Page 143 - 80 guidelines for the treatment of malaria_opt

ANNEX 6. Resistance to antimalarials medicines

resistance to chloroquine is also very rare, and it appears to have arisen and spread only
twice in the world during the first decade of intensive use in the 1950s (24). On the other
hand, resistance to antifolate and atovaquone arises relatively frequently (e.g. antifolate
resistance rose to high levels within two years of the initial deployment of proguanil in
peninsular Malaya in 1947) and it can be induced readily in experimental models (14,
21). Against a background of chloroquine resistance, mefloquine resistance arose over
a six-year period on the north-west border of Thailand (25). Artemisinin derivatives are
particularly effective in combinations with other antimalarials because of their very high
killing rates (parasite reduction rate around 10 000-fold per cycle), lack of adverse effects
and absence of significant resistance (5).
The ideal pharmacokinetic properties for an antimalarial have been much debated. Rapid
elimination ensures that the residual concentrations do not provide a selective filter
for resistant parasites; but drugs with this property (if used alone) must be given for at
least 7 days, and adherence to 7-day regimens is poor. In order to be effective in a 3-day
regimen, elimination half-lives usually need to exceed 24 h. Combinations of artemisinin
derivatives (which are eliminated very rapidly) given for 3 days, with a slowly eliminated
drug, such as mefloquine, provide complete protection against the emergence of resistance
to the artemisinin derivatives if adherence is good, but they do leave the slowly eliminated
“tail” of mefloquine unprotected. Perhaps resistance could arise within the residual
parasites that have not yet been killed by the artemisinin derivative. However, the number
of parasites exposed to mefloquine alone is a tiny fraction (less than 0.00001%) of those
present in the acute symptomatic infection. Furthermore, these residual parasites “see” A6
relatively high levels of mefloquine and, even if susceptibility was reduced, these levels
may be sufficient to eradicate the infection (Fig. A6.2). The long mefloquine tail does,
however, provide a selective filter for resistant parasites acquired from elsewhere, and,
therefore, contributes to the spread of resistance once it has developed. Yet on the north-
west border of Thailand, an area of low transmission where mefloquine resistance had
already developed, systematic deployment of the artesunate-mefloquine combination was
dramatically effective in stopping resistance and also in reducing the incidence of malaria
(25,26). This strategy is thought to be effective at preventing the de novo emergence of
resistance at higher levels of transmission, where high-biomass infections still constitutes
the major source of de novo resistance.

129