Section VIII - Chemotherapy of Microbial Diseases

Malaria, caused by four species of Plasmodium, of which Plasmodium falciparum is the most dangerous, remains the worlds most devastating human parasitic infection. This chapter deals with the properties and uses of important drugs used to treat and prevent this infection. Highly effective agents that act against asexual erythrocytic stages of malarial parasites responsible for clinical attacks include chloroquine, quinine, quinidine, mefloquine, atovaquone, and the artemisinin compounds.
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Section VIII - Chemotherapy of Microbial Diseases Section VII. Chemotherapy of Parasitic Infections Chapter 40. Drugs Used in the Chemotherapy of Protozoal Infections: Malaria Overview Malaria, caused by four species of Plasmodium, of which Plasmodium falciparum is the most dangerous, remains the worlds most devastating human parasitic infection. This chapter deals with the properties and uses of important drugs used to treat and prevent this infection. Highly effective agents that act against asexual erythrocytic stages of malarial parasites responsible for clinical attacks include chloroquine, quinine, quinidine, mefloquine, atovaquone, and the artemisinin compounds. Less effective, slower-acting drugs in this category are proguanil, pyrimethamine, sulfonamides, sulfones, and the antimalarial antibiotics. Primaquine is the only drug used against latent tissue forms of Plasmodium vivax and Plasmodium ovale that cause relapsing infections. No single antimalarial agent has successfully controlled the spread of increasingly drug-resistant strains of P. falciparum. Instead, multidrug regimens are discussed as the optimal strategy to address this problem. Drugs Used in the Chemotherapy of Protozoal Infections: Malaria: Introduction Malaria remains the worlds most devastating human parasitic infection, afflicting more than 500 million people and causing from 1.7 million to 2.5 million deaths each year (World Health Organization, 1997). Infection with Plasmodium falciparum causes much of this mortality, which preferentially affects children less than 5 years of age, pregnant women, and nonimmune individuals. Although mosquito-transmitted malaria virtually has been eliminated from North America, Europe, and Russia, its increasing prevalence in many parts of the tropics, especially sub- Saharan Africa, poses a major local health and economic burden and a serious risk to travelers from nonendemic areas. Practical, inexpensive, effective, and safe drugs, insecticides, and vaccines still are needed to combat malaria. In the 1950s, attempts to eradicate this scourge from most parts of the world failed, primarily because of the development of resistance to insecticides and antimalarial drugs. Since 1960, transmission of malaria has risen in most regions where the infection is endemic; chloroquine-resistant and multidrug-resistant strains of P. falciparum have spread, and the degree of drug resistance has increased. More recently, chloroquine-resistant strains of P. vivax also have been documented in Oceania. Nearly all antimalarial drugs were developed because of their action against asexual erythrocytic forms of malarial parasites that cause clinical illness. Efficacious, rapidly acting drugs in this category include chloroquine, quinine, quinidine, mefloquine, atovaquone, and the artemisinin compounds. Proguanil, pyrimethamine, sulfonamides, sulfones, and antimalarial antibiotics, such as the tetracyclines, are slower acting and less effective. Primaquine is the only drug used clinically to eradicate latent tissue forms that cause relapses of P. vivax and P. ovale infections. Due to the continuing spread of increasingly drug-resistant and multidrug-resistant strains of P. falciparum, no single agent successfully controls infections with these parasites. Instead, use of two or more antimalarial agents with complementary properties is recommended (seeWhite, 1997, 1999). The discovery of techniques for continuous maintenance of P. falciparum in vitro (Trager and Jensen, 1976) led to practical assays of susceptibility of these organisms to antimalarial drugs. This important advance, together with the imminent availability of the sequence of the entire 24.6- megabase P. falciparum genome (Su et al., 1999), should reveal molecular targets for antimalarial drug action and resistance as well as for vaccine development. The biology of malarial infection must be appreciated in order to understand the actions and therapeutic uses of antimalarial drugs. Biology of Malarial Infection Nearly all human malaria is caused by four species of obligate intracellular protozoa of the genus Plasmodium. Although malaria can be transmitted by transfusion of infected blood and by sharing needles, human beings usually are infected by sporozoites injected by the bite of infected female mosquitoes (genus Anopheles). These parasite forms rapidly leave the circulation and localize in hepatocytes, where they transform, multiply, and develop into tissue schizonts (Figure 40–1). This primary asymptomatic tissue (preerythrocytic or exoerythrocytic) stage of infection lasts for 5 to 15 days, depending on the Plasmodium species. Tissue schizonts then rupture, each releasing thousands of merozoites that enter the circulation, invade erythrocytes, and initiate the erythrocytic stage of cyclic infection. Once the tissue schizonts burst in P. falciparum and Plasmodium malariae infections, no forms of the para ...