Resistant Malaria

Dept of Medicine,JSS Medical College

Dr. K.A.Sudarshana Murthy&

Dr.Ravishankar S.B

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)

Proguanil -- Malaya ( 1949 )

Introduction

Pyrimethamine -- Venezuela ( 1962 )

Mepacrine -- Thailand ( 1980 )

Sulphadoxine -

Pyrimethamine -- SE Asia,Thailand, S.America

& S.Africa ( 1980 )

Mefloquine -- Thai, Cambodia, Myanmar

Failure ( 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 4-

aminoquinolones

Multidrug Resistance

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 parasite3. PV is intrinsically insensitive 4. Failure to convert Proquanil to active metabolite : Genetic Polymorphism

Mechanism Of Resistance

Antibacterials

Tetracyclines

Clindamycins

1. Active Efflux

2. Ribosomal Alteration

Artemesinin Derivatives

Alteration in the membrane transport of the drug into the parasite

Chloroquine & Mefloquine resistance is not Chloroquine & Mefloquine resistance is not linked .Evidence shows increseing mefloquine linked .Evidence shows increseing mefloquine resistance increases Chloroquine sensitivity.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 morethan 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

DosageLoading dose 20mg/Kg BW in 500 ml

of DNS over 4hrsMaintenance dose 10mg/Kg BW 8th hrly intervals

Till patient can take orallyTill 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-effectsCardiac ArrthymiasHypersensitivity

Should be used only if parenteral Quinine is not available Loading Dose 15mg/kg BW over 4hrs

7.5 mg/kg BW over 4 hrsrepeat 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

Avoid : Patients on beta-blockersAvoid : Patients on beta-blockers

Toxic Effects

Dizziness, Nausea , Vomiting, Arrythmias

Acute Brain Syndrome

Fatigue, Asthenia, Seizure , psychosis

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

DosageDosage > > 250mg tablets250mg tablets

> 2 tablets 6th hrly for 3 doses, not to > 2 tablets 6th hrly for 3 doses, not to

exceed 1500mgexceed 1500mg Side EffectsSide Effects > QT prolongation> QT prolongation

Conduction delay & ArrythymiasConduction delay & Arrythymias

@ NOT RECOMMENED IN PREGNANCY@ NOT RECOMMENED IN PREGNANCY

@ CROSS RESISTANCE WITH MEFLOQUINE@ CROSS RESISTANCE WITH MEFLOQUINE

Quinhaosu

Also called sweet wormwood.Traditional Chinese Medicine > 2000 yrs

Artemesinin Dihydro-artemesininArtemether ArtesunateArteether

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 countFever, Neurotoxicity in animals

“ NOT SAFE IN FIRST TRIMISTER OF PREGNANCY ”

Quinhaosu

Artesunate Oral /Parentaral

Monotherapy Oral : 10mg/kg over a period

of 3- 5 daysParenteral : 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 Artesunateparanteral > 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

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

Miscellaneous Drugs

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

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

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