This study examines the spatiotemporal trends of antimicrobial resistance patterns among *Staphylococcus aureus* (S. aureus) isolates from outpatient settings in the United States from 2010 to 2019. The primary objectives were to characterize the changes in resistance to non-β-lactam antibiotics, including clindamycin, tetracyclines, sulfonamides (trimethoprim-sulfamethoxazole [TMP-SMX]), and macrolides, and to assess regional variations in resistance rates and geographical heterogeneity in multidrug resistance. - **Data Source:** Veterans Health Administration (VHA) clinics. - **Participants:** Adult outpatients with S. aureus infections in the conterminous 48 states and Washington, DC. - **Exposures:** Resistance to clindamycin, tetracyclines, sulfonamides, and macrolides. - **Main Outcomes:** Spatiotemporal variation in resistance rates, stratified by methicillin-resistant *S. aureus* (MRSA) and methicillin-sensitive *S. aureus* (MSSA), and by US regions. - **Total Isolates:** 382,149 - **Unique Outpatients:** 268,214 - **Mean Age:** 63.4 years (SD 14.8 years) - **Gender Distribution:** 252,910 males (94.29%) - **MRSA Prevalence:** Decreased from 53.6% in 2010 to 38.8% in 2019. - **Tetracycline Resistance:** Increased significantly from 3.6% in 2010 to 12.8% in 2019. - **TMP-SMX Resistance:** Increased significantly from 2.6% in 2010 to 9.2% in 2019. - **Clindamycin Resistance:** Increased modestly but not significantly from 24.2% in 2010 to 30.6% in 2019. - **Macrolide Resistance:** Decreased significantly from 73.5% in 2010 to 60.2% in 2019. - **MRSA Isolates:** Higher rates of resistance to tetracyclines and TMP-SMX. - **MSSA Isolates:** Significant increases in resistance to clindamycin, tetracyclines, and TMP-SMX. - **Regional Patterns:** The Northeast had slightly higher rates of clindamycin resistance but lower rates of tetracycline resistance, while the South had notably higher rates of resistance to tThis study examines the spatiotemporal trends of antimicrobial resistance patterns among *Staphylococcus aureus* (S. aureus) isolates from outpatient settings in the United States from 2010 to 2019. The primary objectives were to characterize the changes in resistance to non-β-lactam antibiotics, including clindamycin, tetracyclines, sulfonamides (trimethoprim-sulfamethoxazole [TMP-SMX]), and macrolides, and to assess regional variations in resistance rates and geographical heterogeneity in multidrug resistance. - **Data Source:** Veterans Health Administration (VHA) clinics. - **Participants:** Adult outpatients with S. aureus infections in the conterminous 48 states and Washington, DC. - **Exposures:** Resistance to clindamycin, tetracyclines, sulfonamides, and macrolides. - **Main Outcomes:** Spatiotemporal variation in resistance rates, stratified by methicillin-resistant *S. aureus* (MRSA) and methicillin-sensitive *S. aureus* (MSSA), and by US regions. - **Total Isolates:** 382,149 - **Unique Outpatients:** 268,214 - **Mean Age:** 63.4 years (SD 14.8 years) - **Gender Distribution:** 252,910 males (94.29%) - **MRSA Prevalence:** Decreased from 53.6% in 2010 to 38.8% in 2019. - **Tetracycline Resistance:** Increased significantly from 3.6% in 2010 to 12.8% in 2019. - **TMP-SMX Resistance:** Increased significantly from 2.6% in 2010 to 9.2% in 2019. - **Clindamycin Resistance:** Increased modestly but not significantly from 24.2% in 2010 to 30.6% in 2019. - **Macrolide Resistance:** Decreased significantly from 73.5% in 2010 to 60.2% in 2019. - **MRSA Isolates:** Higher rates of resistance to tetracyclines and TMP-SMX. - **MSSA Isolates:** Significant increases in resistance to clindamycin, tetracyclines, and TMP-SMX. - **Regional Patterns:** The Northeast had slightly higher rates of clindamycin resistance but lower rates of tetracycline resistance, while the South had notably higher rates of resistance to t