Malaria

Description

Malaria in humans is caused by one of four protozoan species of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, or P. malariae. All species are transmitted by the bite of an infected female Anopheles mosquito. Occasionally, transmission occurs by blood transfusion, organ transplantation, needle-sharing, or congenitally from mother to foetus. Although malaria can be a fatal disease, illness and death from malaria are largely preventable.

Occurrence

Malaria is a major international public health problem, causing 300-500 million infections worldwide and approximately 1 million deaths annually. Information about malaria risk in specific countries (Yellow Fever Vaccine Requirements and Information on Malaria Risk and Prophylaxis, by Country) is derived from various sources, including WHO. The information presented herein was accurate at the time of publication; however, factors that can change rapidly and from year to year, such as local weather conditions, mosquito vector density, and prevalence of infection, can markedly affect local malaria transmission patterns. Updated information may be found on the CDC Travellers' Health website: http://www.cdc.gov/travel.

Malaria transmission occurs in large areas of Central and South America, the island of Hispaniola (the Dominican Republic and Haiti), Africa, Asia (including the Indian Subcontinent, Southeast Asia, and the Middle East), Eastern Europe, and the South Pacific.

The estimated risk for a traveller's acquiring malaria differs substantially from area to area. This variability is a function of the intensity of transmission within the various regions and of the itinerary and time and type of travel. From 1985 through 2002, 11,896 cases of malaria among U.S. civilians were reported to CDC. Of these, 6,961 (59%) were acquired in sub-Saharan Africa; 2,237 (19%) in Asia; 1,672 (14%) in the Caribbean and Central and South America; and 822 (7%) in other parts of the world. During this period, 76 fatal malaria infections occurred among U.S. civilians; 71 (93%) were caused by P. falciparum, of which 52 (73%) were acquired in sub-Saharan Africa.

Thus, most imported P. falciparum malaria among U.S. travellers was acquired in Africa, even though only 467,940 U.S. residents traveled to countries in that region in 2002. In contrast, that year 21 million U.S. residents traveled from the United States to other countries where malaria is endemic (including 19 million travellers to Mexico). This disparity in the risk for acquiring malaria reflects the fact that the predominant species of malaria transmitted in sub-Saharan Africa is P. falciparum, that malaria transmission is generally higher in Africa than in other parts of the world, and that malaria is often transmitted in urban areas as well as rural areas in sub-Saharan Africa. In contrast, malaria transmission is generally lower in Asia and South America, a larger proportion of the malaria is P. vivax, and most urban areas do not have malaria transmission.

Risk to Travellers

Estimating the risk for infection for various types of travellers is difficult. Risk can differ substantially even for persons who travel or reside temporarily in the same general areas within a country. For example, travellers staying in air-conditioned hotels may be at lower risk than backpackers or adventure travellers. Similarly, long-term residents living in screened and air-conditioned housing are less likely to be exposed than are persons living without such amenities, such as Peace Corps volunteers. Travellers should also be reminded that even if one has had malaria before, one can get it again and so preventive measures are still necessary.

Persons who have been in a malaria risk area, either during daytime or nighttime hours, are not allowed to donate blood in the United States for a period of time after returning from the malarious area. Persons who are residents of nonmalarious countries are not allowed to donate blood for 1 year after they have returned from a malarious area. Persons who are residents of malarious countries are not allowed to donate blood for 3 years after leaving a malarious area. Persons who have had malaria are not allowed to donate blood for 3 years after treatment for malaria.

Map 4-6. Malaria-endemic countries in the Western Hemisphere

Map 4-7. Malaria-endemic countries in the Eastern Hemisphere

Clinical Presentation

Malaria is characterised by fever and influenza-like symptoms, including chills, headache, myalgias, and malaise; these symptoms can occur at intervals. Malaria may be associated with anaemia and jaundice, and P. falciparum infections can cause seizures, mental confusion, kidney failure, coma, and death. Malaria symptoms can develop as early as 7 days after initial exposure in a malaria-endemic area and as late as several months after departure from a malarious area, after chemoprophylaxis has been terminated.

Prevention

No vaccine is currently available. Taking an appropriate drug regimen and using anti-mosquito measures will help prevent malaria. Travellers should be informed that no method can protect completely against the risk for contracting malaria.

Personal Protection Measures

Because of the nocturnal feeding habits of Anopheles mosquitoes, malaria transmission occurs primarily between dusk and dawn. Travellers should be advised to take protective measures to reduce contact with mosquitoes, especially during these hours. Such measures include remaining in well-screened areas, using mosquito bed nets (preferably insecticide-treated nets), and wearing clothes that cover most of the body. Additionally, travellers should be advised to purchase insect repellent for use on exposed skin. The most effective repellent against a wide range of vectors is DEET (N, N-diethylmetatoluamide), an ingredient in many commercially available insect repellents. The actual concentration of DEET varies widely among repellents. DEET formulations as high as 50% are recommended for both adults and children >2 months of age (See Protection against Mosquitoes and Other Arthropod Vectors).

Travellers not staying in well-screened or air-conditioned rooms should be advised to use a pyrethroid-containing flying-insect spray in living and sleeping areas during evening and nighttime hours. They should take additional precautions, including sleeping under bed nets (preferably insecticide-treated bed nets). In the United States, permethrin (Permanone) is available as a liquid or spray. Overseas, either permethrin or another insecticide, deltamethrin, is available and may be sprayed on bed nets and clothing for additional protection against mosquitoes. Bed nets are more effective if they are treated with permethrin or deltamethrin insecticide; bed nets may be purchased that have already been treated with insecticide. Information about ordering insecticide-treated bed nets is available at http://www.travmed.com, telephone 1-800- 872 8633, fax: 413-584-6656; or http://www.travelhealthhelp.com, telephone 1-888-621-3952.

Chemoprophylaxis

Chemoprophylaxis is the strategy that uses medications before, during, and after the exposure period to prevent the disease caused by malaria parasites. The aim of prophylaxis is to prevent or suppress symptoms caused by blood-stage parasites. In addition, presumptive anti-relapse therapy (also known as terminal prophylaxis) uses medications towards the end of the exposure period (or immediately thereafter) to prevent relapses or delayed-onset clinical presentations of malaria caused by hypnozoites (dormant liver stages) of P. vivax or P. ovale.

In choosing an appropriate chemoprophylactic regimen before travel, the traveller and the health-care provider should consider several factors. The travel itinerary should be reviewed in detail and compared with the information on areas of risk in a given country to determine whether the traveller will actually be at risk for acquiring malaria. Whether the traveller will be at risk for acquiring drug-resistant P. falciparum malaria should also be determined. Resistance to antimalarial drugs has developed in many regions of the world. Health-care providers should consult the latest information on resistance patterns before prescribing prophylaxis for their patients. (See section "Malaria Hotline" below for details about accessing this information from CDC.)

The resistance of P. falciparum to chloroquine has been confirmed in all areas with P. falciparum malaria except the Dominican Republic, Haiti, Central America west of the Panama Canal, Egypt, and some countries in the Middle East. In addition, resistance to sulfadoxine-pyrimethamine (e.g., Fansidar) is widespread in the Amazon River Basin area of South America, much of Southeast Asia, other parts of Asia, and, increasingly, in large parts of Africa. Resistance to mefloquine has been confirmed on the borders of Thailand with Burma (Myanmar) and Cambodia, in the western provinces of Cambodia, and in the eastern states of Burma (Myanmar).

Tolerability

Malaria chemoprophylaxis with mefloquine or chloroquine should begin 1-2 weeks before travel to malarious areas; prophylaxis with doxycycline, atovaquone/proguanil, or primaquine can begin 1-2 days before travel. Beginning the drug before travel allows the antimalarial agent to be in the blood before the traveller is exposed to malaria parasites. Chemoprophylaxis can be started earlier if there are particular concerns about tolerating one of the medications. Starting the medication 3-4 weeks in advance allows potential adverse events to occur before travel. If unacceptable side effects develop, there would be time to change the medication before the traveller's departure.

The drugs used for antimalarial chemoprophylaxis are generally well tolerated. However, side effects can occur. Minor side effects usually do not require stopping the drug. Travellers who have serious side effects should see a health-care provider. See the section below on "Adverse Reactions and Contraindications" for more detail on safety and tolerability of the drugs used for malaria prevention. The health-care provider should establish whether the traveller has previously experienced an allergic or other reaction to one of the antimalarial drugs of choice. In addition, the health-care provider should determine whether medical care will be readily accessible during travel should the traveller develop intolerance to the drug being used and need to change to a different agent.

General Recommendations for Prophylaxis

Chemoprophylaxis should continue during travel in the malarious areas and after leaving the malarious areas (4 weeks after travel for chloroquine, mefloquine, and doxycycline, and 7 days after travel for atovaquone/proguanil and primaquine). In comparison with drugs with short half-lives, which are taken daily, drugs with longer half-lives, which are taken weekly, offer the advantage of a wider margin of error if the traveller is late with a dose. For example, if a traveller is 1-2 days late with a weekly drug, prophylactic blood levels can remain adequate; if the traveller is 1-2 days late with a daily drug, protective blood levels are less likely to be maintained.

Travel to Areas without Chloroquine-Resistant P. falciparum

For travel to areas of risk where chloroquine-resistant P. falciparum has NOT been reported, once-a-week use of chloroquine alone is recommended for prophylaxis. Persons who experience uncomfortable side effects after taking chloroquine may tolerate the drug better by taking it with meals. As an alternative, the related compound hydroxychloroquine sulfate may be better tolerated. Travellers unable to take chloroquine or hydroxychloroquine should take atovaquone/proguanil, doxycycline, or mefloquine; these antimalarial drugs are also effective against chloroquine-sensitive parasites.

Chloroquine prophylaxis should begin 1-2 weeks before travel to malarious areas. It should be continued by taking the drug once a week, on the same day of the week, during travel in malarious areas and for 4 weeks after a traveller leaves these areas (Table 4-9).

Table 4-9. Drugs used in the prophylaxis of malaria

Drug	Usage	Adult Dose	Paediatric Dose	Comments
Atovaquone / proguanil (Malarone)	Prophylaxis in areas with chloroquine-resistant or mefloquine-resistant P. falciparum.	Adult tablets contain 250 mg atovaquone and 100 mg proguanil hydrochloride. 1 adult tablet orally, daily	Paediatric tablets contain 62.5 mg atovaquone and 25 mg proguanil hydrochloride. 11-20 kg: 1 tablet 21-30 kg: 2 tablets 31-40 kg: 3 tablets 41 kg or more: 1 adult tablet daily	Begin 1-2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Contraindicated in persons with severe renal impairment (creatinine clearance <30 mL/min). Atovaquone / proguanil should be taken with food or a milky drink. Not recommended for prophylaxis for children <11 kg, pregnant women, and women breastfeeding infants weighing <11 kg.
Chloroquine phosphate (Aralen and generic)	Prophylaxis only in areas with chloroquine-sensitive P. falciparum.	300 mg base (500 mg salt) orally, once/week	5 mg/kg base (8.3 mg/kg salt) orally, once/week, up to maximum adult dose of 300 mg base.	Begin 1-2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas. May exacerbate psoriasis.
Doxycycline (Many brand names and generic)	Prophylaxis in areas with chloroquine-resistant or mefloquine-resistant P. falciparum.	100 mg orally, daily	8 years of age: 2 mg/kg up to adult dose of 100 mg/day.	Begin 1-2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in children <8 years of age and pregnant women.
Hydroxychloro- quine sulfate (Plaquenil)	An alternative to chloroquine for prophylaxis only in areas with chloroquine-sensitive P. falciparum.	310 mg base (400 mg salt) orally, once/week	5 mg/kg base (6.5 mg/kg salt) orally, once/week, up to maximum adult dose of 310 mg base.	Begin 1-2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas.
Mefloquine (Lariam and generic)	Prophylaxis in areas with chloroquine-resistant P. falciparum.	228 mg base (250 mg salt) orally, once/week	9 kg: 4.6 mg/kg base (5 mg/kg salt) orally, once/week 10-19 kg: 1/4 tablet once/week 20-30 kg: 1/2 tablet once/week 31-45 kg: 3/4 tablet once/week 46 kg: 1 tablet once/week	Begin 1-2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in persons allergic to mefloquine or related compounds (e.g., quinine and quinidine) and in persons with active depression, a recent history of depression, generalised anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Use with caution in persons with psychiatric disturbances, or a previous history of depression. Not recommended for persons with cardiac conduction abnormalities.
Primaquine	An option for prophylaxis in special circumstances. Call Malaria Hotline (770-488-7788) for additional information.	30 mg base (52.6 mg salt) orally, daily	0.6 mg/kg base (1.0 mg/kg salt) up to adult dose orally, daily	Begin 1-2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Contraindicated in persons with G6PD1 deficiency. Also contraindicated during pregnancy and lactation unless the infant being breastfed has a documented normal G6PD level. Use in consultation with malaria experts.
Primaquine	Used for presumptive anti-relapse therapy (terminal prophylaxis) to decrease the risk of relapses of P. vivax and P. ovale.	30 mg base (52.6 mg salt) orally, once/day for 14 days after departure from the malarious area.	0.6 mg/kg base (1.0 mg/kg salt) up to adult dose orally, once/day for 14 days after departure from the malarious area.	Indicated for persons who have had prolonged exposure to P. vivax and P. ovale or both. Contraindicated in persons with G6PD1 deficiency. Also contraindicated during pregnancy and lactation unless the infant being breastfed has a documented normal G6PD level.

1Glucose-6-phosphate dehydrogenase. All persons who take primaquine should have a documented normal G6PD level prior to starting the medication.

Travel to Areas with Chloroquine-Resistant P. falciparum

For travel to areas of risk where chloroquine-resistant P. falciparum exists, three efficacious options are available, listed in alphabetical order below. In addition, there are new recommendations for the use of primaquine for prophylaxis in special situations.

Atovaquone/proguanil (Malarone). Atovaquone/proguanil is a fixed combination of the two drugs, atovaquone and proguanil. Atovaquone/proguanil prophylaxis should begin 1-2 days before travel to malarious areas and should be taken daily, at the same time each day, while in the malarious areas and daily for 7 days after leaving the area. (See Table 4-9 for recommended dosages.)

Doxycycline (many brand names and generic). Doxycycline prophylaxis should begin 1-2 days before travel to malarious areas. It should be continued once a day, at the same time each day, during travel in malarious areas and daily for 4 weeks after the traveller leaves such areas. Insufficient data exist on the antimalarial prophylactic efficacy of related compounds such as minocycline (commonly prescribed for the treatment of acne). Persons on a long-term regimen of minocycline who are in need of malaria prophylaxis should stop taking minocycline 1-2 days before travel and start doxycycline instead. The minocycline can be restarted after the full course of doxycycline is completed. (See Table 4-9 for recommended dosages.)

Either doxycycline or atovaquone/proguanil (see above) can be used by travellers to areas with mefloquine-resistant strains of P. falciparum (the borders of Thailand with Burma (Myanmar) and Cambodia, western Cambodia, and eastern Burma (Myanmar) (see Map 4-8).

Map 4-8. Geographic distribution of mefloquine-resistant malaria

Mefloquine (Lariam and generic). Mefloquine prophylaxis should begin 1-2 weeks before travel to malarious areas. It should be continued once a week, on the same day of the week, during travel in malarious areas and for 4 weeks after a traveller leaves such areas. (See Table 4-9 for recommended dosages.)

NOTE: In special circumstances and after consultation with malaria experts available through the CDC Malaria Hotline (770-488-7788), primaquine may be used for prophylaxis for travel to areas with or without chloroquine-resistant P. falciparum. This use should generally be reserved for travellers unable to take any of the other chemoprophylaxis regimens recommended for the region of travel. The traveller must have a documented level of G6PD in the normal range prior to being prescribed primaquine. Primaquine prophylaxis should begin 1-2 days before travel to malarious areas, be taken daily at the same time each day while in the malarious areas, and daily for 7 days after leaving such areas. (See Table 4-9 for recommended dosages.)

In those who are G6PD deficient, primaquine can cause haemolysis, which can be fatal. Be sure to document a normal G6PD level before prescribing primaquine.

CDC no longer recommends chloroquine/proguanil as a preventive option for persons travelling to areas with chloroquine-resistant P. falciparum.

Prevention of Relapses of P. vivax and P. ovale: Presumptive anti-relapse therapy (terminal prophylaxis) with primaquine

P. vivax and P. ovale parasites can persist in the liver and cause relapses for as long as 4 years or more after departure from the malarious areas. Travellers to malarious areas should be alerted to this risk and, if they have malaria symptoms after leaving a malarious area, they should be advised to report their travel history and the possibility of malaria to a physician as soon as possible.

Presumptive anti-relapse therapy with primaquine decreases the risk of relapses by acting against the liver stages of P. vivax or P. ovale. Primaquine presumptive anti-relapse therapy is administered for 14 days after the traveller has left a malarious area. When chloroquine, doxycycline, or mefloquine is used for prophylaxis, primaquine is usually taken during the last 2 weeks of post-exposure prophylaxis, but may be taken immediately after those medications are completed. When atovaquone/proguanil is used for prophylaxis, primaquine may be taken either during the final 7 days of atovaquone/ proguanil and then for an additional 7 days, or for 14 days after atovaquone/proguanil is completed. Note that the recommended dose of primaquine for terminal prophylaxis has been increased from 15 mg to 30 mg (base) for adults and from 0.3 mg/kg to 0.6 mg/kg (base) for children. (See Table 4-9 for additional details.)

Because most malarious areas of the world (except Haiti and the Dominican Republic) have at least one species of relapsing malaria, travellers to these areas have some risk for acquiring either P. vivax or P. ovale, although the actual risk for an individual traveller is difficult to define. Presumptive anti-relapse therapy with primaquine for prevention of relapses is generally indicated only for persons who have had prolonged exposure in malaria-endemic areas (e.g., missionaries and Peace Corps volunteers). Most persons can tolerate this regimen of primaquine (30 mg/day for adults if it is taken with food); the main exception is for persons who are deficient in G6PD. (See "Adverse Reactions and Contraindications" and Table 4-9 for recommended dosages.)

Chemoprophylaxis for Infants, Children, and Adolescents

Infants of any age or weight or children and adolescents of any age can contract malaria. Therefore, children travelling to malaria-risk areas should take an antimalarial drug. In the United States, antimalarial drugs are available only in tablet form and may taste quite bitter. Paediatric dosages should be carefully calculated according to body weight but should never exceed adult dosage. Pharmacists can pulverize tablets and prepare gelatin capsules for each measured dose. Parents should prepare the child's dose of medication by breaking open the gelatin capsule and mixing the drug with something sweet, such as applesauce, chocolate syrup, or jelly. Giving the dose on a full stomach may minimize stomach upset and vomiting.

Overdose of antimalarial drugs can be fatal. Medication should be stored in childproof containers out of the reach of infants and children.

Infants, Children, and Adolescents Travelling to Areas without Chloroquine-Resistant P. falciparum. Chloroquine is the drug of choice for children travelling to areas without chloroquine-resistant P. falciparum.

Infants, Children, and Adolescents Travelling to Areas with Chloroquine-Resistant P. falciparum. Mefloquine is an option for use in infants and children of all ages and weights who are travelling to areas with chloroquine-resistant P. falciparum. Doxycycline may be used for children 8 years of age. Atovaquone/proguanil may be used for prophylaxis for infants and children weighing 11 kg (24lbs). At this time, insufficient data are available on the safety and efficacy of atovaquone/proguanil for prevention of malaria in children weighing <11 kg (<24 lbs). Atovaquone/proguanil is available in paediatric tablet form; dosage is based on weight. Paediatric dosing regimens are contained in Table 4-10; additional information on atovaquone/proguanil dosing is found in Table 4-9.

Table 4-10. Paediatric prophylactic doses of atovaquone/proguanil

Body weight1 (lb)	Body weight1 (kg)	Atovaquone/Proguanil Total daily dose (mg)	Dosage regimen
24-45	11-20	62.5/25	1 paediatric tablet daily
46-67	21-30	125/50	2 paediatric tablets daily
68-88	31-40	187.5/75	3 paediatric tablets daily
89	41	250/100	1 adult tablet daily

1Insufficient data are available on the safety and efficacy of atovaquone/proguanil for prevention of malaria in children weighing < 11kg (24 lbs).

Chemoprophylaxis during Pregnancy

Malaria infection in pregnant women can be more severe than in nonpregnant women. Malaria can increase the risk for adverse pregnancy outcomes, including prematurity, abortion, and stillbirth. For these reasons and because no chemoprophylactic regimen is completely effective, women who are pregnant or likely to become pregnant should be advised to avoid travel to areas with malaria transmission if possible. (Also see Malaria during Pregnancy). If travel to a malarious area cannot be deferred, use of an effective chemoprophylaxis regimen is essential.

Travel during Pregnancy to Areas without Chloroquine-Resistant P. falciparum. Pregnant women travelling to areas where chloroquine-resistant P. falciparum has not been reported may take chloroquine prophylaxis. Chloroquine has not been found to have any harmful effects on the foetus when used in the recommended doses for malaria prophylaxis; therefore, pregnancy is not a contraindication for malaria prophylaxis with chloroquine phosphate or hydroxychloroquine sulfate.

Travel during Pregnancy to Areas with Chloroquine-Resistant P. falciparum. Mefloquine is currently the only medication recommended for malaria chemoprophylaxis during pregnancy. A review of mefloquine use in pregnancy from clinical trials and reports of inadvertent use of mefloquine during pregnancy suggest that its use at prophylactic doses during the second and third trimesters of pregnancy is not associated with adverse foetal or pregnancy outcomes. More limited data suggest it is also safe to use during the first trimester.

Because of insufficient data regarding the use during pregnancy, atovaquone/proguanil is not currently recommended for the prevention of malaria in pregnant women. Doxycycline is contraindicated for malaria prophylaxis during pregnancy because of the risk of adverse effects of tetracycline, a related drug, on the foetus, which include discoloration and dysplasia of the teeth and inhibition of bone growth. Primaquine should not be used during pregnancy because the drug may be passed transplacentally to a glucose-6-phosphate dehydrogenase (G6PD)-deficient foetus and cause haemolytic anaemia in utero. Health-care professionals who require additional assistance with the management of pregnant travellers who are unable to take mefloquine chemoprophylaxis should call the CDC Malaria Hotline (770-488-7788).

Antimalarial Drugs during Breastfeeding

Data are available for some antimalarial agents on the amount of drug excreted in breast milk of lactating women. Very small amounts of chloroquine and mefloquine are excreted in the breast milk of lactating women. The amount of drug transferred is not thought to be harmful to a nursing infant. Because the quantity of antimalarial drugs transferred in breast milk is insufficient to provide adequate protection against malaria, infants who require chemoprophylaxis must receive the recommended dosages of antimalarial drugs listed in Table 4-9.

Although there are very limited data about the use of doxycycline in lactating women, most experts consider the theoretical possibility of adverse events to be remote.

No information is available on the amount of primaquine that enters human breast milk; the mother and infant should be tested for G6PD deficiency before primaquine is given to a woman who is breastfeeding.

It is not known whether atovaquone is excreted in human milk. Proguanil is excreted in human milk in small quantities. Based on experience with other antimalarial drugs, the quantity of drug transferred in breast milk is likely insufficient to provide adequate protection against malaria for the infant. Because data are not yet available on the safety of atovaquone/proguanil prophylaxis in infants weighing <11 kg (24 lbs), CDC does not currently recommend it for the prevention of malaria in women breastfeeding infants weighing <11 kg. (Atovaquone/proguanil may be used for the treatment of malaria by women breastfeeding infants weighing >5 kg. However, it can be used for treatment of women who are breastfeeding infants of any weight when the potential benefit outweighs the potential risk to the infant, e.g., treating a breastfeeding woman who has acquired P. falciparum malaria in an area of multidrug-resistant strains and who cannot tolerate other treatment options.)

Adverse Reactions and Contraindications

Following is a summary of the frequent or serious side effects of recommended antimalarial drugs. In addition, physicians should review the prescribing information in standard pharmaceutical reference texts and in the manufacturers' package inserts.

Atovaquone/Proguanil

The most common adverse effects reported in persons using atovaquone/proguanil for prophylaxis or treatments are abdominal pain, nausea, vomiting, and headache. Atovaquone/proguanil should not be used for prophylaxis in children weighing <11 kg, pregnant women, women breastfeeding infants weighing <11 kg, or patients with severe renal impairment (creatinine clearance <30 mL/min).

Chloroquine and Hydroxychloroquine Sulfate

Reported side effects include gastrointestinal disturbance, headache, dizziness, blurred vision, insomnia, and pruritus, but generally these effects do not require that the drug be discontinued. High doses of chloroquine, such as those used to treat rheumatoid arthritis, have been associated with retinopathy; this serious side effect appears to be extremely unlikely when chloroquine is used for routine weekly malaria prophylaxis. Chloroquine and related compounds have been reported to exacerbate psoriasis.

Doxycycline

Doxycycline can cause photosensitivity, usually manifested as an exaggerated sunburn reaction. The risk of such a reaction can be minimized by avoiding prolonged, direct exposure to the sun and by using sunscreens that absorb long-wave UVA radiation. In addition, doxycycline use is associated with an increased frequency of Candida vaginitis. Gastrointestinal side effects (nausea or vomiting) may be minimized by taking the drug with a meal. To reduce the risk of esophagitis, travellers should be advised not to take doxycycline before going to bed. Doxycycline is contraindicated in persons with an allergy to tetracyclines, during pregnancy, and in infants and children <8 years of age. Vaccination with the oral typhoid vaccine Ty21a should be delayed for >24 hours after taking a dose of doxycycline.

Mefloquine

Mefloquine (Lariam) has been associated with rare serious adverse reactions (e.g., psychoses or seizures) at prophylactic doses; these reactions are more frequent with the higher doses used for treatment. Other side effects that have occurred in chemoprophylaxis studies include gastrointestinal disturbance, headache, insomnia, abnormal dreams, visual disturbances, depression, anxiety disorder, and dizziness. Other more severe neuropsychiatric disorders occasionally reported during post-marketing surveillance include sensory and motor neuropathies (including paraesthesia, tremor, and ataxia), agitation or restlessness, mood changes, panic attacks, forgetfulness, confusion, hallucinations, aggression, paranoia, and encephalopathy. On occasions, psychiatric symptoms have been reported to continue long after mefloquine has been stopped.

During prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness, or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative drug substituted.

Mefloquine is contraindicated for use by travellers with a known hypersensitivity to mefloquine or related compounds (e.g., quinine and quinidine) and in persons with active depression, a recent history of depression, generalised anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. It should be used with caution in persons with psychiatric disturbances or a previous history of depression. A review of available data suggests that mefloquine may be used in persons concurrently on beta blockers, if they have no underlying arrhythmia. However, mefloquine is not recommended for persons with cardiac conduction abnormalities. Any traveller receiving a prescription for mefloquine must also receive a copy of the FDA Medication Guide which can be found at the following website: http://www.fda.gov/cder/foi/label/2003/19591s19lbl_Lariam.pdf.

Primaquine

The most common adverse event in G6PD-normal persons is gastrointestinal upset if primaquine is taken on an empty stomach—this problem is minimized or eliminated if primaquine is taken with food. Primaquine can cause haemolysis that can be fatal, in G6PD-deficient persons. Before primaquine is used, G6PD deficiency MUST be ruled out by appropriate laboratory testing.

Medications Acquired Overseas

The medications recommended for chemoprophylaxis and treatment of malaria may also be available at overseas destinations. However, combinations of these medications and additional drugs that are not recommended may be commonly prescribed and used in other countries. Travellers should be strongly discouraged from obtaining chemoprophylactic medications while abroad. These products may not be protective and may be dangerous. These medications may have been produced by substandard manufacturing practices, may be counterfeit, or may contain contaminants. Additional information on this topic can be found in a Food and Drug Administration document "Purchasing Medications Outside the United States" (http://www.fda.gov/ora/import/purchasing_medications.htm).

Medications that are not used in the United States, such as halofantrine (Halfan), are widely available overseas. CDC does not recommend halofantrine for treatment because of cardiac adverse events, including deaths, which have been documented following treatment doses. These adverse events have occurred in persons with and without preexisting cardiac problems and both in the presence and absence of other antimalarial drugs (e.g., mefloquine). Health-care providers should caution travellers not to use medications that are not recommended unless they have been diagnosed with life-threatening malaria and no other options are available.

Changing Medications during Chemoprophylaxis as a Result of Side Effects

The medications recommended for prophylaxis against malaria have different modes of action that affect the parasites at different stages of the life cycle. Thus, if the medication needs to be changed because of side effects before a full course has been completed, there are some special considerations. If a traveller starts prophylaxis with a medication such as mefloquine or doxycycline and then changes to atovaquone/proguanil during or after travel, the standard duration of prophylaxis for atovaquone/proguanil might be insufficient. The atovaquone/proguanil should be continued for 4 weeks after the drug change or 1 week after returning, whichever is longer, but not beyond 4 weeks after return. Health-care professionals who require additional assistance with the management of travellers who need to change medications during prophylaxis should call the CDC Malaria Hotline (770-488-7788).

Treatment

Specific treatment with antimalarial drugs is available. Travellers should be advised that malaria can be treated effectively early in the course of the disease but that delay of appropriate therapy can have serious or even fatal consequences. Travellers who have symptoms of malaria should be advised to seek prompt medical evaluation, including thick and thin blood smears, as soon as possible. If possible, it is advisable to consult with a provider who has specialized travel/tropical medicine expertise or with an infectious disease physician. CDC recommendations for malaria treatment can be found at http://www.cdc.gov/malaria/diagnosis_treatment/treatment.htm.

Self-Treatment

CDC recommends the use of malaria prophylaxis for travel to malarious areas. However, travellers who elect not to take prophylaxis, who do not choose an optimal drug regimen (e.g., chloroquine in an area with chloroquine-resistant P. falciparum) or who require a less than optimal drug regimen are at greater risk for acquiring malaria and needing prompt treatment. Travellers who are taking effective prophylaxis but who will be in very remote areas may decide, in consultation with their health-care provider, to take along a dose of antimalarial medication for self-treatment. Travellers should be advised to take their presumptive self-treatment promptly if they have fever, chills, or other influenza-like illness and if professional medical care is not available within 24 hours. Travellers should be advised that this self-treatment of a possible malarial infection is only a temporary measure and that prompt medical evaluation is imperative.

Recommendations for Presumptive Self-Treatment

Atovaquone/proguanil may be used for presumptive self-treatment for travellers NOT taking atovaquone/proguanil for prophylaxis. The CDC Malaria Branch (Malaria Hotline 770-488-7788) can provide consultation to health-care providers on other potential options for self-treatment if atovaquone/proguanil cannot be used.

Table 4-11. Presumptive self-treatment of malaria

Drug	Adult Dose	Paediatric Dose	Comments
Atovaquone/proguanil (Malarone). Self-treatment drug to be used if professional medical care is not available within 24 hours. Medical care should be sought immediately after treatment	4 tablets (each dose contains 1,000 mg atovaquone and 400 mg proguanil) orally as a single daily dose for 3 consecutive days	Daily dose to be taken for 3 consecutive days: 5-8 kg: 2 paediatric tablets 9-10 kg: 3 paediatric tablets 11-20 kg: 1 adult tablet 21-30 kg: 2 adult tablets 31-40 kg: 3 adult tablets 41 kg: 4 adult tablets	Contraindicated in persons with severe renal impairment (creatinine clearance <30 mL/min). Not recommended for self-treatment in persons on atovaquone/proguanil prophylaxis. Not currently recommended for children <5 kg,1 pregnant women, and women breastfeeding infants weighing < 5 kg

1Note: 5 kg is the cut-off weight for treatment with atovaquone/proguanil; 11 kg remains the recommended cut-off weight for prophylaxis.

Malaria Hotline

Detailed recommendations for the prevention of malaria are available from CDC 24 hours a day from the voice information service (1-877-FYI-TRIP; 1-877-394-8747), the fax information service (1-888-232-3299), or the Internet at http://www.cdc.gov/travel.

Health-care professionals who require assistance with the diagnosis or treatment of malaria should call the CDC Malaria Hotline (770-488-7788) from 8:00 a.m. to 4:30 p.m. Eastern time. After hours or on weekends and holidays, health-care providers requiring assistance should call the CDC Emergency Operation Center at 770-488-7100 and ask the operator to page the person on call for the Malaria Branch. Information on diagnosis and treatment is available on the internet at www.cdc.gov/malaria.

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- Monica Parise, Ann Barber, and Sonja Mali