BOVINE RESPIRATORY DISEASE (BRD) IS THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN BEEF CATTLE, AND MASS ANTIMICROBIAL ADMINISTRATION (METAPHYLAXIS) IS THE MOST EFFECTIVE PREVENTION. METAPHYLAXIS CAN ALSO BE LIFE-SAVING IN OTHER LIVESTOCK AND HUMANS, BUT THE PRACTICE MAY BE COMPROMISED BY SPREAD OF MULTIDRUG RESISTANT (MDR) PATHOGENS. MDR ISOLATES OF THE BRD PATHOGEN MANNHEIMIA HAEMOLYTICA CAN BE FOUND IN 90% OF SOME CATTLE 14 DAYS AFTER METAPHYLAXIS. THE MECHANISMS LEADING TO MDR AFTER METAPHYLAXIS ARE UNKNOWN, BUT RAPID TRANSFER OF MOBILE GENETIC ELEMENTS (MGE) ENCODING ANTIMICROBIAL RESISTANCE (AMR) IS LIKELY. USING A RANDOMIZED FIELD TRIAL ASSESSING TREATED AND UNTREATED CONVENTIONALLY MANAGED CATTLE, WE WILL 1) COMPARE PREVALENCE OF NASOPHARYNGEAL MDR M. HAEMOLYTICA ISOLATES, AMR GENES, AND MGE, USING CULTURE, SUSCEPTIBILITY TESTING, AND WHOLE GENOME SEQUENCING; 2) COMPARE NASOPHARYNGEAL METAGENOMES, USING 16S AMPLICON SEQUENCING; 3) COMPARE THE NASOPHARYNGEAL RESISTOME, USING TARGET-ENRICHED SEQUENCING OF AMR AND MGE GENE SEQUENCES; AND 4) USE TARGET-ENRICHED SEQUENCING TO COMPARE ABSOLUTE ABUNDANCE OF M. HAEMOLYTICA AND SEQUENCES SPECIFIC TO OTHER BRD PATHOGENS. THIS APPROACH WILL PROVIDE UNPRECEDENTED RESOLUTION OF THE ECOLOGY OF RESPIRATORY AMR IN CATTLE RECEIVING METAPHYLAXIS, REVEALING TARGETS FOR MITIGATING AMR. THIS RESEARCH SUPPORTS SUSTAINABILITY OF U.S. AGRICULTURE WITH EVIDENCE-BASED STRATEGIES TO ENSURE LIVESTOCK HEALTH AND LIMIT AMR, BY IMPROVING UNDERSTANDING OF THE EMERGENCE AND TRANSMISSION OF MGE ENCODING AMR TO MEDICALLY IMPORTANT AM, AND DEVELOPING TOOLS TO TRACK AMR GENES IN ANIMAL ENVIRONMENTS.