CHAPTER 7 Malaria General considerations Malaria is a common and life-threatening disease in many tropical and subtropical areas. It is currently endemic in over 100 countries, which are visited by more than 125 million international travellers every year. Each year many international travellers fall ill with malaria while visiting countries where the disease is endemic, and well over 10 000 are reported to fall ill after returning home. Due to under-reporting, the real figure may be up to 30 000. International travellers are at high malaria risk because they are non-immune and often exposed to late or wrong malaria diagnosis when returning to their home country. Fever occurring in a traveller within three months of leaving a malaria-endemic area is a medical emergency and should be investigated urgently. Cause Human malaria is caused by four different species of the protozoan parasite Plasmodium: Plasmodium falciparum, P. vivax, P. ovale and P. malariae. Transmission The malaria parasite is transmitted by various species of Anopheles mosquitoes, which bite mainly between sunset and sunrise. Nature of the disease Malaria is an acute febrile illness with an incubation period of 7 days or longer. Thus, a febrile illness developing less than one week after the first possible exposure is not malaria. The most severe form is caused by P. falciparum, in which variable clinical features include fever, chills, headache, muscular aching and weakness, vomiting, cough, diarrhoea and abdominal pain; other symptoms related to organ failure may supervene, such as: acute renal failure, generalized convulsions, circulatory collapse, followed by coma and death. In endemic areas it is estimated that about CHAPTER 7. MALARIA 1% of patients with P. falciparum infection die of the disease; the mortality in non-immune travellers with untreated falciparum infection is significantly higher. The initial symptoms, which may be mild, may not be easy to recognize as being due to malaria. It is important that the possibility of falciparum malaria is considered in all cases of unexplained fever starting at any time between the seventh day of first possible exposure to malaria and three months (or, rarely, later) after the last possible exposure. Any individual who experiences a fever in this interval should immediately seek diagnosis and effective treatment, and inform medical personnel of the possible exposure to malaria infection. Early diagnosis and appropriate treatment can be life-saving. Falciparum malaria may be fatal if treatment is delayed beyond 24 hours. A blood sample should be examined for malaria parasites. If no parasites are found in the first blood film while there is clinical suspicion of malaria, a series of blood samples should be taken at 6–12-hour intervals and examined very carefully. Pregnant women, young children and elderly travellers are particularly at risk. Malaria in pregnant travellers increases the risk of maternal death, miscarriage, stillbirth and neonatal death. The forms of malaria caused by other Plasmodium species are less severe and rarely life-threatening. Chemoprophylaxis and treatment of falciparum malaria are becoming more difficult because P. falciparum is increasingly resistant to various antimalarial drugs. Chloroquine resistance of P. vivax is rare and was first reported in the late 1980s in Papua New Guinea and Indonesia. Focal “true” chloroquine resistance (i.e. in patients with adequate blood levels at day of failure) or prophylactic and/or treatment failure have later also been observed in Brazil, Columbia, Ethiopia, Guatemala, Guyana, India, Myanmar, Peru, the Republic of Korea, Solomon Islands, Thailand and Turkey. P. malariae resistant to chloroquine has been reported from Indonesia. Geographical distribution The current distribution of malaria in the world on shown in a map. Details for affected countries and territories are listed under countries and territories with malarious area. The risk for travellers of contracting malaria is highly variable from country to country and even between areas in a country. This has to be considered when discussing appropriate preventive measures. In many endemic countries, the main urban areas—but not necessarily the outskirts of towns—are free of malaria transmission. However, malaria can occur INTERNATIONAL TRAVEL AND HEALTH 2005 in main urban areas in Africa and India. There is usually less risk of the disease at altitudes above 1500 metres, but in favourable climatic conditions it can occur at altitudes up to almost 3000 metres. The risk of infection may also vary according to the season, being highest at the end of the rainy season or soon after. There is no risk of malaria in many tourist destinations in South-East Asia, Latin America and the Caribbean. Risk for travellers During the transmission season in malaria-endemic areas, all non-immune travellers exposed to mosquito bites, especially between dusk and dawn, are at risk of malaria. This includes previously semi-immune travellers who have lost (part of) their immunity during stays of 6 months or more in non-endemic areas. Children of people who have migrated to non-endemic areas are particularly at risk when they return to malarious areas to visit friends and relatives. Culturally sensitive approaches are needed to advice different groups at risk. Most cases of malaria in travellers occur because of poor compliance with prophylactic drug regimens, or use of inappropriate medicines or no chemoprophylaxis at all, combined with poor prevention of mosquito bites. Travellers to countries where the degree of malaria transmission varies in different areas should seek advice on the risk of malaria in the specific zones that they will be visiting. If specific information is not available before travelling, it is recommended to prepare as if the highest reported risk for the area or country applies throughout. This applies particularly to individuals backpacking to remote places and visiting areas where diagnostic facilities and medical care are not readily available. Travellers staying overnight in rural areas may be at highest risk. Precautions Travellers and their advisers should note the four principles of malaria protection: — Be Aware of the risk, the incubation period, and the main symptoms. — Avoid being Bitten by mosquitoes, especially between dusk and dawn. — Take antimalarial drugs (Chemoprophylaxis) when appropriate, to prevent infection from developing into clinical disease. — Immediately seek Diagnosis and treatment if a fever develops one week or more after entering an area where there is a malaria risk, and up to 3 months after departure from a risk area. CHAPTER 7. MALARIA Protection against mosquito bites All travellers should be explained that individual protection from mosquito bites between dusk and dawn is their first line of defence against malaria. Practical measures for protection are described in Chapter 3 section Protection against vectors. Chemoprophylaxis The correct dosage of the most appropriate antimalarial drug(s) (if any) for the destination(s) should be prescribed (see Country list and Table 7.1). Travellers and their doctors should be aware that NO ANTIMALARIAL PROPHYLACTIC REGIMEN GIVES COMPLETE PROTECTION, but good chemoprophylaxis (adherence to the recommended drug regimen) does reduce the risk of fatal disease. The following should also be taken into account: . Dosing schedules for children should be based on body weight. . Antimalarials that have to be taken daily should be started the day before arrival in the risk area. . Weekly chloroquine should be started 1 week before arrival. . Weekly mefloquine should be started at least 1 week, but preferably 2–3 weeks before departure, to achieve higher pre-travel blood levels and to allow side- effects to be detected before travel so that possible alternatives can be considered. . Antimalarial drugs must be taken with food and swallowed with plenty of water. . All prophylactic drugs should be taken with unfailing regularity for the duration of the stay in the malaria risk area, and should be continued for 4 weeks after the last possible exposure to infection, since parasites may still emerge from the liver during this period. The single exception is atovaquone/ proguanil, which can be stopped 1 week after return. . Depending on the predominant type of malaria at the destination, travellers should be advised about possible late onset P. vivax and P. ovale. Depending on the malaria risk in the area visited (see Country list), the recommended malaria prevention method may be mosquito bite prevention only, or mosquito bite prevention in combination with chemoprophylaxis, as follows: INTERNATIONAL TRAVEL AND HEALTH 2005 Malaria risk Type of prevention Type I Very limited risk of malaria transmission Mosquito bite prevention only Type II Risk of P. vivax malaria or fully chloroquine-sensitive P. falciparum only Mosquito bite prevention plus chloroquine chemoprophylaxis Type III Risk of malaria transmission and emerging chloroquine resistance Mosquito bite prevention plus chloroquine+proguanil chemoprophylaxis Type IV High risk of falciparum malaria plus drug resistance, or moderate/low risk falciparum malaria but high drug resistance Mosquito bite prevention plus either mefloquine, doxycycline or atovaquone/proguanil (take one that no resistance is reported for in the specific areas to be visited) See Table 7.2 for details on individual drugs. All antimalarial drugs have specific contraindications and possible side-effects. Adverse reactions attributed to malaria chemoprophylaxis are common, but most are minor and do not affect the activities of the traveller. Serious adverse events— defined as constituting an apparent threat to life, requiring or prolonging hospitalization, or resulting in permanent disability or incapacity—are rare and normally only identified once a drug has been in use for some time. With mefloquine the incidence range of serious adverse events has been estimated at 1 per 6000 to 1 per 10 600 travellers, compared to 1 per 13 600 with chloroquine. For malaria prophylaxis with atovaquone/proguanil or doxycycline the risks of rare serious adverse events have not yet been established. The risk of drug- associated adverse events should be weighed against the risk of malaria, especially P. falciparum malaria, and local drug-resistance patterns. Each of the antimalarial drugs is contraindicated in certain groups and individuals, and the contraindications should be carefully considered (see Table 7.2) to reduce the risk of serious adverse reactions. People with chronic illnesses should seek individual medical advice. Any traveller who develops serious side-effects to an antimalarial should stop taking the drug and seek immediate medical attention. This applies particularly to neurological or psychological disturbances on mefloquine prophylaxis. Mild nausea, occasional vomiting or loose stools should not prompt discontinuation of prophylaxis, but medical advice should be sought if symptoms persist. CHAPTER 7. MALARIA Because of the risk of adverse side-effects, chemoprophylaxis should not be prescribed in the absence of malaria risk. It is important to note that malaria is not present in all tropical countries (see map and Country list). Long-term use of chemoprophylaxis The risk of serious side-effects associated with long-term prophylactic use of chloroquine and proguanil is low. However, anyone who has taken 300 mg of chloroquine weekly for over five years and requires further prophylaxis should be screened twice-yearly for early retinal changes. If daily doses of 100 mg chloroquine have been taken, screening should start after three years. Data indicate no increased risk of serious side-effects with long-term use of mefloquine if the drug is tolerated in the short-term. Experience with doxycycline for long- term chemoprophylaxis (i.e. more than 4–6 months) is limited, but available data are reassuring. Mefloquine and doxycycline should be reserved for those at greatest risk of chloroquine-resistant infections. Atovaquone/proguanil is registered in European countries with a restriction on duration of use (varying from 5 weeks to 3 months); in the USA no such restrictions apply. Stand-by emergency treatment An individual who experiences a fever 1 week or more after entering an area of malaria risk should consult a physician or qualified malaria laboratory immediately to obtain correct diagnosis and a safe and effective treatment. Many travellers will be able to obtain proper medical attention within 24 hours of the onset of fever. For others, however, this may be impossible, particularly if they will be staying (1 week or more after entering an endemic area) in a remote location. In such cases, travellers are advised to carry antimalarial drugs for self- administration (“stand-by emergency treatment”). The choice of drugs for standby emergency treatments in relation to the drugs used for prophylaxis is given in Table 7.1. The circumstances of stand-by emergency treatment (SBET) are different from treatment administered by competent medical personnel. SBET is taken by a traveller who (1) is sick in a remote location and cannot easily reach a hospital or qualified health professional, (2) may already be taking antimalarials for prophylaxis, and (3) may have to self-diagnose malaria based on non specific clinical symptoms such as fever. In these circumstances the safety and efficacy of drugs given for SBET are even more critical, and not all antimalarials that are normally used for treatment can be confidently prescribed. INTERNATIONAL TRAVEL AND HEALTH 2005 Stand-by emergency treatment may also be indicated for travellers in some occupational groups, such as aircraft crews, who make frequent short stops in endemic areas over a prolonged period of time. Such travellers may eventually choose to reserve chemoprophylaxis for high-risk areas only. However, they should continue to take rigorous measures for protection against mosquito bites and be prepared for an attack of malaria: they should always carry a course of antimalarial drugs for stand-by emergency treatment, seek immediate medical care in case of fever, and take stand-by emergency treatment if prompt medical help is not available. Stand-by emergency treatment—combined with rigorous protection against mosquito bites—may occasionally be indicated for those who travel for 1 week or more to remote rural areas where there is a very low likelihood of multidrugresistant malaria and the risk of side-effects of prophylaxis outweighs the risk of contracting malaria. This may be the case in certain border areas of Thailand and neighbouring countries in South-East Asia where the risk of side-effects may outweigh the risk of becoming infected. However, most travellers to these areas will be able to access competent medical care within 24 hours of the onset of fever. Studies on the use of rapid diagnostic tests (“dipsticks”) have shown that untrained travellers experience major problems in the performance and interpretation of these tests, with an unacceptably high number of false-negative results. In addition, dipsticks can be degraded by extremes of heat and humidity, becoming less sensitive. Major technical modifications are required before dipsticks can be recommended for use by travellers. Travellers’ behaviour is key for successful SBET, and the health advisor needs to spend time explaining the strategy. Travellers provided with stand-by emergency treatment should be given clear and precise written instructions on the recognition of symptoms, when and how to take the treatment, the treatment regimen, possible side-effects, and the possibility of drug failure. If several people travel together, the individual dosages for SBET should be specified. Travellers should be made aware that self-treatment is a first-aid measure, and that they should seek medical advice as soon as possible. In general, travellers carrying stand-by emergency treatment should observe the following guidelines: . Consult a physician immediately if fever occurs 1 week or more after entering an area with malaria risk. . If it is impossible to consult a physician and/or establish a diagnosis within 24 hours of the onset of fever, start the stand-by emergency treatment and CHAPTER 7. MALARIA seek medical care as soon as possible for complete evaluation and to exclude other serious causes of fever. . Complete the stand-by treatment course and resume antimalarial prophylaxis 1 week after the first treatment dose. Mefloquine prophylaxis, however, should be resumed 1 week after the last treatment dose of quinine. . Vomiting of antimalarial drugs is less likely if fever is first lowered with antipyretics. A second full dose should be taken if vomiting occurs within 30 minutes of taking the drug. If vomiting occurs 30–60 minutes after a dose, an additional half-dose should be taken. Vomiting with diarrhoea may lead to treatment failure because of poor drug absorption. . Do not treat suspected malaria with the same drugs used for prophylaxis, because of the increased risk of toxicity and resistance. Depending on the area visited and the chemoprophylaxis regimen taken, one of the following stand-by treatment regimens can be recommended: chloroquine, (P. vivax areas only), mefloquine, quinine, or quinine plus doxycycline. Artemether/lumefantrine has been registered in Switzerland for use as stand-by emergency treatment for travellers. Some national health authorities recommend atovaquone/proguanil as SBET for areas of multidrug resistance. See Table 7.3 for details on individual drugs. Halofantrine is contra-indicated for stand-by treatment following reports that it can result in ventricular dysrhythmias, prolongation of Q–T intervals and sudden death in susceptible individuals. These risks may be accentuated if halofantrine is taken with other antimalarial drugs that may reduce myocardial conduction. In light of the spread of counterfeit drugs in some resource-poor settings, travellers who may become sick while abroad may opt to buy a reserve antimalarial treatment before departure, so that they can be confident of drug efficacy and safety should they fall ill. Treatment of P. vivax, P. ovale and P. malariae infections P. vivax and P. ovale can remain quiescent in the liver for many months. Relapses caused by the persistent liver forms may appear months, and rarely up to 2 years, after exposure. They are not prevented by current chemoprophylactic regimens. Relapses can be treated with chloroquine (or mefloquine or quinine if resistance is suspected) and further relapses prevented by a course of primaquine, which eliminates any remaining parasites in the liver. In patients with known or INTERNATIONAL TRAVEL AND HEALTH 2005 suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency, expert medical advice should be sought since primaquine may cause haemolysis in G6PDdeficient patients. G6PD deficiency must be excluded before travellers receive antirelapse therapy with primaquine. Blood infection with P. malariae may be present for many years, but it is not life-threatening. It can be treated with chloroquine (or mefloquine or quinine if resistance is suspected). Special groups Some groups of travellers, especially young children and pregnant women, are at particular risk of serious consequences if they become infected with malaria. Pregnant women Malaria in a pregnant woman increases the risk of maternal death, miscarriage, stillbirth and low birth weight with associated risk of neonatal death. Pregnant women should be advised to avoid travelling to areas where malaria transmission occurs. When travel cannot be avoided, it is very important to take effective preventive measures against malaria, even when travelling to areas with transmission of vivax malaria only. Pregnant women should be extra diligent in using measures to protect against mosquito bites, but should take care not to exceed the recommended dosage of insect repellents. In “type II” areas with exclusively P. vivax transmission or where P. falciparum can be expected to be fully sensitive to chloroquine, prophylaxis with chloroquine alone may be used. In “type III” areas, prophylaxis with chloroquine plus proguanil can be safely prescribed, also during the first 3 months of pregnancy. In “type IV” areas, mefloquine prophylaxis may be given during the second and third trimester, but there is limited information on its safety during the first trimester. Doxycycline is contraindicated during pregnancy. Atovaquone/ proguanil has not been sufficiently investigated to be prescribed for chemoprophylaxis in pregnancy. Pregnant women should seek medical help immediately if malaria is suspected; if this is not possible, they should take emergency stand-by treatment with quinine. Medical help must be sought as soon as possible after stand-by treatment. Pregnant women with falciparum malaria may rapidly develop any of the clinical symptoms of severe malaria. They are particularly susceptible to hypoglycaemia and pulmonary oedema. They may develop postpartum haemorrhage, and CHAPTER 7. MALARIA hyperpyrexia leading to fetal distress. Any pregnant woman with severe falciparum malaria should be transferred to intensive care. Because of the risk of quinine-induced hyperinsulinaemia and hypoglycaemia, artesunate and artemether are the drugs of choice for treatment of severe malaria in the second and third trimester. Data on the use of artemisinin derivatives in the first trimester are still limited. However, neither quinine nor artemisinin derivatives should be withheld in any trimester if they are considered life saving for the mother. Information on the safety of drugs during breastfeeding is provided in Tables 7.2 and 7.3. Women who may become pregnant during or after travel Both mefloquine and doxycycline prophylaxis may be taken, but pregnancy should preferably be avoided during the period of drug intake and for 3 months after mefloquine and 1 week after doxycycline prophylaxis is stopped. If pregnancy occurs during antimalarial prophylaxis with mefloquine of doxycycline, this is not considered to be an indication for pregnancy termination. Due to its half-life of 2-3 days in adults, more than 99% of atovaquone will usually be eliminated from the body by 3 weeks after the last dose was taken. Young children Falciparum malaria in a young child is a medical emergency it may be rapidly fatal. Early symptoms are atypical and difficult to recognize, and life-threatening complications can occur within hours of the initial symptoms. Medical help should be sought immediately if a child develops a febrile illness within 3 months (or, rarely, later) of travelling to an endemic area. Laboratory confirmation of diagnosis should be requested immediately, and treatment with an effective antimalarial drug initiated as soon as possible. In infants, malaria should be suspected even in non-febrile illness. Parents should be advised not to take babies or young children to areas with transmission of chloroquine-resistant P. falciparum. If travel cannot be avoided, children must be very carefully protected against mosquito bites and be given appropriate chemoprophylactic drugs. Babies should be kept under insecticide- treated mosquito nets as much as possible between dusk and dawn. The manufacturer’s instructions on the use of insect repellents should be followed diligently, and the recommended dosage must not be exceeded. INTERNATIONAL TRAVEL AND HEALTH 2005 Breastfed, as well as bottle-fed, babies should be given chemoprophylaxis since they are not protected by the mother’s prophylaxis. Dosage schedules for children should be based on body weight. Chloroquine and proguanil are safe for babies and young children but only suitable for areas with low levels of chloroquine resistance. Mefloquine may be given to infants of more than 5 kg body weight. Atovaquone/proguanil can not be recommended for prophylaxis in children who weigh less than 11 kg, because of the lack of data. Doxycycline is contraindicated in children below 8 years of age. Information on the safety of drugs for treatment of young children is provided in Table 7.3. All antimalarial drugs should be kept out of the reach of children and stored in childproof containers. Chloroquine is particularly toxic in case of overdose. Special situations—multidrug-resistant malaria In border areas between Cambodia, Myanmar and Thailand, P. falciparum infections do not respond to treatment with chloroquine or sulfadoxine– pyrimethamine, and sensitivity to quinine is reduced. Treatment failures in excess of 50% with mefloquine are also being reported. In these situations, doxycycline or atovaquone/proguanil can be used for chemoprophylaxis together with rigorous personal protection measures. However, these drugs cannot be given to pregnant women and young children. Since there is no prophylactic regimen that is both effective and safe for these groups in areas of multidrug-resistant malaria, pregnant women and young children should avoid travelling to these malarious areas. Multidrug-resistant malaria has also been reported from Viet Nam and in the Amazon basin of South America, where it occurs in parts of Brazil, French Guiana and Suriname. CHAPTER 7. MALARIA Table 7.1 Choice of stand-by emergency treatment according to recommended chemoprophylactic regimen Note. A drug selected for stand-by emergency treatment should always be different from the drugs used for prophylaxis, and should be one to which no resistance has been reported in the countries to be visited (see Country list). Recommended prophylactic regimen Stand-by emergency treatment None Chloroquine, for P. vivax areas only Mefloquine Quinine Artemether and lumefantrinea Atovaquone/proguanila Chloroquine alone or with proguanil Mefloquine Quinine Mefloquine Quinineb Quinine + doxycycline or tetracycline for 7 daysb Doxycycline Mefloquine Quinine + tetracycline for 7 days Atovaquone/proguanil Quinine + doxycycline/tetracycline for 7 days a There is limited experience at present on drug interactions of artemether/lumefantrine and atovaquone/proguanil with other antimalarial drugs. Therefore, if the patient is already taking an antimalarial as prophylaxis, these drugs should only be used if no other antimalarial treatment option is available. b In these situations, mefloquine prophylaxis should only be resumed 7 days after the last self- treatment dose of quinine. INTERNATIONAL TRAVEL AND HEALTH 2005 Table 7.2 Use of antimalarial drugs for prophylaxis in travellers Use in special groups Generic Duration of Breast-Main name Dosage regimen prophylaxis Pregnancy feeding Children contraindicationsa Commentsa Atovaquone One dose daily. Start 1 day No data, No data, Not recom-Hypersensitivity to atova-Experience with this drug for prophylaxis –proguanil 11–20 kg: 62.5 mg before departure not recomnot recommended quone and/or proguanil; severe in non-immune travellers is still limited. combination atovaquone plus and continue mended mended under renal insufficiency (creatinine It is registered in European countries tablet 25 mg proguanil for 7 days after 11 kg clearance <30 ml/min). for chemoprophylactic use with a (1 paediatric tablet) daily return because restriction on duration of use (varying 21–30 kg: 2 paediatric of lack of from 5 weeks to 3 months) and in tablets daily data Canada with a restriction on 31–40 kg: 3 paediatric body weight (>40 kg). tablets daily In the USA the restrictions do not apply. >40 kg: 1 adult tablet Plasma concentrations of atovaquone (250 mg atovaquone plus are reduced when it is co-administered 100 mg proguanil) daily with rifampicin, rifabutin, metoclopramide or tetracycline. Choroquine 5 mg base/kg weekly in Start 1 week Safe Safe Safe Hypersensitivity to chloroquine; Concurrent use of chloroquine can one dose, or 10 mg base/kg before departure history of epilepsy; psoriasis. reduce the antibody response to weekly divided in 6 daily doses and continue for intradermally administered human Adult dose: 300 mg 4 weeks after diploid-cell rabies vaccine. chloroquine base weekly in return. one dose or If daily doses: 600 mg chloroquine start 1 day before base weekly divided departure. over 6 daily doses of 100 mg base (with one drug-free day per week) Chloroquine– >50 kg: 100 mg Start 1 day Safe Safe Tablet size Hypersensitivity to chloroquine Concurrent use of chloroquine can proguanil chloroquine base before departure not suitable and/or proguanil; liver or reduce the antibody response to combination plus 200 mg proguanil and continue for for persons kidney insufficiency; history of intradermally administered human tablet (1 tablet) daily 4 weeks after of < 50 kg epilepsy; psoriasis. diploid-cell rabies vaccine. return body weight Table 7.2 Use of antimalarial drugs for prophylaxis in travellers (continued) Generic name Dosage regimen Use in special groups Duration of Breast- prophylaxis Pregnancy feeding Children Main contraindicationsa Commentsa Doxycycline Mefloquine 1.5 mg salt/kg daily adult dose: 1 tablet of 100 mg daily 5 mg/kg weekly adult dose: 1 tablet of 250 mg weekly Start 1 day Contra-Contra-Contra-Hypersensitivity to tetra-Doxycycline makes the skin more before indicated indicated indicated cyclines; liver dysfunction. susceptible to sunburn. People with departure and under 8 sensitive skin should use a highly continue for years of protective (UVA) sunscreen and avoid 4 weeks after age prolonged direct sunlight, or switch to return. another drug. Doxycycline should be taken with plenty of water to prevent oesophageal irritation. Doxycycline may increase the risk of vaginal Candida infections. Studies indicate that the monohydrate form of the drug is better tolerated than the hyclate. Start at least Not recom-Safe Not recom-Hypersensitivity to mefloquine; Do not give mefloquine within 12 hours 1 week mended in mended psychiatric (including depresof quinine treatment. Mefloquine and (preferably 2–3 first triunder 5 kg sion) or convulsive disorders; other cardioactive drugs may be given weeks) before mester because history of severe neuropsychiaconcomitantly only under close medical departure and because of of lack of tric disease; concomitant supervision. Ampicillin, tetracycline continue for lack of data data halofantrine treatment; treat-and metoclopramide can increase 4 weeks after ment with mefloquine in mefloquine blood levels. Vaccination return previous 4 weeks; not recomwith live bacterial vaccines (e.g. oral live mended in view of limited data typhoid vaccine, cholera vaccine) should for people performing activities be completed at least 3 days before the requiring fine coordination first prophylactic dose of mefloquine. and spatial discrimination, e.g. pilots, machine operators. Proguanil 3 mg/kg daily adult dose: 2 tablets of 100 mg daily Start 1 day Safe Safe Safe Liver or kidney dysfunction. Use only in combination with before departure chloroquine. Proguanil can interfere with and continue for live typhoid vaccine. 4 weeks after return CHAPTER 7. MALARIA 145 aPlease see package insert for full information on contra-indications and precautions. INTERNATIONAL TRAVEL AND HEALTH 2005 Table 7.3 Use of antimalarial drugs for treatment of uncomplicated malaria in travellers Use in special groups Generic Breast-Main name Dosage regimen Pregnancy feeding Children contraindicationsa Commentsa Amodiaquine 30 mg base/kg taken as 10 mg Apparently Apparently Safe Hypersensitivity to amodiaquine; Use only for malaria caused by P. vivax, base/kg for 3 days safe but safe but hepatic disorders. P. ovale or P. malariae, or for fully limited data limited data chloroquine-sensitive P. falciparum. Artemether/ 3-day course of 6 doses total, taken at No data, not No data, not Not recom-Hypersensitivity to artemether Better absorbed if taken with fatty foods lumefantrine 0, 8, 24, 36, 48, and 60 hours recommen-recommen-mended and/or lumefantrine. combination 5–14 kg: 1 tablet (20 mg artemether ded ded under 5 kg tablet plus 120 mg lumefantrine) per dose because of 15–24 kg: 2 tablets per dose lack of data 25–34 kg: 3 tablets per dose 35 kg and over: 4 tablets per dose Artemisinin Artemisinin: 10 mg/kg daily for 7 days Not recom-Safe Safe Hypersensitivity to artemisinins. Normally taken in combination with and Artemisinin derivatives: 2 mg/kg daily mended in another effective antimalarial, which derivatives for 7 days first trimester reduces the duration of treatment to Artemisinin and its derivatives are given because of 3 days. As monotherapy these drugs with a double divided dose on the first lack of should be taken for a minimum of 7 days, day data to prevent recrudescences. Atovaquone/ One dose daily for three consecutive No data, not No data, not Apparently Hypersensitivity to atovaquone Plasma concentrations of atovaquone proguanil days recommen-recommen-safe in and/or proguanil; severe renal are reduced when the drug is cocombination 5–8 kg: 2 pediatric tablets daily ded ded children insufficiency (creatinine administered with rifampicin, rifabutin, tablet (at 62.5 mg atovaquone plus 25 mg > 5 kg, but clearance < 30 ml/min). metoclopramide or tetracycline. proguanil per tablet) limited data 9–10 kg: 3 pediatric tablets daily 11–20 kg: 1 adult tablet (250 mg atovaquone plus 100 mg proguanil) daily 21–30 kg: 2 adult tablets daily 31–40 kg: 3 adult tablets daily >40 kg: 4 adult tablets (1 g atovaquone plus 400 mg proguanil) daily Table 7.3 Use of antimalarial drugs for treatment of uncomplicated malaria in travellers (continued) Use in special groups Generic Breast-Main name Dosage regimen Pregnancy feeding Children contraindicationsa Commentsa Choroquine 25 mg base/kg divided in daily dose Safe Safe Safe Hypersensitivity to chloroquine; Concurrent use of chloroquine can (10, 10, 5 mg base/kg) history of epilepsy; psoriasis. reduce the antibody response to for 3 days. intradermally administered human diploid-cell rabies vaccine. Use only for malaria caused by P. vivax, P. ovale, P. malariae, or fully sensitive P. falciparum. Clindamycin Under 60 kg: 5 mg base/kg 4 times Apparently Apparently Apparently Hypersensitivity to clindamycin Used in combination with quinine in daily for 5 days safe but safe but safe but or lincomycin; history of gastro-areas of emerging quinine resistance. 60 kg and over: 300 mg base 4 times limited data limited data limited data intestinal disease, particularly daily for 5 days colitis; severe liver or kidney impairment. Doxycycline Adults > 50 kg: 800 mg salt over 7 days, Contra-Contra-Contra-Hypersensitivity to tetracyclines; Used in combination with quinine in taken as 2 tablets (100 mg salt each) indicated indicated indicated liver dysfunction. areas of emerging quinine resistance. 12 hours apart on day 1, followed by under 8 years 1 tablet daily for 6 days of age Children 8 years and older: 25–35 kg: 0.5 tablet per dose 36–50 kg: 0.75 tablet per dose > 50 kg: 1 tablet per dose (Halofantrine) 8 mg base/kg in 3 doses at 6-hour No data, not No data, not Not recom-Allergy to halofantrine; pre-Risk of fatal cardiotoxicity. intervals. Repeat full course after recommen-recommen-mended existing cardiac disease; family To be used only in well-equipped 1 week ded ded under 10 kg history of sudden death or medical facilities under close because of congenital prolongation of the medical supervision, if no other lack of data QTc interval; use of other drugs treatment options are available. or presence of a clinical condition known to prolong the QTc interval; treatment with mefloquine in the previous 3 weeks. CHAPTER 7. MALARIA 147 aPlease see package insert for full information on contra-indications and precautions. INTERNATIONAL TRAVEL AND HEALTH 2005 Table 7.3 Use of antimalarial drugs for treatment of uncomplicated malaria in travellers (continued) Use in special groups Generic name Dosage regimen Pregnancy Breast- feeding Children Main contraindicationsa Commentsa Mefloquine 25 mg base/kg as split dose (15 mg/kg plus 10 mg/kg 6–24 hours apart) Not recom-Safe mended in first trimester because of lack of data Not recommended under 5 kg because of lack of data Hypersensitivity to mefloquine; psychiatric (including depression) or convulsive disorders; history of severe neuropsychiatric disease; concomitant halofantrine treatment; treatment with mefloquine in previous 4 weeks; use with caution in people whose activities require fine coordination and spatial discrimination, e.g. pilots and machine operators. Do not give mefloquine within 12 hours of last dose of quinine treatment. Mefloquine and other related compounds (such as quinine, quinidine, chloroquine) may be given concomitantly only under close medical supervision because of possible additive cardiac toxicity and increased risk of convulsions; co-administration of mefloquine with anti-arrhythmic agents, beta-adrenergic blocking agents, calcium channel blockers, antihistamines including H1-blocking agents, and phenothiazines may contribute to prolongation of QTc interval. Ampicillin, tetracycline and metoclopramide can increase mefloquine blood levels. Primaquine Infections acquired south of the equator: 0.5 mg base/kg for 14 days; Infections acquired north of the equator: 0.25 mg base/kg for 14 days Contraindicated Safe ContraG6PD deficiency; active Anti-relapse treatment of P. vivax and indicated rheumatoid arthritis; lupus P. ovale infections. under 4 years erythematosus; conditions that of age predispose to granulocytopenia; concomitant use of drugs that may induce haematological disorders. aPlease see package insert for full information on contra-indications and precautions. Table 7.3 Use of antimalarial drugs for treatment of uncomplicated malaria in travellers (continued) Use in special groups Generic Breast- name Dosage regimen Pregnancy feeding Children Main contraindicationsa Commentsa Quinine 8 mg base/kg 3 times daily for 7 days Safe Safe Safe Hypersensitivity to quinine or In areas of high-level resistance to quinidine; tinnitus; optic neuritis; quinine: give in combination with haemolysis; myasthenia gravis. doxycycline, tetracycline or clindamycin. Use with caution in persons with Quinine may induce hypoglycaemia, G6PD deficiency, and in particularly in (malnourished) children, patients with atrial fibrillation, pregnant women and patients with cardiac conduction defects, or severe disease. heart block. Quinine may enhance effect of cardiosuppressant drugs. Use with caution in persons using beta blockers, digoxin, calcium channel blockers, etc. Sulfadoxine– 5–60 kg: single dose calculated as pyrimethamine 25 mg/kg of the sulfa component combination 60 kg and over: single dose of tablet 3 tablets (1500 mg sulfadoxine plus 75 mg pyrimethamine) Safe Safe Safe Hypersensitivity to sulfa drugs Cutaneous drug reactions more or pyrimethamine; severe liver common in people infected with HIV. or kidney dysfunction; megalo-Widespread resistance occurs. blastic anaemia; concomitant use of other sulfa drugs or folate antagonists. Tetracycline 25–49 kg: 5 mg salt/kg 4 times daily for 7 days 50 kg and over: 250 mg salt (1 tablet) 4 times daily for 7 days Contraindicated Contraindicated Contraindicated under 8 years of age Hypersensitivity to tetracyclines; Used in combination with quinine in liver or kidney dysfunction; areas of emerging quinine resistance. systemic lupus erythematosus. aPlease see package insert for full information on contra-indications and precautions. CHAPTER 7. MALARIA INTERNATIONAL TRAVEL AND HEALTH 2005 Countries and territories with malarious areas The following list shows all countries where malaria occurs. In some of these countries, malaria is present only in certain areas or up to a particular altitude. In many countries, malaria has a seasonal pattern. These details are provided in the Country list, together with information on the predominant malaria species, status of resistance to antimalarial drugs and recommended chemoprophylactic regimen. (* = P. vivax risk only) Afghanistan Algeria* Angola Argentina* Armenia* Azerbaijan* Bangladesh Belize Benin Bhutan Bolivia Botswana Brazil Burkina Faso Burundi Cambodia Cameroon Cape Verde Central African Republic Chad China Colombia Comoros Congo Congo, Democratic Republic of the (former Zaire) Costa Rica Côte d’Ivoire Djibouti Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Ethiopia French Guiana Gabon Gambia Georgia* Ghana Guatemala Guinea Guinea-Bissau Guyana Haiti Honduras India Indonesia Iran, Islamic Republic of Iraq* Kenya Korea, Democratic People’s Republic of* Korea, Republic of* Kyrgyzstan Lao People’s Democratic Republic Liberia Madagascar Malawi Malaysia Mali Mauritania Mauritius* Mayotte Mexico Morocco* Mozambique Myanmar Namibia Nepal Nicaragua Niger Nigeria Oman Pakistan Panama Papua New Guinea Paraguay Peru Philippines Rwanda Sao Tome and Principe Saudi Arabia Senegal Sierra Leone Solomon Islands Somalia South Africa Sri Lanka Sudan Suriname Swaziland Syrian Arab Republic* Tajikistan Tanzania, United Republic of Thailand Timor-Leste Togo Turkey* Turkmenistan* Uganda Uzbekistan Vanuatu Venezuela Viet Nam Yemen Zambia Zimbabwe CHAPTER 7. MALARIA Further reading WHO Roll Back malaria Department website at http://mosquito.who.int/malariacontrol Management of severe malaria: a practical handbook, 2nd ed. Geneva, WHO, 2000. ISBN: 92 4 154523 2. The use of antimalarial drugs, report of an informal consultation, WHO/CDS/RBM/ 2001.33. WHO Expert Committee on Malaria. Twentieth report. WHO, Geneva, 2000 (WHO Technical Report Series, No. 892).