Chapter 7

Malaria

Key Points:

• Malaria, caused by a parasite transmitted by night-biting female Anopheles mosquitoes, is the most important life-threatening insect-borne infection for travelers to avoid. This disease is preventable.

• In areas where there is chloroquine-resistant malaria, atovaquone/proguanil (Malarone), mefloquine (Lariam) or doxycycline should be used for prophylaxis. Primaquine is a good alternative, but requires a G-6-PD screening blood test.

• No drug is 100% effective in preventing malaria, so mosquito-bite prevention is still very important. (See Chapter 8)

• Because of their longer duration of action, DEET and 20% picaridin repellents are preferred over other non-DEET and biologic repellents for the prevention of malaria.

• The highest risk of acquiring falciparum malaria (the species that is potentially fatal) is in sub-Saharan Africa, the Amazon Basin, and Oceania.

• Approximately 95% of cases of falciparum malaria occur with 30 days after return from travel. Most cases occur within 9 to 14 days after an infectious bite.

• Typically, among all cases of imported malaria with a travel history, >90% of those caused by falciparum malaria originate in sub-Saharan Africa, whereas 80% of those caused by vivax malaria originate in South Asia, the Middle East or Latin America.

• Vivax malaria may occur many months after exposure. You can get a late-onset attack of vivax (or P. ovale) malaria even if you took an antimalarial prophylactic drug during travel. (Exception: primaquine prophylaxis eliminates hepatic hypnozoites of P. vivax and P. ovale and will prevent late-onset attacks of malaria).

• If you develop symptoms of malaria (primarily fever) after returning home, be sure to tell your health-care provider that you visited a malarious area, even if it was a year ago.

• Prevention of malaria in long-term travelers is a complex issue and requires expert advice from travel medicine specialists. Recommendations for prevention of malaria in long-term travelers must be individualized.

What's New

• Atovaquone/proguanil (Malarone®) may now be used for prophylaxis for infants and children weighing at least 5 kg (11lbs).

• The CDC map Geographic Distribution of Mefloquine-Resistant Malaria shows areas in South East Asia with resistance to the anti-malaria drug mefloquine.

• Picardin repellent (20% formulation only) is now recommended by the CDC as an acceptable alternative to DEET to protect against malaria-transmitting mosquito bites. Picaridin is also effective and ticks and flies.
• Plasmodium vivax infection is classified among the so-called benign malarias, but it is increasingly recognized that serious and even life-threatening complications, such as acute respiratory distress syndrome (ARDS), may occur.
• Treatment of severe malaria with parenteral artesunate is associated with a greater reduction in mortality and lesser risk of hypoglycemia in comparison to intravenous quinine, in adults.
• Intravenous artesunate is now available from the CDC to treat severe falciparum malaria.

Extent and Importance of Malaria Worldwide

Malaria is by far the most important insect-borne disease in the world and has been a scourge throughout history, killing more people than all wars and other plagues combined. It remains globally the most important parasitic disease of mankind and claims the lives of more children worldwide than any other infectious disease. In 2006, more than 100 countries were considered malarious, and this disease threatens nearly 40% of the world’s population. More than 500 million acute episodes of illness occur every year, and it is estimated that more than 270 million people are chronically infected with malaria parasites. The World Health Organization (WHO) estimates more than 1s million people die each year of malaria. The majority of malaria deaths occur among children in sub-Saharan Africa, especially in rural areas with inadequate or nonexistent health-care services. Along with tuberculosis and HIV infection, malaria forms a disease triad that accounts for almost one half of all infectious disease mortalities worldwide.

Each year, over seven million Americans travel to countries where malaria occurs and in 2006 nearly 1,500 cases of imported malaria were reported to the CDC. Although sub-Saharan Africa is visited by only 2% of U.S. travelers, this region accounts for 80% of malaria cases reported among U.S. civilian travelers.

If you plan to travel to a malarious region, you must do the following:

• Become informed about your risk of acquiring malaria at your destination.

• Take measures to prevent insect bites, as outlined in Chapter 8. If you prevent mosquito bites, your risk of malaria is basically eliminated.

•  No antimalarial drug is 100% effective. Preventing insect bites gives you backup protection.

• Take a prophylactic drug in countries where there is the risk of Plasmodium falciparum malaria, the species most often responsible for fatal malaria.

• Obtain the most appropriate medication from a health-care provider knowledgeable in travel medicine. To find a travel medicine practitioner in your area, go to one of the following websites:

              www.istm.org

              www.tripprep.com

              www.travmed.com

• Know the symptoms of malaria.

• Seek immediate medical treatment if symptoms of malaria occur. Be aware that symptoms may be delayed for weeks or months after exposure and that you may get malaria (Vivax species) even if you took an appropriate prophylactic drug.

• Always consider malaria if you develop a fever after returning from a malarious area, especially within the first 2 weeks to 2 months after return.

Your Risk of Getting Malaria

The risk of malaria depends on where you travel and varies markedly from country to country. The risk of malaria may also vary within a particular country because the disease may be transmitted only in certain regions within that country, during certain seasons, or below certain altitudes.

Table 7.1 Relative Risk of Malaria among Travelers (Adapted from Freedman D. New Engl J Med 2008;359:603–612)

Region Visited	Relative Risk
Very-low-risk-area (See below)	1.0
Caribbean	3.8
North Africa	6.9
South America	8.3
Southeast Asia	11.5
Central America	37.8
South Asia	53.8
Oceania	76.7
Sub-Saharan Africa	207.6
Approximate relative risk based on 1140 cases of malaria among travelers in the GeoSentinel database, with areas visited as numerators and tourist arrivals in that region as estimates for denominators. Read more.
Very-low-risk-areas are Europe, Northeast Asia, Australia, New Zealand, North America, and the Middle East.

Various categories of travelers are also at different risks. Tourists staying in urban, air-conditioned hotels will be at much lower risk than travelers venturing into low-lying rural areas. For example, travelers to the coastal and urban areas of South America are at virtually no risk, whereas going up the Amazon puts you at very high risk. Travelers at higher risk also include immigrants and their children who have returned to the country of their family’s origin to visit friends and relatives (so-called VFR travelers) and have foregone chemoprophylaxis. VFR travelers returning to the United States who develop malaria are usually returning from sub-Saharan Africa or India.

Travel to sub-Saharan Africa and Oceania (Papua New Guinea, Irian Jaya, the Solomon Islands, and Vanuatu) entails the greatest risk, especially from the potentially fatal P. falciparum malaria. There is intermediate risk in the Indian subcontinent (South Asia) and Central America, the Indian subcontinent and lowest risk in frequently visited tourist sites in South America, Southeast Asia and the Caribbean.

Tropical Africa is a much higher-risk destination compared with Latin America and Asia for the following reasons:

• Tourists in Africa spend considerable time in rural areas such as game parks, where mosquito activity is high.

• Tourists in Latin America and Asia, however, spend more time in urban or resort areas, where there is little, if any, risk of exposure, and they usually travel to rural areas only during daytime hours when there is little malaria-transmitting mosquito activity.

• In Latin America and Asia, malaria transmission is more seasonal, or focally distributed in rural areas away from the usual tourist routes. For example, 52% of the 1.1 million malaria cases reported from the Americas in 1989 were from Brazil, but 97% of these cases were reported from three gold-mining areas rarely visited by tourists. In Asia (e.g., Thailand), most malaria occurs in remote forested areas—places where few tourists go.

• Malaria is transmitted in both urban and rural areas in sub-Saharan Africa, whereas almost all large cities in Latin America (with the exception of Guayaquil, Ecuador) and Southeast Asia are malaria free. There is no malaria in Hong Kong, Bangkok, Kuala Lumpur, Jakarta, Singapore, Rangoon, Phnom-Penh, Manila, and most other major urban areas. There are some exceptions, such as urban areas of Papua New Guinea and some urban areas in India and Pakistan.

• Mosquitoes in Africa are more apt to be carrying malaria parasites. For example, the proportion of infected anopheles mosquitoes in western Kenya may exceed 20%, whereas in Latin America and Asia less than 1% of anopheles mosquitoes are infected.

What Causes Malaria?

Malaria is caused by a single-cell protozoan parasite of the genus Plasmodium. There are four different species of Plasmodium parasites that infect humans:

Plasmodium falciparum, which accounts for 40% to 60% of malaria cases worldwide and more than 95% of all malaria deaths

Plasmodium vivax, which causes 30% to 40% of malaria worldwide, but is rarely fatal

Plasmodium ovale, an uncommon parasite found mostly in West Africa

Plasmodium malariae, also uncommon, but distributed worldwide

Worldwide Distribution of Malaria Species

Of the 4 Plasmodium species that infect humans, Plasmodium falciparum is the one with potential to rapidly progress to severe illness or death. It predominates in sub-Saharan Africa, Hispaniola, and Papua New Guinea. Among the other species, P. vivax is the most common and predominates in South Asia, Eastern Europe and Northern Asia, and Central and most of South America.  Plasmodium ovale occurs mostly in West Africa and is occasionally encountered in Southeast Asia and Papua New Guinea. Plasmodium malariae occurs at low frequency in a patchy distribution worldwide. Plasmodium falciparum accounts for slightly more than 50% and P vivax approximately 25% of reported cases in the United States.

Chloroquine-resistant strains of P falciparum occur in all endemic areas except Central America west of the Panama Canal, Mexico, Hispaniola, and parts of China and the Middle East, and multidrug-resistant strains occur in Southeast Asia, South America, and sub-Saharan Africa. A high prevalence of chloroquine-resistant P vivax (CRPV) is found in Papua New Guinea and Indonesia. There is evidence for rates up to 25% in a few sites in Burma, Malaysia,  Vietnam,8 India, and Turkey.

Malaria is uncommon at high altitudes and cooler climates because reproduction of the parasites is temperature sensitive. At temperatures below 68 degrees Fahrenheit, for example, Plasmodium falciparum cannot complete its 26-day growth cycle in the Anopheles mosquito. For this reason, falciparum malaria rarely occurs over 1,000 meters (3,250 feet) elevation. P. vivax parasites, which are hardier, can reproduce at altitudes as high as 2,000 meters (6,500 feet).

How Malaria Is Transmitted

Malaria is transmitted by anopheles mosquitoes. The female mosquitoes require a blood meal every 3 to 4 days to promote the fertilization and growth of their eggs. Anopheles mosquitoes feed from dusk to dawn, so when evening comes you need to take extra measures to prevent bites. Not every mosquito transmits malaria, but it takes just one bite from an infective insect to give you the infection; therefore, even a brief trip to a malarious area can put you at risk. Malaria may also be transmitted through blood transfusion, or from an infected pregnant woman to her baby at the time of delivery.

Figure 7.2 The Cycle of Malaria Transmission

Source: Freedman, DO. Malaria Prevention in Short-Term Travelers

N Eng J Med; Aug 7, 2008. Used with permission.

Enlarge image

When the anopheles mosquito bites a victim (top) it infects that person with parasites (sporozoites) which enter the blood stream and travel rapidly (within 30 minutes) to the liver where they form  schizonts, which are mother cells which asexually produces daughter cells known as merozoites. Six to 14 days later (approximately), the mature schizonts burst, releasing large numbers of merozoites, that invade red blood cells, where they  form more schizonts which develop and rupture, releasing even more merozoites, triggering an attack of malaria. The merozoites then invade new red blood cells, continuing the process. Plasmodium vivax and Plasmodium ovale parasites also have the unique ability to persist in the liver in forms known as hypnozoites that can cause attacks of malaria months, even years, later. Atovaquone-proguanil, chloroquine, mefloquine, and doxycycline kill malaria parasites only in the blood stage (bottom). Atovaquone/proguanil and primaquine destroy Plasmodium falciparum in the liver stage, but only primaquine eradicates hypnozoites, the dormant forms of P. vivax or P. ovale. Enlarge image

How Malaria Causes Illness

After they are injected into the body by a feeding mosquito, malaria parasites first invade the liver, then the red blood cells, where they again multiply. When the parasite-filled red cells rupture, an attack of malaria occurs.

Falciparum malaria is the most serious form of malaria and accounts for 95% of fatalities. The severity of P. falciparum infections is due to the high percentage of red blood cells (RBCs) that are infected by this species. In extreme infections, up to 80% of RBCs may be parasitized and destroyed. This massive red cell destruction has two primary effects (1) severe anemia, and (2) clogging of small blood vessels (capillaries) to vital organs, particularly the brain and kidneys. This circulatory clogging occurs because the RBCs infected by P. falciparum produce sticky projections that bind the cells to the walls of the blood vessels and to other RBCs, forming obstructing clumps of cells. This is an important cause of cerebral (brain) edema. Also, chemicals (called cytokines) are released as a result of an immune response to the infection, causing fever, malaise, and other signs of inflammation. In contrast, the other three forms of malaria (P. vivax, P. ovale, and P. malariae) are usually not fatal because they infect fewer than 1% of RBCs and, most importantly, these species do not attack the brain.

Severe malaria occurs when more than 5% of RBCs are parasitized. Other criteria defining severe malaria include decreased consciousness (indicates cerebral malaria), severe anemia, hypoglycemia (low blood sugar), kidney/liver failure, pulmonary edema (fluid in the lungs), hyperthermia (high fever), and persistent vomiting and diarrhea.

If you are treated appropriately for malaria, you should improve within 48 to 72 hours. Indications of successful treatment include (1) reduction of fever and (2) at least a 75% reduction in the number of red blood cells that are parasitized.

Delayed Attacks of Malaria

If you acquire P. vivax or P. ovale malaria you may have a delayed attack of malaria because some of the parasites (called hypnozoites) may remain dormant in your liver. In only one third of vivax malaria cases do symptoms develop within 30 days of exposure; about 10% won’t develop symptoms for a year or more.

Prophylactic drugs such as chloroquine, mefloquine, and doxycycline work only in the blood (after the liver phase) to eradicate parasites within red blood cells. By taking these drugs during exposure and for 4 weeks after exposure, parasites released from the liver will be killed, and infections without a dormant liver form (P. falciparum and P. malariae) will be completely eliminated. Primaquine and atovaquone/proguanil act on the liver phase and, therefore, may be discontinued 3 days to 1 week respectively, after exposure. Only primaquine has the ability to eradicate dormant forms of relapsing malarias P. vivax and P. ovale.

Symptoms of Malaria

Malaria makes you feel like you have “the flu”—only worse. Preceding an attack of malaria, you may have 1 or 2 days of headache, fatigue, muscle aches, loss of appetite, and a low-grade fever. The acute attack starts abruptly with chills, followed by a high fever, lasting 2 to 6 hours. During this time you may have a cough and also notice pains in your chest, back, stomach, joints, and muscles. The attack ends with 2 to 3 hours of heavy sweating. Without treatment, symptoms will recur and complications may develop, especially if the attack is caused by P. falciparum. In some cases, malaria fevers recur periodically—every 48 to 72 hours. Death from untreated falciparum malaria may occur within a few days after the onset of symptoms.

Note: Malaria may occur as soon as seven days after an infective bite, and almost all cases of falciparum malaria occur within 60 days after the bite in people not taking a prophylactic drug or in people using inadequate prophylaxis. Other important causes of fever in the returned traveler include typhoid fever, dengue, viral gastroenteritis, hepatitis, urinary tract infections, tick typhus, and, rarely, amebic liver abscess.

Although a blood film is required to make the definitive diagnosis, the most important aspect of diagnosis is always to think of malaria as a possible cause of your illness. This is especially important because not every case of malaria manifests with the typical periodic fever pattern. If you are in a malarious area and you develop fever, and medical care is not available within 24 to 48 hours, it may be advisable for you to start self-treatment before a diagnosis is established. Self-treatment is discussed later, starting on page 127.

Diagnosis

Microscopy of serial blood films to detect the presence of the malaria parasites continues to be the standard for diagnosis because it allows estimation of parasite levels, and identification of the four different Plasmodium species of malaria. The problem with the malaria blood film is its low sensitivity in light infections, and the need for technical expertise in reading it. Parasites may not be observed unless prolonged, repeated searches are done; also, laboratory technicians—especially in facilities where malaria is rarely seen—may not recognize them. Malaria should not be excluded as a diagnosis until three blood films, obtained 12 to 24 hours apart, have been examined.

Point-of-care testing Advances in technology have now made the diagnosis of malaria potentially much easier and faster. Simple-to-use rapid diagnostic tests have been developed that can detect and distinguish between various plasmodium species. The OptiMAL® Rapid Malaria test looks for the presence of the Plasmodium species by testing for the presence of the Plasmodium lactate dehydrogenase enzyme and then uses monoclonal antibodies to identify which of the four malaria species is present. The manufacturer claims that the sensitivity of the test "compares with microscopic observation of a thin blood smear using 100x immersion objective for a period of 30 minutes by a trained technician." Although the test is said to have a sensitivity of >90% when the blood parasite count is high (>500 parasites/µL) a report from Thailand found a 25% sensitivity at low parasites counts. Another report (from Myanmar) found Optimal sensitivity for P. falciparum and non-falciparum parasites 42.6% and 47.1% respectively. The BinaxNOW® Malaria test claims a sensitivity 99.7% for the detection of P. falciparum and a sensitivity of 93.5% for detecting P. vivax. The test  can differentiate falciparum malaria infection from the less virulent infections caused by P. vivax, P. ovale or P. malariae, but these results are for parasite counts >5,000 parasites/µL.

Figure 7.3 The BinaxNOW®Malaria Test is a three-step test hat provides results in 15 minutes (Invernes Medical 800.637.3717).

Presently, dipstick tests have not replaced expert microscopy as a diagnostic standard, but can enhance the speed and accuracy of the diagnosis of malaria in settings where expertise in microscopy is not immediately available. The sensitivity of these tests increase with higher parasite densities.

Note: Although these rapid diagnostic tests for malaria are useful, travelers, especially when ill, may be unable to perform these tests satisfactorily. In addition, the kits must be stored at temperatures not exceeding 20° C (68° F) to 25° C (77° F). Storing the kits under adverse environmental conditions could invalidate the test results.

Malaria Prevention

Virtually all cases of malaria are preventable. Unfortunately, a significant proportion of travelers who acquire malaria do not receive appropriate information on, or do not adhere to, malaria prevention measures. Failure to take or adhere to appropriate prophylactic medication, and to seek prompt medical attention were significant factors in a recent review of deaths of 185 U.S. travelers who died of malaria between 1963 and 2001.

Chemoprophylaxis

Before departing for a malarious area, you and your health-care provider or travel medicine practitioner should decide if prophylaxis is indicated and which drug, if any, you should take. If the risk of malaria is low, the benefits of prophylaxis must be carefully assessed. For brief visits to low-risk areas (especially where P. vivax malaria predominates) and where prompt medical care is available, it may be acceptable not to take a prophylactic drug, but to rely on insect-bite prevention measures and immediate treatment in the event of illness. However, the issue is controversial; the malaria branch of the CDC recommends prophylaxis in any situation, no matter how low the risk or how long the exposure (even for many years).

Figure 7.4 Where Malaria is Endemic

Source: Freedman, DO. Malaria Prevention in Short-Term Travelers

N Eng J Med; Aug 7, 2008. Used with permission.

Factors determining your need for, and choice of, prophylaxis include (1) your itinerary; (2) the intensity and duration of your exposure to mosquito bites, especially those transmitting P. falciparum; (3) your ability to obtain rapid, qualified medical care should symptoms occur; (4) your own knowledge of malaria and its symptoms; (5) your medical history and personal health status; (6) your history of known drug allergies or known ability (or inability) to tolerate certain prophylactic drugs; (7) your use of other medications that may be incompatible with prophylactic drugs; (8) your age; (9) your pregnancy status, if applicable; and unfortunately (10) your financial resources.

The complexity of the situation is one reason why seeing a travel medicine specialist is advisable when exposure to malaria is likely. Remember, though, that the best prophylaxis is still mosquito-bite prevention. If you don’t get bitten, you can’t get malaria!

NOTE: Recent studies have shown that travelers are sometimes diagnosed with malaria even though they are taking a prophylactic drug as directed. When these cases were investigated, it was found that the diagnosis of malaria was incorrect due to poor-quality diagnostic facilities. Travelers who develop fever while on an appropriate prophylactic agent, and are told that they have malaria, should follow the advice of the local medical practitioner with respect to treatment, but should also continue their prophylactic antimalarial drug. One important caveat: those using mefloquine for prophylaxis should not take halofantrine for treatment because of the dangerous interaction of the two drugs.

Drugs Recommended in Areas of

 Chloroquine-Resistant  Malaria

Atovaquone/Proguanil (Malarone)

Malarone, a combination of atovaquone (250 mg) and proguanil (100 mg), is the newest drug for the prevention and treatment of malaria. Atovaquone/ proguanil has been shown to be 95% to 100% effective in preventing chloroquine-resistant and multidrug-resistant strains of P. falciparum malaria.

Atovaquone/proguanil is active against liver-stage parasites, and requires only a short period of pre-exposure and postexposure dosing. This means the drug may be started 1 day before exposure, continued once daily during exposure, and for 1 week after exposure ceases. The brief postexposure requirement for drug use is ideal for the short-term and frequent traveler, allowing the latter to discontinue medication between trips. In addition, it is an ideal drug for overseas workers who travel into rural malarious areas intermittently, requiring protection for only brief periods. With the exception of primaquine and atovaquone/proguanil, most prophylactic drugs must be taken for 4 weeks after exposure.Mefloquine and chloroquine must be started 1 to 2 weeks before exposure. There is a pediatric formulation of atovaquone/proguanil, making it convenient to prescribe for children, especially those under the age of 8 years who should not take doxycycline.

Atovaquone/proguanil is more expensive than other prophylactic drugs and, therefore, it is less likely to be accepted for long-term prophylaxis. However, because many insurance plans now cover the drug, it is more widely used. Because of its convenient dosing schedule, even in chloroquine-sensitive areas many travelers prefer atovaquone/proguanil to chloroquine.

Adult Dosage: One tablet, started the day before travel, taken daily during exposure, and for 7 days after leaving the malarious region.

Child Dosage: A pediatric-strength tablet (25 mg proguanil with 62.5 mg atovaquone) is available. The dosage is based on weight: 10 kg to 20 kg = one pediatric-strength tablet, 21 to 30 kg = two pediatric-strength tablets, 31 to 40 kg = three pediatric-strength tablets, and more than 40 kg = one adult-strength tablet. Atovaquone/proguanil may now be used for prophylaxis for infants and children weighing at least 5 kg (11lbs).

Side Effects: To date, atovaquone/proguanil (Malarone) has an enviable safety record, with no reports of serious adverse side effects. A recent large-scale trial in travelers from industrialized countries to malarious areas showed that only 1% of users of the drug discontinued it because of side effects—compared with 5% of those using mefloquine (Lariam).

Most complaints include stomach upset, skin rash, mouth ulcers, dizziness, and insomnia in up to 20% of users. Tablets should be taken with food or a milky drink at the same time each day. If vomiting occurs within 1 hour after dosing, a repeat dose should be taken. Atovaquone/proguanil is contraindicated during pregnancy and should not be used by those with severe kidney disease.

Mefloquine (Lariam)

Mefloquine (Lariam) is recommended for both short- and long-term travel to countries where there is chloroquine-resistant P. falciparum. The drug is also highly effective against P. vivax, P. ovale, and P. malariae. In western Cambodia and along the border areas of Thailand, however, the incidence of mefloquine-resistant P. falciparum is as high as 50%. Prophylaxis with atovaquone/proguanil (Malarone) or doxycycline is recommended in these areas.

Adult Dosage: One tablet, 250 mg once weekly during travel in malarious areas and for 4 weeks after leaving such areas. Mefloquine should be started at least 1 week before departure.

Child Dosage: Children: 5 to 14 kg, 1/8 tablet weekly; 15 to 19 kg 1/4 tablet weekly; 20 to 30 kg, 1/2 tablet weekly; 31 to 45 kg, 3/4 tablet weekly; and greater than 45 kg, one tablet weekly. For children weighing less than 5 kg, 5 mg/kg should be given.

Side Effects: Mefloquine (Lariam) in prophylactic doses is generally well tolerated, but about 35% of users report mild-to-moderate side effects—sleep disturbances (strange dreams, insomnia), nausea, dizziness, and weakness. Although the gastrointestinal symptoms are the most frequent, it is the neuropsychological side effects (anxiety, dizziness, depression, agitation, nightmares) that cause about 5% of mefloquine users to discontinue the drug. Studies show that men tolerate mefloquine better than women, and infants appear to tolerate the drug well. More severe neuropsychiatric side effects (psychosis, seizures) are extremely rare. Side effects may be reduced by splitting the weekly dose and taking one half tablet twice weekly. Taking the drug with food lessens stomach upset.

Loading Dose of Mefloquine: Some travel clinics give a loading dose (one tablet daily for 3 days, then once weekly) to achieve therapeutic levels rapidly and to “screen” for side effects. If there are to be significant side effects, they will usually occur within 1 week instead of 3 to 7 weeks when the drug is initiated on a weekly basis. The loading dose should be taken 2 weeks before travel. If bothersome side effects occur, there will be enough time to switch to another antimalarial, such as atovaquone/proguanil or doxycycline (Vibramycin, Doryx). Alternatively, one may start mefloquine 4 weeks before departure (one tablet weekly) because the majority of side effects will occur within the first three doses.

Travelers with a history of epilepsy, psychosis, recent depression or anxiety disorder, or cardiac conduction disturbances with arrhythmia should not use mefloquine (Lariam). The drug should probably not be given to those on mood-altering drugs such as Prozac, Celexa, Paxil, etc. Mefloquine (Lariam) should be administered cautiously when the traveler is receiving quinine, quinidine, procainamide, or other drugs that affect cardiac conduction. In addition, in countries where halofantrine (Halfan) is used to treat malaria, halofantrine should not be given to those using mefloquine for prophylaxis because of the risk of severe heart rhythm disturbances. Airline pilots, operators of machinery and heavy equipment, scuba divers, and mountain climbers should be informed that mild dizziness is a possible short-term side effect of mefloquine.

Mefloquine has been shown to be safe for prophylaxis after the first trimester of pregnancy and, by extension, also safe for infants. The drug has not been associated with congenital malformations or adverse postnatal outcomes when used for prophylaxis. There may be a slight trend toward miscarriage when mefloquine is taken during the first trimester, but the data are not firm. Travel medicine physicians will prescribe mefloquine during the first trimester when exposure to chloroquine-resistant falciparum malaria is high and unavoidable. Inadvertent use of mefloquine during the first trimester is not an indication for pregnancy  termination.

Doxycycline (Vibramycin, Doryx)

Doxycycline is an inexpensive tetracycline derivative that is more than 90% effective in all chloroquine-resistant areas of the world, including along the borders of Thailand. In addition to its effectiveness and low price, prophylactic doxycycline also prevents other serious diseases such as tick typhus, relapsing fever, plague, Lyme disease, and leptospirosis. A disadvantage is that doxycycline must be taken every day. One or two missed doses may put the traveler at risk for malaria.

Adult Dosage: 100 mg daily. Doxycycline should be started 1 to 2 days before exposure. It must be continued daily during exposure and for 4 weeks after departure from the malarious area.

Child Dosage; (for children older than 8 years of age) 2 mg per kg of body weight per day up to the adult dose of 100 mg daily.

Side Effects: Most travelers tolerate doxycycline well, but nausea, vomiting, and heartburn can occur. Doxycycline should be swallowed in the upright position with sufficient liquid or food to ensure complete passage of the tablet into the stomach. If the tablet or capsule gets stuck in the lower esophagus it can cause painful mucosal erosions or even esophageal perforation.

Doxycycline may cause phototoxicity, an exaggerated sunburn-type reaction. Avoiding prolonged, direct exposure to the sun, wearing a hat, and using a broad- spectrum sunscreen can reduce the risk, estimated at 2% to 10%. Women taking doxycycline may develop a vaginal yeast infection and are advised to carry a self-treatment dose (one 150 mg tablet) of the antifungal drug fluconazole (Diflucan). Doxycycline is contraindicated for pregnant women and children under the age of 8 unless required for the treatment of a serious infection such as falciparum malaria or ehrlichiosis.

Primaquine

Primaquine phosphate (primaquine-generic only) has long been used for the treatment of relapsing malaria, but in the last decade it has been re-examined for malaria prevention. Primaquine is considered a second-line drug because it is slightly less efficacious than those discussed above and because a G-6-PD enzyme blood test is required before it is recommended (see below). Field trials in Indonesia, East Africa, and Colombia have shown it to be an effective (albeit off-label) prophylactic agent. When taken by adults in a daily dose of 30 mg (or 0.5 mg/kg per day for children), an effectiveness of 85% to 95% against P. falciparum (as well as P. vivax and P. ovale) has been demonstrated. Primaquine prophylaxis is started 1 day before exposure, taken daily during exposure, and for 3 days after exposure ceases. Primaquine is intermediate in cost between doxycycline and mefloquine. It is an ideal drug for Latin America, the Middle East and Asia where P. vivax malaria is most frequent.

Adult dosage: 30 mg daily. Primaquine should be started 1 to 2 days before exposure and continued daily during exposure and for 3 days after departure from the malarious area.

Contraindications and Side Effects: Because primaquine is a potent oxidizing agent which is capable of causing severe breakdown of red blood cells (hemolytic anemia), a G-6-PD enzyme screening test is required before taking this drug. People lacking this enzyme are almost exclusively male, due to the X-linked pattern of inheritance. Primaquine is contraindicated in pregnancy because there is no way to test the fetus for the enzyme deficiency. Take the the drug with food to reduce side effects. Stomach upset, stomach cramps, nausea, vomiting, and loss of appetite may occur especially the first several days, but these adverse effects are usually infrequent.

Fig. 7.5 Drug Regimens for Prophylaxis against Malaria

Enlarge Image

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Source: Freedman, DO. Malaria Prevention in Short-Term Travelers

N Eng J Med; Aug 7, 2008. Used with permission.

Drugs Recommended in Areas of

 Chloroquine-Sensitive Malaria

Chloroquine (Aralen)

For sensitive P. falciparum and P. vivax, chloroquine remains the drug of choice to prevent malaria. The standard doses are generally well tolerated and are safe for pregnant women and children. Because of widespread resistance, however, the use of chloroquine against P. falciparum is limited to persons traveling in Central America, the Caribbean (Haiti and the Dominican Republic), parts of the Middle East, and central China during the malaria transmission season. Although chloroquine remains effective against most strains of Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae as well, P. vivax chloroquine resistance is increasing, particularly in the South Pacific, Southeast Asia, and parts of South America (Guyana).

Adult Dosage: 500 mg salt (300 mg base) once weekly, beginning 1 week before and continuing 4 weeks after leaving the malarious area. Starting chloroquine before you leave gives you a protective blood level and also lets you know if any unusual side effects will occur.

Child Dosage: 8.3 mg/kg salt (5 mg/kg base) once weekly, up to the maximum adult dose of 500 mg salt per week.

Generic chloroquine tablets are sold in the United States in strengths of 250 mg and 500 mg. Only the tablet form of chloroquine is available in the United States. For young children, tablets may be crushed into powder by a compounding pharmacy and the bitter taste masked with syrup. Another strategy is to have a pharmacist pulverize the tablets and prepare gelatin capsules with the proper weekly dose. Mixing the powder from the capsule with food (e.g., chocolate sauce or ice cream) or drink will make the taste more palatable. Liquid chloroquine for pediatric use is available overseas.

Side Effects: Chloroquine is generally well tolerated; nausea, however, is not uncommon. Taking chloroquine with meals may usually control gastrointestinal side effects. Dizziness, headache, blurred vision, and itching may also occur, but these symptoms will rarely require you to stop taking the drug. One large European study has shown that seizures and psychosis may occur very rarely with chloroquine. Itching is a frequent occurrence among people of African descent and is not an allergic reaction. Fears about long-term prophylaxis causing degenerative eye (retinal) changes are unfounded. Chloroquine is safe for pregnant women and children, including infants.

WARNING: An overdose of chloroquine (even one adult tablet in a small child) can be fatal. The drug should be kept in a child-safe container at all times.
Note: Chloroquine interferes with the antibody response to rabies vaccine when the vaccine is administered intradermally. If you are taking chloroquine prophylaxis and need rabies vaccination, the vaccine must be given by the intramuscular routes.

Hydroxychloroquine (Plaquenil)

An alternative to chloroquine phosphate is hydroxychloroquine (Plaquenil). It has the same action as chloroquine, but causes fewer gastrointestinal side effects. (Hydroxychloroquine may also be used to treat chloroquine-sensitive malaria.)

Adult Dosage: 400 mg salt (310 mg/kg base) weekly.

Child Dosage: 6.5 mg/kg salt (5.0 mg base/kg) weekly, up to the adult dosage.

Chloroquine and Proguanil (Paludrine)

In sub-Saharan Africa in particular, proguanil, combined with weekly chloroquine, has been a widely used prophylactic regimen, but it is much less efficacious (<60% efficacy) than mefloquine, doxycycline, and atovaquone/proguanil. This combination should be avoided unless no other regimen can be tolerated. Although the combination is safe for children and in pregnancy, its low efficacy is a reason not to use it in this population that is at greatest risk of severe malaria.

Adult Dosage: Chloroquine, 500 mg weekly, plus proguanil, 200 mg daily, and continued for 4 weeks after exposure.

Side Effects: The relatively high incidence (about 30%) of gastrointestinal side effects, including mouth ulcers, is reported to cause a significant number of travelers to discontinue prophylaxis with this drug.

Chloroquine-Resistant Plasmodium Vivax

Resistance of P. vivax to chloroquine has been confirmed in Myanmar (Burma), Papua New Guinea, the island of Nias (Indonesia), Irian Jaya (Indonesian New Guinea) Sabah, Borneo (Malaysia), Colombia, and Guyana. Atovaquone/proguanil, mefloquine, doxycycline, and primaquine are effective prophylactic agents for these resistant strains.

Other Drugs for Malaria Prevention

Azithromycin (Zithromax) This is a macrolide antibiotic which has been shown to prevent malaria; one 250 mg dose is taken starting 1 to 2 days before exposure, daily during exposure, and for 4 weeks after exposure. Although safe in pregnancy and in children, the drug has limited efficacy and for this reason is used only as a third-line agent when no other more appropriate drug can be used.

Tafenoquine This drug is an analog of primaquine that is not only better tolerated but is more potent and long lasting than the parent drug. In one study, a tafenoquine loading dose (one tablet daily for 3 days) protected against falciparum malaria for 2 months. Because of its long half-life and its effect on liver-stage parasites, the drug can be discontinued when leaving the endemic area. Like primaquine, a G-6-PD level will be required before usage. This drug is not yet available.

PREVENTION OF LATE-ONSET MALARIA 

Some malarious areas of the world put you at risk for having a delayed (late onset) attack of malaria. Late-onset malaria is caused by P. vivax and, rarely, P. ovale parasites that reside in your liver as hypnozoites (Fig. 7.2), out of reach of standard prophylactic drugs (except primaquine). If you harbor these parasites, taking a prophylactic drug suppresses only those parasites entering your blood from the liver. When you discontinue prophylaxis (and are harboring hypnozoites) a delayed attack of malaria can occur months, even years, later. Your risk of relapsing malaria is proportional to your degree of exposure to infective mosquito bites and the extent of P. vivax malaria in the areas where you have traveled. If you were heavily exposed over many months, you have the following three options:

Treat Take primaquine (see later) when the malaria risk is over to eliminate any possible dormant liver parasites. If you were in a high-risk malarious area for more than 2 to 3 months, then your chance of harboring dormant parasites may be high enough to justify treatment (in sub-Saharan Africa the risk of P. vivax is low). Start a 2-week course of primaquine after finishing prophylaxis. Areas of the world with the highest risk of relapsing malaria include Central America, North India, and Oceania.

Adult Dosage: 30 mg base daily. The total dose administered should be 6 mg/kg

Child Dosage: 0.6 mg base per kg daily for 14 days

A G-6-PD enzyme-screening test is required before using this drug. Primaquine is contraindicated during pregnancy. Pregnant women at risk should continue chloroquine prophylaxis during gestation and receive primaquine after delivery.

OR

Wait and Watch: If your exposure was low to moderate, the chance of infection is less. Be alert for symptoms, especially fever. If P. vivax or P. ovale malaria occurs, it must be treated with a drug that acts on the blood phase (e.g., chloroquine) followed by primaquine.

OR

Use Primaquine Prophylaxis: Primaquine is the only antimalarial prophylactic agent that acts not only on the liver phase of the malaria life cycle, but also eradicates the dormant liver forms of P. vivax and P. ovale malaria. When primaquine is used as a prophylactic agent, the likelihood of developing relapsing malaria is very low (except in areas where primaquine resistance occurs—see later). Take primaquine 1 day before exposure, daily during, and for 3 days after exposure.

Adult Dosage: 30 mg (2 tablets) per day for people >60 kg in weight

Child Dosage: 15 mg per day (1 tablet) for people <60 kg in weight

Primaquine-Resistant Plasmodium Vivax

Treatment of relapsing malaria may not be 100% effective because primaquine-resistant strains of Plasmodium vivax are now reported in scattered areas throughout Southeast Asia, Oceania, and Somalia. For adults who fail the standard treatment, a prolonged dose of primaquine is usually given as 30 mg per day for 28 days. Higher doses of primaquine may be required; however, in such cases, blood counts must be carefully monitored to detect significant hemolysis (breakdown of red blood cells).

Malaria Treatment

• CDC Treatment Guidelines for Uncomplicated Malaria

• CDC Treatment Guidelines for Severe Malaria

• CDC Alternative Treatment Guidelines for Pregnant Women

Principles of Malaria Treatment

Malaria is a medical emergency and treatment should be initiated as soon as possible. If you develop a fever and there is the possibility it could be caused by malaria, seek medical care immediately, and, if you are a returning traveler, inform your health-care provider that you have been in a malarious area. If you are carrying standby antimalarial drugs and are still in the tropics, begin self-treatment but seek medical consultation as soon as possible.

Outpatient Treatment of Falciparum Malaria

Not every patient needs to be in hospital, especially for the treatment of vivax malaria. If you have the more serious falciparum malaria, but of the "uncomplicated" variety, you can usually be treated as an outpatient if you have:

• No signs of clinically severe illness
• No vomiting
• Serum bilirubin  <1.3 mg/dL (strongest independent predictor)
• Parasitemia <1% of red blood cells

Other criteria for outpatient treatment are here.

Chloroquine (Aralen)

In areas where chloroquine-resistant P. falciparum or chloroquine-resistant P. vivax are NOT reported, start treatment on the following schedule:

• Day 1. Chloroquine 1 gm (salt) by mouth immediately, then chloroquine, 500 mg (salt), 6 hours later. (500 mg salt = 300 mg base)

• Day 2. Chloroquine, 500 mg orally

• Day 3. Chloroquine, 500 mg orally

A total of 10 tablets (250 mg each) are required.

Severe chloroquine-sensitive malaria requires an intravenous infusion of chloroquine, 0.83 mg/kg/hr (base), or intramuscular chloroquine, 3.5 mg/kg (base) repeated every 6 hours until parasitemia decreases. Oral chloroquine can then be started: the total dose is 25 mg/kg (base).

Note: Because intravenous chloroquine is not readily available in the United States or Canada, intravenous quinidine may be substituted (see later).

Atovaquone/Proguanil (Malarone)

Atovaquone/proguanil (Malarone) now appears to be the most effective treatment for acute uncomplicated falciparum malaria (<5% parasitemia), including multidrug-resistant strains. It has been shown to be effective in regions where high failure rates occur with other antimalarials including chloroquine, mefloquine, and halofantrine. In Thailand, atovaquone/proguanil cured 100% of cases of P. falciparum malaria versus 86% for mefloquine. Elsewhere, an overall success rate of 98.7% has been reported. However, recently, several cases of atovaquone/proguanil treatment failure have been documented.

Adult Dosage: Four tablets once daily for 3 days

Child Dosage: 11-20 kg: one adult tablet daily for 3 days; 21-30 kg: two adult tablets once daily for 3 days; 31-40 kg: three adult tablets once daily for 3 days; more than 40 kg: four adult tablets once daily for 3 days

Side Effects: Nausea, vomiting, loss of appetite, abdominal pain, headache, and itching. Dividing the dose and giving it twice daily may reduce the gastrointestinal effects.

Mefloquine (Lariam)

This drug is highly active against all malaria strains, except in border areas of Thailand, where cure rates of P. falciparum have fallen to 50%-70%.

Dosage 1,250 mg (or a total dose of 15 to 25 mg/kg) is best given as a divided dose of 750 mg (or 15 mg/kg) followed by 500 mg (or 10 mg/kg) 6 to 8 hours later. (25 mg/kg is needed to treat falciparum malaria from Thailand and 15 mg/kg elsewhere.)

Unless safer options are not available, mefloquine should not be used for self-treatment because of the frequency and potential severity of neuropsychiatric adverse effects, and is contraindicated (for treatment, not prophylaxis) in pregnancy.

Pyrimethamine/Sulfadoxine (Fansidar)

Fansidar is a combination of pyrimethamine and sulfadoxine, and has been used in the past for self-treatment. Resistance to the drug is widespread in Southeast Asia and South America and is becoming more of a problem in Africa. It is now considered a second-line drug for treatment and should be avoided unless other more effective treatments are not available.

Halofantrine (Halfan)

Halofantrine is chemically similar to mefloquine, with which it shares cross-resistance. It is highly effective against all four plasmodium species. A 3-day course of treatment is 90% curative but side effects, some of which may be potentially fatal, are also increased. Halofantrine is not to be used to treat mefloquine failures (because the combination of the two drugs may cause severe heart rhythm disturbances) and is contraindicated during pregnancy or breastfeeding. The CDC does not recommend halofantrine for treatment because of the potential cardiac side effects and the availability of safer alternative drugs. The drug is currently available in many countries in Africa and Europe but is not commercially available in the United States or Canada.

Quinine

Quinine is an ancient drug that originated from the cinchona plant.

Quinine is a first-line therapeutic agent for chloroquine-resistant malaria. It is active against all four Plasmodium species but is not used as a prophylactic drug due to its short half-life, and its frequent treatment-associated side effects that include nausea, vomiting, headache, tinnitus, and cardiovascular toxicity. In the United States quinine is available as quinine sulfate in 324 mg capsules under the brand name Qualaquin. This is the only FDA-approved quinine drug product available in the United States. Qualaquin is indicated only for treatment of uncomplicated Plasmodium falciparum malaria. Injectable quinine is not available in the United States and quinidine (a stereoisomer of quinine), or artesunate, is used when parenteral treatment for complicated malaria is required.

Adult Dosage for Uncomplicated Malaria: 2 tablets (650 mg) every 8 hours for 5 to 7 days. Quinine capsules are not approved for patients with severe or complicated P. falciparum malaria.

Note: Quinine by itself may not be adequate for eliminating all parasites permanently from the blood, and recrudescent infections can occur. In addition, resistance to quinine is reported in Thailand and elsewhere, and treatment failures have occurred.

Quinine treatment should be combined with one of the following:

• doxycycline, 100 mg twice daily, OR

• clindamycin, 450-900 mg three times daily

Doxycycline or clindamycin should be administered for 5 to 7 days. The second drug may be administered during or following quinine therapy.

Atovaquone/proguanil, mefloquine, an artemisinin derivative, or artemether/lumafantrine may also be used in combination with quinine.

Dosage for Complicated Malaria: Quinine dihydrochloride salt by intravenous infusion, 20 mg/kg loading dose over 4 hours, followed by 10 mg/kg every 8 hours given over 2 to 4 hours. Oral therapy (see later) with quinine sulfate should be started when there has been clinical improvement and the patient is not vomiting.

Side Effects: (IV and oral routes) Side effects can be a problem with quinine, especially after several days of treatment. Headache and tinnitus (ringing in the ears) are the most common side effects. Nausea, vomiting, abdominal pain, blurred vision, vertigo, and tremors may also occur. Serious, occasionally fatal side effects (hypotension, convulsions, heart block, ventricular fibrillation) can occur with too rapid intravenous injection of the drug. Slow intravenous administration, or oral administration, is usually safe but can cause minor ECG changes (prolongation of the QT interval and T-wave flattening). Quinine can also cause low blood sugar (hypoglycemia) from stimulation of the insulin producing cells of the pancreas; therefore, the intravenous preparation should be administered with glucose, and blood glucose levels must be measured frequently during therapy. Quinine can be used, if necessary, during pregnancy. On the third day of intravenous therapy (in the pregnant or nonpregnant patient), the dose should be reduced by one half to one third.

Quinidine

Quinidine gluconate (the d-isomer of quinine) is a commonly used cardiac drug that can also be used to treat drug-resistant falciparum malaria. In fact, quinidine has the special status of being the only intravenously administered antimalarial drug (except for artesunate) available in the United States indicated for use in the treatment of patients with complicated or life-threatening infections.

Note: Because newer antiarrhythmic cardiac drugs are replacing quinidine in some hospitals, physicians should check with their hospital pharmacies to ensure the availability of this important agent. If there is difficulty in obtaining the drug locally, physicians should contact the Eli Lilly Company (24 hours) at 800-821-0538, or the CDC’s Malaria Branch hotline 770-488-7788; after hours, the on-call person for malaria can be paged.

Table 7.2 Summary of Treatment of Malaria (by oral route)

Dosage: A loading dose of quinidine gluconate, 10 mg/kg (salt), in saline is given intravenously over 1 to 2 hours, followed by a constant infusion at 0.02 mg/kg/minute (1.0 to 1.5 mg/kg/hour). As soon as the parasite density drops below 1% of red cells infected and the patient is not vomiting, intravenous quinidine should be stopped and treatment continued with oral quinine sulfate (as discussed earlier).

Side Effects: Intravenous quinidine therapy should be administered in an intensive care unit. Cardiac effects are similar to those caused by intravenous quinine—dose-related QT interval prolongation and QRS widening.

Artemisinin (Qinghaosu) and Derivatives

Artemisinin and its two derivatives, artesunate and artemether, are the most rapidly acting antimalarial drugs, clearing parasites from the blood faster than quinine, and giving quicker relief of symptoms. Artemisinin is found in the medicinal herb Artemisia annua (sweet wormwood), a common plant that the Chinese call Qinghaosu, and used by traditional Chinese practitioners since ad 341 for the treatment of fever. Artemisinin was isolated in 1972 and is chemically unrelated to any other currently used antimalarial drug.

Artemisinin is effective against P. vivax as well as chloroquine-resistant strains of P. falciparum, but recrudescence of infection is common when the drug is used as sole therapy. To prevent recrudescent infections, as well as drug resistance, artemisinin and its derivatives should always be given in conjunction with another antimalarial drug, such as doxycycline or mefloquine.

Artemisinin is produced for clinical use in China and Vietnam and is presently available in some other countries in Asia. It is now being used in Africa, often as single-drug therapy, for the treatment of falciparum malaria. Oral Dosage: 3 gm (or 50 mg/kg) given over 3 to 5 days. The first dose can be 20 mg/kg.

Intramuscular Dosage: 1.0 to 1.2 gm (adult dose) over 3 to 5 days.

Suppositories: 2,800 mg total dose given over 3 days.

Side Effects: Nausea, vomiting, rash, fever, transient first-degree heart block.

Use in Pregnancy: Artemisinin and its derivatives appear to be safe in the second and third trimesters; limited studies suggest that these drugs may be safe during the first trimester as well. There are several semi-synthetic derivatives of artemisinin.

Artesunate and artmether

• Artesunate is a water-soluble derivative of artemisinin and has been effectively combined with single-dose mefloquine to treat drug-resistant P. falciparum in Southeast Asia.

Oral dosage—100 mg (two tablets) first dose, then 50 mg every 12 hours for 3 to 6 days.

• Artemether is an oil-soluble compound that is also rapidly effective in severe malaria. Oral artemether, given over 5 days, was found to have a higher cure rate, with fewer side effects, than mefloquine against multidrug-resistant P. falciparum in Thailand. In studies done in Malawi, intramuscular artemether acted more rapidly than intravenous quinine in clearing coma and reducing parasite counts in children with cerebral malaria. In Vietnam, intramuscular artemether was as effective as intramuscular quinine in curing severe falciparum malaria.

Oral Dosage: 700 mg, given over 5 days. (1st day—1.6mg/kg twice. On the 2nd, 3rd, 4th, and 5th days—1.6mg/kg, once daily). Intramuscular Dosage: 3.2 to 4 mg/kg initially, followed by 1.6 to 2 mg/kg once daily for 5 days. A single 300-mg dose of artemether, followed by mefloquine, 1,250 mg, in divided doses, has also been very effective. Artemether in oil is supplied in 1.0-mL ampoules containing 80 mg of the drug for intramuscular injection. The average treatment for adults is six ampoules.

Side Effects: Oral artesunate and artemether appear to be among the safest and best-tolerated antimalarial drugs, but their side-effect profile has not been fully delineated.

Intravenous artesunate This water-soluble derivative of artemisinin is more effective than quinine or quinidine for treating severe falciparum malaria. It is available only from the CDC but there is no charge. The drug will be released to a physician by the CDC Drug Service from one of the 20 CDC quarantine stations located throughout the country.

• Dosing schedule: Four equal doses of 2.4 mg per kilogram body weight over a period of 3 days.

• Day 1: 1 Dose every 12 hours.

• Day 2: 1 dose

• Day 3: 1 dose

After the acute phase of illness, artesunate must be partnered with a longer-acting antimalarial to ensure a high probability of cure. These drugs include doxycycline (or clindamycin in pregnant women), or full courses of treatment with atovaquone/proguanil or mefloquine.These drugs can be initiated when the patient can tolerate oral medication.

You must contact the CDC to obtain artesunate. Call the CDC Malaria Hotline:

• 770-488-778 (Monday through Friday from 8 a.m. to 4:30 p.m.  Eastern time)

• 770-488-7100 (At other times: Ask for a clinician in the CDC Malaria Branch)

Artemether/lumefantrine (Coartem, Riamet) This drug combines the fast-acting artemether with the prolonged action of lumefantrine. The drug is currently available in Europe. Unlike halofantrine, lumefantrine is not associated with adverse cardiac effects. A 6-dose regimen over 3 days is reported to cure more than 95% of acute uncomplicated multidrug-resistant falciparum malaria. Because of its rapid onset of action, co-artemether may prevent progression to cerebral malaria. In countries where it is available, the drug is currently recommended as first-line treatment for acute P. falciparum malaria. Travelers from North America who are stopping over in Europe on their way to the tropics can obtain this drug for standby emergency treatment.

Oral Dosage: Four tablets, twice daily ´ 3 days. The second four-tablet dose on day 1 should be taken 8 hours after the initial dose. Total dose: 24 tablets over 3 days.

Table 7.3 Drugs for Self-Treatment in Adults

*When the first signs of drug-resistant malaria appeared in Asia during the Vietnam War, Chinese scientists developed a family of drugs from sweet wormwood, a common shrub that had been used for centuries in traditional medicine. These “artemisinin compounds” are now standard components of malaria treatment in Asia, where they have proved to be the best antimalarial drugs. To circumvent future drug resistance, malaria experts believe the time has come to partner artemisinin with other antimalarial drugs, creating artemisinin combination therapies (ACTs)—the same strategy that underlies the treatment of HIV and tuberculosis. In Africa, deaths from drug-resistant malaria are increasing daily, but the expense of ACT drugs has so far prevented their widespread use on that continent.

Scientists now agree that the most effective treatment against malaria is a combination of drugs using artemisinin derivatives. Artemisinin-based combination therapy (ACT) is the quickest and most reliable way of clearing malaria infection, and it is very well tolerated. Using a combination of drugs shortens the treatment course, and has also been shown to protect each individual drug from resistance. These drugs, however, are not currently available in the United States or Canada. Co-artemether is available in Europe.

In Africa, single, stand-alone treatments for malaria, such as chloroquine, are rapidly losing their effectiveness. In some regions, malaria is resistant to all traditional first-line therapies. As a result, many countries* are moving toward the use of a combination of drugs that include an artemisinin derivative to treat malaria, which helps to slow the development of resistance. To date, no clinical resistance has been documented for ACT therapies, making these drugs the optimal first-line treatment where they are available.

Self-Treatment

Standby emergency medication is a part of malaria protection for a very few, carefully selected, travelers and should be prescribed only by a well-trained travel medicine provider. The traveler must know that use of the standby drug must be followed by a medical consultation as quickly as possible to assess efficacy of treatment and to rule out other causes of fever.

The ideal standby drug should have few adverse effects; act rapidly against all species of malaria parasites, especially drug-resistant P. falciparum; be safe for children and pregnant women; and be simple and straightforward to use. Currently, no one drug satisfies all of these requirements. In the United States and Canada atovaquone/proguanil (Malarone) is emerging as the self-treatment drug of choice because of its effectiveness and relative lack of adverse side effects. In Europe artemether/lumafantrine (Riamet) is gaining favor. (See Table 7.3 for current self-treatment drug options.) Travelers who are potential candidates for self-treatment include the following:

• Travelers to moderate- and high-transmission endemic areas in countries where they will not have access to medical care within 24 to 48 hours.

• Travelers in chloroquine-resistant areas who are taking a less-than-optimal prophylactic drug such as chloroquine, chloroquine/proguanil, or azithromycin.

• Travelers whose exposure to malaria is likely to be so low or brief (especially if they are taking precautions to prevent insect bites) that chemoprophylaxis is not considered essential. This would include travelers to Central America and parts of Southeast Asia.

• Frequent short-term travelers to endemic countries (e.g., airline personnel).

• Expatriates or other long-term travelers whose compliance with regular intake of a prophylactic drug may be a problem. Some travelers are unable to tolerate, unwilling to take, or even unable to afford an optimal chemoprophylactic regimen for prolonged periods.

Fever, without clear evidence of other causes, after a stay of at least 7 days in a risk area is an indication for using the standby drug. Several studies, however, have shown that travelers who carry a self-treatment drug rarely use it appropriately and often do not seek medical attention as soon as possible as is recommended in all cases.

Advice for the Returning Traveler: Fever in the tropics, or in a traveler returning from the tropics, is malaria until proved otherwise, and is a medical emergency. Travelers who develop fever should seek medical attention urgently. If they are at home they should inform their health-care provider of their recent travels and request thick and thin blood films to confirm, or exclude, the diagnosis of malaria. If the first test is negative, examination of the blood should be repeated several more times over the next 12 to 24 hours. Treatment, however, should not be delayed while waiting for the test results if the diagnosis of malaria is strongly suspected.

*Twelve countries have already adopted artesunate plus amodiaquine as their national first-line treatment. These countries are (as of 2004) Indonesia, Burundi, Cameroon, Equatorial Guinea, Gabon, Ghana, Liberia, Mali, Sao Tome, Sierra Leone, South Sudan, and Zanzibar. Five countries have adopted first-line artesunate plus mefloquine. These countries are Cambodia, Myanmar, Thailand, Bolivia, and Peru.

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