How Resistance to Antimalarial Drugs Arises

The emergence of drug-resistant organisms can be considered in two discrete phases: the initial de novo event (a rare genetic occurrence) that first produces the resistant mutant, and the subsequent selection process that leads to its preferential transmission and spread. Resistance arises from spontaneous mutations or gene duplications, which are independent of drug pressure. Once formed, however, resistant mutants have a survival advantage in the presence of antimalarial drugs and, conversely, a survival disadvantage in the absence of at least certain antimalarial drugs. The resulting fitness cost may lead to a declining prevalence of resistance once drug pressure is removed (this pattern has been demonstrated for chloroquine resistance in Malawi although its operational significance is still uncertain).

Factors affecting the development of resistance include: the parasite mutation rate, the degree of resistance conferred by the genetic change, the fitness cost of the resistance mechanism, the proportion of all transmissible infection exposed to the drug, the drug concentration profile, the individual (e.g., dosing, duration, adherence) and community (e.g., quality, availability, distribution) patterns of drug use, and the immunity profile of the community.

The possible role of mass drug administration in accelerating the emergence of antimalarial drug resistance was first highlighted by Payne, who observed that chloroquine resistance in different sites had one common denominator: the long-term, local use of chloroquine for treatment. Later studies in coastal Kenya, Malawi, Mali and Bolivia found a positive correlation between patterns of drug use and in vitro parasite resistance or the prevalence of mutations linked to resistance. A recent study in Uganda observed that the prevalence of chloroquine resistance was higher in sites with high-frequency chloroquine use as reflected in detectable chloroquine metabolites in urine. However, SP resistance was highest in high-transmission sites with relatively low SP use, suggesting that factors in addition to drug pressure influence the spread of SP drug resistance.

The role of drug elimination half-life in the development of parasite resistance has recently been reviewed, and modeled. Drugs with long elimination phases are, in essence, “selective filters,” allowing infection by resistant parasites to flourish while the residual drug levels suppress infection by sensitive parasites. Slowly eliminated drugs such as mefloquine (T 1/2=3 weeks) provide such a filter for months after drug administration. The resulting selection pressure can be enormous.

In Kenya, a potent selective pressure for SP resistance was found to operate even under conditions of supervised drug administration and optimal SP dosing. Plasmodium falciparum infections appearing between days 15 and 52 after SP treatment were more likely to exhibit pyrimethamine resistance in vitro. The selective pressure of home-based use of SP (per the WHO strategy of home-based management of fevers) could accelerate the emergence of SP resistance to an even greater degree.

Finally, drug resistant mutant parasites are statistically more likely to emerge from infections involving large numbers of parasites. Such large parasite biomass infections are more common in non-immune individuals, as demonstrated by the higher prevalence of chloroquine-resistant infections, and chloroquine treatment failures seen in African children compared to adults. Non-immune patients infected with large numbers of parasites who receive inadequate treatment (either because of poor drug quality, adherence, vomiting of an oral treatment, etc.) are another potent source of resistance. This emphasizes the importance of correct prescribing and good adherence to prescribed drug regimens in slowing the emergence of resistance.

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