Transcript Resistant Malaria

Resistant Malaria
Dr. K.A.Sudarshana Murthy
&
Dr.Ravishankar S.B
Dept of Medicine,JSS Medical College
Introduction

Resistance was first noted in the early 1960’s
in SE Asia & S.America within years of
introduction of Chloroquine

In India, Chloroquine resistance first reported
from Assam - 1973

Quinine Resistance - Brazil ( 1910)
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Proguanil -- Malaya ( 1949 )
Introduction

Pyrimethamine
-- Venezuela ( 1962 )

Mepacrine
-- Thailand ( 1980 )
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Sulphadoxine Pyrimethamine
-- SE Asia,Thailand, S.America
& S.Africa ( 1980 )
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Mefloquine
Failure
-- Thai, Cambodia, Myanmar
( 1988 )
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)
What Is Drug Resistance?

In clinical Practice its usage indicates
resistance of PF against blood
schizonticides

Conventionally 

Multidrug Resistance
4- aminoquinolones
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
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
Mechanism Of Resistance
Antibacterials
Tetracyclines
1. Active Efflux
Clindamycins
2. Ribosomal Alteration
Artemesinin
Derivatives
Alteration in the membrane
transport of the drug into the
parasite
Chloroquine & Mefloquine resistance is not
linked .Evidence shows increseing mefloquine
resistance increases Chloroquine sensitivity.
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)
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%
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.
Quinine
Dosage
Loading dose
Maintenance dose
20mg/Kg BW in 500 ml
of DNS over 4hrs
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
Quinidine
 Superior to Quinine in antimalarial acitivity
 Main Drawbacks > Increased Cost
Lethal Side-effects
Cardiac Arrthymias
Hypersensitivity
 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
Amodiaquine
 Used in Chloroquine failure as primary drug.
 More effective in clearing parasitaemia
 Pruritis , Toxic Hepatitis , Fatal
Agranulocytosis prevents its widespread use.
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
Mefloquine
 Not recommened for
children < 5 Kg BW & 3 M
pregnancy, epilepsy, psychosis, hypersensitivity
Toxic Effects
Dizziness, Nausea , Vomiting, Arrythmias
Acute Brain Syndrome
Fatigue, Asthenia, Seizure , psychosis
Avoid : Patients on beta-blockers
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
Halofantrine
Dosage
> 250mg tablets
> 2 tablets 6th hrly for 3 doses, not to
exceed 1500mg
Side Effects
> QT prolongation
Conduction delay & Arrythymias
@ NOT RECOMMENED IN PREGNANCY
@ CROSS RESISTANCE WITH MEFLOQUINE
Quinhaosu
Also called sweet wormwood.
Traditional Chinese Medicine > 2000 yrs
Artemesinin
Artemether
Arteether
Dihydro-artemesinin
Artesunate
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
Quinhaosu
Side Effects
Reduction in reticulocyte count
Fever, Neurotoxicity in animals
“ NOT SAFE IN FIRST TRIMISTER OF
PREGNANCY ”
Quinhaosu
Artesunate
Monotherapy
Oral
Parenteral
Oral /Parentaral
: 10mg/kg over a period
of 3- 5 days
: 2.4mg/kg IV/IM Stat
1.2 mg/kg at 12 & 24 hrs
and then daily
Quinhaosu
Artesunate :
> Sequential therapy with Mefloquine
> More efective & low incidence of side effects
> Useful in endemic & MDR areas
Artemether :
Oral
> Same as Artesunate
paranteral > 3.2 mg/kg IM stat
1.6mg/kg/day for 4 days
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
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
Newer Drugs
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WR - 33O63
 80% cure rate in MDR Strain
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WR - 30090
 90% cure rate ( Volunteers)
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Cysteine & Aspartate protein inhibitors
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Pyronaridine  Similar to Amodiaquine
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Azithromycin
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Atovoquone
 Prompt clinical response
but recrudescence; combined with proquanil
Miscellaneous Drugs
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Benflumentol
Hydroxypiperaquine
Trioxanes, Tetraxanes, Peroxides.
Hydoxynaphthoquinones
Lead Compounds
Antifungals : Ketacanozole, Ampho-B,
Micanozole
Desfuroxamine : Combined with quinine >
resolves complications faster.
Drugs reversing Chloroquine
Resistance >> > Experimental
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Ca-Channel Blockers: Verapamil
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Phenothiazines : Desipramine
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Taxol : Anticancer drug (Both Chlor & Pyr)
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Vitamin E : Deficiency may afford protecton
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Penfluridol : Reverses Mefloquine resistance
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Erythocyte specific Ab encapsulated in
liposomes: to circumvent Chlor-resistance
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.
What the Future May Hold??
 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
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