The Alexander Project indicates an increase in the prevalence of S. pneumoniae resistance to macrolide antibiotics. In some centers, the prevalence of S. pneumoniae macrolide resistance exceeds that of penicillin resistance. Centers with a high level of macrolide resistance tend to also have high levels of penicillin resistance. Antimicrobial use may be an important driver of resistance. The application of pharmacodynamic concepts suggests that bacterial exposure to low and prolonged concentrations of macrolides may have a role in the selection of resistance. Analysis of macrolide prescribing and resistance patterns indicates a correlation between increasing macrolide resistance and the increased use of newer, long-acting macrolides, although further study is required to investigate the causality of this correlation. In order to attempt to prevent the further spread of resistance, antibiotic choice should maximize the opportunity for bacterial eradication.