Genomic Landscape of Macrolide Resistance in High-Burden Bacterial Pathogens: Implications for Antimicrobial Stewardship in Resource-Limited Settings

Background Antimicrobial resistance (AMR) threatens global health, with macrolide resistance emerging as a critical challenge in high-burden pathogens. Understanding taxon-specific resistance mechanisms is essential for guiding interventions in resource-limited settings where diagnostic and therapeutic resources are constrained. Methods We analyzed 9,706 bacterial genomes from the AMRFinderPlus database to characterize macrolide resistance alleles, their distribution across taxa, and associations with multidrug resistance. Statistical and visualization workflows identified taxon-specific patterns and clinical implications. Results Macrolide resistance mechanisms dominated (34% of 1,243 alleles), with 23S rRNA mutations prevalent in Neisseria gonorrhoeae (23S_A2045G: 62%; 23S_A2057G: 58%) and Streptococcus pneumoniae (23S_A2058G: 48%). Efflux pump variants (acrB_R717L/Q) drove multidrug resistance in Escherichia spp . (41%) and Salmonella spp . (33%), correlating with cross-resistance to fluoroquinolones (18%) and tetracyclines (14%). These pathogens disproportionately impact regions like Ghana, where syndromic management and antibiotic misuse amplify resistance. Conclusions These findings underscore the urgent need for precision surveillance and context-specific stewardship to combat macrolide resistance in high-burden pathogens, particularly in resource-limited settings where diagnostic and therapeutic gaps exacerbate AMR threats. Targeted interventions, including affordable molecular diagnostics and antibiotic access reforms, are critical to mitigating global health disparities driven by resistance.