Applying definitions for multidrug resistance, extensive drug resistance and pandrug resistance to clinically significant livestock and companion animal bacterial pathogens

Applying definitions for multidrug resistance, extensive drug resistance and pandrug resistance... Abstract Standardized definitions for MDR are currently not available in veterinary medicine despite numerous reports indicating that antimicrobial resistance may be increasing among clinically significant bacteria in livestock and companion animals. As such, assessments of MDR presented in veterinary scientific reports are inconsistent. Herein, we apply previously standardized definitions for MDR, XDR and pandrug resistance (PDR) used in human medicine to animal pathogens and veterinary antimicrobial agents in which MDR is defined as an isolate that is not susceptible to at least one agent in at least three antimicrobial classes, XDR is defined as an isolate that is not susceptible to at least one agent in all but one or two available classes and PDR is defined as an isolate that is not susceptible to all agents in all available classes. These definitions may be applied to antimicrobial agents used to treat bovine respiratory disease (BRD) caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni and swine respiratory disease (SRD) caused by Actinobacillus pleuropneumoniae, P. multocida and Streptococcus suis, as well as antimicrobial agents used to treat canine skin and soft tissue infections (SSTIs) caused by Staphylococcus and Streptococcus species. Application of these definitions in veterinary medicine should be considered static, whereas the classification of a particular resistance phenotype as MDR, XDR or PDR could change over time as more veterinary-specific clinical breakpoints or antimicrobial classes and/or agents become available in the future. Introduction Currently, there are no accepted definitions for MDR in veterinary medicine despite reports indicating that antimicrobial resistance may be increasing among clinically significant bacteria in certain livestock and companion animals.1–3 Owing to the lack of standardized terminology, assessments of MDR presented in veterinary scientific reports are inconsistent and in some cases are contradictory with widely varying definitions. The foundation for harmonized definitions in veterinary medicine was first established in 2010 by Schwarz et al.,4 who acknowledged there was ‘no universally accepted definition of “multiresistance”’ in animal medicine and therefore proposed a general definition for those veterinary pathogens that had acquired resistance to three or more antibacterial classes. However, this preliminary definition did not allow for delineation of clinical situations where pathogens express an MDR phenotype for which therapeutic options may still be available compared with situations where pathogens express an XDR or pandrug resistance (PDR) phenotype for which therapeutic options may be severely limited or exhausted entirely. Current evidence of MDR among veterinary pathogens suggests that further categorization of MDR into XDR and PDR is needed to communicate the true clinical impact of antimicrobial resistance.5–8 Definitions for MDR, XDR and PDR were later standardized within the human healthcare setting from an international initiative between the ECDC and the US CDC.9 From that initiative, MDR bacteria were defined as bacteria that are non-susceptible to at least one antimicrobial agent in three or more antimicrobial classes, XDR was defined as non-susceptibility to at least one antimicrobial agent in all but two or fewer antimicrobial classes [that is, bacterial isolates remain susceptible to agent(s) in only one or two classes] and PDR was defined as non-susceptibility to all agents in all antimicrobial classes. It was suggested that these definitions be applied to bacterial pathogens that are clinically and epidemiologically significant in human healthcare-associated infections and prone to acquiring antimicrobial resistance. Although the definitions from this international initiative in human medicine provide a more detailed assessment of the clinical implications of highly resistant bacteria, there are some important points that are either unique to veterinary medicine or were not addressed by Magiorakos et al.9 that warrant additional discussion in order to adapt these definitions for use in veterinary medicine. Our objective is to expand upon previously standardized definitions for MDR, XDR and PDR, and apply them to certain pathogens of veterinary significance, and herein we address the unique situations that exist regarding the testing and reporting of highly resistant pathogens in veterinary medicine. We also posit that these standardized definitions are necessary for veterinary medicine in order to describe MDR at the more refined levels of XDR and PDR, thereby allowing researchers and clinicians to more clearly classify ‘degrees’ of antimicrobial resistance, rather than reporting a veterinary pathogen under the general term of ‘MDR’. Extension of MDR to XDR and PDR will allow veterinary practitioners to more accurately assess therapeutic options against bacteria that display highly resistant phenotypes that are now being reported in clinical isolates.1,8 Definitions for MDR, XDR and PDR in veterinary medicine As with Magiorakos et al.,9 it is necessary to apply certain inclusion and exclusion criteria to these definitions for veterinary use for the sake of harmonization, with the understanding that these criteria will limit the application of the definitions. Criteria for our proposed definitions are discussed below and, in general, address how ‘resistance’ is defined and answer specific questions related to which interpretive criteria can be used to define MDR and which methodologies can be used to test for MDR. How is ‘resistance’ defined? As was suggested by Schwarz et al.4 and Magiorakos et al.,9 only acquired resistance is considered in defining MDR, XDR and PDR; that is, agents or classes of antimicrobials to which an organism is intrinsically resistant should be removed from MDR definitions and analysis. Magiorakos et al.9 also suggested that ‘resistance’ be defined as ‘non-susceptibility’ so that classifications of resistant, intermediate or non-susceptible are all included. However, there is some ambiguity associated with the term ‘non-susceptible’ in that it is often used to categorize an isolate that has a susceptible-only clinical breakpoint value and in which an MIC for that isolate is above the susceptible breakpoint value. Therefore, we recommend that for those isolates with available susceptible, intermediate and resistant interpretive criteria, the term ‘not susceptible’ should be used rather than ‘non-susceptible’ when defining MDR. This more conservative approach for categorization may tend to overestimate MDR rates as previously acknowledged.9 As the definitions outlined herein are based on specific interpretive criteria of resistant, intermediate or not susceptible, the question of ‘Which interpretive criteria should be used?’ is raised. We propose that the term ‘resistance’ be reserved for situations that have clinical implications for a patient, that is, an infection is more difficult to treat or therapeutic options are more limited. Therefore, the standard for determining resistance, since it is linked to clinical outcome, should be a species-specific clinical breakpoint. Indeed, this was the approach used by Magiorakos et al.9 when they excluded tigecycline from the list of antibiotics for Acinetobacter spp. While it is not uncommon for veterinary diagnostic laboratories to test and report a combination of antimicrobials with both species-specific and non-species-specific (i.e. human) interpretive criteria, these classifications ignore the potential impact of interspecies pharmacokinetics on clinical outcome. In developing standardized definitions to be used for comparison across studies, we propose that only species-specific interpretive criteria be used to define MDR, XDR and PDR in veterinary pathogens. However, we do not believe it is necessary to restrict the definitions to a single standards-setting organization, as long as the interpretive criteria are linked to clinical outcome in that animal species. The limitation of this approach is that there is currently only one standards-setting organization that develops veterinary-specific criteria, the CLSI subcommittee on Veterinary Antimicrobial Susceptibility Testing (CLSI-VAST), and a limited number of species-specific interpretive criteria in veterinary medicine to which these definitions can be applied. Therefore, we strongly urge the development of more interpretive criteria in veterinary medicine. Currently there are antimicrobial agent(s) in seven drug classes that are available to treat bovine respiratory disease (BRD) caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni (which includes the aminocyclitol, penicillin, cephalosporin, fluoroquinolone, macrolide, phenicol and tetracycline classes) and there are seven drug classes available to treat swine respiratory disease (SRD) caused by Actinobacillus pleuropneumoniae (the penicillin, cephalosporin, fluoroquinolone, macrolide, phenicol, pleuromutilin and tetracycline classes), six for P. multocida (the penicillin, cephalosporin, fluoroquinolone, macrolide, phenicol and tetracycline classes) and five for Streptococcus suis (the penicillin, cephalosporin, fluoroquinolone, phenicol and tetracycline classes), that have species-specific clinical breakpoints to categorize an isolate as not susceptible and to define these pathogens as MDR, XDR or PDR.10 There are agent(s) in six drug classes available for treatment of skin and soft tissue infections (SSTIs) caused by canine Staphylococcus spp. (the aminoglycoside, penicillin, cephalosporin, fluoroquinolone, tetracycline and lincosamide classes) and five classes available for Streptococcus spp. (the aminoglycoside, penicillin, cephalosporin, fluoroquinolone and lincosamide classes)10 and so MDR, XDR and PDR can be defined for these pathogens as well. Table 1 provides a summary of proposed definitions for resistance in these veterinary pathogens in which MDR is defined as an isolate that is not susceptible to at least one agent in at least three antimicrobial classes, XDR is defined as an isolate that is not susceptible to at least one agent in all but one or two available classes and PDR is defined as an isolate that is not susceptible to all agents in all available classes. Table 1. Applying definitions for MDR, XDR and PDR to antimicrobial agents and veterinary bacterial pathogens from livestock and companion animal diseases Animal disease and bacterial species MDR XDR PDR BRD: M. haemolytica, P. multocida, H. somni not susceptible to at least one agent in at least three antimicrobial classes not susceptible to at least one agent in all but one or two antimicrobial classes not susceptible to all agents in all antimicrobial classes SRD: A. pleuropneumoniae, P. multocida, S. suis Canine SSTIs: Staphylococcus spp., Streptococcus spp. Animal disease and bacterial species MDR XDR PDR BRD: M. haemolytica, P. multocida, H. somni not susceptible to at least one agent in at least three antimicrobial classes not susceptible to at least one agent in all but one or two antimicrobial classes not susceptible to all agents in all antimicrobial classes SRD: A. pleuropneumoniae, P. multocida, S. suis Canine SSTIs: Staphylococcus spp., Streptococcus spp. Table 1. Applying definitions for MDR, XDR and PDR to antimicrobial agents and veterinary bacterial pathogens from livestock and companion animal diseases Animal disease and bacterial species MDR XDR PDR BRD: M. haemolytica, P. multocida, H. somni not susceptible to at least one agent in at least three antimicrobial classes not susceptible to at least one agent in all but one or two antimicrobial classes not susceptible to all agents in all antimicrobial classes SRD: A. pleuropneumoniae, P. multocida, S. suis Canine SSTIs: Staphylococcus spp., Streptococcus spp. Animal disease and bacterial species MDR XDR PDR BRD: M. haemolytica, P. multocida, H. somni not susceptible to at least one agent in at least three antimicrobial classes not susceptible to at least one agent in all but one or two antimicrobial classes not susceptible to all agents in all antimicrobial classes SRD: A. pleuropneumoniae, P. multocida, S. suis Canine SSTIs: Staphylococcus spp., Streptococcus spp. Although epidemiological cut-off values (ECVs) are clearly useful in the early detection of decreased susceptibility for surveillance purposes, the use of ECVs to define and categorize MDR is not appropriate. We have, therefore, excluded ECVs from the proposed definitions of MDR, XDR and PDR here. ECVs can only be used to categorize isolates as WT or non-WT, whereas the terms susceptible, intermediate and resistant should be reserved for clinical breakpoints.11 Which methodologies can be used to determine resistance? The definitions for MDR, XDR and PDR extended to veterinary medicine can be applied using phenotypic results obtained from in vitro antimicrobial susceptibility testing of bacterial isolates recovered from animals in the veterinary diagnostic laboratory or clinical setting. Only recognized, standardized susceptibility test methods and interpretive criteria should be used towards MDR, XDR and PDR classification.10,12 Because the interpretive criteria development process involves comparing broth dilution with disc diffusion results, any method of in vitro testing (broth/agar dilution or disc diffusion) would be considered acceptable as long as it is a veterinary-approved method for the antimicrobial agent and organism in question. In situations where susceptibility results are determined by a ‘mix’ of methods (such as the dilution and disc diffusion methods), the categorization of MDR may be appropriately assigned based on results from these multiple test methodologies, provided the methods are standardized and provided that appropriate veterinary breakpoints from each method are used. Therefore, it is acceptable to designate an isolate as MDR using both MIC and agar diffusion methods as long as the appropriate veterinary methodology is used and veterinary breakpoints are used for interpretation. It would be inappropriate to use veterinary breakpoints for the results of an MIC test and human breakpoints for those from an agar diffusion test. In addition to phenotypic results from in vitro susceptibility test methods, genotypic studies that can detect acquired resistance genes and mutations, as described by Schwarz et al.4 and others13, should be done whenever possible. Currently, many diagnostic laboratories do not have access to genotyping methodologies, but as more methods and genotype–phenotype correlations become available and affordable in the future, this may be a more practical option for those laboratories. In this sense, genotypic studies can serve to reinforce the phenotypic results generated from in vitro susceptibility tests by confirming functionally active resistance genes.13 A resistance gene or a resistance-mediating mutation should be associated with a particular resistance phenotype and thus should affect each different antimicrobial class.13 The CLSI-VAST report VET05-R provides exceptions to this rule and highlights that definitions for MDR should be based on the number of antimicrobial classes to which an isolate is resistant, irrespective of the number of resistance genes/mutations.13 We support the recommendation by Magiorakos et al.9 that any methods and interpretive criteria used should be explicit in any reports of future surveillance in veterinary pathogens. Discussion The emergence of MDR bacteria in veterinary medicine over the past decade has limited the therapeutic choices available to clinicians.14–16 Thus, selection of the most appropriate antimicrobial agent for treatment is essential in preserving the future utility of available antimicrobial agents in veterinary medicine, while also ensuring animal welfare. The definition for veterinary pathogens resistant to multiple antimicrobial agents and classes was first proposed by Schwarz et al.,4 who stated that resistance to three or more veterinary antimicrobial classes should be referred to as MDR based solely on acquired resistance. Clinical evidence of XDR and PDR among veterinary pathogens suggests that further categorization of MDR into XDR and PDR is possible for certain significant veterinary pathogens,1–3,5,7 and here we present criteria for assessing MDR in specific livestock and companion animal bacterial pathogens (Table 1) by utilizing definitions proposed earlier by Magiorakos et al.9 for human medicine. Further expansion upon the definition of MDR into XDR or PDR for veterinary use will result in better understanding of therapeutic treatment options, or lack thereof, for the clinician and is a critical step in improving comparability and reporting of surveillance data. The definitions for MDR, XDR and PDR originally proposed for human medicine and applied here for veterinary medicine should be considered static. However, the classification of a particular resistance phenotype as MDR, XDR or PDR may not be static and could change over time as more veterinary-specific clinical breakpoints or antimicrobial agents/classes become available in the future. For example, a PDR M. haemolytica isolate (a veterinary pathogen that is not susceptible to all antimicrobials with interpretive criteria) would be re-classified to being only XDR once a new class of antimicrobial or a new drug in an existing class that is not prone to current resistance mechanisms was introduced for clinical use (with accompanying veterinary-specific interpretive criteria) to which the isolate was susceptible. Although the primary purpose of extending standardized definitions for MDR, XDR and PDR to certain veterinary pathogens is to assist the veterinary clinician with treatment options, these definitions will also be of value for researchers and surveillance programmes. As the need for harmonization among surveillance and other susceptibility testing programmes is recognized and achieved, comparison of MDR rates among veterinary pathogens in various geographical locations becomes possible.13 Furthermore, these definitions allow for distinction of drug resistance at the more clinically significant levels of XDR and PDR, rather than just reporting a pathogen generally as ‘MDR’, which is currently widely used in veterinary publications and reports. Transparency declarations M. T. S. and J. L. W. are employees of Zoetis (formerly Pfizer Animal Health) and have ownership of company stock. B. V. L. has received speaking/consulting fees from Merck Animal Health and Merial. S. S.: none to declare. References 1 Lubbers BV , Hanzlicek GA. Antimicrobial multidrug resistance and coresistance patterns of Mannheimia haemolytica isolated from bovine respiratory disease cases—a three-year (2009-2011) retrospective analysis . J Vet Diagn Invest 2013 ; 25 : 413 – 7 . Google Scholar CrossRef Search ADS PubMed 2 Portis E , Lindeman C , Johansen L et al. A ten year (2000-2009) study of antibacterial susceptibility of bacteria that cause bovine respiratory disease complex—Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni—in the United States and Canada . J Vet Diagn Invest 2012 ; 24 : 932 – 44 . Google Scholar CrossRef Search ADS PubMed 3 Michael GB , Kadlec K , Sweeney MT et al. ICEPmu1, an integrative conjugative element (ICE) of Pasteurella multocida: analysis of the regions that comprise 12 antimicrobial resistance genes . J Antimicrob Chemother 2012 ; 67 : 84 – 90 . Google Scholar CrossRef Search ADS PubMed 4 Schwarz S , Silley P , Simjee S et al. Editorial: assessing the antimicrobial susceptibility of bacteria obtained from animals . J Antimicrob Chemother 2010 ; 65 : 601 – 4 . Google Scholar CrossRef Search ADS PubMed 5 Klima CL , Zaheer R , Cook SR et al. Pathogens of bovine respiratory disease in North American feedlots conferring multidrug resistance via integrative conjugative elements . J Clin Microbiol 2014 ; 52 : 438 – 48 . Google Scholar CrossRef Search ADS PubMed 6 Marques C , Gama LT , Belas A et al. European multicenter study on antimicrobial resistance in bacteria isolated from companion animal urinary tract infections . BMC Vet Res 2016 ; 12 : 213 . Google Scholar CrossRef Search ADS PubMed 7 Walther B , Tedin K , Lübke-Becker A. Multidrug-resistant opportunistic pathogens challenging veterinary infection control . Vet Microbiol 2017 ; 200 : 71 – 8 . Google Scholar CrossRef Search ADS PubMed 8 Perreten V , Kadlec K , Schwarz S et al. Clonal spread of methicillin-resistant Staphylococcus pseudintermedius in Europe and North America: an international multicentre study . J Antimicrob Chemother 2010 ; 65 : 1145 – 54 . Google Scholar CrossRef Search ADS PubMed 9 Magiorakos AP , Srinivasan A , Carey RB et al. Multidrug-resistant, extensively drug-resistant, and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance . Clin Microbiol Infect 2012 ; 18 : 268 – 81 . Google Scholar CrossRef Search ADS PubMed 10 Clinical and Laboratory Standards Institute . Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals: Third Informational Supplement VET01S . CLSI , Wayne, PA, USA , 2015 . 11 Bywater R , Silley P , Simjee S. Antimicrobial breakpoints—definitions and conflicting requirements . Vet Microbiol 2006 ; 118 : 158 – 9 . Google Scholar CrossRef Search ADS PubMed 12 Clinical and Laboratory Standards Institute . Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals—Fourth Edition: VET01-A4 . CLSI , Wayne, PA, USA , 2013 . 13 Clinical and Laboratory Standards Institute . Generation, Presentation, and Application of Antimicrobial Susceptibility Test Data for Bacteria of Animal Origin: Report VET05-R . CLSI , Wayne, PA, USA , 2011 . 14 Michael GB , Freitag C , Wendlandt S et al. Emerging issues in antimicrobial resistance of bacteria from food-producing animals . Future Microbiol 2015 ; 10 : 427 – 43 . Google Scholar CrossRef Search ADS PubMed 15 Guardabassi L , Prescott JF. Antimicrobial stewardship in small animal veterinary practice: from theory to practice . Vet Clin North Am Small Anim Pract 2015 ; 45 : 361 – 76 . Google Scholar CrossRef Search ADS PubMed 16 DeDonder K , Harhay DM , Apley MD et al. Observations on macrolide resistance and susceptibility testing performance in field isolates collected from clinical bovine respiratory disease . Vet Microbiol 2016 ; 192 : 186 – 93 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Applying definitions for multidrug resistance, extensive drug resistance and pandrug resistance to clinically significant livestock and companion animal bacterial pathogens

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Abstract

Abstract Standardized definitions for MDR are currently not available in veterinary medicine despite numerous reports indicating that antimicrobial resistance may be increasing among clinically significant bacteria in livestock and companion animals. As such, assessments of MDR presented in veterinary scientific reports are inconsistent. Herein, we apply previously standardized definitions for MDR, XDR and pandrug resistance (PDR) used in human medicine to animal pathogens and veterinary antimicrobial agents in which MDR is defined as an isolate that is not susceptible to at least one agent in at least three antimicrobial classes, XDR is defined as an isolate that is not susceptible to at least one agent in all but one or two available classes and PDR is defined as an isolate that is not susceptible to all agents in all available classes. These definitions may be applied to antimicrobial agents used to treat bovine respiratory disease (BRD) caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni and swine respiratory disease (SRD) caused by Actinobacillus pleuropneumoniae, P. multocida and Streptococcus suis, as well as antimicrobial agents used to treat canine skin and soft tissue infections (SSTIs) caused by Staphylococcus and Streptococcus species. Application of these definitions in veterinary medicine should be considered static, whereas the classification of a particular resistance phenotype as MDR, XDR or PDR could change over time as more veterinary-specific clinical breakpoints or antimicrobial classes and/or agents become available in the future. Introduction Currently, there are no accepted definitions for MDR in veterinary medicine despite reports indicating that antimicrobial resistance may be increasing among clinically significant bacteria in certain livestock and companion animals.1–3 Owing to the lack of standardized terminology, assessments of MDR presented in veterinary scientific reports are inconsistent and in some cases are contradictory with widely varying definitions. The foundation for harmonized definitions in veterinary medicine was first established in 2010 by Schwarz et al.,4 who acknowledged there was ‘no universally accepted definition of “multiresistance”’ in animal medicine and therefore proposed a general definition for those veterinary pathogens that had acquired resistance to three or more antibacterial classes. However, this preliminary definition did not allow for delineation of clinical situations where pathogens express an MDR phenotype for which therapeutic options may still be available compared with situations where pathogens express an XDR or pandrug resistance (PDR) phenotype for which therapeutic options may be severely limited or exhausted entirely. Current evidence of MDR among veterinary pathogens suggests that further categorization of MDR into XDR and PDR is needed to communicate the true clinical impact of antimicrobial resistance.5–8 Definitions for MDR, XDR and PDR were later standardized within the human healthcare setting from an international initiative between the ECDC and the US CDC.9 From that initiative, MDR bacteria were defined as bacteria that are non-susceptible to at least one antimicrobial agent in three or more antimicrobial classes, XDR was defined as non-susceptibility to at least one antimicrobial agent in all but two or fewer antimicrobial classes [that is, bacterial isolates remain susceptible to agent(s) in only one or two classes] and PDR was defined as non-susceptibility to all agents in all antimicrobial classes. It was suggested that these definitions be applied to bacterial pathogens that are clinically and epidemiologically significant in human healthcare-associated infections and prone to acquiring antimicrobial resistance. Although the definitions from this international initiative in human medicine provide a more detailed assessment of the clinical implications of highly resistant bacteria, there are some important points that are either unique to veterinary medicine or were not addressed by Magiorakos et al.9 that warrant additional discussion in order to adapt these definitions for use in veterinary medicine. Our objective is to expand upon previously standardized definitions for MDR, XDR and PDR, and apply them to certain pathogens of veterinary significance, and herein we address the unique situations that exist regarding the testing and reporting of highly resistant pathogens in veterinary medicine. We also posit that these standardized definitions are necessary for veterinary medicine in order to describe MDR at the more refined levels of XDR and PDR, thereby allowing researchers and clinicians to more clearly classify ‘degrees’ of antimicrobial resistance, rather than reporting a veterinary pathogen under the general term of ‘MDR’. Extension of MDR to XDR and PDR will allow veterinary practitioners to more accurately assess therapeutic options against bacteria that display highly resistant phenotypes that are now being reported in clinical isolates.1,8 Definitions for MDR, XDR and PDR in veterinary medicine As with Magiorakos et al.,9 it is necessary to apply certain inclusion and exclusion criteria to these definitions for veterinary use for the sake of harmonization, with the understanding that these criteria will limit the application of the definitions. Criteria for our proposed definitions are discussed below and, in general, address how ‘resistance’ is defined and answer specific questions related to which interpretive criteria can be used to define MDR and which methodologies can be used to test for MDR. How is ‘resistance’ defined? As was suggested by Schwarz et al.4 and Magiorakos et al.,9 only acquired resistance is considered in defining MDR, XDR and PDR; that is, agents or classes of antimicrobials to which an organism is intrinsically resistant should be removed from MDR definitions and analysis. Magiorakos et al.9 also suggested that ‘resistance’ be defined as ‘non-susceptibility’ so that classifications of resistant, intermediate or non-susceptible are all included. However, there is some ambiguity associated with the term ‘non-susceptible’ in that it is often used to categorize an isolate that has a susceptible-only clinical breakpoint value and in which an MIC for that isolate is above the susceptible breakpoint value. Therefore, we recommend that for those isolates with available susceptible, intermediate and resistant interpretive criteria, the term ‘not susceptible’ should be used rather than ‘non-susceptible’ when defining MDR. This more conservative approach for categorization may tend to overestimate MDR rates as previously acknowledged.9 As the definitions outlined herein are based on specific interpretive criteria of resistant, intermediate or not susceptible, the question of ‘Which interpretive criteria should be used?’ is raised. We propose that the term ‘resistance’ be reserved for situations that have clinical implications for a patient, that is, an infection is more difficult to treat or therapeutic options are more limited. Therefore, the standard for determining resistance, since it is linked to clinical outcome, should be a species-specific clinical breakpoint. Indeed, this was the approach used by Magiorakos et al.9 when they excluded tigecycline from the list of antibiotics for Acinetobacter spp. While it is not uncommon for veterinary diagnostic laboratories to test and report a combination of antimicrobials with both species-specific and non-species-specific (i.e. human) interpretive criteria, these classifications ignore the potential impact of interspecies pharmacokinetics on clinical outcome. In developing standardized definitions to be used for comparison across studies, we propose that only species-specific interpretive criteria be used to define MDR, XDR and PDR in veterinary pathogens. However, we do not believe it is necessary to restrict the definitions to a single standards-setting organization, as long as the interpretive criteria are linked to clinical outcome in that animal species. The limitation of this approach is that there is currently only one standards-setting organization that develops veterinary-specific criteria, the CLSI subcommittee on Veterinary Antimicrobial Susceptibility Testing (CLSI-VAST), and a limited number of species-specific interpretive criteria in veterinary medicine to which these definitions can be applied. Therefore, we strongly urge the development of more interpretive criteria in veterinary medicine. Currently there are antimicrobial agent(s) in seven drug classes that are available to treat bovine respiratory disease (BRD) caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni (which includes the aminocyclitol, penicillin, cephalosporin, fluoroquinolone, macrolide, phenicol and tetracycline classes) and there are seven drug classes available to treat swine respiratory disease (SRD) caused by Actinobacillus pleuropneumoniae (the penicillin, cephalosporin, fluoroquinolone, macrolide, phenicol, pleuromutilin and tetracycline classes), six for P. multocida (the penicillin, cephalosporin, fluoroquinolone, macrolide, phenicol and tetracycline classes) and five for Streptococcus suis (the penicillin, cephalosporin, fluoroquinolone, phenicol and tetracycline classes), that have species-specific clinical breakpoints to categorize an isolate as not susceptible and to define these pathogens as MDR, XDR or PDR.10 There are agent(s) in six drug classes available for treatment of skin and soft tissue infections (SSTIs) caused by canine Staphylococcus spp. (the aminoglycoside, penicillin, cephalosporin, fluoroquinolone, tetracycline and lincosamide classes) and five classes available for Streptococcus spp. (the aminoglycoside, penicillin, cephalosporin, fluoroquinolone and lincosamide classes)10 and so MDR, XDR and PDR can be defined for these pathogens as well. Table 1 provides a summary of proposed definitions for resistance in these veterinary pathogens in which MDR is defined as an isolate that is not susceptible to at least one agent in at least three antimicrobial classes, XDR is defined as an isolate that is not susceptible to at least one agent in all but one or two available classes and PDR is defined as an isolate that is not susceptible to all agents in all available classes. Table 1. Applying definitions for MDR, XDR and PDR to antimicrobial agents and veterinary bacterial pathogens from livestock and companion animal diseases Animal disease and bacterial species MDR XDR PDR BRD: M. haemolytica, P. multocida, H. somni not susceptible to at least one agent in at least three antimicrobial classes not susceptible to at least one agent in all but one or two antimicrobial classes not susceptible to all agents in all antimicrobial classes SRD: A. pleuropneumoniae, P. multocida, S. suis Canine SSTIs: Staphylococcus spp., Streptococcus spp. Animal disease and bacterial species MDR XDR PDR BRD: M. haemolytica, P. multocida, H. somni not susceptible to at least one agent in at least three antimicrobial classes not susceptible to at least one agent in all but one or two antimicrobial classes not susceptible to all agents in all antimicrobial classes SRD: A. pleuropneumoniae, P. multocida, S. suis Canine SSTIs: Staphylococcus spp., Streptococcus spp. Table 1. Applying definitions for MDR, XDR and PDR to antimicrobial agents and veterinary bacterial pathogens from livestock and companion animal diseases Animal disease and bacterial species MDR XDR PDR BRD: M. haemolytica, P. multocida, H. somni not susceptible to at least one agent in at least three antimicrobial classes not susceptible to at least one agent in all but one or two antimicrobial classes not susceptible to all agents in all antimicrobial classes SRD: A. pleuropneumoniae, P. multocida, S. suis Canine SSTIs: Staphylococcus spp., Streptococcus spp. Animal disease and bacterial species MDR XDR PDR BRD: M. haemolytica, P. multocida, H. somni not susceptible to at least one agent in at least three antimicrobial classes not susceptible to at least one agent in all but one or two antimicrobial classes not susceptible to all agents in all antimicrobial classes SRD: A. pleuropneumoniae, P. multocida, S. suis Canine SSTIs: Staphylococcus spp., Streptococcus spp. Although epidemiological cut-off values (ECVs) are clearly useful in the early detection of decreased susceptibility for surveillance purposes, the use of ECVs to define and categorize MDR is not appropriate. We have, therefore, excluded ECVs from the proposed definitions of MDR, XDR and PDR here. ECVs can only be used to categorize isolates as WT or non-WT, whereas the terms susceptible, intermediate and resistant should be reserved for clinical breakpoints.11 Which methodologies can be used to determine resistance? The definitions for MDR, XDR and PDR extended to veterinary medicine can be applied using phenotypic results obtained from in vitro antimicrobial susceptibility testing of bacterial isolates recovered from animals in the veterinary diagnostic laboratory or clinical setting. Only recognized, standardized susceptibility test methods and interpretive criteria should be used towards MDR, XDR and PDR classification.10,12 Because the interpretive criteria development process involves comparing broth dilution with disc diffusion results, any method of in vitro testing (broth/agar dilution or disc diffusion) would be considered acceptable as long as it is a veterinary-approved method for the antimicrobial agent and organism in question. In situations where susceptibility results are determined by a ‘mix’ of methods (such as the dilution and disc diffusion methods), the categorization of MDR may be appropriately assigned based on results from these multiple test methodologies, provided the methods are standardized and provided that appropriate veterinary breakpoints from each method are used. Therefore, it is acceptable to designate an isolate as MDR using both MIC and agar diffusion methods as long as the appropriate veterinary methodology is used and veterinary breakpoints are used for interpretation. It would be inappropriate to use veterinary breakpoints for the results of an MIC test and human breakpoints for those from an agar diffusion test. In addition to phenotypic results from in vitro susceptibility test methods, genotypic studies that can detect acquired resistance genes and mutations, as described by Schwarz et al.4 and others13, should be done whenever possible. Currently, many diagnostic laboratories do not have access to genotyping methodologies, but as more methods and genotype–phenotype correlations become available and affordable in the future, this may be a more practical option for those laboratories. In this sense, genotypic studies can serve to reinforce the phenotypic results generated from in vitro susceptibility tests by confirming functionally active resistance genes.13 A resistance gene or a resistance-mediating mutation should be associated with a particular resistance phenotype and thus should affect each different antimicrobial class.13 The CLSI-VAST report VET05-R provides exceptions to this rule and highlights that definitions for MDR should be based on the number of antimicrobial classes to which an isolate is resistant, irrespective of the number of resistance genes/mutations.13 We support the recommendation by Magiorakos et al.9 that any methods and interpretive criteria used should be explicit in any reports of future surveillance in veterinary pathogens. Discussion The emergence of MDR bacteria in veterinary medicine over the past decade has limited the therapeutic choices available to clinicians.14–16 Thus, selection of the most appropriate antimicrobial agent for treatment is essential in preserving the future utility of available antimicrobial agents in veterinary medicine, while also ensuring animal welfare. The definition for veterinary pathogens resistant to multiple antimicrobial agents and classes was first proposed by Schwarz et al.,4 who stated that resistance to three or more veterinary antimicrobial classes should be referred to as MDR based solely on acquired resistance. Clinical evidence of XDR and PDR among veterinary pathogens suggests that further categorization of MDR into XDR and PDR is possible for certain significant veterinary pathogens,1–3,5,7 and here we present criteria for assessing MDR in specific livestock and companion animal bacterial pathogens (Table 1) by utilizing definitions proposed earlier by Magiorakos et al.9 for human medicine. Further expansion upon the definition of MDR into XDR or PDR for veterinary use will result in better understanding of therapeutic treatment options, or lack thereof, for the clinician and is a critical step in improving comparability and reporting of surveillance data. The definitions for MDR, XDR and PDR originally proposed for human medicine and applied here for veterinary medicine should be considered static. However, the classification of a particular resistance phenotype as MDR, XDR or PDR may not be static and could change over time as more veterinary-specific clinical breakpoints or antimicrobial agents/classes become available in the future. For example, a PDR M. haemolytica isolate (a veterinary pathogen that is not susceptible to all antimicrobials with interpretive criteria) would be re-classified to being only XDR once a new class of antimicrobial or a new drug in an existing class that is not prone to current resistance mechanisms was introduced for clinical use (with accompanying veterinary-specific interpretive criteria) to which the isolate was susceptible. Although the primary purpose of extending standardized definitions for MDR, XDR and PDR to certain veterinary pathogens is to assist the veterinary clinician with treatment options, these definitions will also be of value for researchers and surveillance programmes. As the need for harmonization among surveillance and other susceptibility testing programmes is recognized and achieved, comparison of MDR rates among veterinary pathogens in various geographical locations becomes possible.13 Furthermore, these definitions allow for distinction of drug resistance at the more clinically significant levels of XDR and PDR, rather than just reporting a pathogen generally as ‘MDR’, which is currently widely used in veterinary publications and reports. Transparency declarations M. T. S. and J. L. W. are employees of Zoetis (formerly Pfizer Animal Health) and have ownership of company stock. B. V. L. has received speaking/consulting fees from Merck Animal Health and Merial. S. S.: none to declare. References 1 Lubbers BV , Hanzlicek GA. Antimicrobial multidrug resistance and coresistance patterns of Mannheimia haemolytica isolated from bovine respiratory disease cases—a three-year (2009-2011) retrospective analysis . J Vet Diagn Invest 2013 ; 25 : 413 – 7 . Google Scholar CrossRef Search ADS PubMed 2 Portis E , Lindeman C , Johansen L et al. A ten year (2000-2009) study of antibacterial susceptibility of bacteria that cause bovine respiratory disease complex—Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni—in the United States and Canada . J Vet Diagn Invest 2012 ; 24 : 932 – 44 . Google Scholar CrossRef Search ADS PubMed 3 Michael GB , Kadlec K , Sweeney MT et al. ICEPmu1, an integrative conjugative element (ICE) of Pasteurella multocida: analysis of the regions that comprise 12 antimicrobial resistance genes . J Antimicrob Chemother 2012 ; 67 : 84 – 90 . Google Scholar CrossRef Search ADS PubMed 4 Schwarz S , Silley P , Simjee S et al. Editorial: assessing the antimicrobial susceptibility of bacteria obtained from animals . J Antimicrob Chemother 2010 ; 65 : 601 – 4 . Google Scholar CrossRef Search ADS PubMed 5 Klima CL , Zaheer R , Cook SR et al. Pathogens of bovine respiratory disease in North American feedlots conferring multidrug resistance via integrative conjugative elements . J Clin Microbiol 2014 ; 52 : 438 – 48 . Google Scholar CrossRef Search ADS PubMed 6 Marques C , Gama LT , Belas A et al. European multicenter study on antimicrobial resistance in bacteria isolated from companion animal urinary tract infections . BMC Vet Res 2016 ; 12 : 213 . Google Scholar CrossRef Search ADS PubMed 7 Walther B , Tedin K , Lübke-Becker A. Multidrug-resistant opportunistic pathogens challenging veterinary infection control . Vet Microbiol 2017 ; 200 : 71 – 8 . Google Scholar CrossRef Search ADS PubMed 8 Perreten V , Kadlec K , Schwarz S et al. Clonal spread of methicillin-resistant Staphylococcus pseudintermedius in Europe and North America: an international multicentre study . J Antimicrob Chemother 2010 ; 65 : 1145 – 54 . Google Scholar CrossRef Search ADS PubMed 9 Magiorakos AP , Srinivasan A , Carey RB et al. Multidrug-resistant, extensively drug-resistant, and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance . Clin Microbiol Infect 2012 ; 18 : 268 – 81 . Google Scholar CrossRef Search ADS PubMed 10 Clinical and Laboratory Standards Institute . Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals: Third Informational Supplement VET01S . CLSI , Wayne, PA, USA , 2015 . 11 Bywater R , Silley P , Simjee S. Antimicrobial breakpoints—definitions and conflicting requirements . Vet Microbiol 2006 ; 118 : 158 – 9 . Google Scholar CrossRef Search ADS PubMed 12 Clinical and Laboratory Standards Institute . Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals—Fourth Edition: VET01-A4 . CLSI , Wayne, PA, USA , 2013 . 13 Clinical and Laboratory Standards Institute . Generation, Presentation, and Application of Antimicrobial Susceptibility Test Data for Bacteria of Animal Origin: Report VET05-R . CLSI , Wayne, PA, USA , 2011 . 14 Michael GB , Freitag C , Wendlandt S et al. Emerging issues in antimicrobial resistance of bacteria from food-producing animals . Future Microbiol 2015 ; 10 : 427 – 43 . Google Scholar CrossRef Search ADS PubMed 15 Guardabassi L , Prescott JF. Antimicrobial stewardship in small animal veterinary practice: from theory to practice . Vet Clin North Am Small Anim Pract 2015 ; 45 : 361 – 76 . Google Scholar CrossRef Search ADS PubMed 16 DeDonder K , Harhay DM , Apley MD et al. Observations on macrolide resistance and susceptibility testing performance in field isolates collected from clinical bovine respiratory disease . Vet Microbiol 2016 ; 192 : 186 – 93 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Feb 22, 2018

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