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Ovid: Oxford Handbook of Tropical Medicine

Editors: Eddleston, Michael; Pierini, Stephen; Wilkinson, Robert; Davidson, Robert Title: Oxford Handbook of Tropical Medicine, 2nd Edition Copyright ©2005 Oxford University Press (Copyright 2005 by M. Eddleston, S. Pierini, R. Wilkinson, and R. Davidson) > Table of Contents > Chapter 2 > Chapter 2A – Malaria > Antimalarial chemotherapy Antimalarial chemotherapy

  • Aim to reduce the parasitaemia as quickly as possible, using oral agents if tolerated.
  • Beware local patterns of resistance.
  • If the species is unknown or there is mixed infection, treat as falciparum malaria.
  • Parasite count may paradoxically rise during the first 24 hrs and does not necessarily indicate drug failure. If the parasite count has not fallen by at least 75% 48 hrs after starting therapy, the count should be rechecked and, if confirmed, a different antimalarial drug should be considered.
  • During pregnancy, quinine is still the treatment of choice for severe falciparum malaria despite the remote possibility of induced abortion since preservation of the mother’s life is paramount. Avoid mefloquine in the first trimester of pregnancy.

Antimalarial preparations and their recommended doses

  • Quinine: used in the treatment of falciparum malaria and emergency IV treatment of benign malaria where oral drugs are not tolerated. For uncomplicated disease give 10 mg/kg quinine salt PO tds. Once the parasites have been eradicated, give tetracycline 4 mg/kg PO qds, doxycycline 3 mg/kg PO od, or clindamycin 10 mg/kg PO bd, each for one week. For severe disease give a loading dose of 20 mg/kg of quinine IV over 4 hrs, followed by 10 mg/kg infused over 4 hrs every 8 hrs until oral therapy is tolerated.
    • Oral doses which are vomited out within 1 hr of administration should be repeated immediately.
    • Doses should be reduced by one-third in patients with liver dysfunction and/or in renal failure.
    • Compliance with 7 days of oral quinine is poor because of the bitter taste; shorter regimens are acceptable as long as they are accompanied by a second drug (e.g. doxycycline).
    • IV doses of quinine should be given in 500 ml of 5% dextrose solution into a large vein, over 4 hrs.
    • Check if the patient has already received chloroquine, quinine, or mefloquine — if yes, omit the loading dose. Check that cardiac monitoring is available.
    • Watch for hypoglycaemia (particularly in pregnant women), hyponatraemia, hypokalaemia. Reduce the rate of infusion if cardiac arrhythmias occur. Switch to oral drugs as soon as possible.
    • Where IV access is unavailable, quinine may be given IM (20 mg/kg loading dose followed by 10 mg/kg tds) but beware of tissue damage and risk of heart block. (Tetanus has also been recorded where IM quinine injections have been given — check immunization status.) Dilute the preparation 5-fold and give in divided doses by deep IM injection into the anterior thigh.
  • Artemisinins are highly effective in clearing multidrug-resistant P. falciparum parasites. IM artemether is as effective as IM quinine (although recrudescence rates may be higher). Artesunate suppositories are quick, easy, and free of the risks associated with IV injections. P.31
    For uncomplicated disease give artesunate or artemether 10–12 mg/kg PO in divided doses over 3–7 days, plus a total of 25 mg/kg mefloquine. If used alone, the total dose is given over 7 days (usually 4 mg/kg on day 1, 2 mg/kg on days 2 and 3, and 1 mg/kg on days 4–7). For severe disease, give artesunate 2.4 mg/kg IV or IM initially, followed by 1.2 mg/kg at 12 and 24 hrs, then 1.2 mg/kg od. (60 mg of artesunic acid is dissolved in 0.6 ml of 5% NaHCO3, diluted to 3–5 ml with 5% dextrose and given IV or IM. 1 ampoule = 80 mg.) Or give artemether, 3.2 mg/kg IM initially, followed by 1.6 mg/kg od. Do not give IV.
  • Mefloquine is related to quinine and may be used for multidrug-resistant forms of P. falciparum but can only be taken orally. Adverse neuropsychiatric side-effects have been reported in using this drug both for prophylaxis (severe in 1:1500 cases) and in treatment (in 1:300 cases). The benefit of treating potentially life-threatening multidrug-resistant malaria outweighs this risk. Adverse effects may respond to chlorpromazine. Give 15 mg/kg base PO stat (+/- 2nd dose of 10 mg/kg 8–24 hrs later). (In the USA, 1 tablet = 228 mg base; elsewhere 1 tablet = 250 mg base.)
    • Do not administer mefloquine within 12 hrs of the last quinine dose.
    • Do not use in early pregnancy. Warn women to avoid conception within 3 months of taking mefloquine.
    • Avoid in severe disease because of the risk of neurological syndromes.
    • Do not use for treatment if taken as prophylaxis.
  • Chloroquine: the use of chloroquine for falciparum malaria is no longer recommended due to widespread resistance. However, it is still used in many parts of the world because it is cheap, easy to use, safe (e.g. in pregnancy), and works to some degree. It should not be used if it has been taken as prophylaxis. In these situations, treat with quinine, unless certain of sensitivity. Falciparum malaria in Central America (North of the Panama Canal) and the Middle East is still said to be chloroquine sensitive. Chloroquine is still the drug of choice for benign malaria in most parts of the world, although resistant strains are emerging (see below). For uncomplicated disease, give a total of 25 mg/kg base as 10 mg/kg base PO followed by either 10 mg/kg base at 24 hrs and 5 mg/kg base at 48 hrs, or 5 mg/kg base at 12, 24, and 36 hrs. For P. vivax or P. ovale, add primaquine 0.25 mg base/kg od for 14 days to obtain a radical cure (see below). For patients with G6PD deficiency, use an increased dose and longer intervals for primaquine (usually 45 mg once a week for 6 weeks) to avoid severe haemolysis. Watch out for black urine; reduce the dose if this occurs. IV route administration of chloroquine should be considered if a patient cannot swallow, has D&V, or if IV quinine/quinidine is not available. Rapid IV administration of chloroquine is dangerous and may result in fatal cardiovascular collapse and blindness. Give 10 mg/kg base at a constant rate by IV infusion over 8 hrs, followed by 15 mg/kg base over 24 hrs. If IV route is not available, give 3.5 mg/kg base IM or subcutaneously q6h (up to total of 25 mg/kg base).
  • P.32

  • Tetracycline/doxycycline: used in conjunction with quinine in the treatment of P. falciparum infections and in patients hypersensitive to sulfadoxine-pyrimethamine. See quinine text for doses. Do not give in pregnancy and in young children under the age of 12, and decrease the dose in renal failure.
  • Sulfadoxine-pyrimethamine (Fansidar®): there is now widespread resistance to this drug combination. It is used after initial treatment with quinine, but is no longer routinely recommended. Give 20 mg/kg sulfadoxine plus 1 mg/kg pyrimethamine as a single dose. (3 tablets of Fansidar® is usual adult dose.)
  • Quinidine: if quinine is unavailable, quinidine (a related compound) may be given. It is important to have cardiac monitoring available during IV infusion of this drug as it is more cardiotoxic (largely because less is bound to plasma proteins). Give 7.5 mg/kg base IV at a constant rate over 1 hr, followed by 0.02 mg base/kg/min.
  • Halofantrine: used in the treatment of uncomplicated chloroquine-resistant P. falciparum infections usually when other drugs are unavailable or have failed to work. Give 8 mg/kg PO repeated at 6 and 12 hrs on an empty stomach. Repeat 1 week later in those without immunity.
    • Needs ECG monitoring due to cardiotoxicity.
    • Side-effects include QT interval prolongation and ventricular arrhythmias, particularly in patients with coronary heart disease, cardiomyopathy, and congenital heart disease. Do not take in combination with arrhythmogenic drugs or drugs that cause electrolyte disturbances.
    • Do not use to treat recrudescent infections within 28 days of primary mefloquine therapy.
  • Atovaquone/proguanil (Malarone®): a new drug that is now licensed in some countries for the treatment of uncomplicated falciparum malaria where resistance to other drugs is suspected. It is however expensive. Each tablet contains proguanil hydrochloride 100 mg and atovaquone 250 mg. Give adult and child >40 kgs, 4 tablets od for 3 days; child 11–20 kg, 1 tablet; 21–30 kg, 2 tablets; 31–40 kg, 3 tablets, all od for 3 days.
  • Amodiaquine: can be effective against R1, R2, and R3 chloroquine-resistant P. falciparum (see section on drug resistance). IV preparations are not available, although the related amopyroquin is administered IM.

P.33
Radical cures and primaquine in benign malaria

  • Treatment with a blood schizontocidal drug, such as quinine, will not eliminate parasites from the liver. Therefore, patients infected with P. vivax or P. ovale are also given primaquine to kill the liver hypnozoites and prevent recrudescence later. P. malariae does not produce persistent liver forms.
  • Since primaquine is also gametocidal, it is sometimes given to patients infected with P. falciparum in non-endemic regions. This prevents the blood gametocytes being taken up by local mosquitoes and possibly initiating local foci of infections.
  • A major drawback is primaquine’s ability to cause severe intravascular haemolysis in patients with G6PD deficiency. Weekly doses of 45 mg are better tolerated in such patients than daily doses of 15 mg for 14–21 days.
  • Relatively primaquine-resistant strains of P. vivax have been reported in the Pacific region that require at least 6 mg/kg total dose (~2× normal dose).
Fig. 2A.5 Stage specificity of antimalarial drugs

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