• The number of clinical malaria episodes. [ Time Frame: Per year of follow-up. ] [ Designated as safety issue: No ]
  

• To measure the prevalence of chloroquine resistant parasites, by treatment arm. [ Time Frame: Duration of study. ] [ Designated as safety issue: No ]
  
• To assess the antimalarial drug efficacy, by treatment arm. [ Time Frame: At first administration and during subsequent episodes of malaria. ] [ Designated as safety issue: No ]
  
• To assess the effect of each treatment arm on anemia. [ Time Frame: At the end of study participation. ] [ Designated as safety issue: No ]
  
• To determine the chloroquine blood levels at which chloroquine sensitive and resistant parasites are able to cause infection. [ Time Frame: Analysis. ] [ Designated as safety issue: No ]
  
• Assess the spatial patterns and the environmental determinants of malaria infection. [ Time Frame: Analysis. ] [ Designated as safety issue: No ]
  
• Assess the effect of population movements on the risk of malaria infection. [ Time Frame: Analysis. ] [ Designated as safety issue: No ]
  
• To assess the safety of repeated use of the drugs in each of the study arms. [ Time Frame: Duration of study. ] [ Designated as safety issue: Yes ]
  

Combination therapy is becoming the mainstay of malaria treatment. In general, the goal of combination therapy is to successfully treat resistant infections successfully and to prevent the emergence and spread of resistance. The antimalarial combination therapies currently in use were not designed based on optimal pairing of drugs to deter the development and spread of parasite resistance to the individual partner drugs in settings of high malaria transmission. Careful studies are needed to identify the pharmacokinetic and pharmacodynamic properties of drug combinations that will deter resistance and prolong the useful therapeutic life of the next generation of antimalarial drug combinations. Current in vivo methods for measuring antimalarial drug efficacy in high-transmission areas use a 14 or 28-day follow-up period, but a single-episode study misses several critical factors in assessing the efficacy and impact of antimalarial treatment. When follow-up is extended beyond 28 days, more cases of apparent resistance or treatment failure are found. Single-episode studies cannot assess the impact of therapy on the incidence of malaria over time. These limitations of standard in vivo studies have led the investigators to advocate longitudinal studies of drug efficacy. In addition to measuring efficacy of individual treatments, longitudinal studies measure sustained efficacy with repeated use of the same regimen over time, a scenario that more accurately reflects the real-life use of anti-malarial medication. The primary outcome of interest, the incidence of malaria episodes, as well as the secondary outcomes of anemia and severe malaria, are all highly relevant to public health policy-makers, as they reflect not only the burden of disease but also the utilization of health resources. Longitudinal studies also permit assessment of how pharmacokinetic properties of drugs affect the incidence of treatment episodes. This is a randomized, open-label, longitudinal drug efficacy trial involving approximately 640 children, aged 6 months to 5 years, who are found to have uncomplicated malaria at the Blantyre Malaria Project Research Clinic at the Ndirande Health Centre in Blantyre, Malawi. After enrollment, participants will be randomized to one of four treatment arms: chloroquine alone or chloroquine in combination with artesunate, atovaquone-proguanil (Malarone® or AP), or azithromycin. The treatment outcome will be assessed through a standard 28-day efficacy study. Participants subsequently will be evaluated every four weeks and encouraged to return to the study clinic any time they are ill during the course of one year. If a new episode of uncomplicated malaria is diagnosed, the participant will receive the same therapy as assigned on enrollment. Polymerase chain reaction-corrected 28-day efficacy will be evaluated for each treatment episode. The primary study objective is to compare annual incidence of malaria clinical episodes. Secondary objectives are to: assess anti-malarial drug efficacy at first administration, by treatment arm; assess anti-malarial drug efficacy during subsequent episodes of malaria, by treatment arm; measure prevalence of chloroquine resistant parasites during the trial, by treatment arm; assess effect of each treatment arm on anemia at the end of study participation; assess safety of these drugs with repeated use; determine the chloroquine blood levels at which chloroquine sensitive and resistant parasites are able to cause infection; assess the effect of population movements on the risk of malaria infection; and assess the spatial patterns and the environmental determinants of malaria infection.