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ANNEX 6. Resistance to antimalarials medicines

The subsequent spread of resistant mutant malaria parasites is facilitated by the widespread
use of drugs with long elimination phases. These provide a “selective filter”, allowing
infection by the resistant parasites while the residual antimalarial activity prevents
infection by sensitive parasites. Slowly eliminated drugs, such as mefloquine (terminal
elimination half-life (T½β) 2–3 weeks) or chloroquine (T½β) 1–2 months), persist in the
blood and provide a selective filter for months after drug administration has ceased.

a6.3.1 transmission intensity and the selection and spread of resistance

The recrudescence and subsequent transmission of an infection that has generated a de
novo resistant malaria parasite is essential for resistance to be propagated (5). Gametocytes
carrying the resistance genes will not reach transmissible densities until the resistant
biomass has expanded to numbers close to those producing illness (>107 parasites)
(6). Thus, to prevent resistance spreading from an infection that has generated de novo
resistance, gametocyte production from the recrudescent resistant infection must be
prevented. There has been debate as to whether resistance arises more rapidly in low- or
high-transmission settings (7, 8), but, aside from theoretical calculations, epidemiological
studies clearly implicate low-transmission settings as the source of drug resistance.
Chloroquine resistance and high-level sulfadoxine-pyrimethamine resistance in
P. falciparum both originated in South-East Asia and, subsequently, spread to Africa (9).
In low-transmission areas, the majority of malaria infections are symptomatic and A6
selection, therefore, takes place in the context of treatment. Relatively large numbers
of parasites in an individual usually encounter antimalarials at concentrations that are
maximally effective. But in a variable proportion of patients, for the reasons mentioned
earlier, blood concentrations are low and may select for resistance.
In high-transmission areas, the majority of infections are asymptomatic and infections
are acquired repeatedly throughout life. Symptomatic and sometimes fatal malaria occurs
in the first years of life, but, thereafter, it is increasingly likely to be asymptomatic. This
reflects a state of imperfect immunity (premunition), where the infection is controlled,
usually at levels below those causing symptoms. The rate at which premunition is acquired
depends on the intensity of transmission. In the context of intense malaria transmission,
people still receive antimalarial treatments throughout their lives (often inappropriately
for other febrile infections); but these “treatments” are largely unrelated to the peaks of
parasitaemia, thereby reducing the probability of selection for resistance.
Immunity considerably reduces the emergence of resistance (9). Host defence contributes
to a major anti-parasitic effect, and any spontaneously generated drug-resistant mutant
malaria parasite must contend not only with the concentrations of antimalarial present
but also with host immunity. This kills parasites regardless of their antimalarial resistance,
and reduces the probability of parasite survival (independently of drugs) at all stages of

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