Resistant Malaria

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Resistant Malaria
Dr. K.A.Sudarshana Murthy Dr.Ravishankar S.B

• Dept of Medicine,JSS Medical College

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Introduction

• Resistance was first noted in the early 1960s in
  SE Asia S.America within years of introduction
  of Chloroquine
• In India, Chloroquine resistance first reported
  from Assam - 1973
• Quinine Resistance - Brazil ( 1910)
• Proguanil -- Malaya ( 1949 )

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Introduction

• Pyrimethamine -- Venezuela ( 1962 )
• Mepacrine -- Thailand ( 1980 )
• Sulphadoxine - Pyrimethamine -- SE
  Asia,Thailand, S.America S.Africa ( 1980 )
• Mefloquine -- Thai, Cambodia, Myanmar
  Failure ( 1988 )

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What Is Drug Resistance?

• The ability of a parasite strain to survive
  and/or multiply despite administration
  absorption of a drug given in doses equal to or
  higher than those usually recommended but within
  the limit of tolerance of the subject (
  WHO 1986)

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What Is Drug Resistance?

• In clinical Practice its usage indicates
  resistance of PF against blood schizonticides
• Conventionally ? 4- aminoquinolones
• Multidrug Resistance

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Mechanism Of Resistance
Aminoquinolones, Biguanides Sulfonamides
A. Multiple unlinked mutations encoding for
MDR- pump which produces i) active efflux of
the drug or ii) increased synthesis of a
different haem-polymerase enzyme in the
parasite, protecting the parasite from toxic
Hb degradation
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Mechanism Of Resistance
Aminoquinolones, Biguanides Sulfonamides
B. Role of chloroquine resistant gene (within
200 KB segment of chromosome 7 of PF) 1.
point mutation in DHER gene which reduces
the affinity of the enzyme complex
of the drug. 2. Use of alternative enzymatic
pathway by the parasite 3. PV is
intrinsically insensitive 4. Failure to
convert Proquanil to active metabolite
Genetic Polymorphism
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Mechanism Of Resistance
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Chloroquine Mefloquine resistance is not
linked .Evidence shows increseing mefloquine
resistance increases Chloroquine sensitivity.
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Grading of Resistance
Sensitive (S)
Clearance of parasitaemia within 7 days without
recrudescence
Low Grade Resistance (R1)
Clearance of parasitaemia followed by
recrudescence ( 28 Days after the last dose)
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Grading of Resistance
High Grade ( RII)
Greater than 75 but less than 100 of parasites
cleared within 7 days
High Grade ( RIII)
Parasite count does not fall by more than 75
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Quinine
? Still remains the Best therapy in all
Complicated Malaria ? Reports of Quinine
resistance are quite rare ? Alleged failures ?
Inadequate Dosage Short Course ? Partial
decreae in Sensitivity in some localities in
Siberia -- Bjorkman et al., 1991.
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Quinine
Dosage Loading dose 20mg/Kg BW in 500 ml
of DNS over 4hrs Maintenance dose 10mg/Kg
BW 8th hrly intervals Till patient can take
orally Dose should be reduced to half or 1/3
after 48 hours ( Cumulative effect)
Side Effects Cinchonism, hypoglycemia,
Psychosis, Arrythmia, Haemolysis
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Quinidine
? Superior to Quinine in antimalarial acitivity
? Main Drawbacks gt Increased Cost Lethal
Side-effects Cardiac Arrthymias Hypersen
sitivity ? Should be used only if parenteral
Quinine is not available ? Loading
Dose 15mg/kg BW over 4hrs 7.5 mg/kg BW over 4
hrs repeat every 8hrs
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Amodiaquine
? Used in Chloroquine failure as primary drug.
? More effective in clearing parasitaemia ?
Pruritis , Toxic Hepatitis , Fatal
Agranulocytosis prevents its widespread use.
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Mefloquine
? First synthetic quinolinemethanol compound ?
Sensitivity is independent of resistance to
4-aminoquinolones DHF reductase inhibitors ?
Blood Schizonticidal with high affinity for
erythrocyte membranes - Binds to
phospholipids ? Single dose advantage - 15mg/kg
BW ( Max 1g) Additional 10mg/kg after
8hrs in areas of chloroquine resistance
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Mefloquine
? Not recommened for children lt 5 Kg BW 3
M pregnancy, epilepsy, psychosis,
hypersensitivity Avoid Patients on
beta-blockers
Toxic Effects Dizziness, Nausea , Vomiting,
Arrythmias Acute Brain Syndrome Fatigue,
Asthenia, Seizure , psychosis
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Halofantrine
? Phenantherne - methanol ? Effective aganst
MDR- Strains ? Schizonticidal against all 4
species ? Acts primarily by concentrating
combining with ferriprotoporphyrin-IX in
the parasite to form toxic complex that
damage bio-membranes ? Absorption is
unpredictable ( Water insoluble) ? Can not be
used parentarally
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Halofantrine
Dosage gt 250mg tablets
gt 2 tablets 6th hrly for 3 doses, not to
exceed 1500mg
Side Effects gt QT prolongation Conduction
delay Arrythymias
_at_ NOT RECOMMENED IN PREGNANCY _at_ CROSS RESISTANCE
WITH MEFLOQUINE
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Quinhaosu
Also called sweet wormwood. Traditional Chinese
Medicine gt 2000 yrs
Artemesinin Dihydro-artemesinin Artemether Art
esunate Arteether
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Quinhaosu
Superior to other antimalarial drugs in
Complicated Uncomplicated Malaria Good oral
absorption Should be used in uncomplicated PF
Malaria only if resistance to Mefloquine
and/or Quinine ( WHO) No action on
liver stages Rapid action
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Quinhaosu
Side Effects Reduction in reticulocyte
count Fever, Neurotoxicity in animals NOT
SAFE IN FIRST TRIMISTER OF PREGNANCY
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Quinhaosu
Artesunate Oral /Parentaral Monotherapy Oral
10mg/kg over a period of 3- 5
days Parenteral 2.4mg/kg IV/IM Stat
1.2 mg/kg at 12 24 hrs and then
daily
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Quinhaosu
Artesunate gt Sequential therapy with
Mefloquine gt More efective low incidence of
side effects gt Useful in endemic MDR areas
Artemether Oral gt Same as
Artesunate paranteral gt 3.2 mg/kg IM stat
1.6mg/kg/day for 4 days
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Tetracycline Clindamycin

• Used in combination with Quinine
• Enhances the efficiency in drug resistant Malaria
• Avoided in pregnancy children
• Dosage
• Tetracycline 1-2 G /day for 3- 7 days
• Clindamycin 20mg/ kg / day for 3 - 7 days

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precautions
? Quinine should not be used for 7 days if the
patient was given Mefloquine ? Mefloquine
should not be administered for 12 hours after
the last dose of Quinine ? One should watch
for Hypoglycemia during Quinine
Chloroquine therapy
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Newer Drugs

• WR - 33O63 ? 80 cure rate in MDR Strain
• WR - 30090 ? 90 cure rate ( Volunteers)
• Cysteine Aspartate protein inhibitors
• Pyronaridine ? Similar to Amodiaquine
• Azithromycin
• Atovoquone ? Prompt clinical response but
  recrudescence combined with proquanil

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Miscellaneous Drugs

• Benflumentol
• Hydroxypiperaquine
• Trioxanes, Tetraxanes, Peroxides.
• Hydoxynaphthoquinones
• Lead Compounds
• Antifungals Ketacanozole, Ampho-B, Micanozole
• Desfuroxamine Combined with quinine gt
  resolves complications faster.

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Drugs reversing Chloroquine Resistance gtgt gt
Experimental

• Ca-Channel Blockers Verapamil
• Phenothiazines Desipramine
• Taxol Anticancer drug (Both Chlor Pyr)
• Vitamin E Deficiency may afford protecton
• Penfluridol Reverses Mefloquine resistance
• Erythocyte specific Ab encapsulated in liposomes
  to circumvent Chlor-resistance

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Concept of Combination Therapy

• More Promising than monotherapy
• Moe efficacious retards the resistant strains

Quinine Tetracyclines/ Clindamycin More
effective than Quinine monotherapy Sequential
Mefloquine Artemether Higher overall cure
rate Artesunate Tetracyclines 80 cure
rates Pyronaridine SDX - Pyr or Primaquine
Inhibits development of drug resistance.
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• Drug resistance will remain to be a problem
  world over
• Need for flawless Antimalarial agent
• Consensus to device effective strategies to
  combat
• the problem
• Indiscriminate and irresponsible use of
  antimalarials
• should be stopped
• Constant need to upgrade the treatment of
  Malaria
• Newer antimalarials should be under
  International
• government control

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Vaccines
Types 1. Sporozoite Vaccine Prevent
infection and development of liver
stages 2. Asexual Stage Decrease morbidity
mortality 3. Sexual Stage Expected to block
trasmission