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Guidelines for the treatment of malaria – 2 edition

the transmission cycle. For the blood-stage infection, immunity acts in a similar way to
antimalarials both to eliminate the rare de novo resistant mutants and to stop them being
transmitted (i.e. like a combination therapy). It also improves cure rates with failing drugs
(i.e. drugs falling to resistance), thereby reducing the relative transmission advantage of
resistant parasites. Even if a resistant mutant does survive the initial drug treatment and
multiplies, the chance that this will result in sufficient gametocytes for transmission is
reduced as a result of asexual stage immunity (which reduces the multiplication rate
and lowers the density at which the infection is controlled) and transmission-blocking
immunity. Furthermore, other parasite genotypes are likely to be present in competition
with the resistant parasites for red cells, which increases the possibility of out-breeding of
multigenic resistance mechanisms or competition in the feeding anopheline mosquito (10).

The genetic events that confer antimalarial drug resistance (while retaining parasite
viability) are spontaneous and rare. They are thought to be independent of the drug. The
resistance mechanisms that have been described are mutations in genes or changes in
the copy number of genes relating to the drugs target or pumps that affect intraparasitic
concentrations of the drug. A single genetic event may be all that is required, or multiple
unlinked events may be necessary (epistasis). P. falciparum parasites from South-East Asia
seem constitutionally to have an increased propensity to develop drug resistance.

a6.3.2 antimalarial pharmacokinetics and the selection of resistance

A6.3.2.1 Absorption and disposition
The probability of selecting a de novo mutation that is resistant to antimalarials during
the initial phase of treatment depends on the per-parasite frequency of the genetic
event, the number of parasites present, immunity in the infected individual, and the
relationship between the drug levels achieved and the degree of resistance conferred
by the mutant parasite. If the range of blood concentrations achieved in the patient
considerably exceeds the concentrations giving 90% inhibition of multiplication (IC90
values) for the most resistant mutant (IC90R), then resistance cannot be selected in the
acute phase of treatment as even the resistant mutants are prevented from multiplying.
Conversely, if the degree of resistance provided by the genetic event is very small, the
window of opportunity for selection may be negligible. Provided that there is such a
window of selection, then the broader the range of peak antimalarial concentrations and
the closer the median value approaches IC90R the greater the probability of selecting a
resistant mutant in a patient.

Peak drug concentrations are determined by absorption, distribution volume and dose.
Several antimalarials (notably lumefantrine, halofantrine, atovaquone and, to a lesser
extent, mefloquine) are lipophilic, hydrophobic and very variably absorbed (inter-
individual variation in bioavailability up to 20-fold) (11, 12). Inter-individual variation

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