Supplement

Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers

8. Treatment of Malaria

Malaria, particularly that due to P falciparum, is a medical emergency, and management includes immediate treatment and close follow-up. If the species is not unequivocally identified, the case should be treated as P. falciparum until further identification and, if there is doubt about resistance patterns, P. falciparum should be treated as chloroquine resistant. In Canada, all patients with malaria due to P. falciparum should be considered for admission to hospital or should receive initial treatment in an observation unit to ensure tolerance of treatment and to confirm decreasing parasitemia with treatment. Severe or complicated disease (see Table 5) requires parenteral therapy and close clinical monitoring, preferably in an intensive care unit. If required, assistance in the management of malaria cases can be obtained through access to the Canadian Malaria Network site in the appropriate area (a contact list is available in Appendix VI).

a. General Principles of Management

The initial management of the patient depends on many factors, including 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. The base-salt equivalents of selected antimalarials are shown in Table 6.

Three 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 5)?
   Severe or complicated malaria requires parenteral therapy and sometimes an exchange transfusion.

   Table 5. Criteria for severe falciparum malaria

   EITHER

   History of recent possible exposure and no other recognized pathology

   OR

   Asexual forms of P. falciparum on blood smear

   AND

   Any one or more of the following 11 features:

   1. Impaired consciousness or coma
   2. Severe normocytic anemia
   3. Renal failure
   4. Pulmonary edema or adult respiratory distress syndrome (ARDS)
   5. Hypoglycemia
   6. Circulatory collapse, shock
   7. Spontaneous bleeding/disseminated intravascular coagulation
   8. Repeated generalized convulsions
   9. Acidemia/acidosis
   10. Hemoglobinuria
   11. Parasitemia of > 5% (> 250 000/microlitre) in non-immune individuals

   Adapted from Management of Severe Malaria: A Practical Handbook. 2nd ed. Geneva: World Health Organization, 2000.

3. Has the infection been acquired in an area of known drug-resistant malaria
   (see Appendix 1)?

   Therapy will have to be modified accordingly. When in doubt, treat all falciparum malaria as drug resistant.

   Treatment of malaria does not stop with selection of appropriate antimalarial medications. For all cases of malaria, medical follow-up must be ensured. Clinical assessment and repeat malaria smears should be carried out daily until negative and again 7 and 28 days after treatment, and at any time symptoms recur.

Table 6. Base/salt equivalents of selected antimalarial drugs

Drug	Base (mg)	Salt (mg)
Chloroquine phosphate	150.0	250.0
Chloroquine sulfatea	100.0	136.0
Clindamycin hydrochloride	150.0	225.0
Mefloquine	250.0	274.0
Quinidine gluconate	5.0	8.0
	7.5	12.0
	10.0	16.0
	15.0	24.0
Quinidine sulfateb	7.5	9.0
	10.0	12.0
	15.0	18.0
Quinine dihydrochloride	5.0	6.0
	7.5	9.0
	15.0	18.0
	16.7	20.0
Quinine sulfate	250.0	300.0
a Not available in Canada bIntramuscular preparation should not be used intravenously.

b. Management of Falciparum Malaria

The following guidelines have been derived, in part, from the WHO Division of Control of Tropical Diseases (Management of Severe Malaria: A Practical Handbook. 2nd ed. Geneva: World Health Organization, 2000). 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.
• 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. If hospital admission is not planned, then all cases must be observed during their first dose of therapy to ensure that it has been tolerated before discharge from the emergency department. Before discharge there must be further treatment doses provided, or the patient should be directed to a pharmacy that can fill the prescription appropriately.
• An algorithm for the management of malaria is presented in Figure 3.

Severe P. falciparum

Severe P. falciparum infections, as defined by the criteria in Table 5, may have a mortality rate of 20% or higher. Patients with these infections require immediate hospitalization and urgent, intensive medical management. They are at risk of all the adverse outcomes defined in Table 5 as well as other adverse outcomes, including permanent neurologic deficits, chronic renal insufficiency, and death.

All patients with severe P. falciparum infections and those who are unable to tolerate drugs orally should receive intravenous quinine (see Table 7) available 24 hours per day via the Canadian Malaria Network (see Appendix VI for more information). Less optimally, they can be treated with parenteral quinidine. CATMAT prefers quinine because of the cardiotoxicity of quinidine, necessitating electrocardiographic monitoring and dose reduction with cardiac toxic effects (infusion rates should be decreased if the corrected QT interval is prolonged by more than 25% of baseline). When quinine or quinidine 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; such patients should be monitored electrocardiographically.

Many ancillary treatments have been suggested for the treatment of severe malaria, but few hsave been objectively shown to improve outcome. Only antipyretic drugs (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 recommendation, see Appendix II). In cases of complicated P. falciparum infection (Table 5), 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 VI for contact information).

Figure 3
Algorithm for the management of malaria

Uncomplicated P. falciparum

Uncomplicated cases of P. falciparum can become severe over 12 to 24 hours if not treated and monitored properly. Infections unequivocally acquired in a chloroquine-sensitive zone may be treated with chloroquine alone (as per Table 8). Infections possibly or definitely acquired in drug-resistant regions (most cases of P. falciparum malaria seen in Canada) should be treated with atovaquone/ proguanil or quinine plus a second drug (preferably doxycycline). If the patient can tolerate quinine given orally, then it and the second drug - either doxycycline or, for those in whom doxycycline is contraindicated, clindamycin - may be administered simultaneously or sequentially (start quinine first). If oral medication cannot be tolerated, then parenteral quinine should be administered as per Table 7.

Management of Non-falciparum Malaria (P. vivax, P. ovale, P. malariae)

Outside of New Guinea (Papua New Guinea and Papua [Irian Jaya]), chloroquine remains the treatment of choice for malaria other than falciparum malaria (as per Table 8 ). As with P. falciparum malaria, response to treatment should be documented with a 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 < 30 days after treatment suggests chloroquine-resistant P. vivax; recurrence after 30 days suggests primaquine resistance.

Recent reports have confirmed the presence and high prevalence (80%) of chloroquine-resistant P. vivax in Papua (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 it 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. Standard chloroquine doses (25 mg base/kg every 72 hours) combined with high-dose primaquine (2.5 mg base/kg every 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 (see contact information, Appendix VI).

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. Relapses caused by the persistent liver forms may appear months and, rarely, up to 5 years after exposure. None of the currently recommended chemo-prophylaxis regimens will prevent relapses due to these two species of Plasmodium. 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".

The possibility of G6PD deficiency should be excluded before antirelapse therapy with primaquine is given. In patients with known or suspected G6PD deficiency, expert medical advice should be sought, since primaquine may cause hemolysis in such patients. Primaquine use is contraindicated in pregnancy. P. vivax or P. ovale infections occurring during pregnancy should be treated with standard doses of chloroquine (Table 8). 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 not routinely recommended to prevent relapsing malaria in asymptomatic returning travellers (terminal prophylaxis). However, it is generally indicated for people with prolonged exposure in malaria-endemic areas where vivax or ovale malaria occurs (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 after the last 2 weeks of chemoprophylaxis (see Section 3 and Table 8 for dosage recommendations).

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. Therefore, the recommended dosage of primaquine to prevent relapse has increased to 30 mg (0.5 mg/kg) daily for 14 days.

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

Blood infection with P. malariae may persist for many years, but it is not life-threatening and is easily cured by a standard treatment course of chloroquine (see Table 8).

Table 7. Chemotherapy of severe OR complicated P. falciparum malaria

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