THE REPUBLIC OF BOTSWANA MINISTRY OF HEALTH DEPARTMENT OF PUBLIC HEALTH NATIONAL MALARIA CONTROLPROGRAMME

Transcription

1 THE REPUBLIC OF BOTSWANA MINISTRY OF HEALTH DEPARTMENT OF PUBLIC HEALTH NATIONAL MALARIA CONTROLPROGRAMME GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF MALARIA IN BOTSWANA SEPTEMBER 2007

2 THE REPUBLIC OF BOTSWANA MINISTRY OF HEALTH DEPARTMENT OF PUBLIC HEALTH NATIONAL MALARIA CONTROL PROGRAMME GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF MALARIA IN BOTSWANA SEPTEMBER

3 CONTENTS Preface... 5 Acknowledgment... 6 List of Abbreviations and Acronyms Introduction Overview of national treatment policy and drug resistance pattern Malaria disease Parasite distribution Disease presentation Malaria diagnosis Guidelines for malaria diagnosis in Botswana Parasitological diagnosis Guidelines for Malaria Laboratory Diagnosis in Botswana Microscopy Malaria Rapid Diagnostic Tests (RDTs) RDT in malaria management Management of P. falciparum malaria Treatment of uncomplicated malaria Use of anti-pyretic in uncomplicated malaria Treatment of malaria in specific populations Treatment failure Recurrence after 14 days Pre-referral treatment Management of severe malaria Treatment of Malaria caused by other species Malaria prevention Malaria prevention in pregnancy Chemoprophylaxis in the general travelers Pharmacovigilance Drug Resistance Surveillance Disease management at different level of health care delivery system References Annex I: Pharmacology of drugs in the treatment of malaria in Botswana Annex II: Criteria for Selecting AL Among Other ACT s Annex III: Performing and interpreting Malaria RDTs including plates

4 Annex IV: Decision chart for treatment of malaria Annex V: Glasgow and Blantyre Coma Monitoring Scales Annex VI: List of Technical working group

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6 Acknowledgements This document was developed by a broad based partnership from different institutions as follows: Nyangabgwe Referral Hospital, BEDAP, BDF, WHO and UNICEF. The Ministry of Health would like to acknowledge the Malaria Technical Working Group, which developed the initial draft, and the Malaria Reference Group that finalized the guidelines. In addition the Ministry of Health extends its acknowledgments to the editorial team and those individual contributors who made the revision of these guidelines a success. Finally, the Ministry of Health would like to take this opportunity to express its gratitude to UNICEF and WHO at country, inter-country and headquarter levels for their technical support. 6

7 List of Abbreviations and Acronyms AS + AQ ACT AL AQ AS + SP BEDAP CHW CQ DDT DRU MOH MIP MRG NMCP NRH PHS PV QA/QC Qn RDT SP TWG UNICEF WHO Artesunate-Amodiaquine Artemisinin based Combination Therapy Artemether-Lumefantrine Amodiaquine Artesunate-Sulphadoxine-Pyrimethamine Botswana Essential Drug Action Programme Community Health Worker Chloroquine Dichloro-Diphenyl-Trichloride Drug Regulatory Unit Ministry of Health Malaria in Pregnancy Malaria Reference Group National Malaria Control Programme Nyangabgwe Referral Hospital Public Health Specialist Pharmcovigilance Quality Assurance/Quality Control Quinine Rapid Diagnostic Test Sulphadoxine-Pyrimethamine Technical Working Group United Nations Children Fund World Health Organization 7

8 1. Introduction Malaria remains the most important parasitic disease that kills young children and adults and is a major public health problem in most parts of the world. Malaria is one of the major health problems in Botswana and is classified as a notifiable disease. Transmission is seasonal and closely related to the amount of rainfall. There is therefore significant variation in the degree transmission from year to year and major epidemics may occur in years of heavy rainfall. The country experienced epidemics in 1988, 1993, 1996, and Since then the malaria disease burden has decreased progressively The seasonality of malaria transmission leads to what is referred to as unstable type of malaria. This type confers negligible acquired immunity leaving all age groups at risk of developing severe form of Malaria. The level of malaria transmission varies throughout the country giving rise to three epidemiological belts. Malaria is endemic in the northern part of the country with regular and high transmission, a central belt of intermediate transmission, and a southern belt where little or no malaria occurs. Within the northern and central zones there is significant difference in the levels of transmission in different localities. In years of heavy rainfall when both the distribution and intensity of transmission increases, the transmission belt may move southwards such that outbreaks of malaria occur in the central zone of the country, and sporadic malaria cases occur in traditionally in non malarious areas. 8

9 1.1. Overview of National Treatment Policies and Drug Resistant Pattern Chloroquine was the recommended drug for treatment of uncomplicated malaria in the whole country until mid 1990 s. There were anecdotal reports of apparent increase in chloroquine treatment failures, especially after the 1993 malaria epidemic. Between 1994 and 1997 several chloroquine sensitivity and review studies established that 9

10 parasite resistance to chloroquine and chloroquine treatment failures had reached unacceptable levels. Drug resistance is defined by WHO as the ability of a parasite strain to survive, and/or multiply despite the administration and absorption of drug in doses equal to or higher than that recommended but within the limits of tolerance of the subject. A decision was taken after wide consultations to replace Chloroquine with Sulphadoxine-Pyrimethamine (SP) as first line treatment for uncomplicated malaria. This was achieved successfully in 1996 in the Chobe sub-district and in 1998 in the entire country. Quinine (Qn) has remained the recommended drug for severe malaria or treatment failures with first line drugs; and so far no documented significant Qn resistance is known. Over a period of years, previous reports from the districts indicated that patients were still responding very well to SP as first line treatment for uncomplicated malaria. However, the 2006 SP efficacy studies revealed failure rates of 9%. The findings from the 2006 efficacy studies are in conformity to sub-regional and global situation as regards SP resistance. In view of this level of resistance, and the regional move towards malaria elimination, a decision was taken in 2007 to change the first line drug policy from SP to ACTs. In response to increasing resistance to SP, other countries in the region have changed their treatment policies to Artemisinin-based Combination Therapy (ACTs) following WHO recommendations. To date almost all the countries in the sub region have adapted ACT policy. Artemisininbased Combination therapy is defined as the simultaneous use of two or more blood schizonticidal drugs with different biochemical targets in the parasites and independent modes of action. Artemisinin-based combination therapy is an antimalarial combination therapy with an artemisinin derivative as one component of the combination. 10

11 Artemisinin-based Combination Antimalarial Therapy is preferred over other combinations not containing artemisisnins for the following reasons: Rapid and sustained reduction of the parasite biomass Reduction of gametocyte carriage thus breaks the malaria parasite s life cycle. Rapid resolution of clinical symptoms. Safety profile is high. Excellent tolerability, well tolerated compared to other antimalarials. AL is a fixed dose combination treatment enhancing compliance. High cure rates (more than 95 %). Minimizes emergence of resistance. 11

12 2. Malaria Disease Malaria disease is caused by infection with any of the four species of genus plasmodia known to infect man namely; Plasmodium falciparum, P. ovale, P. vivax and P. malariae. Malaria infection in humans is transmitted mainly through the bite of an infected female anopheles mosquito. In Southern Africa, the most common type is the Anopheles gambiae complex. The most prevalent closely related species of anopheles vector found in Botswana is Anopheles arabiensis. 2.1 Parasite Distribution The major malaria parasite species in Botswana is P. falciparum, which constitutes up to 98% of all malaria cases. P. malariae and P. ovale share the remaining 2%. P. vivax malaria has not been reported in Botswana Disease Presentation Malaria may present clinically as either uncomplicated malaria, severe malaria or remain as asymptomatic infection especially in people living in malaria endemic areas. In Botswana, due to the highly seasonal and epidemic nature of malaria transmission, infection with malaria invariably leads to clinical manifestation of disease. Uncomplicated Malaria: Uncomplicated malaria is defined as symptomatic malaria without signs of severity or evidence of vital organ dysfunction. In acute P. falciparum malaria there is a continuum of presentation ranging from mild to severe forms of malaria. Uncomplicated malaria characteristically presents with fever, but fever may be absent. Other symptoms may include:-: 12

13 Headache, Joint or muscle aches, Chills and rigors. Fatigue, Abdominal discomfort, anorexia, nausea, vomiting. In children malaria may present subtly as refusal to eat, lethargy and irritability. Assessment of Uncomplicated Malaria: The primary goal of assessment of a case of uncomplicated malaria is to be able to: Promptly and effectively treat malaria to prevent progression to severe disease. Limit duration of disease and minimize the risk of the spread of drug resistant parasites. Exclude other common causes of febrile illness. History: In addition to the symptoms, age, place of residence, recent history of travel and drugs taken prior to or during current illness are important. History should focus on asking for; Nature, frequency, duration and pattern of fever and associated chills and rigors, if any In children cough, difficulty of breathing, diarrhea, ear pain, history of measles in last 3 months. Signs: Look for: Prostration, (extreme weakness), irritability, Feel for: Increased body temperature (> 38.5º c) Pallor, especially in children and pregnant women 13

14 Enlarged liver, spleen or both, especially in children Presentation of malaria may mimic other acute febrile diseases or illness. Therefore, it is important to consider malaria in any febrile illness and in travelers coming from malaria endemic regions. The diagnosis of uncomplicated malaria is based on history of fever with high index of suspicion for malaria in the absence of signs of severe malaria and having excluded other possible cause of acute febrile illness. Key is early detection, correct diagnosis and prompts treatment Severe Malaria The definition of severe malaria disease varies in children and adults. The definition of severe disease is described as in a patient with a P. falciparum asexual parasitaemia and no other confirmed cause for symptoms, the presence of one or more of the clinical or laboratory features associated with severe malaria. Clinical features associated with severe malaria Prostration Impaired consciousness Respiratory distress convulsions Circulatory collapse Pulmonary oedema Abnormal bleeding Jaundice Haemoglobinuria Laboratory Features 14 Severe anaemia Hypoglycaemia Acidosis

15 Hyperparasitaemia Renal impairment Diagnosis of severe malaria disease has to always be confirmed by parasitological evidence of the presence of malaria parasites either by blood slide or RDT. However, rapid initiation of treatment is critical for improved outcome for the treatment of malaria. Hence the nonavailability of laboratory results should not delay initiation of treatment of suspected severe malaria as a blood slide or blood sample for RDTs and blood sugar where possible would have been taken. 15

16 3. Malaria Diagnosis Prompt and accurate diagnosis of malaria is part of effective disease management. High sensitivity of malaria diagnosis is important to identify those positive cases in all settings, in particular for the most vulnerable population groups, such as young children, in which the disease can be rapidly fatal. High specificity is also vital to pick negative cases, which can reduce unnecessary treatment with antimalarials and improve differential diagnosis of febrile illness. The diagnosis of malaria is based on clinical criteria (clinical diagnosis) supplemented by the detection of parasites in the blood (parasitological or confirmatory diagnosis) Clinical diagnosis Clinical diagnosis alone has very low specificity, as the signs and symptoms of malaria are non-specific. Malaria is clinically diagnosed mostly on the basis of fever or a history of fever. The following WHO recommendations are still considered valid for clinical diagnosis: a) In settings where the risk of malaria is low, clinical diagnosis of uncomplicated malaria should be based on the degree of exposure to malaria and a history of fever in the previous 3 days with no features of other severe diseases. b) Where the risk of malaria is high, clinical diagnosis should be based on a history of fever in the previous 48h and/or the presence of anaemia, for which pallor of the palms appears to be the most reliable sign in young children. 16

17 3.2. Parasitological Diagnosis Parasitological diagnosis has the following advantages: Improved patient care in parasite-positive patients owing to greater certainty that the patient has malaria Parasite species identification Identification of parasite-negative patients in whom another diagnosis must be sought Prevention of unnecessary exposure to antimalarials, thereby reducing side-effects, drug interactions and selection pressure for drug resistance Cost savings considering the high cost of ACTs Improved health information Confirmation of treatment failures. The two methods in use for parasitological diagnosis are light microscopy and rapid diagnostic tests (RDTs) for detecting parasite antigens. Note: The results of parasitological diagnosis should be available within a short time (less than 2 hours) of the patient presenting. If this is not possible, the patient must be treated on the basis of a clinical diagnosis. In all cases if there is a strong clinical suspicion, the patient should be treated as malaria and the reason for treatment clearly indicated. In the instances were a treatment has been made on clinical diagnosis, a blood slide should have been taken before the initiation of treatment for future classification. 17

18 3.3. Guidelines for Malaria Laboratory Diagnosis in Botswana: All patients suspected of having malaria should have a malaria parasite slide collected and malaria rapid diagnostic test done before commencing on anti-malarial treatment.; Repeat MP slide and RDT after six hours t in all patients in whom there are strong grounds to suspect malaria but the initial slide/rdt was negative All febrile patients living in the endemic areas or with history of travel to malarious areas will have a MP slide/malaria collected and Rapid Diagnostic Test done Clinicians must adhere to the MP slide/rdt result for the management of uncomplicated malaria. Treatment of non confirmed uncomplicated malaria should be on strong clinical reasons or the patient having one or more characteristics of severe malaria as stipulated above, in which case the classification of the disease becomes severe disease. These should be indicated in the patients file as a standard of good clinical the management practice. MP slide results in line with the treatment outcome of the patient should be an indispensable tool for quality assurance in management of malaria. And, there should be a continuous flow of information between laboratory and clinical staff Analysis of MP slide results is an indispensable tool for diagnostic quality assurance in the management of malaria Microscopy Microscopy remains the operational gold standard and will be performed in all health facilities with microscope services. In all other facilities without microscopy, Rapid Diagnostic Test (RDTs) will be 18

19 performed. However, for all cases being suspected for malaria, a peripheral blood smear will be taken and sent to the nearest laboratory, alongside performing RDT. RDT and Microscopy have to be performed concurrently at all health facility levels. As NMCP moves from malaria control to malaria elimination, the two malaria investigation tools are mandatory to improve the quality of diagnosis and surveillance of malaria in Botswana Malaria Rapid Diagnostic Tests (RDTs) Brief Overview Malaria Rapid Diagnostic Test is a device, which detects specific antigens (proteins) produced by malaria parasites. These antigens are present in the blood of infected or recently infected people with malaria. The three main groups of antigens detected by commercially available RDTs are: Histidine-rich protein 2 (HRP2), specific to P. falciparum Plasmodium lactate dehydrogenase (pldh), currently used in products that include P. falciparum-specific, pan-specific, and P. vivax-specific pldh antibodies Aldolase (pan-specific). Presently the RDT used in Botswana is specific for Plasmodium falciparum (Pf) only due to the fact that 98% of the malaria parasites are P.falciparum. The Iatter employs the detection of the Pf Histidine Rich Protein 2 (HRP 2) antigens released from infected red blood cells to the blood. Most RDTs have a sensitivity of 95% at parasite densities of 100/µl of blood. The sensitivity of malaria RDTs is determined by the: Species of parasite Number of parasites present in the blood 19

20 Condition of the RDT Correctness of technique used to perform the test. Correctness of interpretation by the reader. Parasite viability and variation in production of antigen by the parasite Malaria Rapid Diagnostic Tests (RDTs) in Malaria Management Malaria Rapid Diagnostic Tests (RDTs) do provide a useful guide to the presence of clinically significant malaria infection. They complement microscopy based diagnosis where such services are not available. However, RDTs should not replace microscopy as the sole means of malaria diagnosis. The general management of a malaria patient should base treatment decisions not only on results but also other clinical parameters. In case of uncomplicated malaria, the rationale of treatment for a MP slide/rdt negative should be clearly defined by the managing clinician. Like all laboratory procedures the accuracy of an MP slide /RDT is dependent on the care and expertise with which it is prepared and interpreted. 20

21 4. Management of P. falciparum Malaria 4.1. Treatment of Uncomplicated Malaria Treatment Objectives The primary objective of treating uncomplicated malaria is to cure the infection. This is important, as it will prevent progression to severe disease and prevent additional morbidity associated with treatment failure. Cure of the infection means eradication from the body of the parasites that caused the illness. The public health goal of treatment is to reduce transmission of the infection to others, i.e. to reduce the infectious reservoir. A secondary but equally important objective of treatment is to prevent the emergence and spread of resistance to antimalarials. Tolerability, the adverse effect profile and the speed of therapeutic response are also important considerations in choosing the type of treatment to give. 4.1 Treatment of Uncomplicated Malaria The first line medicine/drug for the treatment of uncomplicated malaria in Botswana is Artemether-Lumefantrine (AL). Treatment of acute uncomplicated malaria with AL is effective against malaria caused by P. falciparum even in areas of multidrug resistance. It is also effective against all other malaria species. An advantage of this combination is that Lumefantrine is not available as a monotherapy and has never been used as a monotherapy treatment for malaria. Lumefantrine absorption is enhanced by coadministration with fatty foods. So it is essential that patients or 21

22 caregivers be informed of the need to take these tablets with milk or fatcontaining food or any type of food if such fatty containing food is not available. Dosage; AL is currently available as co-formulated tablets containing 20 mg Artemether and 120 mg Lumefantrine. Weight of patient has to be taken for dosage schedule. Artemether- Lumefantrine is recommended for patients with weight equal to or greater than 5 kg. In areas were there is no weighing scale age could be used as a proxy to the dosing schedule as shown in the table below. The total recommended treatment dosing using AL is a 6 dose regimen for 3 days for optimum effect and reduce chances of recrudescence. The dosing schedule of AL in all age groups is as follows: 1 st dose at clinic under Direct Observed Treatment 2 nd dose given after 8 hours. Subsequently the 3 rd to the 6 th dose is given twice daily (morning and evening) for two more days. Table 1: Dosing schedule for Artemether-Lumefantrine Body Age in Day1 Day 2 Day 3 Weight in Years 1 st dose After 8hrs Give twice Give twice KG a day a day months 1 tablet 1 tablet 1 tablet 1 tablet 2 yrs tablets 2 tablets 2 tablets 2 tablets tablets 3 tablets 3 tablets 3 tablets >34 >14 4 tablets 4 tablets 4 tablets 4 tablets 22

23 Notes: It is important to note that AL is not recommended for infants less than 5 kg body weight. Infants that fall under this weight category will be treated with quinine. Partial treatment should not be given even when the diagnosis is uncertain. A full course of effective treatment should be given once a decision to give antimalarial treatment has been reached. Health Workers are strongly urged to perform and rely on blood slide (BS)/RDTs results for the treatment with AL. However, in instances where BS/ RDTs are not available or the test is negative but the clinician has high index of suspicion, treatment should be initiated on the basis of clinical grounds and justification for treatment provided in the patient record form. NOTE: Some patients cannot tolerate oral treatment (AL) and may require parenteral quinine for 1-2 days until they can swallow and retain oral medication reliably. When they are able to take orally, a full course of AL should be administered Use of Antipyretics In Uncomplicated Falciparum Malaria Fever is a cardinal feature of malaria and is associated with constitutional symptoms of lassitude, weakness, headache, anorexia and nausea. Use of Paracetamol 10 mg/kg in children or mg in adults (1-2 tablets) every 4 hours is safe. It is tolerated well when given orally or as a suppository and is recommended for treating fever (more than > 38.5º C.) 23

24 4.3. Treatment of Uncomplicated Malaria In Specific Populations Management of uncomplicated malaria in specific populations and situations Children Under 5kg Malaria in children under 5 kg is uncommon but potentially fatal. Fevers in such age groups are most likely to be associated with septicemia. As they constitute an acute emergency where possible they should be managed under expert pediatric care. Quinine is the drug of choice for managing malaria in this age group. Pregnant Women AL is not recommended for malaria treatment in first trimester. For second and third trimester AL is the recommended drug of choice for uncomplicated malaria. Oral quinine is the recommended drug of choice for pregnant women in the first trimester who present with uncomplicated malaria. Lactating Women Lactating women who present with uncomplicated malaria will be treated with AL. Patients Co-infected with HIV and AIDS Patient with HIV infection who develops uncomplicated malaria should be treated with AL. The high incidence of HIV related fevers in this category of people requires that confirmatory diagnosis is practiced but treatment should be given when there is high suspicion of malaria. 24

25 Malnourished Patients Although there are many reasons why drug kinetics may be different in malnourished patients, there is insufficient evidence to suggest changing current dosage recommendation of anti-malarial drugs. AL remains the drug of choice for treatment of uncomplicated malaria in malnourished patients. Supportive Treatment Ensure temperature stabilization. Give Paracetamol oral or rectal, if temperature >38.5 degree Celsius. Expose child by uncovering and do tepid sponging as a supportive measure. Avoid aspirin in children. Maintain adequate nutrition by offering small, frequent, high energy density foods 4.4. Treatment Failures Patients with uncomplicated malaria who deteriorate by developing features of severe disease or do not improve whilst on Artemether- Lumefantrine treatment taken correctly for at least 48 hours showing persistent parasitemia should be considered Artemether-Lumefantrine treatment failures. For any treatment failure, the recommended 2 nd line drug is Quinine. This should be given for seven days, preferably supervised. The table below is based on a dose of 10 mg salt/kg of body weight 8 hourly for 7 days using tablets of 300 mg salt. Treatment failure also refers to at least 2 episodes of confirmed Malaria within a period of 14 days. Treat with Quinine. The entire 7 days course may be given orally if the patient does not present with severe malaria. The treatment should preferably be supervised. 25

26 Table 2: Dosage schedule for quinine in case of treatment failure Age (years) NUMBER OF TABLETS < As adapted from guidelines for treatment and diagnosis in the African Region The following condition should be considered in treatment failure. Persistence or arising parasitaemia Progression from uncomplicated to severe malaria At least two episodes of malaria within 14 days 4.5. Recurrence after 14 days Recurrence of fever and parasitaemia more than two weeks after treatment, which could result either from new infection or recrudescence, should be treated with first line treatment- AL. Parasitological confirmation is desirable but not a pre-condition. In both cases, the treatment is with AL and should be supervised 4.6. Pre-Referral Treatment Intramuscular (IM) Quinine IM Quinine is the recommended pre-referral treatment of choice in Botswana. This is an alternative to IV Quinine in the treatment of all 26

27 cases of severe malaria, especially cerebral malaria, in facilities that are not capable of starting an IV line and/or constituting and adequately monitoring a Quinine IV infusion. This refers particularly to remote clinics and health posts. A stat dose of 20mg/kg body weight if no prior ingestion of Chloquine, mefloquine, quinidine or quinine in the last one week. Otherwise- 10mg/kg body weight should be used. It is understood that a patient with severe malaria started on IM Quinine shall be transferred to a higher-level facility as soon as possible. The IM Quinine is meant to ensure that appropriate antimalarial treatment is not delayed. Once the patient reaches the hospital, the Quinine should be continued by the intravenous (IV) route until the patient is ready to take oral medication. In the event that referral is not possible, IM quinine should be continued 8 hourly until the patient is able to take orally. After two days of IM injection, the dose should be reduced to 5-7mg/kg body weight, if there is still justifiable need Management of Severe Malaria Management Objectives The main objective is to prevent the patient from dying; secondary objectives are prevention of recrudescence, transmission or emergence of resistance and prevention of disabilities. 27

28 Death from severe malaria often occurs within hours of admission to hospital or clinic, and so it is essential that therapeutic concentrations of antimalarials are achieved as soon as possible Treatment Recommendations for Severe Malaria Parenteral quinine is the recommended drug for the treatment for severe malaria. The importance of supportive or ancillary measures is emphasized. Patients with severe malaria will be treated with parenteral Quinine for at least 48 hours. Thereafter if they are able to take oral medication the patient will be discharged home on a full course of AL. Patients in whom AL is contraindicated must complete a seven days course of oral Quinine, preferably supervised. Initial Treatment Considerations for Severe Malaria Clear and maintain the airway. Position semi-prone or on side. Weigh the patient (if possible) and calculate dosage. Make rapid clinical assessment. Exclude hypoglycaemia/meningitis. Start antimalarial chemotherapy. Start treatment for hypoglycaemia/meningitis where indicated. Measure and monitor urine output. If necessary insert urethral catheter. Take blood for diagnostic smear, haematocrit and other laboratory tests. Monitor blood glucose. Plan first 8 hours intravenous fluids, including diluents for antimalarial drug, glucose therapy and blood transfusion. 28

29 If l temperature exceeds 37.5 o C, remove patient s clothes, tepid sponge, and fan, use cooling blanket and give antipyretic. Give anticonvulsant therapy if there is convulsion. Consider need for additional drugs (vitamin K, antibiotic etc.). Treatment Schedule for Severe Malaria Disease A loading dose of intravenous (IV) quinine 20mg/kg (to a maximum of 1.2g quinine) diluted in IV solution containing 5% dextrose (1-2ml/kg) is infused over four hours; Then four hours after completing the loading dose (i.e. 8hrs after commencing quinine) give 10mg per kg infused over 4 hours and continue the same dose 8hrly. If the patient requires IV quinine for more than 48hrs reduce the dose to 5-7 mgs per kg per dose 8hrly Note: The loading dose is not given if quinine, Chloroquine, or Mefloquine have been given in any form during the previous one week. In this case commence with a dose of 10 mg/kg of body weight. IV fluids given with quinine should be based on hydration status, urine output, etc. Once the IV fluid rate has been decided then quinine is added to the amount of IV fluid to be infused over 4 hour period or as a separate IV infusion or piggy bag in 5% Dextrose. Monitor blood sugar with dextrostix every 4 hours and whenever symptom of hypoglycemia occurs, e.g. convulsions or changing level of consciousness. Patient with severe malaria will be treated with quinine as long as they remain in hospital and the treatment is supervised. If the patient is well enough to be discharged home before completing 7 (seven) day treatment, a full course of AL should be given. 29

30 How to Give IM Quinine Weigh the patient or (in children) estimate the weight using the formula: 2 x age (years) + 8 = weight in kg (gives a good estimate up to age 10 Years) Draw up 5 ml sterile normal saline. Draw up 300 mg (1 ml) Quinine from an ampoule into the same syringe. The syringe now has 50 mg Quinine per ml of solution Give 10 mg (0.2 ml) per kg body weight by IM injection into the upper thigh. If the volume to be injected is more than 3 ml, give half into each thigh. Note: The adult dose for IM Quinine is the same as for children, i.e. 10 mg/kg. In the case of heavy adults who might require up to 16 ml of the diluted Quinine preparation the total will need to be divided into 3 or 4 parts of 3 or 4 ml, each which can be injected into different sites. The Quinine that is used for IM injection is the same preparation, which is given IV. In other words there is no difference in the ampoules, which can therefore be used for either IM or IV administration. However when given IM it must be diluted as described above. 30

31 Treatment of Complications of Severe Malaria Disease. Table 3: Treatment of Other Severe Malaria Complications. Manifestation/ complication Coma (cerebral malaria) Hyperpyrexia Convulsions Hypoglycaemia (blood glucose concentration of <2.2 mmol/l; <40 mg/100ml) Severe anaemia (haemoglobin <5 g/100ml or packed cell volume <15%) Immediate management Maintain airway, place patient on his or her side, exclude other treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis); avoid harmful ancillary treatment such as corticosteroids, heparin and adrenaline; intubate if necessary. Administer tepid sponging, fanning, cooling blanket and antipyretic drugs. Maintain airways; treat promptly with intravenous or rectal diazepam or intramuscular paraldehyde. Check blood glucose, correct hypoglycaemia and maintain with glucose-containing infusion. Transfuse with screened fresh whole blood Acute oedema pulmonary Prop patient up at an angle of 45 o, give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory pressure/continuous positive airway pressure in life-threatening hypoxaemia. Acute renal failure Spontaneous bleeding and coagulopathy Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis. The benefits of diuretics/dopamine in acute renal failure are not proven. Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets if available); give vitamin K injection. Metabolic acidosis Exclude or treat hypoglycaemia, hypovolaemia and septicemia. If severe add haemofiltration or haemodialysis. Shock Suspect septicemia, take blood for cultures; give potential antimicrobials, correct haemodynamic disturbances. Monitor frequently As adapted from the Guideline for the treatment and Diagnosis of malaria in the Africa region. NB: IV Quinine shall continue to be the initial treatment of choice for severe malaria in hospitals until the patient is ready to take oral medication. 31

32 5. Treatment of Malaria Caused By Other Species AL is the recommended 1 st line treatment of choice for all types of uncomplicated malaria species including P. vivax, malariae and ovale. 6. Malaria Prevention 6.1. Malaria Prevention in Pregnancy Effective chemoprophylaxis during the second and third trimester of pregnancy greatly reduces the impact of malaria on low birth weight and episodes of clinical malaria. This led to the recommendation of systematic regular chemoprophylaxis for pregnant women exposed to malaria (WHO, 1990). The implementation of this policy has been limited by a number of factors: increased drug resistance, particularly to chloroquine; poor compliance associated with routine chemoprophylaxis; patient beliefs about side effects; acceptability and access to antenatal services; cost of efficacious antimalarial drugs. Presently, use of chloroquine alone as a prophylactic in pregnancy is not recommended in areas where P. falciparum resistance to chloroquine is high. In areas of low to moderate levels of chloroquine resistance, WHO recommends three interventions for malaria prevention and control during pregnancy. These are effective case management, prevention by use of ITNs and Intermittent Preventive Treatment (IPT) in areas of high transmission. In Botswana where malaria transmission is low, intermittent treatment with SP (IPT) is not recommended. A combined regimen of chloroquine and proquanil continues to be recommended in Botswana. The recommended dose for Proquanil 200 mg daily and for chloroquine is 5 32

33 mg/kg of body weight weekly, i.e. 300 mg base given weekly throughout pregnancy. This combination provides substantial protection. In Botswana, there is need to evaluate the impact of routine chemoprophylaxis in pregnancy against the overall malaria burden in pregnant women Chemoprophylaxis in the General Travelers There is no safe, effective and affordable anti-malarial drug that can be used for chemoprophylaxis on a large scale. Secondly, it should be well understood that no drug can guarantee absolute and complete protection against malaria. Therefore, the use of personal protective measures such as the use of ITNs, insect repellents and protective clothing is recommended. Chloroquine and proguanil is a recommended drug of choice for chemoprophylaxis for local travelers in Botswana against all species of plasmodium. For prophylaxis, chloroquine 5 mg/kg base preferably weekly beginning two weeks before arrival with daily proguanil 200mg/day, throughout the period of stay and continued 4 weeks after the last possible exposure. Mefloquine prophylaxis is recommended for travelers to foreign countries. Consultations are underway to review prophylaxis for local travelers in Botswana. Table 4: showing Mefloquine dosage Weight (Kg) Age(Years) Number of Tablets per week <5 <3 month Not recommende4d month 1/4 13-= / /

34 7. Pharmacovigilance The use of a new drug or combination of dugs in the population requires careful monitoring of adverse drug reactions that maybe associated with the use of such drugs in the broader population. WHO defines pharmacovigilance (PV) as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem. Pharmacovigilance therefore is a critical component for the implementation of the new drug policy. Hence, the monitoring, documentation and reporting of adverse drug reaction by health workers cannot be over emphasized. All health care providers and patients are therefore advised to identify report and document all new and already noted adverse effects and report to Ministry of Health National Malaria Control Programme. The programme will have a policy and programme for PV and a set of reporting forms to allow ease of reporting and transmission at all levels. Pharmacovigilance of AL is important as it will go a long way in providing information thereby providing a tool for decision making to preventing harm to our patients. 8. Drug Resistance Surveillance Antimalarial drug resistance has emerged as a leading threat to ongoing malaria control efforts. As resistance to one or more antimalarial drugs occurs more frequently, malaria control programmes and other concerned institutions need to be able to evaluate antimalarial drug efficacy in a way that provides timely, relevant, reliable, and understandable information. Data derived from these evaluations are essential not only for maintaining confidence that current treatment recommendations are adequate in relation to malaria patients' needs, 34

35 but also, should that not be the case, for generating convincing evidence that current treatment recommendations are in need of change. When such evaluations are conducted consistently over time and in a reasonable and representative selection of sites, programmes should be able to monitor drug efficacy in a way that will allow changes in treatment recommendations or policies to be made early enough to minimize the impact of a failing treatment regimen. WHO has standardized protocols for Monitoring Drug Efficacy. Botswana will adopt these guidelines to suit country situation. AL drug sensitivity and resistance survey of Plasmodium parasite has to be done periodically. The frequency of the study has to be every 2 years after the start of using AL for the treatment of uncomplicated malaria. Currently the treatment efficacy sentinel sites are in Chobe, Ngami, Okavango, Boteti and Tutume. 35

36 9. Disease Management at Different Levels of the Health Care Delivery System The goals of malaria case management are stated against each level. It is hoped that this will serve as a useful guide in focusing the use of this training manual to the desired target group. HEALTH CARE FACILITY Tertiary Referral Hospitals CADRE OF STAFF Consultant, Specialists, Medical officers, Nurses, Pharmacy and Medical Laboratory Personnel EXPECTED HEALTH CARE LEVEL Intensive care for severe disease as well as all the services listed under primary and secondary care levels Secondary District, Primary, Mission, Mines and Private Hospitals Medical officers, Nurses Pharmacy and Medical Laboratory Personnel. In-patient care Basic laboratory support for confirming diagnosis and monitoring. Assessing complications Primary Clinics with/without maternity, Health Posts and Mobile Stops Medical officers and Nurses Syndromic approach focusing on disease identification, initiation of appropriate treatment and urgent referral of severe malaria, Rapid test 36

37 REFERENCES: 1. Guidelines for the Treatment of Malaria, World Health Organization, Malaria Manual for Health workers In Botswana, Second Edition, The Diagnosis and Management of Uncomplicated and Severe Malaria, facilitators Guide, Republic of Botswana, June The Diagnosis and Management of Uncomplicated and Severe Malaria, Learners guide, Republic of Botswana, June Malaria case management operational manual draft. World Health Organization Use of Antimalarial Drugs. Report of an Informal Consultation. World Health Organization The Use of Rapid Diagnostic Test, World Health Organization, Novartis; Coartem Monograph WHO: Report of World Health Organization Technical Consultation, October (Pre- Publication Copy). 10. Malaria Diagnosis and Treatment Guidelines for Health Workers in Ethiopia, July World Health Organization. Management of Severe Malaria- a Practical Handbook, 2 nd edition

38 Annex I: Pharmacology of the Drugs used for the treatment of malaria in Botswana 1. Pharmacology of Artemether - Lumefantrine Mode of Actions of AL: The precise anti-malarial action of Artemether and Lumefantrine is unknown, although both appear to act on the parasite s cell structures. Artemether contains an endoperoxide bridge, which interacts with iron in the hemoglobin to generate reactive oxygen radicals which damage the parasite leading to its death. Lumefantrine is thought to interfere with haem polymerizations, a critical detoxifying pathway for the malaria parasite. Artemether rapidly reduces parasite biomass and quickly resolves clinical symptoms while long acting Lumefantrine prevents recrudescence. This dual effect also appears to reduce the selective pressure on the parasite to develop resistance. Adverse/Side Effects and Their Management: Artemether- Lumefantrine is relatively safer compared to other antimalarial drugs. The side effects are minimal and these may include: 38 Common side effects: Gastrointestinal disturbances such as abdominal pain, anorexia, nausea, vomiting, diarrhea, central nervous system such as headache, dizziness which cannot be distinguished from symptoms of acute malaria. Less common side effects: Pruritus and rash (<2% of patients) others include neutropenia, liver enzymes elevation. Cardiovascular effects- bradycardia, palpitation and prolongation of QT interval. Sleep disturbances, cough, asthenia, arthralgia, and myalgia. Most of these side effects will resolve without discontinuing treatment. However, in severe cases, treatment with AL must be discontinued and the recommended second line antimalarial prescribed.

39 Some of the side effects may be managed as follows; Anorexia:-Encourage the patients to eat any food that he/she enjoys or is palatable to him/her. Nausea and vomiting: - Patients should be advised to take the medication with food. Diarrhoea: - Patients should be advised to drink water often or use ORS. Rash and Pruritus (mild): Reassure the patient that it will stop after a short time, if severe, discontinue. Precautions; Caution should be applied in patients known to have, electrolyte disturbances, hepatic and renal impairment. Concomitant use AL with drugs known to cause QT-interval prolongation (e.g. quinine and mefloquine) should be discouraged. Monitor patients who are unable to take food while on AL therapy, as they are at greater risk of recrudescence. Contra indications: AL is contraindicated in patients with history of arrhythmias, clinically relevant bradycardia, heart failure, family history of sudden death or of congenital, QT interval prolongation and persons with known hypersensitivity to either of the components in AL. It is contraindicated in children weighing less than 5 Kg. It is also contraindicated in severe malaria and first trimester of pregnancy. However if AL is the only available antimalarial, it may be used even in the first trimester to save the life of the pregnant woman. Drug Interaction: Patients should avoid grapefruit juice, antiarrhythmic such as amiodarone, disopyramide, flecainide, procainamide and quinidine; antibacterials such as macrolides and quinolones, all antidepressants, antifungals such as imidazoles and triazoles; terfenadine ;other antimalarials, all antipsychotic drugs; and beta 39

40 blockers, such as metoprolol and sotalol. However, there is no evidence that co-administration with these drugs would be harmful especially in short term treatment. But where possible, avoid concomitant administration of AL with any of the drugs above or administer giving a sufficient time in-between the drugs. 2. Pharmacology of Quinine Quinine is an alkaloid derived from the bark of the Cinchona tree. Quinine is the L-stereoisomer of quinidine. It acts principally on the mature trophozoite stage of parasite development and does not prevent sequestration or further development stage of circulating ring stages of P. falciparum. It also kills the sexual stages of P. vivax, P.malariea and p. ovale but not mature gametocytes of P. falciparum. It does not kill the pre-erythrocytic stages of malaria parasites. The mode of action is thought to involve inhibition of parasite haem detoxification in the food vacuole, but are not well understood. It is also believed to depress oxygen uptake and carbohydrate metabolism; intercalates into DNA, disrupting the parasites replication and transcription. Pharmacokinetics: The pharmacokinetic properties of quinine are altered significantly by malaria infection, with reduction in apparent volume of distribution and clearance in proportion to disease severity. The concentration is slightly higher in older children and adult with severe malaria than in children under 2 years of age. Quinine is rapidly and completely absorbed from Gastro Intestinal Tract (GIT) and peak plasma concentration is reached in 1-3 hours after oral administration of the sulphate. Also it is well absorbed in after I.M administration in severe malaria. Quinine is widely distributed through out the body including the cerebrospinal fluid, breast milk and placenta. Extensively metabolized in liver and the elimination of more polar metabolites is mainly renal. Excretion is increased in acid urine. The mean elimination 40

41 half-life is around 11 h in healthy subjects, 16 h in uncomplicated malaria and 18 in severe malaria. Small amount appear in the bile and saliva. Adverse effects/ Toxicity: Quinine causes complex of symptoms known as cinchonism which could be mild or severe. Mild symptoms include tinnitus, impaired hearing, headache, dizziness and dysphoria and disturbed vision. Severe manifestations include vomiting, abdominal pain, diarrhea and severe vertigo. Others include hypersensitivity reactions such as urticaria, bronchospasm, flushing, and fever, thrombocytopenia and haemolytic anaemia. The most important adverse effect is hyperinsulinaemic hypoglycemia and this is particularly common in pregnancy. I.M injection of quinine HCL causes pain, focal necrosis and in some cases abscess formation. Hypotension and cardiac arrest may result from rapid intravenous injection. I.V quinine should be given by infusion never injection. It causes prolongation of the electrocardiograph QT interval. Quinine has been used as an abortificient, but there is no evidence that it causes abortion, premature labour or fetal abnormalities in therapeutic use. Stability: Protect from light. Precautions: Use with caution in patients with cardiac arrhythmias and patients with myasthenia gravis. Contraindication: Quinine is should not be used in patients with tinnitus, optic neuritis, G-6-Phosphat Dehydrognase deficiency, hypersensitivity to quinine or any component, history of black water fever (massive haemolysis with renal failure) 41

42 Drug interactions: Quinine may not be given concurrently with drugs that cause prolongation of QT interval Flecainide and amidiarone, should probably be avoided. There might be an increased risk of ventricular arrhythmias with antihistamines such as terfenadine and with antipsychotic drugs such as pimozide and thioridiazine. Halofantrine, which causes marked QT prolongation, should be avoided but combination with other antimalarials, such as lumefantrine and mefloquine is safe. Quinine increases the plasma concentration of digoxin. Cimetidiine inhibits quinine metabolism, causing increased quinine levels and rifampicin metabolic clearance leading to low plasma concentrations and an increased therapeutic failure rate. 3. Pharmacology of Chloroquine Chloroquine is a 4-aminoquinoline that has been used extensively for the treatment and prevention of malaria. Widespread resistance has now rendered it virtually useless against P. falciparum infections in most parts of the world, although it still maintains considerable efficacy for the treatment of P. vivax, P. ovale and P. malariae infections. As with other 4-aminoquinolines, it does not produce radical cure. Chloroquine interferes with parasite haem detoxification (1, 2). Resistance is related to genetic changes in transporters (PfCRT, PfMDR), which reduce the concentrations of chloroquine at its site of action, the parasite food vacuole. Formulations: Tablets containing 100 mg or 150 mg of chloroquine base as hydrochloride, phosphate or sulfate. Pharmacokinetics: Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract when taken orally, although peak plasma concentrations can vary considerably. Absorption is also very rapid following intramuscular and subcutaneous administration (3 42