1. Malaria Prevention and Treatment Javier F Sevilla Mártir, MD Associate Professor, Department of Family Medicine, IU School of Medicine Kristal Williams, PharmD, CDE Assistant Professor, Department of Pharmacy Practice, Butler University Clinical Instructor, Department of Family Medicine, IU School of Medicine Lauren Bley – Kenning, PharmD PGY – 2 Resident, Department of Pharmacy Practice, Butler University / Department of Family Medicine, IU School of Medicine AAFP Global Health Workshop; Denver, 2009

2. Objectives Discuss current trends in malaria for various regions of the world Discuss current trends in malaria for various regions of the world Describe the WHO Global Malaria program and specific experiences from participants Describe the WHO Global Malaria program and specific experiences from participants Discuss geographically appropriate prophylaxis and treatment of malaria based on WHO specified resistance patterns Discuss geographically appropriate prophylaxis and treatment of malaria based on WHO specified resistance patterns

3. Introduction According to the WHO Malaria Report: Malaria is the most important tropical disease, remaining widespread throughout the tropics and also occurring in many temperate regions. Malaria is the most important tropical disease, remaining widespread throughout the tropics and also occurring in many temperate regions. It exacts a heavy toll of illness and death, especially amongst children and pregnant women. It also poses a risk to travelers and immigrants, with imported cases increasing in non-endemic areas. It exacts a heavy toll of illness and death, especially amongst children and pregnant women. It also poses a risk to travelers and immigrants, with imported cases increasing in non-endemic areas. WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

4. Introduction (cont) Malaria has become a global problem. It is endemic in 105 countries and is responsible for over 300 to 500 million clinical cases and more than one million deaths each year. Malaria has become a global problem. It is endemic in 105 countries and is responsible for over 300 to 500 million clinical cases and more than one million deaths each year. Treatment and control have become more difficult with the spread of drug-resistant strains of parasites and insecticide-resistant strains of mosquito vectors. Treatment and control have become more difficult with the spread of drug-resistant strains of parasites and insecticide-resistant strains of mosquito vectors. WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

5. Introduction (cont) Health education, improved case management, enhanced control tools and concerted action are needed to limit the burden of disease. Health education, improved case management, enhanced control tools and concerted action are needed to limit the burden of disease. Numerous epidemiologic and ecologic factors play a vital role in determining the effect of malaria on human health and the intensity of transmission. Immunological status is a predictor of disease severity. Numerous epidemiologic and ecologic factors play a vital role in determining the effect of malaria on human health and the intensity of transmission. Immunological status is a predictor of disease severity. WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

6. WHO Malaria Key Facts A child dies of malaria every 30 seconds A child dies of malaria every 30 seconds Malaria is preventable and curable Malaria is preventable and curable Approximately half of the world is at risk for developing malaria Approximately half of the world is at risk for developing malaria Travelers to “hot spots” are especially vulnerable Travelers to “hot spots” are especially vulnerable Malaria causes a significant economic burden Malaria causes a significant economic burden WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

7. WHO Malaria Region Profiles Europe From 1995-2007, the reported number of malaria cases in the Region declined from 90,712 to 1226. From 1995-2007, the reported number of malaria cases in the Region declined from 90,712 to 1226. Presently, malaria continues to pose a challenge in 6 out of the 53 member countries of the Region, namely Azerbaijan, Georgia, Kyrgyzstan, Tajikistan, Turkey and Uzbekistan. Presently, malaria continues to pose a challenge in 6 out of the 53 member countries of the Region, namely Azerbaijan, Georgia, Kyrgyzstan, Tajikistan, Turkey and Uzbekistan. http://www.euro.who.int/malaria/ctryinfo/ctryinfotop WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

8. WHO Malaria Region Profiles Africa An estimated 247 million episodes in 2006 An estimated 247 million episodes in 2006 Eighty-six percent, or 212 million cases, occurred in the African Region Eighty-six percent, or 212 million cases, occurred in the African Region 80% of African cases were in 13 countries 80% of African cases were in 13 countries Over half of the cases in Africa were in Nigeria, Democratic Republic of the Congo, Ethiopia, United Republic of Tanzania and Kenya. Over half of the cases in Africa were in Nigeria, Democratic Republic of the Congo, Ethiopia, United Republic of Tanzania and Kenya. http://www.afro.who.int/malaria/country-profile/ WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

9. WHO Malaria Region Profiles EMR 50% of the population (approximately 248 million people) in the Eastern Mediteranean Region (EMR) reside in areas of risk for malaria transmission. 50% of the population (approximately 248 million people) in the Eastern Mediteranean Region (EMR) reside in areas of risk for malaria transmission. Reported malaria cases (about 6.1 million in 2000; 4.5 million in 2003; and 2.7 million in 2005) represent only a fraction of true incidence. Reported malaria cases (about 6.1 million in 2000; 4.5 million in 2003; and 2.7 million in 2005) represent only a fraction of true incidence. It is estimated that about 10 million malaria episodes and 49,000 malaria-related deaths occurs yearly in the region. It is estimated that about 10 million malaria episodes and 49,000 malaria-related deaths occurs yearly in the region. http://www.emro.who.int/rbm/Epidemiology-current.htm WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

10. WHO Malaria Country Profiles SEA 687 million people in the South-East Asia Region (SEA) are at high risk for malaria, with an estimated 90-160 million infections and more than 120,000 deaths occurring each year 687 million people in the South-East Asia Region (SEA) are at high risk for malaria, with an estimated 90-160 million infections and more than 120,000 deaths occurring each year http://www.searo.who.int/EN/Section10/Section21.htm WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

11. WHO Malaria Country Profiles WPR Malaria is still endemic in 10 countries of the Western Pacific Region (WPR), associated with poverty and retarding progress towards economic well-being among the affected communities. Malaria is still endemic in 10 countries of the Western Pacific Region (WPR), associated with poverty and retarding progress towards economic well-being among the affected communities. http://www.wpro.who.int/health_topics/malaria/general_info.htm WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

12. WHO Malaria Country Profiles Americas From more than 1.1 million cases reported in 2000, the Region lowered malaria morbidity to approximately 775,000 in 2007, a 32% decrease. From more than 1.1 million cases reported in 2000, the Region lowered malaria morbidity to approximately 775,000 in 2007, a 32% decrease. The overall decreased incidence in 16 countries and increase in 5 countries were monitored in the context of strengthened health surveillance systems. The overall decreased incidence in 16 countries and increase in 5 countries were monitored in the context of strengthened health surveillance systems. http://www.paho.org/english/ad/dpc/cd/malaria.htm WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

13. Causative Agents of Malaria Caused by parasites of the species Plasmodium Caused by parasites of the species Plasmodium  P. falciparum (highest mortality)  P. vivax (most common)  P. ovale  P. malariae WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

14. The Vector / Transmission Infected female mosquitoes of the anopheles species Infected female mosquitoes of the anopheles species More than 400 Plasmodium species More than 400 Plasmodium species 30 - 40 species capable of disease transmission 30 - 40 species capable of disease transmission WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

15. www.dpd.cdc.gov/dpdx

16. Clinical Manifestations Malaria parasites multiply rapidly in the liver, then in red blood cells. Malaria parasites multiply rapidly in the liver, then in red blood cells. One to two weeks after a person is infected, the first symptoms of malaria appear. Symptoms commonly include: One to two weeks after a person is infected, the first symptoms of malaria appear. Symptoms commonly include:  Fever  Headache  Chills  Malaise  Joint pain  Vomiting WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

17. Clinical Manifestations (cont) If not treated promptly with effective medicines, malaria may cause mortality by infecting and destroying red blood cells which clog the capillaries carrying blood to the brain or other vital organs potentially causing the following: If not treated promptly with effective medicines, malaria may cause mortality by infecting and destroying red blood cells which clog the capillaries carrying blood to the brain or other vital organs potentially causing the following:  Renal failure  Hypoglycemia  Anemia  Pulmonary edema  Shock and coma WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

18. Diagnosis Light microscopy Light microscopy –Gold standard is thick & thin blood smears Fluorescent microscopy Fluorescent microscopy –Quantitative Buffy-Coat (QBC) method PCR-based detection PCR-based detection –Sensitivity and specificity essentially 100% Antigen detection Antigen detection –Finger-prick dipstick test WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

19. Prevention in Travelers Chemoprophylaxis Chloroquine (Aralen ® ) and hydroxychloroquine (Plaquenil ® ) Chloroquine (Aralen ® ) and hydroxychloroquine (Plaquenil ® ) ̶First-line in non-resistance areas Atovaquone/Proguanil (Malarone ® ) Atovaquone/Proguanil (Malarone ® ) Doxycycline Doxycycline Mefloquine (Lariam ® ) Mefloquine (Lariam ® ) Primaquine Primaquine WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

20. The ABCD’s of Malaria Protection A. Be Aware of the risk, incubation period and main symptoms. B. Avoid being Bitten by mosquitoes, especially between dusk and dawn. C. Take Chemoprophylaxis (antimalarial drugs) to suppress infection when appropriate. D. Immediately seek Diagnosis and treatment if a fever develops one week or more after entering an area where there is a malaria risk, and up to 3 months after departure. WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

21. WHO Global Malaria Program Diagnosis and treatment Diagnosis and treatment Vector control Vector control Capacity development Capacity development Surveillance, monitoring and evaluation Surveillance, monitoring and evaluation Research Research WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

22. Treatment Goals Uncomplicated Malaria Uncomplicated Malaria Eradication of infection Eradication of infection Reduce transmission Reduce transmission Prevent development and extension of antimalarial Prevent development and extension of antimalarial resistance resistance Complicated Malaria Complicated Malaria Prevention of: Prevention of: — — Mortality — Recrudescence WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

23. Resistance to Antimalarials Rising resistance to all antimalarial classes, except artemisinin derivatives Rising resistance to all antimalarial classes, except artemisinin derivatives Frequent, non-selective utilization of antimalarials induces severe resistance Frequent, non-selective utilization of antimalarials induces severe resistance Resistance is minimized by: Resistance is minimized by: –Use of combination therapy utilizing different mechanisms of action –Complete adherence to treatment regimen WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

24. Impact of Antimalarial Resistance Failure of symptom resolution / infection eradication secondary to inactivity of pharmacological treatment Failure of symptom resolution / infection eradication secondary to inactivity of pharmacological treatment Reduced interval between primary infection and recrudescence Reduced interval between primary infection and recrudescence Increased malaria transmission Increased malaria transmission Low levels of resistance may, at first, go unnoticed in areas of low prevalence, but later lead to rising incidence and mortality Low levels of resistance may, at first, go unnoticed in areas of low prevalence, but later lead to rising incidence and mortality WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

25. Distribution of Chloroquine Resistance in Plasmodium falciparum WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

26. Distribution of Sulfadoxine- Pyrimethamine Resistance in Plasmodium falciparum WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

27. Distribution of Malaria Resistance P. falciparum Resistance documented for amodiaquine, chloroquine, Resistance documented for amodiaquine, chloroquine, mefloquine, quinine, and sulfadoxine-pyrimethamine mefloquine, quinine, and sulfadoxine-pyrimethamine No resistance observed for artemisinin and derivatives No resistance observed for artemisinin and derivatives Degree of resistance varies by geographical location Degree of resistance varies by geographical location WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

28. Distribution of Malaria Resistance (cont) P. malariae Sensitive to chloroquine Susceptible for amodiaquine, mefloquine, and artemisinin derivatives P. ovale Susceptible to amodiaquine, mefloquine, and artemisinin derivatives WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

29. Distribution of Malaria Resistance (cont) P. vivax Commonly resistant to sulfadoxine-pyrimethamine Commonly resistant to sulfadoxine-pyrimethamine Chloroquine resistance is present in Indonesia, East Chloroquine resistance is present in Indonesia, East Timor, Papau New Guinea, and other regions of Oceania Timor, Papau New Guinea, and other regions of Oceania and Peru and Peru Sensitivity to chloroquine remains in South-East Asia, the Sensitivity to chloroquine remains in South-East Asia, the Middle East, north-east Africa, Indian subcontinent, Middle East, north-east Africa, Indian subcontinent, Korean peninsula, and the majority of Central and South Korean peninsula, and the majority of Central and South America America Generally susceptible to most other antimalarials Generally susceptible to most other antimalarials WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

30. Presentation of Evidence Strength of recommendations are classified according to the following, in order from the strongest level of evidence Strength of recommendations are classified according to the following, in order from the strongest level of evidence WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

31. Antimalarial Treatment Policy Recommendations Alter first-line therapy recommendation when treatment failure surpasses 10% Alter first-line therapy recommendation when treatment failure surpasses 10% –Must consider location-specific factors Define cure rates, by parasite, after at least 28 days of treatment Define cure rates, by parasite, after at least 28 days of treatment WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

32. Antimalarial Treatment Policy Recommendations (cont) Differentiate new-onset infection from recrudescence with PCR genotyping Differentiate new-onset infection from recrudescence with PCR genotyping Newly recommended first-line treatment should cure at least 95% cases in clinical trials Newly recommended first-line treatment should cure at least 95% cases in clinical trials WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

33. Treatment of Uncomplicated P. falciparum Malaria

34. Antimalarial Combination Therapy Antimalarial combination therapy is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and thus unrelated biochemical targets in the parasite. WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

35. Rationale for MCT Benefits of Combination Therapy Increased efficacy with combination regimens Increased efficacy with combination regimens Potential de novo resistance of parasite is addressed Potential de novo resistance of parasite is addressed Prevents / delays development of resistance Prevents / delays development of resistance Disadvantages of Combination Therapy Increased possibility of adverse effects Increased possibility of adverse effects Greater costs Greater costs Recommendation Combination treatment with at least 2 antimalarials Combination treatment with at least 2 antimalarials with different mechanisms (Levels S, T, O) with different mechanisms (Levels S, T, O) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

36. Treatment Options for Uncomplicated P. falciparum Malaria First – Line Therapy (Level S) Artemisinin – based combination therapy (ACT) Artemisinin – based combination therapy (ACT) Artemisinin derivatives:  Artemether  Artemotil  Artesunate  Dihydroartemisinin Active against all 4 species of malaria that infect humans reducing gametocyte carriage and thus reducing transmission. WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

37. Recommended ACT Combinations First – Line Therapy (Level S, T, O) First – Line Therapy (Level S, T, O) Artemether – lumefantrine (oral AL) Artemether – lumefantrine (oral AL) – 6 dose regimen Artesunate + amodiaquine (AS + AQ) Artesunate + amodiaquine (AS + AQ) Artesunate + mefloquine (AS + MQ) Artesunate + mefloquine (AS + MQ) Artesunate + sulfadoxine – pyrimethamine (AS+SP) Artesunate + sulfadoxine – pyrimethamine (AS+SP) (Listed in alphabetical order) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

38. Recommended ACT Combinations (cont) If resistance to artesunate plus amodiaquine If resistance to artesunate plus amodiaquine (AS + AQ) is greater than 20%, use: (AS + AQ) is greater than 20%, use:  AS+MQ or AL  AQ+SP - interim option if ACTs are unavailable and if both drugs are unavailable and if both drugs are efficacious (Level E) efficacious (Level E) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

39. Artemisinin-Based Combination Therapy Artemisinin derivatives are rapidly eliminated. The duration of therapy of the regimen will depend on whether ACT is used with rapidly eliminated compounds or slowing eliminated antimalarials. WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

40. Artemisin Derivatives Given in Combination with: Treatment Duration Slowly eliminated antimalarials Amodiaquine (AQ) Mefloquine (MQ) Sulfadoxine-pyrimethamine (SP) 3 days Rapidly eliminated antimalarials Tetracycline Clindamycin 7 days Artemisinin-Based Combination Therapy (cont) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

41. Selection of ACT Options Geographical pattern of resistance for medications paired with an artemisinin derivative will direct treatment selectio n Recommendation In South-East Asia, or other areas of multi- In South-East Asia, or other areas of multi- drug resistance: AS+MQ or AL (Level E) drug resistance: AS+MQ or AL (Level E) In Africa: AL, AS+ AQ, or AS+SP (Level S) In Africa: AL, AS+ AQ, or AS+SP (Level S) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

42. Treatment Options for Uncomplicated P. falciparum Malaria Second – Line Therapy Non – artemisinin based combination therapy Non – artemisinin based combination therapy –Sulfadoxine – pyrimethamine w/ chloroquine (SP+CQ) OR –Sulfadoxine – pyrimethamine w/ amodiaquine (SP+AQ) Prevailing high level of resistance has compromised the efficacy of these combinations. WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

43. Non-ACT combinations Sulfadoxine-pyrimethamine + chloroquine (SP+CQ) Sulfadoxine-pyrimethamine + amodiaquine (SP+AQ) Recommendations SP+CQ as efficacious as SP due to spreading resistance  Combination therapy NOT recommended SP+AQ may have greater efficacy than monotherapy  Consider use as an interim therapy if ACT unavailable and drugs remain effective Non-Artemisinin (non-ACT) Based Combination Therapy WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

44. Antimalarial Combination Therapy The following are NOT considered as combination therapy: The following are NOT considered as combination therapy: –Sulfadoxine-pyrimethamine –Sulfalene-pyrimethamine –Proguanil-dapsone –Chlorproguanil-dapsone –Atovaquone-proguanil –Any regimen including non-antimalarial medication WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

45. Rationale for Antimicrobial Exclusion from Treatment Recommendations Chlorproguanil-dapsone Insufficient safety and efficacy data Insufficient safety and efficacy data Atovaquone-proguanil High cost High cost Halofantrine Concerns regarding safety Dihydroartemisinin (artenimol)-piperaquine Not manufactured according to good Not manufactured according to good manufacturing practices manufacturing practices Lack of efficacy data for South America and Africa Lack of efficacy data for South America and Africa WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

46. Practical Aspects of Treatment with AL Improved absorption if taken with fat-containing food/drinkImproved absorption if taken with fat-containing food/drink Available as artemether / lumefantrine 20 / 120 tablets WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

47. Practical Aspects of Treatment with AS + AQ Recommendation: 4mg/kg AS plus 10mg/kg AQ daily x 3 daysRecommendation: 4mg/kg AS plus 10mg/kg AQ daily x 3 days Available as AS / AQ 50 / 153 tablets WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

48. Practical Aspects of Treatment with AS + SP Recommendation: 4mg/kg AS daily for 3 days plus SP 25/1.25 mg base/kg on day 1Recommendation: 4mg/kg AS daily for 3 days plus SP 25/1.25 mg base/kg on day 1 Available separately as AS 50mg tablets and SP 500 / 25 tablets WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

49. Practical Aspects of Treatment with AS + MQ Recommendation: 4mg/kg AS given daily for 3 days and 25mg base/kg MQ split over 2-3 daysRecommendation: 4mg/kg AS given daily for 3 days and 25mg base/kg MQ split over 2-3 days Available separately as AS 50mg tablets and MQ 250mg WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

50. Practical Aspects of Treatment with AS + MQ (cont) To limit nausea / vomiting and maximize absorption of mefloquine, the 25mg/kg dose is generally split: To limit nausea / vomiting and maximize absorption of mefloquine, the 25mg/kg dose is generally split: 15 mg/kg on the 2nd day PLUS 10mg/kg on the 3rd day OR 8.3 mg/kg daily for 3 days WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

51. Practical Aspects of Treatment with AS + MQ (cont) Lower dose of 15 mg base / kg is associated with inferior efficacy and is NOT recommended Lower dose of 15 mg base / kg is associated with inferior efficacy and is NOT recommended Declining efficacy against falciparum malaria on the Cambodia-Thailand border Declining efficacy against falciparum malaria on the Cambodia-Thailand border WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

52. Incorrect Treatment Approaches Incorrect Approach: Incorrect Approach: –Ordering an initial dose of treatment for unconfirmed malaria with the plan of initiating a full treatment course later if diagnosis confirmation occurs (Level E) Recommended Approach: Recommended Approach: –Always give a full treatment course once the decision to treat has been made (Level E) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

53. Incorrect Treatment Approaches (cont) Incorrect Approach: Incorrect Approach: –Ordering partial treatment with efficacious medications (inappropriate for patients without immunity) for patients who are semi-immune to malaria (Level E) Recommended Approach: Recommended Approach: –Artemisinins and derivatives should NOT be used as monotherapy (Level E) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

54. Advanced Aspects of Clinical Management Patients unable to tolerate oral medication: Patients unable to tolerate oral medication: –Parenteral or rectal formulations may be administered for 1-2 days until the patient is able to begin taking medication orally –Patients should receive treatment for severe malaria regardless of initial presentation WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

55. Advanced Aspects of Clinical Management (cont.) Hyperparasitemia ( > 5% RBC with parasites) with no signs of severe infection: Hyperparasitemia ( > 5% RBC with parasites) with no signs of severe infection: –Order oral ACTs for uncomplicated malaria –Monitor more closely for adherence and tolerance of medications and symptom resolution –May require longer duration of therapy WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

56. Use of Antipyretics for Fever Despite concern over antipyretics potentially compromising host defenses, there is no reason to withhold antipyretics in patients with malaria WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

57. Use of Antipyretics for Fever in Pediatric Patients For T >38.5°C may treat with: (Level S, E) For T >38.5°C may treat with: (Level S, E) − Paracetamol (acetaminophen)  15mg/kg orally or as a suppository every 4 hours − Ibuprofen  5mg/kg as an alternate therapy − Aspirin  Avoid due to risk of Reye’s Syndrome − Tepid sponging WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

58. Management of Treatment Failure Within 14 Days Treatment failure unlikely; 1-7% reported Treatment failure unlikely; 1-7% reported Always confirm whether patients have received treatment during the past 8 weeks Always confirm whether patients have received treatment during the past 8 weeks –Recurrence may result from reinfection or recrudescence Confirm by blood slide examination when possible Confirm by blood slide examination when possible Failures result from lack of adherence, antimalarial resistance, and individuals’ kinetic differences Failures result from lack of adherence, antimalarial resistance, and individuals’ kinetic differences Recommendation: second-line antimalarial regimen Recommendation: second-line antimalarial regimen WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

59. Management of Treatment Failure After 14 Days May result from recrudescence or reinfection May result from recrudescence or reinfection Parasitological confirmation is desirable Parasitological confirmation is desirable Re-treat with first-line ACT Re-treat with first-line ACT –Will likely remain effective in recrudescence If mefloquine was an initial treatment within the past 28 days, second-line therapy should be used If mefloquine was an initial treatment within the past 28 days, second-line therapy should be used Treat further recurrences with second-line therapy Treat further recurrences with second-line therapy WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

60. Second-Line Antimalarial Treatment Recommendations 7 day quinine regimens are commonly poorly tolerated Adherence often poor unless treatment is observed WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

61. Treatment of Pregnant Women Important not to delay treatment of pregnant women Malaria infection is associated with reduced birth weights WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

62. Treatment of Lactating Women WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

63. Treatment of Infants In endemic countries, malaria occurs frequently in children less than 2 years old In endemic countries, malaria occurs frequently in children less than 2 years old Acquired immunity fades 3-6 months after birth Acquired immunity fades 3-6 months after birth Pharmacokinetic differences in children compared to adults Pharmacokinetic differences in children compared to adults Lack of pediatric dosage forms commonly leads to inaccurate and inconsistent dosing Lack of pediatric dosage forms commonly leads to inaccurate and inconsistent dosing WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

64. Treatment of Infants (cont) Difficulties ensuring consistent treatment due to dosage volume, poor taste of drugs, and potential vomiting Instruct caregivers to re-administer dose if child vomits / regurgitates the dose WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

65. Travelers

66. Treatment in Patients With Coexisting HIV Infection Increasing frequency of co-infection with HIV and malaria Increasing frequency of co-infection with HIV and malaria As immunosuppression worsens, severity of symptoms and treatment failure rates increase As immunosuppression worsens, severity of symptoms and treatment failure rates increase Malaria control measures are of greater importance due to increased risk of asymptomatic parasitemia Malaria control measures are of greater importance due to increased risk of asymptomatic parasitemia WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

67. Treatment in Patients With Coexisting HIV Infection (cont) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

68. Severe Malnutrition Malnutrition is a commonly co-existing condition Malnutrition is a commonly co-existing condition Diarrhea and vomiting may alter drug absorption Diarrhea and vomiting may alter drug absorption Diminished muscle mass may complicate intramuscular injections Diminished muscle mass may complicate intramuscular injections Hypoalbuminemia may lead to increased concentrations of unbound, or free drug Hypoalbuminemia may lead to increased concentrations of unbound, or free drug WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

69. Severe Malnutrition (cont) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

70. Treatment of Severe P. falciparum Malaria

71. Treatment of Severe Malaria General Rule Full doses of parenteral antimalarial treatment should be initiated without delay. Use whatever effective therapy is available; Use whatever effective therapy is available; options include: options include: – Quinine (dihydrochloride most widely used) – Quinidine – Artemisinin derivatives WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

72. Cinchona Alkaloids in the Treatment of Severe Malaria Quinine Parenteral, rate controlled infusion NTE 5 mg salt/kg bw (preferred) Parenteral, rate controlled infusion NTE 5 mg salt/kg bw (preferred) –Intramuscular (alternative), –Rectal (use when IV or IM not available) Use loading dose of quinine 20 mg salt/kg to quickly reach therapeutic levels Use loading dose of quinine 20 mg salt/kg to quickly reach therapeutic levels Renal dose adjustment needed Renal dose adjustment needed WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

73. Cinchona Alkaloids in the Treatment of Severe Malaria (cont) Quinidine Considered more toxic than quinine; should only be used if no other effective parenteral drugs are available Considered more toxic than quinine; should only be used if no other effective parenteral drugs are available ECG and frequent monitoring of vital signs are required ECG and frequent monitoring of vital signs are required WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

74. Artemisinin Derivatives in the Treatment of Severe Malaria Artesunate Pharmacokinetically superior to artemether and artemotil Pharmacokinetically superior to artemether and artemotil IV/IM 1 st line therapy in areas of low-malaria transmission IV/IM 1 st line therapy in areas of low-malaria transmission New parenteral maintenance dose: 2.4 mg/kg bw New parenteral maintenance dose: 2.4 mg/kg bwArtemether IM erratically absorbed in severe cases, especially in shock IM erratically absorbed in severe cases, especially in shock IM acceptable alternative to quinine IM acceptable alternative to quinineArtemotil Insufficient evidence, consider when alternates unavailable Insufficient evidence, consider when alternates unavailable WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

75. Treatment of Severe Malaria Treatment Options NOT Recommended Sulfadoxine – pyrimethamine Sulfadoxine – pyrimethamine Chloroquine Chloroquine –(not recommended secondary to widespread resistance) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

76. Recommendations for Treatment of Severe Malaria WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

77. Use of Rectal Formulations Rectal Artemisinin Derivatives PK studies suggest highly variable, but adequate PK studies suggest highly variable, but adequate absorption of rectal artemisinin and artesunate absorption of rectal artemisinin and artesunate Rectal formulations were developed for pre- Rectal formulations were developed for pre- referral use referral use Use for complete treatment only when parenteral treatment (referral) is not possible Use for complete treatment only when parenteral treatment (referral) is not possible Continue rectal therapy until patient is able to Continue rectal therapy until patient is able to tolerate oral, then prescribe full course of the tolerate oral, then prescribe full course of the recommended ACT for uncomplicated malaria recommended ACT for uncomplicated malaria WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

78. Use of Rectal Formulations (cont) Rectal Quinine Insufficient evidence to recommend unless parenteral therapy is not possible and no other effective options are available WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

79. Rectal Artesunate Dosing WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

80. Rectal Artesunate Dosing (cont) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

81. Oral Antimalarial Therapy for Treatment of Severe Malaria Initiate parenteral treatment, once patient tolerates oral therapy Initiate parenteral treatment, once patient tolerates oral therapy Continuing and completing treatment with an effective oral antimalarial is essential Continuing and completing treatment with an effective oral antimalarial is essential Current practice: continue same medication orally as given parenterally to complete a full 7 days of treatment Current practice: continue same medication orally as given parenterally to complete a full 7 days of treatment Although following parenteral treatment with a full course of oral ACT (AS+AQ or AL) is theoretically a good alternative, evidence is lacking WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

82. Non-Pregnant Women Non-Pregnant Women –Doxycycline is added to either quinine, artesunate or artemether for 7 days  Doxycycline, the preferred tetracycline, can be given once daily, and does not accumulate in renal failure Children and Pregnant Women Children and Pregnant Women –When available, use clindamycin instead of doxycycline Oral Antimalarial Therapy for Treatment of Severe Malaria (cont) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

83. Pre – Referral Treatment Options Recommendation: 1 st dose of treatment should be given using the parenteral route, if possible, or rectally, prior to referral (unless referral time is very short) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

84. Treatment of Malaria Caused by P. vivax, P. ovale or P. malariae

85. P. vivax P. vivax –Causes 40% cases worldwide –Dominant species outside of Africa –Rare in Africa with the exception of the Horn –Low transmission rates result in little immunity and risk for all age groups P. malariae and P. ovale P. malariae and P. ovale –Much less prevalent –Distributed across the world / African tropical regions WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

86. Treatment of Uncomplicated Vivax Malaria Blood Stage Infection Blood Stage Infection –May have improved treatment outcomes with ACT treatment compared to falciparum malaria  Exception: sulfadoxine-pyrimethamine regimens due to more quickly developing resistance –Chloroquine-resistant vivax malaria  Amodiaquine, mefloquine, quinine, and the artemisinin derivatives shown to be effective WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

87. Treatment of Uncomplicated Vivax Malaria (cont) Liver Stage Infection Liver Stage Infection –Give primaquine (for 14 days) to prevent relapses and achieve radical cure –Relapse patterns vary with geography  50-60% infections in South-East Asia will relapse  15-20% relapse on the Indian subcontinent WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

88. Treatment of Uncomplicated Vivax Malaria (cont) WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

89. Treatment of Severe Vivax Malaria May be severe and debilitating despite consideration as a benign malaria May be severe and debilitating despite consideration as a benign malaria Avoiding treatment delay is important Avoiding treatment delay is important Utilize same treatment recommendations as for severe and complicated falciparum malaria Utilize same treatment recommendations as for severe and complicated falciparum malaria WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

90. Treatment of Severe Vivax Malaria (cont) Monitoring Therapeutic Efficacy Monitoring Therapeutic Efficacy –Should parasitemia recur within 16 days, relapse is not likely; however, determining between a relapse and recrudescence is not likely after this time –Any infection which recurs within 28 days of treatment is chloroquine resistant WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

91. Treatment of Malaria due to P. ovale and P. malariae P. malariae P. malariae –Treat as vivax malaria with standard chloroquine regimen –Does not require radical cure with primaquine due to absence of hypnozoites P. ovale P. ovale –Occurs most often in high stable transmission regions with high risk of re-infection –Treatment with primaquine is not necessary WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html

92. Summary Awareness and health education are essential for success in defeating malaria Awareness and health education are essential for success in defeating malaria Collaboration with existing prevention programs within the host country is ideal Collaboration with existing prevention programs within the host country is ideal Proactive approach for diagnosis and treatment is vital Proactive approach for diagnosis and treatment is vital WHO Guidelines for the Treatment of Malaria 2006 www.apps.who.int/malaria/treatmentguidelines.html