Antimicrobial usage and resistance in beef production

Andrew Cameron; Tim McAllister

doi:10.1186/s40104-016-0127-3

Antimicrobial usage and resistance in beef production

Cameron, Andrew; McAllister, Tim 2016-12-12 00:00:00 Antimicrobials are critical to contemporary high-intensity beef production. Many different antimicrobials are approved for beef cattle, and are used judiciously for animal welfare, and controversially, to promote growth and feed efficiency. Antimicrobial administration provides a powerful selective pressure that acts on the microbial community, selecting for resistance gene determinants and antimicrobial-resistant bacteria resident in the bovine flora. The bovine microbiota includes many harmless bacteria, but also opportunistic pathogens that may acquire and propagate resistance genes within the microbial community via horizontal gene transfer. Antimicrobial-resistant bovine pathogens can also complicate the prevention and treatment of infectious diseases in beef feedlots, threatening the efficiency of the beef production system. Likewise, the transmission of antimicrobial resistance genes to bovine-associated human pathogens is a potential public health concern. This review outlines current antimicrobial use practices pertaining to beef production, and explores the frequency of antimicrobial resistance in major bovine pathogens. The effect of antimicrobials on the composition of the bovine microbiota is examined, as are the effects on the beef production resistome. Antimicrobial resistance is further explored within the context of the wider beef production continuum, with emphasis on antimicrobial resistance genes in the food chain, and risk to the human population. Keywords: Antibiotics, Antimicrobial resistance, Antimicrobial usage, Beef production, Bovine pathogens, Bovine microbiota, Cattle, Enteropathogens, Fecal bacteria, Resistome Background particular attention, antimicrobials are also widely used The emergence of antimicrobial resistance in bacterial in companion animals and in plant agriculture (e.g. pathogens is a serious global issue. Antimicrobial use in oxytetracycline and streptomycin), for feed crops, and livestock, aquaculture, pets, crops, and humans selects for tomatoes, citrus, and many other fruits [4]. Here, the for antimicrobial-resistant (AMR) bacteria that reside in focus is on large-scale beef production, where antimicro- agricultural and clinical biomes. Besides pathogens, bials are routinely used to support animal welfare, and AMR bacteria include many harmless and beneficial controversially, to promote growth and production microbes acting as a genetic reservoir of AMR gene efficiency. In this review, the usage of antimicrobials in determinants (‘the resistome’ [1, 2]), which can be cattle will be summarized along with recent studies on transferred via mechanisms of horizontal gene transfer AMR explored within the context of the beef production (HGT) (reviewed in [3]) throughout the microbial system. community. With alarming frequency, untreatable human and animal pathogens with multiple AMR deter- Beef production minants arise. AMR in pathogens is commonly accepted Worldwide, beef production is the third largest meat as a result of widespread use and abuse of antimicrobials industry (~65 million t globally), behind swine and poultry in agriculture and medicine. Although the use of anti- [5]. In 2015, the major beef producing countries included microbials in livestock and aquaculture has attracted the United States (US) (11.4 million t), Brazil (9.6 million t), the 28 member countries of the European Union (EU) (7.5 * Correspondence: tim.mcallister@agr.gc.ca 2 million t), China (6.7 million t), and India (4.5 million t) Agriculture and Agri-Food Canada, Lethbridge, AB, Canada Full list of author information is available at the end of the article (Fig. 1a) [6] with the global beef cattle population © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 2 of 22 Fig. 1 Major beef-producing countries and antimicrobial consumption. a Beef and veal production in select countries (t). Data from: ‘Livestock and Poultry: World Markets and Trade’. USDA. Foreign Agricultural Service [6]. b Antimicrobial sales, excluding ionophore sales, in reporting countries (t active substance). Data complied from multiple sources: [19–23] c Sales of antimicrobials authorised only for food‐producing animals, by species (t active substance) [22, 23]. d Weighted animal population (in PCU) [20, 21, 23]. e Proportion of sales of total antibiotic products by antimicrobial class (t active ingredient) [19–23] exceeding 1 billion [6]. Beef production is complex and Infections spread rapidly in high-density feedlots, and involves multiple stages, wherein calves are birthed, despite herd management procedures, both endemic and raised and fed for slaughter, and processed for meat. exotic diseases can be introduced by importation of The raising of cattle in high-throughput production diseased animals into the beef production system. typically involves the movement of animals from (I) Globally, 4.7 million cattle are exported to beef produ- cow-calf systems (a permanent herd used to produce cing countries, with the top exporters being Mexico, young beef cattle), to (II) backgrounding (post-weaning Australia, and Canada, exporting >1.3, >1.2, and >1.0 intermediate feeding, typically forage-based diets), and million cattle, respectively. These cattle are sent primar- (III) feedlot/finishing operations (concentrated animal ily to the US, which received >2.2 million cattle in 2015 feeding, typically with high-energy grain-based diets). [6]. The risk of disease transmission creates significant After finishing, animals are transported to a slaughter- economic pressure for antimicrobial usage to prevent in- house and processed. Antimicrobials may be given to live fectious bovine diseases. cattle at any production stage for therapeutic and non- therapeutic purposes. Therapeutic and non-therapeutic use of antimicrobials Antimicrobial use in cattle is unavoidable for the treat- Antimicrobial usage in beef production ment of infections for which vaccines, bacterins, or alter- Rationale for antimicrobial use nate therapies are not available. A prevalent, controversial Antimicrobials are used in beef cattle for the therapeutic practice involves antimicrobials used in non-therapeutic treatment of infections caused by bacteria or other applications. Judicious antimicrobial use typically requires microbes. Cattle can be afflicted by a variety of endemic that diseased cattle are treated individually to maximize infectious diseases, which may exist ubiquitously in therapeutic efficacy and reduce the spread of AMR, but the ranching environment [7]. Endemic pathogens often entire herds are often dosed with in-feed antimicrobials. go unnoticed, but compromise animal health—affecting This is the typical administration route for practices such herd growth performance and farm profitability. as (I) prophylaxis, (II) metaphylaxis, and (III) growth Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 3 of 22 promotion. These practices are described by inconsistent could compromise future efficacy, especially in the and often agenda-driven terminology. For example, case of AMR genes that are genetically linked in prophylaxis and metaphylaxis are considered therapeutic clusters, as is often the case in multi-drug resistant uses by the American Veterinary Medical Association and (MDR) organisms. the US Food and Drug Administration (FDA) [8, 9], but others consider such practices ‘sub-therapeutic’, ‘non- Global veterinary antimicrobial usage therapeutic’,or ‘production usage’. More recently, the Antimicrobial usage data is scarce: most countries do FDA uses ‘production purposes’ to refer to antimicrobial not survey or collect usage data, and cattle producers usage with the intent of growth and feed efficiency en- and pharmaceutical companies have little incentive to hancement [10]. Prophylaxis is action taken to prevent report such information. Where usage data exists, typic- disease and involves the administration of antimicrobials ally in high-income countries, it takes the form of vol- to an individual that is perceived to be at risk of develop- ume sales data rather than actual usage. The caveat of ing disease. Metaphylaxis refers to the treatment of a antimicrobial sales and distribution data is that it does larger cohort or entire herd to provide: (I) therapy to not accurately indicate how or if antimicrobials were infected animals, and (II) prophylaxis to uninfected or used. In a global analysis of antimicrobial usage, Van potentially susceptible animals. Metaphylaxis is often Boeckel et al. [18] estimated the worldwide consumption applied to herds receiving new animals. Growth promo- of antimicrobials in food animal production at ≥57,000 t tion refers to the use of antimicrobial growth promoters (1 t = 1,000 kg) and projected a 67% increase in total (AGPs) for extended duration to improve feed efficiency usage by 2030 to ≥95,000 t. Total food-animal anti- (the ratio of feed consumed vs. animal weight gain). microbial sales in the US was reported to be approxi- ‘Sub-therapeutic’ typically refers to low-dose concentrations mately 9,475 t (2014) [19], 8,122 t in the EU (2013) [20], of antimicrobials in feeds over an extended duration. The 1,127 t in Canada (2012) [21], 644 t in Australia (2010) FDA Centre for Veterinary Medicine defines sub-therapeutic [22], and 429 t in the United Kingdom (UK) (2014) [23] as amounts <200 g per ton (US) of feed for 12 wk [11]. (Fig. 1b; excludes ionophores sales). Based on these sales data, and estimations of food animal populations, Van Complexity of production usage of antimicrobials Boeckel et al. projected that the top countries consum- Although prophylaxis/metaphylaxis may be a more ing antimicrobials in livestock production are China, the judicious use of antimicrobials than growth promotion, US, India, Brazil and Germany, with China accounting growth promotion is often a benefit of either treatment. for 23% of global consumption [18]. For example, antimicrobial treatment and prevention of Data for antimicrobial usage by animal type is not cattle liver abscesses simultaneously provides prophylac- routinely available, such that the proportion and type of tic/metaphylactic therapy and growth promotion. Liver antimicrobials sold exclusively for use in cattle is largely abscesses occur frequently in cattle, and are common in unknown or estimated. Some information can be feedlots, where high-energy grain-based diets can cause gleaned from country data where specific antimicrobial acidosis, leading to ruminal lesions that predispose cattle formulations with indicated routes of administration to hepatic disease caused by invasive bacteria [12]. Cattle (e.g. in-feed, injection etc.) are provided for specific live- with liver abscesses have reduced production efficiency stock (Fig. 1c). However, this data is largely unreliable (reduced feed intake and weight gain) [12]. Thus, feedlot because (I) most antimicrobials are approved for use in cattle receiving antimicrobials for liver abscess control multiple food-animal species, (II) off-label non-intended can also indirectly exhibit growth promotion as a result usage of antimicrobials is a common practice worldwide, of disease prevention. Some antimicrobials are approved and (III) the antimicrobial may not have actually been for both growth promotion and therapeutic applications administered to the animal. Data on therapeutic vs. non- [13, 14]. Some countries, particularly in the EU, have therapeutic use is not collected, and difficult to estimate. banned the use of AGPs in beef and other meat produc- Without reliable antimicrobial usage data to link to tion industries (the EU ban was implemented in 2006 AMR, it is challenging to create scientific policies to [15]). In 2012, the US introduced a voluntary ‘ban’ on optimize veterinary antimicrobials. Thus, judicious use AGPs, and a similar program is expected in Canada [16]. policies in some countries are the subject of debate, with While such policies are laudable, their effectiveness is critics decrying heavy-handed bans and regulations, and questionable. For example, the volume of agricultural proponents criticizing ineffective and optional compli- antimicrobials used within the EU has not decreased, ance schemes. and the EU ban may also have resulted in compensatory One method to improve antimicrobial usage estimate increases in the usage of antimicrobials with even greater by species is to take into account (I) the size of the animal relevance to human health [17]. Regardless, bacterial population (demographics), and (II) the average theoret- resistance acquired in response to any antimicrobial usage ical weight of the animal species at time of treatment Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 4 of 22 (physiology). This is the population correction unit (PCU), and another class of AGPs called flavophospholipols, most and is used in the UK Veterinary Medicines Directorate veterinary antimicrobials are identical or structurally simi- UK-VARSS report [23], the EU European Medicines lar to antimicrobials used in human medicine. Stringent Agency ESVAC report [20], and the Public Health Agency EU policies regulate the use of in-feed antimicrobials, and of Canada’s CIPARS report [21]. Briefly, 1 PCU = 1 kg of penicillins sales are proportionally high-from a low of livestock, such that the amount of antimicrobials sold can 11.9% in France to as high as 61.3% in Sweden of all vet- be normalized by species weight, allowing for a compara- erinary antimicrobials sold [20]. Sweden was the first tive indication of overall usage between species (Fig. 1d). country to ban AGPs in 1986 [17], a policy that likely con- Van Boeckel et al. used PCU values to estimate global tributed to high therapeutic use of penicillins. Resistance consumption of antimicrobials per kg of animal produced to an agricultural antimicrobial may confer resistance to at 45 mg/PCU (= mg/kg) for cattle, 148 mg/PCU for the human drug, many of which are considered to be es- chickens, and 172 mg/PCU for pigs [18]. This trend is sential medicines by the World Health Organization consistent with UK-VARSS data, in which cattle (WHO) [27]. Significant veterinary antimicrobials gener- consumed 8 mg / PCU of antimicrobials compared to ally include tetracyclines, penicillin (penam) and other β- 172 mg / PCU for swine and poultry [24]. This ap- lactams, macrolides, sulfonamides, and aminoglycosides proach gives an appreciation for the overall use of (Fig. 1e). Other antimicrobials represent a miniscule antimicrobials within a livestock species, but does not fraction of veterinary antimicrobials sold and distributed indicate usage within the various segments of the pro- (each <2%), but they are not unimportant. Thus, cephalo- duction system. These are limitations of using antimicro- sporins, lincosamides, phenicols, and fluoroquinolones bial sales and distribution data as a proxy for actual (among others) include some of the most effective anti- usage data [23]. microbials in veterinary and clinical medicine. In some countries, the majority of antimicrobials man- ufactured or sold are used in food animals rather than in Antimicrobial resistance in bovine pathogens human medicine (e.g. US: ~10,670 t active ingredient for Much focus on AMR in food animals concerns the haz- food animals (2014) vs. ~3,290 t for humans (2012) [19, ards for human health, but AMR is also a veterinary 25]; EU: ~7,982 t active ingredient for food animals vs. problem. Knowledge about resistance in exclusively ~3,399 t (2012) [26] (food animal values exclude iono- bovine pathogens is also exceptionally poor compared to phores and other non-medically important antimicro- that of bovine zoonotic enteric pathogens, such as bials)). However, direct human-animal antimicrobial use Campylobacter, Salmonella, E. coli and Enterococcus spp. comparisons are limited by differences in estimation and These species are typically used as ‘indicators’ of AMR measurement methodology (e.g. antimicrobials sold vs. in production animals as they (I) are of importance in prescribed), differences in animal physiology and anti- human disease, (II) are relatively easy to culture, (III) microbial use practices, and are further complicated by can be isolated from healthy animals, and (IV) have the inclusion/exclusion of antimicrobials irrelevant to established AMR minimum inhibitory concentration human medicine (e.g. ionophores). Thus, food animal vs. (MIC) breakpoints (for human infections). To reiterate, human antimicrobial consumption comparisons must be for several of the bacterial species discussed below, the interpreted with caution. Since food animals outnum- designation of “resistant” or “sensitive” is often author- ber/outweigh the human population, volume usage is determined because clear criteria have not been estab- less surprising than the concurrent use of antimicrobials lished by relevant standardization bodies, such as the essential for human medicine. The FDA reports that Clinical Laboratory Standards Institute (CLSI), and the medically important antimicrobials accounted for 62% of European Committee on Antimicrobial Susceptibility sales of all antimicrobials approved for use in food- Testing (EUCAST). Surveillance programs monitoring producing animals [19], with 74% of clinically relevant AMR in beef production are typically constrained to antimicrobials administered in-feed [19]. Of the 38% of human enteropathogens and sentinel AMR indicator antimicrobials sold that were not medically important, species, but independent research from many countries 80% were ionophores (e.g. monensin). Ionophores are not gives rough estimates of AMR in cattle pathogens. Several used in human medicine, have no human counterpart, and recent studies have found strong correlations between the do not appear to promote AMR. However, ionophores are level of use of specific antimicrobials and the level of important for animal welfare, and are administered for resistance observed [28, 29]. production and therapeutic indications for the treatment/ Scientific literature pertaining to AMR in pathogens of prevention of coccidiosis, a disease associated with significance to beef production was reviewed, and the Eimeria spp. infestations [24]. In the EU, ionophores are median percent resistance of 16 different pathogens to defined as anticoccidials/coccidiostats, and are not re- antimicrobials was collected from 58 scientific reports ported as antimicrobials [20, 23]. Besides the ionophores ([30–88]; 2000-present), shown in Fig. 2 (see Methods Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 5 of 22 Fig. 2 Most frequently reported antimicrobial resistance in pathogens from diseased bovines. Diameter of circle indicates the percent resistance of phenotypic resistance to antimicrobials, by class. The percent resistance was determined via the median of percent values obtained from journal articles (references [30–88]) that reported the percentage of resistance among isolates collected from diseased animals or from passive a,b c,d,e surveillance (as indicated). Notes: includes resistance data from healthy animals; includes data from healthy animals, sub-clinical, and clinical mastitis; includes isolates from feces. Data compiled from multiple sources for details). Reports were selected if they contained an Antimicrobial resistance in bovine respiratory pathogens antibiogram of isolates without prior antimicrobial selec- Bovine Respiratory Disease (BRD) is the most frequent tion, and in most cases, if the isolates were obtained from and economically important of the primary cattle diseases diseased animals. In general, differing levels of tetracycline [89]. Approximately 15% of cattle in North America are resistance were present in most cattle-associated bacteria. treated for BRD, which accounts for ~70% of cattle mor- Macrolide resistance was often reported in BRD patho- bidity, and ~40% of all mortality in feedlots [90]. BRD gens, and in liver abscess pathogens. For almost every spe- control is thus a major target of antimicrobial usage [90, cies there was a report of resistance to at least one 91], and possibly an important source of AMR pathogens. antimicrobial from each major antimicrobial class. A cav- BRD involves a complex of etiological agents including eat of many of the studies selected is that MIC resistance/ Mannheimia haemolytica, the predominant agent [92], sensitivity breakpoint criteria have not been defined for Pasteurella multocida,and Histophilus somni [92, 93]. H. many cattle pathogens, as well as some antimicrobials somni occurs sporadically, and can cause fatal septicemia (e.g. streptomycin). Complicating a general view of resist- in cattle. Mycoplasma bovis is also frequently associated ance across multiple species are the following caveats: (I) with BRD [94]. These ubiquitous pathogens are often de- some studies do not test the same antimicrobials as scribed as commensals because colonization is asymptom- others, (II) for some species, reports are very scarce, (III) atic in most healthy animals. As opportunistic pathogens, some studies test relatively few isolates for resistance, (IV) respiratory disease may develop with detrimental changes in some cases, designation of resistance is defined by the to the immune status of the host animal as a result of author and not via standardized interpretive criteria, and stress (e.g. transportation, weaning) or viral infections (e.g. (V) the median value of percent of resistance is biased Bovine Herpes Virus-1, Bovine Respiratory Syncytial towards values for which there are fewer comparative data Virus) [89]. Typing of M. haemolytica isolates obtained points. Thus, the data presented in Fig. 2 should be viewed from fatal pneumonia cases in calves show substantial with caution. diversity [95], suggesting that outbreaks of BRD are not due Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 6 of 22 to the herd-wide transmission of a single virulent strain, in M. haemolytica to 6 antimicrobial classes including but originate from formerly commensal strains [95, 96]. In ceftiofur, danofloxacin and enrofloxacin, florfenicol, oxy- North America and many countries, macrolides are often tetracycline, spectinomycin, tilmicosin and tulathromy- given as BRD metaphylaxis to asymptomatic animals in the cin. They found that in 2009, ~5% of isolates were presence of diseased animals. Individual cattle symptomatic resistant to 5 or more antimicrobials as compared to for BRD may also be treated with a wide range of antimi- ~35% in 2011 [102]. M. haemolytica isolates resistant to crobials, with the fluoroquinolone marbofloxacin used in oxytetracycline were 3.5-fold more likely to be resistant this manner [97]. Clinical symptoms may only become ap- to 1 or more antimicrobials, compared to non- parent after pulmonary damage has occurred. Conse- oxytetracycline-resistant isolates [102]. MDR has been quently, metaphylactic control of BRD often improves the detected in P. multocida and H. somni. Klima et al. [92] welfare of cattle as well as financial returns through cost isolated M. haemolytica, P. multocida and H. somni savings achieved by reduction in morbidity and mortality from BRD mortalities, and determined that 72% of M. [98]. haemolytica and 50% of P. multocida isolates exhibited In calves experimentally infected with M. haemolytica AMR. Surprisingly, 30% of M. haemolytica and 12.5% (4 × 10 CFU), Lhermie et al. [97] demonstrated that of P. multocida were resistant to >7 antimicrobial clas- low-dose (2 mg/kg) marbofloxacin 12 h after inoculation ses, including aminoglycosides, penicillins, fluoroquino- eliminated this pathogen from all calves, but at 45 h lones, lincosamides, macrolides, pleuromutilins, and post-inoculation a high-dose (10 mg/kg) failed to do so. tetracyclines [92]. The MDR isolates originated from Since M. haemolytica persisted after this high-dose, a feedlots in Texas or Nebraska. MDR was found in mul- higher risk for AMR development may have been cre- tiple M. haemolytica populations, suggesting that a ated by a practice thought to be more judicious than clonal population was not responsible for this observa- mass medication [97]. Thus, although metaphylactic tion [92]. MDR was due to a tandem array of AMR approaches may expose more bacteria to antimicrobial genes concentrated within an Integrative and Conjugable selection, they may also reduce pathology, and eliminate Element (ICE), a mobile genetic element (MGE) [92]. pathogens more effectively than single-dose therapeutic These elements constitute a diverse group of MGEs approaches. In another study, continuous sub-therapeutic found in both Gram-positive and -negative bacteria, and administration of the macrolide tylosin (Tylan, Elanco; are notable for encoding the conjugation machinery re- 11 mg/kg in-feed) had no effect in reducing carriage of M. quired for mobilisation of ICE to other bacteria, where haemolytica in beef cattle, compared to substantial reduc- they often integrate into multi-copy genes such as tions after therapy with a single subcutaneous injection of tRNAs and rRNAs. ICEs also frequently encode virulence tilmicosin (Micotil, Elanco; 10 mg/kg) or tulathromycin factors, heavy metal transporters, and toxin-antitoxin sys- (Draxxin, Pfizer; 2.5 mg/kg) [99]. Antimicrobial usage in tems, thought to ensure the stability of chromosomally- single animals has been shown to increase the risk of iso- inserted ICE within cells. lating both susceptible and MDR M. haemolytica from A putative ICE, designated ICEMh1, was recently de- pen mates, highlighting the importance of bacterial trans- tected in M. haemolytica strain 42548 by Eidam et al. mission in the dissemination of AMR [100]. Furthermore, that carried resistance to aminoglycosides (aphA-1, strA, Klima et al. [101] found that MDR occurred more fre- strB genes), tetracyclines (tet(H) gene), and sulfonamides quently in diseased than healthy cattle (37% vs. 2%) in M. (sul2 gene) [103, 104]. ICEMh1 has a size of 92,345 bp, haemolytica collected from healthy cattle vs. cattle with harbors ~107 genes, and shares a high degree of similar- clinical BRD. In that study, tetracycline resistance ity with ICEPmu1, an ~82 kb element identified in P. (18%) was the most prevalent resistance phenotype [101]. multocida that encodes ~88 genes [104]. The structure Resistant M. haemolytica and P. multocida can also be re- of ICEPmu1 is depicted in Fig. 3a. ICEPmu1 integrates Leu covered from diseased antimicrobial non-treated cattle. into a chromosomal copy of tRNA [105]. Eleven re- Via the pan-European VetPath susceptibility monitoring sistance genes are encoded within two gene clusters, program, de Jong et al. [45] analyzed isolates collected conferring resistance to tetracyclines (tetR-tet(H) genes), between 2002 and 2006 from diseased cattle with no streptomycin (strA and strB), streptomycin/spectino- antimicrobial exposure for at least 15 d prior to sampling, mycin (aadA25), gentamicin (aadB), kanamycin/neomy- and found that 14.6% of M. haemolytica (231 total iso- cin (aphA1), phenicols (floR), sulfonamides (sul2), lates) were resistant to tetracycline, and 5.7, 3.5 and 0.4% macrolides/lincosamides (erm(42) gene) or tilmicosin/ of P. multocida (138 total isolates) were resistant to tetra- tulathromycin (msr(E)-mph(E) genes) [92, 105]. cycline, spectinomycin, and florfenicol, respectively [45]. ICEPmu1 was shown to conjugatively transfer in vivo MDR has also been reported in BRD agents. Lubbers into recipient P. multocida, M. haemolytica and E. coli −4 −5 −6 et al. [102] evaluated records from 2009 to 2011 from at frequencies of 1.4 × 10 , 1.0 × 10 and 2.9 × 10 re- the Kansas State Diagnostic Laboratory for co-resistance spectively [105]. E. coli transconjugants demonstrated up Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 7 of 22 Fig. 3 Antimicrobial resistance determinants in mobile genetic elements. a Organization of the Integrative and Conjugative Element (ICE) ICEPmu1 found in the BRD agent Pasteurella multocida [179]. Resistance gene clusters 1 and 2 are shown expanded in grey. b Circular distribution of antimicrobial resistance genes by class, and abundance in total annotated antimicrobial genes found six plasmid metagenomes from the influent and sludge from two wastewater treatment plants (modified and reproduced with permission from [192]) to 64-fold higher MIC values for florfenicol, suggesting (pCCK381; 10.8 kb) and Dichelobacter nodosus (pDN1; better functional activity of FloR in E. coli [105]. A β- 5.1 kb). Collectively, these findings reveal the importance lactam oxacillinase (bla ) was also present, and con- and diversity of AMR and HGT mechanisms in BRD OXA-2 ferred greater ampicillin resistance in E. coli harboring pathogens. ICEPmu1 [105]. As many of the ICEPmu1 resistance genes may not be indigenous to Pasteurellaceae, acquisi- Antimicrobial resistance in liver abscess pathogens tion of AMR determinants from Enterobacteriaceae is Liver abscesses in beef cattle result from aggressive likely [105]. ICEPmu1 and ICEMh1 were isolated from grain-feeding, and represent an economic liability. Liver feedlot BRD cases in Nebraska in 2005 and Pennsylvania abscess incidence in North American feedlot cattle in 2007, respectively [104, 105]. There is currently little ranges from 12 to 32% [12]. Fusobacterium necro- information on the prevalence of these or similar ICE el- phorum, an anaerobic rumen bacterium, is the major ements in herds, but the presence of AMR-ICEs in BRD etiological agent isolated from condemned livers, agents represents a critical risk for the efficacy of future followed closely by Trueperella pyogenes [12]. Hepatic antimicrobial therapy. Simultaneous and rapid acquisi- disease is detected after slaughter since cattle with ab- tion of multiple resistance genes via a single HGT event scesses are usually asymptomatic. Liver perforation that could severely limit therapeutic options. leads to systemic infection is rare. In-feed antimicrobials, Besides HGT via MGEs, AMR determinants arise such as the FDA-approved tylosin, chlortetracycline, spontaneously via mutation. In some isolates of M. hae- oxytetracycline, bacitracin, and the streptogramin, virgi- molytica and P. multocida, high-level (MIC ≥ 64 mg/L) niamycin, are approved for liver abscess prevention in macrolide resistance has been attributed to mutations in many countries. In a study of ~7,000 feedlot cattle, tylo- the multicopy 23S rRNA genes (e.g. M. haemolytica sin reduced the incidence of liver abscesses by up to A2058G; P. multocida A2059G) [106]. Resistance to 70%, and increased weight gain by 2.3% [12, 109]. Al- macrolides, lincosamides and other ribosome-targeting though a common rumen inhabitant, F. necrophorum is antibiotics has been shown to be conferred by mono- an opportunistic pathogen also associated with calf diph- methylation of the M. haemolytica and P. multocida 23S theria and foot rot [110]. In a 2-year comparison of flora rRNAs at position A2058 [107]. Methylation is catalyzed isolated from liver abscesses in cattle fed with or without by a novel monomethyltransferase, designated erm(42), tylosin, Nagaraja et al. [111] found that the incidence of which appears to have been disseminated among the T. pyogenes in mixed culture with F. necrophorum was Pasterellaceae [107]. Plasmid borne transfer of AMR higher in abscesses from tylosin-fed cattle (53% vs. 10% genes may also be significant among BRD bacteria. In in the non-tylosin fed cattle). In contrast, the incidence the first report of a floR florfenicol resistance gene in M. of F. necrophorum was higher in cattle that were not fed haemolytica, Katsuda et al. [108] identified pMH1405, a tylosin (61%), as compared to those that were (33%). 7.7 kb florfenicol resistance plasmid, which appears to No differences in tylosin susceptibility between isolates be remarkably similar to plasmids from P. multocida from antimicrobial-free or tylosin-exposed cattle were Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 8 of 22 identified [111]. AMR in Fusobacterium spp. isolated economy-damaging, or largely untreatable pathogens. from humans is also relatively rare [112, 113], suggesting For cattle, notifiable diseases include (I) abortive agents: that AMR in this genera is yet to present a major risk to Brucella abortus (Brucellosis), Coxiella burnetti (Q beef production or human medicine. AMR in bovine T. fever), and Leptospira spp. (Leptospirosus); (II) bovine pyogenes is of greater concern, due to the versatility of pneumonia agents: Mycoplasma mycoides subsp. the bacterium as a cause of liver, skin, joint, and visceral mycoides small colony type (Contagious bovine pleuro- abscesses, and roles in mastitis and abortion [114]. Tylosin pneumonia), and Mycobacterium bovis (Bovine tubercu- resistance has been documented and linked to the pres- losis); and (III) enteritis agents: Mycobacterium avium ence of erm(X) or an erm(B) gene similar to that found on subsp. paratuberculosis (Johne’s disease), and Bacillus the Enterococcus faecalis MDR plasmid pRE25 [115, 116]. anthracis (Anthrax) [123]. Although it might be as- This suggests AMR transfer occurs between these human sumed that AMR would be a major issue in these patho- and cattle pathogens. Jost et al. [116] examined 48 T. pyo- gens, for the most part AMR has not been studied in genes isolates, of which 27 were derived from cattle, and these pathogens or is rare. Besides the rarity of cases, identified erm(X) as the most prevalent tylosin resistance other reasons for this include: (I) the notifiable pathogen determinant. An erm(X) tylosin and tetracycline tet(33) re- is already intrinsically resistant to many antimicrobials sistance plasmid, pAP2, was also identified [116]. Other (e.g. Mycobacterium spp.); (II) the pathogen resides in an studies have found high prevalence of tetracycline and sul- antimicrobial-exclusive intracellular niche that renders fonamide resistance, and suggest that AMR in T. pyogenes antimicrobial therapy impractical (e.g. Brucella abortus may of greater significance in bovine mastitis as compared and Coxiella burnetti); or (III) a secreted toxin causes to liver abscesses [117, 118]. pathology (e.g. Bacillus anthracis). Control of outbreaks of these diseases rarely involves antimicrobial therapy Antimicrobial resistance in keratoconjunctivitis pathogens and relies on animal segregation, herd control, or de- Infectious bovine keratoconjunctivitis is a painful ocular population [13]. disease caused primarily by non-self-limiting infections AMR susceptibility tests of human clinical isolates of with Moraxella bovis and bovoculi. The disease is com- Mycobacterium bovis have been performed because of mon worldwide in cattle, transmitted by flies, and if un- the role of M. bovis in human tuberculosis (TB). Al- treated, may result in ulceration and cornea rupture. In though it can infect many species, the main reservoir of the US, only oxytetracycline and tulathromyin are ap- M. bovis is cattle, and transmission to humans is primar- proved for the treatment of bovine keratoconjunctivitis, ily via contact with infected animals and drinking although penicillin may be used in other countries. In a unpasteurized milk [124]. In clinical isolates of M. tuber- study of 32 Moraxella spp. isolated from cattle and culosis and M. bovis collected over 15 yr, Bobadilla-del sheep, Maboni et al. [119] found that 40% of isolates Valle et al. [125] found that 16.6% of isolates from human were penicillin-resistant and 20% were tetracycline- TB cases were M. bovis. Susceptibility testing to first-line resistant, but most were susceptible to other antimicro- anti-TB drugs revealed that 10.9% of M. bovis were bials. Dickey et al. [120] published the genome sequence streptomycin-resistant, and 7.6% were MDR (isoniazid- for an AMR isolate of Moraxella bovoculi, Mb58069. It and rifampin-resistant). The aminoglycoside streptomycin was found to be resistant to florfenicol, oxytetracycline, is approved for use in cattle against aerobic Gram- sulfonamides, and displayed intermediate resistance to negatives such as enteritis-causing E. coli and Salmonella macrolides. Ten AMR determinants were co-located on spp. [14]. Bovine-human transmission of AMR M. bovis a >27 kb genomic island [120]. The biofilm-forming cap- appears to be rare in developed countries, but may occur abilities of Moraxella bovis may also enhance antimicro- more frequently in developing countries [124, 126]. bial resistance. Prieto et al. [121] found that Moraxella bovis readily forms biofilms, increasing resistance to Antmicrobial resistance in zoonotic human ampicillin, chloramphenicol, gentamicin, and oxtetracy- enteropathogens cline by 256-, 1,024-, 512-, and 1,024-fold as compared Antimicrobial resistance in bovine-origin Escherichia coli to when this bacterium grows planktonically [122] Thus, Cattle are E. coli reservoirs, with most strains harmless antimicrobial susceptibility via standard disk diffusion commensals. Some E. coli, particularly invasive and and microtiter MIC determinations failed to reflect the enterohemorrhagic E. coli (EHEC) cause septicemia in true level of resistance of this isolate. neonatal calves, but are primarily pathogenic to humans. E. coli strains from bovines and other food production Antimicrobial resistance in notifiable/reportable bovine animals serve as indicators of AMR prevalence in bacterial pathogens Gram-negative bacterial populations, thus sentinel ‘generic’ Many countries maintain registries of notifiable diseases E. coli help establish and track the persistence of AMR associated with zoonotic, unvaccinable, highly infectious, genes in environments affected by beef production and Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 9 of 22 other human activities. For example, in a recent survey of product. All cephalosporin-resistant E. coli isolated were AMR in E. coli from Nebraska cattle feedlot runoff catch- resistant to ampicillin, ceftiofur, and ceftriaxone, and ment ponds and the effluent of municipal wastewater 64% of isolates harbored bla , conferring additional CMY treatment plants, Agga et al. [127] found that the diversity resistance to clavulanate/amoxicillin and cefoxitin [135]. of AMR genes in human-associated samples was greater These reports suggest that hygienic practices in beef than from environments impacted by cattle. Interestingly, processing are effective against AMR bacteria. rd E. coli resistant to 3 generation cephalosporins and tri- methoprim/sulfamethoxazole were found at equivalent Antimicrobial resistance in bovine-origin Salmonella high-frequency (>70% of E. coli isolates) in both livestock Non-typhoidal Salmonella spp. (often Salmonella enter- and municipal wastewater environments [127]. ica serotype Typhimurium or Enteritidis) are frequent Extended-spectrum β-lactamases (ESBLs) that inacti- laboratory-confirmed infectious agents of gastroenteritis. vate newer cephalosporins are a major focus of sentinel Although the enteritis is usually self-limiting, invasive S. E. coli susceptibility testing. Cottell et al. [128] evaluated enterica spp. infections often require antimicrobial ther- E. coli originating from 88 steers that were treated with apy. Cattle are infected/colonized by many Salmonella ceftiofur and/or chlortetracycline in an experimental US species, and ground beef is a vehicle of Salmonella trans- feedlot. The ESBL bla , was detected in mission, implicated in 45% of outbreaks linked to beef CTX-M-32 cefoxatime-resistant E. coli in 29 animals, and was found [136]. In cattle, susceptible adults develop enteritis, and to be present on a self-transmissible IncN-family plas- calves may also develop septicemia. S. enterica serotypes mid (reviewed in [129]). In Germany, bla was the Dublin and Newport are associated with bovine salmon- CTX-M-1 predominant ESBL in E. coli, found on 87% of assessed ellosis, and adult cattle may carry and shed Salmonella farms [130]. In a Swiss study of the wider food process- asymptomatically for many years. In humans, serotype ing chain, Geser et al. [131] screened for ESBL in fecal Dublin has the highest proportion of invasive infections samples collected at slaughter as well as in raw milk, resulting in hospitalization and mortality [137]. Due to and minced beef. They found that of 124 bovine fecal the frequency of infections, the development of AMR in samples 13.7% hosted ESBL-producing bacteria, 98% of Salmonella is a risk to human health. In North America, which were E. coli. Despite enrichment for ESBL- MDR Salmonella are on average resistant to 7 antimi- producing organisms, ESBL were not detected in raw crobials [138]. In the US, Salmonella (and other entero- milk or minced beef samples. The ESBLs detected in the pathogens) are collected from humans, animals, and study included bla , bla bla , bla retail meat for the National Antimicrobial Resistance CTX-M-1 TEM-1 CTX-M-14 CTX- , and bla . Many of the ESBL-positive iso- Monitoring System (NARMS) [137]. In 2013, Salmonella M-117 CTX-M-15 lates were frequently co-resistant to tetracycline (76%), was isolated from 7.9% of beef cattle, and in 0.9% of trimethoprim/sulfamethoxazole (76%), nalidixic acid ground beef samples [137]. MDR (>3 antimicrobials) (47%), at least one aminoglycoside (76%), chloram- was found in 20% of all ground beef serotype Dublin phenicol (65%) and ciprofloxacin (41%). The authors isolates, many of which were resistant to ampicillin, suggested that slaughter hygiene prevented the transmis- chloramphenicol, streptomycin, sulfonamides, and tetra- sion of ESBLs into the food chain [131]. Similarly, the cycline [137]. Worse still, the prevalence of ceftriaxone rd prevalence of AMR E. coli O157:H7 was investigated in resistance (3 generation cephalosporin) in bovine- 510 fecal, hide, carcass, and raw meat samples from 4 origin serotype Dublin increased from 0 to 86% between beef slaughterhouses in China. STEC was detected in 1996 and 2013 [137]. As this is a major risk to human 1.4% of fecal and hide sample, but not in pre- and post- health, adoption and adherence to good practices during evisceration carcasses, nor in raw meat samples, with all beef processing and proper cooking are critical to pre- isolates sensitive to 16 relevant antimicrobials [132]. vent transmission [136, 139, 140]. During slaughter, cattle hides are major contributors to carcass contamination [133, 134]. In another study Antimicrobial resistance in bovine-origin Campylobacter rd tracking E. coli resistant to 3 -generation cephalospo- Campylobacter is the most frequent cause of human rins or trimethoprim/sulfamethoxazole, Schmidt et al. bacterial gastroenteritis in the developed world, with [135] determined the prevalence of generic and AMR E. Campylobacter jejuni responsible for >90% of Campylo- coli at various sites along the beef processing continuum. bacter infections [141]. Mostly a self-limiting infection The prevalence of cephalosporin-resistant and trimetho- in humans, severe cases of campylobacteriosis are prim/sulfamethoxazole-resistant E. coli in fecal samples treated with drugs such as erythromycin or ciprofloxa- at processing was 75 and 95%, respectively. Prevalence cin. Campylobacter are frequent colonizers of chickens, in pre-evisceration carcasses was 3 and 33%, and resist- but cattle are an important reservoir, and can carry high ant isolates were only found in 0.5% of final carcasses, numbers of Campylobacter asymptomatically [142]. and no isolates were associated with the final striploin Susceptible cattle can suffer from enteritis, and Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 10 of 22 Campylobacter fetus subsp. fetus and subsp. venerealis for their presumptive importance as AMR determinant can cause venereal bovine genital campylobacteriosis, sentinels/reservoirs. leading to infertility and abortion [13, 142]. In the NARMS report, Campylobacter was isolated from 42% Antimicrobials and the bovine microbiota of beef cattle, with 14% of isolates resistant to ciproflox- Cattle house a dense (>10 microbes/ml; rumen fluid acin [137]. In a Japanese study of beef cattle, C. jejuni [152]) consortia of microbial species in the distinct was isolated from 36% of cattle on 88% of the farms physiological niches of the rumen and lower digestive surveyed: ~40% of C. jejuni isolates were enrofloxacin- tract [153]. Different host compartments functionally se- and nalidixic acid-resistant, but none were lect for, and are shaped by, distinct microbial communi- erythromycin-resistant [143]. In a Swiss study of 97 ties that are essential for the proper physiology and Campylobacter isolates obtained from a beef processing development of the host [154, 155]. Cattle are dependent plant, Jonas et al. [144] found that 31% were on rumen microbes for feed digestion, and the micro- fluoroquinolone-resistant and ~1% were erythromycin- biome collectively degrades complex polysaccharides, resistant. Wieczorek et al. [145] examined Campylobac- converting plant mass into volatile fatty acids for absorp- ter abattoir prevalence on 812 bovine hides and corre- tion by the host animal. Core microbial species in the sponding carcasses, and found Campylobacter on 25.6% rumen include Prevotella, Butyrivibrio, Ruminococcus,as of hides, and 2.7% of carcasses. The isolates obtained well as many unclassified organisms [156, 157]. Other were equally resistant to nalidixic acid and ciprofloxacin bovine niches harbor unique microbial communities, (38.3%), streptomycin (24.3%), tetracycline (20.9%), such as the nasopharyngeal and vaginal tracts [153, 158, erythromycin (4.3%), and gentamicin (2.6%) [145]. 159]. The microbial community in the jejunum also has a role in feed digestion, and influences feed efficiency [160]. The fecal microbiota is dominated by Firmicutes Antimicrobial resistance in bovine-origin Enterococcus and Bacteroidetes, but also contains Proteobacteria and Enterococcus spp. are ubiquitous Firmicutes in the human enteropathogens, which are shed in feces [154, healthy intestinal microbiota of both humans and cattle, 161, 162]. Collectively, the intestinal microbiota hosts a and indicate fecal contamination. Most Enterococcus portion of the cattle resistome. spp. are not foodborne pathogens, nor are they bovine Unlike in humans and experimental animal models, pathogens [13]. Despite this, isolates of Enterococcus fae- there is currently limited information concerning the ef- calis and faecium may cause life-threatening human in- fect of antimicrobials on the bovine microbiota/resis- fections, such as UTIs and meningitis. Control of tome. However, much work describes the effect of enterococci infections is complicated by high-level MDR therapeutic and sub-therapeutic administration of anti- [146]. Enterococci are referred to as ‘drug-resistance microbials on the prevalence of specific bacteria in bo- gene traffickers’ due to their omnipresence, robustness, vines. These studies typically involve antimicrobial and capability of transferring AMR to other species and administration to a controlled animal cohort, followed pathogens [147, 148]. E. faecalis transferred gentamicin by culture-dependent collection of an organism-of- resistance plasmids to transplanted human flora in a interest for susceptibility testing. These approaches pro- BALB/c mouse model [149]. The US NARMS report in- vide a biased snapshot of microbiome changes. Newer dicates that Enterococcus were recovered from ~90% of methods include culture-independent collection of meta- cattle, and ~80% of retail ground beef tested. The inci- genomic DNA for detection and quantitation of specific dence of MDR (>3 antimicrobials) in both E. faecium AMR genes by PCR-based methodology, or for high- and faecalis was lower in cecal isolates from beef cattle throughput sequencing and functional AMR gene annota- (19 and 14%, respectively) than in cecal samples from tion (Table 1). There are currently few studies describing chickens (67 and 46%, respectively) or turkeys (25 and the effects of antimicrobials on microbial population 58%, respectively) [137]. Other studies of AMR Entero- diversity in bovines using high-resolution sequencing coccus typically focus on the emergence of resistance to methodology. vancomycin— an antimicrobial used in the treatment of MRSA and other Gram-positive infections [122, 150]. Effect of antimicrobials on the bovine microbiota Vancomycin or linelozid resistance was not detected in Pereira et al. [163] characterized the gut microbiota bovine-origin Enterococcus spp. in the United States or (fecal samples) of pre-weaned dairy calves fed raw milk Canada [137, 151], but ~30% of E. faecium NARMS iso- spiked with ‘residual’ concentrations of ceftiofur (ceftio- lates were found to be quinupristin/dalfopristin-resistant fur sodium; 0.1 μg/mL), ampicillin (ampicillin sodium; [137]. Overall, despite the possibility for transmission of 0.01 μg/mL), penicillin (penicillin G sodium; 0.005 μg/ pathogenic strains to humans, Enterococcus spp. in the mL), and oxytetracycline (oxytetracycline hydrochloride; beef production environment have been studied mainly 0.3 μg/mL) using 16S rRNA Illumina MiSeq-based Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 11 of 22 Table 1 Selected studies on the effect of antimicrobials on the cattle microbial resistome Study Livestock Antibiotic tested (class) Experimental treatment Sample Characterization methodology Outcome or notable findings (animals in type study) Chambers et al. Dairy cattle Ceftiofur Administration of therapeutic Fecal Metagenomic DNA: Illumina HiSeq Increase in bacterial sequences associated rd 2015 [165] (6 Holstein (3 generation ceftiofur over 3 d trial of total DNA with MG-RAST and with resistance to β-lactam and multidrug cows) cephalosporin) ARDB annotation resistance Benedict et al. Beef cattle Various (5 difference Correlation between routine Fecal Bacterial isolation and susceptibility Exposures to tetracycline, streptomycin, and 2015 [175] (>10,000 antimicrobial drug classes antimicrobial usage in a feedlot testing. trimethoprim-sulfamethoxazole were animals) system and antimicrobial significantly associated with increased resistance in non-type Escherichia abundance of antimicrobial resistance genes coli over 3 yr rd Kanwar et al. Beef cattle Ceftiofur (3 generation Administration of therapeutic Fecal Metagenomic DNA: qPCR of select AMR Increase in ceftiofur resistance genes and 2014 [164] (176 steers) cephalosporin) ceftiofur and/or chlortetracycline genes decrease in tetracycline resistance genes Chlortetracycline over 26 d trial following ceftiofur treatment (tetracycline) Increase in ceftiofur and tetracycline resistance genes following chlortetracycline treatment Zaheer et al. Beef cattle Tylosin Administration of either Fecal Bacterial isolation and susceptibility Both sub-therapeutic and therapeutic 2013 [99] (40 steers) Tulathromycin sub-therapeutic tylosin or testing. PCR of select AMR genes macrolide treatment increased abundance Tilmicosin therapeutic tulathromycin or of macrolide resistant Enterococci (macrolide) tilmicosin Thames et al. Dairy cattle Neomycin (aminoglycoside) Administration of either Fecal Metagenomic DNA; qPCR of select AMR Sub-therapeutic antibiotic treatment had 2012 [219] (41 calves) Oxytetracycline sub-therapeutic or therapeutic genes no effect on abundance of tested resistance (tetracycline) neomycin or oxytetracycline determinants. over 50 d milk-replacement Therapeutic treatment with oxytetracycline trial increased abundance of tetracycline resistance genes Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 12 of 22 sequencing. Exposure resulted in Genus-level differ- Utilizing advanced total community metagenomic se- ences, but taxa above the Family level were not altered quencing, Chambers et al. [165] examined the effect of [163]. The microbiota of exposed calves was also less di- ceftiofur treatment on the prevalence of AMR genes in verse than treatment-free calves [163]. Similarly, Reti et the bovine fecal microbiome. Holstein cows were al. [162] examined the effects of a sub-therapeutic AGP injected subcutaneously with ceftiofur (CCFA, Excede, on the abundance and composition of microflora in the Zoetis; 1 mg per 45.4 kg body weight) and fecal samples small and large intestine of adult beef cattle. The US- were collected prior to and post-treatment. Total DNA and Canada-approved chlortetracycline/sulfmethazine was sequenced on the Illumina HiSeq platform, and AGP (Aureo S-700 G, Alpharma) was administered at AMR genes were detected using the antibiotic resistance 350 mg of each antimicrobial per head per day for 28 d genes database (ARDB) [166]. The proportion of β- [14]. Compared to non-treated control cattle, beef cattle lactam and MDR sequences were found to be higher in administered the AGP showed no differences in bacterial ceftiofur-treated cows relative to control cows. The β- abundance or richness/diversity composition (deter- lactamase genes cfxA2 and cfxA3 were most abundant, mined via quantitative PCR and terminal restriction and have previously been associated with Prevotella—a fragment length polymorphism analyses) [162]. Studies common rumen microbe [167]. Ceftiofur also changed using advanced 16S rRNA metagenomic sequence-based the fecal bacterial community composition, increasing and whole metagenome methodologies may be of Bacteroidia and decreasing Actinobacteria. This study greater significance in future work exploring the effect was also notable because metagenomic data was function- of antimicrobials on the microbiota. ally assessed with MG-RAST [168], allowing examination of antimicrobial-induced changes to the metagenome. Functional ceftiofur-associated shifts included increased Effect of therapeutic and sub-therapeutic antimicrobial prevalence of genes associated with stress, chemotaxis, usage on AMR gene prevalence and resistance to toxic compounds [165]. This work and Kanwar et al. [164] recently explored the effects of dif- others like it likely represent the future direction of AMR ferential treatment strategies on the prevalence of AMR surveillance research. determinants in the fecal metagenome. In a 26-day field Sub-therapeutic antimicrobial administration is one of trial, 176 beef steers were divided into 4 cohorts and the most controversial beef production practices with given therapeutic doses of ceftiofur (ceftiofur crystalline- many studies exploring this topic in the context of AMR free acid (CCFA), Excede, Zoetis; 6.6 mg/kg body weight) development. Alexander et al. [169] investigated effects and/or chlortetracycline (Aureomycin, Alpharma; 22 mg/ of chlortetracycline/sulfamethezine AGPs (Aureu S-700 kg body weight). One of the four cohorts included steers G, Alpharma; 44 mg/kg each in-feed) on the prevalence in which only 1 of the animals was administered ceftiofur of AMR E. coli in the beef production continuum. With and chlortetracycline, while the remaining animals re- respect to treated and non-treated cattle, E. coli was col- ceived chlortetracycline alone. Via quantitative PCR, the lected from live-animal feces, hides, intestinal digesta, authors determined gene copies/g of wet feces of bla carcasses, and ground beef. Animals fed chlortetracyc- CMY-2 and bla (ceftiofur resistance), tet(A) and tet(B) line/sulfamethezine harbored more tetracycline-resistant CTX-M (tetracycline resistance), and 16S rRNA genes in fecal E. coli than non-treated animals (50.9% vs. 12.6%), but community DNA from the pens of each treated cohort. there were no differences in the prevalence or profile of Pens where all cattle were treated with ceftiofur had AMR E. coli between treatments in the hide, carcass or greater numbers of bla and bla ceftiofur resist- ground beef samples [169]. To the authors this sug- CMY-2 CTX-M ance determinants than single-animal treatment pens gested that AMR E. coli can enter the food chain at [164]. Chlortetracycline treatment increased the levels of slaughter regardless of AGP administration [169]. Sub- bla and bla gene copies compared to cattle in therapeutic administration of tetracycline/sulfamethazine CMY-2 CTX-M pens that did not receive chlortetracycline. In contrast, also increased the prevalence of tetracycline-resistant or- tetracycline AMR gene prevalence decreased in pens ganisms, and increased the frequency of ampicillin- where all cattle received ceftiofur compared to pens where resistant E. coli, in agreement with similar studies using only one animal received ceftiofur [164]. The authors the same antimicrobials [170]. Another study found that discussed these findings in the context of expansion sub-therapeutic tylosin treatment (Tylan, Elanco; 11 mg/ or suppression of singly- or co-resistant AMR popula- kg in-feed) increased the frequency of Enterococcus spp. tions under antimicrobial selection, which served to harboring erm(B) and/or msrC (a macrolide/streptogra- highlight the complexity of the effects of antimicro- min efflux pump gene) [171]. The authors of that study bials on the resistome, and the potential for discrep- concluded that the diversity of Enterococcus decreased in ancies between culture- and non-culture-based AMR the period between when cattle entered and exited the quantitation methodologies [164]. feedlot, and that the AMR Enteroccocus were derived Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 13 of 22 from strains present in the intestinal microbiota before contradictory reports where no such association exists tylosin administration [171]. Selection for co-resistance [99, 175]. and MDR is one of the main arguments against AGPs. Heavy metal supplementation and AMR Cattle also receive trace mineral supplements that in- Effect of BRD-related antimicrobial usage clude elements with AGP activity. Some heavy metals, Given the importance of antimicrobials in the treatment such as zinc, manganese, and copper may be given as of BRD agents, much research examines the effect of salt-mixes, injected, or administered in slow-release ru- antimicrobial treatment on AMR development in BRD minal capsules [14]. Copper and zinc promote growth, bacteria. Investigated the effects of therapeutic and sub- potentially via suppression of pathogens and alteration therapeutic macrolide administration on the nasopha- of microbiota [176, 177]. In other production animals, ryngeal and enteric microbiota, with specific focus on zinc and copper can select for AMR [178]. This may be M. haemolytica and Enterococcus, respectively. Forty due in part to MGEs such as ICE, in which AMR deter- beef steers were injected once with tilmicosin (Micotil, minants are co-localized with heavy-metal resistance Elanco; 10 mg/kg) or tulathromycin (Draxxin, Pfizer; genes. For example, in addition to multiple AMR deter- 2.5 mg/kg) or fed sub-therapeutic tylosin (Tylan, Elanco; minants, ICEPmu1 (Fig. 3a) encodes for a multi-copper 11 mg/kg in-feed) continuously over 28 d. Therapeutic oxidase, which is potentially involved in resistance to tilmicosin and tulathromycin decreased nasopharyngeal copper and other heavy metals [179]. Thus, heavy metal carriage of M. haemolytica: at the beginning of the trial, exposure can co-select for AMR. Jacob et al. [180] stud- 60% of the steers tested positive for M. haemolytica, at ied the effect of elevated copper and zinc fed to heifers 7 d post- injection, none of the steers treated with tilmi- receiving high-energy rations by isolating and character- cosin harbored M. haemolytica, and only one steer izing AMR E. coli and Enterococcus from fecal samples. treated with tulathromycin was positive for M. haemoly- Resistance to copper and zinc in E. coli isolates was in- tica. Sub-therapeutic tylosin had no effect on nasopha- creased, and abundance of the tetracycline resistance de- ryngeal carriage, and tylosin-exposed M. haemolytica terminant tet(M) was elevated following heavy metal isolates did not acquire macrolide resistance. In contrast, supplementation [180]. In a study combining tylosin a significant proportion of the bystander Enterococcus (Tylan, Elanco; 0 or 10 mg/kg in-feed) with copper acquired erm(B) erythromycin resistance following treat- (CuSO ; 10 or 100 mg/kg in-feed), Amachawadi et al. ment with either injectable tilmicosin or tulathromycin, [181] investigated fecal Enterococcus spp. to determine if or in-feed tylosin, and were 76-fold more likely to be elevated copper supplementation co-selects for macro- erythromycin-resistant than those recovered from non- lide resistance. The transferable copper resistance gene antimicrobial-treated steers. Catry et al. [172] correlated tcrB was identified in 8.5% of Enterococcus from ele- 2-year of Belgian farm-standard antimicrobial usage to vated copper- and tylosin-fed cattle, compared to copper the occurrence of AMR in rectum and nasal flora, repre- alone (4.5%), tylosin alone (3.5%), or the low copper/no sented by E. coli and Pasteurellaceae, respectively. Nar- tylosin control (2.0%) [181, 182]. All the tcrB-positive row spectrum penicillins were the most frequently isolates proved to be E. faecium, and interestingly, all administered parenteral antimicrobials, often in combin- tcrB-positive isolates harbored tetracycline tet(M) and ation with an aminoglycoside, such as neomycin or dihy- erythromycin resistance erm(B) determinants [181]. The drostreptomycin [172]. Among rectal E. coli, 20.6% were authors concluded that elevated dietary copper could resistant to least one antimicrobial. The most frequent co-select for AMR in feedlot cattle [181]. Thus, heavy resistance patterns were ampicillin-tetracycline- metal supplementation should also be considered as a streptomycin (15.9%), tetracycline-streptomycin (11.4%), selective pressure with the potential to promote the dis- and ampicillin-streptomycin (9.8%) [172]. Among 206 P. semination AMR determinants, and is a practice that multocida isolates and 42 M. haemolytica isolates origin- likely needs to be revisited as these minerals may be ating from the nasal cavity, the predominant resistance added to the diet in excess of the animal’s requirement. found was to the aminoglycoside spectinomycin [172]. The authors confirmed that antimicrobials altered the The bovine resistome & the wider environment prevalence of AMR in the digestive and respiratory tracts The primary concern relating to antimicrobials in agri- and highlighted that the route of administration affected culture is the potential for AMR determinants to expand resistance outcomes. Individual therapy was linked to in- and spread via the food chain. Although urban lifestyles creased but transient resistance, whereas in-feed antimi- rarely bring people into direct contact with livestock, the crobials were linked to higher levels of MDR [172]. Others animal production continuum extensively connects with have also suggested that the route of administration affects numerous industries, infrastructure, and ecologies. For overall AMR prevalence [173, 174], but there are also example, manure from antimicrobial-treated animals Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 14 of 22 may be applied to crops, or waste from farms may drain prevalent in anaerobic and aerobic sludge accounting for into rivers, reservoirs, and wastewater treatment plants. 35.95 and 58.36% of annotated reads, respectively, In the US, cattle produce between 0.86 and 6.4 million t followed by Firmicutes (16.31 and 6.08%, respectively) of manure daily [183]. AMR can thus be transferred to [191]. Concerning AMR genes 747 reads (0.0081%) and the wider environment, increasing the risk of contact 877 reads (0.0101%) in anaerobic and aerobic sludge, re- with a human pathogen. At present, knowledge about spectively, were assigned to 54 and 42 types of known the identity, diversity, distribution, and patterns of co- AMR genes [191]. MDR efflux transporters were most resistance in beef-related AMR genes, and how they common, followed by tetracycline and sulfonamide re- compare to determinants in other ecosystems is scarce, sistance genes (>20% of AMR-associated reads) [191]. due in part to the difficulty in defining the bovine resis- The authors also detected MGEs in tannery DNA sam- tome in the context of the larger environmental resis- ples, but limitations in methodology restricted investi- tome. AMR genes are widely present in both pristine gating linkages with AMR genes. Taking a similar and human-impacted environments [184], so the occur- approach, Li et al. [192] examined the resistome of plas- rence of AMR in any specific biome does not necessarily mids harvested from influent, activated sludge, and validate the impact of antimicrobial usage. However, digested sludge of two Hong Kong wastewater treatment with the advent of next-generation sequencing and total plants receiving domestic and slaughterhouse (cattle and metagenomics, and resources like ARDB, and CARD other production animals) sewage. AMR genes were de- (the Comprehensive Antibiotic Resistance Database; tected in all of the plasmid metagenomes: the most [185]), high-throughput AMR gene profiling resistomics abundant were tetracycline resistance genes (29% of all is shedding light on these relationships. AMR gene sequences), quinolone resistance genes (17%), and β-lactam resistance genes (12%) [192]. The Resistome characterization via shotgun metagenomics AMR gene distribution and abundance in each wastewa- Noyes et al. [186] examined AMR genes of 1,741 beef ter treatment plant sample is shown Fig. 3b, in circular cattle as they moved longitudinally through the produc- relationship format [192, 193]. This plasmid-centric tion chain, characterizing feedlot, slaughter, and beef study highlights the mobile resistome and plasmid fates product resistomes via shotgun metagenomics per- more so than a total metagenome study, and future ex- formed on the Illumina HiSeq platform, and assessed periments could involve comparisons between plasmid against the Resfinder [187], ARG-ANNOT [188], and and total resistomes to explore HGT of AMR determi- CARD [185] AMR gene databases. This identified 300 nants. This paper also highlights a methodology to unique AMR genes, and showed that, the diversity of examine MGE-associated AMR genes that is not con- the AMR genes decreased while cattle were in the feed- founded by environmental AMR genes or host DNA lot, indicative of selective pressure imposed by antimi- contamination. crobials, consistent with other studies showing diversity reduction following antimicrobial exposure [163]. Exam- Resistome characterization via functional metagenomic ination of post-slaughter samples obtained from belts library screening and tables in the slaughterhouse, meat trimmings, and Sequence-based metagenomic AMR gene profiling is market-ready samples revealed no AMR genes [186]. also limited to those genes with similarity to already The authors concluded that effective practices at slaugh- known AMR genes, and metagenomic shotgun read ter minimized the likelihood of AMR gene being passed lengths present difficulties for the characterization of the through the food chain. However, the high prevalence of AMR genomic context. Functional metagenomic library- bovine DNA complicates shotgun metagenomics and based approaches have proved to be complementary in may result in low sensitivity of AMR gene detection. the identification, quantification, and characterization of Despite this, this study exemplifies the powerful utility novel resistance determinants. Wichmann et al. [194] of metagenomic approaches in the study of AMR gene examined the resistome of dairy cow manure with ecology. large-insert (>35 kb) fosmid libraries constructed from Metagenomics have also proved useful in the examin- 5 manure samples. The resulting E. coli-based librar- ation of AMR genes found in wastewater treatment ies (containing 25.9 Gb of DNA) were screened for plants associated with tanneries and slaughterhouses. resistance to kanamycin, chloramphenicol, tetracyc- Wastewater treatment plants are thought to be HGT line, and the β-lactams carbenicillin (penicillin) and hotspots because of high bacterial diversity and density ceftazidime (cephalosporin). Of 87 AMR E. coli clones [189, 190]. Wang et al. [191] profiled AMR genes and with genes conferring resistance to at least one of the MGEs in wastewater sludge from a Chinese leather tan- antimicrobials tested, 80 carried unique AMR genes, nery via Illumina HiSeq and assessment with MG-RAST suggesting that the cow microbiome harbors AMR [168] and ARDB [166]. Proteobacteria were most- genes that are unique or unidentified elsewhere. A Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 15 of 22 novel clade of chloramphenicol acetyltransferases was studies utilizing libraries and shotgun metagenomics, or also described [194]. Flanking sequence analysis indi- emerging long-read sequencing technologies. cated that the AMR determinants originated from An example of risk and source determination may be typical cattle microbes: Firmicutes were predominant given by the long-term global epidemics of ground beef- (50% of sequenced clones), followed by Bacteroidetes associated MDR S. enterica serotype Typhimurium (23%) and Proteobacteria (14%) [194]. Another phage type DT104, which may express resistance to powerful advantage of the fosmid library approach is ampicillin, chloramphenicol, streptomycin, sulfameth- the ability to examine AMR gene context: i.e. co- oxazole, and tetracycline (resistance-type ACSSuT) occurrence with other AMR genes, or association with [203–205]. In some isolates, these AMR genes are MGEs. Wichmann et al. found 2 kanamycin-resistant E. hosted in a 13 kb MDR region, residing in a larger coli clones with >5 putative genes with predicted AMR or chromosome-encoded ~43 kb region called Salmonella MGE functions [194]. Thus, library-based functional genomic island 1 (SGI1). The MDR region harbors Class metagenomic approaches combined with next-generation I integrons—genetic elements capable of consolidating sequencing are a powerful way to screen for AMR deter- multiple AMR gene cassettes [206]. Integrons are often minants associated with MGEs, plasmids, or phages [195]. found in conjunction with MGEs; in the case of DT104, HGT can occur via phage-mediated transfer [207]. Al- Linking antimicrobial use in beef production to though veterinary antimicrobial usage and food animals human health risk have long been the chief culprit for the origin and dis- Assessing the differential risk, importance, and source of semination of DT104, Mather et al. [208, 209] chal- AMR genes lenged the perception that DT104 originated from a Given the ubiquity of AMR determinants in bovine and single zoonotic population by whole-genome sequencing other microbial communities, it is difficult to appraise Scottish DT104 collections. In total, 135 isolates from the relative risk any particular determinant presents for humans and 83 from cattle were sequenced and com- the likelihood of transfer into a human pathogen and pared against 111 other DT104 isolates from diverse clinical therapy failure. Confounding the issue are AMR host animals and countries. Using phylogenetic diffusion determinants that are expressed or silent in different models, the authors found that AMR DT104 populations hosts, as well as AMR determinants akin to housekeep- were distinguishable between cattle and humans, and ing genes [196]. For the latter, ‘decontextualized’ house- that animal-to-human and human-to-animal transitions keeping genes, such as those harbored on MGEs, pose a were rare, and occurred at the same frequency [209]. greater risk [1, 197]. Prioritizing the differential human This suggested that most human infections were unlikely health risk posed by an AMR gene is complicated by to originate from the local cattle. AMR diversity was such issues, but risk ranking schemes have been greater in human isolates, resulting from multiple, discussed [1, 198, 199]. Greatest risk may be presented independent recombination events in SGI1’s MDR re- by AMR genes already hosted on MGEs in human gion [209]. In part, this suggested that most human in- pathogens, and known to cause therapy failure. An ex- fections were acquired from humans, and that DT104 ample of this is the recently detected plasmid-mediated circulated separately in the animal and human populations, colistin (polymyxin E) resistance gene (mcr-1)in E. coli and/or unique sources infected humans vs. animals [209]. isolates from poultry, swine, and infected humans [200, Mather et al. emphasized the importance of integrating 201]. A beef-related example is the ~38 kb R plasmid veterinary and clinical data to make evidence-based found in S. enterica serotype Newport, which confers judgments concerning the sources of AMR infections. resistance to tetracycline, ampicillin, and carbenicillin [202]. This caused severe penicillin-unresponsive sal- Direct evidence of human health impact of beef monellosis linked to contaminated hamburger meat antimicrobial usage [202]. The next level of risk may be from functional Linking on-farm antimicrobial use to human infection is AMR genes conferring resistance to human antimicro- difficult. While antimicrobial usage evidently selects for bials, but which are hosted in MGEs in non-pathogenic drug-resistant organisms, there is a gap in knowledge bacteria. These might include the AMR determinants connecting usage to the flow of AMR determinants from encoded by ICEPmu1 and ICEMh1 found in P. multo- the bovine microbiota to outbreaks of human AMR cida and M. haemolytica, respectively [103, 104]. Ele- diseases. To bridge this gap, a number of studies com- vated risk is credited to MGEs because the acquisition pared outbreak clinical isolates to animal isolates taken and selection of an AMR determinant in a MGE might at similar times from nearby locations [210–212]. Typic- be the initial step for transmission to a human pathogen. ally, isolates were examined for similar AMR/genetic In the future, more focus should be devoted to AMR in profiles, and if identical, this provided some evidence of the context of MGEs, particularly for total resistome the AMR outbreak source. Direct links to specific Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 16 of 22 antimicrobial usage is rarely identified for outbreaks. A Conclusions & future focus caveat of many studies is that transfer is assumed to be As in most environments, AMR determinants exist ubi- from cattle to humans, or remains unknown. Several quitously in the beef production biome, regardless of AMR E. coli and Salmonella outbreaks have been associ- antimicrobial exposure. Nevertheless, the use of antimi- ated with beef [213–215], but there are few examples crobials for bovine welfare and growth promotion con- where those AMR determinants have been traced back tributes selective pressure that increases the abundance to AMR bacteria in cattle [210]. This reinforces the need of AMR genes and their host bacteria, and promotes the for greater integration of human and veterinary data. genesis and dissemination of MDR organisms. The pres- For beef production, tracing the source of an AMR out- ence or absence of connections between AMR in bovine break is complicated by system complexity, herd move- microbial populations to human health threats are likely ment, and lack of industry motivation. And although to become clearer with the increasing application of beef production is a major industry, more focus has been whole-genome sequencing and metagenomic resis- on the human health impact of AMR transfer in dairy tomics. The role of MGEs in AMR propagation is likely cattle, and in the swine and poultry industries (reviewed to be an important focus for understanding the impact in [214]). Dairy-related outbreaks may be easier to docu- of veterinary antimicrobials. Future investigations may ment because the source animal population is main- validate mitigation strategies, such as the separation of tained, whereas the beef, swine, and poultry populations antimicrobials for use in beef cattle from those used in are consumed. Selected examples of outbreaks and humans. Proper and judicious use of antimicrobials will human health threats posed by bovine AMR bacteria help prolong the usefulness of both clinical and veterin- are listed in Table 2. These demonstrate that the ary antimicrobials, but ever-increasing usage of anti- most convincing molecular and epidemiological AMR microbials in food-animal production suggests that links are found when the infected human is directly microbes will only continue to acquire resistance. Of connected to the animal population on farms or via particular concern for cattle are the MDR BRD agents: farm workers [211, 216, 217]. Direct exposure to live- in the future, respiratory infections may become untreat- stock is a known risk factor for zoonotic transmission able with current antimicrobials. On a positive note, sev- (reviewed in [218]). eral studies reveal that adequate hygiene and appropriate Table 2 Selected examples of cattle-related AMR human health threats Source Bacterial Human AMR profile Mechanism Notes Study species outbreak Calves S. enterica Veterinarian’s Ampicillin, chloramphenicol, Ceftriaxone An isolated, domestically acquired case [216] serotype child tetracycline, sulfisoxazole, resistance conferred requiring hospitalization. Failure of Typhimurium kanamycin, streptomycin, by bla on a ampicillin and sulbactam therapy, but CMY-2 cephalothin, ceftriaxone and conjugable plasmid recovery with amoxicillin/clavulanate. ceftiofur, aztreonam, cefoxitin, Direct molecular evidence linking MDR gentamicin, and tobramycin isolates from herds treated by the patient’s father Cattle, MRSA ST130 Two farmers Cefoxitin and penicillin Resistance conferred Direct transfer of mecC-MRSA from [211] Sheep by mecC(mecA cattle and sheep to humans resulting in homologue), wound infections SCCmec type XI [220] Veal MRSA ST398 Asymptomatic Methicillin and others Resistance conferred Asymptomatic human MRSA carriage [217] calves carriage by by mecA, SCCmec rates associated with prevalence in farm not stated calves and frequency of animal contact. employees MRSA carriage in calves associated with antimicrobial use rd Cattle, E. coli, Potential, Ceftriaxone, with high-levels 3 generation Potential transfer of bla plasmids [210] CMY-2 Swine Salmonella sporadic of co-resistance to cephalosporin between E. coli and Salmonella. Close transmission chloramphenicols, tetracycline, resistance conferred relationship between bla plasmids CMY-2 to humans sulfisoxazole, streptomycin, by plasmid-born in E. coli found in bovines and humans gentamicin, tobramycin, and bla CMY-2 ciprofloxacin Ground S. enterica Large Ampicillin, chloramphenicol, MDR genes Multi-state outbreak, potentially [213] beef, serotype clustered streptomycin, sulfemethoxazole, potentially encoded affecting >2200 people. Severe illness, possibly Typhimurium human and tetracycline (R-type ACSSuT) on Salmonella with a high proportion of patients from dairy DT104 outbreak genomic island 1 receiving intravenous rehydration and cows requiring hospitalization Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 17 of 22 treatment at slaughterhouse and wastewater treatment Funding AC is supported by an NSERC Postdoctoral Fellowship and the program as a facilities are efficacious at reducing or eliminating trans- whole is supported by the Beef Cattle Research Council BCRC – Agriculture mission of AMR organisms and genes. Thus, such and Agri-Food Canada beef cluster. procedures and facilities should be explored further, and Availability of data and materials promoted in deficient areas of food-animal production. Not applicable. Methods Authors’ contributions AC and TAM researched and co-wrote the review. Both authors read and ap- Literature search proved the final manuscript. The literature search was conducted from January to March 2016 via Google Scholar and PubMed. Recent Competing interests The authors declare that they have no competing interests. (2012-present) studies that described AMR or usage in context with beef production, bovine pathogens, com- Consent for publication mensal bacteria, metagenomics, the resistome, and cattle Obtained. were included. Older reports, or studies referring to Ethics approval dairy operations were excluded, except for where beef Not applicable. production information was sparse. Author details Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. Comparison of most frequently reported AMR in bovine Agriculture and Agri-Food Canada, Lethbridge, AB, Canada. pathogens Received: 17 May 2016 Accepted: 28 October 2016 A literature search was conducted for AMR in bovine pathogens. Journal articles ([30–88], 2000-present) were collected if the AMR data was presented in a format References 1. 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EFSA (European Food Safety Authority) and EMA

Publisher: Springer Journals
Copyright: Copyright © 2016 by The Author(s).
Subject: Life Sciences; Agriculture; Biotechnology; Food Science; Animal Genetics and Genomics; Animal Physiology
eISSN: 2049-1891
DOI: 10.1186/s40104-016-0127-3
Publisher site: See Article on Publisher Site

Abstract

Antimicrobials are critical to contemporary high-intensity beef production. Many different antimicrobials are approved for beef cattle, and are used judiciously for animal welfare, and controversially, to promote growth and feed efficiency. Antimicrobial administration provides a powerful selective pressure that acts on the microbial community, selecting for resistance gene determinants and antimicrobial-resistant bacteria resident in the bovine flora. The bovine microbiota includes many harmless bacteria, but also opportunistic pathogens that may acquire and propagate resistance genes within the microbial community via horizontal gene transfer. Antimicrobial-resistant bovine pathogens can also complicate the prevention and treatment of infectious diseases in beef feedlots, threatening the efficiency of the beef production system. Likewise, the transmission of antimicrobial resistance genes to bovine-associated human pathogens is a potential public health concern. This review outlines current antimicrobial use practices pertaining to beef production, and explores the frequency of antimicrobial resistance in major bovine pathogens. The effect of antimicrobials on the composition of the bovine microbiota is examined, as are the effects on the beef production resistome. Antimicrobial resistance is further explored within the context of the wider beef production continuum, with emphasis on antimicrobial resistance genes in the food chain, and risk to the human population. Keywords: Antibiotics, Antimicrobial resistance, Antimicrobial usage, Beef production, Bovine pathogens, Bovine microbiota, Cattle, Enteropathogens, Fecal bacteria, Resistome Background particular attention, antimicrobials are also widely used The emergence of antimicrobial resistance in bacterial in companion animals and in plant agriculture (e.g. pathogens is a serious global issue. Antimicrobial use in oxytetracycline and streptomycin), for feed crops, and livestock, aquaculture, pets, crops, and humans selects for tomatoes, citrus, and many other fruits [4]. Here, the for antimicrobial-resistant (AMR) bacteria that reside in focus is on large-scale beef production, where antimicro- agricultural and clinical biomes. Besides pathogens, bials are routinely used to support animal welfare, and AMR bacteria include many harmless and beneficial controversially, to promote growth and production microbes acting as a genetic reservoir of AMR gene efficiency. In this review, the usage of antimicrobials in determinants (‘the resistome’ [1, 2]), which can be cattle will be summarized along with recent studies on transferred via mechanisms of horizontal gene transfer AMR explored within the context of the beef production (HGT) (reviewed in [3]) throughout the microbial system. community. With alarming frequency, untreatable human and animal pathogens with multiple AMR deter- Beef production minants arise. AMR in pathogens is commonly accepted Worldwide, beef production is the third largest meat as a result of widespread use and abuse of antimicrobials industry (~65 million t globally), behind swine and poultry in agriculture and medicine. Although the use of anti- [5]. In 2015, the major beef producing countries included microbials in livestock and aquaculture has attracted the United States (US) (11.4 million t), Brazil (9.6 million t), the 28 member countries of the European Union (EU) (7.5 * Correspondence: tim.mcallister@agr.gc.ca 2 million t), China (6.7 million t), and India (4.5 million t) Agriculture and Agri-Food Canada, Lethbridge, AB, Canada Full list of author information is available at the end of the article (Fig. 1a) [6] with the global beef cattle population © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 2 of 22 Fig. 1 Major beef-producing countries and antimicrobial consumption. a Beef and veal production in select countries (t). Data from: ‘Livestock and Poultry: World Markets and Trade’. USDA. Foreign Agricultural Service [6]. b Antimicrobial sales, excluding ionophore sales, in reporting countries (t active substance). Data complied from multiple sources: [19–23] c Sales of antimicrobials authorised only for food‐producing animals, by species (t active substance) [22, 23]. d Weighted animal population (in PCU) [20, 21, 23]. e Proportion of sales of total antibiotic products by antimicrobial class (t active ingredient) [19–23] exceeding 1 billion [6]. Beef production is complex and Infections spread rapidly in high-density feedlots, and involves multiple stages, wherein calves are birthed, despite herd management procedures, both endemic and raised and fed for slaughter, and processed for meat. exotic diseases can be introduced by importation of The raising of cattle in high-throughput production diseased animals into the beef production system. typically involves the movement of animals from (I) Globally, 4.7 million cattle are exported to beef produ- cow-calf systems (a permanent herd used to produce cing countries, with the top exporters being Mexico, young beef cattle), to (II) backgrounding (post-weaning Australia, and Canada, exporting >1.3, >1.2, and >1.0 intermediate feeding, typically forage-based diets), and million cattle, respectively. These cattle are sent primar- (III) feedlot/finishing operations (concentrated animal ily to the US, which received >2.2 million cattle in 2015 feeding, typically with high-energy grain-based diets). [6]. The risk of disease transmission creates significant After finishing, animals are transported to a slaughter- economic pressure for antimicrobial usage to prevent in- house and processed. Antimicrobials may be given to live fectious bovine diseases. cattle at any production stage for therapeutic and non- therapeutic purposes. Therapeutic and non-therapeutic use of antimicrobials Antimicrobial use in cattle is unavoidable for the treat- Antimicrobial usage in beef production ment of infections for which vaccines, bacterins, or alter- Rationale for antimicrobial use nate therapies are not available. A prevalent, controversial Antimicrobials are used in beef cattle for the therapeutic practice involves antimicrobials used in non-therapeutic treatment of infections caused by bacteria or other applications. Judicious antimicrobial use typically requires microbes. Cattle can be afflicted by a variety of endemic that diseased cattle are treated individually to maximize infectious diseases, which may exist ubiquitously in therapeutic efficacy and reduce the spread of AMR, but the ranching environment [7]. Endemic pathogens often entire herds are often dosed with in-feed antimicrobials. go unnoticed, but compromise animal health—affecting This is the typical administration route for practices such herd growth performance and farm profitability. as (I) prophylaxis, (II) metaphylaxis, and (III) growth Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 3 of 22 promotion. These practices are described by inconsistent could compromise future efficacy, especially in the and often agenda-driven terminology. For example, case of AMR genes that are genetically linked in prophylaxis and metaphylaxis are considered therapeutic clusters, as is often the case in multi-drug resistant uses by the American Veterinary Medical Association and (MDR) organisms. the US Food and Drug Administration (FDA) [8, 9], but others consider such practices ‘sub-therapeutic’, ‘non- Global veterinary antimicrobial usage therapeutic’,or ‘production usage’. More recently, the Antimicrobial usage data is scarce: most countries do FDA uses ‘production purposes’ to refer to antimicrobial not survey or collect usage data, and cattle producers usage with the intent of growth and feed efficiency en- and pharmaceutical companies have little incentive to hancement [10]. Prophylaxis is action taken to prevent report such information. Where usage data exists, typic- disease and involves the administration of antimicrobials ally in high-income countries, it takes the form of vol- to an individual that is perceived to be at risk of develop- ume sales data rather than actual usage. The caveat of ing disease. Metaphylaxis refers to the treatment of a antimicrobial sales and distribution data is that it does larger cohort or entire herd to provide: (I) therapy to not accurately indicate how or if antimicrobials were infected animals, and (II) prophylaxis to uninfected or used. In a global analysis of antimicrobial usage, Van potentially susceptible animals. Metaphylaxis is often Boeckel et al. [18] estimated the worldwide consumption applied to herds receiving new animals. Growth promo- of antimicrobials in food animal production at ≥57,000 t tion refers to the use of antimicrobial growth promoters (1 t = 1,000 kg) and projected a 67% increase in total (AGPs) for extended duration to improve feed efficiency usage by 2030 to ≥95,000 t. Total food-animal anti- (the ratio of feed consumed vs. animal weight gain). microbial sales in the US was reported to be approxi- ‘Sub-therapeutic’ typically refers to low-dose concentrations mately 9,475 t (2014) [19], 8,122 t in the EU (2013) [20], of antimicrobials in feeds over an extended duration. The 1,127 t in Canada (2012) [21], 644 t in Australia (2010) FDA Centre for Veterinary Medicine defines sub-therapeutic [22], and 429 t in the United Kingdom (UK) (2014) [23] as amounts <200 g per ton (US) of feed for 12 wk [11]. (Fig. 1b; excludes ionophores sales). Based on these sales data, and estimations of food animal populations, Van Complexity of production usage of antimicrobials Boeckel et al. projected that the top countries consum- Although prophylaxis/metaphylaxis may be a more ing antimicrobials in livestock production are China, the judicious use of antimicrobials than growth promotion, US, India, Brazil and Germany, with China accounting growth promotion is often a benefit of either treatment. for 23% of global consumption [18]. For example, antimicrobial treatment and prevention of Data for antimicrobial usage by animal type is not cattle liver abscesses simultaneously provides prophylac- routinely available, such that the proportion and type of tic/metaphylactic therapy and growth promotion. Liver antimicrobials sold exclusively for use in cattle is largely abscesses occur frequently in cattle, and are common in unknown or estimated. Some information can be feedlots, where high-energy grain-based diets can cause gleaned from country data where specific antimicrobial acidosis, leading to ruminal lesions that predispose cattle formulations with indicated routes of administration to hepatic disease caused by invasive bacteria [12]. Cattle (e.g. in-feed, injection etc.) are provided for specific live- with liver abscesses have reduced production efficiency stock (Fig. 1c). However, this data is largely unreliable (reduced feed intake and weight gain) [12]. Thus, feedlot because (I) most antimicrobials are approved for use in cattle receiving antimicrobials for liver abscess control multiple food-animal species, (II) off-label non-intended can also indirectly exhibit growth promotion as a result usage of antimicrobials is a common practice worldwide, of disease prevention. Some antimicrobials are approved and (III) the antimicrobial may not have actually been for both growth promotion and therapeutic applications administered to the animal. Data on therapeutic vs. non- [13, 14]. Some countries, particularly in the EU, have therapeutic use is not collected, and difficult to estimate. banned the use of AGPs in beef and other meat produc- Without reliable antimicrobial usage data to link to tion industries (the EU ban was implemented in 2006 AMR, it is challenging to create scientific policies to [15]). In 2012, the US introduced a voluntary ‘ban’ on optimize veterinary antimicrobials. Thus, judicious use AGPs, and a similar program is expected in Canada [16]. policies in some countries are the subject of debate, with While such policies are laudable, their effectiveness is critics decrying heavy-handed bans and regulations, and questionable. For example, the volume of agricultural proponents criticizing ineffective and optional compli- antimicrobials used within the EU has not decreased, ance schemes. and the EU ban may also have resulted in compensatory One method to improve antimicrobial usage estimate increases in the usage of antimicrobials with even greater by species is to take into account (I) the size of the animal relevance to human health [17]. Regardless, bacterial population (demographics), and (II) the average theoret- resistance acquired in response to any antimicrobial usage ical weight of the animal species at time of treatment Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 4 of 22 (physiology). This is the population correction unit (PCU), and another class of AGPs called flavophospholipols, most and is used in the UK Veterinary Medicines Directorate veterinary antimicrobials are identical or structurally simi- UK-VARSS report [23], the EU European Medicines lar to antimicrobials used in human medicine. Stringent Agency ESVAC report [20], and the Public Health Agency EU policies regulate the use of in-feed antimicrobials, and of Canada’s CIPARS report [21]. Briefly, 1 PCU = 1 kg of penicillins sales are proportionally high-from a low of livestock, such that the amount of antimicrobials sold can 11.9% in France to as high as 61.3% in Sweden of all vet- be normalized by species weight, allowing for a compara- erinary antimicrobials sold [20]. Sweden was the first tive indication of overall usage between species (Fig. 1d). country to ban AGPs in 1986 [17], a policy that likely con- Van Boeckel et al. used PCU values to estimate global tributed to high therapeutic use of penicillins. Resistance consumption of antimicrobials per kg of animal produced to an agricultural antimicrobial may confer resistance to at 45 mg/PCU (= mg/kg) for cattle, 148 mg/PCU for the human drug, many of which are considered to be es- chickens, and 172 mg/PCU for pigs [18]. This trend is sential medicines by the World Health Organization consistent with UK-VARSS data, in which cattle (WHO) [27]. Significant veterinary antimicrobials gener- consumed 8 mg / PCU of antimicrobials compared to ally include tetracyclines, penicillin (penam) and other β- 172 mg / PCU for swine and poultry [24]. This ap- lactams, macrolides, sulfonamides, and aminoglycosides proach gives an appreciation for the overall use of (Fig. 1e). Other antimicrobials represent a miniscule antimicrobials within a livestock species, but does not fraction of veterinary antimicrobials sold and distributed indicate usage within the various segments of the pro- (each <2%), but they are not unimportant. Thus, cephalo- duction system. These are limitations of using antimicro- sporins, lincosamides, phenicols, and fluoroquinolones bial sales and distribution data as a proxy for actual (among others) include some of the most effective anti- usage data [23]. microbials in veterinary and clinical medicine. In some countries, the majority of antimicrobials man- ufactured or sold are used in food animals rather than in Antimicrobial resistance in bovine pathogens human medicine (e.g. US: ~10,670 t active ingredient for Much focus on AMR in food animals concerns the haz- food animals (2014) vs. ~3,290 t for humans (2012) [19, ards for human health, but AMR is also a veterinary 25]; EU: ~7,982 t active ingredient for food animals vs. problem. Knowledge about resistance in exclusively ~3,399 t (2012) [26] (food animal values exclude iono- bovine pathogens is also exceptionally poor compared to phores and other non-medically important antimicro- that of bovine zoonotic enteric pathogens, such as bials)). However, direct human-animal antimicrobial use Campylobacter, Salmonella, E. coli and Enterococcus spp. comparisons are limited by differences in estimation and These species are typically used as ‘indicators’ of AMR measurement methodology (e.g. antimicrobials sold vs. in production animals as they (I) are of importance in prescribed), differences in animal physiology and anti- human disease, (II) are relatively easy to culture, (III) microbial use practices, and are further complicated by can be isolated from healthy animals, and (IV) have the inclusion/exclusion of antimicrobials irrelevant to established AMR minimum inhibitory concentration human medicine (e.g. ionophores). Thus, food animal vs. (MIC) breakpoints (for human infections). To reiterate, human antimicrobial consumption comparisons must be for several of the bacterial species discussed below, the interpreted with caution. Since food animals outnum- designation of “resistant” or “sensitive” is often author- ber/outweigh the human population, volume usage is determined because clear criteria have not been estab- less surprising than the concurrent use of antimicrobials lished by relevant standardization bodies, such as the essential for human medicine. The FDA reports that Clinical Laboratory Standards Institute (CLSI), and the medically important antimicrobials accounted for 62% of European Committee on Antimicrobial Susceptibility sales of all antimicrobials approved for use in food- Testing (EUCAST). Surveillance programs monitoring producing animals [19], with 74% of clinically relevant AMR in beef production are typically constrained to antimicrobials administered in-feed [19]. Of the 38% of human enteropathogens and sentinel AMR indicator antimicrobials sold that were not medically important, species, but independent research from many countries 80% were ionophores (e.g. monensin). Ionophores are not gives rough estimates of AMR in cattle pathogens. Several used in human medicine, have no human counterpart, and recent studies have found strong correlations between the do not appear to promote AMR. However, ionophores are level of use of specific antimicrobials and the level of important for animal welfare, and are administered for resistance observed [28, 29]. production and therapeutic indications for the treatment/ Scientific literature pertaining to AMR in pathogens of prevention of coccidiosis, a disease associated with significance to beef production was reviewed, and the Eimeria spp. infestations [24]. In the EU, ionophores are median percent resistance of 16 different pathogens to defined as anticoccidials/coccidiostats, and are not re- antimicrobials was collected from 58 scientific reports ported as antimicrobials [20, 23]. Besides the ionophores ([30–88]; 2000-present), shown in Fig. 2 (see Methods Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 5 of 22 Fig. 2 Most frequently reported antimicrobial resistance in pathogens from diseased bovines. Diameter of circle indicates the percent resistance of phenotypic resistance to antimicrobials, by class. The percent resistance was determined via the median of percent values obtained from journal articles (references [30–88]) that reported the percentage of resistance among isolates collected from diseased animals or from passive a,b c,d,e surveillance (as indicated). Notes: includes resistance data from healthy animals; includes data from healthy animals, sub-clinical, and clinical mastitis; includes isolates from feces. Data compiled from multiple sources for details). Reports were selected if they contained an Antimicrobial resistance in bovine respiratory pathogens antibiogram of isolates without prior antimicrobial selec- Bovine Respiratory Disease (BRD) is the most frequent tion, and in most cases, if the isolates were obtained from and economically important of the primary cattle diseases diseased animals. In general, differing levels of tetracycline [89]. Approximately 15% of cattle in North America are resistance were present in most cattle-associated bacteria. treated for BRD, which accounts for ~70% of cattle mor- Macrolide resistance was often reported in BRD patho- bidity, and ~40% of all mortality in feedlots [90]. BRD gens, and in liver abscess pathogens. For almost every spe- control is thus a major target of antimicrobial usage [90, cies there was a report of resistance to at least one 91], and possibly an important source of AMR pathogens. antimicrobial from each major antimicrobial class. A cav- BRD involves a complex of etiological agents including eat of many of the studies selected is that MIC resistance/ Mannheimia haemolytica, the predominant agent [92], sensitivity breakpoint criteria have not been defined for Pasteurella multocida,and Histophilus somni [92, 93]. H. many cattle pathogens, as well as some antimicrobials somni occurs sporadically, and can cause fatal septicemia (e.g. streptomycin). Complicating a general view of resist- in cattle. Mycoplasma bovis is also frequently associated ance across multiple species are the following caveats: (I) with BRD [94]. These ubiquitous pathogens are often de- some studies do not test the same antimicrobials as scribed as commensals because colonization is asymptom- others, (II) for some species, reports are very scarce, (III) atic in most healthy animals. As opportunistic pathogens, some studies test relatively few isolates for resistance, (IV) respiratory disease may develop with detrimental changes in some cases, designation of resistance is defined by the to the immune status of the host animal as a result of author and not via standardized interpretive criteria, and stress (e.g. transportation, weaning) or viral infections (e.g. (V) the median value of percent of resistance is biased Bovine Herpes Virus-1, Bovine Respiratory Syncytial towards values for which there are fewer comparative data Virus) [89]. Typing of M. haemolytica isolates obtained points. Thus, the data presented in Fig. 2 should be viewed from fatal pneumonia cases in calves show substantial with caution. diversity [95], suggesting that outbreaks of BRD are not due Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 6 of 22 to the herd-wide transmission of a single virulent strain, in M. haemolytica to 6 antimicrobial classes including but originate from formerly commensal strains [95, 96]. In ceftiofur, danofloxacin and enrofloxacin, florfenicol, oxy- North America and many countries, macrolides are often tetracycline, spectinomycin, tilmicosin and tulathromy- given as BRD metaphylaxis to asymptomatic animals in the cin. They found that in 2009, ~5% of isolates were presence of diseased animals. Individual cattle symptomatic resistant to 5 or more antimicrobials as compared to for BRD may also be treated with a wide range of antimi- ~35% in 2011 [102]. M. haemolytica isolates resistant to crobials, with the fluoroquinolone marbofloxacin used in oxytetracycline were 3.5-fold more likely to be resistant this manner [97]. Clinical symptoms may only become ap- to 1 or more antimicrobials, compared to non- parent after pulmonary damage has occurred. Conse- oxytetracycline-resistant isolates [102]. MDR has been quently, metaphylactic control of BRD often improves the detected in P. multocida and H. somni. Klima et al. [92] welfare of cattle as well as financial returns through cost isolated M. haemolytica, P. multocida and H. somni savings achieved by reduction in morbidity and mortality from BRD mortalities, and determined that 72% of M. [98]. haemolytica and 50% of P. multocida isolates exhibited In calves experimentally infected with M. haemolytica AMR. Surprisingly, 30% of M. haemolytica and 12.5% (4 × 10 CFU), Lhermie et al. [97] demonstrated that of P. multocida were resistant to >7 antimicrobial clas- low-dose (2 mg/kg) marbofloxacin 12 h after inoculation ses, including aminoglycosides, penicillins, fluoroquino- eliminated this pathogen from all calves, but at 45 h lones, lincosamides, macrolides, pleuromutilins, and post-inoculation a high-dose (10 mg/kg) failed to do so. tetracyclines [92]. The MDR isolates originated from Since M. haemolytica persisted after this high-dose, a feedlots in Texas or Nebraska. MDR was found in mul- higher risk for AMR development may have been cre- tiple M. haemolytica populations, suggesting that a ated by a practice thought to be more judicious than clonal population was not responsible for this observa- mass medication [97]. Thus, although metaphylactic tion [92]. MDR was due to a tandem array of AMR approaches may expose more bacteria to antimicrobial genes concentrated within an Integrative and Conjugable selection, they may also reduce pathology, and eliminate Element (ICE), a mobile genetic element (MGE) [92]. pathogens more effectively than single-dose therapeutic These elements constitute a diverse group of MGEs approaches. In another study, continuous sub-therapeutic found in both Gram-positive and -negative bacteria, and administration of the macrolide tylosin (Tylan, Elanco; are notable for encoding the conjugation machinery re- 11 mg/kg in-feed) had no effect in reducing carriage of M. quired for mobilisation of ICE to other bacteria, where haemolytica in beef cattle, compared to substantial reduc- they often integrate into multi-copy genes such as tions after therapy with a single subcutaneous injection of tRNAs and rRNAs. ICEs also frequently encode virulence tilmicosin (Micotil, Elanco; 10 mg/kg) or tulathromycin factors, heavy metal transporters, and toxin-antitoxin sys- (Draxxin, Pfizer; 2.5 mg/kg) [99]. Antimicrobial usage in tems, thought to ensure the stability of chromosomally- single animals has been shown to increase the risk of iso- inserted ICE within cells. lating both susceptible and MDR M. haemolytica from A putative ICE, designated ICEMh1, was recently de- pen mates, highlighting the importance of bacterial trans- tected in M. haemolytica strain 42548 by Eidam et al. mission in the dissemination of AMR [100]. Furthermore, that carried resistance to aminoglycosides (aphA-1, strA, Klima et al. [101] found that MDR occurred more fre- strB genes), tetracyclines (tet(H) gene), and sulfonamides quently in diseased than healthy cattle (37% vs. 2%) in M. (sul2 gene) [103, 104]. ICEMh1 has a size of 92,345 bp, haemolytica collected from healthy cattle vs. cattle with harbors ~107 genes, and shares a high degree of similar- clinical BRD. In that study, tetracycline resistance ity with ICEPmu1, an ~82 kb element identified in P. (18%) was the most prevalent resistance phenotype [101]. multocida that encodes ~88 genes [104]. The structure Resistant M. haemolytica and P. multocida can also be re- of ICEPmu1 is depicted in Fig. 3a. ICEPmu1 integrates Leu covered from diseased antimicrobial non-treated cattle. into a chromosomal copy of tRNA [105]. Eleven re- Via the pan-European VetPath susceptibility monitoring sistance genes are encoded within two gene clusters, program, de Jong et al. [45] analyzed isolates collected conferring resistance to tetracyclines (tetR-tet(H) genes), between 2002 and 2006 from diseased cattle with no streptomycin (strA and strB), streptomycin/spectino- antimicrobial exposure for at least 15 d prior to sampling, mycin (aadA25), gentamicin (aadB), kanamycin/neomy- and found that 14.6% of M. haemolytica (231 total iso- cin (aphA1), phenicols (floR), sulfonamides (sul2), lates) were resistant to tetracycline, and 5.7, 3.5 and 0.4% macrolides/lincosamides (erm(42) gene) or tilmicosin/ of P. multocida (138 total isolates) were resistant to tetra- tulathromycin (msr(E)-mph(E) genes) [92, 105]. cycline, spectinomycin, and florfenicol, respectively [45]. ICEPmu1 was shown to conjugatively transfer in vivo MDR has also been reported in BRD agents. Lubbers into recipient P. multocida, M. haemolytica and E. coli −4 −5 −6 et al. [102] evaluated records from 2009 to 2011 from at frequencies of 1.4 × 10 , 1.0 × 10 and 2.9 × 10 re- the Kansas State Diagnostic Laboratory for co-resistance spectively [105]. E. coli transconjugants demonstrated up Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 7 of 22 Fig. 3 Antimicrobial resistance determinants in mobile genetic elements. a Organization of the Integrative and Conjugative Element (ICE) ICEPmu1 found in the BRD agent Pasteurella multocida [179]. Resistance gene clusters 1 and 2 are shown expanded in grey. b Circular distribution of antimicrobial resistance genes by class, and abundance in total annotated antimicrobial genes found six plasmid metagenomes from the influent and sludge from two wastewater treatment plants (modified and reproduced with permission from [192]) to 64-fold higher MIC values for florfenicol, suggesting (pCCK381; 10.8 kb) and Dichelobacter nodosus (pDN1; better functional activity of FloR in E. coli [105]. A β- 5.1 kb). Collectively, these findings reveal the importance lactam oxacillinase (bla ) was also present, and con- and diversity of AMR and HGT mechanisms in BRD OXA-2 ferred greater ampicillin resistance in E. coli harboring pathogens. ICEPmu1 [105]. As many of the ICEPmu1 resistance genes may not be indigenous to Pasteurellaceae, acquisi- Antimicrobial resistance in liver abscess pathogens tion of AMR determinants from Enterobacteriaceae is Liver abscesses in beef cattle result from aggressive likely [105]. ICEPmu1 and ICEMh1 were isolated from grain-feeding, and represent an economic liability. Liver feedlot BRD cases in Nebraska in 2005 and Pennsylvania abscess incidence in North American feedlot cattle in 2007, respectively [104, 105]. There is currently little ranges from 12 to 32% [12]. Fusobacterium necro- information on the prevalence of these or similar ICE el- phorum, an anaerobic rumen bacterium, is the major ements in herds, but the presence of AMR-ICEs in BRD etiological agent isolated from condemned livers, agents represents a critical risk for the efficacy of future followed closely by Trueperella pyogenes [12]. Hepatic antimicrobial therapy. Simultaneous and rapid acquisi- disease is detected after slaughter since cattle with ab- tion of multiple resistance genes via a single HGT event scesses are usually asymptomatic. Liver perforation that could severely limit therapeutic options. leads to systemic infection is rare. In-feed antimicrobials, Besides HGT via MGEs, AMR determinants arise such as the FDA-approved tylosin, chlortetracycline, spontaneously via mutation. In some isolates of M. hae- oxytetracycline, bacitracin, and the streptogramin, virgi- molytica and P. multocida, high-level (MIC ≥ 64 mg/L) niamycin, are approved for liver abscess prevention in macrolide resistance has been attributed to mutations in many countries. In a study of ~7,000 feedlot cattle, tylo- the multicopy 23S rRNA genes (e.g. M. haemolytica sin reduced the incidence of liver abscesses by up to A2058G; P. multocida A2059G) [106]. Resistance to 70%, and increased weight gain by 2.3% [12, 109]. Al- macrolides, lincosamides and other ribosome-targeting though a common rumen inhabitant, F. necrophorum is antibiotics has been shown to be conferred by mono- an opportunistic pathogen also associated with calf diph- methylation of the M. haemolytica and P. multocida 23S theria and foot rot [110]. In a 2-year comparison of flora rRNAs at position A2058 [107]. Methylation is catalyzed isolated from liver abscesses in cattle fed with or without by a novel monomethyltransferase, designated erm(42), tylosin, Nagaraja et al. [111] found that the incidence of which appears to have been disseminated among the T. pyogenes in mixed culture with F. necrophorum was Pasterellaceae [107]. Plasmid borne transfer of AMR higher in abscesses from tylosin-fed cattle (53% vs. 10% genes may also be significant among BRD bacteria. In in the non-tylosin fed cattle). In contrast, the incidence the first report of a floR florfenicol resistance gene in M. of F. necrophorum was higher in cattle that were not fed haemolytica, Katsuda et al. [108] identified pMH1405, a tylosin (61%), as compared to those that were (33%). 7.7 kb florfenicol resistance plasmid, which appears to No differences in tylosin susceptibility between isolates be remarkably similar to plasmids from P. multocida from antimicrobial-free or tylosin-exposed cattle were Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 8 of 22 identified [111]. AMR in Fusobacterium spp. isolated economy-damaging, or largely untreatable pathogens. from humans is also relatively rare [112, 113], suggesting For cattle, notifiable diseases include (I) abortive agents: that AMR in this genera is yet to present a major risk to Brucella abortus (Brucellosis), Coxiella burnetti (Q beef production or human medicine. AMR in bovine T. fever), and Leptospira spp. (Leptospirosus); (II) bovine pyogenes is of greater concern, due to the versatility of pneumonia agents: Mycoplasma mycoides subsp. the bacterium as a cause of liver, skin, joint, and visceral mycoides small colony type (Contagious bovine pleuro- abscesses, and roles in mastitis and abortion [114]. Tylosin pneumonia), and Mycobacterium bovis (Bovine tubercu- resistance has been documented and linked to the pres- losis); and (III) enteritis agents: Mycobacterium avium ence of erm(X) or an erm(B) gene similar to that found on subsp. paratuberculosis (Johne’s disease), and Bacillus the Enterococcus faecalis MDR plasmid pRE25 [115, 116]. anthracis (Anthrax) [123]. Although it might be as- This suggests AMR transfer occurs between these human sumed that AMR would be a major issue in these patho- and cattle pathogens. Jost et al. [116] examined 48 T. pyo- gens, for the most part AMR has not been studied in genes isolates, of which 27 were derived from cattle, and these pathogens or is rare. Besides the rarity of cases, identified erm(X) as the most prevalent tylosin resistance other reasons for this include: (I) the notifiable pathogen determinant. An erm(X) tylosin and tetracycline tet(33) re- is already intrinsically resistant to many antimicrobials sistance plasmid, pAP2, was also identified [116]. Other (e.g. Mycobacterium spp.); (II) the pathogen resides in an studies have found high prevalence of tetracycline and sul- antimicrobial-exclusive intracellular niche that renders fonamide resistance, and suggest that AMR in T. pyogenes antimicrobial therapy impractical (e.g. Brucella abortus may of greater significance in bovine mastitis as compared and Coxiella burnetti); or (III) a secreted toxin causes to liver abscesses [117, 118]. pathology (e.g. Bacillus anthracis). Control of outbreaks of these diseases rarely involves antimicrobial therapy Antimicrobial resistance in keratoconjunctivitis pathogens and relies on animal segregation, herd control, or de- Infectious bovine keratoconjunctivitis is a painful ocular population [13]. disease caused primarily by non-self-limiting infections AMR susceptibility tests of human clinical isolates of with Moraxella bovis and bovoculi. The disease is com- Mycobacterium bovis have been performed because of mon worldwide in cattle, transmitted by flies, and if un- the role of M. bovis in human tuberculosis (TB). Al- treated, may result in ulceration and cornea rupture. In though it can infect many species, the main reservoir of the US, only oxytetracycline and tulathromyin are ap- M. bovis is cattle, and transmission to humans is primar- proved for the treatment of bovine keratoconjunctivitis, ily via contact with infected animals and drinking although penicillin may be used in other countries. In a unpasteurized milk [124]. In clinical isolates of M. tuber- study of 32 Moraxella spp. isolated from cattle and culosis and M. bovis collected over 15 yr, Bobadilla-del sheep, Maboni et al. [119] found that 40% of isolates Valle et al. [125] found that 16.6% of isolates from human were penicillin-resistant and 20% were tetracycline- TB cases were M. bovis. Susceptibility testing to first-line resistant, but most were susceptible to other antimicro- anti-TB drugs revealed that 10.9% of M. bovis were bials. Dickey et al. [120] published the genome sequence streptomycin-resistant, and 7.6% were MDR (isoniazid- for an AMR isolate of Moraxella bovoculi, Mb58069. It and rifampin-resistant). The aminoglycoside streptomycin was found to be resistant to florfenicol, oxytetracycline, is approved for use in cattle against aerobic Gram- sulfonamides, and displayed intermediate resistance to negatives such as enteritis-causing E. coli and Salmonella macrolides. Ten AMR determinants were co-located on spp. [14]. Bovine-human transmission of AMR M. bovis a >27 kb genomic island [120]. The biofilm-forming cap- appears to be rare in developed countries, but may occur abilities of Moraxella bovis may also enhance antimicro- more frequently in developing countries [124, 126]. bial resistance. Prieto et al. [121] found that Moraxella bovis readily forms biofilms, increasing resistance to Antmicrobial resistance in zoonotic human ampicillin, chloramphenicol, gentamicin, and oxtetracy- enteropathogens cline by 256-, 1,024-, 512-, and 1,024-fold as compared Antimicrobial resistance in bovine-origin Escherichia coli to when this bacterium grows planktonically [122] Thus, Cattle are E. coli reservoirs, with most strains harmless antimicrobial susceptibility via standard disk diffusion commensals. Some E. coli, particularly invasive and and microtiter MIC determinations failed to reflect the enterohemorrhagic E. coli (EHEC) cause septicemia in true level of resistance of this isolate. neonatal calves, but are primarily pathogenic to humans. E. coli strains from bovines and other food production Antimicrobial resistance in notifiable/reportable bovine animals serve as indicators of AMR prevalence in bacterial pathogens Gram-negative bacterial populations, thus sentinel ‘generic’ Many countries maintain registries of notifiable diseases E. coli help establish and track the persistence of AMR associated with zoonotic, unvaccinable, highly infectious, genes in environments affected by beef production and Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 9 of 22 other human activities. For example, in a recent survey of product. All cephalosporin-resistant E. coli isolated were AMR in E. coli from Nebraska cattle feedlot runoff catch- resistant to ampicillin, ceftiofur, and ceftriaxone, and ment ponds and the effluent of municipal wastewater 64% of isolates harbored bla , conferring additional CMY treatment plants, Agga et al. [127] found that the diversity resistance to clavulanate/amoxicillin and cefoxitin [135]. of AMR genes in human-associated samples was greater These reports suggest that hygienic practices in beef than from environments impacted by cattle. Interestingly, processing are effective against AMR bacteria. rd E. coli resistant to 3 generation cephalosporins and tri- methoprim/sulfamethoxazole were found at equivalent Antimicrobial resistance in bovine-origin Salmonella high-frequency (>70% of E. coli isolates) in both livestock Non-typhoidal Salmonella spp. (often Salmonella enter- and municipal wastewater environments [127]. ica serotype Typhimurium or Enteritidis) are frequent Extended-spectrum β-lactamases (ESBLs) that inacti- laboratory-confirmed infectious agents of gastroenteritis. vate newer cephalosporins are a major focus of sentinel Although the enteritis is usually self-limiting, invasive S. E. coli susceptibility testing. Cottell et al. [128] evaluated enterica spp. infections often require antimicrobial ther- E. coli originating from 88 steers that were treated with apy. Cattle are infected/colonized by many Salmonella ceftiofur and/or chlortetracycline in an experimental US species, and ground beef is a vehicle of Salmonella trans- feedlot. The ESBL bla , was detected in mission, implicated in 45% of outbreaks linked to beef CTX-M-32 cefoxatime-resistant E. coli in 29 animals, and was found [136]. In cattle, susceptible adults develop enteritis, and to be present on a self-transmissible IncN-family plas- calves may also develop septicemia. S. enterica serotypes mid (reviewed in [129]). In Germany, bla was the Dublin and Newport are associated with bovine salmon- CTX-M-1 predominant ESBL in E. coli, found on 87% of assessed ellosis, and adult cattle may carry and shed Salmonella farms [130]. In a Swiss study of the wider food process- asymptomatically for many years. In humans, serotype ing chain, Geser et al. [131] screened for ESBL in fecal Dublin has the highest proportion of invasive infections samples collected at slaughter as well as in raw milk, resulting in hospitalization and mortality [137]. Due to and minced beef. They found that of 124 bovine fecal the frequency of infections, the development of AMR in samples 13.7% hosted ESBL-producing bacteria, 98% of Salmonella is a risk to human health. In North America, which were E. coli. Despite enrichment for ESBL- MDR Salmonella are on average resistant to 7 antimi- producing organisms, ESBL were not detected in raw crobials [138]. In the US, Salmonella (and other entero- milk or minced beef samples. The ESBLs detected in the pathogens) are collected from humans, animals, and study included bla , bla bla , bla retail meat for the National Antimicrobial Resistance CTX-M-1 TEM-1 CTX-M-14 CTX- , and bla . Many of the ESBL-positive iso- Monitoring System (NARMS) [137]. In 2013, Salmonella M-117 CTX-M-15 lates were frequently co-resistant to tetracycline (76%), was isolated from 7.9% of beef cattle, and in 0.9% of trimethoprim/sulfamethoxazole (76%), nalidixic acid ground beef samples [137]. MDR (>3 antimicrobials) (47%), at least one aminoglycoside (76%), chloram- was found in 20% of all ground beef serotype Dublin phenicol (65%) and ciprofloxacin (41%). The authors isolates, many of which were resistant to ampicillin, suggested that slaughter hygiene prevented the transmis- chloramphenicol, streptomycin, sulfonamides, and tetra- sion of ESBLs into the food chain [131]. Similarly, the cycline [137]. Worse still, the prevalence of ceftriaxone rd prevalence of AMR E. coli O157:H7 was investigated in resistance (3 generation cephalosporin) in bovine- 510 fecal, hide, carcass, and raw meat samples from 4 origin serotype Dublin increased from 0 to 86% between beef slaughterhouses in China. STEC was detected in 1996 and 2013 [137]. As this is a major risk to human 1.4% of fecal and hide sample, but not in pre- and post- health, adoption and adherence to good practices during evisceration carcasses, nor in raw meat samples, with all beef processing and proper cooking are critical to pre- isolates sensitive to 16 relevant antimicrobials [132]. vent transmission [136, 139, 140]. During slaughter, cattle hides are major contributors to carcass contamination [133, 134]. In another study Antimicrobial resistance in bovine-origin Campylobacter rd tracking E. coli resistant to 3 -generation cephalospo- Campylobacter is the most frequent cause of human rins or trimethoprim/sulfamethoxazole, Schmidt et al. bacterial gastroenteritis in the developed world, with [135] determined the prevalence of generic and AMR E. Campylobacter jejuni responsible for >90% of Campylo- coli at various sites along the beef processing continuum. bacter infections [141]. Mostly a self-limiting infection The prevalence of cephalosporin-resistant and trimetho- in humans, severe cases of campylobacteriosis are prim/sulfamethoxazole-resistant E. coli in fecal samples treated with drugs such as erythromycin or ciprofloxa- at processing was 75 and 95%, respectively. Prevalence cin. Campylobacter are frequent colonizers of chickens, in pre-evisceration carcasses was 3 and 33%, and resist- but cattle are an important reservoir, and can carry high ant isolates were only found in 0.5% of final carcasses, numbers of Campylobacter asymptomatically [142]. and no isolates were associated with the final striploin Susceptible cattle can suffer from enteritis, and Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 10 of 22 Campylobacter fetus subsp. fetus and subsp. venerealis for their presumptive importance as AMR determinant can cause venereal bovine genital campylobacteriosis, sentinels/reservoirs. leading to infertility and abortion [13, 142]. In the NARMS report, Campylobacter was isolated from 42% Antimicrobials and the bovine microbiota of beef cattle, with 14% of isolates resistant to ciproflox- Cattle house a dense (>10 microbes/ml; rumen fluid acin [137]. In a Japanese study of beef cattle, C. jejuni [152]) consortia of microbial species in the distinct was isolated from 36% of cattle on 88% of the farms physiological niches of the rumen and lower digestive surveyed: ~40% of C. jejuni isolates were enrofloxacin- tract [153]. Different host compartments functionally se- and nalidixic acid-resistant, but none were lect for, and are shaped by, distinct microbial communi- erythromycin-resistant [143]. In a Swiss study of 97 ties that are essential for the proper physiology and Campylobacter isolates obtained from a beef processing development of the host [154, 155]. Cattle are dependent plant, Jonas et al. [144] found that 31% were on rumen microbes for feed digestion, and the micro- fluoroquinolone-resistant and ~1% were erythromycin- biome collectively degrades complex polysaccharides, resistant. Wieczorek et al. [145] examined Campylobac- converting plant mass into volatile fatty acids for absorp- ter abattoir prevalence on 812 bovine hides and corre- tion by the host animal. Core microbial species in the sponding carcasses, and found Campylobacter on 25.6% rumen include Prevotella, Butyrivibrio, Ruminococcus,as of hides, and 2.7% of carcasses. The isolates obtained well as many unclassified organisms [156, 157]. Other were equally resistant to nalidixic acid and ciprofloxacin bovine niches harbor unique microbial communities, (38.3%), streptomycin (24.3%), tetracycline (20.9%), such as the nasopharyngeal and vaginal tracts [153, 158, erythromycin (4.3%), and gentamicin (2.6%) [145]. 159]. The microbial community in the jejunum also has a role in feed digestion, and influences feed efficiency [160]. The fecal microbiota is dominated by Firmicutes Antimicrobial resistance in bovine-origin Enterococcus and Bacteroidetes, but also contains Proteobacteria and Enterococcus spp. are ubiquitous Firmicutes in the human enteropathogens, which are shed in feces [154, healthy intestinal microbiota of both humans and cattle, 161, 162]. Collectively, the intestinal microbiota hosts a and indicate fecal contamination. Most Enterococcus portion of the cattle resistome. spp. are not foodborne pathogens, nor are they bovine Unlike in humans and experimental animal models, pathogens [13]. Despite this, isolates of Enterococcus fae- there is currently limited information concerning the ef- calis and faecium may cause life-threatening human in- fect of antimicrobials on the bovine microbiota/resis- fections, such as UTIs and meningitis. Control of tome. However, much work describes the effect of enterococci infections is complicated by high-level MDR therapeutic and sub-therapeutic administration of anti- [146]. Enterococci are referred to as ‘drug-resistance microbials on the prevalence of specific bacteria in bo- gene traffickers’ due to their omnipresence, robustness, vines. These studies typically involve antimicrobial and capability of transferring AMR to other species and administration to a controlled animal cohort, followed pathogens [147, 148]. E. faecalis transferred gentamicin by culture-dependent collection of an organism-of- resistance plasmids to transplanted human flora in a interest for susceptibility testing. These approaches pro- BALB/c mouse model [149]. The US NARMS report in- vide a biased snapshot of microbiome changes. Newer dicates that Enterococcus were recovered from ~90% of methods include culture-independent collection of meta- cattle, and ~80% of retail ground beef tested. The inci- genomic DNA for detection and quantitation of specific dence of MDR (>3 antimicrobials) in both E. faecium AMR genes by PCR-based methodology, or for high- and faecalis was lower in cecal isolates from beef cattle throughput sequencing and functional AMR gene annota- (19 and 14%, respectively) than in cecal samples from tion (Table 1). There are currently few studies describing chickens (67 and 46%, respectively) or turkeys (25 and the effects of antimicrobials on microbial population 58%, respectively) [137]. Other studies of AMR Entero- diversity in bovines using high-resolution sequencing coccus typically focus on the emergence of resistance to methodology. vancomycin— an antimicrobial used in the treatment of MRSA and other Gram-positive infections [122, 150]. Effect of antimicrobials on the bovine microbiota Vancomycin or linelozid resistance was not detected in Pereira et al. [163] characterized the gut microbiota bovine-origin Enterococcus spp. in the United States or (fecal samples) of pre-weaned dairy calves fed raw milk Canada [137, 151], but ~30% of E. faecium NARMS iso- spiked with ‘residual’ concentrations of ceftiofur (ceftio- lates were found to be quinupristin/dalfopristin-resistant fur sodium; 0.1 μg/mL), ampicillin (ampicillin sodium; [137]. Overall, despite the possibility for transmission of 0.01 μg/mL), penicillin (penicillin G sodium; 0.005 μg/ pathogenic strains to humans, Enterococcus spp. in the mL), and oxytetracycline (oxytetracycline hydrochloride; beef production environment have been studied mainly 0.3 μg/mL) using 16S rRNA Illumina MiSeq-based Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 11 of 22 Table 1 Selected studies on the effect of antimicrobials on the cattle microbial resistome Study Livestock Antibiotic tested (class) Experimental treatment Sample Characterization methodology Outcome or notable findings (animals in type study) Chambers et al. Dairy cattle Ceftiofur Administration of therapeutic Fecal Metagenomic DNA: Illumina HiSeq Increase in bacterial sequences associated rd 2015 [165] (6 Holstein (3 generation ceftiofur over 3 d trial of total DNA with MG-RAST and with resistance to β-lactam and multidrug cows) cephalosporin) ARDB annotation resistance Benedict et al. Beef cattle Various (5 difference Correlation between routine Fecal Bacterial isolation and susceptibility Exposures to tetracycline, streptomycin, and 2015 [175] (>10,000 antimicrobial drug classes antimicrobial usage in a feedlot testing. trimethoprim-sulfamethoxazole were animals) system and antimicrobial significantly associated with increased resistance in non-type Escherichia abundance of antimicrobial resistance genes coli over 3 yr rd Kanwar et al. Beef cattle Ceftiofur (3 generation Administration of therapeutic Fecal Metagenomic DNA: qPCR of select AMR Increase in ceftiofur resistance genes and 2014 [164] (176 steers) cephalosporin) ceftiofur and/or chlortetracycline genes decrease in tetracycline resistance genes Chlortetracycline over 26 d trial following ceftiofur treatment (tetracycline) Increase in ceftiofur and tetracycline resistance genes following chlortetracycline treatment Zaheer et al. Beef cattle Tylosin Administration of either Fecal Bacterial isolation and susceptibility Both sub-therapeutic and therapeutic 2013 [99] (40 steers) Tulathromycin sub-therapeutic tylosin or testing. PCR of select AMR genes macrolide treatment increased abundance Tilmicosin therapeutic tulathromycin or of macrolide resistant Enterococci (macrolide) tilmicosin Thames et al. Dairy cattle Neomycin (aminoglycoside) Administration of either Fecal Metagenomic DNA; qPCR of select AMR Sub-therapeutic antibiotic treatment had 2012 [219] (41 calves) Oxytetracycline sub-therapeutic or therapeutic genes no effect on abundance of tested resistance (tetracycline) neomycin or oxytetracycline determinants. over 50 d milk-replacement Therapeutic treatment with oxytetracycline trial increased abundance of tetracycline resistance genes Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 12 of 22 sequencing. Exposure resulted in Genus-level differ- Utilizing advanced total community metagenomic se- ences, but taxa above the Family level were not altered quencing, Chambers et al. [165] examined the effect of [163]. The microbiota of exposed calves was also less di- ceftiofur treatment on the prevalence of AMR genes in verse than treatment-free calves [163]. Similarly, Reti et the bovine fecal microbiome. Holstein cows were al. [162] examined the effects of a sub-therapeutic AGP injected subcutaneously with ceftiofur (CCFA, Excede, on the abundance and composition of microflora in the Zoetis; 1 mg per 45.4 kg body weight) and fecal samples small and large intestine of adult beef cattle. The US- were collected prior to and post-treatment. Total DNA and Canada-approved chlortetracycline/sulfmethazine was sequenced on the Illumina HiSeq platform, and AGP (Aureo S-700 G, Alpharma) was administered at AMR genes were detected using the antibiotic resistance 350 mg of each antimicrobial per head per day for 28 d genes database (ARDB) [166]. The proportion of β- [14]. Compared to non-treated control cattle, beef cattle lactam and MDR sequences were found to be higher in administered the AGP showed no differences in bacterial ceftiofur-treated cows relative to control cows. The β- abundance or richness/diversity composition (deter- lactamase genes cfxA2 and cfxA3 were most abundant, mined via quantitative PCR and terminal restriction and have previously been associated with Prevotella—a fragment length polymorphism analyses) [162]. Studies common rumen microbe [167]. Ceftiofur also changed using advanced 16S rRNA metagenomic sequence-based the fecal bacterial community composition, increasing and whole metagenome methodologies may be of Bacteroidia and decreasing Actinobacteria. This study greater significance in future work exploring the effect was also notable because metagenomic data was function- of antimicrobials on the microbiota. ally assessed with MG-RAST [168], allowing examination of antimicrobial-induced changes to the metagenome. Functional ceftiofur-associated shifts included increased Effect of therapeutic and sub-therapeutic antimicrobial prevalence of genes associated with stress, chemotaxis, usage on AMR gene prevalence and resistance to toxic compounds [165]. This work and Kanwar et al. [164] recently explored the effects of dif- others like it likely represent the future direction of AMR ferential treatment strategies on the prevalence of AMR surveillance research. determinants in the fecal metagenome. In a 26-day field Sub-therapeutic antimicrobial administration is one of trial, 176 beef steers were divided into 4 cohorts and the most controversial beef production practices with given therapeutic doses of ceftiofur (ceftiofur crystalline- many studies exploring this topic in the context of AMR free acid (CCFA), Excede, Zoetis; 6.6 mg/kg body weight) development. Alexander et al. [169] investigated effects and/or chlortetracycline (Aureomycin, Alpharma; 22 mg/ of chlortetracycline/sulfamethezine AGPs (Aureu S-700 kg body weight). One of the four cohorts included steers G, Alpharma; 44 mg/kg each in-feed) on the prevalence in which only 1 of the animals was administered ceftiofur of AMR E. coli in the beef production continuum. With and chlortetracycline, while the remaining animals re- respect to treated and non-treated cattle, E. coli was col- ceived chlortetracycline alone. Via quantitative PCR, the lected from live-animal feces, hides, intestinal digesta, authors determined gene copies/g of wet feces of bla carcasses, and ground beef. Animals fed chlortetracyc- CMY-2 and bla (ceftiofur resistance), tet(A) and tet(B) line/sulfamethezine harbored more tetracycline-resistant CTX-M (tetracycline resistance), and 16S rRNA genes in fecal E. coli than non-treated animals (50.9% vs. 12.6%), but community DNA from the pens of each treated cohort. there were no differences in the prevalence or profile of Pens where all cattle were treated with ceftiofur had AMR E. coli between treatments in the hide, carcass or greater numbers of bla and bla ceftiofur resist- ground beef samples [169]. To the authors this sug- CMY-2 CTX-M ance determinants than single-animal treatment pens gested that AMR E. coli can enter the food chain at [164]. Chlortetracycline treatment increased the levels of slaughter regardless of AGP administration [169]. Sub- bla and bla gene copies compared to cattle in therapeutic administration of tetracycline/sulfamethazine CMY-2 CTX-M pens that did not receive chlortetracycline. In contrast, also increased the prevalence of tetracycline-resistant or- tetracycline AMR gene prevalence decreased in pens ganisms, and increased the frequency of ampicillin- where all cattle received ceftiofur compared to pens where resistant E. coli, in agreement with similar studies using only one animal received ceftiofur [164]. The authors the same antimicrobials [170]. Another study found that discussed these findings in the context of expansion sub-therapeutic tylosin treatment (Tylan, Elanco; 11 mg/ or suppression of singly- or co-resistant AMR popula- kg in-feed) increased the frequency of Enterococcus spp. tions under antimicrobial selection, which served to harboring erm(B) and/or msrC (a macrolide/streptogra- highlight the complexity of the effects of antimicro- min efflux pump gene) [171]. The authors of that study bials on the resistome, and the potential for discrep- concluded that the diversity of Enterococcus decreased in ancies between culture- and non-culture-based AMR the period between when cattle entered and exited the quantitation methodologies [164]. feedlot, and that the AMR Enteroccocus were derived Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 13 of 22 from strains present in the intestinal microbiota before contradictory reports where no such association exists tylosin administration [171]. Selection for co-resistance [99, 175]. and MDR is one of the main arguments against AGPs. Heavy metal supplementation and AMR Cattle also receive trace mineral supplements that in- Effect of BRD-related antimicrobial usage clude elements with AGP activity. Some heavy metals, Given the importance of antimicrobials in the treatment such as zinc, manganese, and copper may be given as of BRD agents, much research examines the effect of salt-mixes, injected, or administered in slow-release ru- antimicrobial treatment on AMR development in BRD minal capsules [14]. Copper and zinc promote growth, bacteria. Investigated the effects of therapeutic and sub- potentially via suppression of pathogens and alteration therapeutic macrolide administration on the nasopha- of microbiota [176, 177]. In other production animals, ryngeal and enteric microbiota, with specific focus on zinc and copper can select for AMR [178]. This may be M. haemolytica and Enterococcus, respectively. Forty due in part to MGEs such as ICE, in which AMR deter- beef steers were injected once with tilmicosin (Micotil, minants are co-localized with heavy-metal resistance Elanco; 10 mg/kg) or tulathromycin (Draxxin, Pfizer; genes. For example, in addition to multiple AMR deter- 2.5 mg/kg) or fed sub-therapeutic tylosin (Tylan, Elanco; minants, ICEPmu1 (Fig. 3a) encodes for a multi-copper 11 mg/kg in-feed) continuously over 28 d. Therapeutic oxidase, which is potentially involved in resistance to tilmicosin and tulathromycin decreased nasopharyngeal copper and other heavy metals [179]. Thus, heavy metal carriage of M. haemolytica: at the beginning of the trial, exposure can co-select for AMR. Jacob et al. [180] stud- 60% of the steers tested positive for M. haemolytica, at ied the effect of elevated copper and zinc fed to heifers 7 d post- injection, none of the steers treated with tilmi- receiving high-energy rations by isolating and character- cosin harbored M. haemolytica, and only one steer izing AMR E. coli and Enterococcus from fecal samples. treated with tulathromycin was positive for M. haemoly- Resistance to copper and zinc in E. coli isolates was in- tica. Sub-therapeutic tylosin had no effect on nasopha- creased, and abundance of the tetracycline resistance de- ryngeal carriage, and tylosin-exposed M. haemolytica terminant tet(M) was elevated following heavy metal isolates did not acquire macrolide resistance. In contrast, supplementation [180]. In a study combining tylosin a significant proportion of the bystander Enterococcus (Tylan, Elanco; 0 or 10 mg/kg in-feed) with copper acquired erm(B) erythromycin resistance following treat- (CuSO ; 10 or 100 mg/kg in-feed), Amachawadi et al. ment with either injectable tilmicosin or tulathromycin, [181] investigated fecal Enterococcus spp. to determine if or in-feed tylosin, and were 76-fold more likely to be elevated copper supplementation co-selects for macro- erythromycin-resistant than those recovered from non- lide resistance. The transferable copper resistance gene antimicrobial-treated steers. Catry et al. [172] correlated tcrB was identified in 8.5% of Enterococcus from ele- 2-year of Belgian farm-standard antimicrobial usage to vated copper- and tylosin-fed cattle, compared to copper the occurrence of AMR in rectum and nasal flora, repre- alone (4.5%), tylosin alone (3.5%), or the low copper/no sented by E. coli and Pasteurellaceae, respectively. Nar- tylosin control (2.0%) [181, 182]. All the tcrB-positive row spectrum penicillins were the most frequently isolates proved to be E. faecium, and interestingly, all administered parenteral antimicrobials, often in combin- tcrB-positive isolates harbored tetracycline tet(M) and ation with an aminoglycoside, such as neomycin or dihy- erythromycin resistance erm(B) determinants [181]. The drostreptomycin [172]. Among rectal E. coli, 20.6% were authors concluded that elevated dietary copper could resistant to least one antimicrobial. The most frequent co-select for AMR in feedlot cattle [181]. Thus, heavy resistance patterns were ampicillin-tetracycline- metal supplementation should also be considered as a streptomycin (15.9%), tetracycline-streptomycin (11.4%), selective pressure with the potential to promote the dis- and ampicillin-streptomycin (9.8%) [172]. Among 206 P. semination AMR determinants, and is a practice that multocida isolates and 42 M. haemolytica isolates origin- likely needs to be revisited as these minerals may be ating from the nasal cavity, the predominant resistance added to the diet in excess of the animal’s requirement. found was to the aminoglycoside spectinomycin [172]. The authors confirmed that antimicrobials altered the The bovine resistome & the wider environment prevalence of AMR in the digestive and respiratory tracts The primary concern relating to antimicrobials in agri- and highlighted that the route of administration affected culture is the potential for AMR determinants to expand resistance outcomes. Individual therapy was linked to in- and spread via the food chain. Although urban lifestyles creased but transient resistance, whereas in-feed antimi- rarely bring people into direct contact with livestock, the crobials were linked to higher levels of MDR [172]. Others animal production continuum extensively connects with have also suggested that the route of administration affects numerous industries, infrastructure, and ecologies. For overall AMR prevalence [173, 174], but there are also example, manure from antimicrobial-treated animals Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 14 of 22 may be applied to crops, or waste from farms may drain prevalent in anaerobic and aerobic sludge accounting for into rivers, reservoirs, and wastewater treatment plants. 35.95 and 58.36% of annotated reads, respectively, In the US, cattle produce between 0.86 and 6.4 million t followed by Firmicutes (16.31 and 6.08%, respectively) of manure daily [183]. AMR can thus be transferred to [191]. Concerning AMR genes 747 reads (0.0081%) and the wider environment, increasing the risk of contact 877 reads (0.0101%) in anaerobic and aerobic sludge, re- with a human pathogen. At present, knowledge about spectively, were assigned to 54 and 42 types of known the identity, diversity, distribution, and patterns of co- AMR genes [191]. MDR efflux transporters were most resistance in beef-related AMR genes, and how they common, followed by tetracycline and sulfonamide re- compare to determinants in other ecosystems is scarce, sistance genes (>20% of AMR-associated reads) [191]. due in part to the difficulty in defining the bovine resis- The authors also detected MGEs in tannery DNA sam- tome in the context of the larger environmental resis- ples, but limitations in methodology restricted investi- tome. AMR genes are widely present in both pristine gating linkages with AMR genes. Taking a similar and human-impacted environments [184], so the occur- approach, Li et al. [192] examined the resistome of plas- rence of AMR in any specific biome does not necessarily mids harvested from influent, activated sludge, and validate the impact of antimicrobial usage. However, digested sludge of two Hong Kong wastewater treatment with the advent of next-generation sequencing and total plants receiving domestic and slaughterhouse (cattle and metagenomics, and resources like ARDB, and CARD other production animals) sewage. AMR genes were de- (the Comprehensive Antibiotic Resistance Database; tected in all of the plasmid metagenomes: the most [185]), high-throughput AMR gene profiling resistomics abundant were tetracycline resistance genes (29% of all is shedding light on these relationships. AMR gene sequences), quinolone resistance genes (17%), and β-lactam resistance genes (12%) [192]. The Resistome characterization via shotgun metagenomics AMR gene distribution and abundance in each wastewa- Noyes et al. [186] examined AMR genes of 1,741 beef ter treatment plant sample is shown Fig. 3b, in circular cattle as they moved longitudinally through the produc- relationship format [192, 193]. This plasmid-centric tion chain, characterizing feedlot, slaughter, and beef study highlights the mobile resistome and plasmid fates product resistomes via shotgun metagenomics per- more so than a total metagenome study, and future ex- formed on the Illumina HiSeq platform, and assessed periments could involve comparisons between plasmid against the Resfinder [187], ARG-ANNOT [188], and and total resistomes to explore HGT of AMR determi- CARD [185] AMR gene databases. This identified 300 nants. This paper also highlights a methodology to unique AMR genes, and showed that, the diversity of examine MGE-associated AMR genes that is not con- the AMR genes decreased while cattle were in the feed- founded by environmental AMR genes or host DNA lot, indicative of selective pressure imposed by antimi- contamination. crobials, consistent with other studies showing diversity reduction following antimicrobial exposure [163]. Exam- Resistome characterization via functional metagenomic ination of post-slaughter samples obtained from belts library screening and tables in the slaughterhouse, meat trimmings, and Sequence-based metagenomic AMR gene profiling is market-ready samples revealed no AMR genes [186]. also limited to those genes with similarity to already The authors concluded that effective practices at slaugh- known AMR genes, and metagenomic shotgun read ter minimized the likelihood of AMR gene being passed lengths present difficulties for the characterization of the through the food chain. However, the high prevalence of AMR genomic context. Functional metagenomic library- bovine DNA complicates shotgun metagenomics and based approaches have proved to be complementary in may result in low sensitivity of AMR gene detection. the identification, quantification, and characterization of Despite this, this study exemplifies the powerful utility novel resistance determinants. Wichmann et al. [194] of metagenomic approaches in the study of AMR gene examined the resistome of dairy cow manure with ecology. large-insert (>35 kb) fosmid libraries constructed from Metagenomics have also proved useful in the examin- 5 manure samples. The resulting E. coli-based librar- ation of AMR genes found in wastewater treatment ies (containing 25.9 Gb of DNA) were screened for plants associated with tanneries and slaughterhouses. resistance to kanamycin, chloramphenicol, tetracyc- Wastewater treatment plants are thought to be HGT line, and the β-lactams carbenicillin (penicillin) and hotspots because of high bacterial diversity and density ceftazidime (cephalosporin). Of 87 AMR E. coli clones [189, 190]. Wang et al. [191] profiled AMR genes and with genes conferring resistance to at least one of the MGEs in wastewater sludge from a Chinese leather tan- antimicrobials tested, 80 carried unique AMR genes, nery via Illumina HiSeq and assessment with MG-RAST suggesting that the cow microbiome harbors AMR [168] and ARDB [166]. Proteobacteria were most- genes that are unique or unidentified elsewhere. A Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 15 of 22 novel clade of chloramphenicol acetyltransferases was studies utilizing libraries and shotgun metagenomics, or also described [194]. Flanking sequence analysis indi- emerging long-read sequencing technologies. cated that the AMR determinants originated from An example of risk and source determination may be typical cattle microbes: Firmicutes were predominant given by the long-term global epidemics of ground beef- (50% of sequenced clones), followed by Bacteroidetes associated MDR S. enterica serotype Typhimurium (23%) and Proteobacteria (14%) [194]. Another phage type DT104, which may express resistance to powerful advantage of the fosmid library approach is ampicillin, chloramphenicol, streptomycin, sulfameth- the ability to examine AMR gene context: i.e. co- oxazole, and tetracycline (resistance-type ACSSuT) occurrence with other AMR genes, or association with [203–205]. In some isolates, these AMR genes are MGEs. Wichmann et al. found 2 kanamycin-resistant E. hosted in a 13 kb MDR region, residing in a larger coli clones with >5 putative genes with predicted AMR or chromosome-encoded ~43 kb region called Salmonella MGE functions [194]. Thus, library-based functional genomic island 1 (SGI1). The MDR region harbors Class metagenomic approaches combined with next-generation I integrons—genetic elements capable of consolidating sequencing are a powerful way to screen for AMR deter- multiple AMR gene cassettes [206]. Integrons are often minants associated with MGEs, plasmids, or phages [195]. found in conjunction with MGEs; in the case of DT104, HGT can occur via phage-mediated transfer [207]. Al- Linking antimicrobial use in beef production to though veterinary antimicrobial usage and food animals human health risk have long been the chief culprit for the origin and dis- Assessing the differential risk, importance, and source of semination of DT104, Mather et al. [208, 209] chal- AMR genes lenged the perception that DT104 originated from a Given the ubiquity of AMR determinants in bovine and single zoonotic population by whole-genome sequencing other microbial communities, it is difficult to appraise Scottish DT104 collections. In total, 135 isolates from the relative risk any particular determinant presents for humans and 83 from cattle were sequenced and com- the likelihood of transfer into a human pathogen and pared against 111 other DT104 isolates from diverse clinical therapy failure. Confounding the issue are AMR host animals and countries. Using phylogenetic diffusion determinants that are expressed or silent in different models, the authors found that AMR DT104 populations hosts, as well as AMR determinants akin to housekeep- were distinguishable between cattle and humans, and ing genes [196]. For the latter, ‘decontextualized’ house- that animal-to-human and human-to-animal transitions keeping genes, such as those harbored on MGEs, pose a were rare, and occurred at the same frequency [209]. greater risk [1, 197]. Prioritizing the differential human This suggested that most human infections were unlikely health risk posed by an AMR gene is complicated by to originate from the local cattle. AMR diversity was such issues, but risk ranking schemes have been greater in human isolates, resulting from multiple, discussed [1, 198, 199]. Greatest risk may be presented independent recombination events in SGI1’s MDR re- by AMR genes already hosted on MGEs in human gion [209]. In part, this suggested that most human in- pathogens, and known to cause therapy failure. An ex- fections were acquired from humans, and that DT104 ample of this is the recently detected plasmid-mediated circulated separately in the animal and human populations, colistin (polymyxin E) resistance gene (mcr-1)in E. coli and/or unique sources infected humans vs. animals [209]. isolates from poultry, swine, and infected humans [200, Mather et al. emphasized the importance of integrating 201]. A beef-related example is the ~38 kb R plasmid veterinary and clinical data to make evidence-based found in S. enterica serotype Newport, which confers judgments concerning the sources of AMR infections. resistance to tetracycline, ampicillin, and carbenicillin [202]. This caused severe penicillin-unresponsive sal- Direct evidence of human health impact of beef monellosis linked to contaminated hamburger meat antimicrobial usage [202]. The next level of risk may be from functional Linking on-farm antimicrobial use to human infection is AMR genes conferring resistance to human antimicro- difficult. While antimicrobial usage evidently selects for bials, but which are hosted in MGEs in non-pathogenic drug-resistant organisms, there is a gap in knowledge bacteria. These might include the AMR determinants connecting usage to the flow of AMR determinants from encoded by ICEPmu1 and ICEMh1 found in P. multo- the bovine microbiota to outbreaks of human AMR cida and M. haemolytica, respectively [103, 104]. Ele- diseases. To bridge this gap, a number of studies com- vated risk is credited to MGEs because the acquisition pared outbreak clinical isolates to animal isolates taken and selection of an AMR determinant in a MGE might at similar times from nearby locations [210–212]. Typic- be the initial step for transmission to a human pathogen. ally, isolates were examined for similar AMR/genetic In the future, more focus should be devoted to AMR in profiles, and if identical, this provided some evidence of the context of MGEs, particularly for total resistome the AMR outbreak source. Direct links to specific Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 16 of 22 antimicrobial usage is rarely identified for outbreaks. A Conclusions & future focus caveat of many studies is that transfer is assumed to be As in most environments, AMR determinants exist ubi- from cattle to humans, or remains unknown. Several quitously in the beef production biome, regardless of AMR E. coli and Salmonella outbreaks have been associ- antimicrobial exposure. Nevertheless, the use of antimi- ated with beef [213–215], but there are few examples crobials for bovine welfare and growth promotion con- where those AMR determinants have been traced back tributes selective pressure that increases the abundance to AMR bacteria in cattle [210]. This reinforces the need of AMR genes and their host bacteria, and promotes the for greater integration of human and veterinary data. genesis and dissemination of MDR organisms. The pres- For beef production, tracing the source of an AMR out- ence or absence of connections between AMR in bovine break is complicated by system complexity, herd move- microbial populations to human health threats are likely ment, and lack of industry motivation. And although to become clearer with the increasing application of beef production is a major industry, more focus has been whole-genome sequencing and metagenomic resis- on the human health impact of AMR transfer in dairy tomics. The role of MGEs in AMR propagation is likely cattle, and in the swine and poultry industries (reviewed to be an important focus for understanding the impact in [214]). Dairy-related outbreaks may be easier to docu- of veterinary antimicrobials. Future investigations may ment because the source animal population is main- validate mitigation strategies, such as the separation of tained, whereas the beef, swine, and poultry populations antimicrobials for use in beef cattle from those used in are consumed. Selected examples of outbreaks and humans. Proper and judicious use of antimicrobials will human health threats posed by bovine AMR bacteria help prolong the usefulness of both clinical and veterin- are listed in Table 2. These demonstrate that the ary antimicrobials, but ever-increasing usage of anti- most convincing molecular and epidemiological AMR microbials in food-animal production suggests that links are found when the infected human is directly microbes will only continue to acquire resistance. Of connected to the animal population on farms or via particular concern for cattle are the MDR BRD agents: farm workers [211, 216, 217]. Direct exposure to live- in the future, respiratory infections may become untreat- stock is a known risk factor for zoonotic transmission able with current antimicrobials. On a positive note, sev- (reviewed in [218]). eral studies reveal that adequate hygiene and appropriate Table 2 Selected examples of cattle-related AMR human health threats Source Bacterial Human AMR profile Mechanism Notes Study species outbreak Calves S. enterica Veterinarian’s Ampicillin, chloramphenicol, Ceftriaxone An isolated, domestically acquired case [216] serotype child tetracycline, sulfisoxazole, resistance conferred requiring hospitalization. Failure of Typhimurium kanamycin, streptomycin, by bla on a ampicillin and sulbactam therapy, but CMY-2 cephalothin, ceftriaxone and conjugable plasmid recovery with amoxicillin/clavulanate. ceftiofur, aztreonam, cefoxitin, Direct molecular evidence linking MDR gentamicin, and tobramycin isolates from herds treated by the patient’s father Cattle, MRSA ST130 Two farmers Cefoxitin and penicillin Resistance conferred Direct transfer of mecC-MRSA from [211] Sheep by mecC(mecA cattle and sheep to humans resulting in homologue), wound infections SCCmec type XI [220] Veal MRSA ST398 Asymptomatic Methicillin and others Resistance conferred Asymptomatic human MRSA carriage [217] calves carriage by by mecA, SCCmec rates associated with prevalence in farm not stated calves and frequency of animal contact. employees MRSA carriage in calves associated with antimicrobial use rd Cattle, E. coli, Potential, Ceftriaxone, with high-levels 3 generation Potential transfer of bla plasmids [210] CMY-2 Swine Salmonella sporadic of co-resistance to cephalosporin between E. coli and Salmonella. Close transmission chloramphenicols, tetracycline, resistance conferred relationship between bla plasmids CMY-2 to humans sulfisoxazole, streptomycin, by plasmid-born in E. coli found in bovines and humans gentamicin, tobramycin, and bla CMY-2 ciprofloxacin Ground S. enterica Large Ampicillin, chloramphenicol, MDR genes Multi-state outbreak, potentially [213] beef, serotype clustered streptomycin, sulfemethoxazole, potentially encoded affecting >2200 people. Severe illness, possibly Typhimurium human and tetracycline (R-type ACSSuT) on Salmonella with a high proportion of patients from dairy DT104 outbreak genomic island 1 receiving intravenous rehydration and cows requiring hospitalization Cameron and McAllister Journal of Animal Science and Biotechnology (2016) 7:68 Page 17 of 22 treatment at slaughterhouse and wastewater treatment Funding AC is supported by an NSERC Postdoctoral Fellowship and the program as a facilities are efficacious at reducing or eliminating trans- whole is supported by the Beef Cattle Research Council BCRC – Agriculture mission of AMR organisms and genes. Thus, such and Agri-Food Canada beef cluster. procedures and facilities should be explored further, and Availability of data and materials promoted in deficient areas of food-animal production. Not applicable. Methods Authors’ contributions AC and TAM researched and co-wrote the review. Both authors read and ap- Literature search proved the final manuscript. The literature search was conducted from January to March 2016 via Google Scholar and PubMed. Recent Competing interests The authors declare that they have no competing interests. (2012-present) studies that described AMR or usage in context with beef production, bovine pathogens, com- Consent for publication mensal bacteria, metagenomics, the resistome, and cattle Obtained. were included. Older reports, or studies referring to Ethics approval dairy operations were excluded, except for where beef Not applicable. production information was sparse. Author details Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. Comparison of most frequently reported AMR in bovine Agriculture and Agri-Food Canada, Lethbridge, AB, Canada. pathogens Received: 17 May 2016 Accepted: 28 October 2016 A literature search was conducted for AMR in bovine pathogens. Journal articles ([30–88], 2000-present) were collected if the AMR data was presented in a format References 1. 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Antimicrobial usage and resistance in beef production

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