Chloroquine
For those limited geographic regions not yet experiencing CRPF [see Figure 5], the chemoprophylactic agent of choice is chloroquine, given as either chloroquine phosphate (Aralen) or hydroxychloroquine sulfate (Plaquenil).1 Chloroquine phosphate, 500 mg (300 mg of chloroquine base), or hydroxychloro-quine sulfate, 400 mg (310 mg of hydroxychloroquine base), should be taken once weekly beginning 1 to 2 weeks before travel and continuing during the stay and for 4 weeks after departure from malarious areas. Minor side effects, including gastrointestinal disturbances, dizziness, blurred vision, and headache, may be alleviated by taking the drug after meals. Serious side effects are rare. Specifically, retinal injury, which can occur when high doses of chloroquine are used to treat rheumatoid arthritis, does not occur with the weekly dosages used for malaria prevention, even when such a regimen is continued for 5 years. However, deaths from malaria have occurred among tourists from the United States who avoided chloroquine prophylaxis out of a misguided concern for ocular toxicity.
Mefloquine
Mefloquine (Lariam) is active against CRPF and against P. fal-ciparum that is resistant to sulfadoxine with pyrimethamine (Fan-sidar). With the now-widespread geographic prevalence of CRPF [see Figure 5], either mefloquine or atovaquone-proguanil is for many travelers the mainstay of malarial chemoprophylaxis. Strains of P. falciparum that are resistant to mefloquine, however, have been recognized in Africa and along the border between Thailand and Cambodia. Mefloquine, 250 mg, is taken once a week, beginning 1 to 2 weeks before travel and continuing during the stay and for 4 weeks after departure from a malarious area.1 (This schedule is similar to that for chloroquine.) For travelers who will be immediately arriving in malarious areas, a loading dose of mefloquine (250 mg daily for the first 3 days) is advisable.
Despite the benefits of mefloquine to travelers in regions with CRPF malaria, mefloquine has acquired an unsalutary reputation. Mefloquine causes side effects, including nausea, dizziness, vertigo, light-headedness (described as an inability to concentrate), bad dreams, seizures, and psychosis. These reactions occur principally when the drug is given at therapeutic doses, which are higher than those given for prophylaxis. The incidence of psychosis or seizures has been about one per 10,000 travelers treated with chemoprophylactic mefloquine, which is comparable to the incidence associated with chloroquine use.21 Other controlled trials have demonstrated that mefloquine is reasonably well tolerated in groups receiving this agent.22-24 Thus, the uncommon and self-limited, but bothersome, side effects of mefloquine are to be weighed against the very real risks of serious and fatal malaria in many nonimmune travelers.
Mefloquine use has also been associated with sinus bradycar-dia and prolongation of the QT interval. Therefore, mefloquine probably should not be used by persons with cardiac conduction abnormalities but may be used by patients without arrhythmias who are taking beta blockers.1 Other contraindications to meflo-quine include a history of serious neuropsychiatric disorders or seizures. Mefloquine appears to be safe and effective for young children.25 Studies indicate that use of mefloquine in pregnancy during the second and third trimesters is not associated with adverse fetal or pregnancy outcomes; more limited data suggest that mefloquine is probably safe during the first trimester.26-28 Mefloquine has no deleterious effects on fine motor skills, such as those required by airplane pilots.29
Atovaquone-Proguanil
Atovaquone-proguanil (Malarone) is available in many countries, including the United States, for the chemoprophylaxis of malaria. Atovaquone-proguanil is formulated as a fixed-dose tablet in adult strength (250 mg atovaquone/100 mg proguanil) and in pediatric strength (62.5 mg atovaquone/25 mg proguanil). For prophylaxis, one tablet is taken daily, beginning 1 to 2 days before travel and continuing for the duration of travel and for 1 week after departure from malarious areas. One, two, or three pediatric-strength tablets are taken by children weighing 11 to 20 kg, 21 to 30 kg, or 31 to 40 kg, respectively.
Atovaquone-proguanil is well tolerated; side effects, which are uncommon, are abdominal pain, nausea, vomiting, headache, and rash. Atovaquone-proguanil is safe and efficacious for prophylaxis of P. vivax and P. falciparum malaria, including CRPF. For P. vivax and P. ovale malaria, atovaquone-proguanil, like mefloquine and chloroquine, does not prevent development of hepatic hypnozoite stages, so treatment with primaquine (so-called terminal prophylaxis) may be necessary to prevent relapses with these species [see Primaquine, below]. Atovaquone-proguanil, therefore, is an alternative to mefloquine for malaria chemoprophylaxis1 in regions of Thailand, Myanmar (Burma), and Cambodia where mefloquine-resistant P. falciparum malaria is present.
Doxycycline
Doxycycline, taken alone, is an alternative chemoprophylactic agent.1 It should be taken in a dosage of 100 mg daily, beginning 1 to 2 days before travel and continuing for 4 weeks after departure from malarious areas. The use of doxycycline is appropriate for persons who are intolerant of sulfonamides, pyrimethamine, chloroquine, or mefloquine and for persons who are planning short-term visits in forested areas of Thailand, Myanmar (Burma), or Cambodia, where strains of malaria that are resistant to chloroquine, mefloquine, and sulfadoxine with pyrimethamine (Fansidar) are present.1 Doxycycline may cause photosensitivity skin reactions and is contraindicated in pregnant women and in children younger than 8 years.
Proguanil
Proguanil (Paludrine) is not available in the United States but is available in Canada, Europe, and much of Africa. This agent, like pyrimethamine, is a dehydrofolate reductase inhibitor, and some strains of malaria are resistant to it. Proguanil (200 mg) is taken daily in combination with a weekly dose of chloroquine. The combination of proguanil and chloroquine, however, is much less effective than mefloquine or atovaquone-proguanil against chloroquine-resistant P. falciparum malaria and hence is not recommended.1,30
Primaquine
Primaquine may be used either as a single agent taken daily for chemoprophylaxis against all species of malaria or as an agent to eradicate residual intrahepatic stages of P. vivax and P. ovale. For the latter purpose, primaquine is administered during the last weeks of or just after a course of prophylaxis with either chloroquine or mefloquine. When intended as terminal prophylaxis, primaquine may be administered as 30 mg of the base daily for 14 days. Such terminal prophylaxis is generally reserved for persons who have had more than a casual potential exposure to P. vivax or P. ovale; other persons may be followed clinically and evaluated if they become symptomatic. For use as a primary chemoprophylactic agent, 30 mg of primaquine base is taken daily starting 1 day before travels and continuing for 2 days after departure from a malarious area.31
Because primaquine can cause severe hemolysis in patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency, this disorder must be excluded before the drug is administered. As a chemoprophylactic agent, primaquine is reserved for the rare individual who is unable to take other recommended chemoprophylactic regimens. CDC suggests primaquine be used only after consultation with malaria experts, including those at the CDC Malaria Hotline (1-770-488-7788).1
Sulfadoxine with Pyrimethamine
For chemoprophylaxis in areas where CRPF malaria occurs, it was formerly recommended that a single tablet of Fansidar, which contains 500 mg of long-acting sulfadoxine and 25 mg of pyrimethamine, be taken once a week along with chloroquine beginning 1 to 2 weeks before arrival in an endemic area and continuing for 4 weeks after departure from such an area. However, severe mucocutaneous reactions, including erythema mul-tiforme, Stevens-Johnson syndrome, and toxic epidermal necrol-ysis, have developed after the use of two or more doses of Fansi-dar. These reactions produced fatalities with an incidence of about one per 11,000 to 20,000 travelers from the United States. Moreover, P. falciparum malaria is increasingly resistant to antifo-late agents. Consequently, Fansidar is not recommended for chemoprophylactic use.
Orophylaxis during pregnancy
Malaria infections represent a major health hazard to the mother and fetus.32,33 Infections are potentially more serious during pregnancy and increase the risks of stillbirths, abortions, and other adverse pregnancy outcomes. For pregnant women who cannot defer travel or residence in malarious areas, chloroquine, which is without established teratogenicity, may be used.1 Mefloquine appears to be safe in pregnancy.26-28 For the pregnant traveler in regions with CRPF malaria, the benefits of effective mefloquine chemoprophylaxis need to be balanced with any potential, but as yet not recognized, adverse effects of mefloquine in pregnancy. Sulfadoxine should be avoided before delivery because of the risk of neonatal jaundice. Pyrimethamine, which is teratogenic in animals because it interferes with folate metabolism, is generally avoided but probably could be used. Doxycy-cline should not be used during pregnancy because of the effects of tetracyclines on the fetus, which include dental discoloration and dysplasia and inhibition of bone growth. To avoid the risk of inducing hemolytic anemia in utero in a G6PD-deficient fetus, primaquine should not be taken during pregnancy. The safety of malarone in pregnancy has not been established.
Travel-Related Illness
In a study of more than 10,000 Swiss who had traveled in developing countries for less than 3 months, 15% experienced health problems, and 3% were unable to work for an average of 15 days.34 Infections with the greatest incidence per month abroad included giardiasis (seven cases per 1,000 months abroad), amebiasis (four cases per 1,000), hepatitis (four cases per 1,000), and gonorrhea (three cases per 1,000). Malaria, syphilis, and helminthic infections occurred at a lower incidence (fewer than one case per 1,000). No cases of typhoid fever or cholera were reported. The most common modes of acquisition of infection were enteral and sexual. Travelers should be cautioned about sexual contacts, especially in areas where hepatitis B or HIV is prevalent, and be advised to use condoms and barrier protection during sexual encounters.
Because of the global prevalence of HIV, postexposure anti-retroviral prophylaxis may be germane for travelers who may have occupational exposures (e.g., health care workers) and for students and workers who are traveling and may be at risk for HIV exposure. The availability of local postexposure prophylactic medications should be ascertained at overseas work or study sites. Options for two- or three-drug regimens of postexposure antiretroviral therapy are discussed elsewhere [see 7:XXX1II HIV and AIDS]. If selected antiretroviral therapy is not assuredly available at work or study sites, sufficient medication should be carried by the traveler to ensure that a 28-day course of antiretro-viral therapy is available.
Stays at major resorts and first-class hotels are associated with less risk than stays in less frequented locales or rural dwellings or encampments. In areas where sanitation and personal hygiene may be poor, it is prudent to be careful of food and water, although such care does not necessarily diminish the risk of diarrheal disease. Fruit that is peeled by the traveler is safe, whereas vegetables may be contaminated with fecally passed organisms in the soil and should not be consumed raw. Unpasteurized dairy products should be avoided, as should inadequately cooked fish or meat. If water is of uncertain quality, travelers should avoid drinking it or using ice made from it. Boiling will render water safe. Chlorination will kill most bacterial and viral pathogens, but protozoal cysts of Giardia lamblia and Entamoeba histolytica may survive. Carbonated beverages, beer, wine, and drinks made from boiled water are safe.
In areas where schistosomiasis is prevalent, swimming in freshwater should be avoided, although swimming in chlorinated or saltwater is safe. Even short exposures to infested water during rafting or swimming have caused the onset of acute schistosomiasis.
Most infections acquired during travels will present within weeks of travel, but some may not manifest themselves until much later; hence, knowledge of a patient’s travel history is important.
Altitude illness
Altitude illnesses may develop in travelers who arrive at heights between 6,000 and 8,000 ft (1,829 and 2,438 m) above sea level.1 Travelers may arrive at these altitudes rapidly by flying into an airport at these elevations or more slowly by driving or climbing. Altitude illness includes three syndromes: acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema (HACE). AMS, the most common form of altitude illness, may occur at altitudes between 4,000 and 6,000 ft. Symptoms include headache, fatigue, loss of appetite, nausea, and, sometimes, vomiting. AMS usually develops 6 to 12 hours after arrival at the higher altitude. HACE is a progression of AMS characterized by extreme lethargy, confusion, and an ataxic gait during a tandem gait test.
HAPE may develop alone or in conjunction with HACE. Symptoms include increasing breathlessness. HAPE is more likely than HACE to be fatal. Travelers who develop HACE or HAPE must immediately descend to lower altitudes. Travelers to elevated altitudes need to be cautioned about the symptoms of these syndromes [see 14:X Pulmonary Edema], advised about the gravity of HACE and HAPE, and admonished not to delay descent to lower altitudes if these potentially lethal syndromes develop.
Three medications can be used to prevent and treat altitude illnesses. Acetazolamide can prevent AMS if taken before ascent; it also can hasten recovery. Dosing is 125 mg every 12 hours beginning the day of ascent. Dexamethasone (4 mg every 6 hours) can be used to prevent and treat AMS and HACE. Some investigators recommend relying on acetazolamide for prophylaxis and reserving dexamethasone for treatment of symptoms.1 Persons who have experienced HAPE are at increased risk of its recurrence. If travel to high altitudes is unavoidable, nifedipine (10 to 20 mg every 8 hours) can prevent and ameliorate HAPE in those prone to experience this syndrome.
Traveler’s diarrhea
Diarrhea is the most common illness of travelers.35 Infectious agents, primarily bacterial but also viral and parasitic pathogens, are responsible for traveler’s diarrhea. Over 75% of cases of traveler’s diarrhea are caused by bacteria, with enterotoxigenic Es-cherichia coli being the most frequent cause. Other common bacterial causes of traveler’s diarrhea include Shigella species, Campylobacter jejuni, Aeromonas species, Plesiomonas shigelloides, Salmonella species, and noncholera Vibrio species.35 Rotavirus and Norwalk agent are the most common viral causes; Giardia, Cryp-tosporidium, Cyclospora, and, less commonly, Dientamoeba fragilis, Isospora belli, Balantidium coli, Strongyloides stercoralis, and E. his-tolytica are parasitic causes.
In addition to exercising caution about food and water,36 travelers may take either of two approaches: chemoprophylaxis and postonset treatment.
Chemoprophylaxis
The benefits of chemoprophylaxis may be offset by the risks of taking chemoprophylactic agents. Side effects of short-term prophylactic doses of bismuth subsalicylate may include tinnitus, blackening of the stool and tongue, and impaired absorption of doxycycline, which is important if doxycycline is used as daily antimalarial chemoprophylaxis. Side effects of antibiotics may include skin rashes and vaginal candidiasis, photosensitivity skin eruptions (especially with doxycycline), and, in rare instances, potentially life-threatening bone marrow suppression, mucocutaneous reactions, or anaphylaxis. Although these potential side effects temper the routine use of chemoprophylaxis, specific needs or wishes of travelers may dictate its use. Patients with underlying medical conditions that may be aggravated by a serious diarrheal illness, including active inflammatory bowel disease, type 1 (insulin-dependent) diabetes mellitus, and heart disease in the elderly, as well as patients whose activities during travel cannot tolerate interruption by an episode of diarrheal illness, should consider chemoprophylaxis. Several regimens are available [see Table 3]. Bismuth subsalicylate, which should not be taken by persons with peptic ulcer disease, coagulopathies, or allergies to salicylates, is not as completely effective as quinolone antibiotics but has fewer side effects and enables the use of quinolone antibiotics, if they are needed for therapy.
Table 3 Chemoprophylaxis and Treatment of Traveler’s Diarrhea
|
Drug |
Dose |
|
Prophylaxis Bismuth subsalicylate |
Two 262 mg tablets chewed q.i.d. with meals and at bedtime |
|
Quinolone antibiotics |
|
|
Norfloxacin |
400 mg/day |
|
Ciprofloxacin |
500 mg/day |
|
Ofloxacin |
300 mg/day |
|
Levofloxacin |
500 mg/day |
|
Doxycycline |
100 mg/day |
|
Treatment |
|
|
Loperamide |
4 mg loading dose, then 2 mg after each loose stool, to a maximum of 16 mg/day |
|
Quinolone antibiotics |
|
|
Norfloxacin |
400 mg b.i.d. for up to 3 days |
|
Ciprofloxacin |
500 mg b.i.d. for up to 3 days |
|
Ofloxacin |
300 mg b.i.d. for up to 3 days |
|
Levofloxacin |
500 mg/day for up to 3 days |
|
Azithromycin |
1,000 mg single dose or 500 mg/day for 3 days |
|
Rifaximin |
200 mg t.i.d. for 3 days |
Resistance among bacterial causes of traveler’s diarrhea is not common at present for the quinolone antibiotics (except for quinolone-resis-tant Campylobacter infection prevalent in Thailand) but is quite common for trimethoprim-sulfamethoxazole and doxycycline, limiting their efficacy. Chemoprophylactic medications should be started on the first day of arrival and continued for 1 to 2 days after returning home but not for more than 3 weeks.
Postonset Treatment
A generally preferable alternative to chemoprophylaxis is early therapy for traveler’s diarrhea [see Table 3]. Because of the likelihood of bacterial resistance, trimethoprim-sulfamethoxa-zole is less effective than regimens employing quinolone antibiotics. Antibiotics will shorten the duration of traveler’s diarrhea to a range of 16 to 30 hours, compared with a range of 59 to 93 hours in those not receiving antibiotics. The use of lop-eramide, which diminishes intestinal motility and fluid and electrolyte losses, together with antibiotics can further abbreviate symptoms. In a study of patients with dysentery caused by Shigella or enteroinvasive E. coli, the use of loperamide with ciprofloxacin, in comparison with ciprofloxacin alone, led to briefer (median, 19 hours versus 42 hours) and milder (median, two stools versus 6.5 stools) diarrheal illness, without untoward effects.37 Loperamide has not been studied in children, and adults with prolonged fever or bloody stools should be advised to cease loperamide use and seek medical attention. Azithromycin is an alternative to quinolone antibiotics that can be used by pregnant patients; it is the agent of choice where quinolone-resistant Campylobacter infection is prevalent. Rifax-imin (Xifaxan, from Salix), a nonabsorbable agent, is approved by the FDA for traveler’s diarrhea caused by noninvasive strains of Escherichia coli.38 Rifaximin should not be used if dysentery is suspected (i.e., if symptoms include fever and bloody stools) or if other causes of diarrhea (e.g., Campylobacter, Shigella, or invasive E. coli) are possible or isolated.
For any diarrheal illness, maintenance of hydration is of cardinal importance and can often be achieved by oral replacement of lost fluid and electrolytes. Convenient and inexpensive packets of oral rehydration salts formulated according to World Health Organization recommendations (i.e., 3.5 g of sodium chloride, 1.5 g of potassium chloride, 20 g of glucose, and 2.9 g of trisodi-um citrate in each packet) are available in both developed and developing countries. Each packet of oral rehydration salts is added to a liter of boiled or treated water and should be consumed or discarded within 12 hours if kept at ambient temperature or within 24 hours if kept refrigerated.
Medical issues during transit
Cruise ships that dock at ports in the United States are inspected for sanitation by officials from the CDC. Inspections are aimed at minimizing the potential for outbreaks of gastrointestinal disease on board. Travelers may obtain information on whether specific cruise ships meet sanitation standards from travel agents, state health departments, or the CDC.1 Outbreaks of influenza have occurred aboard cruise ships in the past 10 years in various regions, including Alaska and the Yukon Territory. Travelers older than 50 years should consider influenza vaccination.
Because jet aircraft are not pressurized to sea level, passengers will be exposed to high-altitude environments. The atmospheric pressure maintained within the cabin of an airplane flying at 27,000 to 42,000 ft is equivalent to the pressure at an altitude of 3,000 to 8,000 ft, so that at a cruising altitude of 35,000 ft, the cabin pressure is about 600 mm Hg. Because of the decreased pressure, the arterial oxygen tension (PaO2) of normal persons will fall to about 68 mm Hg. In patients with chronic obstructive lung disease, the PaO2 will fall even lower. However, despite a fall in PaO2, patients may not show symptoms of hypoxia. Although hypoxia occurs in pregnant women, jet air travel has no deleterious effects on them or their fetuses. It is difficult to establish precise criteria for the use of supplemental oxygen for air travelers. Caution is indicated, however, for patients with impaired car-diopulmonary function: supplemental oxygen may be administered during flights at altitudes higher than 22,500 ft.
Scuba divers should wait 12 to 48 hours, depending on the length of their diving exposures, before boarding a commercial aircraft. This measure is important for avoiding the occurrence of aeroembolism, commonly known as the bends, which could develop in an underpressurized cabin if nitrogen gas dissolved in the person’s fat cells is mobilized.
In patients with upper respiratory tract infections, differential air pressures between blocked eustachian tubes or sinuses and the cabin may develop on ascent or descent and impair hearing or cause pain in the ears or sinuses; symptoms can be relieved by the use of decongestants. Persons prone to motion sickness should take a prophylactic medication. Prolonged immobilization during flight may cause venous thrombosis in persons with preexisting thrombotic or venous disease [see 1:XVIII Venous Thromboembolism]. The exact risks and rates for developing venous thromboembolism during air travel are not yet defined.39 Leg exercise and walking during the flight and use of below-the-knee stockings have been suggested to be beneficial, but evidence is lacking.
