Outline # 20: A. McCarthy
Geographic risk, prevention, transmission, possible symptoms and appropriate referral/triage of: Diseases Associated with Vectors
Malaria
These notes are extracted mostly from current as of March 03 Shoreland’s medical information on malaria and are compatible with recommendations by CATMAT, CDC, and WHO.
Some general notes on malaria issues:
DISEASE INFORMATION
General Description
Malaria is caused by a protozoan parasite that is transmitted by the bite of an Anopheles mosquito that is found in almost all countries in the tropics and subtropics. Transmission usually occurs between dusk and dawn because the Anopheles mosquitoes feed at night. Occasionally malaria is transmitted through blood transfusion, congenitally from mother to fetus, or through contaminated needles and syringes. Four Plasmodium species cause malaria: P. falciparum (the most serious, potentially lethal form), P. vivax, P. ovale, and P. malariae.
Malaria occurs in many parts of the world, including Central and South America, Africa, the Indian subcontinent, Southeast Asia, the Middle East, and islands of the South Pacific. Risk depends on the traveler's itinerary, the length of the trip, the season, the location within a country (e.g., urban vs. rural), and where the traveler will spend the evening and nighttime hours. Malaria usually (but not always) can be prevented by the use of antimalarial drugs and personal protection measures against mosquito bites.
Most cases of imported falciparum malaria among U.S. travelers have been acquired in Africa south of the Sahara.
For persons not using drugs to prevent malaria, the relative risk of malaria in sub-Saharan Africa is 1:50 (1 out of every 50 persons) per month of stay. Vivax malaria, on the other hand, is most often acquired in India where the risk is approximately 1:250 travelers (1 out of every 250 travelers) not using preventive drugs. Anyone experiencing symptoms suggestive of malaria should seek medical attention immediately, since treatment delay can lead to serious consequences. While illness caused by P. vivax, P. ovale, or P. malariae is not usually life threatening, it can pose serious risks to the very young, the elderly, or persons with underlying illnesses. If malaria is left untreated, symptoms may recur intermittently for months or even years; prolonged symptoms may also occur in those who are partially immune to P. falciparum (i.e., those who have been infected on numerous occasions).
Symptoms
Malaria is characterized by fever and "flu-like" symptoms (chills, sweats, myalgia, and headache) that may occur at intervals. Vomiting, diarrhea, abdominal cramping, and cough also may occur, and the disease may be associated with anemia and jaundice. Symptoms may develop as early as 7 to 8 days after initial exposure in a malaria-endemic area and as late as months or years after departure.
Malaria caused by P. falciparum usually occurs about 10 to 12 days after infection. Without prompt treatment, it can proceed to respiratory and kidney failure, shock, coma, and death. Symptoms caused by the other 3 malaria species may appear from 14 days to many months after infection. Classically, symptoms may recur periodically at intervals from 48 to 72 hours; however, a cyclical pattern of fever may be absent and is rarely seen in those with P. falciparum malaria.
It should never be assumed that the traveler has "the flu" or some other disease without ordering thick and thin blood films to diagnose malaria. In short: "Fever from the tropics is a medical emergency and is malaria until proven otherwise."
Travelers should be educated about malaria symptoms and informed that:
Risk
The estimated risk of acquiring malaria varies markedly within various regions, depending on the intensity of transmission in both urban and rural areas, as well as the itinerary, season, duration, and type of travel. For example, short-term travelers living in urban centers and staying in air-conditioned hotels will be at much lower risk than long-stay, adventurous travelers living in rural areas.
As a general rule, malaria is transmitted in urban and rural areas only in sub-Saharan Africa and South Asia. In most other parts of the world, malaria transmission occurs only in rural areas. The risk of malaria is highest in Oceania (Papua New Guinea, Irian Jaya, the Solomon Islands, etc.), followed in order by sub-Saharan Africa, the Indian subcontinent, Southeast Asia, South America, and Central America.
Annually, approximately 1,000 cases of malaria among U.S. civilians are reported to the CDC. There are between 400 and 1000 cases reported annually in Canda.
Due to underreporting, this represents only a small proportion of the actual number of cases diagnosed. In the US almost half of the imported cases are due to P. falciparum, most of which (90%) are acquired in sub-Saharan Africa. P. vivax makes up the majority of the remaining cases and is most frequently acquired on the Indian subcontinent. Travelers to Africa are at risk in most rural and many urban areas and tend to spend considerable time, including evening and nighttime hours, in rural areas where malaria risk is highest. Most travelers to Asia, however, spend much of their time in urban or resort areas where there is limited, if any, risk of exposure, and they travel to rural areas mainly during daytime hours when there is limited risk of infection.
All travelers to malarious areas should be advised to use an appropriate drug regimen and personal protection measures to prevent malaria; however, travelers should be informed that regardless of methods employed malaria still may be contracted.
Persons who plan to make a blood donation after a trip to a malarious area should be advised to check with their blood center about its screening requirements. It is likely that they will be required to wait at least 2 years from the time they have completed their trip and/or finished taking preventive medications before donating blood. Anyone with a history of malaria restricted, lifelong, from blood donation in Canada.
CHEMOPROPHYLAXIS
Indications
The travel itinerary should be reviewed in detail and compared with information on risk areas within a given country to determine whether the traveler will actually be at risk of acquiring malaria. Because Anopheles mosquitoes bite from dusk to dawn, antimalarial drugs are only recommended for travelers who will have exposure during those hours in malaria risk areas. Additional factors should be considered, including whether the traveler has previously experienced an allergic or other reaction to the antimalarial drug of choice and whether medical care will be readily accessible during travel.
Malaria chemoprophylaxis should begin 1 week before travel to malarious areas (except for doxycycline, primaquine, and atovaquone/proguanil, which should begin 1 day before travel). In addition to helping build up adequate blood levels of the drug, this regimen allows any potential side effects to be evaluated and treated by the traveler's health care provider and an alternative drug to be prescribed. As a rule, malaria chemoprophylaxis should be continued as long as exposure occurs, even for many years if necessary, and for 4 weeks after leaving the area of exposure (except for atovaquone/proguanil and primaquine, which must be continued for 1 week after leaving the area of risk).
Drug Resistance
Resistance of P. falciparum to chloroquine has been confirmed or is probable in all malarious areas except for the following: North Africa, most countries in the Middle East, the Newly Independent States (former USSR) in Asia, portions of China, Haiti and the Dominican Republic, Central America west of the Panama Canal, and temperate South America. Resistance to both chloroquine and Fansidar is widespread in Thailand, Myanmar (formerly called Burma), Cambodia, the Amazon basin area of South America, and many areas in sub-Saharan Africa. Mefloquine (Lariam) resistance has been confirmed along the eastern and western borders of Thailand. Resistance of P. vivax to chloroquine has been confirmed in Papua New Guinea, Indonesia, India, Colombia, and Brazil; however, this has little clinical significance since chloroquine is not recommended for these countries.
CHEMOPROPHYLACTIC REGIMENS FOR ADULTS
General
Using chemoprophylaxis in addition to personal protection measures against mosquito bites is an equally important safeguard for persons traveling to malarious areas. Travelers should be reminded that no matter which medication is used to prevent malaria there is always the risk of side effects. However, the risk of side effects must be weighed against the risk of a potentially fatal infection with Plasmodium falciparum.
It is important to note that there is no consensus globally, even among physicians within one's own country, as to the optimal drug to prevent malaria. For example, in some countries, notably the United Kingdom, unwarranted and exaggerated media reports concerning mefloquine side effects have led to decreased use of the drug. However, in North America, mefloquine has remained an important drug for the prevention of malaria. Therefore, travelers should be instructed that when they are confronted with conflicting views concerning their chemoprophylactic agent, they should smile politely and ignore the advice of fellow travelers and overseas health care providers.
Antimalarials such as chloroquine, mefloquine, doxycycline, and azithromycin act in the blood after the liver phase of parasite development and therefore must be continued for 4 weeks after exposure to eradicate any parasites that may have been released from the liver. However, newer antimalarials such as primaquine and the atovaquone/proguanil combination prevent parasite development in the liver and therefore can be discontinued 1 week after exposure.
The current drugs of choice to prevent chloroquine-resistant falciparum malaria include atovaquone/proguanil, doxycycline and primaquine. Although limited data are available concerning atovaquone/proguanil, it appears to be as effective as the alternatives and has fewer side effects. However, for the longer-stay traveler (1 month or more) it is considerably more expensive. The choice of drug will be determined by its efficacy, the traveler's willingness to accept potential side effects, the convenience of the regimen (weekly vs. daily), the cost, and, of course, whether or not there are any contraindications to the drug.
Because product recommendations (particularly for scheduling, compatibility, adverse reactions, contraindications, and precautions) are subject to change, always check information provided on the package insert of the lot currently in use (check with manufacturer if product has been stored for a prolonged period).
A known or suspected allergy to an antimalarial is a contraindication to its use, and concomitant or chronic illness should be a consideration in the use of antimalarials as it would be in the use of any medication.
Chloroquine
Chloroquine is still effective in specific regions, as noted above. Chloroquine prophylaxis should be started 1 week before travel to malarious areas, continued weekly while there, and continued for 4 weeks after leaving the malarious area. Limited data indicate that the combination of chloroquine with daily proguanil (Paludrine) is more effective than chloroquine alone in sub-Saharan Africa; however, this combination has considerably lower efficacy than the drugs recommended above for the prevention of chloroquine-resistant malaria. Travelers who elect to use chloroquine or chloroquine/proguanil in chloroquine-resistant areas should be given a treatment dose of Malarone or quinine and doxycycline to be carried along.
Precautions and Contraindications
Chloroquine is contraindicated for persons with an allergy to chloroquine or related compounds.
Adverse Effects
Chloroquine rarely causes serious adverse reactions when taken at prophylactic doses for malaria. Minor side effects may occur, such as gastrointestinal disturbance, headache, dizziness, blurred vision, and pruritus (especially in African Americans), but generally these effects do not require discontinuation of the drug. The few people who experience uncomfortable side effects may tolerate the drug better by taking it with meals or in divided, twice-weekly doses. Also, chloroquine may exacerbate psoriasis.
High doses of chloroquine, as used in the treatment of rheumatoid arthritis, have been linked with retinopathy, but this side effect does not appear to be associated with routine weekly malaria prophylaxis. If long-term chloroquine therapy is being considered, refer to the package insert for recommendations regarding the need for periodic ophthalmologic examinations.
Atovaquone/Proguanil (Malarone)
Malarone, a fixed combination of atovaquone (250 mg) and proguanil (100 mg) in 1 tablet (adult tablet), is licensed in North America for the treatment and prevention of chloroquine-resistant P. falciparum malaria. The drug has equal efficacy to mefloquine, doxycycline, and primaquine and appears to be very safe (but expensive for the long-stay traveler). Cost considerations aside, for many practitioners it has become the drug of choice both for the prevention of malaria among short-term travelers and for self-treatment of malaria.
Atovaquone/proguanil is also effective along the borders of Thailand where chloroquine resistance and mefloquine resistance are well documented. (Doxycycline is an equally effective option.)
Atovaquone/proguanil should be started 1 day before travel to malarious areas, continued daily while there, and continued for only 1 week after departure from a malarious area. In the United States, a pediatric formulation contains one-fourth of the adult dose (not available in Canada).
Precautions and Contraindications
Atovaquone/proguanil is contraindicated for pregnant women and for persons with allergy to the drugs in the combination.
Adverse effects
Since side effects from the atovaquone/proguanil drug were no different from the placebo in several prophylaxis studies, it appears to be very safe. However, when the drug is used for treatment, symptoms such as nausea, vomiting, diarrhea, and abdominal pain occur occasionally; seizures and rash are rare.
Doxycycline
Travelers to risk areas where chloroquine-resistant or mefloquine-resistant malaria is endemic may use doxycycline or atovaquone/proguanil. Doxycycline and atovaquone/proguanil are equally effective prophylactic drugs for travelers visiting the Thai/Myanmar and Thai/Cambodian borders. Doxycycline prophylaxis should begin on the day before entering a malarious area, be continued daily while there, and continue for 4 weeks after departure. If doxycycline is used, there is no need to take other preventive drugs.
Precautions and Contraindications
This drug is contraindicated for:
· persons with an allergy to doxycycline or tetracycline
· women during their entire pregnancy
· children less than 8 years old
Adverse Effects
Doxycycline may cause photosensitivity, usually manifested as an exaggerated sunburn reaction. Risk of such reaction can be minimized by avoiding prolonged, direct exposure to the sun, using sunscreens that absorb long-wave ultraviolet (UVA) radiation, and wearing a hat. Doxycycline use is associated with an increased frequency of candida vaginitis. This complication should be discussed with female patients before prescribing the drug; an antifungal agent should be carried for self-treatment. Gastrointestinal side effects (nausea or vomiting) may be minimized by taking the drug with a meal, in an upright position, and with a liberal amount of fluids.
Mefloquine
For travel to areas of risk where chloroquine-resistant malaria exists, use of mefloquine alone is recommended. Mefloquine is usually well tolerated and can be used for long-term prophylaxis. Mefloquine prophylaxis should be started 1-2 weeks before travel to malarious areas, be continued weekly while remaining in those areas, and continue for 4 weeks after departure.
Note: In some foreign countries a fixed combination of mefloquine and Fansidar is marketed under the name Fansimef. Fansimef should not be confused with mefloquine and, because of serious adverse reactions associated with its prophylactic use, it is not recommended for malaria prophylaxis.
Recent studies suggest that adverse events of mefloquine can be predicted by using a loading dose (off-label use) of 1 tablet daily for 3 days and then weekly thereafter. The adverse events of mefloquine will occur within the first week of a loading dose compared with the third to seventh weeks when weekly dosing is initiated. If adverse events occur, the drug can be stopped and an alternative can be initiated prior to departure. Adverse events associated with a loading dose are similar to those with the weekly regimen. Alternatively, weekly dosing of mefloquine can be started 3 weeks prior to departure, and if adverse events occur, an alternative can be initiated prior to departure.
Precautions and Contraindications
Mefloquine generally is not recommended for self-treatment because of the increased frequency of side effects (hallucinations, psychosis, convulsions) that have been associated with high dosages used for treatment. These occur in the order of 1:100 to 1:1500 users, 10-fold higher than when the drug is used for prophylaxis. Mefloquine is not recommended for persons with:
· an allergy to mefloquine or related compounds
· a history of epilepsy
· active depression or recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorder
Mefloquine should be used with caution in patients with previous history of depression. If psychiatric symptoms occur during prophylactic use, they may be prodromal to a more serious event and the drug should be discontinued and an alternative medication substituted.
Mefloquine may be given to individuals concurrently using calcium channel or beta-blockers or to those with a rhythm disturbance if they do not have a cardiac conduction defect. Per the manufacturer's insert, risks and benefits of administering mefloquine should be weighed against the possibility of adverse effects when used concurrently with quinine, quinidine, or other drugs that alter cardiac conduction. Persons planning to drive, pilot aircraft, or operate machines while using mefloquine should be informed that mild dizziness is among the possible short-term side effects. Persons on mefloquine prophylaxis should not use halofantrine (Halfan), an antimalarial drug licensed in the United States but not commercially available there, although it is available in many other countries for the treatment of malaria. (See "Self-Treatment.")
Adverse Effects
The side effects of mefloquine have been greatly exaggerated in the media. Nine prospective, randomized, placebo-controlled trials show that the risk of disabling neuropsychological problems (such as insomnia, nightmares, irritability, and depression) occurs in the order of 1:200 to 1:500 users. On the other hand, severe side effects such as seizures and psychosis occur rarely, in the order of 1:10,000 to 1:13,000 users. Approximately 97% of mefloquine users are able to tolerate the drug without discontinuing it.
Minor side effects (such as gastrointestinal disturbance and dizziness) observed with prophylactic doses tend to be mild and temporary. There have been occasional reports of more severe neuropsychiatric disorders such as tremor, ataxia, mood changes, or panic attack, and infrequent reports of chest pain, edema, and dyspnea. Rare cases of suicide have been reported although no relationship to the administration of mefloquine has been confirmed.
Per the manufacturer, unexplained acute anxiety, depression, restlessness, or confusion may be prodromal to a more serious event and therefore the drug should be discontinued and an alternative medication substituted. See also "Compatibility."
Azithromycin (Zithromax)
Azithromycin, a macrolide antibiotic, has shown some efficacy in the prevention of chloroquine-resistant falciparum malaria (an off-label use); however, the drug is a suboptimal antimalarial because it is less effective than other antimalarials (mefloquine, atovaquone/proguanil, doxycycline, primaquine) used for the prevention of chloroquine-resistant falciparum malaria and is very, very expensive. Azithromycin has been shown to be safe in pregnant women and young children, the precise populations for whom a suboptimal drug should not be used. However, it might be considered for a pregnant woman who must travel in a chloroquine-resistant area but who cannot take mefloquine
Azithromycin should be started 1 week prior to entry to malarious areas, continued daily during exposure, and continued for 4 weeks after departure.
Precautions and Contraindications
Azithromycin is contraindicated for those with an allergy to the drug.
Adverse Effects
Gastrointestinal side effects (nausea, vomiting, abdominal pain, diarrhea) are infrequent. Liver dysfunction and hematological abnormalities (leukopenia, pancytopenia) are rare.
Primaquine
Primaquine is used in 2 different ways to prevent malaria.
Precautions and Contraindications
Primaquine is a potent oxidizing agent and therefore should not be given to those with a G6PD (Glucose-6-phosphate dehydrogenase) deficiency. G6PD deficiency is most frequently found among African Americans, Mediterraneans, South Asians, and Orientals. Before primaquine is recommended, a G6PD level is mandatory to ensure that the enzyme level is normal. In persons with a genetic deficiency of methemoglobin reductase, methemoglobinemia may occur at 30 mg/day and more rarely at 15 mg/day of primaquine.
Primaquine is contraindicated in those with low levels of G6PD and in pregnant women.
Primaquine should be administered with food to reduce gastrointestinal upset.
Adverse Effects
Nausea, vomiting, and abdominal pain are frequent unless the drug is given with food. In those with G6PD deficiency, hemolytic anemia may occur. In those with a genetic deficiency of methemoglobin reductase, methemoglobinemia may occur at 30 mg/day and more rarely at 15 mg/day of primaquine.
Prophylaxis During Pregnancy
Malaria infection in pregnant women may be more severe than in nonpregnant women, and it may increase the risk of adverse pregnancy outcomes, including prematurity, miscarriage, and stillbirth. Pregnant women planning to travel to a malaria risk area should be aware of the risk of such travel and consider whether a change in itinerary is possible, to avoid malaria exposure. They should also consult with a travel medicine expert, should maximize personal protection measures to avoid mosquito bites, and should take appropriate prescription drugs to prevent malaria. For pregnant women who travel to areas without chloroquine-resistant Plasmodium falciparum, chloroquine has been used for malaria chemoprophylaxis for decades with no documented increase in birth defects. For pregnant women who travel to areas with chloroquine-resistant P. falciparum, mefloquine should be recommended for chemoprophylaxis during the second and third trimesters. For women in their first trimester, most evidence suggests that mefloquine prophylaxis causes no significant increase in spontaneous abortions or congenital malformations if taken during this period.
Doxycycline is contraindicated for malaria prophylaxis during pregnancy. Adverse effects of tetracyclines on the fetus include discoloration and dysplasia of the teeth and inhibition of bone growth. Tetracyclines would be indicated in pregnancy only if required to treat life-threatening infections due to multi-drug-resistant P. falciparum.
Primaquine should not be used during pregnancy because the drug may be passed transplacentally to a G6PD-deficient fetus and cause hemolytic anemia in utero. Whenever radical cure or terminal prophylaxis with primaquine is indicated during pregnancy, chloroquine should be given once a week until delivery, at which time primaquine may be given.
Atovaquone/proguanil is contraindicated during pregnancy.
Proguanil (not available in the United States) has been used widely for several decades, and no adverse effects on pregnancy or fetus have been established. However, the combination of chloroquine/proguanil has lower efficacy than other drugs of choice. Similarly, azithromycin is safe during pregnancy but also has lower efficacy than drugs of choice indicated above.
Prophylaxis While Breast-feeding
Very small amounts of antimalarial drugs are secreted in breast milk, but the amount of drug transferred is not thought to be harmful to the nursing infant. Because the quantity of antimalarials transferred in breast milk is insufficient to provide adequate protection against malaria, infants who require chemoprophylaxis should receive the recommended dosages of antimalarials.
CHEMOPROPHYLAXIS FOR CHILDREN
All children traveling to malaria risk areas, including young infants, should use personal protection methods to avoid mosquito bites and should take antimalarial drugs. The indications for most preventive drugs are the same as for adults; however, it is essential that the correct dosage be used, based on the child's age and/or weight. Do not give doxycycline to children younger than 8 years of age. Young children should avoid travel to areas with chloroquine-resistant P. falciparum unless they can take a drug that is highly effective, such as mefloquine, atovaquone/proguanil, primaquine, or doxycycline.
Pediatric doses should be calculated carefully according to body weight. Pharmacists can pulverize tablets and prepare gelatin capsules with calculated pediatric doses. Chloroquine and mefloquine may be mixed in juice, jelly, ice cream, or chocolate sauce to hide the extremely bitter taste. Alternatively, chloroquine is widely available overseas as suspensions that generally contain 10 mg of chloroquine base in each mL; the dosage is usually indicated on the bottle or package. Parents should calculate the dose and volume to be administered based on body weight, because the concentration of chloroquine base varies in different suspensions.
Overdose of antimalarial drugs can be fatal. Medication should be stored in childproof containers out of children's reach.
SELF-TREATMENT
General
Given the high degree of efficacy of current antimalarials, the need for travelers to carry medication for self-treatment is limited to those who will travel in remote areas where they will not have access to medical care for 24 - 48 hours or more, especially those who are using suboptimal antimalarials in drug-resistant areas (e.g., use of chloroquine/proguanil, or azithromycin in chloroquine-resistant areas). Travelers who elect to carry self-treatment should be given a treatment dose(s) of the medication that is to be carried along; the medication should be taken promptly if they have a febrile illness during travel and medical care is not readily available within 24 hours. Travelers should be aware that self-treatment of a possible malarial infection is only a temporary measure, that prompt medical evaluation is imperative, and that malaria can be fatal if treatment is delayed. The drug used for self-treatment should not be the same as the one being used to prevent malaria. After self-treatment, travelers should continue their preventive medication. Travelers to underdeveloped countries where antimalarial drugs may not be available at all should also consider carrying a treatment dose of antimalarials to deal with physician-diagnosed chemoprophylaxis breakthroughs.
Atovaquone/proguanil (Malarone)
Atovaquone/proguanil is licensed in the United States for treatment and prevention of malaria. The atovaquone/proguanil combination is the drug of choice for self-treatment of malaria. Treatment doses are associated with nausea, vomiting, abdominal pain, diarrhea, increased transaminases, and, rarely, rash and/or seizures. See "Prescription Drugs for Self-Treatment of Malaria." The drug is contraindicated during pregnancy.
Quinine plus doxycycline
The combination of quinine and doxycycline is a standard therapy for the treatment of P. falciparum malaria. As a self-treatment regimen it is very effective but somewhat complicated, involving multiple doses over at least 1 week, and frequently is associated with adverse events. This combination should be reserved for individuals who are likely to be compliant with this complicated regimen. Side effects from quinine are frequent and include tinnitus, dizziness, hearing loss, nausea, headache, and blurred vision. Cardiac conduction disturbances occur occasionally. Gastrointestinal upset is a frequent complication of doxycycline (see "Doxycycline" for preventive therapy).
Mefloquine
Mefloquine should be avoided for self-treatment because of the frequency of side effects (hallucinations, psychosis, convulsions) that have been associated with high dosages used for treatment. These severe symptoms occur in 1:100 to 1:1500 of those who are treated with the drug. Mefloquine may increase the risk of fetal loss when used for treatment during pregnancy, especially during the first trimester.
Pyrimethamine-sulfadoxine (Fansidar)
Fansidar resistance is well documented in Southeast Asia, the Amazon basin of Brazil, and increasingly throughout subsaharran Africa, and therefore Fansidar should be avoided in these areas. The drug appears to be safe during pregnancy. Fansidar is contraindicated for:
In rare instances, use of Fansidar has been associated with severe reactions, including Stevens-Johnson Syndrome and toxic epidermal necrolysis. See "Prescription Drugs for Self-Treatment of Malaria."
DRUGS USED FOR MALARIA TREATMENT IN OTHER COUNTRIES
Travelers should be aware that the medical management of malaria in countries where the disease routinely occurs may differ from their country of origin, such as the United States. In countries where malaria is endemic there may be a limited number of effective medications available for treatment. In fact, some of the drugs used may be ineffective for those without partial immunity to malaria or may be associated with unacceptable adverse effects.
Artemisinin (qinghaosu) derivatives — including Artesunate, Artemether, Arteether, Dihydroartemisinin (sold as Cotexin in Africa) — are naturally occurring antimalarials available in oral, suppository, and injectable forms. They result in rapid clearance of parasites and fever but do not decrease mortality compared to quinine. They have high recrudescent rates (about 10% to 50%) when used as monotherapy and are therefore used in combination with other drugs such as mefloquine, tetracycline, or lumefantrine. Coartmether (Riamet in Europe; Coartem in Africa), a combination of artemether and lumefantrine, currently is licensed in some European countries and soon will be widely distributed in Africa for treatment of malaria. Combination therapy results in > 90% cure rates of primary and recrudescent P. falciparum infections. Artemisinin derivatives have been used in over 1 million patients and are well tolerated. Although there are some concerns about neurotoxicity in animals, to date no clinical neurologic events have been observed in humans. The safety of qinghaosu derivatives in pregnancy has not been established.
Common antimalarials may be known by other brand names abroad; these include mefloquine (Lariam, mephaquine) and chloroquine (Resochin, Avochlor, Nivaquine).
Halofantrine (Halfan) is a derivative related to mefloquine and quinine available in an oral formulation that has recently been withdrawn from the market due to concerns about cardiotoxicity. It does remain widely available in the tropics and travelers should be made aware of the danger of this drug. The World Health Organization has reported cardiac deaths associated with the use of halofantrine and no longer recommends its use. Other cardioactive antimalarials should be used with caution and only with close cardiac monitoring in patients who have received halofantrine in the previous week.
PREVENTION OF RELAPSES
Relapsing Malaria
Because most malarious areas of the world (except Haiti) have at least 1 species of relapsing malaria, travelers to these areas have some risk of acquiring either P. vivax or P. ovale, but this risk is extremely difficult to quantify. These forms of malaria can persist in the liver and cause relapses for months or even years after routine chemoprophylaxis is discontinued. Travelers to malarious areas should be alerted to this risk.
Primaquine decreases the risk of relapses by acting against the liver stages of P. vivax and P. ovale; however, it is not indicated for all travelers. Prophylaxis with primaquine generally is indicated for persons who have had prolonged exposure for greater than 6 months in malaria-endemic areas. It should not be used during pregnancy (see "Prophylaxis During Pregnancy"). Most people can tolerate the standard regimen of primaquine, except persons deficient in glucose-6-phosphate dehydrogenase (G6PD). In persons with G6PD deficiency, primaquine may cause hemolytic anemia. In those with a genetic deficiency of methemoglobin reductase, methemoglobinemia may occur even at 30 mg/day and more rarely at 15 mg/day of primaquine. Before use, G6PD deficiency should be ruled out by appropriate laboratory testing. Primaquine is administered after the traveler has left a malarious area—usually during the last 2 weeks of prophylaxis with chloroquine, mefloquine, or doxycycline, or during the last week of prophylaxis with Malarone and continued for 1 week after completion of Malarone. Relapse prevention is not 100% effective due to primaquine-resistant P. vivax documented in Somalia, Southeast Asia, and Oceania.
DRUG COMPATIBILITY
Immunization with oral typhoid (a live bacterial vaccine) should be delayed at least 24 hours if mefloquine has been administered.
Taking doxycycline concurrently with antacids or bismuth subsalicylate (Pepto Bismol) may hinder absorption.
FDA, CDC, and Canadian package inserts recommend against the use of proguanil for at least 10 days after completing the oral typhoid vaccine series. Proguanil used for malaria prophylaxis at 200 mg/day has been shown to interfere with the immune response to oral typhoid vaccine (Ty21a).
Although Malarone (atovaquone/proguanil) contains proguanil (at 100 mg/day), specific controlled studies show no effect by Malarone on the antibody response to either Ty21a or oral cholera vaccine (CVD 103-Hgr). Thus Malarone can be commenced at any time with respect to use of these 2 vaccines.