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Will antimicrobial resistance of BRD pathogens impact BRD management in the future?

Published online by Cambridge University Press:  20 November 2014

Gordon W. Brumbaugh
Gordon W. Brumbaugh*
Affiliation:
Caine Veterinary Teaching Center, University of Idaho, Caldwell, Idaho, USA
*
Corresponding author. E-mail: gordonb@uidaho.edu
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Abstract

Resistance is a qualitative interpretation of antimicrobial activity in vitro. Critical to management of bovine respiratory disease (BRD) is the clinical response in vivo. Attempts to connect activity in vitro to response in vivo have been complicated by the complexity of BRD, interpretation of antimicrobial activity in vitro, and inconsistent measures of clinical success or failure. During recent history, the discovery, development, and commercialization of antimicrobials have decreased. In response to resistance, voluntary and imposed restrictions on use of antimicrobials have been implemented. Resistance can be reversed using technology and knowledge of mechanisms of resistance. Perhaps approaches that reverse resistance will be used in clinical management of BRD in the future. The short answer to the question posed in the title is, ‘yes.’ Since antimicrobial drugs were discovered, resistance has been a consideration for selection of treatment of any infectious disease and BRD is not unique. In the opinion of the author, the more important question is, ‘How will antimicrobial resistance of BRD pathogens impact BRD management in the future?’

Keywords

bovine respiratory diseaseantimicrobial resistancepathogensclinical management
Type
Review Article
Information
Animal Health Research Reviews , Volume 15 , Issue 2 , December 2014 , pp. 175 - 177
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Copyright
Copyright © Cambridge University Press 2014 

Resistance is one of three qualitative interpretative categories (‘susceptible’, ‘intermediate’ or ‘resistant’) based on measures of antimicrobial activity in vitro, and is defined in the USA by the Clinical and Laboratory Standard Institute (CLSI) as follows: ‘This category implies that there will not be a favorable clinical outcome, because the achievable systemic concentrations of the agent will be lower than the minimum inhibitory concentration (MIC) of the causative organism with normal dosage schedules and/or fall in the range where specific microbial resistance mechanisms are likely (e.g. beta-lactamase), and clinical efficacy has not been reliable in treatment studies’ (CLSI, 2002a, b; Silley, Reference Silley2012). Break-points are semi-quantitative (arguably) measures (usually MIC, or diameter of the zone of inhibition) that distinguish among the three qualitative categories. There are no details about how data from ‘treatment studies’ are considered during the establishment of breakpoints (CLSI, 2002a, b).

Standard procedures described by the CLSI are designed to be optimal for the pathogen, and are used for identification of the pathogen as well as for assessment of antimicrobial activity in vitro.

Confusion about how to interpret results in vitro is multi-factorial, as is the nature of bovine respiratory disease (BRD) (Taylor et al., Reference Taylor, Fulton, Lehenbauer, Step and Confer2010a, Reference Taylor, Fulton, Lehenbauer, Step and Conferb). Many of the simple questions have not been answered. If more than one pathogen is isolated, what is the fractional contribution of each? What is the influence of resistance with one pathogen but not the other(s)? Are resistant organisms found in animals that do not have clinical signs? Do they remain in treated and recovered animals?

‘Concerns’ about antimicrobial resistance are not new. Before penicillin was commercially available, Dr Fleming raised awareness that bacteria could change after exposure to penicillin (Rosenblatt-Farrell, Reference Rosenblatt-Farrell2009). Surveillance/monitoring of in vitro activity of antimicrobials began in 1951 (Giles and Shuttleworth, Reference Giles and Shuttleworth1958). Focus on antimicrobial activity in vitro has been intense, perhaps because it is the easiest to identify of the factors that contribute to clinical failure. However, clinical correlation of those data has not been evaluated effectively. Using non-standardized procedures for studies in vivo further confuses attempts to correlate in vitro activity and response in vivo (O'Connor et al., Reference O'Connor, Wellman, Rice and Funk2010).

Resistance is not to blame for all clinical failures. Clinical response is the net effect of all factors that contribute to BRD – including antimicrobial resistance. Factors other than antimicrobial resistance play a role in the death of feedlot cattle with BRD (Lamm et al., Reference Lamm, Love, Krehbiel, Johnson and Step2012). Is there a point (percent resistance) at which medications should not be selected for clinical use? Should selection only include compounds for which susceptibility (what percent?) is identified? Patterns of practice for human patients with community acquired pneumonia (CAP) were ‘shifting in response to the perception that current levels of drug resistance necessitate changes in treatment patterns. This is unfortunate because it severely limits one's ability to continue to monitor the effectiveness of available therapies in light of changing patterns of antibacterial drug resistance’ (Metlay, Reference Metlay2004). Dr Metlay summarized, ‘…antibacterial drug resistance has not reduced substantially the effectiveness of first-line treatments for CAP. Whether levels of drug resistance will continue to increase or decline is unknown. Therefore, carefully designed outcomes studies likely will continue to be essential to help define optimal therapy for patients who have CAP.’ Could those statements apply to BRD?

Antimicrobial resistance and clinical failure are not directly, quantitatively correlated (Lamm et al., Reference Lamm, Love, Krehbiel, Johnson and Step2012; McPherson et al., Reference McPherson, Aschenbrenner, Lacey, Fahnoe, Lemmon, Finegan, Tadakamalla, O'Donnell, Mueller and Tomaras2012). Likewise, clinical success is not inseparable from antimicrobial susceptibility. Basic definitions distinguish them; and, the labeling of antimicrobial products contains statements similar to the following: ‘The correlation between in vitro susceptibility data and clinical effectiveness is unknown.’ Treatment failures occurred when susceptible organisms were isolated; and, treatment successes occurred when resistant organisms were isolated (Apley, Reference Apley2003; McClary et al., Reference McClary, Loneragan, Shryock, Carter, Guthrie, Corbin and Mechor2011). Clinical failure, when BRD is associated with susceptible organisms, cannot be due to antimicrobial failure! The association of clinical response with antimicrobial activity in vitro is not the same for all BRD pathogens (McClary et al., Reference McClary, Loneragan, Shryock, Carter, Guthrie, Corbin and Mechor2011). Virulence of the organism, the host's resistance to infection, and the host's tolerance to presence of pathogens are also distinct considerations deserving of greater attention (Beceiro et al., Reference Beceiro, Tomás and Bou2013; Jamieson et al., Reference Jamieson, Pasman, Yu, Gamradt, Homer, Decker and Medzhitov2013). Antimicrobial medications are important; but, the entirety of clinical response is not the responsibility of the medication.

The strongest evidence for clinical decisions is derived from head-to-head, randomized, controlled clinical studies (Karriker, Reference Karriker2007). Techniques such as risk assessment and survival analysis could contribute greatly to evaluating clinical response and the relationship of antimicrobial activity in vitro with clinical response. Appropriate economic evaluation of treatments is also warranted (Simoens, Reference Simoens2010).

Driven by fear of resistance, pharmaceutical companies in the USA have re-labeled products to clarify indicated therapeutic uses and decreased research of new antimicrobial agents (Spellberg et al., Reference Spellberg, Powers, Brass, Miller and Edwards2004; Silley, Reference Silley2012; FDA GFI #213, 2013; Wright, Reference Wright2013). Regulatory activities are directed toward reclassifying products so that they will be available only with ‘veterinary oversight’ and have the stated purpose of reducing resistance (FDA GFI #213, 2013).

Realistic considerations for the future should be to include management of fears of resistance, to utilize understanding of mechanisms of virulence and mechanisms of antimicrobial resistance, to improve designs of clinical studies, and to develop technologies or products that could reverse resistance (Spellberg et al., Reference Spellberg, Powers, Brass, Miller and Edwards2004; Tillotson and Echols, Reference Tillotson and Echols2008; Wright, Reference Wright2013). Clinical studies with appropriate designs will require many animals and considerable financial investment.

Non-traditional methods of treating infectious diseases have included technologies that reverse resistance. The dogma that mutations only progress toward resistance is wrong. Genetic mutations can be induced to reverse resistance (Cirz and Romesberg, Reference Cirz and Romesberg2006; Ricci et al., Reference Ricci, Tzakas, Buckley, Coldham and Piddock2006; Katsuda et al., Reference Katsuda, Kohmoto, Mikami and Uchida2009). Bacteriophages have been used to reduce bacterial contamination of food, change virulence of bacterial pathogens, alter damage created by bacterial pathogens or enhance the host's tolerance of the pathogen, or reverse antimicrobial resistance (Abuladze et al., Reference Abuladze, Li, Menetrez, Dean, Senecal and Sulakvelidze2008; Rasko and Sperandio, Reference Rasko and Sperandio2010; Abedon et al., Reference Abedon, Kuhl, Blasdel and Marin Kutter2011; Beceiro et al., Reference Beceiro, Tomás and Bou2013; Wright, Reference Wright2013; Hong et al., Reference Hong, Pan and Ebner2014; Vale et al., Reference Vale, Fenton and Brown2014). Might it be possible to administer a vaccine that targets BRD pathogens in the upper respiratory tract of cattle and cause those bacteria to become susceptible to treatment, or concurrently administer medications that reverse/prevent resistance while others inhibit or kill the pathogen? ‘Concerns’ and ‘perceptions’ are driving regulations, corporate decisions, public response, and therapeutic decisions. Are results of a scientifically based future of treatment of BRD worth the risks of taking that ‘bull by the horns’?

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