic countries. Endemic countries include Malaysia, Myanmar, Cambodia, Laos, Nepal, Philippines, Sri Lanka, Taiwan, northern Thailand, and Vietnam.

Vaccination is rarely recommended for short-term tourists. Travelers who plan to live in endemic areas during transmission season should be considered for the vaccine.

The inactivated viral vaccine, JEVax, has an efficacy rate of > 90%. It is given in three separate 1.0-mL doses on days 0, 7, and 28. There is a significant occurrence of systemic side effects including hypersensitivity reactions. Reactions may be delayed up to 72 h; it is therefore recommended that the last dose of the series be administered at least 10 days before departure.

Table 89-9. Recomended doses of currently licensed hepatitis B vaccines.

 

Dose (µg)

Group1

Recombivax HB2

EngerixB2

Infants of HBsAG-negative mothers and children < 11 y old

2.5

10

Infants of HBsAG-positive mothers; prevention of perinatal infection

5.0

10

Children and adolescents 11–19 y old

5.0

10

Adults ≥ 20 y old

10.0

20

Dialysis patients and other immunocompromised persons

40.03

404

1HBsAG, Hepatitis B surface antigen.
2Both vaccines are routinely administered in a three-dose series. Engerix-B also has been licensed for a four-dose series administered at 0, 1, 2, and 12 months.
3Special formulation (40 µg in 1.0 mL).
4Two 1.0-mL doses given at one site, in a four–dose schedule at 0, 1, 2, 6 months.

  • Plague.Plague is a bacterial illness caused by infection with Yersinia pestis (see also Chapter 60). The disease is spread to humans from the bite of the rodent flea. Human bubonic plague disease is manifested by adenopathy (bubo), sepsis, multiorgan failure, and death. Plague pneumonia can be transmitted via infected cough aerosols. In recent years human plague has been reported in Angola, India, Kenya, Lesotho, Madagascar, Mozambique, Namibia, South Africa, Botswana, Tanzania, Uganda, Zimbabwe, Zaire, Myanmar, China, Mongolia, Vietnam, the United States, the former Soviet Union, Brazil, Bolivia, Ecuador, and Peru.

Table 89-10. Recommended doses of HAVRIX1

Group

Age (Years)

Dose (EL.U.)2

Volume (mL)

No. Doses

Schedule (Months)3

Children and adolescents4

2–18

720

0.5

2

0, 6–12

Adults

> 18

1400

1.0

2

0, 6–12

1Hepatitis A vaccine, inactivated, SmithKline Beecham Biologicals.
2EL.U = ELISA units.
30 months represents timing of the initial dose; subsequent numbers represent months after the initial dose.
4An alternate formulation and schedule (three doses) are available for children and adolescents and consist of 360 EL.U./0.5–mL dose at 0, 1, and 6–12 months of age.

Risk to travelers, even those traveling to areas where disease has been reported, is low. Because of this low risk, plague vaccination is recommended only for persons having direct contact with diseased rodents or infected animals. See Table 89-13 for plague vaccine doses and intervals.

  • Typhoid Fever.Typhoid fever is a systemic febrile infection caused by Salmonella enterica serovar Typhi (see also Chapter 53). Infection is caused when water or food is contaminated by an infected human carrier. Risk of acquisition of disease depends on sanitation standards; thus risk is greater for travelers to developing countries. Vaccination should be considered for travelers anticipating prolonged exposure to potentially contaminated food and water. The approved vaccinations may not offer complete protection, and, as always, preventive steps against food and water contamination should be taken.

Three typhoid vaccines are available in the United States, an oral live-attenuated vaccine, a parenteral heat-phenol–inactivated vaccine, and a capsular polysaccharide vaccine. The parenteral heat-phenol–inactivated vaccine is an older vaccine, has more associated side effects, and is no longer commonly used. The vaccines have comparable efficacy rates. See Table 89-14 for doses and schedules.

  • Yellow Fever.Yellow fever is caused by a flavivirus that is transmitted via Aedes aegypti and Aedes sylvatic mosquito vectors (see also Chapter 43). Clinical manifestations of disease vary from fever and headache to the classic triad of diseases found in severe infections: jaundice, hemorrhages, and severe albuminuria. Risk of transmission is low; however, this is a vaccine-preventable disease that is associated with high mortality and for which there is no treatment.

Yellow fever vaccination is the only required immunization for admission to certain countries including endemic areas of Africa and Central and South America. It is also required in areas where human infection may induce epidemics or cause transmission. Yellow fever vaccine must be administered at an approved yellow fever vaccination center, because International Certificates of Vaccinations are required for country admission. To be valid, the vaccination must occur ≥ 10 days before desired admission to the country.

Yellow fever vaccine is an attenuated live-virus vaccine. It is given to travelers > 9 months of age as a single dose. A booster dose is required every 10 years. Vaccination should not be given to pregnant women, and special consideration should be taken before immunization of immunocompromised hosts.

Table 89-11. Recommended doses of VAQTA1

Group

Age (Years)

Dose (U)2

Volume (mL)

No. doses

Schedule (months)3

Children and adolescents

2–17

25

0.5

2

0, 6–18

Adults

> 17

50

1.0

2

56

1Hepatitis A vaccine, inactivated, Merck & Company, Inc.
2Units
30 months represents timing of the initial dose; subsequent numbers represent months after the initial dose.

  • Dengue Fever.Dengue fever is caused by the Dengue virus, a member of the family Flaviviridae, and it is usually transmitted by Aedes mosquitoes. It is a disease most commonly seen in urban areas of the Indian subcontinent, Southern China, Southeast Asia, and South and Central America.

Dengue virus causes a sudden onset of high fever, severe headaches, myalgia, and arthralgia. It is associated with a rash that occurs 3–4 days after the onset of symptoms.

Currently, no vaccine is available. There is, however, a vaccine in development. Because the disease is acquired via mosquito transmission, preventive measures should be taken (see Pretravel Evaluation above). Treatment is primarily supportive. Medication to reduce fever should be avoided.

Table 89-12. Immune globulin for protection against viral hepatitis A.

Length of Stay

Body Weight

Dose Volume2(ml)

Comments

lb

kg1

Short-term travel (< 3 mos)

<50
50–100
>100

<23
23–45
>45

0.5
1.0
2.0

Dose volume depends on body
weight and length of stay

Long-term travel (3–5 mo)

<22
<50
50–100
>100

<10
<23
23–45
>45

0.5
1.0
2.5
5.0

1Kg = ~ 2.2 lbs.
2For intramuscular injection.

  • Cholera.Cholera is a bacterial diarrheal illness caused by Vibrio cholera (see also Chapters 20 and 57). Disease is spread via contaminated food and water. Clinical manifestation of disease ranges from mild, self-limited diarrhea to the voluminous watery diarrhea that quickly leads to dehydration and death.

The risk of cholera to the traveler is very low. The licensed vaccine in the United States offers only 50% effectiveness. Because of the low risk and the low benefit, cholera vaccine is indicated only for high-risk people working and living in endemic areas and in poor sanitary conditions. Endemic areas are present in South and Central America, Africa, and Asia. The vaccine is given as two subcutaneous, intradermal, or intramuscular doses at least 1 week apart. An additional booster dose is required every 6 months. See Table 89-15 for dosing recommendations.

  • Meningococcal Meningitis.Neisseria meningitidis causes a bacterial meningitis that is responsible for multiple epidemics of disease (see also Chapters 7 and 52). Epidemic areas include sub-Saharan Africa during the dry season (December–June). This area is know as the “meningitis belt.” Recent epidemics have also occurred in Kenya, Tanzania, Burundi, and Mongolia. All travelers planning to visit countries in the meningitis belt during the dry season or any of the above-mentioned countries should receive the meningitis vaccine. The vaccination is required for pilgrims to Mecca, Saudi Arabia, for the annual Hajj.

The formulation of meningococcal polysaccharide vaccine available in the United States offers activity against serotypes A, C, Y, and W135. Serotype A is responsible for most of the disease outside the United States and Europe. Serotype C is now the most common cause of Neisseria meningitis and is part of the vaccine. Quadrivalent A/C/Y/W135 vaccine can be given in a single subcutaneous dose, in the volume indicated by the manufacturer.

Table 89-13. Plague vaccine.

Dose

Dose volume1 (mL) ≥ 18–61 Years of Age2

Comments

Primary series
   1
   2 & 3

1.0
0.2

Give doses 1 and 2, 1–3 mo apart; dose 3 is given 5–6 mo after dose 2

Booster

0.2

Give booster doses 1–3 at 6–mo intervals for persons with ongoing exposure risks; give booster doses 4 and above at 1–2 year intervals after the preceding booster dose

1For intramuscular injection.
2No recommendations are given for other age groups because of insufficient data.

DISEASES REQUIRING SPECIAL ATTENTION

  1. TRAVELERS' DIARRHEA

General Considerations

Diarrhea is the most common illness affecting international travelers today (see also Chapter 20). Disease prevalence varies by destination, from a 5% incidence during travel to the United States and Canada to a 20%–50% incidence upon visiting tropic/subtropic developing countries. Although travelers' diarrhea tends to be a self-limited illness with very few people requiring medical attention (4%), even fewer requiring hospitalization (< 1%), and almost no one dying, the high incidence of the disease makes it exceedingly important. Frequently, travel time is limited, and there is no time for postponement or rescheduling because of illness.

Bacterial agents are most commonly responsible for travelers' diarrhea. The pathogen frequencies change depending on destination and season. Multiple studies conducted in the 1970s found that enterotoxigenic Escherichia coli is the major cause of the illness. Viral and protozoan causes of traveler's diarrhea are less frequent. See Table 89-16 for pathogens associated with traveler's diarrhea.

Table 89-14. Dosage and schedules for typhoid fever vaccination.

Vaccination

Age

Dosage

Dose/Mode of administration

Number of Doses

Interval Between Doses

Boosting Interval

Oral live-attenuated Ty21a vaccine

   Primary series

≥ 6 y

1 Capsule1

4

48 h

5

   Booster

≥ 6 y

1 Capsule1

4

48 h

Every 5 y

Vi capsular Polysaccharide vaccine

   Primary series

≥ 2 y

0.50 mL2

1

   Booster

≥ 2 y

0.50 mL2

1

Every 2 y

Heat-pheno–inactivated parenteral vaccine

   Primary series

6 mo–10 y
≥ 10 y

0.25 mL3
0.50 mL3

2
2

≥ 4 wk
≥ 4 wk

   Booster

6 mo–10 y
≥ 10 y
≥ 6 mo

0.25 mL3
0.50 mL3
0.10 mL4

1
1
1



Every 3 y
Every 3 y
Every 3 y

1Administer with cool liquid no warmer than 37°C (98.6°F).
2Intramuscularly.
3Subcutaneously.
4Intradermally.
5—, Not applicable.

 

Clinical Findings

Clinical symptoms of loose bowel movements, urgency, abdominal pain and cramping, low-grade fever, and nausea usually start soon after arrival at the travel destination. One study found the highest onset of symptoms on travel day 3. The mean duration of symptoms without treatment is 4.1 days. This can be shortened to 24 h when antidiarrheal medication is used.

Diagnosis

The diagnosis of traveler's diarrhea is a clinical one. Traveler's diarrhea is caused by a variety of bacteria, viruses, and parasites. The majority of cases are secondary to bacterial agents. Because cultures are time consuming and the natural course of the illness is relatively short, a clinical diagnosis and antibiotic treatment are an appropriate approach to treating this disease.

Treatment

  • Oral Rehydration.Oral rehydration is the cornerstone of therapy for uncomplicated traveler's diarrhea. Parents should be warned that infants and young children who are unable to communicate their thirst and fluid needs are at risk of dehydration. Most often, increased water intake is all that is necessary for otherwise healthy adults. For children or persons with severe dehydration, several oral rehydration formulations are currently marketed, or a rehydration solution can be made with simple ingredients: a half-teaspoon of salt can be mixed with 8 teaspoons of sugar in 1 liter of water.

Table 89-15. Cholera vaccine.

Doses

Intradermal Route1

Subcutaneous or Intramuscular Route

Comments

5 y of age and over

6 mo–4 y of Age

5–10 y of Age

>10 years of Age

Primary series
1 & 2

0.2 mL

0.2 mL

0.3 mL

0.5 mL

Give 1 wk to 1 mo or more apart

Booster

0.2 mL

0.2mL

0.3 mL

0.5 mL

1 dose every 6 mo

1Higher levels of protection (antibody)may be achieved in children < 5 years of age by the subcutaneous or intramuscular routes.

  • Antimotility Drugs.Antimotility drugs such as loperamide (Immodium) are safe to use for relief of symptoms in typical cases of traveler's diarrhea. Loperamide has been shown to decrease intensity of symptoms and shorten the course of the illness. Should the traveler experience prolonged diarrhea, high fevers, or blood or mucoid stools, antimotility agents should be discontinued and medical attention sought.
  • Antimicrobial Agents.Antimicrobial agents as presumptive treatment for acute traveler's diarrhea may be beneficial and should be initiated at the onset of abdominal cramps and loose stools. Multiple placebo-controlled trials have shown faster recovery rates in patients who received fluoroquinolones than those who did not. Trimethoprim-sulfa has also been shown to decrease symptoms and duration of diarrhea. Fluoroquinolones are not approved for use in children or pregnant women. Trimethoprim-sulfa is safe to use in children. See Table 89-17 for antimicrobial agents and dosages used in treatment of travelers' diarrhea.

Table 89-16. Etiologic agents associated with traverlers' diarrhea. 1

Agent

Latin America

Asia

ETEC2

28–72%

20–39%

Shigella spp.

0–30%

4–17%

Salmonella spp.

0–16%

4–15%

Rotavirus

0–36%

*3

Protozoa (Giardia spp. Entamoeba histolytica)

0–9%

*

Campylobacter spp.

*

*

Vibrio parahemolyticus

*

1–16%

1Adapted from Black 1986 and Taylor & Echeverria 1986.
2ETEC, Enterotoxigenic E coli.
3*, Not studied.

Although most travelers' diarrhea is self limited, travelers should be warned to seek medical attention if diarrhea is severe or does not resolve within several days, diarrhea is bloody or mucoid, diarrhea is associated with high fevers or shaking chills, or the patient is unable to maintain oral fluids, and dehydration becomes an issue.

Prevention

Because of the large number of agents responsible for this disease, vaccination is not an ideal form of prevention. Although investigation is underway directed at enterotoxigenic E coli, the most common pathogen, travelers will remain at risk of infections by the other etiologic agents.

Current forms of prevention can be directed at two routes—careful selection of food and water or chemoprophylaxis. As discussed earlier, it is extremely important for advising physicians to educate their patient regarding selection of food and water (see discussion of general travel advice above). Treatment of water or consumption of bottled carbonated drinks along with careful selection of fully cooked, peeled, or steamed hot foods is essential. Despite good advice, several studies have found that travelers are unable to strictly adhere to recommended water and food choices. In a study of Swiss travelers, 98% consumed food or beverages that they were warned to avoid.

Chemoprophylaxis has been well studied in travelers' diarrhea. It is well accepted that antimicrobial prophylaxis is highly effective. DuPont and Ericcson (1993) found that fluoroquinolone prophylaxis prevents ≤ 90% of disease. If trimethoprim-sulfa is used, prevention is still provided, although to a lesser extent. Despite the effectiveness of antimicrobial agents, most clinicians agree that these should not be routinely provided for prophylaxis. There are numerous problems with routine chemoprophylaxis: (1) adverse drug reactions, such as skin rash, photosensitivity, Steven-Johnson syndrome, or bone marrow suppression; (2) colonic bacterial overgrowth; (3) interference with other medications; and (4), perhaps most importantly, the promotion of resistance to antimicrobial agents.

Table 89-17. Antimicrobial treatment of traverlers' diarrhea.

Agent

Dose

TMP-SMX

160 mg TMP/800 SMX twice daily for 1–3 d

Ciprofloxacin

500 mg twice daily for 1–3 d

Ofloxacin

400 mg twice daily for 1–3 d

The decision to provide antimicrobial prophylaxis for travelers' diarrhea should be based on a risk-benefit analysis and recommended only in rare and unusual circumstances. For most travelers, the illness is self-limiting and non-life threatening. A patient who is chronically ill or immunosuppressed may benefit more from prevention, because the risk of acquisition of travelers' diarrhea could be life threatening.

Bismuth subsalicylate (eg, Pepto Bismol) is another consideration in chemoprophylaxis. As with antimicrobial agents, prophylaxis with bismuth subsalicylate has reduced the incidence of travelers' diarrhea. An analysis in the late 1970s of students studying abroad in Mexico revealed that prophylactic use of bismuth subsalicylate reduced the incidence of traveler's diarrhea by 62%. Despite the evidence in this single trial, the CDC does not recommend the use of bismuth subsalicylate as prophalaxis for travelers' diarrhea, based on risk of salicylate toxicity and other uncertain risks.

No antiperistaltic agents are effective in prevention of travelers' diarrhea. In fact, prophylactic use of antiperistaltic drugs may actually increase the incidence of disease.

  1. TYPHOID FEVER

General Considerations

Typhoid fever is an enteric fever syndrome caused by S enterica serovar Typhi (see also Chapter 53). At one time, typhoid fever was one of the most common bacterial infections in the United States. With improved sanitation, the incidence of typhoid fever has declined. There is still some risk involved with international travel to developing countries and exposure to contaminated food and water. Acquisition of disease associated with all international travel is estimated to be 1:30,000. Travel to India, Peru, or North and West Africa can greatly increase risk of acquisition.

S enterica serovar Typhi infection is caused by contaminated food and water. It is strictly a human pathogen. The bacteria attach and penetrate intestinal mucosa and cause damage to the mucosa directly or via bacterial toxins. The bacteria then invade and multiply within macrophages and therefore reach systemic circulation and cause systemic disease.

Clinical Findings

Clinical manifestations vary from asymptomatic carriage (eg, as occurred with “Typhoid Mary”) to gastroenteritis to enteric fever and bacteremia. Symptoms of enteric fever usually occur 1–2 weeks after exposure. Cough, sore throat, myalgia, and abdominal pain are early symptoms. With time, fever becomes prominent with changes in mental status. The patient may experience diarrhea or constipation. Significant physical findings include bradycardia associated with fever and hepatosplenomegaly.

Diagnosis

Diagnosis is made by isolation of the bacteria in a blood culture. Stool cultures may be negative both early and late in the illness.

Treatment

Treatment is different depending on disease manifestations. The treatment of chronic carriers is important because they are the likely source of disease spread. Eradication of the pathogen is difficult. Current therapeutic options are outlined in Table 89-18. If antibacterial therapy is not successful, cholecystectomy may become necessary because the bacteria tend to live in the scarred biliary tree or in the presence of gallstones.

The treatment of choice for enteric fever is a fluoroquinolone. If antimicrobial-agent resistance is a problem, trimethoprim-sulfa can be used.

Prevention

Prevention of typhoid fever via vaccination (Table 89-14) is recommended for travelers to developing countries who will have prolonged exposure to contaminated food and water. As always, careful selection of food and drink is strongly encouraged (see Pretravel Evaluation above and Table 89-2).

  1. MALARIA

General Considerations

Malaria is a febrile illness caused by four different species of the genus Plasmodium: P falciparum, P ovale, P vivax, and P malariae (see also Chapter 80). These plasmodia infect humans via the bite of the female Anopheles mosquito. Rarely, malaria has been linked to blood transfusions and congenital transmission.

The risk of acquisition of these plasmodia depends on the country visited, the type of area visited (ie, rural or urban), the time of year (ie, dry or rainy season), and the duration of the visit. There are 300–500 million cases of acute symptomatic malaria annually and 1.5–2.7 million deaths. The majority of the cases occur in sub-Saharan Africa, with Southeast Asia and Central and South America coming in a very distant second and third, respectively.

Table 89-18. Antimicrobial treatment of typhoid fever.

Agent

Dose

Ciprofloxacin

500 mg twice daily for 10 d

Ceftriaxone

2.0 gm i.v. daily for 5 d

Chloramphenicol

500 mg four times dialy for 14 d

Ofloxacin

15 mg/kg i.v. daily for 2–3 d

The high rate of disease and the continuing emergence of antimicrobial-agent resistance are concerns with malaria treatment. Chloroquine-resistant P falciparum is now reported in all countries except the Dominican Republic, Haiti, Central America west of the Panama Canal Zone, Egypt, and most of the Middle East (Figure 89-1). Pyrimethamine-sulfadoxine (Fansidar) resistance has been reported in Thailand, Myanmar, Cambodia, the Amazon area of South America, and sporadically in sub-Saharan Africa.

Clinical Findings

Cyclic fevers are the hallmark of plasmodium infection. The fevers occur as the red blood cells lyse, releasing new plasmodium into the bloodstream. Typically, the victim experiences a cold or chilling stage, followed by a febrile stage lasting several hours, followed by a third sweating stage. The timing of the fevers differs depending on the infecting species—48 h for P vivax and P ovale and 72 h for P malariae. P falciparum usually causes a continuous fever with intermittent spikes. Most victims also experience shaking chills, hypotension, cough, headache, and back ache. Complications of the illness vary but can include CNS involvement with delirium, seizures, coma, and renal failure. Clinical manifestations vary somewhat depending on species.

P falciparum causes the most severe manifestations. The complications are thought to result from diffuse microvascular disease secondary to adherent, parasitized red blood cells that aggregate and obstruct blood flow. Infection with P falciparum can lead to severe anemia, renal failure, pulmonary edema, and CNS complications, referred to as “cerebral malaria,” which has a range of manifestations from impaired consciousness to seizures.

P vivax and P ovale typically cause less severe illness. The red blood cells do not aggregate with these infections; thus the microvascular manifestations are not seen. There is a dormant stage in the life cycle of these plasmodia; therefore, a late secondary illness can manifest as late as 12 months or longer after initial infection.

P malariae causes a low parasitemic infection, and associated symptoms are typically mild. Parasitized red blood cells do not aggregate; thus, with this infection, as well as with P vivax and P ovale, no microvascular damage is seen later in the infection. An immune complex glomerulonephritis is sometimes seen. The actual infection may persist for years.

The typical laboratory findings seen with malaria are related to the parasitized red blood cells and cell lysis. Anemia and increased lactate dehydrogenase, bilirubin, and reticulocyte counts are typically seen. Depending on the extent of the disease, increased blood urea nitrogen and creatinine associated with acute renal failure and thrombocytopenia can also be seen.

 

Figure 89-1. Distribution of malaria and chloroquine-resistant Plasmodium falciparum, 1997. Republished from Centers for Disease Control and Prevention: Health Information for International Travelers 1999–2000. CDC, 2000.

Diagnosis

The standard diagnosis of plasmodium infection is by Giesma-stained blood smears to visualize the parasite. The infected red blood cells can usually be seen on a Wright's stain as well. If the clinical suspicion is strong, and the initial blood smear is negative, the blood smear should be repeated in 6–12 h.

Treatment

Successful treatment of malaria requires rapid diagnosis and initiation of treatment. The species responsible should be confirmed via a peripheral blood smear before initiation of treatment. The selection of the antimalarial agent will depend on the infecting species and whether the patient is able to take oral medications.

Patients with P falciparum infection should be hospitalized until the physician is certain that serious complications such as cerebral malaria, adult respiratory distress syndrome, and renal failure will not occur. The obvious supportive treatments such as fluid resuscitation and management of complications should be done. Exchange transfusions may be helpful with severe parasitemia. The appropriate drug therapy depends on the Plasmodium species involved. Treatment therapies and doses are outlined in Table 89-19.

  • Treatment of P vivaxand P ovale Infections. Effective treatment of P vivax and P ovale infections can be obtained with chloroquine and primaquine. Chloroquine phosphate along with primaquine phosphate is recommended. Chloroquine is the only antimalarial agent approved for use during pregnancy. Primaquine is unsafe for use in pregnant women.
  • Treatment of Chloroquine-Sensitive P falciparum and P malariaeInfection. Infection with chloroquine-sensitive plasmodia can be treated with chloroquine. Side effects are minimal.
  • Treatment of Chloroquine-Resistant P falciparumInfection. Multiple drugs are available for treatment of resistant P falciparum malaria. The treatment drug chosen should be different from the drug used for prophylaxis.

Quinine was one of the first drugs used for treatment of malaria. Its use became less frequent with the development of new synthetic antimalarial agents, but, as resistance continues to increase, quinine has again become popular. Lower cure rates have been reported in Southeast Asia, including Thailand, Myanmar, Vietnam, and Cambodia. Quinine is currently a first-line drug for use in chloroquine-resistant P falciparum infections.

If the infection was acquired in Southeast Asia, quinine should be extended to 10 days, and doxycycline should be added. Tetracyclines are not safe to use during pregnancy. If a patient in the United States is unable to use oral medications, a continuous intravenous infusion of quinidine gluconate is used.

Malarone (Atovaquone 250 mg plus proguanil 100 mg) has been approved for the treatment of mild to moderate malaria where the patient can take oral medication. It is given as four tablets as a single dose daily for 3 d. It is contraindicated in infants, pregnancy, and while breast feeding. Side effects are rare and include nausea, vomiting, abdominal pain, and headache. It should not be used in patients with severe renal impairment.

Table 89-19. Drugs used in treatment of malaria.1

Species

Drug and Dosages

Side Effects and Contraindications

P vivax, P ovale

Chloroquine phosphate, 1.0 g initially, then 500 mg at 6 h, then 500 mg daily for 2 d (Pediatric dose, 10 mg base/kg orally, then 5 mg/kg BASEat 12, 24, and 36 h
PLUS 
Primiquine phosphate, 26.3 mg daily for 14 d (Pediatric dose, 0.25 mg BASE/kg/d orally for 14 d

Side effects include nausea, anorexia, and pruritis; safe for use in pregnancy

Contraindicated for use in G6PD-deficient patients secondary to hemolysis risk; Contrainidicated in pregnancy

Chloroquine-sensitive
   P falciparium or
   P malariae

Chloroquine phosphate, 1 g orally, then 500 mg in 6 h, then 500 mg daily for 2 d (Pediatric dosing as above)

As above

Chloroquine-resistant
   P falciparum

Quinine sulfate, 600 mg (500 mg base), three times daily for 7 d
PLUS 
Doxycycline 100 mg, two times dialy for 7 d

Not recommended for patients using cardiac beta blockers or those with epilepsy or psychiatric disorders

Contraindicated in pregnancy and children under 8 y old

Malarone

Atovaquone 250 mg PLUS Proguanil
100 mg, 4 tablets daily for 3 d

Side effects include nausea, vomiting, abdominal pain, and headache
Contraindicated in pregnancy, in infants, while breast feeding and severe renal insufficiency

1Adapted from Sanford et al 2000. G6PD, Glucose-6-Phosphatase deficiency.

Prevention

Prevention against Plasmodium infection is twofold, consisting of personal-protection measures and chemoprophylaxis. Despite complete compliance with both medication and personal-protection measures, infection with Plasmodium spp. is still possible. This information should be stressed to the traveler, because a febrile illness after exposure should be taken seriously.

Table 89-20. Malaria chemoprophalactic regimens.1

Regimen

Drug and Dose

Side Effects and Contraindications

Travel to areas where chloroquine resistance has not been reported

Chloroquine, 500 mg/wk. Start 2 wk before travel and continue 4 wk after leaving malarious area [Pediatric dose 8.3 mg/kg/wk (maximum 500 mg)]

Mild; nausea, vomiting, puritis reported; safe for use in pregnancy

Travel to areas where chloroquine resistance has been reported

Mefloquine, 250 mg/wk; start 1 wk before travel and continue for 4 wk after leaving malarious area (Pediatric doses: 15–19 kg = 1/4 tablet/wk; 20–30 kg = 1/2 tablet/wk; 31–45 kg = 3/4 tablet/wk; > 45 kg = 1 tablet/wk)

Contraindicated in 1st trimester of pregnancy and in travelerswith history of neuropsychiatric disorders or seizures; side effects include seizures and psychosis reported in 1/13,000 users, nausea, dizziness, and insomnia

OR

Doxycycline,2100 mg/d: start 1–2 d before travel and continue daily for 4 wk after leaving malarious area [Pediatric dose (after age 8 only): 1 mg/kg/d; maximum 100 mg/d]

Contraindicated in pregnancy and children < 8 y old

OR

Malarone (atovaquone 250 mg PLUS proguanil 100 mg), start one day before travel and continue daily for 7 d after leaving the malaria area (Pediatric dosing: 11–20 kg 62.5/25, 21–30 kg 125/50, 31–40 kg 187.5/75, >40 kg adult dose)

Contraindicated in pregnancy, infants, nursing mothers, and renal insufficiency Side effects nausea, vomiting, abdominal pain, and headaches

1Adapted from Sanford et al 2000.
2Only effective drug currently in Thailand.
3Only available in Canada, Africa, and Europe

Personal-protection measures include the general arthropod protection steps discussed above. Most importantly, travelers should avoid the outdoors during the feeding time of the Anopheles mosquito, which is dusk to dawn. DEET-containing repellent and pyrethroid-containing flying-insect spray should be used in living and sleeping areas during evening and nighttime hours (see Table 89-3). Additional protection can be provided by treating clothing with permethrin spray.

Chemoprophylaxis is provided to travelers based on information regarding their risk of acquisition, risk of encountering drug-resistant P falciparum, and accessibility to medical care. Chemoprophylaxis should be started 1–2 weeks before travel and continued for 4 weeks after leaving the malaria-risk area. There are three chemoprophylaxis regimens. These regimens are outlined in Table 89-20 and described below:

  • For travel to areas where chloroquine resistance has not been reported, chloroquine alone is recommended. Use of chloroquine may be associated with side effects such as mild nausea and skin rash reported in some users.
  • For travel to areas where chloroquine resistance has been reported, if the traveler has no history of mefloquine sensitivity, neuropsychiatric problems, or seizures, mefloquine is recommended. This is a very effective means of malaria prophylaxis. It does have significant side effects that may limit its use. Evidence of CNS toxicity, such as seizures and psychotic behavior, has been reported in 1 European traveler per 13,000. Mefloquine is not recommended for use in combination with beta blockers.

Mefloquine is safe to use in the second and third trimester of pregnancy. Limited data suggest that it may also be safe in the first trimester. Studies are still underway on the use of mefloquine in the first trimester, and women who choose to use the drug are asked to report the use to the CDC for registry in pregnancy outcomes research.

  • Other options include doxycycline, starting on the day of arrival at risk destination and continuing for 4 weeks after leaving the area.

Doxycycline is unsafe for use in pregnancy or in children. Common side effects include photosensitivity and gastrointestinal toxicity.

  • Malarone (Atovaquone 250 mg plus proguanil 100 mg) is approved for the prophylaxis of chloroquine-resistant malaria and is given as one tablet daily starting 1 d before arriving in a malaria area and continuing for 7 d after leaving the area. Side effects are rare and include nausea, vomiting, abdominal pain, and headache.

REFERENCES

Avery ME, Snyder JD: Oral therapy for acute diarrhea. The underused simple solution. N Engl J Med 1990; 323:891.

Black RE: Pathogens that cause travelers' diarrhea in Latin America and Africa. Rev Infect Dis 1986;8(Suppl 2): S131.

Centers for Disease Control and Prevention. Dengue Fever. CDC Document no. 221030. CDC, 1994.

Centers for Disease Control and Prevention. Health Information for International Travel 1996–97. CDC,1996.

Dupont HL, Ericsson CD: Prevention and treatment of travelers diarrhea. N Engl J Med 1993;328:1821.

Dupont HL, et al: Antimicrobial agents in the prevention of travelers' diarrhea. Rev Infect Dis 1986;8(Suppl 2): S167.

Dupont HL, et al: Prevention of travelers' diarrhea by the tablet formulation of bismuth subsalicylate. J Am Med Assoc 1987;257:1347.

Dupont HL, et al: Antimicrobial therapy for travelers' diarrhea. Rev Infect Dis 1986;8(Suppl 2):S217.

Gilbert DN, et al: The Sanford Guide to Antimicrobial Therapy 1998. Antimicrobial Therapy, Inc., 1998.

Hargarten SW, Baker TD, Guptill K: Overseas fatalities of United States citizen travelers: an analysis of deaths related to international travel. Ann Emerg Med 1991; 20:622.

Hoke CH, et al: Protection against Japanese encephalitis by inactivated vaccines. N Engl J Med 1988;219:608.

Jarroll EJ, Bingham AK, Meyer EA: Giardia cyst destruction: effectiveness of six small-quantity water disinfection methods. Am J Trop Med Hyg 1980;29:8.

Johnson PC, et al: Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. J Am Med Assoc 1986;255:757.

Steffen R. Epidemiologic studies of travelers diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis 1986;8(Suppl 2):S122.

Steffen R, et al: Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting East Africa. Lancet 1993;341:848.

Steffen R, Gsell O: Prophalaxis of travellers' diarrhoea. J Trop Med Hyg 1981;84:239.

Steffen R, et al: Health problems after travel to developing countries. J Infect Dis 1987;156:84.

Taylor DN, Echeverria P: Etiology and epidemiology of travelers' diarrhea in Asia. Rev Infect Dis 1986;8(Suppl 2):S136.

Taylor DN, Polland RA, Blake PA: Typhoid in the United States and the risk to international travelers. J Infect Dis 1983;148:615.

World Health Organization. WHO World Survey of Rabies. WHO, 1993.

World Health Organization: Wkly Epidemiol Rec 1997; 72:269.