1. Anti-Malaria Chemotherapy
Causal Prophylaxis
prevent infection (ie, liver stage)
Suppressive Prophylaxis
prevent clinical disease (ie, blood stages)
Treatment Therapy (or clinical cure)
relieve symptoms
eliminate blood stage parasites
Curative Therapy (or radical cure)
eliminate parasites w/o regard to symptoms
Anti-Relapse Treatment
eliminate hypnozoites

2. Selected Anti-Malarials

3. Treatment Strategies chloroquine sensitive (all species) chloroquine
CQ + primaquine (vivax/ovale)
chloroquine resistance (or unknown)
Fansidar, mefloquine, quinine, artemesin derivatives
severe malaria
i.v. infusion of quinine or quinidine (or CQ, if sensitive)
i.v. artemisinin derivatives (if available)

4. Chemoprophylaxis recommended for transient visits to endemic areas
choice of drug depends on risk of malaria and degree of resistance in that area
many non-toxic drugs of limited use because of resistance
eg., choloroquine, pyrimethamine, proquanil
presumptive (or ‘standby’) treatment
carry Fansidar, mefloquine, quinine

5. Drug Action drugs function by interacting with a cellular 'target'
eg, protein, DNA, RNA, lipids
many targets are enzymes (eg, inhibitors)

6. Selective Toxicity of Drugs
unique target in parasite
food vacuole and chloroquine
discrimination between host and parasite targets
pyrimethamine and DHFR
target is more important to parasite than host
DNA synthesis (antifolates)
drug activation by parasite
anaerobes and nitroimidazoles
greater drug accumulation by parasite

7. Antifolates and Nucleotide Metabolism
dihydrofolate is necessary co-factor for nucleotide (i.e., DNA) synthesis
sulfadoxine inhibits folate synthesis (DHPS)
parasite cannot salvage folates
host only salvages
pyrimethamine preferentially inhibits parasite DHFR

9. Drug Resistance defined by treatment failures rule out other factors:
non-compliance
bad quality
wrong dose
vomiting
28-day or other tests (RI, RII, RIII levels of resistance)

10. Modified Protocol introduced by WHO in 1996 based on clinical outcome:
adequate clinical response (ACR)
late treatment failure (LTF)
early treatment failure (ETF)
more practical in areas of intense transmission
difficult to distinguish re-infection from recrudescense
parasitemia in the absence of clinical symptoms is common
ACR
no recrudescence by day 14
LTF
recrudescence during days 4-14
ETF
persistence during days 1-3

11. Drug Resistance Mechanisms
mutations in target gene
 production of target
 drug accumulation (includes  efflux)
drug inactivation
Drug
Gene
Major Mutations
Fansidar
DHPS
A437G (K540E, A581G)
DHFR
S108N (N51I, C59R, I164L)
Chloroquine
CRT
K76T
MDR1
N86Y

12. Factors Contributing to Development and Spread of Drug Resistance
self treatment
poor compliance
mass administration
long drug half-life
high transmission intensity

13. Spread of Chloroquine Resistance
slow to emerge
spread rapidly
probably multigenic