ARCHIVED - Supplement: Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers

7. Treatment of Malaria

Uncomplicated malaria refers to symptomatic malaria without evidence of severe disease or evidence of vital organ dysfunction. The objective of treating uncomplicated malaria is to cure the infection. This is important since treatment will, in cases of P. Falciparum, help prevent progression to severe disease. When choosing treatment regimens, drug tolerability, the adverse effect profile and the speed of therapeutic response are important considerations.

Severe or complicated malaria refers to symptomatic malaria with hyperparasitemia (= 5%) or evidence of end organ damage/complications, as listed in Table 3. The primary objective of treatment is to prevent death. For cerebral malaria, prevention of neurological deficits is also an important objective.

In the treatment of severe malaria in pregnancy, saving the life of the mother is the primary objective. The prevention of recrudescence and avoidance of minor adverse effects are secondary.

In Canada, all patients (especially children) with malaria due to P. Falciparum should be considered for admission to hospital or should receive initial treatment in an observation unit to ensure that treatment can be tolerated and to confirm decreasing parasitemia with treatment. Severe or complicated disease (Table 3) or the inability to tolerate oral therapy 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 (CMN ) in the appropriate area (see contact information in Appendix V).

* In a patient with P. Falciparum asexual parasitemia and no other obvious cause of symptoms, the presence of one or more of the clinical or laboratory features in the Table classifies the patient as suffering from severe malaria.
Adapted from: Guidelines for the treatment of malaria, World Health Organization. 2006, Geneva⁽¹²⁶⁾.

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. At times, management decisions may be necessary before parasitology laboratory results become available. When managing malaria, there are three questions that need to be addressed in order to initiate effective treatment:

1. Is this infection caused by P. Falciparum? Treatment varies according to the species of malaria (see below).
2. Is this a severe or complicated infection? (see Table 3) Severe or complicated malaria usually requires parenteral therapy and sometimes an exchange transfusion. Parenteral artesunate and/or quinine are available through the CMN (see Appendix V).
3. Has the infection been acquired in an area of known drug-resistant malaria? (see Appendix I) Treatment should be adjusted accordingly.

Management of Falciparum Malaria The following guidelines have been derived, in part, from the WHO Guidelines for the Treatment of Malaria(126) and Management of Severe Malaria (175). The interested reader is referred to these documents for a more detailed discussion of these issues. As a rule, all non-immune patients and all children with P. Falciparum malaria, whether severe or not, should be considered for admission to hospital in order to ensure that antimalarial drugs are tolerated 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 the drug has been tolerated before discharge from the emergency department. To prevent adverse outcomes, prior to discharge further treatment doses should be 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 1. This algorithm is based on two essential requirements, a timely (within 2 hours) parasitology laboratory result, and the timely (within 1-2 hours) availability of an appropriate antimalarial drug. Malaria management when these important prerequisites are not available is discussed below. Treatment of malaria does not stop with the selection of appropriate antimalarial medications. For all malaria cases clinical assessment should be carried out daily until fever ends, and at any time there is a recurrence of symptoms; for P. Falciparum cases, repeat malaria smears should be carried out daily until negative.

Severe malaria

Treatment of severe malaria is the same for all species of Plasmodium. Severe malaria is usually due to Falciparum infection. Although P. vivaxis considered to be a benign infection, it very occasionally leads to severe disease, including severe anemia, severe thrombocytopenia, pancytopenia, jaundice, splenic rupture, acute renal failure and acute respiratory distress syndrome(176, 177, 178, 179). Prompt and effective treatment and case management should be the same as for severe and complicated Falciparum malaria (see next). Severe P. Falciparum infections may have a mortality rate of 20% or higher. Patients with these infections require immediate hospitalization and urgent, intensive medical management, ideally, in an intensive care unit(180). Clinical observations should be made as frequently as possible and should include vital sign monitoring, with accurate assessment of respiratory rate and pattern, coma score and urine output. Blood glucose should be monitored every 4 hours using rapid stick tests, especially in unconscious patients. Seizures should be treated promptly with benzodiazepines; however, there is no role for prophylactic antiseizure medication(126). Individuals with severe Falciparum malaria are at risk of all the adverse outcomes defined in Table 3, as well as other adverse outcomes, including permanent neurologic deficits, chronic renal insufficiency and death.

Two classes of drugs are effective for the parenteral treatment of severe malaria, cinchona alkaloids (quinine and quinidine) and the artemesinin derivatives (artesunate, artemether and artemotil). A recent report of an open-labeled, randomized controlled trial in 1,461 patients with severe Falciparum malaria in Asia demonstrated a 35% reduction in mortality (15% vs 22%). The authors, along with the WHO, advocate that artesunate should become the treatment of choice for severe Falciparum malaria in adults^{(126,133, 181)}.

All patients with severe P. Falciparum infections and all those who are unable to tolerate drugs orally should receive parenteral therapy. Intravenous artesunate and/or quinine (see Table 4) are available 24 hours per day through the CMN (see Appendix V for more information). When available, the use of parenteral artesunate is preferable to parenteral quinine for 1) the treatment of severe malaria, 2) when the patient is unable to take or tolerate oral medications or 3) when there is a quinine intolerance, contraindication or failure. If neither parenteral artesunate nor parenteral quinine or quinidine is available within an hour of the diagnosis of severe malaria, oral quinine can be started, if necessary after a dose of an anti-emetic to decrease the risk of vomiting or by nasogastric tube, while awaiting parenteral therapy. Parenteral quinine is preferred over quinidine because the cardiotoxicity of quinidine requires 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 not receive a loading dose of therapy and should be monitored electrocardiographically.

Many ancillary treatments have been suggested for the management of severe malaria, but few have been shown to improve outcome(126). Fluid resuscitation should be individualized on the basis of estimated deficit. The optimal rate of resuscitation, the role of colloids versus crystalloids, and the optimal electrolyte composition of the resuscitation solution have not been established. Hypoglycemia (potentially exacerbated by quinine therapy, which stimulates insulin release) should be suspected in any patient who deteriorates suddenly and should be treated immediately. The use of steroids to treat severe or cerebral malaria has been associated with worse outcomes and should be avoided(182). In cases of complicated P. Falciparum infection with high parasitemia (> 10%), exchange transfusion has been used on an experimental basis as a potentially life-saving procedure. The rational for the use of exchange blood transfusion includes the following: 1) the removal of infected red blood cells (RBCs ) from the circulation and thereby reduction of the parasite load; 2) rapid reduction of the antigen load and burden of parasitederived toxins and metabolites; 3) removal of hostderived toxic mediators; and 4) replacement of rigid unparasitized RBCs with normal functioning cells, which thereby reduces microcirculatory obstruction. Exchange blood transfusion requires a safe blood supply, intensive nursing and multiple units of packed red blood cells (PRBC ). There is no consensus on the indications or on the volume of blood to be exchanged; however, a volume of 5-10 PRBC units should be anticipated(183, 184). 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 for the CMN ).

Table 4: Chemotherapy of severe or complicated P Falciparum malaria

Parenteral artesunate therapy and/or quinine is available 24 hours per day through the Canadian Malaria Network. For contact information see Appendix V or http://www.travelhealth.gc.ca.
Note: A switch to oral therapy should be made as soon as possible.

PARENTERAL ARTESUNATE
Artesunate is given, over 1-2 minutes, as a 2.4 mg/kg intravenous bolus at 0, 12, 24 and 48 hours, and then therapy is continued with oral medications (e.g., doxycycline, atovaquone/proguanil or clindamycin). If oral medications are not possible, daily artesunate doses can continue for a total of 7 days

PLUS (start 4 hours after final dose of artesunak)

1. Atovaquone/proguanil: adults, 4 tablets daily for 3 days; pediatric, 20 mg/kg atovaquone and 8 mg/kg proguanil once daily x 3 days OR
2. Doxycycline: adults, 100 mg orally twice daily for 7 days; pediatric dose, 2 mg/kg (to a maximum of 100 mg) twice daily (contraindications: pregnancy, breast-feeding or if age < 8 years). OR
3. Clindamycin: 10 mg/kg (loading dose) intravenously, followed by 5 mg/kg every 8 hours for a total of 7 days (should be used only if patient is unable to take doxycycline or atovaquone/proguanil).

PARENTERAL QUININE*

1. If an infusion pump is available: quinine (base) 5.8 mg/kg loading dose (quinine dihydrochloride [salt] 7 mg/kg) intravenously by infusion pump over 30 minutes followed immediately by 8.3 mg base/kg (quinine dihydrochloride [salt] 10 mg/kg) diluted in 10 mL/kg isotonic fluid by intravenous infusion over 4 hours (maintenance dose), repeated 8 hourly until the patient can swallow, then quinine tablets to complete 3 to 7 days of treatment (7 days for SE Asia).
2. Without an infusion pump: quinine (base) 16.7 mg/kg loading dose, (quinine dihydrochloride [salt] 20 mg/kg) by intravenous infusion over 4 hours, then 8.3 mg base/kg (quinine dihydrochloride [salt] 10 mg/kg) diluted in 10 mL/kg isotonic fluid by intravenous infusion over 4 hours (maintenance dose), repeated 8 hourly until the
   patient can swallow, then quinine tablets to complete 5 to 7 days of treatment (7 days for SE Asia).
   PLUS (either concurrently or immediately after quinine)
3. Atovaquone/proguanil: 4 tablets once daily for three days (see Table 6, Chapter 8, for pediatric dosage).
   OR
4. Doxycycline: 100 mg orally twice daily for 7 days; pediatric dose, 2 mg/kg (to a maximum of 100 mg) twice daily (contraindications: pregnancy, breast-feeding or if age < 8 years). OR
5. Clindamycin: 10 mg/kg (loading dose) intravenously, followed by 5 mg/kg every 8 hours until blood is clear of sexual parasites (should be used only if patient is unable to take doxycycline or atovaquone/proguanil).

*Loading dose should not be used if patient received quinine or quinidine within the preceding 24 hours or mefloquine within the preceding 2 weeks. Parenteral quinine dihydrochloride may be obtained through the Canadian Malaria Network (see Appendix V for contact information).
Switch to oral therapy as soon as possible. In patients requiring > 48 hours of parenteral therapy, reduce the quinine maintenance dose by one third to one-half.

Note: Parenteral quinidine should be used only if parenteral quinine is unavailable. Because of increased risk of cardiac toxic effects with quinidine, cardiac monitoring is required. Parenteral quinidine gluconate may be obtained on a patient-by-patient basis with authorization from the Special Access Programme, Therapeutic Products Directorate, 2nd Floor, Holland Cross, Tower A 11 Holland Ave., A.L. 3002C Ottawa, ON, K1A 0K9. TEL: (613) 941-2108 FAX: (613) 941-3194; E-MAIL: SAPdrugs@hc-sc.gc.ca (613) 941-3061 (after hours).

 

Figure 1: Algorithm for the management of malaria

Uncomplicated P. Falciparum

Uncomplicated cases of P. Falciparum can progress to severe malaria if not treated and monitored properly. Infections acquired in a chloroquine-sensitive zone may be treated with chloroquine alone (as per Table 6, Chapter 8). The WHO advocates the use of oral combination therapy containing artemesinin derivatives as the first choice for oral therapy(126). Until these agents are available in Canada, 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 and a second drug (preferably doxycycline). If the patient can tolerate quinine orally, quinine and doxycycline (or clindamycin for those in whom doxycycline is contraindicated) should be administered simultaneously or sequentially (start quinine first). If oral medication cannot be tolerated, parenteral artesunate or quinine should be administered as per Table 6, Chapter 8.

Chloroquine remains the treatment of choice for nonFalciparum malaria outside of New Guinea (Papua New Guinea and Papua [Irian Jaya]) as per Table 6, Chapter 8. A clinical assessment should be carried out daily until fever ends and any time there is a recurrence of symptoms. A recurrence of asexual parasitemia < 30 days after treatment suggests chloroquine-resistant P. vivax; recurrence after 30 days suggests primaquine-resistant P. vivax.

Recent reports have confirmed the presence and high prevalence (80%) of chloroquine-resistant P. vivaxin Irian Jaya. Sporadic cases of chloroquine-resistant P. vivaxmalaria have been reported elsewhere (e.g., in Indonesia, Papua New Guinea, the Solomon Islands, Myanmar and Guyana⁽⁷²⁾). At present, chloroquine can no longer be relied upon either for chemoprophylaxis or treatment of P. vivaxacquired in New Guinea, and the optimal treatment is unknown. A 7-day course of quinine is often required to cure P. vivaxinfection from New Guinea^{(126, 175)}. Mefloquine and halofantrine have been shown to be efficacious in small clinical trials, but each is limited by safety issues associated with therapeutic doses⁽¹²⁶⁾.

Standard chloroquine doses (25 mg base/kg over 72 hours) combined with high-dose primaquine (0.5 mg base/kg daily for 14 days) have been suggested as treatment for chloroquine-resistant P. vivaxacquired in Irian Jaya but have failed in cases from Guyana. Limited data also suggest that a combination of standard dose atovaquone/ proguanil (4 tablets daily x 3 days) in combination with primaquine (0.5 mg base/kg daily x 14 days) may be effective⁽¹⁸⁵⁾. Expert advice from an infectious or tropical disease specialist should be sought for the management of these cases (see CMN contact information, Appendix V).

Management of Malaria When Laboratory Results or Treatment Drugs Are Delayed

When a case is diagnosed as a severe or complicated P. Falciparum infection and parenteral quinine or artesunate is indicated but will not be available for more than an hour, it is appropriate to start quinine orally (after a dose of gravol or by nasogastric tube if necessary) until the parenteral drug becomes available. If fever, travel history and initial laboratory findings (low white blood count and/or platelets) suggest a diagnosis of malaria and the malaria smear is delayed more than 2 hours, it is appropriate to start an antimalarial.

Primaquine Treatment

P. vivax and P. ovale have a persistent liver phase (hypnozoites) that is responsible for relapses and susceptible only to treatment with primaquine. Relapses caused by the persistent liver forms may appear months and, rarely, up to 5 years after exposure. None of the currently recommended chemoprophylaxis regimens will prevent relapsedue to these two species of Plasmodium. In order to reduce the risk of relapse following the treatment of symptomatic P. vivaxor 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. A recent retrospective study of 63,302 US army personnel found G6PD deficiency in 2.5% of males and 1.6% females. The highest rates were among African American males (12.2%), followed by Asian males (4.3%), African American females (4.1%), Hispanics (males 2%; females 1.2%), and Asian females (0.9%). The rates among Caucasians were low (0.3% males and 0/4018 females). None had class I deficiency; however, 46 males and one female had class II deficiency, which can be associated with severe, life-threatening hemolysis(186).

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. vivaxor P. ovale infections during pregnancy should be treated with standard doses of chloroquine (Table 6, Chapter 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 Chapter 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 Chapter 3 and Table 6 for dosage recommendations).

P. vivaxisolates with a decreased responsiveness to primaquine are well documented in Southeast Asia, in particular Papua New Guinea and Papua. Recently, primaquine radical treatment failure has been reported from Thailand and Somalia. As well, there have been reports of primaquine radical treatment failure from other areas⁽¹⁸⁷⁾. Therefore, the recommended dosage of primaquine to prevent relapse has increased to 30 mg (0.5 mg/kg) base daily for 14 days. 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 6).

Plasmodium knowlesi has emerged as a threat in Southeast Asia. It can be confused by microscopists as P. malariae but has a higher (> 1%) parasitemia than is seen in P. malariae infections. Systemic symptoms and complications can mimic P. Falciparum malaria. It is suggested that patients from Southeast Asia with parasite levels > 1% and a parasite morphology resembling that of P. malariae be diagnosed as P. knowlesi. Treatment with chloroquine is reportedly effective, but systemic symptoms and complications similar to hyperparasitemic P. Falciparum infections require very close monitoring and careful management^{(1, 188)}.

 

Self-treatment of Presumptive Malaria

Self-treatment of malaria has received little study, yet it is a frequent occurrence that demands guidelines and good advice for the traveller. Counsel is of particular value for all travellers to regions of high malaria endemicity, remote access or limited medical resources. Ninety percent of global episodes of malaria morbidity and mortality occur in sub- Saharan Africa; therefore, particular focus should be given to persons travelling to that region. Reasons for self-treatment include travel to remote regions where health care is a problem and travel to regions where malaria risk is small and the traveller would rather use self-treatment rather than long-term prophylaxis(125, 191, 192, 193). If presumptive self-therapy is prescribed, the traveller should be informed of the following points.

• Travellers to high-risk regions should never rely exclusively on a self-treatment regimen^{(20, 75, 193, 194)}.
• Individuals at risk of malaria and unable to seek medical care within 24 hours or adequate malaria treatment drugs should carry medication for self-treatment of presumptive malaria⁽¹⁹³⁾.
• The signs and symptoms of malaria are nonspecific; malaria can be mimicked by influenza, dengue, typhoid, meningitis and febrile gastroenteritis.
• Self-treatment should never be undertaken lightly as there are potential adverse reactions to malaria therapy.
• Neither expatriates nor physicians can diagnose malaria without a malaria laboratory test^{(121, 195, 196)}.
• A combination drug treatment is better than a single drug⁽¹²⁶⁾.
• Although not recommended by the WHO, semiimmune locals may benefit from partial treatment; the non-immune traveller must always take full treatment(126).
• Both false-negative and false-positive malaria smears are reported to varying degree by all
  malaria diagnostic laboratories.
• Self-treatment is not definitive treatment but, rather, a temporary, life-saving measure while
  medical attention is sought within 24 hours.
• Presumptive treatment with a drug being used by the traveller for suppression is not appropriate^{(20, 125, 193)}.