Malaria Treatment Guideline 2012

MalariMalariaa

ByByEbson Anak NgumbangEbson Anak Ngumbang

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 Malaysia

Source: WHO, 2011

Malaria Trend in Malaysia 1995-2010

Malaria Transmission Cycle

Parasite undergoes sexual reproduction in the mosquito

Some merozoites differentiate into male or female gametocyctes

Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts

Dormant liver stages (hypnozoites) of P. vivax and P. ovale

Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood

MOSQUITO HUMAN

Sporozoites injected into human host during blood meal

Parasites mature in mosquito midgut and migrate to salivary glands

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

uncomplicated malaria

in special groups (young children, pregnant women, HIV /AIDS)

in travellers (from non-malaria endemic regions)in epidemics and complex emergency situations

4 | Guidelines for the Treatment of Malaria

severe malaria

Clinical features and classification of malaria

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

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 oedemaAbnormal bleeding (Disseminated Intravascular coagulopathy)JaundiceHaemoglobinuria (black water fever)Acute renal failure - presenting as oliguria or anuriaSevere anaemia (Haemoglobin < 5g/dl or Haematocrit < 15%)High feverHypoglycaemia (blood glucose level < 2.2.mmol/l)

Confusion, or drowsiness with extreme weakness (prostration).In addition, the following may develop:

defined as the detection of P. falciparum in the peripheral blood

Guidelines for the Treatment of Malaria

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]).

Differential diagnosis for uncomplicated malaria

Consider 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 malaria

Consider other illness, such as:measles, meningitis, tonsilitis,, dengue, otitis

media (ear infection), influenza, pneumonia, typhoid fever, tuberculosis, hypoglycemia.

THE PHARMACOLOGY OF ANTIMALARIALS

Class Definition Examples

Class Definition Examples Class Definition Examples

Blood schizonticidal drugs

Act on (erythrocytic) stage of the parasite thereby terminating clinical illness

Quinine, artemisinins, amodiaquine, chloroquine, lumefantrine, tetracyclinea , atovaquone, sulphadoxine, clindamycina , proguanila

Tissue schizonticidal drugs

Act on primary tissue forms of plasmodia which initiate the erythrocytic stage. They block furtherdevelopment of theinfection

Primaquine, pyrimethamine,proguanil, tetracycline

Gametocytocidal drugs

Destroy sexual forms of theparasite thereby preventing transmission of infection tomosquitoes

Primaquine, artemisinins,quinineb

a Slow acting, cannot be used alone to avert clinical symptomsb Weakly gametocytocidal

THE PHARMACOLOGY OF ANTIMALARIALS (cont.)

Class Definition Examples

Class Definition Examples Class Definition Examples

Hypnozoitocidal drugs These act on persistentliver stages of P.ovaleand P.vivax which causerecurrent illness

Primaquine, tafenoquine

Sporozontocidal drugs These act by affectingfurther development ofgametocytes into oocyteswithin the mosquito thusabating transmission

Primaquine, proguanil,chlorguanil

1. Treatment of severe falciparum malaria

Preferred regime Alternative regime

IV Artesunate (60mg): 2.4mg/kg on admission, followed by 2.4mg/kg at 12h & 24h, then once daily for 7 days.

Once the patient can tolerate oral therapy, treatment should be switched to a complete dosage of Riamet (artemether/lumefantrine) for 3 day.

IV Quinine loading 7mg salt /kg over 1hr followed by infusion quinine 10mg salt/kg over 4 hrs, then 10mg salt/kg Q8H or IV Quinine 20mg/kg over 4 hrs, then 10mg/kg Q8H.PlusAdult & child >8yrs old: Doxycycline (3.5mg/kg once daily)or Pregnant women & child < 8yrs old: Clindamycin (10mg/kg twice daily). Both drug can be given for 7 days.

Reconstitute with 5% Sodium Bicarbonate & shake 2-3min until clear solution obtained. Then add 5ml of D5% or 0.9%NaCl to create total volume of 6ml.Slow IV injection with rate of 3-4ml/min or IM injection to the anterior thigh.The solution should be prepared freshly for each administration & should not be stored.

Dilute injection quinine in 250ml od D5% and infused over 4hrs.

Infusion rate should not exceed 5 mg salt/kg per hour.

2. Treatment of uncomplicated p.falciparum

Dosage and administration Plasmodium falciparum for young infant

Age GroupWeight group

Artesunate or *Quinine

0 - 4 months

<5 kg

** IM first dose Artesunate 1.2 mg/kg or IM Arthemeter 1.6 mg/kg)

***Oral Artesunate 2mg/kg/day day 2 to day 7

Oral Quinine 10 mg/kgTDS for 4 days then 15-20 mg/kg TDS for 4 days

Source: Malaria in Children, Department of tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University.

** Preferably Artesunate/Artemether IM on day 1 if available *** When Artesunate/Artemether IM is unavailable, give oral Artesunate from day 1 to day 7* Treat the young infant with Quinine when oral Artesunate is not available

Children under 5 kg or below 4 months should not be given Riamet instead treat with the following regimen (see table).

3. Treatment of malaria caused by p.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 be taken with fluid and encourage patient to resume normal eating as soon as food can be tolerated.Watch all patients swallowing the first dose of Riamet® and observe for 1 hour after the intake. In the event of vomiting within one hour of administration, a repeat dose should be taken.For small children Riamet® can be crushed, diluted in water and then put either directly into the mouth using a syringe or given with a spoon.Riamet may cause fatigue and dizziness. Warn patient not to drive or use machines.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(150 mg base/tab) 25 mg base/kg

divided over 3 days

PRIMAQUINE(7.5 mg base/tab)

Day 1 Day 2 Day 3 Start concurrently with CHLOROQUINE 0.5 mg base/kg Q24H for 2 weeksTake with foodCheck G6PD status before start primaquineIn mild-to-moderate G6PD deficiency, primaquine 0.75 mg base/kg body weight given once a week for 8 weeks. In severe G6PD deficiency, primaquine is contraindicated and should not be used.

10mg base/kg

stat, then 5mg

base/kg

5mg base/kg Q24H

5mg base/kg Q24H

1 tab of chloroquine phosphate 250mg equivalent to 150mg base. Calculation of dose for chloroquine is based on BASE, not SALT form. 1 tab of primaquine phosphate contains 7.5mg base.

Treatment in specific population & situations

Specific populations

Preferred regime Alternative regime

Pregnancy Quinine plus clindamycin to be given for 7 day

Artesunate plus Clindamycin for 7 days is indicated if first line treatment fails

Lactating women

Should receive standard antimalarial treatment (including ACTs) except for dapsone, primaquine and tetracyclines, which should be withheld during lactation

Hepatic impairment

Chloroquine: 30-50% is modified by liver, appropriate dosage adjustment is needed, monitor closely.Quinine : Mild to moderate hepatic impairment-no dosage adjustment, monitor closely. Artemisinins : No dosage adjustment

Renal Impairment

Chloroquine : ClCr<10ml/min-50% of normal dose.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/treatment

Come (Cerebral malaria) Monitor & record level of consciousness using Glaslow coma scale, temperature, respiratory, and depth, BP and vital signs.

Hyperpyrexia (rectal body temperature >40°C)

Treated by sponging, fanning &with an antipyretic drug.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 conc. <2.8mmol/L)

Correct with 50% dextrose (as infusion fluids). Check blood glucose Q4-6H in the first 48hrs.

Severe anaemia (hb < 7g/dl)

Transfuse with packed cells. Monitor carefully to avoid fluid 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/treatment

Acute renal failure (urine output <400ml in 24hrs in adults or 0.5ml/kg/hr, failing to improve after rehydration & a serum creatinine of >265μmol/L)

Exclude pre-renal causes by assessing hydration status. Rule out urinary tract obstruction by abdominal examination or ultrasound.Give intravenous normal salineIf in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis.

Disseminated intravascularCoagulopathy (DIVC)

Transfuse with packed cell, clotting factors or platelet.Usual regime: Cryoprecipitate 10units,platelets 4-8units, 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 systolic blood pressure <70mmHg)

Suspect septicaemia, take blood for cultures; give parenteral broad-spectrum antimicrobials, correct haemodynamic 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 perweek

< 5 kg < 3 months Not recommended

5 - 12 kg 3 - 23 months 1/413 - 24 kg 2 - 7 yrs 1/225 - 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 Contraindicated25 - 35 8 - 10 ½36 - 50 11 - 13 ¾50+ 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