1. Malaria Prevention and Treatment Javier F Sevilla Mártir, MD Associate Professor, Department of Family Medicine, IU School of Medicine AAFP Global Health Workshop Denver, 2009

2. Objectives Discuss current Malaria trends in different regions of the world Discuss current Malaria trends in different 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 treatment and prophylaxis of Malaria appropriate to different regions based on resistance according to the WHO Discuss treatment and prophylaxis of Malaria appropriate to different regions based on resistance according to the WHO

3. Introduction According to the WHO malaria Report: Malaria is the most important tropical disease, remaining widespread throughout the tropics, but also occurring in many temperate regions. Malaria is the most important tropical disease, remaining widespread throughout the tropics, but 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. 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 a 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 a million deaths each year.

4. Introduction (cont.) 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. Health education, better case management, better control tools and concerted action are needed to limit the burden of the disease. Health education, better case management, better control tools and concerted action are needed to limit the burden of the disease. Numerous epidemiologic and ecologic factors play a vital role in determining the effect of malaria on human health and in the intensity of disease transmission. The immunological status of a person also has a bearing on the severity of the disease. Numerous epidemiologic and ecologic factors play a vital role in determining the effect of malaria on human health and in the intensity of disease transmission. The immunological status of a person also has a bearing on the severity of the disease.

5. 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 Malaria Approximately half of the world is at risk for Malaria Travelers to “hot spots’ are specially vulnerable Travelers to “hot spots’ are specially vulnerable Malaria takes a significant economic toll Malaria takes a significant economic toll

6. WHO Malaria Country Profiles Europe http://www.euro.who.int/malaria/ctryinfo/ctryinf otop http://www.euro.who.int/malaria/ctryinfo/ctryinf otop http://www.euro.who.int/malaria/ctryinfo/ctryinf otop http://www.euro.who.int/malaria/ctryinfo/ctryinf otop 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. At present, 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. At present, 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.

7. WHO Malaria Country Profiles Africa http://www.afro.who.int/malaria/country-profile/ http://www.afro.who.int/malaria/country-profile/ http://www.afro.who.int/malaria/country-profile/ There were an estimated 247 million episodes of malaria in 2006 There were an estimated 247 million episodes of malaria in 2006 Eighty-six percent, or 212 million cases, were in the African Region. Eighty-six percent, or 212 million cases, were in the African Region. Eighty percent of the cases in Africa were in 13 countries Eighty percent of the cases in Africa were in 13 countries and over half were in Nigeria, Democratic Republic of the Congo, Ethiopia, United Republic of Tanzania and Kenya. and over half were in Nigeria, Democratic Republic of the Congo, Ethiopia, United Republic of Tanzania and Kenya.

8. WHO Malaria Country Profiles EMR http://www.emro.who.int/rbm/Epidemiology-current.htm http://www.emro.who.int/rbm/Epidemiology-current.htm http://www.emro.who.int/rbm/Epidemiology-current.htm 50% of the regional population (approximately 248 million people), reside in areas of various risk of malaria transmission. 50% of the regional population (approximately 248 million people), reside in areas of various risk of 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 episode and 49 000 malaria related deaths occurs every year in the Region. It is estimated that about 10 million malaria episode and 49 000 malaria related deaths occurs every year in the Region.

9. WHO Malaria Country Profiles SEA http://www.searo.who.int/EN/Section10/S ection21.htm http://www.searo.who.int/EN/Section10/S ection21.htm http://www.searo.who.int/EN/Section10/S ection21.htm http://www.searo.who.int/EN/Section10/S ection21.htm 687 million people 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 are at high risk for malaria, with an estimated 90-160 million infections and more than 120, 000 deaths occurring each year

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

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

12. Malaria Caused by parasites of the species Plasmodium Caused by parasites of the species Plasmodium P. falciparum (most lethal) P. falciparum (most lethal) P. vivax ( most common) P. vivax ( most common) P. ovale P. ovale P. malariae. P. malariae.

13. The Vector/Transmission Infected female mosquitoes of the anopheles species Infected female mosquitoes of the anopheles species More than 400 species More than 400 species 30-40 can transmit the disease 30-40 can transmit the disease

15. Clinical Manifestations Malaria parasites multiply rapidly in the liver and then in red blood cells. Malaria parasites multiply rapidly in the liver and then in red blood cells. One to two weeks after a person is infected the first symptoms of malaria appear: usually fever, headache, chills, malaise, join pains and vomiting. One to two weeks after a person is infected the first symptoms of malaria appear: usually fever, headache, chills, malaise, join pains and vomiting. If not treated promptly with effective medicines, malaria can kill by infecting and destroying red blood cells and by clogging the capillaries that carry blood to the brain or other vital organs causing renal failure, hypoglycemia, anemia, pulmonary edema, shock and coma If not treated promptly with effective medicines, malaria can kill by infecting and destroying red blood cells and by clogging the capillaries that carry blood to the brain or other vital organs causing renal failure, hypoglycemia, anemia, pulmonary edema, shock and coma

16. Diagnosis Light microscopy Light microscopy Gold standard is thick & thin blood smears Gold standard is thick & thin blood smears Fluorescent microscopy Fluorescent microscopy Quantitative Buffy-coat (QBC) method Quantitative Buffy-coat (QBC) method PCR-based detection PCR-based detection Sensitivity and specificity essentially 100% Sensitivity and specificity essentially 100% Antigen detection Antigen detection Finger-prick dipstick test Finger-prick dipstick test

17. Prevention in Travelers Chemoprophylaxis Chemoprophylaxis Chloroquine (Aralen) and hydroxychloroquine (Plaquenil) are first-line in non-resistance areas Atovaquone/Proguanil (Malarone) Doxycycline Mefloquine (Lariam) Primaquine

18. The ABCD of Malaria Protection A. Be Aware of the risk, the incubation period and the main symptoms. A. Be Aware of the risk, the incubation period and the main symptoms. B. Avoid being Bitten by mosquitoes, especially between dusk and dawn. B. Avoid being Bitten by mosquitoes, especially between dusk and dawn. C. Take antimalarial drugs (Chemoprophylaxis) to suppress infection when appropriate. C. Take antimalarial drugs (Chemoprophylaxis) 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. 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 Global Malaria Program WHO Global Malaria Program

19. WHO Global Malaria Program and the Honduras Experience Diagnosis and Treatment Diagnosis and Treatment Vector control Vector control Capacity development Capacity development Surveillance, monitoring and evaluation Surveillance, monitoring and evaluation Research Research

20. Treatment Goals 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 Prevention of: Prevention of: — Mortality — Recrudescence

21. 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: –Combination therapy utilizing different mechanisms of action –Complete adherence to treatment regimen

22. 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

23. Distribution of Chloroquine Resistance in Plasmodium falciparum

24. Distribution of Sulfadoxine-Pyrimethamine Resistance in Plasmodium falciparum

25. 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 P. malariae Sensitive to chloroquine Sensitive to chloroquine Susceptible for amodiaquine, mefloquine, and artemisinin Susceptible for amodiaquine, mefloquine, and artemisinin derivatives derivatives

26. Distribution of Malaria Resistance P. vivax Commonly resistant to sulfadoxine-pyrimethamine Commonly resistant to sulfadoxine-pyrimethamine Chloroquine resistance is present in Indonesia, East Timor, Chloroquine resistance is present in Indonesia, East Timor, Papau New Guinea, and other regions of Oceania and Peru Papau New Guinea, and other regions of Oceania 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, Korean Middle East, north-east Africa, Indian subcontinent, Korean peninsula, and the majority of Central and South America peninsula, and the majority of Central and South America Generally susceptible to most other antimalarials Generally susceptible to most other antimalarials P. ovale Susceptible to amodiaquine, mefloquine, and artemisinin Susceptible to amodiaquine, mefloquine, and artemisinin derivatives derivatives

27. 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

28. 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 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

29. Treatment of Uncomplicated P. falciparum Malaria

30. 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.

31. Rational for MCT Benefits of Combination Therapy Increased efficacy of combination regimens commonly Increased efficacy of combination regimens commonly documented documented Potential de novo resistance of parasite is addressed by Potential de novo resistance of parasite is addressed by second antimalarial second antimalarial 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 with different mechanisms (Levels S, T, O) Combination treatment with at least 2 antimalarials with different mechanisms (Levels S, T, O)

32. 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 reduce transmission.

33. 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) If >20% resistance to AQ and SP, use AS+MQ or AL AQ+SP is an interim option if ACTs are unavailable, if both drugs are efficacious (Level E)

34. 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. Artemisinin Derivative Given in Combination with: Treatment Duration Slowly eliminated antimalarials Amodiaquine (AQ) Amodiaquine (AQ) Mefloquine (MQ) Mefloquine (MQ) Sulfadoxine-pyrimethamine (SP) Sulfadoxine-pyrimethamine (SP) 3 days Rapidly eliminated antimalarials Tetracyclines Tetracyclines Clindamycin Clindamycin 7 days

35. Selection of ACT Options Geographical pattern of resistance for medications paired with an artemisinin derivative will direct regimen selection Recommendation In South-East Asia, or other areas of multi- drug resistance: AS+MQ or AL (Level E) In South-East Asia, or other areas of multi- 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)

36. Treatment Options for Uncomplicated P. Falciparum Malaria Second – Line Therapy Non – artemisinin based combination therapy Non – artemisinin based combination therapyIncludes: –Sulfadoxine – pyrimethamine with chloroquine (SP+CQ) OR –Sulfadoxine – pyrimethamine with amodiaquine (SP+AQ) Prevailing high level of resistance has compromised the efficacy of these combinations.

37. Non-Artemisinin (non-ACT) Based Combination Therapy Non-ACT combinations Non-ACT combinations –Sulfadoxine-pyrimethamine + chloroquine (SP+CQ) –Sulfadoxine-pyrimethamine + amodiaquine (SP+AQ) Recommendations Recommendations –SP+CQ as efficacious as SP due to spreading resistance Combination therapy NOT recommended 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 Consider use as an interim therapy if ACT unavailable and drugs remain effective

38. 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

39. 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 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

40. Practical Aspects of Treatment with AL Improved absorption if taken with fat-containing food / drink Improved absorption if taken with fat-containing food / drink Available as artemether/lumefantrine 20/120 tablets Available as artemether/lumefantrine 20/120 tablets

41. Practical Aspects of Treatment with AS + AQ Recommendation: 4mg/kg AS plus 10mg/kg AQ daily x 3 days. Available as AS/AQ 50/153 tablets Recommendation: 4mg/kg AS plus 10mg/kg AQ daily x 3 days. Available as AS/AQ 50/153 tablets

42. Practical Aspects of Treatment with AS + SP Available separately as AS 50mg tablets and SP 500/25 tablets Available separately as AS 50mg tablets and SP 500/25 tablets Recommendation: 4mg/kg AS daily for 3 days plus SP 25/1.25 mg base/kg on day 1 Recommendation: 4mg/kg AS daily for 3 days plus SP 25/1.25 mg base/kg on day 1

43. Practical Aspects of Treatment with AS + MQ Available separately as AS 50mg tablets and MQ 250mg Available separately as AS 50mg tablets and MQ 250mg Recommendation: 4mg/kg AS given daily for 3 days and 25mg base/kg MQ split over 2-3 days Recommendation: 4mg/kg AS given daily for 3 days and 25mg base/kg MQ split over 2-3 days

44. Practical Aspects of Treatment with AS + MQ (cont.) Lower dose of 15 mg base/ kg associated with inferior efficacy and is NOT recommended Lower dose of 15 mg base/ kg associated with inferior efficacy and is NOT recommended To limit nausea/ vomiting and maximize absorption, 25mg/kg dose is generally split: To limit nausea/ vomiting and maximize absorption, 25mg/kg dose is generally split: Declining efficacy against falciparum malaria on the Cambodia-Thailand border Declining efficacy against falciparum malaria on the Cambodia-Thailand border 15 mg/kg on the 2nd day plus 10mg/kg on the 3rd day OR 8.3 mg/kg daily for 3 days

45. Incorrect Treatment Approaches 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) 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) –Always give a full treatment course once the decision to treat has been made (Level E) Ordering partial treatment with efficacious medications (inappropriate for patients without immunity) for patients who are semi-immune to malaria (Level E) Ordering partial treatment with efficacious medications (inappropriate for patients without immunity) for patients who are semi-immune to malaria (Level E) –Artemisinins and derivatives should NOT be used as monotherapy (Level E)

46. Advanced Aspects of Clinical Management Unable to tolerate oral medications: Unable to tolerate oral medications: –Parenteral or rectal formulations may be administered for 1-2 days until the patient is able to take medication orally –Patients should receive treatment for severe malaria regardless of initial presentation Hyperparasitaemia without signs of severe infection: Hyperparasitaemia without 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

47. Use of Antipyretics for Fever Despite concern over antipyretics potentially compromising host defenses, there is no reason to withhold antipyretics in patients with malaria Despite concern over antipyretics potentially compromising host defenses, there is no reason to withhold antipyretics in patients with malaria Pediatric Recommendations for fever (T>38.5°C) (Level S, E): Pediatric Recommendations for fever (T>38.5°C) (Level S, E): –Paracetamol (acetaminophen) 15mg/kg orally or as a suppository every 4 hours –Ibuprofen 5mg/kg: alternate therapy –Aspirin: avoid due to risk of Reye’s Syndrome –Tepid sponging

48. Management of Treatment Failure Within 14 Days Unlikely; 1-7% reported Unlikely; 1-7% reported Identification may be missed if patients are not asked whether they have received treatment during the past 8 weeks Identification may be missed if patients are not asked whether they have received treatment during the past 8 weeks –Recurrence may result from reinfection or recrudescence (treatment failure) Confirm parasitologically by blood slide examination when possible Confirm parasitologically by blood slide examination when possible Failures result from lack of adherence, antimalarial resistance, and patient specific kinetic differences Failures result from lack of adherence, antimalarial resistance, and patient specific kinetic differences Treat with second-line antimalarial regimen Treat with second-line antimalarial regimen

49. 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 initiated If Mefloquine was an initial treatment within the past 28 days, second-line therapy should be initiated Further recurrences should be treated with second-line therapy Further recurrences should be treated with second-line therapy

50. Second-Line Antimalarial Treatment Recommendations

51. Treatment of Pregnant and Lactating Women Pregnant Women Lactating Women

52. Treatment of Infants Malaria occurs frequently in children less than 2 years old, in endemic countries Malaria occurs frequently in children less than 2 years old, in endemic countries 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

53. Travelers

54. 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 parasitaemia Malaria control measures are of greater importance due to increased risk of asymptomatic parasitaemia

55. Severe Malnutrition Malnutrition is a commonly co-existing condition Malnutrition is a commonly co-existing condition Diarrhea and vomiting may alter absorption Diarrhea and vomiting may alter 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

56. Treatment of Severe P. falciparum Malaria

57. Treatment of Severe Malaria General Rule Full doses of parenteral antimalarial treatment should be initiated without delay. Use whatever effective therapy is available. Options: Quinine (dihydrochloride most widely used) Quinine (dihydrochloride most widely used) Quinidine Quinidine Artemisinin Derivatives Artemisinin Derivatives

58. Cinchona Alkaloids in the Treatment of Severe Malaria Quinine Quinine –Dihydrochloride salt most widely used –Parenteral, rate controlled infusion NTE 5 mg salt/kg bw (preferred), Intramuscular (alternative), rectal (insufficient data, using if IV or IM is not available) –Use loading dose of quinine 20 mg salt/kg to quickly reach therapeutic levels –Renal dose adjustment needed Quinidine Quinidine –Considered more toxic than quinine; should only be used if none of the other effective parenteral drugs are available –ECG and frequent monitoring of vital signs are required

59. Artemisinin Derivatives in the Treatment of Severe Malaria Artesunate Artesunate –Pharmacokinetically superior to artemether and artemotil –IV/IM 1 st line therapy in areas of low-malaria transmission –New parenteral maintenance dose: 2.4 mg/kg bw Artemether Artemether –IM erratically absorbed in severe cases, especially in shock –IM acceptable alternative to quinine Artemotil Artemotil –Insufficient evidence, suitable option when alternatives are unavailable

60. Treatment of Severe Malaria Not Recommended Sulfadoxine – pyrimethamine Sulfadoxine – pyrimethamine Chloroquine Chloroquine –(not recommended secondary to widespread resistance)

61. Recommendations for Treatment of Severe Malaria

62. Use of Rectal Formulations Rectal Quinine Insufficient evidence to recommend unless parenteral Insufficient evidence to recommend unless parenteral therapy is not possible and no other effective options therapy is not possible and no other effective options are available are available Rectal Artemisinin Derivatives PK studies suggest highly variable but adequate absorption of PK studies suggest highly variable but adequate absorption of rectal artemisinin and artesunate. rectal artemisinin and artesunate. Rectal formulations were developed for pre-referral use. Rectal formulations were developed for pre-referral use. For complete treatment only when parenteral treatment For complete treatment only when parenteral treatment (referral) is not possible. (referral) is not possible. Continue rectal therapy until able to tolerate oral, then Continue rectal therapy until able to tolerate oral, then prescribe full course of the recommended ACT for prescribe full course of the recommended ACT for uncomplicated malaria uncomplicated malaria

63. Rectal Artesunate Dosing

64. Rectal Artesunate Dosing (cont.)

65. 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 medicine orally as given parenterally to complete a full 7 days of treatment Current practice: continue same medicine 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

66. Non-pregnant Women: doxycycline is added to either quinine, artesunate or artemether for 7 days 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: where available, use clindamycin instead of doxycycline Children and Pregnant Women: where available, use clindamycin instead of doxycycline Oral Antimalarial Therapy for Treatment of Severe Malaria (cont.)

67. 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)

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

69. 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 and tropical regions in Africa

70. Treatment of Uncomplicated Vivax Malaria Blood Stage Infection Blood Stage Infection –Less data than for falciparum malaria –May have improved treatment outcomes with ACT treatment compared to falciparum malaria Exception: sulfadoxine-pyrimethamine regimens due to more quickly developing resistance Exception: sulfadoxine-pyrimethamine regimens due to more quickly developing resistance –Chloroquine-resistant vivax malaria Amodiaquine, mefloquine, quinine, and the artemisinin derivatives have been shown to be effective Amodiaquine, mefloquine, quinine, and the artemisinin derivatives have been shown to be effective

71. Treatment of Uncomplicated Vivax Malaria (cont.) Liver Stage Infection Liver Stage Infection –Give primaquine to prevent relapses and achieve radical cure –Relapse patterns/ frequency varies with geography 50-60% infections in South-East Asia result in relapse 50-60% infections in South-East Asia result in relapse 15-20% relapse on the Indian subcontinent 15-20% relapse on the Indian subcontinent –Treat with 14 days of primaquine

72. Treatment of Uncomplicated Vivax Malaria (cont.)

73. Treatment of Severe Vivax Malaria Treatment of severe vivax malaria Treatment of severe vivax malaria –May be severe and debilitating despite consideration as a benign malaria –Avoiding treatment delay is important –Utilize same treatment recommendations as for severe and complicated falciparum malaria 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

74. 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 P. ovale P. ovale –Occurs most often in high stable transmission regions with high risk of re-infection –Treatment with primaquine is not necessary

75. 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 host country prevention programs is ideal Collaboration with existing host country prevention programs is ideal Proactive approach for diagnosis and treatment is vital Proactive approach for diagnosis and treatment is vital