Page 142 - 80 guidelines for the treatment of malaria_opt

nd
Guidelines for the treatment of malaria – 2 edition

a6.3.3 spread of resistance
Several mathematical models have been devised to examine the spread of antimalarial
drug resistance (10,15,18,19). Spread of resistance is determined by the reproductive
advantage conferred by the resistance mechanism. This derives from the increased
gametocyte carriage associated with treatment failure (both from the primary infection
and from the subsequent recrudescences), the “donors”, and the selective pressure from
residual concentrations of slowly eliminated antimalarial in potential recipients. A long
elimination half-life results in long periods of post-treatment chemoprophylaxis.
Resistance encoded by multiple mutations at a single locus may occur in two overlapping
phases: Phase 1 where the drug is better tolerated by the parasites, but the therapeutic
doses still usually clear the infection; and Phase 2 where clinical failures start to occur.
This second phase is very rapid, and it is essential that surveillance programmes are in
place and capable of monitoring the change from the first to the second phase. Phase 1
may occur faster, in areas of high transmission, but the subsequent phase is slower.
Combination therapy significantly slows the rate of evolution of resistance, but it should
be instigated before significant resistance to either component is present.

a6.4 prevention of resistance by use of combination therapy

The theory underlying combination treatment of tuberculosis, leprosy and HIV infection
is well known, and it has recently been applied to malaria (4,5,18,20–23). If two drugs with
different modes of action and, therefore, different resistance mechanisms are used in
combination, then the per-parasite probability of developing resistance to both drugs is
the product of their individual per-parasite probabilities.
For example, if the per-parasite probabilities of developing resistance to drug A and drug
B are both 1 in 1012, then a simultaneously resistant mutant will arise spontaneously in
1 in 1024 parasites. As it is postulated that there are approximately 1017 parasites in the
entire world, and a cumulative total of less than 1020 in one year, such a simultaneously
resistant parasite would arise spontaneously roughly once every 10 000 years – provided
the drugs always confronted the parasites in combination. Thus, the lower the de novo
per-parasite probability of developing resistance, the greater the delay in the emergence
of resistance.
Stable resistance to the artemisinin derivatives has not yet been identified, and cannot
yet be induced in the laboratory, which suggests that it may be very rare indeed. De novo

128