The document provides information on the definition, causative agents, species, transmission, diagnosis and treatment of malaria. It discusses the different species of plasmodium that cause malaria, transmitted via female anopheles mosquitoes. Diagnosis methods include clinical diagnosis, parasitological diagnosis using microscopy and rapid diagnostic tests. WHO guidelines for treatment of uncomplicated and complicated falciparum malaria using various antimalarial drugs alone or in combination are presented.

1. DR.SHWETA PAGARE

2. INTRODUCTION
 Definition: Malaria is an acute and chronic illness
characterized by paroxysms of fever ,chills ,sweats , fatigue
, anaemia and splenomegaly .
 Causative agent: intracellular plasmodium protozoa.
 Species :P.falciparum , P.malariae , P.ovale , P.vivax.
(P.knowlesi -documented in malaysia ,
, indonesia,singapur,phillippines)
o Transmission: Female anopheles mosquitoes.
( Also transmitted through blood transfusion ,use
of contaminated needles, from pregnant women to fetal)

3. DIAGNOSIS
 Clinical diagnosis-WHO recommendation
1.Low risk area-based on possibility of exposure to malaria and h/o fever
in previous 3 days with no features of other disease.
2.High risk area-h/o fever in previous 24 hr &/or anaemia ,for which
pallor is +ent to be more reliable.
Parasitological diagnosis-
1.light microscopy –
by it we able to detect asexual parasites at densities of fewer than 10/µl
Typical field condition the limit of sensitivity is app 100/µl.
Stain used-giemsa staining and oil immersion microscopy.

4. 2.Rapid diagnostic test
 Immunochromatographic test that detect parasite specific
antigen in finger prick blood sample.
WHO recommends - RDT should have a sensitivity of >95% in
detecting plasmodium at densities of more than 100 parasites
/µl. .
Based on-detection of histidine rich protein (HRP2)which are
specific for p.falciparum, panspecific or species specific
plasmodium lactate dehydrogenase or panspecific aldolase.
SENSITIVITY->90 %at 100-500 parasites/µl of blood.(for p.falciparum)
Causes of poor sensitivity-poor test manufacture, damage due to exposure
to high temp and humidity , variation in target antigen
.

5. Advantage-1.rapid result
2.fewer requierment for training and skilled personnel.
Disadvantage-1.the likelihood of misinterpreting a positive result
as indicating malaria in patients with parasitaemia incidental to
another illness,when host immunity is high.
 2.the inability, in the case of some RDT to distinguish new
infections from a recently and effectively treated infection. its
due to persistence of certain target antigens(HRP2) in the blood
for 1-3 weeks after effective treatment.
 Immunodiagnosis and PCR based molecular
detection method-
1.Detection of antibodies to parsites.
2.Detect parasite DNA based on PCR

6. OTHER LAB INVESTIGAION-
Complete blood count.
Blood urea .sugar, creatinine
ABG
CSF

7. Comparative properties of antimalarial drug
Pre- Erythro eryhrocytic Exo- Gametes
DRUG erythro
Falci vivax Fal viv
.
chloroquine + +
-
Mefloquine +
Quinine +
proguanil + ± + * *
pyrimethamine + + * *
primaquine + + ± + + +
sulfonamide ±
artemisinin + + +
tetracycline + +

9. WHO Guidelines for malaria
Treatment of uncomplicated P.falciparum malaria.
 1.Artemisinin based combination therapies (ACTs)are recommended.
 Choice of ACTs based of level of resistance of the partner medicine in
combination.
 Artemisinin derivative should not be used as monotherapy.
 Recommended ACTs –1.Artemether +lumefantrine
2.artesunate+mefloquine
3.Aretesunate +sulfadoxine –pyrimethamine
DOSING-
Lumifantrin - 120 mg artemether -20 mg
dose -10 -16 mg /kg/dose dose -1.4 to 4 mg/kg/day
5 -14 kg 1 tab
15 -24 kg 2 tab BD for 3 days
25 -34 kg 3 tab
>34 kg 4 tab

10. Artesunate +amodiaquine
artesunate - 2 to 10 mg/kg/day
amodiaquine – 7.5 – 15 mg /kg/day
(availablity – 25/67.5mg 50/135 mg 100/270mg)
Artesunate+mefloquine
target dose 4 mg/kg/day OD for 3 days artesunate
&25 mg/kg/day meflaquine either split in 2 doses 15 & 10
or 3 doses 8.3 mg/kg/day OD
(Availabilty-50/250 mg base)
Artesunate+sulfadoxine-pyrimethamine
Target dose 4 mg/kg/day OD for 3 days –artesunate
25/1.25 mg/kg sulfadoxine pyrimethamine on day 1.
(availabilty-50mgartesunate 500 mg sulfadoxine 25mg pyrimethamine)

11.  2.Second line antimalarial treatment
 alternative ACT known to be effective in the region.
 Artesunate +tetracycline or doxycycline or clindamycine any of these
combination to be given for 7 days.
 Quinine +tetracycline or doxycyline or clindamycine any of these
should be given for 7 days.
 Addition of a single dose primaquine (0.75 mg/kg)to ACT treatment
for uncomplicated falciparum malaria as an antigametocytes medicine
3.Travellers returning to nonendemic countries.
.
Atovaquine +proguanil
Artemeter +lumefantrine
Quinine +doxycycline or clindamycine.
Dihydroartemisinin +piperaquine is an option for the first line treatment
of uncomplicated malaria worldwide

12.  Artesunate +tetracycline or doxycycline or clindamycine
Artesunate 2mg /kg OD + tetracycline 4 mg /kg qid or doxycycline 3.5
mg /kg OD a day. Or clindamycine 10 mg/kg BD a day. Used for
7days.
Treatment of uncomplicated P.vivax malaria
 Chloroquine 25 mg base /kg body weight divided over 3 day,combined with
primaquine 0.25 mg base /kg bw,taken with food once daily for 14 days is the
treatment of choice for chloroquine sensitive infection.
 ACTs combined with primaquine for chloroquine resistant vivax malaria.
 In mild to moderate G6PD deficiency,primaquine 0.75mg/kg/BW –once a week
for 8 weeks.
In severe G6PD deficiency- primaquine is contraindicated

13. Complicated p.falciparum malaria
Presence of one or more of the following clinical
features-
Severe complicated P.FALCI
1.impaired conciousness
2.Prostrarion
3.Convulsion >2 episode in 24 hrs
4.Acidotic breathing
5.Shock –SBP<50mm Hg
6.Hemglobinuria
7.Pulmonary edema
8.Abnormal spontaneous bleeding

14. investigation
1.–blood glucose<40mg/dl
2.Metabolic acidosis –bicaronate <15mmol/l
3.Anaemia –hb-<5g/dl , pcv <15%
4.Hyperparasitaemia >2% 1 lac/µl, in low intesity
transmission area.
>5% or 250000/µl –high stable malaria transmission
intensity
5.Hyperlactaemia (lactate>5 mmol/l)
6.Serum creat>265µmol/l or >3 mg /dl UOP < 0.5 ml/kg hr

15. TREATMENT OF COMPLICATED P.FALCIPARUM
MALARIA
 Its a medical emergency.
 Artesunate-2.4 mg/kg BW IV/IM time=o than 12 hr and 24 hr.than once a
day..
OR
 Artemether-3.4 mg/kg BW im given on admission then 1.6 mg/kg BW .
OR
quinine 20 mg salt/kg BW on admission than 10 mg mg/kg BW every 8
hr.infusion rate should not be >5mg salt/kg bw/hr.
Thereafter course should be completed by-
Artemether +lumifantrine artesunate +amodiaquine
Dihydroartemisinin +piperaquine artesunate+sulfadoxine-
pyrimethamine
Quinine+clindamycine or doxycycline

16.  Supportive treatment
1.antipyretic- paracetamol 15 mg /kg/dose q 4 -6 hr.
2.t/t of hypoglycemia.
3.Anticonvulsant drug
4.Blood transfusion
5.ARF-maintanace dose of quinine should be reduced to ½ to 1/3.
peritonial dialysis-persistent oliguria and rising creatinine
6.antibiotics-indication-
a)fever persists 48 hr after starting antimalarial t/t
b).Presence of shock and respiratory distress
c)Age <1yr
d)Presence of severe anaemia

17. EXCHANGE OF BLOOD TRANSFUSION
Rational for EBT
Removing rapidly RBC from the circulation and therefore lowering the
parasite.
Removing rapidly both the antigen load and burden of parasite derived
toxin, metabolite and toxic mediators produced by host.
Removing the rigid unparasitized red cells by more deformable cells
therefore alleviating microcirculatory obstruction.
Used in case of –parasitemia >10 % and evidence of complication in case
of p. Falciparum.

18. Treatment failure &Resistance
Treatment failure-
 its a faliure to clear malarial parasitaemia &/or resolve
clinical symptoms within 2 weeks of treatment .
Treatment failure in presence of parasites,despite the
blood conc.>10 ng/ml is the good marker of resistance of
p.vivax to chloroquine.
Causes-1.resistance
2.recrudescence
3.inadequete dosing and inappropriate use of drug
4.new infection
All treatment filure cases should be confirmed by
parasitologicly and should asked about prevous drug
history and course of thearpy.

19.  Treatment faliure
 Within 14 days after 14 days(pcr)
 Initial therapy should be
2nd line therapy
7 days course
recrudescence new
infection
1st line treatment
1st line
treatment
Reuse of meflaquine should be avoided.

20. RESISTANCE OF ANTIMALARIAL DRUGS
Definition-Ability of a parasite strain to survive &/or
multiply despite the proper administration and absorption
of antimalarial drug in the dose normally recommended.
 Only patients who meet the following criteria are classified
as RESISTANCE CASE:
 persistence of parasites 7 days after treatment or
recrudescence within 28 days after the start of treatment
 adequate plasma concentration of DRUG
 prolonged time to parasite clearance

21. F actors that influence the development of
antimalarial drug resistance
 • the intrinsic frequency with which the genetic changes occur;
 • the degree of resistance conferred by the genetic change;
 • the proportion of all transmissible infectious agents exposed to
the drug (selection pressure);
 • the number of parasites exposed to the drug;
 • the concentrations of drug to which the parasites are exposed;
 • the pharmacokinetics and pharmacodynamics of the
antimalarial medicine;
 • individual (dosing, duration, adherence) and community
(quality, availability, distribution) patterns of drug use;
 • the immunity profile of the community and the individual;
 • the simultaneous presence of other antimalarial drugs or
substances

22. Molecular basis of resistance-
 chloroquine-resistant parasites, there is a decrease in the accumulation
of drug within the food vacuole. Genetic crosses have identified the
role of the Plasmodium falciparum chloroquine resistance transporter
(Pf CRT, Pf MDR)
 When present in a mutated form, it is associated with decreased
chloroquine accumulation.
 Pf MDR N86, the chloroquine susceptible allele has been proposed as a
molecular marker for lumefantrine resistance
.
 PfATP6, is an ortholog of the mammalian sarcoendoplasmic reticulum
Ca2+ ATPase (SERCA)-mutation shows artimissinin compounds
resistance.
 Resistance to antifolate drugs is the result of the accumulation of
mutations in DHFR and DHPS.

23. Pharmacological contributing to drug
resistance
 When used as monotherapy, artemisinins are associated
with recurrent parasitemia unless the medication is
administered for 5–7 days..
 Artemether acts rapidly, with a half-life of 1 to 3 hours,
while lumefantrine, with a half-life of three to six days, is
responsible for preventing the recurrent parasitemia
associated with short course artemisinin therapy.
 As a result, the artemisinins are administered with longer
acting partner drugs in a fixed-dose combination treatment
regimen that is used to protect against recrudescent
infections

24. Immunity profile determining resistance
 All infected individuals develop symptomatic infection, and the
infections always prompt treatment with an antimalarial drug. It is
possible that the difference in the extent of drug pressure on the parasite
population drives the spread of drug resistance.
 HIV infection leads to an increase in the parasite biomass
by 18% . Increased biomass raises the possibility that
mutations associated with drug resistance may emerge
more frequently than in the absence of co-infection.
 There is evidence that antimalarials in patients with
hemoglobinopathies have different pharmacokinetic
properties , and that standard doses of antimalarials may
be less efficacious .

25. How to overcome resistance
I. use combination therapy
II. Drug therapy monitoring
III. Notified treatment failure
IV. 2nd line drug if treatment failure proportion is more
than 10 %.

26. key messages
 SP should be avoided 1st week of life.
 Primaquine should be avoided in 1st month in severe
G6PDdeficiency .
 Tetracycline avoided throughout infancy and in
children <8yr.
 Parentral treatment should be continued until the
parasitemia is < 1 % which usual occurs within 48
hrs.and pt can tolerate oral medication.

27.  REFRENCE:
1.PARK –prevention and social medicine
2.NELSON –textbook of pediatrics
3.GUIDLINES FOR THE TREATMENT OF MALARIA
:WHO
4.MEHERBAN SINGH –emergency medicine

28. THANKS.................

29. Memorable points
 Chloroquine - interferes with parasite haem detoxification.
resistance is related to genetic changes in transporters
(PfCRT ,PfMDR) which reduce the conc.of drug at its site of action.
 Toxicity-1.headache ,skin eruption, GI disturbance,convulsion and
mental change.
2.chronic use-keratopathy and retinopathy
3.myopathy,reduced hearing ,photosensitivity,loss of hair,aplastic
anaemia.
 Acute overdose- drowsy with headache and GI upset ,visual
loss, convulsion,hypokalamia,hypotension,cardiac arrhythmias.
t/t-diazpam and epinephrine (no any specific treatment)
Cloroquine+halofantrine-cardiac toxicity
Cloroquine+meflaquine-convulsion.

30.  There are a number of human genetic polymorphisms
that offer protection against malaria, including
enzyme deficiencies such as glucose-6-phosphate
dehydrogenase deficiency and pyruvate kinase
deficiency and hemoglobin variants such as
thalassemia and hemoglobin S . Little is known about
how effectively patients with these polymorphisms
respond to antimalarial drugs. In human populations
with high prevalence of these hemoglobinopathies,
drug efficacy may seem impaired, even in the absence
of intrinsic resistance or may be threatened by even
minimal increases in IC50s.

31.  Emergence and spread of antimalarial resistance
 Malaria continues to cause hundreds of millions
of infections per year
 Resistance to chloroquine and sulfadoxine-
pyrimethamine has fueled the on-going burden
of Plasmodium falciparum malaria. In response,
the World Health Organization (WHO) has
recommended the use of combination treatments
that include artemisinin derivatives as first-line
therapy

32. Human host
 The host immune response to malaria infection likely
influences the speed of spread of drug resistance and also
the extent to which drug resistance translates into clinical
drug.
 . In high transmission settings, children are susceptible to
symptomatic and severe malaria infection, while adults are
considered semi-immune because they can acquire
infection, but are not at risk for severe disease and often
experience asymptomatic infection. Malaria parasites in
these semi-immune adults are not under drug pressure
because infection is not usually recognized or treated. In
contrast, individuals in low and sporadic transmission
settings, such as Southeast Asia, are not exposed to malaria
with enough frequency to develop immunity
 . As a result .

33. Denova folate synthesis is essential for
parasite survivel.
The antifolate medications interrupt this
process by targeting two enzymes:
pyrimethamine and proguanil target
dihydrofolate reductase (DHFR), and sulfa
drugs such as sulfadoxine target
dihydropteroate synthase (DHPS).
multidrug resistance in cancer cells
glycoproteins found in mammals that mediate
 The gene encoding the PfMDR is an ortholog of P-
resistance gene
Plasmodium falciparum multidrug