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Guidelines for the treatment of malaria – 2 edition

resistance, in particular resistance to anti-tuberculosis drugs where, as for malaria,
transferable resistance genes are not involved in the emergence of resistance (1–3). In
experimental models, drug-resistant mutations can be selected without mosquito passage
(i.e. without meiotic recombination) by exposure of large numbers of malaria parasites
(either in vitro, in animals, or, as was done in the past, in volunteers) to sub-therapeutic
drug concentrations (4).
Various factors determine the propensity for antimalarial drug resistance to develop (5):
• the intrinsic frequency with which the genetic changes occur:
• the degree of resistance (the shift in the concentration-effect relationship, figure A6.1)
conferred by the genetic change;
• the fitness cost of the resistance mechanism;
• the proportion of all transmissible infections that are exposed to the drug (the selection
pressure);
• the number of parasites exposed to the drug;
• the concentrations of drug to which these parasites are exposed;
• the pharmacokinetic and pharmacodynamic properties of the antimalarial;
• individual (dosing, duration, adherence) and community (quality, availability,
distribution) patterns of drug use;
• the immunity profile of the community and the individual;
• the simultaneous presence of other antimalarials or substances in the blood to which
the parasite is not resistant.
The emergence of resistance can be thought of in terms of the product of the probabilities
of de novo emergence (a rare event) and subsequent spread. Resistant parasites, if
present, will be selected when parasites are exposed to “selective” (sub-therapeutic)
drug concentrations. “Selective” in this context means a concentration of drugs that
will eradicate the sensitive parasites but will still allow growth of the resistant parasite
population so that it eventually transmits to another person. Because de novo resistance
arises randomly among malaria parasites, non-immune patients infected with large
numbers of parasites who receive inadequate treatment (either because of poor drug
quality, poor adherence, vomiting of an oral treatment, etc.) are a potent source of de
novo resistance. This emphasizes the importance of correct prescribing, good adherence
to prescribed drug regimens, and also provision of treatment regimens that are still
highly effective in hyperparasitaemic patients. The principle specific immune response
that controls the primary symptomatic infection in falciparum malaria is directed by the
variant surface antigen (PfEMP1). The parasite population evades this immune response
by switching its surface antigen in a specific sequence of changes. The probability of
selecting a resistant parasite from the primary infection is the product of the switch rate
and the rate of formation of viable resistant parasites.

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