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 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 parasite 3. 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 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 20mg/Kg BW in 500 ml of DNS over 4hrs Maintenance dose10mg/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 Dose15mg/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 Avoid : Patients on beta-blockers Avoid : 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 Dosage > 250mg tablets > 2 tablets 6th hrly for 3 doses, not to > 2 tablets 6th hrly for 3 doses, not to exceed 1500mg exceed 1500mg Side Effects > QT prolongation Conduction delay & Arrythymias Conduction delay & NOT RECOMMENED IN CROSS RESISTANCE WITH MEFLOQUINE

Quinhaosu Also called sweet wormwood. Traditional Chinese Medicine > 2000 yrs ArtemesininDihydro-artemesinin ArtemetherArtesunate Arteether

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 ArtesunateOral /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

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 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  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 J More Promising than monotherapy J 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?? Ø Drug resistance will remain to be a problem world over Ø Need for flawless Antimalarial agent Ø Consensus to device effective strategies to combat the problem Ø Indiscriminate and irresponsible use of antimalarials should be stopped Ø Constant need to upgrade the treatment of Malaria Ø 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