Malaria: an update on treatment of adults in non-endemic countries

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Abstract
Treating uncomplicated falciparum malaria The key is to give an effective antimalarial at an appropriate dose and ensure that patients complete the course. Several oral drugs have good activity against falciparum malaria, but drug resistance means that drug combinations are always preferable. Most trials of antimalarials have been conducted in endemic countries where there is at least some immunity to malaria, and this means they may overestimate the efficacy of these drugs in non-immune patients (because patients with immunity tend to clear parasites more readily). There are a few systematic reviews of antimalarials, but most are for drugs that are not appropriate for use in Western countries in non-immune people (such as amodiaquine). Systematic reviews, and in particular meta-analyses, are of limited use for assessing the efficacy of drugs such as antimalarials, for which resistance patterns vary widely both in place and time. The Health Protection Agency Advisory Committee on Malaria Prevention for UK Travellers has reviewed the recent data and considers that the best options for treating uncomplicated malaria are: Quinine, either for five days or until the parasites have been cleared from the blood, followed by Doxycycline for seven days or Clindamycin for seven days or Sulfadoxine-pyrimethamine (Fansidar) Artemether-lumefantrine for three days (six dose regimen) Atovaquone-proguanil for three days. Clinical failures can occur with any of these combinations, but failure rates are low if the course is completed. The agency's advice is frequently updated and can be accessed at www.hpa.org.uk/infections/topics_az/malaria/guidelines.htm Special cases In patients from South East Asia there is evidence of partial quinine resistance, and the non-quinine combinations may be preferable. Summary points Malaria is common: you should assume that patients who are unwell on returning from tropical areas, especially Africa, have malaria until proved otherwise. They do not have to have a fever, although most will have history of fever The severity of falciparum malaria is easily underestimated: patients can deteriorate rapidly despite treatment. You should admit patients to hospital for initial treatment. Patients with non-falciparum malaria seldom need admission For patients with a mild or moderate attack of falciparum malaria, consider oral quinine (followed by a second drug), atovaquone-proguanil, or artemether-lumefantrine. The choice of drug may depend on where they have visited; rates of drug resistance vary from country to country For a patient with severe or potentially complicated disease, you should use parenteral quinine or artesunate. You should give a loading dose for quinine In pregnant women quinine is advised because its side effect profile in pregnancy is known: it is generally safe, although it increases the risk of hypoglycaemia and may induce labour. Doxycycline is contraindicated in pregnancy. There are insufficient data on atovaquone-proguanil to advise its use in pregnancy. There are concerns about using artemether in early pregnancy, and it should be avoided in the first trimester unless there is a clear reason (such as drug resistance) to recommend it until more data are available. Quinine followed by a second drug This is the standard treatment against which other combinations are assessed in the UK. Resistance to sulfadoxine-pyrimethamine monotherapy is now high outside west Africa. Side effects Quinine—Nausea, mild deafness, and mild tinnitus (cinchonism) occur almost invariably in patients taking quinine. These are reversible when the patient stops taking the drug. Quinine can induce arrhythmias in people with a pre-existing cardiac condition, although this does not often happen at the doses used in oral treatment. Sulfadoxine-pyrimethamine—In common with other sulphur containing drugs, this can cause skin rashes, and rare cases of Stevens-Johnson syndrome have been reported. Doxycycline—This can cause gastritis, photosensitivity, and all the problems associated with broad spectrum antibiotics. Clindamycin—Possible increased risk of colitis from Clostridium difficile. Evidence Quinine became established as the standard treatment for falciparum malaria before the development of modern trial methods. No placebo controlled studies were performed, and none would now be ethical. Many studies have compared new treatments against quinine, and its continuing effectiveness in Africa has been repeatedly shown. There is reasonable evidence quinine has become less effective in South East Asia. Dose Quinine—600 mg (in adults) three times a day for five days, or until parasites have cleared from the peripheral blood, followed by Sulfadoxine-pyrimethamine three tablets once only or Doxycycline 100 mg daily for seven days or Clindamycin 450 mg every eight hours for seven days. Atovaquone-proguanil (Malarone) This probably has a slightly higher failure rate than quinine combinations, but it is reported to be slightly better tolerated. Evidence for both these statements is weak, with few properly powered comparisons with other effective drug regimens in non-immune adults. Currently, no part of the world has specific problems with atovaquone-proguanil resistance. However, if patients have been taking it as prophylaxis, atovaquone-proguanil is not the best choice for treatment because of the risk that the malaria parasite will be resistant. Side effects—Gastritis and nausea are relatively common. Evidence—One systematic review of eight trials found it had equivalent efficacy to that of other regimens for treating uncomplicated falciparum malaria.1 Dose—Four tablets once daily for three days in adults. Artemether-lumefantrine (Coartemether, Coartem, Riamet) A four dose regimen for this drug has not been proved to be effective, but a six dose regimen seems to be effective against parasites from all parts of the world. It should be taken...

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