Title: Spatio-temporal Dynamics of Antibiotic Resistant Staphylococcus aureus in the United States

Abstract: Antibiotics are regularly used to treat bacterial infections. However, their extended use has caused antimicrobial resistance to develop in some bacteria, making these infections more difficult to treat. Rising resistance in the bacteria Staphylococcus aureus (S. aureus), a leading opportunistic pathogen in humans, to commonly used antibiotics is particularly concerning. This dissertation aims to describe how resistance in S. aureus varies across the United States, how it changes over time, and what factors may contribute to these patterns. Using clinical resistance data from S. aureus cases, we showed that the risk of resistance and change over time varied across locations. These results suggest that factors influencing these patterns operate at the local level. We then examined how local county-level factors and patient-level factors were associated with resistance and found that antibiotic use was the primary risk factor, while rural residence was generally associated with lower resistance, although the relationship differed in the Midwest. The variation across counties, however, was still not explained. Using a nationwide genomic dataset, we found that the distribution of different S. aureus strains varied across regions, and strain diversity increased over time. Two common strains also showed different trends of resistance to several antibiotics, with increases in resistance occurring as the strains evolved into new groups and expanded. Because different strains have different resistance profiles, their distribution across space may help explain geographic variation in resistance observed in clinical data. These findings highlight the importance of local surveillance and genomic data to help guide the appropriate use of antibiotics and slow the spread of resistance.