** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** ANTIMICROBIAL RESISTANCE (AMR) IS A SIGNIFICANT PUBLIC HEALTH THREAT, AND THE USE OF ANTIMICROBIALS IN FOOD PRODUCING ANIMALS HAS RECEIVED A GREAT AMOUNT OF SCRUTINY. ADDRESSING AMR IS A HIGH PRIORITY FOR BOTH ANIMAL AGRICULTURE AS WELL AS THE PUBLIC HEALTH SINCE MANY OF THE MEDICALLY IMPORTANT ANTIMICROBIALS ARE USED TO TREAT OR PREVENT INFECTIONS IN ANIMALS. BOVINE RESPIRATORY DISEASE (BRD) IS A MAJOR REASON FOR THE METAPHYLACTIC USE OF ANTIMICROBIALS IN THE BEEF INDUSTRY AND HAS MAJOR ECONOMIC AND ANIMAL HEALTH AND WELFARE IMPLICATIONS. A NUMBER OF MEDICALLY IMPORTANT ANTIBIOTICS ARE WIDELY USED IN THE TREATMENT AND PREVENTION OF BRD IN CATTLE. THEREFORE, BRD TREATMENT AND CONTROL ARE A MAJOR CONCERN FOR EMERGENCE AND DISSEMINATION OF AMR. THE GOAL OF THE PROPOSED PROJECT IS TO GENERATE DATA ON THE IMPACT OF CHLORTETRACYCLINE (CTC) PLUS MACROLIDE ANTIMICROBIAL COMBINATION ON ANIMAL HEALTH AND PERFORMANCE AND TO DEVELOP MITIGATION STRATEGIES WITH THE GOAL TO REDUCE THE USE OF ANTIMICROBIAL METAPHYLAXIS IN BEEF CATTLE. TREATMENT CHOICES CAN DRIVE PATTERNS OF AMR PREVALENCE. METAPHYLACTIC ADMINISTRATION OF IN-FEED CHLORTETRACYCLINE (CTC) AND INJECTABLE MACROLIDE ARE COMMONLY USED IN THE FEEDLOT INDUSTRY TO CONTROL BRD AND OTHER INFECTIONS.WE SEEK TO GUIDE MITIGATION STRATEGIES TOWARD A GOAL OF REDUCING THE USE OF ANTIMICROBIAL METAPHYLAXIS IN FEEDLOT CATTLE. A FIELD STUDY WITH HIGH-RISK CALVES IN A COMMERCIAL FEEDYARD IS PROPOSED FOR EVALUATING IN-FEED CTC (ONE AND TWO PULSES) WITH INJECTABLE TULATHROMYCIN AS METAPHYLAXIS. FECAL, NASAL, FEED, AND WATER SAMPLES WILL BE COLLECTED FROM EACH PEN OF CATTLE ON DAYS 0, 6, 12, 28, AT REIMPLANT, AND PRIOR TO CLOSEOUT FOR ANALYSES TO DETERMINE PREVALENCE, ABUNDANCE OF TETRACYCLINE AND MACROLIDE RESISTANCE GENES, AND ANTIMICROBIAL SUSCEPTIBILITY PATTERNS OF BRD PATHOGENS, GUT COMMENSALS AND FOODBORNE PATHOGENS. A SUBSET OF THE SAMPLES WILL BE SUBJECTED TO SHOTGUN METAGENOMICS ANALYSIS TO IDENTIFY BACTERIAL COMMUNITY COMPOSITION AND AMR GENES (RESISTOME).WE WILL SURVEY FEEDLOT MANAGERS TO IDENTIFY METAPHYLAXIS PRACTICES, ANTIMICROBIAL RESISTANCE PERCEPTIONS, AND POTENTIAL KNOWLEDGE GAPS. RESULTS FROM THE FIELD STUDY WILL BE INCORPORATED INTO TRAINING AND OUTREACH MATERIALS FOR FEEDLOT PRODUCERS, NUTRITIONISTS, VETERINARIANS, STAKEHOLDERS, REGULATORY AGENCIES, AND CONSUMERS TO RECOMMEND ANTIMICROBIAL USE PRACTICES, ANTIMICROBIAL RESISTANCE AND EFFECTIVE MITIGATION STRATEGIES IN FEEDLOT CATTLE. THE PROPOSED STUDY ADDRESSES THE GOALS OF THE PROGRAM PRIORITY AREA TO SPECIFICALLY DESCRIBE AND QUANTIFY THE RISK OF AMR PATHOGENS AND ALSO TO DETERMINE IMPROVED, BEST-MANAGEMENT PRACTICES AND APPROACHES IN ANTIBIOTIC STEWARDSHIP.