1988), 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 (Diourte et al., 1999; Nzila et al., 2000). 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 (Talisuna et al., 2002b). 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 (Hastings et al., 2002). 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 (Watkins and Mosobo, 1993). 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 (Watkins and Mosobo, 1993). 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 (Talisuna et al., 2004).

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 nonimmune individuals, as demonstrated by the higher prevalence of chloroquine-resistant infections, and chloroquine treatment failures seen in African children compared to adults (Dorsey et al., 2000; Djimde et al., 2001; Talisuna et al., 2002a). Nonimmune 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.

Recrudescence and onward transmission of a de novo resistant malaria parasite are essential for the propagation of resistance. Killing the transmis-

Front Matter (R1-R20)

Executive Summary (1-16)

Part 1: A Response to the Current Crisis1 Malaria Today (17-60)

2 The Cost and Cost-Effectiveness of Antimalarial Drugs (61-78)

3 The Case for a Global Subsidy of Antimalarial Drugs (79-111)

4 An International System for Procuring Anitmalarial Drugs (112-122)

Part 2: Malaria Basics5 A Brief History of Malaria (123-135)

6 The Parasite, the Mosquito, and the Disease (136-167)

7 The Human and Economic Burden of Malaria (168-196)

8 Malaria Control (197-251)

9 Antimalarial Drugs and Drug Resistance (252-298)

Part 3: Advancing Toward Better Malaria Control10 Research and Development for New Antimalarial Drugs (299-311)

11 Maximizing the Effective Use of Antimalarial Drugs (312-328)

Acronyms and Abbreviations (329-333)

Glossary (334-346)

Index (347-364)