The artemisinin derivatives (oral formulations) and partner medicines of ACTs are not recommended as monotherapy
http://www.akademisains.gov.my/download/tropical/Lokman.pdf http://www.who.int/malaria/publications/country-profiles/profile_mys_en.pdf Proportion of Vivax malaria increases every year. On the other hand, the falciparum malaria infection rate in Sabah,Kedah, P. Pinang & Kelantan is still High. Even though the control activities for vivax & falciparum malaria are the same, risk of complications and treatment differs. For falciparum malaria, risk of developing resistance to existing treatment (non ACT based)
The life cycle of the parasite is complicated and involves two hosts, humans and AnophelesAnopheles mosquito bites a person and injects the malaria parasites (sporozoites) into the blood. Sporozoites travel through the bloodstream to the liver, mature, and eventually infect the human red blood cells. While in red blood cells, the parasites again develop until a mosquito takes a blood meal from an infected human and ingests human red blood cells containing the parasites. Then the parasites reach the Anopheles mosquito's stomach and eventually invade the mosquito salivary glands. When an Anopheles mosquito bites a human, these sporozoites complete and repeat the complex Plasmodium life cycle. P. ovale and P. vivax can further complicate the cycle by producing dormant stages (hypnozoites) that may not develop for weeks to years. mosquitoes.
young children in stable transmission areas who have not yet developed protective immunity against the most severe forms of the disease; non-immune pregnant women as malaria causes high rates of miscarriage and can lead to maternal death; semi-immune pregnant women in areas of high transmission. Malaria can result in miscarriage and low birth weight, especially during first and second pregnancies; semi-immune HIV-infected pregnant women in stable transmission areas, during all pregnancies. Women with malaria infection of the placenta also have a higher risk of passing HIV infection to their newborns; people with HIV/AIDS ; international travellers from non-endemic areas because they lack immunity; immigrants from endemic areas and their children living in non-endemic areas and returning to their home countries to visit friends and relatives are similarly at risk because of waning or absent immunity.
Malaria can be classified as either uncomplicated or severe based on clinical presentation.
Uncomplicated malaria. Symptomatic infection with malaria parasitaemia without signs of severity and/or evidence of vital organ dysfunction.
This is a life threatening manifestation of malaria, and is defined as the detection of P. falciparum in the peripheral blood in the presence of any of one or more of the clinical or laboratory features listed below: Prostration -(inability or difficulty to sit upright, stand or walk without support in a child normally able to do so, or inability to drink in children too young to sit)
Rapid diagnostic tests (RDTs) are immunochromatographic tests based on detection of specific parasite antigens. Tests which detect histidine-rich protein 2 (HRP2) are specific for P.falciparum while those that detect parasite lactate dehydrogenase (pLDH) or aldolase have the ability to differentiate between P.falciparum and non-P.falciparum malaria (vivax, malariae and ovale). With the appropriate training, RDTs are simple to use and are sensitive in detecting low parasitaemia The use of RDTs is however not recommended for follow-up as most of the tests remain positive for between 2 to 3 weeks following effective antimalarial treatment and clearance of parasites. They also cannot be used to determine parasite density. When using RDTs, it is important to adhere strictly to the manufacturer’s instructions especially the time of reading the results. Remember to observe safe medical waste disposal at all times. The recommended RDTs for use in Kenya will be according to the WHO recommendations produced annually.
Severe malaria is most often caused by P. falciparum Quinine must never be given by intravenous bolus injection, as lethal hypotension may result. Quinine dihydrochloride should be given by rate-controlled infusion in saline or dextrose solutions at a rate not exceeding 5 mg salt/kg body weight per hour. Give parenteral antimalarials in the treatment of severe malaria for a minimum of 24 h, once started (irrespective of the patient’s ability to tolerate oral medication earlier), and, thereafter, complete treatment by giving a complete course of: – artemether plus lumefantrine, – artesunate plus amodiaquine, – dihydroartemisinin plus piperaquine, – artesunate plus sulfadoxine-pyrimethamine, – artesunate plus clindamycin or doxycycline, – quinine plus clindamycin or doxycycline.
Riamet:Whenever possible, the dose should be taken immediately after food. Patients with acute malaria are frequently averse to food. Patients should be encouraged to resume normal eating as soon as food can be tolerated since this improves absorption of artemether and lumefantrine (see “Pharmacokinetics–Absorption”). In the event of vomiting within 1 hour of administration, a repeat dose should be taken. Quinine:This drug may cause headache, sweating, dizziness, blurred vision, diarrhea, nausea, and vomiting.  Instruct patient to report signs/symptoms of hypersensitivity reactions, thrombocytopenia, or unusual bleeding and/or bruising.  Advise patient to take drug with food to decrease gastric irritation.  Instruct patient with an infection to take the full course of treatment. Do not stop taking medication, unless approved by a physician, even if symptoms have improved.  Advise patient there are multiple significant drug-drug interactions for this drug. Consult a healthcare professional prior to new drug use (including over-the-counter and herbal drugs).  In the event of a missed dose, counsel patient not to double the dose. If more than 4 hours have passed since the missed dose, skip the missed dose and maintain a regular dosing schedule.  Quinine (Oral route, Capsule, Tablet, Tablet, Extended Release) artemether plus lumefantrine, ■ artesunate plus amodiaquine, ■ artesunate plus mefloquine, ■ artesunate plus sulfadoxine-pyrimethamine,7 ■ dihydroartemisinin plus piperaquine.
Chloroquine: This drug may cause diarrhea, loss of appetite, nausea, stomach cramps, amnesia, or vomiting. Instruct patients to report muscle weakness or signs/symptoms of retinopathy, especially if on long-term therapy. Patient should not take antacids or kaolin within 4 h before or after chloroquine phosphate. Tell patient to not take ampicillin within 2 h before or after chloroquine phosphate. If a patient on once-weekly dosing misses a dose, instruct patient to take the missed dose as soon as possible and then wait 7 days before taking the next dose. primaquine:Patients should report recent use of quinacrine prior to initiation of therapy. This drug may cause abdominal pain. Advise patient to report signs/symptoms of leukopenia or hemolytic anemia. Tell patient to take drug with food to minimize gastric irritation. Because primaquine can cause hemolytic anemia in G6PD-deficient persons, G6PD screening must occur prior to starting treatment with primaquine. Primaquine must not be used during pregnancy For P. vivax and P. ovale infections, primaquine phosphate for radical treatment of hypnozoites should not be given during pregnancy. Pregnant patients with P. vivax and P. ovale infections should be maintained on chloroquine prophylaxis for the duration of their pregnancy. The chemoprophylactic dose of chloroquine phosphate is 300 mg base (=500 mg salt) orally once per week. After delivery, pregnant patients who do not have G6PD deficiency should be treated with primaquine.
Pregnant women diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy. The dosage of artemisinin derivatives does not need adjustment in vital organ dysfunction. Quinine (and quinidine) levels may accumulate in severe vital organ dysfunction. If the patient remains in acute renal failure or has hepatic dysfunction, then the dose should be reduced by one third after 48 h. Dosage adjustments are not necessary if patients are receiving either haemodialysis or haemofiltration.
Cerebral malaria. Severe P. falciparum malaria with cerebral manifestations, usually including coma (Glasgow coma scale < 11, Blantyre coma scale < 3). Malaria with coma persisting for > 30 min after a seizure is considered to be cerebral malaria.
Mefloquine is available as tablets of 274mg mefloquine hydrochloride containing 250mg base or tablets of 250mg mefloquine hydrochloride containing 228mg base (United States only). Mefloquine is administered as a weekly dose of 250mg for adults or 5mg base/kg body weight for persons below 36 kg.
Side effects Nausea, vomiting, abdominal pain and diarrhoea. These are most common but are dose related and self-limiting. Other CNS related ones include dysphoria, dizziness, ataxia, headache, some visual and auditory disturbances, sleep disturbances and nightmares, convulsions. Contraindications Š. The first trimester of pregnancy Š. Do not administer to patients less than 5 kg. Š. Avoid use in history of seizures and in severe neuro-psychiatric disturbance Š. Do not administer concomitantly with quinine and avoid quinine use after administration of mefloquine Caution Š. Mefloquine can compromise adequate immunisation with the live typhoid vaccine. Mefloquine should be taken 12 hours after administration of the last quinine dose Š. Care should be taken when administering concomitant medications that interfere with cardiac function Patient should be advised that any live vaccines should be completed at least 3 days before initiation of therapy. Patient should avoid activities requiring mental alertness or coordination until drug effects are realized. This drug may cause bradycardia, diarrhea, nausea, dizziness, somnolence, or mental disorder. Instruct patient to report depression, anxiety, psychosis or unusual changes in behavior. Patient should take tablet with food and an 8-ounce glass of water. Patient should not take with or following halofantrine treatment. Patient should avoid concomitant use of quinine, quinidine, or chloroquine therapy. Instruct patient to repeat full dose if vomiting occurs within 30 min of dose, or to repeat 1/2 dose if vomiting occurs within 30 to 60 min of dose.
Side effects GIT irritation, increased vulnerability to sun-burn (phototoxic reaction), transient depression of bone growth and discoloration of teeth, vaginal candidiasis. Contraindications Doxycycline shouldn’t be used in . Children under 8 years of age . Pregnant and lactating mothers . Persons with hepatic insufficiency . Persons with known hypersensitivity to tetracyclines Caution Doxycycline should not be used for prophylaxis for periods exceeding 4 months. Antacids and milk impair absorption of tetracycline and concurrent administration should be avoided. Instruct patient to report severe diarrhea and consult healthcare professional prior to taking anti-diarrhea medicine. Drug causes sun-sensitivity. Advise patient to use sunscreen and avoid tanning beds. Drug may decrease effectiveness of oral contraceptives with concurrent use. Recommend additional form of birth control. This drug may cause a gastrointestinal disturbance. Advise patient to take drug with adequate fluid to prevent esophageal irritation or ulceration. Patient may take tablet and suspension with food, milk, or a carbonated beverage if gastric irritation occurs. Doxycycline (Oral route, Capsule, Capsule, Extended Release, Powder for Suspension, Syrup, Tablet, Tablet, Delayed Release) Doxycycline (Intravenous route, Powder for Solution) Doxycycline (Subgingival route, Kit)
Introduction• Malaria is a tropic life threatening disease.• A disease caused by members of the protozoan genus Plasmodium, a widespread group of sporozoans that pasitize the human liver and red blood cells.• Humans are infected with Plasmodium protozoa when bitten by an infective female Anopheles mosquito vector.• Symptoms may appear within weeks to months or even years.• There are 4 species: – plasmodium falciparum – plasmodium vivax – plasmodium ovale – plasmodium malariae
Malaria in Malaysia• Malaysia is situated in the hot, humid equatorial region and thereforeis receptive and vulnerable for the transmission of malaria.• The number of cases has shown a tremendous reduction from 181,495 cases at the start of the Eradication Programme in 1967 Tto 44,226 cases at the end of the Eradication Programme in 1980.
Distribution of malaria cases in MalaysiaSource: WHO, 2011
Malaria Transmission Cycle Exo-erythrocytic (hepatic) Cycle: Sporozoites injected Sporozoites infect liver cells and into human host during develop into schizonts, which release blood meal merozoites into the bloodParasitesmature inmosquitomidgut and Dormant liver stages MOSQUITO HUMANmigrate to (hypnozoites) of P.salivary vivax and P. ovaleglands Erythrocytic Cycle: Merozoites infect red Parasite undergoes Some merozoites blood cells to form sexual reproduction in differentiate into male or schizonts the mosquito female gametocyctes
Who is at risk?• young children• pregnant women• people with HIV/AIDS• international travelers from non-endemic areas• immigrants from endemic areas and their children
Clinical features and classification of malaria uncomplicated malaria severe malaria in special groups (young children, pregnant women, HIV/AIDS) in travellers (from non-malaria endemic regions) in epidemics and complex emergency situations
UNCOMPLICATED MALARIA (all species) – Uncomplicated malaria definition:Fever and any of the following:• Headache,• Body and joint pains• Feeling cold and sometimes shivering• Loss of appetite and sometimes abdominal pains• Diarrhoea, nausea and vomiting.• Hepatospleenomegaly
SEVERE COMPLICATED MALARIA Confusion, or drowsiness with extreme weakness (prostration). In addition, the following may develop: Alteration in the level of consciousness (ranging from drowsiness to deep coma) Cerebral malaria (unrousable coma not attributable to any other cause in a patient with falciparum malaria) Respiratory distress (acidotic breathing) Multiple generalized convulsions (2 or more episodes within a 24 hour period) Shock (circulatory collapse, septicaemia) Pulmonary oedema Abnormal bleeding (Disseminated Intravascular coagulopathy) Jaundice Haemoglobinuria (black water fever) Acute renal failure - presenting as oliguria or anuria Severe anaemia (Haemoglobin < 5g/dl or Haematocrit < 15%) High fever Hypoglycaemia (blood glucose level < 2.2.mmol/l)defined as the detection of P. falciparum in the peripheral blood
Malaria Diagnosis• All clinically suspected malaria cases require laboratory examination and confirmation.• Only in case where laboratory confirmation is not possible start treatment immediately.• Parasitological confirmation is done by thin- thick blood smear microscopy examination or by dipstick (Rapid Diagnostic Test [RDT]).Guidelines for the Treatment of Malaria
Differential diagnosis for uncomplicated malariaConsider other illnesses, such as:• Upper respiratory tract infection (Pharyngitis, tonsillitis, ear infection), pneumonia , measles, dengue, influenza, typhoid fever.Remember that the patient may be sufferingfrom more than one illness.
Differential diagnosis for severe malariaConsider other illness, such as:measles, meningitis, tonsilitis,, dengue, otitis media (ear infection), influenza, pneumonia, typhoid fever, tuberculosis, hypoglycemia.
THE PHARMACOLOGY OF ANTIMALARIALS Class Definition Class Definition Examples Class Definition Examples Examples Blood Act on (erythrocytic) stage of the Quinine, artemisinins, schizonticidal parasite thereby terminating amodiaquine, chloroquine, drugs clinical illness lumefantrine, tetracyclinea , atovaquone, sulphadoxine, clindamycina , proguanila Tissue Act on primary tissue forms of Primaquine, pyrimethamine, schizonticidal plasmodia which initiate the proguanil, tetracycline drugs erythrocytic stage. They block further development of the infection Gametocytocidal Destroy sexual forms of the Primaquine, artemisinins, drugs parasite thereby preventing quinineb transmission of infection to mosquitoesa Slow acting, cannot be used alone to avert clinical symptomsb Weakly gametocytocidal
THE PHARMACOLOGY OF ANTIMALARIALS (cont.)Class Definition Class Definition Examples Class DefinitionExamples ExamplesHypnozoitocidal drugs These act on persistent Primaquine, liver stages of P.ovale tafenoquine and P.vivax which cause recurrent illnessSporozontocidal drugs These act by affecting Primaquine, proguanil, further development of chlorguanil gametocytes into oocytes within the mosquito thus abating transmission
1. Treatment of severe falciparum malaria Preferred regime Alternative regimeIV Artesunate (60mg): 2.4mg/kg on IV Quinine loading 7mg salt /kg over 1hradmission, followed by 2.4mg/kg at 12h & followed by infusion quinine 10mg salt/kg over24h, then once daily for 7 days. 4 hrs, then 10mg salt/kg Q8H or IV Quinine 20mg/kg over 4 hrs, then 10mg/kg Q8H.Once the patient can tolerate oral therapy, Plustreatment should be switched to a complete Adult & child >8yrs old: Doxycycline (3.5mg/dosage of Riamet (artemether/lumefantrine) kg once daily)for 3 day. or Pregnant women & child < 8yrs old: Clindamycin (10mg/kg twice daily). Both drug can be given for 7 days.Reconstitute with 5% Sodium Bicarbonate & Dilute injection quinine in 250ml od D5%shake 2-3min until clear solution obtained. and infused over 4hrs.Then add 5ml of D5% or 0.9%NaCl to createtotal volume of 6ml. Infusion rate should not exceed 5 mg salt/kgSlow IV injection with rate of 3-4ml/min or per hour.IM injection to the anterior thigh.The solution should be prepared freshly foreach administration & should not be stored.
Children under 5 kg or below 4 months should not be given Riamet instead treat with the following regimen (see table). Dosage and administration Plasmodium falciparum for young infant Weight Age Group Artesunate or *Quinine group Oral ** IM first dose Quinine 10 ***Oral Artesunate 1.2 mg/kgTDS 0-4 Artesunate <5 kg mg/kg or IM for 4 days months 2mg/kg/day Arthemeter 1.6 then 15-20 day 2 to day 7 mg/kg) mg/kg TDS for 4 days Source: Malaria in Children, Department of tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University.referably Artesunate/Artemether IM on day 1 if availableWhen Artesunate/Artemether IM is unavailable, give oral Artesunate from day 1 to day 7eat the young infant with Quinine when oral Artesunate is not available
3. Treatment of malaria caused byp.knowlesi & mixed infection (p. falciparum+ p. vivax)• Treat as p. falciparum
Important notesRiamet tablets should be taken with or after food.Patient with acute malaria re frequently averse to food, the dose may betaken with fluid and encourage patient to resume normal eating as soon asfood can be tolerated.Watch all patients swallowing the first dose of Riamet® and observe for 1hour after the intake. In the event of vomiting within one hour ofadministration, a repeat dose should be taken.For small children Riamet® can be crushed, diluted in water and then puteither directly into the mouth using a syringe or given with a spoon.Riamet may cause fatigue and dizziness. Warn patient not to drive or usemachines.Instruct patient to report signs/symptoms of QT interval prolongation.
4. Treatment of of malaria caused by p.vivax, p. ovale or p. malariae. CHLOROQUINE PRIMAQUINE(150 mg base/tab) 25 mg base/kg (7.5 mg base/tab) divided over 3 days Day 1 Day 2 Day 3 Start concurrently with CHLOROQUINE 0.5 mg base/kg Q24H for 2 weeks Take with food 10mg Check G6PD status before start primaquinebase/kg 5mg In mild-to-moderate G6PD deficiency, stat, 5mg base/ base/kg primaquine 0.75 mg base/kg body weight then kg Q24H Q24H given once a week for 8 weeks. 5mg In severe G6PD deficiency, primaquine isbase/kg contraindicated and should not be used.1 tab of chloroquine phosphate 250mg equivalent to 150mg base. Calculation of dose forchloroquine is based on BASE, not SALT form. 1 tab of primaquine phosphate contains7.5mg base.
Treatment in specific population & situationsSpecific Preferred regime Alternative regimepopulationsPregnancy Quinine plus clindamycin to be given for Artesunate plus Clindamycin for 7 day 7 days is indicated if first line treatment failsLactating Should receive standard antimalarial treatment (including ACTs) exceptwomen for dapsone, primaquine and tetracyclines, which should be withheld during lactationHepatic Chloroquine: 30-50% is modified by liver, appropriate dosage adjustmentimpairment is needed, monitor closely. Quinine : Mild to moderate hepatic impairment-no dosage adjustment, monitor closely. Artemisinins : No dosage adjustmentRenal Chloroquine : ClCr<10ml/min-50% of normal dose.Impairment Hemodialysis, peritoneal dialysis: 50% of normal dose. Continuous Renal Replacement Therapy(CRRT) :100% of normal dose. Quinine : .ClCr 10-50ml/min : Administer Q8-12H, CLCr<10ml/min : administer Q24H,Severe chronic renal failure not on dialysis : initial dose: 600mg followed by 300mg Q12H, Hemo- or peritoneal dialysis: administer Q24H ,Continuous arteriovenous or hemodialysis: Administer Q8-12H. Artemisinin : no dosage adjustment.
Treatment of complications of malaria• Severe & complicated falciparum or knowlesi malaria is a medical emergency that requires intervention and intensive care as rapidly as possible.• Fluid, electolyte glucose & acid-base balance must be monitored.Intake & output should be carefully recorded.
Immediate clinical management of severe manifestations and complications of P. falciparum malariaDefinitive clinical features Immediate management/treatmentCome (Cerebral malaria) Monitor & record level of consciousness using Glaslow coma scale, temperature, respiratory, and depth, BP and vital signs.Hyperpyrexia (rectal body Treated by sponging, fanning &with an antipyretic drug.temperature >40°C) Rectal paracetamol is preferred over more nephrotoxic drugs (e.g. NSAIDs)Convulsions A slow IV injection of diazepam(0.15mg/kg, maximum 20mg for adults).Hypoglycaemia (glucose Correct with 50% dextrose (as infusion fluids). Check bloodconc. <2.8mmol/L) glucose Q4-6H in the first 48hrs.Severe anaemia (hb < Transfuse with packed cells. Monitor carefully to avoid fluid7g/dl) overload. Give small IV dose of frusemide, 20mg, as necessary during blood transfusion to avoid circulatory overload.Acute pulmonary oedema Prop patient upright (45°), give oxygen, give IV diuretic (but most patient response poorly to diuretics), stop intravenous fluids. Early mechanical ventilation should be considered.
Immediate clinical management of severe manifestations and complications of P. falciparum malaria (cont.)Definitive clinical features Immediate management/treatmentAcute renal failure (urine Exclude pre-renal causes by assessing hydration status.output <400ml in 24hrs in Rule out urinary tract obstruction by abdominal examinationadults or 0.5ml/kg/hr, or ultrasound.failing to improve after Give intravenous normal salinerehydration & a serum If in established renal failure add haemofiltration orcreatinine of >265μmol/L) haemodialysis, or if unavailable, peritoneal dialysis.Disseminated Transfuse with packed cell, clotting factors or platelet.intravascular Usual regime: Cryoprecipitate 10units,platelets 4-8units,Coagulopathy (DIVC) fresh frozen plasma(10-15ml/kg). For prolonged PT, give vitamin K, 10mg by slow IV injection.metabolic acidosis Infuse sodium bicarbonate 8.4% 1mg/kg over 30min and repeat if needed. if severe, add haemodialysis.Shock (hypotension with Suspect septicaemia, take blood for cultures; give parenteralsystolic blood pressure broad-spectrum antimicrobials, correct haemodynamic<70mmHg) disturbances.
Monitoring & follow-up• Blood smear should be repeated daily (twice daily in severe infection). Within 48-72 hr after start of treatment, patients usually become afebrile and improve clinically except in complicated cases.• All patients should be investigated with repeated blood film of malarial parasite one month upon recovery of malarial infection, to ensure no recrudescence.
Prevention•Avoid mosquito bites:Wearing long sleeves, trousers.Insecticide Treated BednetsRepellent creams or sprays.
Chemoprophylaxis• Indicated for travellers travel to endemic areas in Malaysia.• Mefloquinine 250mg weekly (up to 1 year) or doxycycline 100mg daily (up to 3 month), to start 1 week before and continue till 4 weeks after leaving the area.
Dosing schedule for mefloquine Weight Age No of tablets per week < 5 kg < 3 months Not recommended 5 - 12 kg 3 - 23 months 1/4 13 - 24 kg 2 - 7 yrs 1/2 25 - 35 kg 8 - 10 yrs 3/4 36 and above 11 yrs and above 1
Dosing schedule for doxycycline Weight in kg Age in years No of tablets < 25 <8 Contraindicated 25 - 35 8 - 10 ½ 36 - 50 11 - 13 ¾ 50+ 14+ 1
Tx failure of uncomplicated• A failure to clear malarial parasitaemia and/or resolve clinical symptoms despite the administration of an antimalarial. So while drug resistance may lead to treatment failure, not all treatment failures are caused by drug resistance.• Treatment failure can also be the result of incorrect dosing, problems of treatment adherence (compliance), poor drug quality, interactions with other drugs, compromised drug absorption, or misdiagnosis of the patient. Apart from leading to inappropriate case management, all these factors may also accelerate the spread of true drug resistance by exposure of the parasites to inadequate drug levels.
Tx failure for uncomplicated malaria• Treatment failures within 14 days of initial treatment should be treated with a second-line antimalaria.• the following second-line treatments are recommended,• in order of preference:• ■ an alternative ACT known to be effective in the region,• ■ artesunate plus tetracycline or doxycycline or clindamycin (given for a total of 7 days),• ■ quinine plus tetracycline or doxycycline or clindamycin (given for a total of 7 days).
References• WHO Guidelines for the treatment of malaria -- 2nd edition.(2010)• Management of severe malaria : a practical handbook. – 2nd ed.(2000)• MICROMEDEX 2.0• NATIONAL GUIDELINES FOR THE DIAGNOSIS, TREATMENT AND PREVENTION OF MALARIA IN KENYA.THIRD EDITION 2010.• http://www.akademisains.gov.my/download/tropical/Lokman.pdf• http://www.who.int/malaria/publications/country-profiles/profile_mys_en.pdf