Bovine Respiratory Disease and Antimicrobial Resistance
By Keith D. DeDonder, DVM, PhD
Bovine respiratory disease (BRD) remains a major disease both from an economic and an animal welfare standpoint in beef production systems. Antimicrobial administration is a mainstay in both the control of and in the therapeutic treatment of acute BRD. However, the pipeline of novel antimicrobial classes has remained dry for well over a decade and according to most published accounts, antimicrobial resistance among BRD pathogens is increasing. Therefore, judicious antimicrobial usage is vital for continued efficacy. The biggest challenge is targeting the ideal scenario of maximizing clinical efficacy and minimizing antimicrobial resistance. The host-pathogen-drug interaction is very complex and despite current sophisticated technology, this interaction is still not well understood for many infectious diseases.
Within the last several years, the presence of integrative conjugative elements (ICE) have been recognized in bacteria associated with BRD. These ICE contain the genetic code necessary for bacteria to express resistance to nearly all of the major drug classes used in the treatment of BRD. Additionally, the ICE are mobile genetic elements that mediate their own excision from the host chromosome, form a circular intermediate and encode their own machinery to transfer themselves by conjugation, and are then able to integrate and replicate as a part of the host chromosome.
In 2013, a research trial was conducted to investigate the effect of treatment for control of BRD and treatment of acute BRD with a macrolide (gamithromycin) on the development of macrolide resistance. One objective of this study was to describe gamithromycin susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni isolates, post-treatment for control and/or for treatment of acute BRD with this antimicrobial. Another objective was to characterize the macrolide resistance genes present in genetically subtyped M. haemolytica isolated from cattle that had either been treated on arrival for control of BRD or sham saline injection (CON).
One hundred and eighty cattle perceived to be at high risk for BRD were brought into a research feedyard in Manhattan, KS. Sixty head were purchased each at a single salebarn in Missouri, Tennessee, and Kentucky. Cattle were purposefully bought from as many different sources as possible at each salebarn. Upon receiving, cattle were subject to practices typical in the industry (vaccinations, anthelmintic and growth hormone administration). However, cattle were randomly allocated within state of origin to receive either gamithromycin (MM) or a sham saline injection (CON), serving as a negative control. Cattle were divided within state of origin into two pens such that there were 30 head of MM cattle in one pen and 30 head of CON in the other pen resulting in a total of six pens in the study.
Following administration of the MM and CON, cattle were monitored for signs of BRD for 28 days. Cattle receiving MM had a post treatment interval of 7 days while cattle in the CON group were immediately eligible for diagnosis and treatment of BRD. Diagnosis of BRD was performed in the pen by a veterinarian masked to treatment allocation using a clinical scoring system based on clinical symptoms attributable to BRD. Cattle meeting the clinical score necessary for inclusion were pulled from the home pen and a rectal temperature determined in a chute. Cattle with a rectal temperature ≥104.0 °F were included in the study and if the rectal temperature was <104.0 °F were sent back to their home pen for further observation. Cattle enrolled in the study were subjected to a sampling scheme consisting of bacterial culture of deep nasopharyngeal swabs (NPS) and/or bronchoalveolar lavage (BAL) fluid prior to drug administration and again at either 12 or 24 hours after administration. All cattle had both NPS and BAL samples submitted five days after treatment for bacterial culture and subsequent gamithromycin minimum inhibitory concentration (MIC) determination.
As many as 12 isolates of M. haemolytica from each culture sample were subjected to MIC determination and genomic analysis for the determination of the macrolide resistance genes erm(42), msr(E), and mph(E). Further, up to 6 isolates of Pasteurella multocida and Histophilus somni were isolated and subjected to MIC determination. Determination of MIC was by broth microdilution. Whole genome sequencing of M. haemolytica isolates was utilized for the construction of phylogentic trees to determine the relatedness of each isolate and to identify the presence of macrolide resistance genes within ICE when they were found to be present. Generalized linear mixed models were built for data analysis.
In total there were 276 M. haemolytica, 253 P. multocida, and 78 H. somni that were isolated from the 26 head of feedlot cattle that were included in this study. Of the 26 head of cattle that were included in the study (diagnosed with acute BRD) only four calves were determined to be failures (two from each treatment group).
Resistance was overrepresented by a single genetic subtype of M. haemolytica. There was not a significant difference between MM and CON groups in regards to the likelihood of culturing a resistant or intermediate isolate of M. haemolytica or P. multocida. The likelihood of culturing a resistant or intermediate isolate of M. haemolytica differed significantly by state of origin and further investigation in this area is warranted. A single M. haemolytica genetic subtype correlated with nearly all of the observed resistance.
Clear associations between the use of gamithromycin for control and treatment of BRD and a statistically significantly increased likelihood of macrolide resistance were not found. However, there were just four treatment failures and two harbored resistant bacteria at the end of the sampling period and two did not. Therefore, the fact that there was not a statistical difference might have been due to an insufficiently powered study.
Interestingly, as another part of this study not discussed here, a poor correlation was found between MIC (susceptible or resistant) and case outcome (success or failure). However, the number of failures was quite low and this finding deserves further research.
Additional studies to elucidate the relationship between resistance and clinical response to antimicrobials are necessary to inform judicious use of antimicrobials in the context of relieving animal disease and suffering.