Malaria Treatment

This Section was written by:
Professor T.M.E. Davis B. Med Sc (Hons), MB BS, D Phil (Oxon), MRCP, FRACP,
University Department of Medicine,
Fremantle Hospital, Western Australia.

P.falciparum

This species was originally sensitive to chloroquine.  However, strains resistant to this and other antimalarial drugs are now commonplace.  Because the parasite is able to multiply very rapidly and sequester within the microvasculature, a life threatening illness may develop in a very short space of time.

Uncomplicated malaria (where patients can take oral therapy) can usually be treated effectively with one of three regimens:

• Quinine sulphate 10 mg salt/kg 8 hourly for seven days plus doxycycline 100 mg daily for 7 days.  Patients will usually develop ‘cinchonism’ (tinnitus, high-tone hearing loss, nausea, dysphoria) after 2-3 days but should be encouraged to complete the full course to avoid recrudescence.  Tetracycline (4mg/kg daily for seven days) or the combination drug Fansidar^TM (25mg/kg sulfadoxine plus 1.25mg/kg pyrimethamine as a single dose) can be given as less expensive alternatives to doxycycline.
  
  
• Malarone^TM (atovaquone 250 mg plus proguanil 100 mg) 4 tablets daily for three consecutive days.  This combination therapy is relatively new and appears to be very effective but it is also very expensive.  Resistance to this drug combination has already been reported in a patient from Nigeria (Malaria J. 2002; 1:1).
  
  
• Mefloquine (Larium^TM) given as 15 mg/kg in a divided dose followed by 10 mg/kg the following day.  Antipyretic and antiemetic agents may need to be given prior to mefloquine administration to reduce the risk of vomiting.

With the advent of widespread chloroquine resistance, this drug (dose 25mg base/kg in divided doses over 2-3 days; see P. vivax treatment regimen below) can be combined with others such as Fansidar^TM (25mg/kg sulfadoxine plus 1.25mg/kg pyrimethamine as a single dose) in areas where background immunity to malaria contributes to parasite clearance and alternative regimens are too expensive.

Lapdap (chlorproguanil 2mg/kg plus dapsone 2.5mg/kg) daily for three days is an inexpensive combination of well established compounds being assessed in African trials.

Choice of regimen is based on:

• Local cost and availability of antimalarial drugs.
  
  
• Area of malaria acquisition (i.e. drug resistance pattern of P. falciparum).
  
  
• Prior chemoprophylaxis.
  
  
• Known allergies.
  
  
• Concomitant illnesses other than malaria.
  
  
• Age and pregnancy.
  
  
• Likely patient compliance with therapy.
  
  
• Risk of re-exposure to malaria after treatment.

In uncomplicated cases in which nausea and vomiting preclude oral therapy, quinine dihydrochloride 10 mg salt/kg base can be given i.v. in 5% w/v dextrose or normal saline as a 4-hour infusion 8-hourly until the patient can take medication by mouth.

Severe malaria (where patients have coma, jaundice, renal failure, hypoglycaemia, lactic acidosis, severe anaemia, high parasite count, hyperpyrexia) is ideally treated in an intensive care or high dependency unit where patients can be monitored closely both clinically and biochemically.  Intravenous quinine is the treatment of choice but rapid injection can lead to hypotension, dysrhythmias and death.

In patients who have not received quinine in the previous 48 hours, one of two regimens can be used:

• Quinine dihydrochloride 20 mg salt/kg base given i.v. in 5% w/v dextrose or normal saline as a once-only 4 hour infusion followed, 4 hours later, by quinine dihydrochloride 10 mg salt/kg base 4-hour infusions, 8 hourly.
  
  
• Where a syringe pump or other accurate infusion device is available, quinine dihydrochloride 7 mg salt/kg base over 30 minutes followed immediately by quinine dihydrochloride 10 mg salt/kg base over 4 hours then, starting 4 hours later, quinine dihydrochloride 10 mg salt/kg base as 4 hour infusions, 8 hourly.

Electrocardiographic monitoring can be done if available but is not essential unless additional cardiac risks are present.

Where patients have received quinine within the previous 24 hours, give quinine dihydrochloride 10 mg salt/kg base i.v. in 5% w/v dextrose or normal saline as 4-hour infusions 8-hourly.

Hypoglycaemia may occur in patients with severe malaria, particularly in those treated with quinine, and careful monitoring is required.  Steroids should not be used in patients with severe malaria.

P.vivax

Most strains of P. vivax are still sensitive to chloroquine, although some chloroquine resistant strains have been reported in Papua New Guinea, Indonesia, Thailand and India.  This drug will clear the erythrocyte stages of the parasite but it has no effect on the exo-erythrocytic liver stage and a course of primaquine (an 8-amino-quinoline) is required for radical cure.  The Chesson strain of P. vivax found in New Guinea shows some resistance to primaquine and an increased dose is required but may still not result in radical cure.  If primaquine is not given, the patient may suffer a relapse which will occur weeks, months or sometimes years after the original attack.

Adult treatment.
Based on Chloroquine tablets containing 150mg base.

The primaquine is preferably started after the chloroquine, at a dose of 3.5mg/kg given as a divided daily dose over 14 days.  When the infection is acquired in New Guinea, up to 6mg/primaquine may be necessary (0.43mg/kg/day) should be given over 14 days.  In the case of a relapse, repeat both chloroquine and primaquine treatment. Several relapses may occur before the parasite is finally eliminated.  Unfortunately there is no other effective treatment.

Tafenoquine is a newly developed long-acting, potent primaquine-like drug which may be available soon for radical cure.  It can be given over 3 days instead of 14 but may not offer any advantage in efficacy over primaquine.

Patients should have their G6PD status checked before primaquine (or tafenoquine) is prescribed.  Those with G6PD deficiency may experience haemolysis if given a daily dose of primaquine and it is recommended that these patients be given 30-45mg once a week for 8 weeks.

Malarone^TM may also be used to treat P. vivax malaria but a course of primaquine will still be required to eliminate liver forms.

P. malariae, P. ovale

Treatment for the eradication of these two strains of malaria is the same as that for P. vivax except it is not necessary to give primaquine to those patients with P. malariae.

Artemisinins

Artemisinin has been used for many years by the Chinese as a traditional treatment for fever and malaria.  It is a sesquiterpene lactone derived from the wormwood plant Artemisia annua.  Semi-synthetic derivatives including artemether and artesunate are now widely available in the tropics.  These compounds are being increasingly used in a number of countries and are both cheap and effective.  They are starting to be licensed in Western countries.

They are particularly valuable in the treatment of multidrug-resistant falciparum malaria.  Unless used with a second antimalarial as described below there is likely to be a high recrudescent rate.  Side-effects have been reported but these are comparartively rare and seldom severe.  Artemisinin derivatives are recommended for treatment but not for prophylaxis.  If an artemisinin drug is used to treat vivax malaria, it should be accompanied by a course of primaquine.

Artemisinin (500mg tablets) give 10-20 mg/kg on day 1 (500-1,000 mg) orally then 500mg for 4 days.  Then give mefloquine 15mg base/kg or split dose 25mg base/kg.

Artemisinin (200mg suppositories): for severe malaria 600-1200mg stat, 400-600mg after 4 hours then 400-800mg twice daily for 3 days.  Give mefloquine as above.

Artesunate (50 & 60 mg vials for intravenous use): for severe malaria 120mg I.V. stat. 60 mg at 4, 24 and 48 hours, 50-60 mg on days 3-5.  Give mefloquine as above.

Dihydroartemisinin (20 mg tablets): First dose 120mg then 60mg daily for 4-6 days then give mefloquine as above.

Artemeter (vials for intramuscular use): For severe malaria 3.2 mg/kg intramuscularly stat then 1.6mg twice daily for 3-7 days.  Give mefloquine as above.

Caution: A recent report on the sale of artesunate in South East Asia found that 38% of the artesunate purchased was fake (Lancet 2001; 357:1948-49).  Fake artesunate can be identified by a dye test (J Pharm Biomed Anal 2000;24: 65-70).  Other fake drugs including mefloquine can also be found in South East Asian markets.

Artemisinin-based combination therapies, some comprising a fixed co-formulation are being developed:

Artesunate plus mefloquine is used in several Asian countries, some using blister packs to simplify dosing and increase compliance.  The mefloquine component, which is usually given on the third day of artesunate treatment, is relatively expensive and side-effects are common.

Artemether plus Iumefantrine (Co-artem^TM or Riamet^TM) is an oral combination treatment but has problems with bioavailability of the fat-soluble lumefantrine component. Six doses have better efficacy than four, but cure rates have been variable.

Dihydroartemisinin plus piperaquine (Artekin^TM, Artecom^TM, CV8, Duo-Cotexin) in a four-dose regimen has proved highly effective and well tolerated in South East Asian trials.

Artesunate plus pyronaridine is under development in WHO-sponsored trials.