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Treatment of Malaria
- 1. Treatment of Malaria Dr Vishnu P D DNB medicine student Noble Hospital Pune
- 2. Etiology
- 4. Epidemiology Plasmodium species Distribution P. falciparum Africa, New Guinea, Hispaniola (i.e., the Dominican Republic and Haiti) , India , Eastern Asia and Oceania P. vivax Central and South America, India , Eastern Asia and Oceania P. ovale Africa P. malaria sub-Saharan Africa P. knowlesi Islands of Borneo, Southeast Asia
- 5. Epidemiological triad of malaria Humans
- 9. Genetic disorders which confer protection against malaria Sickle cell trait (Hb A/S) Hemoglobins C and E Hereditary ovalocytes G6PD deficiency
- 10. Clinical features Fever with rigors Headache Fatigue Myalgia Fatigue Abdominal discomfort Nausea and vomiting
- 13. Poor prognosis in severe malaria
- 15. Diagnosis
- 16. Aims of treatment Aims Causation Therapy Drugs To alleviate symptoms Symptoms are caused by blood forms of the parasite Blood schizonticidal drugs Chloroquine, quinine, artemisinin combinations To prevent relapses Relapses are due to hypnozoites of P. vivax / P. ovale Tissue schizonticidal drugs Primaquine To prevent spread Spread is through the gametocytes Gametocytocidal drugs Primaquine for P. falciparum, chroquine for all other
- 17. Principles of Treatment Type of infection. Severity of infection. Status of the host. Associated conditions/ diseases.
- 18. Type of infection P vivax Chloroquine 25mg/kg + Primaquine for 14 days P falciparum Artemisinin based combination therapy + Primaquine as gametocidal Mixed infections Blood schizonticidal as for P falciparum + Primaquine as for P vivax
- 19. Severity of infection All cases of severe malaria should be presumed to have P. falciparum malaria or treated as such. If there is any uncertainty about the drug sensitivity of the parasite, it is safer to treat these cases as chloroquine resistant malaria with drugs like quinine or artemisinin. All cases of severe malaria should be admitted to the hospital for proper evaluation, treatment and monitoring. All cases of severe malaria should be treated with injectable antimalarials (quinine, artemisinin derivatives) so as to ensure adequate absorption and plasma drug levels. Once the patient is able to take oral medications, artimisinin combination therapy must be used as per recommendations. All associated conditions should be carefully assessed and treated.
- 20. Status of the host Patient’s age and weight should be recorded so as to administer adequate doses of anti malarial drugs. Functional capacity- independent, dependent, bed ridden etc. Patients with nausea and vomiting should be given anti emetic drugs to ensure adequate treatment. Adequate hydration should be ensured.
- 21. Associated conditions/ diseases Pregnancy Epilepsy Cardiac disease Hepatic insufficiency Renal failure
- 22. Pregnancy Chloroquine can be used safely in all trimesters of pregnancy. Artemisinin can be safely used in the second and third trimester. Quinine can be used in pregnancy but one should be watchful about hypoglycaemia.
- 23. Pregnancy Mefloquine in first trimester Pyrimethamine/ Sulphadoxine in first and last trimester Halofantrine Tetracycline Doxycycline Primaquine
- 24. Epilepsy Malaria as well as anti malarials can trigger convulsions Mefloquine is better avoided
- 25. Cardiac disease High grade fever of malaria can exacerbate left ventricular failure Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, tetracyclines and primaquine can be safely used Quinine can also be used carefully Mefloquine and halofantrine are better avoided in patients with known cardiac illness.
- 26. Hepatic insufficiency None of the antimalarial drugs have any direct hepatotoxic effect Chloroquine is not advisable in patients with severe hepatic insufficiency
- 27. Renal failure The initial dose of antimalarial drugs need not be reduced The dose can be reduced by one third to half of usual doses if requiring parenteral antimalarials even after 3 days.
- 28. P vivax and P ovale Chloroquine Primaquine 25mg/kg in divided doses 0.5mg/kg 1st dose 600mg Daily OD for 14 days 2nd dose 300mg Mild G6PD deficiency, 0.75 mg/kg once weekly for 8 weeks. 3rd dose 300mg Primaquine should not be given in severe G6PD Deficiency 4th dose 300mg
- 29. Dose spacing for chloroquine 1st dose 2nd dose 3rd dose 4th dose If the patient comes in the morning and treatment can be started by mid-day Stat After 6 h After 24 h After 48 h If the patient comes in the afternoon and treatment is started by evening Stat After 12 h After 24 h After 36 h If the patient is coming from a far off place and /or if the MP test report is available only next day Stat ( as presumptive) 2nd and 3rd doses together after 24 hours After 48 h
- 30. P. malaria Chloroquine 25mg/kg in divided doses 1st dose 600mg 2nd dose 300mg 3rd dose 300mg 4th dose 300mg
- 31. Chloroquine
- 32. Hydroxychloroquine 800 mg (620 mg base) PO, then 400 mg (310 mg base) PO at 6 hr, 24 hr, and 48 hr after initial dose Weight-based dosing: 13 mg/kg (10 mg/kg base), not to exceed 800 mg (620 mg base) followed by 6.5 mg/kg (5 mg/kg base), not to exceed 400 mg (310 mg base), PO at 6 hr, 24 hr, and 48 hr after initial dose
- 33. HCQS 2 tablets stat followed by 1 tablet after 6h , 12h and 48h
- 34. Chloroquine resistant vivax malaria Amodiaquine 30mg/kg divided over 3 days as 10mg/kg daily once. Artesunate 2mg/kg qd for 7 days or quinine 10mg/kg tid for 7 days Plus 1 of the following 3: Tetracycline 4mg/kg qid for 7 days Doxycycline 3mg/kg qd for 7 days Clindamycin 10mg/kg bid for 7 days
- 35. Parenteral chloroquine Intravenous infusion 10 mg / kg (max.600mg) in isotonic fluid, over 8 hours; followed by 15 mg / kg (max.900mg) over 24 hours. Intramuscular or subcutaneous injections 3.5 mg of base/ kg (max.200 mg) every 6 hours or 2.5 mg of base/ kg (max.150mg) every 4 hours.
- 36. Parenteral CQ
- 37. Uncomplicated P. falciparum malaria Artemisinin-based Combination Therapy (ACT) Primaquine 0.75mg/kg on day 2
- 38. Artemisinin-based Combination Therapy (ACT) Artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. When given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective. When given in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required.
- 39. Global Deployment of Artemisinin Combination Therapy ACT Countries Using Failure Status Artemether + Lumefantrine 56 (Africa, SE Asia, Brazil, Venezuela) 0.8%-13% No more in Cambodia Artesunate + Amodiaquine 27 (Africa, Vietnam, Indonesia) >10% Used only in countries with failure rate <10% Artesunate + Mefloquine 8 (S America, SE Asia) <10% Artesunate + Sulfadoxine- Pyrimethamine 11 (India, Middle east) 0-1.5% Dihydroartemisinin + Piperaquine 8 (China, SE Asia) <10%
- 40. Treatment of uncomplicated P. falciparum ACT Day 1 Day 2 Day 3 Artesunate (AS) + Sulfadoxine– Pyrimethamine(SP) AS 4mg/kg (200mg) SP 25/1.25mg/kg (750+37.5mg )x 2 AS 4mg/kg (200mg) PQ 0.75mg/kg (15mg)x 3 AS 4mg/kg (200mg) - Artesunate (AS) + Amodiaquine (AQ) AS 4mg/kg (200mg) AQ 10mg/kg (600mg) AS 4mg/kg (200mg) AQ 10mg/kg (600mg) AS 4mg/kg (200mg) AQ 10mg/kg (600mg) Artesunate (AS) + Mefloquine (MQ) AS 4mg/kg (200mg) MQ 8mg/kg (500mg) AS 4mg/kg (200mg) MQ 8mg/kg (500mg) AS 4mg/kg (200mg) MQ 8mg/kg (500mg) - MQ 15mg/kg (1000mg) MQ 10mg/kg (500mg)
- 41. Treatment of uncomplicated P. falciparum ACT Day 1 Day 2 Day 3 Artemether (AM) + Lumefantrine (LUM) AM 1.5mg/kg + LUM 9mg/kg (80 + 480mg) bid AM 1.5mg/kg + LUM 9mg/kg (80 + 480mg) bid AM 1.5mg/kg + LUM 9mg/kg (80 + 480mg) bid Dihydroartemisinin (DHA) + Piperaquine (PIP) DHA 4mg/kg + PIP 18mg/kg (40+320mg)x 3-5 tab DHA 4mg/kg + PIP 18mg/kg (40+320mg)x 3-5 tab DHA 4mg/kg + PIP 18mg/kg (40+320mg)x 3-5 tab
- 43. Artesunate + Mefloquine 2 tablets per day for 3 days
- 44. Artemether Lumefantrine 1 tablet twice a day for 3 days
- 45. Uncomplicated P. falciparum malaria ACT-AL in North Eastern States ACT-SP in Other States
- 46. Mixed infection Full course of ACT and Primaquine 0.25 mg per kg body weight daily for 14 days.
- 47. Second line treatment Artesunate 2mg/kg qd for 7 days or quinine 10mg/kg tid for 7 days Plus 1 of the following 3: Tetracycline 4mg/kg qid for 7 days Doxycycline 3mg/kg qd for 7 days Clindamycin 10mg/kg bid for 7 days Atovaquone-proguanil (20/8 mg/kg qd for 3 days with food)
- 48. Malaria in Pregnancy P. vivax P. falciparum Chloroquine. Until delivery no Primaquine, but weekly 300mg Chloroquine Quinine 10mg/kg tid + Clindamycin 10mg/kg bid for 7 days ACT - ASP or AL Quinine + Clindamycin 1st trimester 2nd and 3rd trimester
- 49. Quinine 1 tablet thrice a day 2 tablets thrice a day
- 50. Severe Malaria Parenteral Artemisinin Available Not available Artesunate 2.4 mg/kg stat IV followed by 2.4 mg/kg at 12 and 24 h and then daily if necessary Artemether 3.2 mg/kg stat IM followed by 1.6 mg/kg qd Quinine dihydrochloride 20 mg /kg infused over 4 h, followed by 10 mg/kg infused over 2–8 h q8h Quinidine 10 mg /kg infused over 1–2 h, followed by 1.2 mg /kg per hour with ECG monitoring
- 51. Artesunate 120mg (1vial) stat f/b 120mg at 12h, then 24h and then OD.
- 52. Artemether 3.2 mg/kg stat IM followed by 1.6 mg/kg daily
- 53. Quinine 2amp (1200mg) in 500ml DNS over 5h f/b 1amp (600mg) infused over 2-8 hrs 8 hourly ( tid)
- 54. Severe Malaria First drug Follow- up Artesunate AS+SP AS+AQ AS+clindamycin or doxycycline Artemether AM+LUM Quinine Quinine 10 mg/kg three times a day for total 7 days (incl. iv )+ Doxycycline 100mg BID for 7 days OR Clindamycin 5mg/kg (300mg) for 7 days in children and pregnant women. Quinidine *Primaquine 0.75mg/kg on day 2
- 57. Drugs used in prophylaxis of malaria Drug Usage Adult dose Comments Chloroquine phosphate Prophylaxis only in areas with chloroquine- sensitive P. falciparumc or areas with P. vivax only 300 mg of base (500 mg of salt) PO once weekly Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Chloroquine phosphate may exacerbate psoriasis.
- 58. Drugs used in prophylaxis of malaria Drug Usage Adult dose Comments Hydroxychloroquine sulfate An alternative to chloroquine for primary prophylaxis only in areas with chloroquine- sensitive P. falciparum or areas with P. vivax only 310 mg of base (400 mg of salt) PO once weekly Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Hydroxychloroquine may exacerbate psoriasis.
- 59. Drugs used in prophylaxis of malaria Drug Usage Adult dose Comments Doxycycline Prophylaxis in areas with chloroquine- or mefloquine-resistant P. falciparum 100 mg PO qd Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 4 weeks after leaving such areas. Doxycycline is contraindicated in children aged <8 years and in pregnant women after 15 weeks of gestation.
- 60. Drugs used in prophylaxis of malaria Drug Usage Adult dose Comments Mefloquine Prophylaxis in areas with chloroquine- resistant P. falciparum 228 mg of base (250 mg of salt) PO once weekly Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. MQ is contraindicated in persons allergic to this drug or related compounds (e.g., quinine and quinidine) and in persons with active or recent depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Use with caution in persons with psychiatric disturbances or a history of depression. MQ is not recommended for persons with cardiac conduction abnormalities.
- 61. Drugs used in prophylaxis of malaria Drug Usage Adult dose Comments Primaquine For prevention of malaria in areas with mainly P. vivax 30 mg of base (52.6 mg of salt) PO qd Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 7 days after leaving such areas. Primaquine is contraindicated in persons with G6PD deficiency. It is also contraindicated during pregnancy.
- 62. “Thank you.”
Editor's Notes
- The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites . (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver (if untreated) and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony ), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony ). Merozoites infect red blood cells . The ring stage trophozoites mature into schizonts, which rupture releasing merozoites . Some parasites differentiate into sexual erythrocytic stages (gametocytes) . Blood stage parasites are responsible for the clinical manifestations of the disease. The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal . The parasites’ multiplication in the mosquito is known as the sporogonic cycle . While in the mosquito’s stomach, the microgametes penetrate the macrogametes generating zygotes . The zygotes in turn become motile and elongated (ookinetes) which invade the midgut wall of the mosquito where they develop into oocysts . The oocysts grow, rupture, and release sporozoites, which make their way to the mosquito’s salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.
- Adhesion of infected erythrocytes to vascular endothelial cell Infected erythrocytes express parasite derived PfEMP-1 proteins on the cell surface. These proteins have a high affinity for membrane receptors such as CD36 and ICAM-1 expressed on vascular endothelial cells. These structural changes in the infected red cells and the resulting increase in their rigidity and adhesiveness are major contributors to the virulence for P. falciparum malaria. Owing to the increased adhesiveness, the red cells infected with late stages of P. falciparum (during the second half of the 48 hour life cycle) adhere to the capillary and postcapillary venular endothelium in the deep microvasculature (cytoadherence). The infected red cells also adhere to the uninfected red cells, resulting in the formation of red cell rosettes (rosetting). Cytoadherence leads to sequestration of the parasites in various organs such as the heart, lung, brain, liver, kidney, intestines, adipose tissue, subcutaneous tissues, and placenta. Sequestration of the growing P. falciparum parasites in these deeper tissues provides them the microaerophilic venous environment that is better suited for their maturation and the adhesion to endothelium allows them to escape clearance by the spleen and to hide from the immune system. These factors help the falciparum parasites to undergo unbridled multiplication, thereby increasing the parasite load to very high numbers. Due to the sequestration of the growing parasites in the deeper vasculature, only the ring-stage trophozoites of P. falciparum are seen circulating in the peripheral blood, while the more mature trophozoites and schizonts are bound in the deep microvasculature, hence seldom seen on peripheral blood examination. If the cytoadherence-rosetting-sequestration of infected and uninfected erythrocytes in the vital organs goes on uninhibited, it ultimately blocks blood flow, limits the local oxygen supply, hampers mitochondrial ATP synthesis, and stimulates cytokine production – all these factors contributing to the development of severe disease. The microvascular congestion, secondary to adhesion between parasitized RBCs and endothelial cells, results in protean clinical manifestations. Complications generally occur in the tissues most sensitive to hypoxia and ischemia. Alterations in cerebral blood flow cause mental status changes, including disorientation, headache, coma, and death. Hepatic and gastrointestinal involvement may result in jaundice and enterocolitis, respectively. Involvement of the alveolar capillaries causes noncardiogenic pulmonary edema, which may be exacerbated by fluid retention secondary to renal failure. Oxygen exchange may be further compromised with the development of adult respiratory distress syndrome. Acute renal failure is multifactorial and results from the renal overload of free hemoglobin and malarial pigment, as well as the microvascular compromise and associated hypoxia. Microvascular damage may result in activation of the coagulation and thrombolytic cascades. Disseminated intravascular coagulation exacerbates the hemolytic anemia and further compromises an already insufficient microvascular circulation.
- Innate immune response to Plasmodium falciparum Control of the malaria parasite growth is dependent on a strong cell-mediated immune response mainly due to the pro-inflammatory cytokines IL-12 and INF-a. Furthermore, the innate immune responses to merozoites occurs by stimulation of toll like receptors, namely TLR2, which binds GPI and TLR9 that binds parasite dsDNA. Once these receptors are stimulated they cause secretion of the pro-inflammatory cytokines IL-1, IL-6 and TNF-a that cause fever, the hallmark of malaria infections. Adaptive immune response to Plasmodium falciparum Specific immune responses are required to control the infection at multiple points in the parasite life cycle. Both humoral and cell-mediated responses are invoked. Antibodies to sporozoites are the first immune response designed to prevent the parasite from reaching the liver. If they get to the liver then within the liver CD8+ cytotoxic T lymphocytes destroy infected hepatocytes via HLA class I antigen recognition. Thereafter, antibodies to free merozoites work to block infection of new erythrocytes. If the parasite has succeeded in infecting more erythrocytes antibodies to parasite proteins on the surface of infected erythrocytes bring about removal by phagocytosis, especially in the spleen. The final response is the formation of antibodies to gametocytes which hinders the development of parasites in the mosquito vector.
- The cytokines of the proinflammatory cascade like tumor necrosis factor, interleukins, interferon-γ, and nitric oxide act as double-edged swords in the pathogenesis of malaria. Cytokines act as homeostatic agents and an early proinflammatory cytokine response helps in limiting the infection, with the cytokines inhibiting the growth of malarial parasites in lower concentrations. On the other, failure to down-regulate this inflammatory response results in progressive immune pathology, leading to complications. Excessive levels of cytokines can lead to decreased mitochondrial oxygen use and enhanced lactate production; increased cytoadherence that in turn causes microvascular obstruction and more hypoxia; disturbed auto-regulation of local blood flow leading to poor circulation and further tissue hypoxia; dyserythropoiesis, poor red cell deformability and multifactorial anemia; reduced gluconeogenesis and hypoglycemia; myocardial depression and cardiac insufficiency; loss of endothelial integrity and vascular damage in the lungs and brain; selective upregulation of vascular and intercellular adhesion molecules (ICAMs), particularly in the brain and placenta leading to cerebral malaria and placental dysfunction; and activation of leukocytes and platelets, promoting procoagulant activity.[2-5,20,22-28] It can therefore be said that the outcome of malaria infection is determined by the balance between the pro- and anti-inflammatory cytokines.[2,5,22] Some of the complications seen in P. vivax malaria may be related to cytokine-mediated injury. P. vivax has been reported to induce a greater inflammatory response than P. falciparum (with equal or greater parasite load), resulting in higher levels of cytokine release. The pyrogenic threshold is also lower in P. vivax infections, resulting in fever at lower levels of parasitemia.
- Sickle cell trait: Hemoglobin S–containing RBCs impair parasite growth at low oxygen tensions, and P. falciparum–infected RBCs containing hemoglobin S or C exhibit reduced cytoadherence because of reduced surface presentation of the adhesin PfEMP1. Ovalocytes: rigid erythrocytes resist merozoite invasion, and the intraerythrocytic milieu is hostile.
- Malaria cannot be diagnosed clinically with accuracy, but treatment should be started on clinical grounds if laboratory confirmation is likely to be delayed. In areas of the world where malaria is endemic and transmission rates are high, low-level asymptomatic parasitemia is common in otherwise healthy people. Thus malaria may not be the cause of a fever, although in this context the presence of >10,000 parasites/μL (~0.2% parasitemia) does indicate that malaria is the cause. Antibody and polymerase chain reaction (PCR) tests have no role in the diagnosis of malaria except that PCR is increasingly used for genotyping and speciation in mixed infections and for detection of low-level parasitemia in asymptomatic residents of endemic areas. Asexual parasites/200 WBCs × 40 = parasite count/μL (assumes a WBC count of 8000/μL). P. falciparum gametocytemia may persist for days or weeks after clearance of asexual parasites. Gametocytemia without asexual parasitemia does not indicate active infection. Parasitized RBCs (%) × hematocrit × 1256 = parasite count/μL. The presence of >100,000 parasites/μL (~2% parasitemia) is associated with an increased risk of severe malaria, but some patients have severe malaria with lower counts. At any level of parasitemia, the finding that >50% of parasites are tiny rings (cytoplasm thickness less than half of nucleus width) carries a relatively good prognosis. The presence of visible pigment in >20% of parasites or of phagocytosed pigment in >5% of polymorphonuclear leukocytes (indicating massive recent schizogony) carries a worse prognosis. fPersistence of PfHRP2 is a disadvantage in high-transmission settings, where many asymptomatic people have positive tests, but can be used to diagnostic advantage in low-transmission settings when a sick patient has previously received unknown treatment (which, in endemic areas, often consists of antimalarial drugs). In this situation, a positive PfHRP2 test indicates that the illness is falciparum malaria, even if the blood smear is negative.
- Parenteral chloroquine (rarely needed these days) may be needed in patients with drug sensitive malaria with persistent vomiting. It should never be used as a bolus injection. Intramuscular injection can cause fatal hypotension, especially in children.
- They reduce parasite numbers by a factor of approximately 10 000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000-fold per cycle). Artemisinin and its derivatives are eliminated rapidly.
- AM+LUM: Fat-containing food (like milk or butter) enhances the absorption of this ACT
- Mefloquine is the only drug advised for pregnant women traveling to areas with drug-resistant malaria; this drug is generally considered safe in the second and third trimesters of pregnancy. Intermittent preventive treatment to pregnant women(IPTp): involves giving treatment doses of sulfadoxine-pyrimethamine at each antenatal visit (maximum, once monthly) in the second and third trimesters of pregnancy.
- Mefloquine is the only drug advised for pregnant women traveling to areas with drug-resistant malaria; this drug is generally considered safe in the second and third trimesters of pregnancy. Intermittent preventive treatment to pregnant women(IPTp): involves giving treatment doses of sulfadoxine-pyrimethamine at each antenatal visit (maximum, once monthly) in the second and third trimesters of pregnancy.