Fortnightly Review: Malaria prophylaxis: guidelines for travellers from BritainBMJ 1995; 310 doi: http://dx.doi.org/10.1136/bmj.310.6981.709 (Published 18 March 1995) Cite this as: BMJ 1995;310:709
- David J Bradley, codirectora,
- David C Warhurst, codirectora a meeting convened by the Malaria Reference Laboratory
- a Malaria Reference Laboratory of the Public Health Laboratory Service, London School of Hygiene and Tropical Medicine, London WC1E 7HT
- This report was prepared by Professor Bradley and Dr Warhurst on behalf of the committee listed in the appendix. Correspondence to: Professor Bradley.
Travellers to malarious areas must avoid mosquito bites, take chemoprophylaxis, and urgently seek early diagnosis and treatment for febrile illness
The key to preventing malaria is avoiding infective mosquito bites by using repellents, covering up at night, and sleeping with bednets if mosquitos cannot be excluded from the room
Appropriate chemoprophylaxis is essential when travelling to endemic areas—drug resistance is increasing in many areas so recommended regimens have changed
Doses and choice of drug may have to be altered in those with concomitant illness
Standby treatment may be given to those who will be unable to reach medical services for extended periods
No prophylaxis is infallible so all fever and flu-like illnesses occurring within a year of returning from malarious regions need to be urgently investigated with malaria in mind
Malaria prophylaxis for travellers has to reflect changes in malaria epidemiology, travel habits, and drug resistance of the parasites. A detailed discussion was published in May 1993 with recommendations.1 Subsequent experience was reviewed at a meeting of British malaria specialists in 1994, and simpler, more prescriptive advice was agreed. This report discusses changes and new issues arising since 1993 and sets out revised recommendations. It should be read together with the previous report for a full understanding of many issues that are not repeated here. Moreover, doctors should beware of simply using the tables of regimens without reading the text of the two reports as background.
Changing issues in malaria prevention
Drug resistance of Plasmodium falciparum to chloroquine has increased in both intensity and geographical distribution over the past year. Almost all countries of sub-Saharan Africa now have chloroquine resistant malaria, and it has become a big problem in West Africa as well as East and Central Africa. There are some reports of chloroquine resistant P vivax in Oceania. Resistance to the newer antimalarial, mefloquine, is now a problem in parts of Cambodia, Thailand, and Myanmar.
Confidence in mefloquine has increased. Although neuropsychiatric side effects have continued to trouble some patients, they have not prevented its widespread use for travellers to East Africa, and the committee considered it appropriate for high malaria risk areas throughout sub-Saharan Africa. American travellers taking mefloquine long term have not encountered additional side effects and it seems safe for over a year's continuous use. The data sheet is being changed to reflect this. It also seems safe in the second and third trimesters of pregnancy.
Further experience with halofantrine, previously recommended as a standby drug, has shown adverse effects on the heart. Consequently, the committee no longer recommends its use as a standby drug for travellers.
In areas of mefloquine resistant falciparum malaria and for travellers at high risk of chloroquine resistant falciparum malaria who are unable to take mefloquine, doxycycline has been used effectively and is now recommended by the committee for use in these special circumstances. Some guidelines are given for travellers with concomitant diseases.
Four general issues have become clearer. Firstly, bednets impregnated with pyrethroid insecticides give substantial protection for those sleeping outside screened accommodation. Secondly, more severe malaria results from non-compliance with the recommended regimen than from taking the wrong drug. Thirdly, tragedies continue to occur because travellers and their doctors forget that protection is not 100%. Even when all precautions are taken there is still an appreciable risk of malaria. Lastly, there is concern about overprescription of standby drugs. These are intended for travellers who will be far from medical advice during their journeys or in places where access to effective chemotherapy for malaria may be difficult. They are a first aid measure for such people not an alternative to proper medical care.
Principles of prevention
Four principles of malaria prevention should receive attention from both travellers and their advisers.
BE AWARE OF RISK
All travellers to malarious areas must be aware of the malaria risk, act to reduce the risk, and urgently seek medical advice if they get a fever.
AVOID BEING BITTEN BY MOSQUTTOES
Sleep in properly screened rooms and spray the room with a knockdown insecticide before evening to kill any mosquitoes that may have entered the room during the day
When sleeping elsewhere use mosquito nets around the bed at night, checking that there are no holes in the net. The net should be impregnated with pyrethroids—for example, permethrin, 0.2 g/ m2 of material every six months—and the net should be long enough to fall to the floor all round the bed or be tucked under the mattress
An electric mat should be used to vaporise synthetic pyrethroids overnight or mosquito coils may be burned. Electronic buzzers, which are sometimes marketed as repellents, are not effective
Long sleeved clothing and long trousers should be worn if out of doors after sunset
Preparations containing diethyltoluamide repel mosquitoes effectively and may be applied to exposed skin. Do not exceed the manufacturer's recommendations, particularly with small children. Impregnating cotton garments with 30 ml of diethyltoluamide in 250 ml water makes it repellent. Refined lemon eucalyptus oil is also repellent on skin.
TAKE CHEMOPROPHYLAXIS WHERE APPROPRIATE
This is the most complex aspect of malaria prevention for travellers, with different recommendations for particular countries. Four principles apply to all chemoprophylaxis:
Compliance is essential; most deaths are in those who do not comply fully
Continue to take chemoprophylaxis for four weeks after returning to Britain. Most infections will be prevented by four weeks of continued prophylaxis after leaving malarious areas
Start chemoprophylaxis one week before departure for the malarious area, because it will get the traveller into the habit of taking antimalarial drugs, may show toxicity in those for whom the drug is unsuitable, and may facilitate a desirable rise in the blood concentrations of some antimalarials. Some favour giving mefloquine for two weeks before departure since most substantial side effects will occur in Britain and alternatives can be considered
Take antimalarials after meals to minimise minor side effects.
SEEK EARLY DIAGNOSIS AND TREATMENT
Medical advice should be sought promptly for any febrile or flu-like illness occurring within a year, and especially within three months, of returning from an endemic area even if all recommended precautions have been taken.
Key drugs for chemoprophylaxis
The usual regimens for chemoprophylaxis for adults and children are given in tables I and II.
PROGUANIL AND CHLOROQUINE
Either of these two drugs gives good protection in areas without chloroquine resistant malaria parasites. The standard prophylaxis is 300 mg chloroquine (base) weekly. In areas of limited to moderate chloroquine resistant P falciparum this dose is combined with 200 mg proguanil daily to provide substantial protection, though less than that provided by mefloquine. Serious side effects are rare (and deaths almost unknown), but minor ones include mouth ulcers, gastrointestinal upsets, occasional skin eruptions, and worsening of psoriasis. There are fewer neuropsychiatric side effects than with mefloquine. The theoretical problem of retinal toxicity from chloroquine when the total dose exceeds 100 g (this amounts to over six years of continuous prophylaxis) is based on high daily doses for treating other diseases and is highly unlikely at antimalarial doses. Efficacy is limited in sub-Saharan Africa and low in South East Asia. Chloroquine is universally available locally in malarious areas but may be of poor quality in some places. Proguanil is not registered everywhere and has limited availability in some tropical areas. Proguanil may affect the dose of anticoagulants needed for those on long term treatment, and it is best to restabilise the anticoagulant dose in the presence of proguanil before going abroad. Both drugs are safe in pregnancy, but the doses need to be reduced in renal failure, or an alternative used. Chloroquine is not appropriate for those with a history of epilepsy when proguanil alone may be used as an alternative to chloroquine alone.
Experience suggests this is the preferred antimalarial for those at high risk of highly chloroquine resistant falciparum malaria who are not in the first trimester of pregnancy, not liable to become pregnant within three months of stopping mefloquine, and not lactating. One 250 mg tablet a week is required as mefloquine is excreted slowly. It gives greater protection than other regimens in sub-Saharan Africa. Until recently the drug has been recommended only for visits of under three months, but there is now sufficient evidence to recommend use for up to a year. Cumulative evidence from those inadvertently given mefloquine during pregnancy has not confirmed initial fears about its effects, and mefloquine may be given during the second and third trimesters with confidence though it is not recommended for the first trimester and, as the drug is excreted slowly, pregnancy is best avoided for three months after stopping prophylactic mefloquine. However, inadvertent pregnancy under these circumstances is not considered an indication for termination of pregnancy.
The main problems with mefloquine have been neuropsychiatric side effects. These may include anxiety, depression, sleep disturbances, nightmares, hallucinations, and, in a few people, overt psychotic attacks or convulsions. They usually occur early in the use of the drug, 70% from the first three doses. The frequency of neuropsychiatric effects is unclear. In a survey severe effects occurred in 0.01%, but British experience points to a greater frequency, though not high enough to interfere with recommending mefloquine for areas with a high risk of highly chloroquine resistant falciparum malaria. It should not be given to those with a history of convulsions, epilepsy in first degree relatives, or serious psychiatric disorder. Concern has been expressed that mefloquine may impair precision movements. Mefloquine is unsuitable for those with liver impairment.
Doxycycline is becoming useful for prophylaxis in areas of mefloquine resistant falciparum malaria in South East Asia and as a second line drug for those visiting high risk areas but unable to take chloroquine or mefloquine. It has been used with considerable success by United Nations forces in Cambodia. It is unsuitable for children and during pregnancy and lactation and it is expensive. Among side effects, photosensitisation is uncommon but sometimes severe and prolonged. Excessive exposure to sun should be avoided. The drug may provoke diarrhoea, although it provides some protection against the bacterial causes of traveller's diarrhoea. Doxycycline must be taken after meals and with copious quantities of fluid to avoid oesophagitis. Avoid lying down immediately after taking the drug. Use for more than about three months is to be avoided. Use of doxycycline for malaria prophylaxis is not yet on the data sheet.
This fixed dosage combination of pyrimethamine (12.5 mg) and dapsone (100 mg) has provided considerable protection against chloroquine resistant falciparum malaria in the western Pacific and Papua New Guinea, where it has been used at a dose of one tablet weekly together with chloroquine 300 mg base weekly. It has now been superseded by mefloquine but remains a second line drug for Oceania and elsewhere when other drugs are not usable. The therapeutic ratio is low, and the adult dose must not exceed one tablet weekly because of the risk of agranulocytosis.
OTHER ANTIMALARIAL DRUGS
The following drugs are no longer recommended in chemoprophylaxis of malaria: pyrimethamine alone, because resistance to it is so widespread; amodiaquine because of the high risk of agranulocytosis; and pyrimethamine-sulfadoxine (Fansidar) because of the risk of severe and sometimes fatal Stevens-Johnson syndrome or toxic epidermal necrolysis. The last two drugs may have a role in treatment and Fansidar is useful for standby treatment.
Travellers who will be unable to get to medical advice within 24 hours of becoming ill may be provided with a standby course of antimalarials for self treatment (and similar provision may help those with access to advice where suitable drugs are unavailable). Criteria for providing standby drugs should be quite restrictive, and clear instructions for their use should be provided in writing. These drugs are not needed for those overseas for less than a week.
Standby drugs for areas without chloroquine resistance are chloroquine if no prophylaxis is being taken and Fansidar for those taking chloroquine prophylaxis. In areas with chloroquine resistance, Fansidar, mefloquine, or quinine (alone or with another drug) is appropriate. Halofantrine, which seemed a promising and convenient standby drug, has been found to lengthen the QT interval, especially in those taking prophylactic mefloquine. Sudden deaths have occurred, and it is no longer appropriate for standby treatment.
Table III details the recommended standby regimens. Quinine alone can be used for seven days but few will persevere with quinine for the full course because of increasing side effects. There is a significant risk of neuropsychiatric side effects with a therapeutic dose of mefloquine, but the hazards of untreated malaria are greater. Pregnant women should avoid situations where standby treatment may be needed; the only appropriate drug in necessity is quinine. Those who use standby treatment should subsequently seek medical advice. In areas with multidrug resistance where mefloquine or doxycycline is being used for prophylaxis, quinine with tetracycline or with Fansidar is appropriate. Smaller doses of quinine have been suggested as more appropriate after mefloquine, but malaria breakthrough in those taking mefloquine poses the greater risk. In areas of low risk but malaria highly resistant to chloroquine and other drugs, where no chemoprophylactic drug is being taken, quinine plus tetracycline, or mefloquine alone, would be the most suitable standby treatment.
Malaria prophylaxis in those with concomitant illnesses
Other illnesses or the drugs they require can affect the appropriate antimalarial precautions. Many need specialist advice, but epilepsy and renal failure are two common problems.
Epilepsy—Both mefloquine and chloroquine are unsuitable. For malarious areas without chloroquine resistance, proguanil alone (200 mg daily) is recommended. For areas with a high risk of chloroquine resistant malaria, such as sub-Saharan Africa, doxycycline should be considered despite its side effects. However, there is evidence that phenytoin, carba-mazepine, and barbiturates shorten the half life of doxycycline, so in theory the dose should be increased for patients taking these drugs. There is, however, little experience with an increased dose against malaria. Maloprim is an alternative.
Renal failure—Chloroquine and proguanil are excreted by the kidney and their prophylactic use is liable to be affected by renal failure. Two approaches are possible, to reduce the dose of proguanil (table IV) or to use an alternative drug. In areas of high risk of chloroquine resistant malaria mefloquine or doxycycline may be used since they are largely metabolised and excreted through the liver. The dose is unchanged even when patients are on dialysis.
Splenectomy—Travellers who are asplenic are at particular risk of severe malaria and need to take meticulous precautions against contracting the disease. This involves careful use of antimosquito measures, strict compliance with appropriate chemoprophylaxis, and avoiding unnecessary visits to malarious areas.
Pregnancy—Pregnant women are at particular risk of severe malaria and should avoid visiting endemic areas if feasible. Chloroquine and proguanil have a long history of safe use during pregnancy and mefloquine can also be used in the second and third trimesters.
Recommendations by area
Advice is given by continent in the tables. One main recommendation is usually given for each place (for each country whenever possible), but an alternative is given for those who are unable or unwilling to follow the recommended regimen. Measures to avoid mosquito bites are always applicable. If transmission is seasonal or local the months or places with risk are indicated. Space does not permit details of localised transmission in each country. Those visiting parts of a country where transmission is patchy and who will be off the tourist routes should visit a travel clinic or consult the Malaria Reference Laboratory giving their precise itinerary.
NORTH AFRICA AND THE MIDDLE EAST (TABLE V)
Malaria risk is very low in the areas most visited by tourists and advice for many areas is to avoid mosquito bites and remember the remote possibility of malaria in the event of fever within a year of returning to Britain. This applies to all North Africa (except for the El Faiyum area of Egypt south west of Cairo) and to Turkish tourist areas as far east as Antalya. Eastwards along the coast from Antalya to the Syrian border and inland in south east Turkey, and in parts of Syria and Iraq, chloroquine prophylaxis is recommended against vivax malaria. In Oman, some emirates, Yemen, Iran, and Afghanistan, falciparum malaria occurs and is often resistant to chloroquine.
SUB-SAHARAN AFRICA (TABLE VI)
All travellers to this area should have adequate protection against biting mosquitoes and chemoprophylaxis as the risk is high, except in the extreme south, and chloroquine resistant P falciparum common. Deaths from malaria in British travellers are usually from malaria contracted in Africa, especially Kenya. Breakthroughs occur on all regimens so it is essential to investigate all fevers and flu-like illnesses occurring within a year of visiting Africa as a matter of emergency. Mefloquine is now recommended for most of sub-Saharan Africa but proguanil plus chloroquine also gives substantial protection and is an alternative (especially for those at risk of or in early pregnancy). In the infected areas of South Africa, Namibia, and Botswana proguanil plus chloroquine is recommended. Some highland areas of Ethiopia and Kenya are malaria free, as is central Nairobi, but the surroundings are malarious.
SOUTH ASIA (TABLE VII)
Visitors to all parts of the Indian subcontinent, except for the high mountains, are at risk of malaria, both in rural areas and some cities. P vivax predominates, but falciparum malaria is also present and often resistant to chloroquine; mixed infections occur. Immigrants to Britain and their families are at special risk when revisiting friends and relations in Asia as many left during the malaria eradication campaigns and may be unaware that the areas are now malarious. Measures against mosquito bites protect against malaria and other mosquito borne diseases, and the appropriate chemoprophylaxis is proguanil plus chloroquine.
SOUTH EAST ASIA (TABLE VIII)
Malaria transmission varies greatly, with low risk in many areas, but multidrug resistant falciparum malaria predominates and transmission is intense in some hilly forested areas along international borders. Mefloquine resistance is prevalent on the Thai-Cambodian and Thai-Burmese borders. For many areas no chemoprophylaxis is necessary, but travellers should take measures to avoid being bitten by mosquitoes, particularly at night, and if in remote areas should carry standby treatment. The major cities of the region and the tourist sites in Thailand such as Bangkok, Pattaya, Phuket, and Chiangmai are malaria free but some of the places of interest in northern Thailand are forested, with some risk. Those backpacking should use impregnated bednets, repellents, and mefloquine. Other tourists need not take prophylaxis but should seek immediate medical advice in the event of a fever. Adults visiting areas of highly mefloquine resistant transmission in Thailand, Cambodia, and neighbouring countries should use doxycycline prophylaxis.
OCEANIA (TABLE IX)
In Papua New Guinea, Solomon Islands, and Vanuatu transmission of chloroquine resistant falciparum malaria is intense. There are some reports of chloroquine resistant vivax malaria. Mefloquine is now the recommended regimen, with Maloprim plus chloroquine as an alternative for those unable to take mefloquine.
LATIN AMERICA AND CARIBBEAN (TABLE X)
A high risk of highly chloroquine resistant malaria exists in the basin of the river Amazon, chiefly the area of Brazil comprising the “legal Amazon” (the Amazon region, Mato Grosso, and Maranhao) but also affecting adjacent countries to the north and west. Mefloquine is the most suitable antimalarial for the Amazon valley and other malarious areas of Colombia.
Other South American countries have patchy transmission with a predominance of P vivax but some chloroquine resistant falciparum malaria. Central America, where vivax also predominates, is free of chloroquine resistance. There is no malaria risk in most of the Caribbean islands, but the island that includes Haiti and the Dominican Republic has predominantly falciparum malaria sensitive to chloroquine. The risk is substantial in Haiti and, although much lower in the Dominican Republic, the chloroquine regimen should be followed.
Surveillance and further advice
Doctors diagnosing malaria must report all cases of imported malaria to the Malaria Reference Laboratory and also report adverse effects of antimalarials to the Committee on Safety of Medicines, as these reports provide part of the basis for sound recommendations.
Advice on malaria prevention for travellers may be obtained from the Malaria Reference Laboratory and other centres listed in the BNF. Doctors and practice nurses requiring more detailed advice than is given in this paper, for specific problems, may ring 0171 927 2437. Travellers can obtain advice from the helpline 0891 600350 (calls are charged at 49p per minute, standard rate and at 39p per minute cheap rate).
Contributors to the recommendations were P Barrett, R Behrens, M Blaze, C J Box, A Breckenridge, A Bryceson, N Byrne, L Calvert, B Carroll, P Chiodini, P Clarke, C Conlon, C Dow, J Dunlop, C Ellis, C Facer, H Gilles, A Geddes, P Golightly, A Green, M Janosi, F Jones, G Lea, J Leese, K McAdam, B Mandal, A Miller, M Molyneux, G Pasvol, W Peters, T Peto, P Phillips-Howard, V Smith, B Southgate, J Stewart, G Targett, E Walker, D Warrell, W Weir, J Whitworth, G Wyatt, M J World.