Page 141 - 80 guidelines for the treatment of malaria_opt

ANNEX 6. Resistance to antimalarials medicines

in distribution volumes tends to be lower (usually less than fivefold) but, taken together
with variable absorption, the outcome is considerable inter-individual variation in peak
antimalarial blood concentrations. The main sources of underdosing globally are incorrect
self-medication, because of poor adherence to the correctly prescribed drug regimen, poor
quality drugs, uncontrolled drug availability and purchase of incorrect dose regimens,
use of substandard drugs purchased in shops or markets, and incorrect administration
in the home. The acute infection is the principal source of de novo resistance selection.
Quality assured drugs, education, correct prescribing, good adherence, and optimized
packaging and formulations, therefore, play pivotal roles in preventing the emergence of
antimalarial drug resistance.

A6.3.2.2 Drug elimination rates
In some areas of the world, transmission intensities may be as high as three infectious
bites per person per day. A person, in this context, who takes antimalarial treatment for
symptomatic malaria exposes not only the parasites causing that infection to the drug,
but it also exposes any newly acquired infections that emerge from the liver during the
drug’s elimination phase; the longer the terminal elimination half-life, the greater the
exposure. The length of the terminal elimination half-life is an important determinant of
the propensity for an antimalarial to select for resistance (13–15). Some rapidly eliminated
antimalarials (e.g. artemisinin derivatives) never present an intermediate drug concentration
to infecting malaria parasites, because they are eliminated completely within the two-day A6
life-cycle of the asexual parasite. Others (e.g. mefloquine, chloroquine) have elimination
half-lives of weeks or months, and they present a lengthy selection opportunity.
With the exception of the artemisinin derivatives, maximum antimalarial parasite reduction
ratios (kill rates) do not exceed 1000-fold per cycle (16). Following hepatic schizogony,
exposure of at least two asexual cycles (4 days) to therapeutic drug concentrations is,
therefore, required to eradicate the blood-stage parasites emerging from the liver. Even
with maximum kill rates in the sensitive parasites and maximum growth rates in the
resistant parasites, the resistant parasites only “overtake” the sensitive parasites in the
third asexual cycle. Thus, rapidly eliminated drugs (such as the artemisinin derivatives
or quinine) cannot select during the elimination phase. Obviously, the greater the degree
of resistance conferred by the resistance mutation (i.e. the higher the IC90R relative to the
IC90 for susceptible parasites, IC90S), the wider the window of selection opportunity.

Patent gametocytaemia is more likely in recrudescent than primary infections. Therefore,
if de novo resistance arose in an acute symptomatic treated infection, the transmission
probability from the subsequent recrudescent infection (bearing the new resistance genes)
would be higher than from an infection newly acquired during the elimination phase of
the antimalarial given for a previous infection. This is true even if it attained the same
parasite densities (17).

127