Active Bacterial Core surveillance (ABCs) performs laboratory- and population- based surveillance for severe group A streptococcal disease within 10 different states, currently assessing a population of more than 34.5 million individuals. During the period of 2015-2019 the proportions of invasive group A streptococcal resistance to macrolides (primarily associated with co-resistance to lincosamides) increased from approximately 14% to 20%. During this period, invasive GAS disease incidence increased from 4.8 to 7.6 cases per 100,000 population. During 2015-2019 we also found a near perfect concordance of GAS exhibiting slight decreases in susceptibilities to different β-lactam antibiotics with 26 different amino acid substitution variants of the penicillin binding protein 2X amino acid sequence. Although individual Pbp2x variant strains were widespread within up to 10 different ABCs states, including one Pbp2x variant that was co-resistant to erythromycin and clindamycin, the overall proportion of such variants remained stable at less than 3% of the isolates.