Malaria Prophylaxis

The ABCD of malaria prophylaxis:¹

• Awareness of the risk of malaria
• Bites - reducing likelihood of bites from anopheline mosquitoes
• Chemoprophylaxis
• Diagnosis and prompt treatment to prevent complications

No single measure is 100% effective, but the combination of measures will significantly lessen the risk.

Risk assessment should include:

• Geographical destination - information online at Department of Health's Overseas Travel website is very helpful⁴
• Travellers to remote locations should seek expert advice (see resources for patients, below)
• Current highest risk areas:
  • Most of Africa south of the Sahara (most cases of falciparum malaria, reported in England and Wales, are from East, West or Central Africa)
  • The Indian subcontinent (30% of those cases reported in Britain, mainly due to P. vivax)
  • Papua New Guinea, Irian Jaya, the Solomon Islands and Vanuatu (P. vivax and P. falciparum)
  • The whole Amazon basin in South America
• Type of travel: higher risk for tourists travelling outside urban areas to countryside or game parks, business travellers to downtown offices, overland backpackers, prolonged travellers expatriates intending to reside in the area
• High-risk categories - pregnant women, asplenic patients and young children

A useful template for risk assessment and summary of advice given can be found on the Health Protection Agency website.⁵

• Avoidance of bites is important, particularly because chemoprophylaxis is never 100% effective, there are increasing problems of drug resistance, and there is evidence that the risk of contracting malaria is proportional to number of bites. Bites occur mainly between dusk and dawn, although some species of mosquito which can transmit dengue fever bite during the day also.
• Reduce exposure in evenings. The World Health Organisation (WHO) recommend wearing long-sleeved shirts and long trousers confers protection, although the evidence base is slim.⁷
• There is good evidence that covering exposed limbs with diethyltoluamide-containing repellant (DEET) is effective. When sunscreen is applied, it should be used before DEET. It is suitable for all adults including children over the age of 2 months. 50% is the recommended strength. There is no evidence of serious toxicity, even in small children and pregnant women. Some patients develop an allergic or irritant response, in which case lower strengths are available. Preparations weaker than 50% will require more frequent application. There is no evidence of effectiveness of strengths of less than 20%.
• Picaridin (KBR3023) (1-piperidinecarboxylic acid, 2-(2-hydroxyethyl)-,1-methyl-propylester) is
  reported to have repellent properties comparable to those of DEET. Picaridin is sold in Europe as a 20%formulation whilst a 7% picaridin formulation is on sale in the US. If a traveller elects to use picaridin for mosquito bite prevention, a 20% preparation should be used.
• Permethrine spray on clothing, renewed every two weeks, is likely to be beneficial but large-scale studies only done in military circumstances.
• Patients should be advised to sleep in air-conditioned rooms if possible, or screened accommodation.
• Use of sprays with knockdown insecticide or electrical pyrethroid vapourisers every evening after dusk is recommended.
• Insecticide-treated nets should be used if sleeping outdoors or in unscreened rooms. The effectiveness is about 50%. Pyrethroid-impregnated nets improve protection and should be re-impregnated every 6-12 months. Nets which incorporate the insecticide into the fabric are now available and will last from 3 to 5 years.

• Reinforce that prophylaxis is not absolute, breakthrough infection can occur, and risk avoidance still necessary.
• Consider risks versus benefits based on risk assessment.
• Start weekly drug regimes one or two weeks before departure (exceptions: 1-2 days for malarone, two to three weeks for mefloquine) to get used to side effects before travelling. Take after meals.
• Continue until four weeks after return to deal with infection contracted towards the end of the stay. Discuss possible side effects, and recommend seeking advice if there is any concern or medication has to be stopped.
• Warn that anti-malarials bought abroad or purchased over the internet made be fake, and should be avoided.
• Seek specialist advice if the patient has severe hepatic or renal impairment.
• Where a journey requires two regimes, use the regime for the higher risk area for the whole journey. Warn settled immigrants or long-term visitors to the UK they may have lost some of their immunity and that previously uninfected areas may now be malarious.
• Malaria chemoprophylaxis is not prescribable on FP10. Chloroquine and proguanil can be bought OTC. Mefloquine, doxycycline, and atovaquone with proguanil (Malarone) require a private prescription.

• Chloroquine:
  • Chloroquine is rarely appropriate as single therapy due to emerging resistance.
  • It is taken at a dose of 300 mg (two tablets) weekly for adults. It is also available as a syrup (equivalent to chloroquine base 50 mg/5 ml).
  • It remains effective against most P. vivax, all P. ovale and virtually all P. malariae. It will however not prevent dormant liver stages of vivax and ovale malaria which can present up to a year after travel.
• Chloroquine plus proguanil:
  • Proguanil is rarely given as a single agent due to resistance, but combined with chloroquine it may be used in areas with moderate chloroquine resistance. The combination provides less protection than mefloquine.It is no longer recommended for travel to sub-Saharan Africa.
  • Folate supplements are recommended during pregnancy.
  • The dose for adults is: chloroquine 300 mg (two tablets) weekly and proguanil 200 mg (two tablets) daily.
  • Common adverse reactions are nausea, diarrhoea, dyspepsia and itching.
  • Chloroquine is available as syrup for young children. Proguanil tablets need to be crushed and can be administered in jam or butter.
• Mefloquine:
  • This is used for areas where there is a high incidence chloroquine resistant falciparum malaria (e.g sub-Saharan Africa).
  • The usual adult dose is 250 mg weekly.
  • It can be recommended for journeys up to one year.
  • It exhibits 90% efficacy in Africa, but resistance is high in other areas (e.g. there is significant resistance of P. falciparum to mefloquine in some areas of south-East Asia, and it is reported sporadically in the Amazon basin).
  • Major adverse events (convulsions, coma and psychotic disturbances) are rare - 1 in every 10,000 users, but they have been given high media profile. There is no evidence tat mefloquine use
    increases the risk of first-time diagnosis of depression and no association between mefloquine prescriptions and hospitalisation.
  • Lesser side effects are similar to chloroquine and proguanil.
  • Avoid in patients with history of epilepsy or psychiatric disorder.
  • It should not be used routinely in pregnancy but if there is an unavoidable visit to an area where there is a high risk of choloroquine-resistant falciparum malaria, use cautiously during the second and third trimester. Data suggests it is safe in the first trimester.
  • It is not for routine use in lactation as it is secreted in breast milk.
• Malarone:
  • This is a combination of proguanil and atovaquone.
  • Its effectiveness against falciparum is in excess of 90%.
  • It is licensed in the UK for adults for up to 28 days.
  • It can be used as alternative to mefloquine or doxycycline for adults travelling to choloroquine resistant areas, especially Africa and SE Asia.
  • It is taken as a single daily dose, and only needs to be continued for seven days after travel.
  • Adverse effects are few, mainly gastrointestinal and headaches.
• Doxycycline:
  • This has comparable efficacy to mefloquine.
  • It may be recommended as first line for travel to Africa where high levels of protection are desirable but mefloquine is unsuitable.
  • The main side effects are diarrhoea, photosensitive dermatitis and vaginal thrush.
  • It is not recommended for children under 12, pregnancy or lactation.
  • It should be used with caution in patients with hepatic impairment, myasthenia gravis and systemic lupus erythematosus.
  • Its use is limited to six months.

Prescribing for children^8,9

• Prophylactic doses are based on guidelines from UK malaria experts and may differ from advice in the product literature.
• Weight is a better guide than age.
• There are no large-scale studies supporting the effectiveness of antimalarial drugs in children, although encouraging results have been reported in a study using intermittent sulfadoxine-pyrimethamine in Gabon.¹⁰
• If in doubt telephone prophylaxis advice centres (see below).

• If chemoprophylaxis is contra-indicated or of limited effectiveness and it is necessary to travel to high-risk areas where access to medical expertise within 24 hours of the onset of fever is unlikely, medication may be prescribed to self-treat an episode of malaria.
• Patient must be carefully counselled regarding presenting symptoms, indications, and safe use of drugs.
• Treatment should be started if unable to seek medical help within eight hours of onset of symptoms. Other preventive measures should be continued.
• The standard treatment course should be completed and antimalarial chemoprophylaxis commenced one week after taking the first treatment dose, except in the case of mefloquine prophylaxis, which should be resumed 1 week after the last treatment dose if quinine was used for
  standby treatment.
• Antipyretics should be used to treat fever.
• A second full treatment dose of the antimalarial should be taken if vomiting occurs within 30 minutes of taking it (half-dose if vomiting occurs after 30–60 minutes).
• The drug used for emergency standby treatment should differ from that used for chemoprophylaxis, both to minimise drug toxicity and due to concerns over drug resistance.
• Warn the patient concerning the adverse reactions of quinine - e.g. tinnitus, headache, flushed skin, nausea.

Seek specialist advice.

• Chloroquine and proguanil are the only drugs licensed for long-term use, but there effectiveness is reduced in some areas due to resistance. They can be used indefinitely (but check for retinopathy if chloroquine is used for more than 6 years).
• Licensing restrictions can be mitigated by switching from one regime to another. Occasionally, strategies such as reliance on standby treatment or ignoring licensing restrictions have been employed.
• Mefloquine is licensed for up to 1 year (though has been used for up to 3 years without problems).
• Doxycycline can be used for up to 2 years.
• Malarone is licensed for up to 28 days, but can be safely used for up to 3 months (and possibly 6 months or longer).
  

  LONG-TERM MALARIA CHEMOPROPHYLAXIS FOR ADULTS MALARIA CHEMOPROPHYLAXIS ACMP ADVICE ON LONG-TERM USE Chloroquine Considered safe for long-term use.* Consider ophthalmic examination 6 to 12 monthly, commencing at 6 years’ prophylactic usage Proguanil Considered safe for long-term use* Mefloquine No evidence of harm in long-term use if tolerated in the short term. Suggest can be used safely for up to three years in the absence of side effects. Doxycycline No evidence of harm in long-term use. Evidence suggests that it may be used safely for periods of at least up to two years. Atovaquone/ Proguanil No evidence of harm in long-term use. Suggest can be used confidently for travel up to one year and possibly longer, but only with caution until more post-licensing experience is available. *Considered safe for long-term use but considerable concern regarding level of protective efficacy of the combination of chloroquine plus proguanil in certain geographical areas where the regimen used to be useful.

Advise patients regarding symptoms of malaria, to report any illness within 3 months of return and make doctor aware of history of malaria exposure, and to monitor for malaria symptoms for up to one year after travel.

• Epilepsy:
  • Chloroquine and mefloquine are unsuitable.
  • In areas without chloroquine resistance prescribe proguanil 200 mg daily.
  • In areas with chloroquine resistance, consider doxycycline or Malarone.
  • The dose of anticonvulsant may need to be increased as doxycycline can reduce plasma concentration.
• Asplenia and severe splenic dysfunction - these patients are at high risk of severe malaria. If travel is unavoidable take rigorous precautions and use drugs that give good protection.
• Renal impairment:
  • Avoid or reduce the dosage of proguanil as it is excreted by the kidneys.
  • Avoid Malarone in patients with low creatinine clearance (less than 30 ml/minute).
  • Chloroquine only needs dosage reduction in severe renal impairment.
  • Mefloquine and doxycycline can be used in normal dosage.
• Liver impairment:
  • Mefloquine and doxycycline are contraindicated as excreted via the liver.
  • Proguanil and chloroquine can be used in mild impairment and proguanil in moderate impairment.
  • In severe liver failure, seek specialist advice.
• Pregnancy:
  • Evidence suggests pregnant women are twice as likely to be bitten by anopheline mosquitoes than non-pregnant women, the malaria is more severe, and the disease can cause miscarriage.
  • Avoid travel to malarious areas if possible.
  • If unavoidable, give chloroquine and proguanil in usual doses in areas where P. falciparum strains are sensitive. A large trial using chloroquine as prophylaxis against P. vivax demonstrated a reassuring safety profile.¹³
  • If proguanil is used, prescribe folic acid 5 mg daily.
  • Mefloquine is suitable in the second and third trimesters; in the first trimester lack of safety data concerning miscarriages suggests that caution should be exerted before prescribing.
  • Avoid doxycycline; Malarone should not be used due to lack of safety data.
  • Consult prophylaxis advice centres for travel to resistant areas.
• Lactation:
  • Chloroquine, proguanil, and mefloquine are suitable for lactating mothers. Doxycycline is contraindicated.
  • There is lack of safety data concerning Malarone but this may be considered if there is no suitable alternative.
  • Prophylaxis is required in breast-fed infants, as the amount of antimalarials present in milk are too variable to give reliable protection.