[Table of Contents]

Volume: 26S2 - March 2000

2000 Canadian recommendations for the prevention and treatment of malaria among international travellers
prepared by the
COMMITTEE TO ADVISE ON TROPICAL MEDICINE AND TRAVEL (CATMAT)

8. TREATMENT OF MALARIA

a. General Principles of Management

This depends on the infecting species of malaria, the severity of infection, the patient's age, the pattern of drug resistance in the area of acquisition, as well as the safety, availability, and cost of antimalarial drugs. Three critical questions need to be addressed in order to initiate effective treatment:

1. Is this infection caused by P. falciparum?
   This is critical, as treatment varies according to the species of malaria.

2. Is this a severe or complicated infection (see Table 3, below)?
   Severe or complicated malaria requires parenteral therapy and sometimes an exchange transfusion.

3. Has the infection been acquired in an area of known drug-resistant malaria (see Appendix I)?
   Therapy will have to be modified accordingly.

When in doubt treat all falciparum malaria as drug resistant.

TABLE 3 Criteria for Severe Falciparum Malaria

b. Management of Falciparum Malaria

The following guidelines have been derived, in part, from the World Health Organization Division of Control of Tropical Diseases (Severe and complicated malaria. 2nd ed. Trans Roy Soc Trop Med Hyg 1990;84[Suppl 2]). The interested reader is referred to this document for a more detailed discussion of these issues.

A detailed geographic history is essential to the management of malaria. P. falciparum malaria acquired in areas where drug resistance is known to occur should be treated as chloroquine resistant.

Severe P. falciparum infections, as defined by the criteria in Table 3 may have a mortality rate of 20% or higher. These patients require immediate hospitalization, and urgent, intensive medical management. As a general rule, all non-immune patients with P. falciparum malaria, whether severe or not, should be considered for admission to hospital in order to ensure tolerance of antimalarial drugs and to detect complications or early treatment failure. All patients with severe P. falciparum infections and those who are unable to tolerate drugs orally should receive intravenous quinine or, less optimally, quinidine (see Table 4 ). In the treatment of severe malaria, parenteral preparations of quinine and quinidine are equivalent. Quinine is preferred by CATMAT because of the cardiotoxicity of quinidine. Patients treated with intravenous quinidine should receive electrocardiographic monitoring, and infusion rates should be decreased if the corrected QT interval is prolonged by more than 25% of baseline. Intravenous quinine and quinidine are no longer readily available in Canada.

Because of the potential for adverse outcome with delays in acquiring parenteral malaria therapy, every effort has been made to ensure that parenteral quinine is available throughout Canada for the treatment of severe malaria. A nation-wide network of Malaria Centres of Excellence (see Appendix V) is being established to facilitate the storage and rapid distribution of parenteral quinine for the treatment of severe P. falciparum infections. The Centres will also provide expertise in the management of malaria cases. As well, each Centre will provide surveillance data to LCDC on cases treated with parenteral quinine.

Parenteral quinidine gluconate dosing is provided in Table 4. It is as effective as parenteral quinine in the treatment of severe malaria, but the risk of cardiotoxicity necessitates cardiac monitoring. Parenteral quinidine gluconate can be obtained on a patient-by-patient basis with authorization from Health Canada's Special Access Program, see footnote, Table 4, for contact information. Parenteral quinidine sulfate is an intramuscular preparation that is not recommended for intravenous use.

Uncomplicated P. falciparum infections unequivocally acquired in a chloroquine-sensitive zone may be treated with chloroquine alone (as per Table 2). Those infections that were possibly or definitely acquired in drug-resistant regions should be treated with Malarone^® or quinine and a second drug. If the patient can tolerate oral quinine, then it and the second drug - either doxycycline, Fansidar^®, or clindamycin - may be administered simultaneously or sequentially (start quinine first), either orally (as per Table 2) or, if necessary, parenterally (as per Table 4). The base-salt equivalents of selected antimalarials are shown in Table 5.

TABLE 4 Chemotherapy of Severe Falciparum Malaria

TABLE 5 Base/Salt Equivalents of Selected Antimalarial Drugs

When quinine is administered to a patient who has taken mefloquine or halofantrine in the previous 2 weeks, there is a risk of drug-induced cardiac arrhythmia; if possible, such patients should be monitored electrocardiographically.

Approximately 5% or more of patients may fail treatment for falciparum malaria. Most patients fail within 1 month of treatment. To ensure that patients are cured, it is important to repeat a thick and thin blood film on day 7 and day 28 after therapy, and at any time there is recurrence of symptoms.

c. Ancillary Treatment of Severe Malaria

Many ancillary treatments have been suggested for the treatment of severe malaria, but few have been objectively shown to improve outcome. Only antipyretics (acetaminophen) and anticonvulsants (prophylactic phenobarbitol) have been supported by sufficient evidence to warrant their use. The use of steroids to treat severe or cerebral malaria has been associated with worse outcomes and should be avoided (E I - evidence-based medicine recommendations - see Appendix II). In cases of complicated P. falciparum infection (Table 3) or if there is high parasitemia (>= 10%), exchange transfusion has been used on an experimental basis as a potentially life-saving procedure.

When managing a patient with severe or complicated falciparum malaria, consultation with an infectious or tropical disease expert is strongly recommended (see Appendix V, for contact information).

d. Management of Non-Falciparum Malaria

Outside of New Guinea (Papua New Guinea and Irian Jaya), chloroquine remains the treatment of choice for malaria other than falciparum (as per Table 2). Recent reports have confirmed the presence and high prevalence (80%) of chloroquine-resistant P. vivax in Irian Jaya. Sporadic cases of chloroquine-resistant P. vivax malaria have been reported elsewhere (e.g. in Indonesia, Papua New Guinea, the Solomon Islands, Myanmar, and Guyana). At present, chloroquine can no longer be relied upon either for chemoprophylaxis or treatment of P. vivax acquired in New Guinea, and the optimal treatment is unknown. Although effective, a prolonged course of quinine (> 3 days) is often required to cure P. vivax infection from New Guinea and is poorly tolerated.

Mefloquine and halofantrine have been shown to be efficacious in small clinical trials, but each is limited by safety issues associated with therapeutic doses (see sections 3f, and 9e). Standard chloroquine doses (25 mg base/kg/72 hours) combined with high dose primaquine (2.5 mg base/kg/48 hours) have been suggested as treatment for chloroquine-resistant P. vivax acquired in Irian Jaya, but have failed in cases from Guyana. Expert advice from an infectious or tropical disease specialist should be sought for the management of these cases.

As with falciparum malaria, response to treatment should be documented with repeat of thick and thin blood films on day 7 and day 28 after therapy, and at any time there is recurrence of symptoms. A recurrence of parasitemia less than 30 days after treatment suggests chloroquine-resistant P. vivax; recurrence after more than 30 days suggests primaquine resistance.

e. Prevention of Relapses of Malaria Due to P. vivax or P. ovale

P. vivax and P. ovale have a persistent liver phase that is responsible for relapses and is susceptible only to treatment with primaquine or related drugs. None of the currently recommended chemoprophylaxis regimens will prevent relapses due to these two species of malaria. In order to reduce the risk of relapse following the treatment of symptomatic P. vivax or P. ovale infection, primaquine is indicated to provide "radical cure". Primaquine is not routinely recommended to prevent relapsing malaria in asymptomatic returning travellers (terminal prophylaxis). However, terminal prophylaxis with primaquine is generally indicated for persons with prolonged exposure in malaria-endemic areas (e.g. long-term travellers or expatriates, see section 5). For terminal prophylaxis primaquine is administered after the traveller has departed from a malaria-endemic area, usually during or following the last 2 weeks of chemoprophylaxis. (See Table 2, for dosage recommendations).

Primaquine use is contraindicated in pregnancy. P. vivax or P. ovale infections occurring during pregnancy should be treated with standard doses of chloroquine (Table 2). Relapses can be prevented by weekly chemoprophylaxis with chloroquine until after delivery, when primaquine can be safely used for mothers with normal G6PD levels.

Primaquine is generally well tolerated but may cause nausea and abdominal pain; this may be diminished by taking the drug with food. More importantly, primaquine may cause oxidant-induced hemolytic anemia in those with a deficiency of G6PD, as well as methemoglobinemia. Those of Mediterranean, African, and Asian ethnic origin or those receiving > 15 mg base/day have a greater risk of hemolysis. All individuals should have their G6PD level measured before primaquine therapy is initiated.

Primaquine is contraindicated in those with severe G6PD deficiency. In mild variants of G6PD deficiency, primaquine has been used safely at a lower dose (0.8 mg base/kg/week; adult dose 45 mg base once weekly for 6 weeks) for radical cure of P. vivax or P. ovale malaria. Primaquine should be initiated for radical cure after chloroquine therapy has been completed and the acute febrile illness is over (about 1 to 2 weeks). Patients should be advised to stop their medication and report to a physician immediately if jaundice or abnormally dark or brown urine is noted.

f. P. vivax Resistance to Primaquine

P. vivax isolates with a decreased responsiveness to primaquine are well documented in Southeast Asia and, in particular, Papua New Guinea and Irian Jaya. Recently, primaquine radical treatment failure has been reported from Thailand and Somalia.

When P. vivax malaria relapses following primaquine therapy there are two issues to be considered: (1) the treatment of the acute vivax malaria (see section 8d), and (2) prevention of further relapses by doubling the standard dose of primaquine, i.e. 30 mg (0.5 mg/kg/day) of primaquine base daily for 14 days (B I - evidence-based medicine recommendations - see Appendix II).

Response to treatment should be documented with repeat of thick and thin blood films on day 7 and day 28 after therapy, and at any time there is recurrence of symptoms. A recurrence of parasitemia less than 30 days after treatment suggests chloroquine-resistant P. vivax; recurrence after more than 30 days suggests primaquine resistance.

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