Tulathromycin metaphylaxis increases nasopharyngeal isolation of multidrug resistant Mannheimia haemolytica in stocker heifers

Authors: CROSBY, WILLIAM - Mississippi State University; KARISCH, BRANDY - Mississippi State University; Hiott, Lari; PINNELL, LEE - Texas A&M University; PITTMAN, ALEXANDRA - Mississippi State University; Frye, Jonathan; Jackson, Charlene; LOY, DUSTIN - University Of Nebraska; EPPERSON, WILLIAM - Mississippi State University; BLANTON, JOHN - Purdue University; MORLEY, PAUL - Texas A&M University; WOOLAMS, AMELIA - Mississippi State University

Submitted to: Frontiers in Veterinary Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/25/2023
Publication Date: 11/20/2023
Citation: Crosby, W.B., Karisch, B.B., Hiott, L.M., Pinnell, L.J., Pittman, A., Frye, J.G., Jackson, C.R., Loy, D.J., Epperson, W.B., Blanton, J., Morley, P.S., Woolams, A.R. 2023. Tulathromycin metaphylaxis increases nasopharyngeal isolation of multidrug resistant Mannheimia haemolytica in stocker heifers. Frontiers in Veterinary Science. 2023(10). https://doi.org/10.3389/fvets.2023.1256997.
DOI: https://doi.org/10.3389/fvets.2023.1256997

Interpretive Summary: Bovine respiratory disease (BRD) is a leading cause of illness in feedlot and stocker calves and is commonly associated with the bacterium, Mannheimia haemolytica (Mh). One of the most effective means of controlling the disease is through metaphylaxis, which is administering antimicrobials to all animals at high risk of developing BRD. However, increasing prevalence of multidrug resistant Mh may reduce effectiveness of metaphylaxis. This study aimed to find the effect of tulathromycin metaphylaxis and BRD treatment on antimicrobial resistance in MH isolated from stocker calves. Also evaluated was the effect of metaphylaxis and treatment for BRD on animal health and comparing the genetic relationship of Mh isolated. Crossbred beef heifers at high risk for BRD were randomly assigned to either receive metaphylaxis (META) or not (NO META). Nasopharyngeal swabs were collected from calves at arrival, three weeks, and ten weeks later. Mh was isolated from swabs and isolates were tested for antimicrobial susceptibility and their whole genomes were sequenced. Statistical analysis was used to find risk factors for isolation of Mh and multidrug resistant Mh at three and ten weeks, and BRD morbidity. Animals in the META group were more likely to have multidrug resistant isolates of Mh at three weeks and ten weeks after arrival. There was no difference in META or NO META calves shedding any Mh (resistant or susceptible) at all time points. Animals in the NO META group had three times higher odds of being treated for BRD. Antimicrobial resistance genes found in Mh isolates were associated with integrative conjugative elements. The study demonstrated that tulathromycin metaphylaxis increased risk of shedding multidrug resistant Mh and that the increase in multidrug resistant Mh is associated with integrative conjugative elements carrying antimicrobial resistance genes. This may have important implications for the future ability of antimicrobials to control and treat BRD.

Technical Abstract: Background: Bovine respiratory disease (BRD) is a leading cause of disease in feedlot and stocker calves and is commonly associated with Mannheimia haemolytica (MH). One of the most effective means of controlling BRD is through metaphylaxis, which involves administering antimicrobials, particularly macrolides, to all animals at high risk of developing BRD. However, increasing prevalence of multidrug resistant (MDR) MH may reduce efficacy of metaphylaxis. Primarily, this randomized, controlled study aimed to determine the effect of tulathromycin metaphylaxis and subsequent BRD treatment on antimicrobial resistance (AMR) in MH isolated from stocker calves. Secondary objectives included evaluating the effect of metaphylaxis and treatment for BRD on animal health and comparing the genetic relationship of MH isolated. Crossbred beef heifers (n=331, mean weight=232, SD= 17.8 kg) at high risk for BRD were randomly assigned to receive tulathromycin metaphylaxis (META, n=167) or not (NO META, n=164). Nasopharyngeal swabs were collected for MH isolation, antimicrobial susceptibility testing and whole genome sequencing at arrival and 3 (WK3) and 10 (WK10) weeks later. Mixed-effects logistic regression was used to identify risk factors for isolation of MH and MDR MH (resistant to = 3 antimicrobial drug classes) at 3 and 10 weeks, BRD morbidity. Results: Animals in the META group had higher odds of recovery of MDR MH at 3 weeks (OR (95 % CI)=13.08 (5-30.9), P<0.0001) and 10 weeks (OR (95% CI)=5.92 (1.34-26.14), P=0.019) after arrival. There was no difference in risk of shedding of any MH (resistant or susceptible) between META and NO META groups at all timepoints. Animals in the NO META group had 3 times higher odds of being treated for BRD (WK3: OR (95% CI)=3.07 (1.70-5.52), P=0.0002; WK10: OR (95% CI)=2.76 (1.59-4.80), P=0.0002). Antimicrobial resistance genes found within isolates were associated with integrative conjugative element (ICE) genes. Conclusions: Tulathromycin metaphylaxis increased risk of shedding MDR Mh and in this population, the increase in MDR Mh appeared to be associated with ICE containing antimicrobial resistance genes for multiple antimicrobial classes. This may have important implications for future efficacy of antimicrobials for control and treatment of BRD.