Antibacterial resistance: an emerging 'zoonosis'?

Review

Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/25/14 For personal use only.

Antibacterial resistance: an emerging ‘zoonosis’? Expert Rev. Anti Infect. Ther. 12(12), 1441–1461 (2014)

Marie-The´re`se Labro*1 and Jean-Marie Bryskier2 1

Poˆle Expertise Collective Inserm, Hoˆpital Paul Brousse (Villejuif), 94804 Villejuif, Cedex, France 2 DMV, 02880 Crouy, France *Author for correspondence: Tel.: +33 014 559 6057 [email protected]

Antibacterial resistance is a worldwide threat, and concerns have arisen about the involvement of animal commensal and pathogenic bacteria in the maintenance and spread of resistance genes. However, beyond the facts related to the occurrence of resistant microorganisms in food, food-producing animals and companion animals and their transmission to humans, it is important to consider the vast environmental ‘resistome’, the selective pathways underlying the emergence of antibacterial resistance and how we can prepare answers for tomorrow. KEYWORDS: antibacterial resistance • antibiotics • companion animal • food • livestock • resistome • veterinary medicine • zoonosis

‘ The continued advance in medicine will produce more problems than it solves’ . Hunterian Society debate, 17 November 1952 (Reports of societies. Brit. Med. J. 1952;2:1202) As soon as antibiotics were introduced in modern medicine, ‘a note of warning’ was delivered by Fleming himself [1]. ‘There may be a danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them’. Seventy years later, the book of infectious diseases has not been closed. Having spent many years in gaining knowledge about bacteria, we are now facing what has been called ‘the resistance tsunami’ [2], and questions arise as whether we are going to the end of the antibiotic era [3]. Among the passionate disputes about the origin, spread and maintenance of resistance, the role of animals as main involuntary effectors has been claimed. It is currently admitted that more than 60% of the emerging infectious diseases that have been discovered since 1940 and about 50% of bacteria that infect humans are zoonotic [4]. Resistance in bacteria isolated from food-producing livestock, companion animals and wildlife is also widely documented [5] and there is evidence that bacteria do spread from animals to humans and vice versa from humans to animals [6]. This review intends to approach the problem of antibacterial resistance as a potential ‘zoonosis’. After general definitions and a brief historical overview, the emergence of bacterial resistance will be envisaged in food, foodinformahealthcare.com

10.1586/14787210.2014.976611

producing animals, aquaculture and companion animals. The underlying hypothesized mechanisms will be presented before concluding on the problems and hopes of the future. Antibacterial resistance Definitions

Roughly speaking, bacterial antibacterial resistance refers to the capacity of a microorganism to resist the bacteriostatic/bactericidal activity of an antibacterial agent beyond the intrinsic susceptibility of the specific bacterial species. MICs are the key bacteriological in vitro determinant. The Clinical and Laboratory Standards Institute (CLSI), formerly known as National Committee for Clinical Laboratory Standards (in the USA, and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are the major international contributors to antimicrobial susceptibility testing, but national committees also make valuable contributions [7]. Exchanges of information occur between EUCAST and the CLSI, but a formal collaboration does not exist in setting breakpoints. EUCAST focuses principally on setting human breakpoints while the CLSI has separate standing subcommittees for human medicine and veterinary medicine. EUCAST and CLSI breakpoints are updated on a yearly basis. In the USA, most microbiology laboratories use the CLSI interpretive criteria for MICs. EUCAST differentiates between clinical resistance and the associated clinical breakpoints, and microbiological resistance and epidemiological cutoff values [8]:

2014 Informa UK Ltd

ISSN 1478-7210

1441


Review

Labro & Bryskier

‘A microorganism is defined as susceptible by a level of antimicrobial activity associated with a high likelihood of therapeutic success; a microorganism is defined as resistant by a level of antimicrobial activity associated with a high likelihood of therapeutic failure. A microorganism is categorized as susceptible (S), intermediate (I) or resistant (R) by applying the appropriate breakpoint in a defined phenotypic test system. Minimal inhibitory concentrations (MICs) are the primary breakpoints. Epidemiological cut-off value (ECOFF) is the MIC value identifying the upper limit of the wild type population, characterized by the absence of acquired and mutational mechanisms of resistance to the agent’. Since ECOFF is not depending on sampling time, source (human, animal, environmental) or geographical origin, this parameter is used as a sensitive indicator of resistance development in surveillance studies. However, the complexity of antimicrobial resistance cannot be reduced to mere technical definitions [9,10]. Microbiological resistance (in vitro resistance), which relies on breakpoints, and pharmacological resistance, based on pharmacokinetic parameters, will finally result in clinical resistance (in vivo resistance). Several biochemical and physiological mechanisms are involved in antibacterial resistance which may be intrinsic (a characteristic of a bacterial species or genus) or acquired when a susceptible strain has become resistant as a consequence of either a spontaneous mutation, or the acquisition of a specific resistance gene by horizontal gene transfer secondary to conjugation, transformation and transduction. Historical approach

The first papers related to bacterial resistance appeared as early as 1945 [11,12], leading rapidly to the worrisome observation that ‘the selection pressure of the drug favours elimination of the susceptible micro-organisms and survival and propagation of the most resistant ones’ [13]. The first methicillin-resistant Staphylococcus aureus (MRSA) was described in 1961, just 2 years after the introduction of methicillin in therapeutics in England, but MRSA were already present in some countries before ‘celbenin’ (methicillin) entered the clinical use [14]. Progressively other resistant microorganisms have emerged, such as the ESKAPE pathogens (Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.), capable of ‘escaping’ the biocidal action of antibacterials [15]. Over time, resistance to a single class of antibiotics has evolved to multiresistance, up to extreme drug resistance. According to WHO, a post-antibiotic era is far from being an apocalyptic fantasy, but a very real possibility for the 21st century [16]. Each year in the USA, 2,049,442 illnesses are caused by bacteria and fungi that are resistant to at least some classes of antibiotics with a total of 23,000 deaths [17]. The report of the US CDC define three ‘urgent’ threats: carbapenem-resistant Enterobacteriaceae, antibiotic-resistant Neisseria gonorrheae and Clostridium difficile. ‘Serious’ threats include multidrug-resistant (MDR) Acinetobacter and P. aeruginosa, vancomycin-resistant enterococci, drug-resistant foodborne organisms (Campylobacter, 1442

Salmonella typhi and non-typhoidal Salmonella and Shigella), MRSA, drug-resistant Streptococcus pneumoniae, extendedspectrum b-lactamase-producing Enterobacteriaceae (ESBLs), fluconazole-resistant Candida and drug-resistant Mycobacterium tuberculosis. (With regards to C. difficile, it is important to note that the problem linked to this commensal pathogen is not its natural antibacterial resistance, but its overgrowth and toxin production in the gut of patients receiving long-term and broad-spectrum antibiotics). By comparison, the European Antimicrobial Resistance Surveillance Network has insisted on the high level of resistance for Escherichia coli and K. pneumoniae isolates in Europe, with an increase in the percentage of carbapenem resistance among K. pneumoniae isolates during 2012 [18]. Carbapenem resistance and resistance to multiple antimicrobial groups are also common in P. aeruginosa and Acinetobacter spp. isolates. MRSA remains a public health priority as the percentage is still above 25% in 7 of the 30 reporting countries. Another threat concerns the resistance to daptomycin, the latest natural antibiotic introduced in 2006 in clinical practice. Because of its innovative mechanism of action (depolarization of the cell membrane), it has been supposed that resistance to daptomycin is difficult to generate. However, an increasing number of reports stress the development of daptomycin resistance [19,20], even in patients without prior treatment with this antibiotic [21,22]. Antibacterial resistance & zoonosis: the facts

Early attention on the possible animal origin of human pathogens was given in the 70s as a Salmonella Heidelberg epidemic in a hospital was traced to infected calves. Since then, an abundant literature has been devoted to this question and the emergence of antimicrobial resistance has been noted in commensal and pathogenic bacteria present in healthy and diseased animals. With regard to potential resistant zoonotic bacteria, four important issues concern MRSA, ESBL-producing organisms, carbapenem-resistant Enterobacteriaceae and enterococci. Key issues Methicillin-resistant Staphylococcus aureus

Worldwide concerns arise for MRSA, a major cause of healthcareassociated (HA), community-associated (CA) and livestockassociated (LA) infections [23]. The term ‘new zoonosis’ has been quoted for MRSA infections considering three groups of patients at risk for ‘zoonotic’ MRSA: individuals in contact with farm animals, contacts of household pets and veterinarian staff [24]. First recognized in the mid-1970s as an animal pathogen, MRSA is now reported frequently from different animal species and from both healthy and diseased animals. The first reported animal MRSA isolate was recovered from milk from dairy cows in 1972 in Belgium [25]. Characterization of CA, LA or HA strains is based on molecular biology. Multilocus sequence typing and whole-genome sequencing (WGS) support the universal nomenclature currently used to characterize S. aureus epidemiology. Sequence types (ST) are based on seven ‘housekeeping’ genes and unique allelic profiles; they are associated with different host Expert Rev. Anti Infect. Ther. 12(12), (2014)


Antibacterial resistance

species, and identify potential zoonotic clones with the capacity of pandemic spread in humans. For instance, about 2200 STs have been identified for different S. aureus genotypes with host-specific phenotypes. These STs are grouped into clonal complexes (CC), which define host-specific clonal lineages with host restriction. Methicillin resistance is due to a modified penicillin-binding protein PBP2a, encoded by the mecA gene, located on one of six types of staphylococcal chromosomal cassettes. In the 1980s, MRSA strains were mostly international epidemic hospital strains, named HA-MRSA belonging to only five CC (CC5, 8, 22, 30 and 45). This was followed in the 1990s by the occurrence of MRSA infections in non-hospitalized patients with strains called CA-MRSA characterized by different STs (ST1, 8, 30, 59, 80 and 93) [26]. The 3rd wave of this ‘dynamic landscape’ of MRSA evolution [27] was the unexpected discovery of MRSA in livestock, pigs in particular, and humans in contact with them, supporting the description of these strains as LAMRSA. LA-MRSA isolates mostly belong to CC398 but other clonal lineages (CC5, 9 and 97) have also been detected in livestock [28]. As livestock are in close contact with part of the human population (farmers, farm co-workers, veterinarians, etc.), and also are involved in the food chain, they might serve as convenient reservoirs for bacterial transfer to human population. Another problem for MRSA concerns the emergence of mecC-producers [29]. The two major lineages of mecCproducing organisms (CC130 and ST425) are considered as animal-adapted lineages of S. aureus, suggesting that mecCMRSA arose in animals, possibly ruminants, before spreading to humans [29]. MRSA isolates carrying the new mecC gene have been identified in livestock in the UK, Ireland and Denmark with likely zoonotic transmission to humans [30–32]. The prevalence in human isolates in Denmark has increased from 1.9% in 2010 to 2.8% in 2011, but in Germany and the UK the prevalence is still low (0.06 and 0.45%, respectively), without variation between 2004/05 and 2010/11 for Germany [29]. ESBL-producing organisms

ESBLs hydrolyze penicillins and extended-spectrum cephalosporins. They were first described in 1979 and are frequently plasmidencoded. These plasmids may carry genes conferring resistance to other antibiotics, for instance, aminoglycosides. These bacteria spread rapidly among humans and there is evidence of spread among animal populations. AmpC b-lactamases can also be present in extended-spectrum cephalosporin-resistant Gram-negative bacteria. They are usually encoded on the chromosome but may also be carried on plasmids. The emergence of plasmid-encoded AmpC blactamases and ESBLs in both Gram-negative pathogens and commensals isolated from animals (livestock and companion animals) is a public health concern [5,33,34]. Carbapenem-resistant Enterobacteriaceae

Carbapenems are broad-spectrum b-lactam antibiotics considered last-line therapy for infections caused by MDR Gramnegative bacteria. Microorganisms with acquired carbapenemases and ESBL-producing bacteria have emerged in livestock, informahealthcare.com

Review

companion animals and wildlife. Carbapenemase-producing E. coli, Salmonella spp. and Acinetobacter spp. have been reported in poultry, cattle, swine and their environment, in companion animals (cats, dogs or horses), wild birds and ectoparasites [35]. Enterococci

Enterococci are commensal bacteria in the gut of humans and domestic animals and can be detected in the environment. They are intrinsically resistant to cephalosporins but can acquire resistance to quinolones, macrolides, tetracyclines, streptogramins and glycopeptides. Enterococcus faecalis and E. faecium are responsible for life-threatening HA infections. Vancomycin-resistant E. faecium have been first detected in 1993 in farm animals in the UK [36], but they have been now isolated from cats, dogs, horses, wild birds, livestock, environment, sewage and stool samples from farmers and nonhospitalized humans in the community [37–39]. Kelesidis has proposed that de novo daptomycin resistance in enterococci emerges from the environmental ‘resistome’ (see section ‘Anti baeterial resistance & zoonosis: controversies Antibiotics inthe environment’) and is so transported from animals to humans directly or through the food chain [40–42]. Antibacterial resistance in other zoonotic bacteria

Listeria species remain susceptible to most antibiotics. However, the occurrence of MDR Listeria spp. from various sources has been noticed. Oxacillin resistance is the most common resistance phenotype, with a medium prevalence of resistance to clindamycin (39.3%) and low prevalence of resistance to tetracycline (3.9% isolates) [43]. Resistance to clindamycin, daptomycin and oxacillin has emerged among L. monocytogenes and L. innocua, with intermediate resistance to fluoroquinolones [44]. The analysis of duck and goose intestinal contents has shown that resistance to tetracycline was common in Listeria (48.3%) and Salmonella spp. (63.6%) [45]. The emergence of multiresistant Listeria strains both in nature and in dairy products, could represent a potential threat to human health [46], but to date no Listeria infection in humans have been antibiotic resistant. Antibacterial resistance has also emerged in Brucella spp. [47,48]. Although antibiotic treatment is prohibited in ruminants, this recommendation is not observed in all countries and uncontrolled antibiotics use in animals may also cause the development of trimethoprim/sulfamethoxazole-resistant B. melitensis strains [47]. Antibiotics and public health measures have not yet allowed eradication of plague, which is now considered a re-emerging disease and could be the next sword of Damocles [49]. Streptomycin, chloramphenicol and tetracycline are used for treatment and tetracycline and sulfonamides for prophylaxis. A MDR Yersinia pestis has been isolated in 1995 in Madagascar from a patient with bubonic plague [50]. This strain was resistant not only to all the antibiotics recommended for therapy and prophylaxis, but also to alternative drugs (ampicillin, kanamycin and minocycline); it remained susceptible to cephalosporins, other aminoglycosides, quinolones and trimethoprim. The 1443


Review

Labro & Bryskier

resistance determinants were carried by a conjugative plasmid pIP1202 originating in the Enterobacteriaceae family and highly transferable in vitro to other strains of Y. pestis. This common plasmid backbone is broadly disseminated among MDR zoonotic pathogens [51] and conjugative transfer of a streptomycin resistance plasmid from E. coli to Y. pestis in the midgut of fleas has been documented [52]. However, a recent survey does not indicate the emergence of resistance in isolates obtained worldwide [53]. Antibacterial resistance in bacteria from food & food-producing animals

Concerning the prevalence of resistant organisms in food animals, the source of samples is important. If a sample came from a clinical test, then under Hazard Analysis and Critical Control Point procedures, this animal and any of its by-products should not enter the food chain due to its illness. More important are findings of resistant organisms in retail food products, as these represent the most immediate source of exposure and risk to consumers of ingesting an antimicrobial resistance organism. The risk among clinical cases (animals) is more to their handlers/farm owners and much lower to the general public. Food can be contaminated with antimicrobial resistant bacteria by various mechanisms: presence of resistant bacteria in animals, presence of resistance genes in bacteria intentionally added during the processing of food starter cultures, probiotics or cross-contamination with antimicrobial resistant bacteria during food processing [54,55]. For instance, even though the original source of the zoonotic bacteria was feces, the primary source of contamination on meat from cattle has been shown to be the hide, so that the contamination event could be an indirect transfer via an environmental source [56]. According to the recent EU Summary Report on antimicrobial resistance [57], Salmonella and Campylobacter are the most common causes of zoonotic foodborne infections. Antimicrobial resistance is detected commonly in isolates from human cases, food-producing animals and food, with 28.9% of isolates being MDR. The highest antibacterial resistance rate for Salmonella isolates is observed in fattening turkeys, broiler meat, turkeys and broilers of chickens (46.0–86.2%). High resistance to fluoroquinolones is observed in Campylobacter isolates of food and animal origin, ranging from 32.0% in isolates from pigs to 82.7% in isolates from broiler meat. Methicillin-resistant Staphylococcus aureus

MRSA can be isolated from cattle, pig, chickens in slaughterhouses and meat samples. The first case of LA-MRSA ST398 occurring in rabbits raised intensively for meat production has just been described [58]. The European Food Safety Authority (EFSA) and the European Centre for Disease Prevention and Control have gathered data submitted by 26 EU Member States for zoonotic and indicator bacteria in 2012 [59]: MRSA can be detected in different types of food, for example, meat or raw milk, when animal producers are colonized by MRSA. LA-MRSA, CA-MRSA and 1444

even HA-MRSA can be present on human food and contamination from humans during processing has been suspected. Various studies have confirmed the presence of LA-MRSA clones on many different meat products [26]. In Germany, national surveillance programs reveal that chicken and pig meat at retail are contaminated with MRSA in 42 and 16% of samples, respectively, mostly isolates belonging to CC398, although other genotypes (principally CC9 and CC5) accounted for about 27% of all MRSA isolated from chicken and 10% from pig meat [28]. Another livestock-derived food product to be considered as a possible origin for MRSA transmission is raw milk used for the production of cheese. LA-MRSA CC398 has been isolated from bulk tank milk from five geographically dispersed farms in the UK suggesting that it is established in livestock [60] and it has also been found in Belgian cattle [61]. In slaughter houses in North Dakota (USA), 34.7% of the animals have been reported positive for S. aureus [62]: the highest prevalence was observed in pigs (50.0%) and sheep (40.6%); 47.6% of raw meat samples (chicken 67.6%; pork 49.3%) and 13.0% of deli meat was positive. However, MRSA was only found in five pork samples (7.0%) (three ST398 and two ST5). All exhibited penicillin resistance and four were MDR. Among all S. aureus isolates, multidrug resistance was also observed in pigs, pork and sheep. MDR isolates from pork were mainly ST398 (60%) and ST9 (30%). The presence of other resistance genes in MRSA isolates has been reported by other authors. A LA-MRSA isolate belonging to CC398, which carried two small and one large plasmids has been identified from broiler farms: the small ones carried only an erm(C) gene (macrolide/ lincosamide resistance) and the large one carried the resistance genes tet(L) (tetracycline resistance), dfrK (trimethoprim resistance) and aadD (kanamycin/neomycin resistance) [63]. MRSA of human origin, for instance, the well-known human clones, USA300 (ST8-MRSA-IV) and USA100 (ST5-MRSA-II) have also been detected in food products [26]. However, various reports and studies conclude that ‘foodstuffs play a negligible role, if any, in the spread of MRSA’ [64] and MRSA cannot be considered as foodborne pathogen [65]. ESBL-producing bacteria

The detection of ESBL-producing E. coli in production animals and retail meat has been confirmed in Europe, Asia, Africa and the USA. In France, in 2012, a prevalence of 29.4% of ESBL producers has been reported in the fecal flora of healthy veal calves, which could be considered as a major ESBL-producing organism reservoir in food animals [66]. ESBL-producing E. coli and K. pneumoniae have been isolated from cases of clinical bovine mastitis in the UK [67]. Emergence of extended-spectrum AmpC b-lactamases (ESAC) in cattle has also been reported [68]. The prevalence of ESAC-producing E. coli in cattle in France was investigated over a 6-year period of 2005–2010 and estimated at 0.37% (23/6158) in clinical isolates. ESAC producers were mostly detected in diarrheic calves, however, a subset of 607 E. coli isolates from healthy cattle revealed an even higher ESAC Expert Rev. Anti Infect. Ther. 12(12), (2014)


prevalence compared with diseased ones (5/607, 0.82%). In Belgium, ESBL/AmpC-producing Salmonella isolates have been reported in chickens (12.8%) and less frequently in pigs (1.9%) [69]. Animal model studies suggest that horizontal transfer of resistance genes between E. coli (and other Gram-negative bacteria) may occur in the intestine [70].


Carbapenem-resistant Enterobacteriaceae

The global emergence of carbapenem-resistant organisms has become a ‘public health emergency’ [71,72]. To date, only sporadic studies have reported the occurrence of carbapenemaseproducing bacteria in food-producing animals and their environment. VIM-1 producing E. coli and Salmonella infantis have been isolated from pigs and poultry in Germany, OXA-23-producing Acinetobacter spp. from cattle and horses in France and Belgium and New Delhi metallo-b-lactamase (NDM)-producing Acinetobacter spp. from pigs and poultry in China [73]. Several studies show that the bacteria can persist on the farm, spread among animals (including insects and rodents) and reach the environment via manure [74,75]. Other antibacterial resistances

Various reports outline the widespread decreased susceptibility of Salmonella and E. coli isolates from poultry to critically important antimicrobials, such as fluoroquinolones [76–78]. In a recent study, 85–93% of isolates from broilers, chicken meat and turkey meat showed resistance to at least one antimicrobial class (e.g., sulfonamides, tetracyclines, fluoroquinolones and third-generation cephalosporins), and even to several classes in 73–84% of isolates [78]. Resistance to at least one antimicrobial was low (16%) in dairy cows, but reached 43–73% in veal calves, veal and pork. In addition, high resistance rates to cephalosporins were observed in broilers and chicken meat (5.9 and 6.2% of the isolates) and 3.3% of the isolates from veal calves showed resistance to ceftazidime. Ciprofloxacin resistance was rare except for E. coli isolates from veal calves (13.3%). High frequency of ciprofloxacin resistance has been observed among E. coli isolates of different origins in China, and the prevalence of (plasmid-mediated quinolone resistance) genes in food animal isolates seems to have increased over time (from 38.7 in 2004 to 69.8% in 2011) [77]. In Europe, resistance to ampicillin, streptomycin, sulfonamides and tetracyclines in indicator (commensal) E. coli isolates is commonly reported in chickens and pigs (29.5–54.7%) and in cattle (24.5–30.6%) [57]. Resistance to macrolides and lincosamides has emerged in animal pathogens and has been detected in bacteria isolated from pigs and cattle [79]. Antibacterial resistance in aquaculture

Aquaculture products are an important food supply. There is a wide range of species and methods, from small ponds to intensive industrial scale production systems. Antibacterial agents are commonly used in aquaculture to treat or prevent infectious diseases. They can be introduced as food components or informahealthcare.com

Review

directly into water ponds, which implies flock treatment with important quantities, leading to deposition of drug residues in sediments and promoting continuous selective pressure [80]. Quinolones, sulfonamides and tetracyclines are commonly used [81], although macrolides and b-lactams can also be employed. Data on the quantity of antibacterial agents used are scarce. In North America and in Europe, licensing and regulation of the use of antibacterial agents in aquaculture is strictly enforced, and involve veterinary professionals. However, unauthorized use of antibacterial agents can occur: according to a recent global survey, the use of quinolones was reported in North America where they are prohibited in aquaculture [82]. In addition, about 80–90% of the total aquaculture production takes place in countries, mainly from Asia, with few regulations. It has been clearly demonstrated that fish pathogens and other aquatic bacteria can develop resistance as a consequence of exposure to antibacterial agents. For instance, in an experimental aquaculture station in northern Portugal, 51 strains identified as belonging to the genus Aeromonas were isolated from rainbow trout skin and kidney samples, and from water samples. A high level of resistance to amoxicillin, carbenicillin and ticarcillin was observed. Unexpected resistance to imipenem was also detected, suggesting a transfer to the Aeromonas population from the environment [83]. The analysis of sediments collected in a fish farm in the Adriatic Sea has suggested that farm sediments can be reservoirs of dormant antibioticresistant bacteria, including enterococci [84]. Some bacterial pathogens belong to the same genera as human pathogens, which likely increases the probability of spread of antibacterial resistance from aquaculture to humans. Plasmids that harbor MDR determinants can be transferred to E. coli from various bacteria present in the aquatic environment. Direct contact with water, fishes or other organisms, handling or consumption of aquaculture products are the main pathways for human contamination. Individuals at risk are mainly found among people frequently exposed to fish, their products or their environment, and among people with specific dietary choices (e.g., live and fresh seafood). Between 1988 and 2007, seafood consumption accounted for 6.8% of globally reported outbreaks of foodborne diseases [85]. In a recent study, a high percentage (42%) of resistance has been found in 81% of bacteria isolated from ready-to-eat shrimps, including E. coli, Enterococcus species, Salmonella species, Shigella flexneri, Staphylococcus species and Vibrio species, and the authors suggested that widespread trade of this product could provide an avenue for international dissemination of antibacterial-resistant pathogens [86]. In January 2014, a carbapenemase-producing organism was isolated from a squid originating from Korea, and sold in a food store in Canada [87]. Although this organism with 95.5% sequence identity to Pseudomonas fluorescens may not be a pathogen, its contribution to the resistome and the potential for lateral gene transfer to clinically relevant bacteria has raised concern. These data, among others, point to aquaculture as a risk for international transport of antibacterial resistance genes. 1445

Review

Labro & Bryskier


Antibacterial resistance in bacteria from companion animals Early attention

Compared with the amount of literature devoted to foodproducing animals, the possible emergence of resistant bacteria in companion animals has only been questioned recently [88,89]. Actually, with companion animals, two aspects have to be considered: resistance of bacteria in infected animals (therapeutic problem) and carriage of resistant bacteria by healthy animals (‘zoonotic’ problem). Antibacterial agents used in humans also belong to the armamentarium for small animal veterinary practice, often including broad-spectrum agents such as aminopenicillins plus clavulanic acid, cephalosporins and fluoroquinolones. Increases in antibacterial resistance of animal pathogens have been reported in the USA and Europe during the 1990s and nosocomial infections with MDR isolates of A. baumannii, E. coli and Salmonella enterica, and MRSA may occur in hospitalized dogs [90,91]. The MDR Pseudomonas species have also been reported [92]. Carriage of resistant bacteria raises the question of pets as potential reservoirs for transmission of these strains to humans. Staphylococci

During the past few years, there has been confusion about the classification of staphylococcal species colonizing companion animals, but molecular techniques have clarified that S. pseudintermedius, and not S. intermedius, is the species of the S. intermedius group that colonizes and causes infections in dogs and cats, although some reports maintain the term of S. intermedius. In this review, the terms are used as they are mentioned in the literature analyzed. Infections associated with methicillin and MDR staphylococci are increasing in veterinary practice and are frequently associated with empiric therapeutic failures [93]. The overall prevalence of methicillin-resistant S. pseudintermedius, determined in 16,103 clinical specimens from veterinary facilities in Germany in 2007, was low (0.45%), with 0.58% for samples from small animals and 0.10% from equidaes [94]. High rate of MDR isolates toward fluoroquinolones, aminoglycosides and macrolides was also observed. Generally, MRSA strains from companion animals differ from those in livestock and meat production animals. This is probably because MRSA acquisition is primarily a humanosis, and in some cases, an infected human can be traced as a potential source of MRSA. A survey in Germany (2010–2012) has determined the occurrence of MRSA among wound swabs of companion animals [95]. S. aureus was identified in 5.8, 12.2 and 22.8% of canine, feline and equine swabs, respectively and MRSA were identified respectively in 62.7, 46.4 and 41.3% of these isolates. Since all samples were pooled, it was not possible to propose a trend in the prevalence of MRSA in companion animals. By comparison in humans, according to the Eurosurveillance report [57], a decreasing trend in the population-weighted MRSA has been observed for seven individual countries (including Germany) in the EU over the period 2009–2012, with about 15.4% MRSA 1446

human isolates in Germany. The predominance of CC22 and CC5 MRSA lineages in dogs and cats is also observed for human wound infections within Germany. Several studies have looked for resistant staphylococci carriage in healthy companion animals. Coagulase-positive (CoPS) and coagulase-negative (CoNS) staphylococci are normal commensals of the skin and mucosa of dogs. In the UK, 99% of a group of healthy dogs carried staphylococci: 95% carried CoNS and 47% carried CoPS; 58% of the dogs carried at least one CoNS isolate with phenotypic methicillin resistance and 42% carried a methicillin-resistant mecA-positive isolate, but methicillin resistance was not found in CoPS isolates [96]. In another study, in the UK, a high prevalence (55.1%) of nasal carriage of staphylococci was observed in dogs but only 7 dogs (1%) carried MRSA, identified as the dominant UK HA strain (EMRSA-15, ST22) [97]. MR-CoNS were detected in 5.5% of dogs but no MR S. pseudintermedius. Multidrug resistance was found in 87.5% of CoNS and 21.8% of CoPS staphylococci. In the USA, in a study involving 276 healthy dogs and cats, CoNS and CoPS staphylococci have been isolated from various body sites of approximately 5% of the animals (12 dogs, 2 cats); among the 23 isolates, all CoPS (11 S. aureus, 4 S. pseudintermedius), and 3 CoNS (1 S. sciuri, 1 S. simulans and 1 out of 6 S. warneri) were resistant to oxacillin. The majority of isolates were also MDR [98]. Methicillin-resistant S. intermedius have been collected in 16.7% of a random sample of 36 healthy dogs in Hong Kong, but these strains were sensitive to vancomycin, gentamicin and co-trimoxazole [99]. MRSA have been identified in 5.7% of healthy dogs enrolled in the MRSA active surveillance program at The Ohio State University-Veterinary Medical Center over a 1-year period [100]; dogs of veterinary students were 20.5-times more likely to be MRSA-positive than other dogs. Cats may also harbor multiresistant S. pseudintermedius isolates and genotypic characteristics points toward an exchange with strains previously seen in dogs [101]. Muniz et al. have evaluated the antimicrobial susceptibility of Staphylococcus species isolated from oral mucosa of cats [102]. Coagulase-negative species were found in 89.6% of isolates; coagulase-positive species (10.4%) were distributed among S. aureus (4.7%) and S. intermedius (5.7%)groups. Antimicrobial resistance was found in 83.9% of isolates and high rates of resistance were observed for penicillin and tetracycline (56.1%). All staphylococci isolates were resistant to methicillin. These results must be considered for the treatment of cats’ bites. Methicillin-resistant staphylococci have also been isolated from nasal swabs of 35.2% of healthy horses [103]. A review of the published literature (1980–2013) to investigate the evolution in antibacterial resistance in clinical and commensal methicillin-resistant and methicillin-susceptible S. pseudintermedius isolated from dogs in 27 countries has not revealed a significant increase over time, except for penicillin and ampicillin among methicillin susceptible [104]. This review also highlights the lack of harmonization for antimicrobial susceptibility testing methods and interpretation criteria, and the benefits of systematic surveillance at the country-level or even at EU level. Expert Rev. Anti Infect. Ther. 12(12), (2014)



Gram-negative bacteria

The prevalence of ESBL, carbapenemase and AMPc-producing Enterobacteriaceae in companion animals seems to be increasing [105]. Most reports deal with E. coli [106,107], but Enterobacter sp., K. pneumoniae, Citrobacter sp. and S. enterica serovar Newport have also been identified. In a recent French study, 3.7% of E. coli isolates from clinical infections in cats and dogs produced ESBLs, and 74%of them carried blaCTX-M IncFII plasmids [108]. The human origin of resistant bacteria has been proposed. The E. coli B2-O25b-ST131 is a pandemic clone which produces the ESBL CT X-M-15, and is associated with difficult-totreat human infections. Ewers et al. [109] have analyzed 177 E. coli isolates, collected from eight European countries from companion animals with urinary tract infections, wound infections and diarrhea: 5.6% of ESBL-producing E coli belonged to this pandemic clone. This clone has also been isolated in a dog with a urinary tract infection in Portugal [106], in clinical specimens from UK dogs [110], and in dogs, cats and humans in Northern Kenya, where extended-spectrum cephalosporins are used very rarely [111]. A new group of pathogenic E. coli (E. coli D-ST648-CTX-M) has recently been identified in dogs, cats and horses, and combines multiresistance to most non-b-lactams and extraintestinal virulence [112]. Carbapenems are no registered for use in animals and carbapenem resistance among Gram-negative bacteria isolated from companion animals is rarely reported, partly because most veterinary diagnostic laboratories do not test clinical isolates and veterinarians do not tend to take samples or send them for testing beyond identification of the organism [113]. However, offlabel veterinary use of carbapenem in dogs has been reported for the treatment of urinary tract infection and post-operative infection caused by MDR E. coli [114] and MDR P. aeruginosa pneumonia after kidney transplantation [115]. The NDMencoding gene (NDM-1) has been detected in MDR strains of E. coli recovered from companion animals in the USA [116], and OXA-48-producing bacteria have been isolated from hospitalized dogs in Germany [117]. The plasmids containing bla-NDM-1 and bla-OXA-48 may transfer readily between different bacterial species in the gut of companion animals and provide a carbapenem resistance reservoir. Multiresistance is also observed in Gram-negative organisms. ESBL-producing and fluoroquinolone-resistant C. freundii have been isolated from clinical infections in companion animals [118]. The first molecular analysis of A. baumannii responsible for infections in pets and horses has shown various patterns similar to those present in A. baumannii of human origin, such as resistance to aminoglycosides and quinolones and the hyperproduction of chromosomal b-lactamases [119]. Rectal colonization of dogs with ESBL-producing E. coli (33%), AmpC (23.8%) and resistant to ciprofloxacin has been reported in Korea [120]. It is important to trace the source of the bacterial contamination. Interestingly, a recent paper [121] identifies the presence of several resistance genes (blaCTX-M-15, bla CMY-4, blaVEB-4-like and bla OXA-48-like carbapenemases) in pet food, informahealthcare.com

Review

suggesting that original ingredients and/or the production processes were highly contaminated with resistant bacteria. Environmental or human contamination source(s) may have taken place during the various steps of the production process. Owing to the preparation procedures employed, it is unlikely that these resistance genes could be transmitted to the bacterial flora of animals fed with this food. However, it is important to identify the contamination source(s) because it might be an original niche of clinically important MDR bacteria. Most papers devoted to companion animals refer to dogs, cats and horses, but other species (ornamental fishes, birds, reptiles) are frequently found as household companions. They may represent potential bacterial reservoirs [122–125]. In particular, reptiles might be a vector for resistant Salmonella Kentucky with serious public health consequences [126]. Other bacterial species

The presence of MDR enterococci has been reported in dog feces. Resistance to clindamycin, tetracycline, erythromycin, ampicillin and aminoglycoside was found, respectively, in 86.3, 65.7, 60.3, 47.9 and 65.7% of isolates. Resistance to three or more antibiotics and six or more antibiotics were observed in 67 and 38.4% of isolates, respectively [127]. Wild life

Wild life has been considered as a ‘melting pot’ of antibacterial resistance [128] and the presence of MDR bacteria has been reported in wild birds and mammals. For instance, wild birds harbor multiresistant CoNS and ESBL-producing Enterobacteriaceae; they could serve as reservoirs and, for migratory birds, extensive diffusion across countries can be suggested [129–131]. The mecC gene has been found in S. aureus belonging to CC isolated from various wild species such as chaffinches, squirrels, seals or hedgehogs [132]. The possible origins of multiresistant strains outside a strong antibiotic pressure will be discussed in the section ‘Anti baeterial resistance & zoonosis: controversies Antibiotics inthe environment’. Consequences of resistant bacteria present in animals: transmission to humans, colonization, infection

Few papers provide strong evidence of animal to man transmission. Indirect evidence comes from single nucleotide polymorphisms studies and phylogenetic analysis of human and animal isolates [133]. For instance, the transmission of MRSA (particularly ST 398) from colonized livestock, for example, pigs, to farm workers, abattoir workers and veterinarians who are in contact with such animals has been acknowledged [134]. The transmission of S. pseudintermedius from dogs to humans has also been clearly demonstrated, particularly in veterinarians [135]. Veterinarians harbor much more resistant strains of S. aureus than professions without contact with animals. In the Netherlands, the prevalence of MRSA carriage in veterinary students and veterinarians reaches 4.6%, and other surveys have reported MRSA colonization rates of 6.5–30%, largely exceeding the values observed in the general population (0.03–3%) [24]. Livestock veterinarians can carry LA-MRSA CC398 for prolonged 1447


Review

Labro & Bryskier

periods, and they can carry and transmit different strains at the same time [136]. Although LA-MRSA is highly prevalent in horses and veterinary personnel at equine clinics in Europe, healthy horses from the general population do not seem to represent a significant MRSA reservoir [137]. Pigs seem to be a particular source of resistant bacteria, which is not surprising as many antimicrobials have widely been used in pig production, leading to development of coresistance and acquisition of class 1 integrons [138]. In a recent survey, isolates from pig farmers and veterinarians were resistant to tetracycline and clarithromycin (52 and 21%, respectively) and similar resistance levels were found in isolates from pigs (39 and 23%, respectively); isolates from persons without contact with agriculture displayed no (tetracycline) or low (3%, clarithromycin) resistance level [139]. An increased risk of MRSA carriage has also been reported for household members of pig farmers in relation to their exposure to pigs on the farm, and by persons living on fattening turkey farms in Germany, with access to the turkey accommodation. About 10% of pigs and related workers in Taiwan carry LA-MRSA ST9 in nares, and cross-species transmission of LA-MRSA has been documented [140]. In Hong Kong, the carriage of MRSA is significantly higher in butchers than in the general community, with a high incidence of CC9, suggesting cross-contamination from pork [141]. Interestingly, although S. aureus and MRSA nasal carriage prevalence was similar (around 40% for S. aureus and 7% for MRSA), LA methicillin and MDR S. aureus (tetracycline-resistant, CC398) have been detected only among industrial but not antibiotic-free livestock operation workers in North Carolina [142]. All these findings raise questions about a potential risk for occupational exposure to opportunistic and drug-resistant pathogens, which may be of broad public health importance in hospitals and the community. In a German region characterized by a high density of livestock production, the prevalence of LA-MRSA was determined among 14,036 MRSA human isolates (January 2008–June 2012) [28]. LA-MRSA CC398 was found in 18.6% of all human isolates and a varying proportion among isolates from clinical specimens (8% in blood cultures, 14% in deep respiratory fluids). Recently, it has been reported that several clones of MRSA belonging to CC97, a leading cause of bovine mastitis worldwide, have been transmitted from livestock to humans, and after host-adaptive evolution, have become established in human populations, one of which demonstrates a worldwide dissemination [143]. The possibility that LA-MRSA is able to transfer between humans has been discussed [26]. Rodriguez-Rivera et al. [144] have also identified multiresistant Salmonella isolates from healthy cattle and farm environments in the USA, with a number of serovars commonly associated with human clinical cases. In this study, 10 of the 26 serovars isolated were reported among the 20 most commonly isolated serovars from human clinical cases in 2009, suggesting that not only clinically affected animals, but also healthy animals and farm environments can be possible sources of MDR Salmonella. 1448

As regards to companion animals, it is likely that the close contacts between them and humans are associated with important risks of bacteria transmission, and some observations outline the role of healthy but colonized pets as vectors of MRSA [145]. Having a pet [146] or owning a horse [147] may also represent an independent risk factor for colonization with ESBL E. coli (odds ratio: 6.7 and 4.69, respectively). In this last study, the prevalence strongly increased in people having contact with both horses and other companion animals [147]. The authors also observed that, interestingly, living in an area of high broiler chicken density was actually protective against colonization, but this result may be due to the overall high broiler density in the country studied (the Netherlands) and mobility of individuals between municipalities and provinces [147]. Therapy animals (trained pets used as part of certain therapeutic schemes in nursing homes, hospitals or rehabilitation centers) can also become the reservoir or source of MRSA colonization and/or infections of humans in healthcare facilities (see section ‘Humanosis’). The transmission route of zoonotic pathogens is not ascertained. For species colonizing farms, bioaerosols could play an important role. For instance, the presence of MRSA has been detected in the air of pig farms and pig fattening units [148], suggesting that the bacteria could colonize humans via simple inhalation of contaminated air. These bioaerosols could also be dispersed and contaminate humans and animals living close to the farms. It must me also noticed that transmission from companion animals to humans may occur indirectly by giving pet food (raw food diet, feeder mice for snakes, etc.), which could be associated with the carriage of resistant organisms and possible transmission to humans [149]. Although transmission from animals to humans and colonization by zoonotic bacteria are recognized, serious invasive infections are rarely documented [28,135,150]. Antibacterial resistance & zoonosis: mechanisms

It is out the scope of this review to detail the microbiological mechanisms of antibacterial resistance. Rather, there is emphasis on the underlying facts which concur in the emergence of resistance in bacteria present in animals. The main factor implicated in the emergence of resistance refers to the use of antibacterial agents. Antibiotic pressure

Microorganisms have produced natural antibiotics, long before mankind utilized their therapeutic potential. Antibiotic exposure in the neighborhood of the antibiotic-producing organisms may have created a selective pressure for bacteria, but only at a limited scale. In 1965, Smith published a report on hedgehogs as ‘a hitherto unrecognized reservoir of penicillin resistant strains of S. aureus’. The outstanding feature of these strains was the high percentage (86.3%) resistant to penicillin and only penicillin, due to penicillinase production [151]. In fact, in a accompanying paper, the author observed that chronic mycotic infection of hedgehog’s skin resulted in selection of Expert Rev. Anti Infect. Ther. 12(12), (2014)



penicillin-resistant staphylococci. The ‘antibiotic substance’ produced in vitro by Trichophyton mentagrophytes var. erinacei closely resembled penicillin G [152]. The therapeutic utilization of antibacterial agents has led to strong antibiotic selection pressures, considered as one of the determinant factors of the above-mentioned ‘tsunami’. As regards to the animal origin of resistant bacteria, two aspects are involved: the use of antibiotics as growth promoter and their therapeutic consumption. Growth promoter

The discovery that antibiotics were able to stimulate the growth of young animals has initiated a large non-therapeutic use of these drugs in commercial feed for food animals [153]. A special committee set up in 1960 considered that the current practices and legislation were satisfactory with economic benefits superior to ‘theoretical hazards’. However, the possible effects of long-term use of antimicrobial agents were of concern in the scientific community [154,155]. In the early 1970s, regulations within the EU began to restrict antimicrobial use for growth promotion with compounds not used in human therapy (Directive 70/524/EEU) [155]. Progressively, as a response to the rise of antibiotic resistance in clinical settings, strengthening of monitoring and enforcement efforts have involved the agricultural sector [156]. The selective pressure of antibiotic as growth promoter has been illustrated by the emergence in farm animals of vancomycin-resistant E. faecium secondary to the use of another glycopeptide, avoparcin, as an additive in feed. Several studies have shown that vancomycin-resistant E. faecium can persist for an extended time after the banning of avoparcin [157]. In Europe, the use of antimicrobial agents for growth promotion in food animals was abandoned in 1 January 2006. However, food of animal origin is exported and imported in many countries, a number of which do not have any current restrictions. Canada, China (excluding Hong Kong), Australia, Brazil and Ukraine do not have any formal national restrictions on antimicrobial use for the purposes of growth promotion [158]. In the USA, antibiotics are often distributed at subtherapeutic doses to healthy farm animals. In 2012, the FDA proposed new guidance calling for the ‘judicious use’ of antibiotics on farms [159]. The compliance is voluntary for farmers to reduce the use of antibiotics for growth promotion and for drugmakers to change labels [160]. The latest version of the FDA draft requires veterinary oversight for use of antibiotics in livestock and limits their preventive use [161].

Review

Quantitative comparisons are generally based on antimicrobial sales surveys in human and veterinary medicine which do not necessarily correspond to annual usage, especially when reforms interfere with drug distribution. It must be kept in mind that, ‘while it is agreed that antimicrobial usage data are important, and indeed essential, to monitor and interpret resistance trends in both animals and people, these data should never be used as definitive proof of a causal association between the two’ [162]. In veterinary medicine, antibiotics can also be given to animals not currently suffering from infections, but at high risk of acquiring one. Prophylaxis may be proposed (as in human medicine), after surgery or severe trauma, or to manage infection-promoting disease conditions such as urolithiasis; also, herds and flocks may be given antibiotics (metaphylaxis) to prevent an outbreak of infectious disease. In poultry and livestock, administration of antibiotics is often practiced when young animals have to be moved, or to prevent respiratory and intestinal diseases, etc. The amounts of drug used may be considerable and increase the selective pressure within the animals and the environment. Prudent stewardship of antimicrobials is the only option to minimize the impact of veterinary antimicrobial therapeutics. As an example, a recent paper analyses the link between consumption and antibacterial resistance in veterinary medicine in Europe [163]. The amount of antimicrobial agents used in nine European countries, from 2005 to 2011, and the relative consumptions of five different antimicrobial classes (tetracycline, penicillins, cephalosporins, quinolones and macrolides) have been analyzed. Geographical variations were observed in the amount of antimicrobials used to produce 1 kg of meat: in 2011, France and The Netherlands were the highest users (117.2 and 113.9 mg/kg, respectively), while Norway had the lowest consumption (3.7 mg/kg). The total sales of active ingredient have decreased during the 7-year period, but a peak of antimicrobial consumption was detected for most of the countries during 2007. The withdrawal of antibiotic as growth promoter in 2006 may explain this increase due to the consumption of therapeutic antibiotics to counteract a possible detrimental effect for the animal production. From 1992 to 2008, antimicrobial consumption per kilogram of pig produced in Denmark decreased by >50%, with improvement in productivity, suggesting that long-term swine productivity was not negatively impacted by a ban on the use of antibiotic growth promoters [164]. In the USA, the quantity of antimicrobials sold for use in food animals is approximately four-times greater than the quantity sold for use in humans [165].

Therapeutic consumption animals

Much has been debated about the role of veterinary versus human therapeutic use of antimicrobials in the emergence and dissemination of antibacterial resistance. Any antimicrobial use leads to selection and dissemination of resistant subpopulations of bacteria, and restriction of veterinary antimicrobials would have severe consequences for animal (and human) health and welfare. It is not the scope of this review to compare human and animal data with the volume of antibiotic sales. informahealthcare.com

Antibacterial resistance & absence of antibiotic pressure

Despite a very low consumption of antimicrobial agents, Norway has a relatively high prevalence of cephalosporinresistant E. coli in the broiler production chain. The import of breeding animals and hatching eggs has been suggested to be the source of these resistant bacteria [166,167]. Various studies have compared the resistance of bacterial species in animals reared in intensive and extensive antimicrobial-free 1449

Review

Labro & Bryskier

production systems with few differences for prevalence or antimicrobial resistance of Campylobacter species in swine, poultry or lamb production [168–170]. The finding of ciprofloxacin resistance in antimicrobial-free swine herds suggests the existence of risk factors or selective pressures other than antimicrobial use in production chains [171].


Other selective pressures

An interesting feature is the appearance of antimicrobial resistance associated with selective pressures other than antibiotics. Heavy metals have been implicated for their ability to increase antibiotic resistance in bacteria collected from polluted waters, independent of antibiotic exposure. For instance, in pigs, the concurrent finding of high levels of zinc tolerance in LA-MRSA, but not in LA-MSSA presents an alternative selective factor, given the widespread use of zinc as a feed additive to control enteric disease in weaned pigs [172]. Also, three novel erm(T)-carrying multiresistance plasmids that harbor cadmium and copper resistance determinants have been isolated from porcine and human MRSA [173]. When specific pathogen-free Leghorn chickens were given lead acetate in the drinking water, fecal swabs, but not intestinal samples, from leadexposed birds contained isolates with elevated antibiotic resistance [174]. The co-localization of antimicrobial resistance genes and genes that confer resistance to heavy metals may facilitate their persistence, co-selection and dissemination. Another factor of selection of antibacterial resistance is the use of biocides and their dissemination in the environment [175]. The mechanisms of resistance both for biocides and antibiotics could involve the induction of efflux pumps. As an example, an association between reduced susceptibility to the disinfectant didecyl dimethyl ammonium chloride, and high-level aminoglycoside resistance and aminopenicillin resistance has been reported in E. faecium from blood and feces of hospitalized humans [176]. Whether such association exists in resistant bacteria isolated from animals has not been studied. Other factors of selection can come from plant-derived products in the environment [177], or exposure to endogenous antimicrobial peptides. This has been observed in patients and in experimental animal model [178,179]. Antibacterial resistance & zoonosis: controversies

The role of animals as antibacterial resistance reservoirs, with the fear of a new zoonosis, must be interpreted in the wider concept of ‘One health’ [180], men and animals (and plants, and microorganisms) are part of the same environment, and are submitted to the same driving forces. Humanosis

A mechanism for animals to acquire resistant bacteria, and subsequently serve as a transmission vehicle or reservoir of infections for other humans, is to be infected/colonized by human pathogens. Molecular biology studies enable to ascertain the human/animal origin of the strains. The emergence of MRSA in animals has raised questions about a probable human origin. The frequent identification of 1450

specific STs in livestock, identical or similar to common human STs, suggests that the anthroponotic transfer of S. aureus may have occurred, as for instance, the poultry-associated ST5 and LA-MRSA ST398 clones [181]. A S. aureus clone which is spread in broilers seems to have evolved from a single human to poultry host jump, about 40 years ago, in or near Poland, followed by genetic diversification, acquisition of novel mobile genetic elements and dissemination throughout continents [182]. Similarly, the genotypes of MRSA isolated from companion animals seem to mimic the genetic backgrounds of the human strains endemic to a particular region [183]. MRSA associated with veterinary nosocomial infections (e.g., ST8 and ST254 in horses, ST22 in small animals) could have their origin in healthcare facilities [184]. In support of these findings, several studies [185,186] have shown that pet therapy dogs are at risk of acquiring MRSA (and Clostridium difficile), particularly when they have close contacts with patients. In France, over a 5-year period (2006–2010), the proportion of MRSA infections in pets appears to be low (1.8%), but most isolates (87.0%) belong to human clones [187]. Other observations that sustain anthroponotic transfer have been provided. The profession of the owner is clearly a risk factor associated with MRSA carrier dogs: in the study by Hoet et al., dogs owned by veterinary students were 20.5-times more MRSApositive than dogs owned by clients with different occupations [100]. Human-to-animal transmission has also been observed in pigs: the Panton-Valentine Leukocidin gene, a cytotoxin usually associated with CA-MRSA infection, was found for the first time, in 88% of MRSA swine isolates in the US farms [188]. Another problem comes from what has been quoted as ‘synanthropization’ [189], a new environmental reality which has a serious veterinary epidemiological significance. Sinanthropy (from the Greek, Sýn, sin. together and avropoV, anthropos, human being) means the sharing of human environment by other (nondomestic) living beings. Progressive urban growth leads to increasing contacts between humans and wild animals, for example, foxes, raccoons, boars and bats. A potential risk for human and animal health is the exchange of microbiota, including resistant bacteria. For instance, Navarro-Gonzalez et al. [190] have isolated in urban wild boars, in Barcelona, various indicator bacteria resistant to different antibiotics; 95% of the isolates of E. faecium were resistant to at least one antimicrobial agent, followed by E. faecalis (50%) and E. coli (10%). For the first time, one isolate of E. faecalis was resistant to linezolid, a completely synthetic agent that is used only in humans. Contamination of captive animals, due to direct or indirect contact with humans, has also been proposed [191]. Janatova et al. [192] have investigated antibacterial resistance in gastrointestinal Enterobacteriaceae of wild mammals and people in a protected area, in Central African Republic. Resistant microorganisms were observed both in habituated and unhabituated gorillas, and in other wild mammals. Although transmissions of resistant gastrointestinal bacteria between wildlife and humans were not frequent, a CTX-M-15-producing K. pneumoniae, found in a habituated gorilla, and a multiresistant E. coli isolate with a fluoroquinolone-resistant gene, in an Expert Rev. Anti Infect. Ther. 12(12), (2014)



Review

unhabituated gorilla, suggest that these animals have been in contact with human-contaminated environments.

new substrates and horizontal transfer of antibacterial resistance genes has been observed in their digestive tract [206].

Antibiotics in the environment

Monitoring

The environment has been defined as a volcano of resistance genes, quoted as the ‘resistome’ [193,194]. To date, the problem of antibacterial resistance has been considered mainly because of the consequences for therapeutic options, and pathogens remain the targets of the studies. However, the origins of antibiotic production rely on environmental (soil) organisms, which are just coming to the front scene [193]. Soil-dwelling bacteria (either or not antibiotic producers) harbor resistance genes, which may occur even in the absence of antibiotic pressure, for example, in bacteria without contact with antibiotics for 4 million years [195]. Nucleotide mutations present in daptomycin non-susceptible enterococci isolates have also been described in many soil bacteria, for example, Actinomycetes demonstrate very high levels of daptomycin resistance [196]. Resistance genes such as blaCTX-M, qnrA and blaNDM have been identified in environmental bacteria, and these genes involved could have a physiological role more important than antibiotic resistance [193]. Universal mechanisms, such as efflux pumps, may exist to overcome natural antibiotics or toxins [197]. The discovery of trimethoprim resistance in soil bacteria supports the existence of an alternative function for the related gene [193]. Outside the natural occurrence of antibacterial resistance genes, the environment is also susceptible to antibiotic pressure [198]. Besides their therapeutic potential, antibacterials are (have been) used in agriculture, aquaculture, but a reasonable (not quantified) source of antibiotic pollution of the environment may come from the elimination of antibiotics from treated patients and animals in excreta, accumulation in manure, waste disposal and surface waters [199–201]. Phages may also contribute to mobilization and spread of resistance genes [202]. Consumption of vegetables and fruits has been recently implicated in severe infectious diseases. The use of human and animal manure may lead to contamination of fruits and vegetables with antibiotic-resistant pathogens [203]. Horizontal transfer of genes exists between the components of the ‘microbiome’ present in soil, manure, water and plants themselves. The term ‘phytonosis’, parallel to zoonosis has been coined to infections originating in plants [204]. In agriculture, antibiotics may be used as aerosols for controlling or preventing bacterial infections, for example, fire blight. Although streptomycin application for fire blight control does not seem to increase resistance genes in orchards, the aerosols can be carried and diluted at considerable distances in the environment, and workers who apply antibiotics, are also exposed if they do not wear personal protection equipment, which is required by law in some countries [205]. At the present time, antibiotic use on plants is considered as a ‘drop in the bucket with negligible splash’ and it is likely that this use will not stop in the near future. Insects (and wild life in general) are proposed to provide a link between the different compartments of potential reservoirs: they may carry antibiotic-resistant bacteria, transmit them to

The emergency of controlling the antibacterial resistance pandemics has led to common efforts in the ‘prudent use of antibiotics’ both in humans and animals. Surveillance programs have also been established to preclude extension of resistance [207,208].

informahealthcare.com

Surveillance

National surveillance programs have been set up in Europe, Canada, Japan and the USA. Not all programs survey antibacterial resistance both in healthy and diseased animals, with cross-analysis with resistance in humans (healthy or diseased). These programs are mainly devoted to food and foodproducing animals, and few data are available for companion and wild animals. An important step in monitoring programs is the surveillance of indicator organisms (E. coli and Enterococcus spp.) to assess the presence of resistance genes reservoirs, and possibly the selective pressure caused by the general use of antimicrobials in animal production. Some supranational programs exist. In Europe, data from national European surveillance programs for zoonotic and commensal bacteria are analyzed by EFSA. However, differences such as sampling and testing methodology, epidemiological cutoff values or clinical breakpoints hamper this analysis. The antibacterial resistance monitoring programs of the European Animal Health Study Centre, which stands upon a collaboration of veterinary pharmaceutical companies, comprise two sets of projects: the European Antimicrobial Susceptibility Surveillance in Animals program, surveys foodborne bacteria at slaughter from healthy animals, and the pathogen programs (VetPath, MycoPath and ComPath) collect pathogens from diseased animals. These projects are based upon a strict harmonization for sampling and identification, with a central laboratory for quantitative susceptibility testing [207]. Most of EFSA’s monitoring recommendations have been covered by European Antimicrobial Susceptibility Surveillance in Animals since the start of the program in 1998 [209]. WHO, Food and Agriculture Organization of the United Nations and The World Organization for Animal Health (OIE) are working closely to fight antibacterial resistance issues at the animal–human interface. The Global Foodborne Infections Network (GFN) [210] promotes integrated, laboratory-based surveillance with multidisciplinary collaboration targeting human health, veterinary and food-related disciplines. Since its beginning in 2001, GFN has developed 5-year strategic plans (2001– 2005, 2005–2010 and 2011–2015). Based on a laboratory surveillance of animals, food and humans, the plan aims both to detect and prevent foodborne pathogens from entering or spreading through the food chain, and to identify foodborne disease outbreaks to set up appropriate control measures. GFN also provides training courses to enhance and build capacity in understanding antibacterial resistance and in developing integrated surveillance systems, and intends to increase the quality of the 1451

Review

Labro & Bryskier

laboratory output produced by its member laboratories. In 2008, Advisory Group on Integrated Surveillance of Antimicrobial Resistance has been established to assist WHO on matters related to the integrated surveillance of antimicrobial resistance and the containment of food-related antimicrobial resistance.


Antibiotic use in animals

Recommendations as to the prudent use of antibiotics in veterinary medicine have been provided very early. This regulatory stewardship involves a series of practical measures, which have been reviewed by Teale and Moulin [211], along with the responsibilities of those involved at all levels in the administration of antimicrobials to animals, including national regulatory authorities. Some countries have national agencies in charge of monitoring antimicrobial usage and rates of antimicrobial resistance in food animals, food and/or people (National Antimicrobial Resistance Monitoring System in the USA, Canadian Integrated Program for Antimicrobial Resistance in Canada, Observatoire National de Epide´miologie de la Re´sistance Bacte´rienne aux Antibiotiques in France, The Danish Integrated Antimicrobial Resistance Monitoring and Research Programme in Denmark, etc.). In 2003, the Food and Agriculture Organization of the United Nations/OIE/WHO Expert Workshops on non-human antimicrobial usage and antimicrobial resistance has established the concept of ‘critically important’ and in 2005, WHO developed a list of ‘Critically Important Antimicrobials for Human Medicine’. However, antibacterial resistance has also an impact on animal health. In some situations, there are few alternatives for the treatment of infections in animals (e.g., MR S. pseudintermedius). OIE has provided a list of antimicrobial agents of veterinary importance and give recommendations on restriction of the use of antimicrobials that are critically important for both animal and human health (fluoroquinolones and thirdand fourth-generation cephalosporins). Carbapenem should be reserved specifically for the treatment of severe MDR diseases in humans, and not used in food-producing animals. The first report of the European Surveillance of Veterinary Antimicrobial Consumption project, launched by the EMA in September 2009, showed that the situation in Europe was improving [162]. For eight countries, the sales of all veterinary antimicrobial agents decreased by about 8% in the period 2005–2009. However, it is important to note that the dosages of the antimicrobial agents (tetracyclines) mainly responsible for the overall decrease are substantially higher than the dosages of those (e.g., fluoroquinolones, cephalosporins, pleuromutilins and penicillins) whose sales had increased. In addition, whether the increased sales were attributed to their use for food-producing animals or for companion animals could not be clarified. In addition, some of the changes could also be linked to changes in animal populations, which could have lower/higher needs for antibiotic use. The last report by Grave et al. shows substantial variations in the sales patterns and in the magnitude of sales of veterinary antimicrobial agents in 25 European countries for 2011, particularly with respect to pharmaceutical forms [212]. 1452

To gain a better insight into the decision-making process of veterinarians in Europe, the Heads of Medicines Agencies and the Federation of Veterinarians of Europe has organized a survey involving 3004 practitioners (volunteering to answer the survey) from 25 European countries [213]. Training, published literature and experience were the most important factors recorded in the decision-making process, as well the risk for increase in antibiotic resistance and ease of administration. Since antibiotic sensitivity testing is usually performed in case of treatment failure, significant differences were observed according to types of practitioners and country. When the use of these tests is strongly recommended in national guidelines (e.g., Germany), it is performed more regularly. France, Germany and The Netherlands could render these tests mandatory before the prescription of antibiotics defined as critically important for use in humans. Other measures

WHO has declared that antimicrobial resistance ‘is a complex problem driven by many interconnected factors; single, isolated interventions have little impact’ [214]. Environment must be protected from unnecessary antibacterial contamination, which requires outreach, education, communication, monitoring and transparency [215]. Management of terrestrial agriculture, treatment of wastewater (from municipalities, pharmaceutical manufacturing and hospitals) and aquaculture are particularly important. For veterinary practice, there is a general need to apply good standards of infection prevention and control. For MRSA, control measures have been proposed such as screening of all incoming cases for infection and/or nasal carriage at admission to a veterinary hospital; hygiene measures undoubtedly the most important (hand washing, gloves, masks, eye protection, disposable aprons for contact with wounds, body fluids or other contaminated, cleaning and disinfection); isolation of all suspect cases of MRSA infection [23]. Similarly, Suthar et al. have assessed a model to reduce the transmission of resistant bacteria in a veterinary hospital: the most important measures seem to be the reduction of the average length of stay of patients and hygiene measures for the staff and transmission points [216]. Keeping animals healthy is also necessary to reduce the usage of antibiotics. These ideal management practices (low animal density, improved nutritional measures) can help to control the dissemination of resistance genes between animals and from animal manure to aquatic systems and agricultural resources. Removal of antibiotic growth promoter (AGP) can generate a substantial increase in the incidence of infectious diseases in livestock and poultry, and leads to a parallel increase in the therapeutic use of antibiotics. Alternatives to AGP (e.g., plant extracts and derived substances such as tannins) are being successfully used as additives in poultry feed [217]. Antibiotic pressure could also be reduced by the availability of reliable alternative control measures such as bacteriophage treatments and vaccinations [5,218–220]. For instance, with regards to aquaculture, vaccines may help alleviate the need for antibiotics, and this option has been tried with success in Norway [221]. Expert Rev. Anti Infect. Ther. 12(12), (2014)



To contain the spread of resistant bacteria in food-producing animals, national and international communication and cooperation are required between medical, veterinary and regulatory authorities, with controls on animal trade and trade of animal by-products. Alternative methods of control of bacterial diseases of plants are an ongoing challenge. In this context, the rediscovery of kasugamycin has raised great hopes [205], but the possibility of selection for streptomycin resistance through application of kasugamycin has been suggested [222]. Conclusion: zoonosis, phytonosis, humanosis & the bacterial world

The widespread use of antibiotics has generated a selective pressure for bacterial evolution. In humans, animals and the environment, bacteria are frequently exposed to low-level, subinhibitory concentrations of drugs, which may play an important role in the emergence and spread of antibioticresistant bacteria among both humans and animals. Low antibiotic concentrations allow the selection of pre-existing resistant bacteria and favors de novo resistance; they also increase the rate of adaptive evolution by increasing mutagenesis and/or recombination, and influence various physiological activities, such as virulence or biofilm formation [223]. However, antibiotic usage as the leading cause of the occurrence of antibacterial resistance is just the top of the iceberg. The resistome, a vast environmental reservoir of resistance genes, has existed and may persist even in the absence of antibiotic pressure. Will control of (reduction in) antibiotic use improve the situation? According to Andersson and Hughes [224], compensatory mechanisms to the fitness cost of antibacterial resistance can stabilize resistant bacterial populations in the absence of antibiotics. The reversal of resistance may considerably differ in individuals, in community and in hospital settings. In hospital settings, modifications in antibiotic use can rapidly (in the order of days to months) alter the frequency of antibacterial resistance. By contrast, removal of the antibiotic pressure in community settings will not modify the frequency of resistance before a long time (months to years). The phenomenon of heteroresistance, a cooperative behavior between antibiotic-resistant bacteria and less resistant members, may still render more difficult the treatment of infectious diseases [225]. The definition of antimicrobial resistance as a ‘new zoonosis’ also needs to be adjusted. Who began, hen or egg, is not easy to settle, and we just are facing the facts: men and animals are part of the adaptive bacterial world. Human activity, travels, contact with wild animals, climate changes, all participate in the dissemination of these mobile genetic resistance determinants [146,226]. An ecological framework has been provided, which looks at the roots rather than the consequences of antibacterial resistance [227]. Do we have means to counteract the future of a microbedominated era? The pipeline for antibacterials remains lean. Few novel molecules have been proposed for treatment of the ESKAPE pathogens [228]. Research is still ongoing with future hopes such as the fungal natural product, aspergillomarasmine, informahealthcare.com

Review

a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant metallo-b-lactamase, VIM-2, which fully restores in vitro the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM- or NDM-type alleles and in animal models [229]. We have other tricks up our sleeves: antibiotic alternatives include the potential utility of phages, probiotics, antimicrobial peptides, herbal medicines, vaccination and immune modulation for treating (preventing) human and animal infections [230–234]. Modulation of virulence mechanisms is an interesting perspective. ‘Working collaboratively across disciplines is essential in order to better understand and challenge an important human and animal health problem: antimicrobial resistance’ [235]. ‘ Should we make peace with bacteria?’ Stuart Levy cited in [9]. Expert commentary

Because of the extraordinary adaptive potential of bacteria, the search for new antibacterial agents appears as an endless run. A better way could be (should be?) to fight indirectly with bacteria by altering their virulence mechanisms. In addition, since it appears that ‘reversibility’ of antibacterial resistance ‘in clinical settings is expected to be slow or nonexistent’ [166], antibiotic research should concentrate on drugs for which the resistance mechanism needs a heavy fitness cost for the pathogen with low and slow compensatory escape pathways. Reducing the release of antibiotics in the environment is mandatory with, particularly, the worldwide suppression of AGP, control of release from pharmaceutical plants and, whether possible, control of antibiotic release from treated patients into the general sewage system. As regards to the ‘zoonotic’ potential of resistant bacteria, a better antibiotic stewardship is already recommended, but other measures could be beneficial. Prevention of infections is more important than treating them: this implies vaccination (whenever possible) and good hygiene standards in veterinary clinics and animal husbandry as well. Five-year view

‘ Difficulties increase the nearer we get to the goal’ . Goethe. The worldwide fear of ‘antibacterial’ resistance, in the wider context of microorganism (parasites, fungi) resistance moves the scientific community. The reversibility of this phenomenon is difficult, and we have to do some agreements with bacteria. The stewardship of ‘old’ antibiotics is already running in human and veterinary medicine, and novel drugs will certainly appear on the market, with new targets in the viewfinder. The concern also reaches the non-scientific community and efforts will certainly be made in the food chain with reinforcements of controls, particularly in animal husbandry, and a better welfare for animals will be claimed by the community. At last, the general issue of improving the quality of our environment can also be achieved by effective controlling of all antibiotic wastes. 1453

Review

Labro & Bryskier

Acknowledgements

The authors are indebted to J Acar for fruitful comments and criticisms. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial

conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.


Key issues • Antibacterial resistance is a worldwide threat, and concerns have arisen about the involvement of animal commensal and pathogenic bacteria in the maintenance and spread of resistance genes. • Salmonella and Campylobacter are the most common pathogens involved in foodborne infections and antimicrobial resistance is detected commonly in isolates from human cases, food-producing animals and food, with 28.9% of isolates being MDR in Europe. • Other important issues of livestock reservoirs for resistant bacteria concern methicillin-resistant Staphylococcus aureus (MRSA), extendedspectrum b-lactamase (ESBL)-producing organisms and enterococci. • With regards to zoonoses, resistance has emerged in Listeria spp., Brucella spp. and Y. pestis. • Resistant bacteria are also detected in companion animals: methicillin-resistant and MDR staphylococci, and ESBL, carbapenemase and AMPc-producing Enterobacteriaceae are increasing in veterinary practice and are frequently associated with empiric therapeutic failures. • Transmission of resistant bacteria from colonized livestock and companion animals to humans has been acknowledged, but serious invasive infections are rarely documented. • The use of antibiotics as growth promoter (AGP) in food animals and their therapeutic consumption (livestock and pets) are the main underlying factors of antibacterial resistance in animals. In Europe, the use of AGP has been banned since 1 January 2006. However, food of animal origin is exported and imported in many countries, a number of which do not have any current restrictions. • Other risk factors or selective pressures have been identified as heavy metals, biocides and plant-derived products in the environment. • On the other hand, anthroponotic transfer of resistant bacteria to animals has been demonstrated and ‘synanthropization’, contamination of wild animals in urban areas, is a new environmental reality with serious veterinary epidemiological significance. • The environment must be considered as a melting pot of antibacterial resistance genes, the ‘resistome’, which exists outside antibiotic contact. The pollution by antibiotics derived from treated animals and humans, waste disposals and pharmaceutical plants, amplifies the emergence of resistant microorganisms, which can easily transfer their mobile genetic elements to human and animal pathogens. • The emergency of controlling the antibacterial resistance pandemics has led to common efforts in the ‘prudent use of antibiotics’ both in humans and animals. Surveillance programs have also been established to preclude extension of resistance. • Antibiotic pressure in animals could be reduced by worldwide removal of AGP, and alternative control measures such as bacteriophage treatments, good hygiene, animal welfare and vaccinations.

animals. Curr Pharm Des 2013;19(2): 239-49

References 1.

2.

3.

Fleming A. Penicillin. Nobel Lecture December 11, 1945. Available from: www. nobelprize.org/nobel_prizes/medicine/ laureates/1945/fleming-lecture.pdf [Last accessed on 18 April 2014] Prescott JF. The resistance tsunami, antimicrobial stewardship, and the golden age of microbiology. Vet Microbiol 2014;171:273-8

6.

7.

8.

Hancock REW. The end of an era? Nat Rev Drug Discov 2007;6:28

4.

Morse SS, Mazet JA, Woolhouse M, et al. Prediction and prevention of the next pandemic zoonosis. Lancet 2012;380(9857): 1956-65

5.

Trott D. b-lactam resistance in gram-negative pathogens isolated from

1454

9.

Woolhouse ME, Ward MJ. Microbiology. Sources of antimicrobial resistance. Science 2013;341(6153):1460-1 Silley P. Susceptibility testing methods, resistance and breakpoints: what do these terms really mean? Rev Sci Tech 2012; 31(1):33-41 Brown D. EUCAST Definitions (and breakpoint table, MIC and zone distribution website conventions) Milan 2011. Available from: www.eucast.org/fileadmin/src/media/ PDFs/EUCAST_files/ EUCAST_Presentations/2011/ EW1_Brown_Definitionsf2.pdf Acar JF, Moulin G. Antimicrobial resistance: a complex issue. Rev Sci Tech 2012;31(1):23-31

10.

Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 2010;74(3):417-33

11.

Demerec M. Production of Staphylococcus strains resistant to various concentrations of penicillin. Proc Natl Acad Sci USA 1945;31:16-24

12.

Klein M, Kimmelman L.J. The role of spontaneous variants in the acquisition of streptomycin resistance by the Shigellae. J. Bact 1946;52:471-9

Jawetz E. Antibiotics revisited: problems and prospects after two decades. Br Med J 1963; 2(5363):951-5 ¨ . Staphylococci Resistant 14. C ¸ etin ET, Ang O to Methicillin (“Celbenin”) Br Med J. 1962;2(5296):51-2 13.

15.

Pendleton JN, Gorman SP, Gilmore BF. Clinical relevance of the ESKAPE

Expert Rev. Anti Infect. Ther. 12(12), (2014)


pathogens. Expert Rev Anti Infect Ther 2013;11(3):297-308


16.

World Health Organization 2014 Antimicrobial resistance: global report on surveillance. Available from: www.who. int/drugresistance/documents/ surveillancereport/en/

17.

CDC. Available from: www.cdc.gov/ drugresistance/threat-report-2013/

18.

European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2012. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC 2013

19.

20.

21.

22.

23.

24.

25.

Velazquez A, DeRyke CA, Goering R, et al. Daptomycin non-susceptible Staphylococcus aureus at a US medical centre. Clin Microbiol Infect 2013;19(12):1169-7

41.

Kelesidis T, Chow AL. Proximity to animal or crop operations may be associated with de novo daptomycin-non-susceptible Enterococcus infection. Epidemiol Infect 2014;142(1):221-4

42.

Kelesidis T. Transport of daptomycin resistance genes between animals and humans as a possible mechanism for development of de novo daptomycin resistance in enterococci. Epidemiol Infect 2013;141(10):2185-6

43.

Go´mez D, Azoń E, Marco N, et al. Antimicrobial resistance of Listeria monocytogenes and Listeria innocua from meat products and meat-processing environment. Food Microbiol 2014;42C: 61-5

44.

Moreno LZ, Paixaõ R, Gobbi DD, et al. Characterization of antibiotic resistance in Listeria spp. isolated from slaughterhouse environments, pork and human infections. J Infect Dev Ctries 2014;8(4):416-23

45.

Rubin JE, Ekanayake S, Fernando C. Carbapenemase-producing organism in food, 2014. Emerg Infect Dis 2014;20(7): 1264-5

Jamali H, Radmehr B, Ismail S. Prevalence and antimicrobial resistance of Listeria, Salmonella, and Yersinia species isolates in ducks and geese. Poult Sci 2014;93(4): 1023-30

46.

34.

Report by the Joint Working Group of DARC and ARHAI. ESBLs – A threat to human and animal health? Available from: www.gov.uk/government/uploads/system/ uploads/attachment_data/file/215180/ dh_132534.pdf

Rodas-Sua´rez OR, Quinõnes-Ramı´rez EI, Fernańdez FJ, Va´zquez-Salinas C. Listeria monocytogenes strains isolated from dry milk samples in Mexico: occurrence and antibiotic sensitivity. J Environ Health 2013;76(2):32-7

47.

35.

Guerra B, Fischer J, Helmuth R. An emerging public health problem: acquired carbapenemase-producing microorganisms are present in food-producing animals, their environment, companion animals and wild birds. Vet Microbiol 2014;171:290-7

Ilhan Z, Solmaz H, Ekin IH. In vitro antimicrobial susceptibility of Brucella melitensis isolates from sheep in an area endemic for human brucellosis in Turkey. J Vet Med Sci 2013;75(8):1035-40

48.

Abdel-Maksoud M, House B, Wasfy M, et al. In vitro antibiotic susceptibility testing of Brucella isolates from Egypt between 1999 and 2007 and evidence of probable rifampin resistance. Ann Clin Microbiol Antimicrob 2012;11:24

49.

Centers for Disease Control and Prevention (CDC). Human plague – United States, 1993-1994. MMWR Morb Mortal Wkly Rep 1994;43:242-6

50.

Galimand M, Guiyoule A, Gerbaud G, et al. Multidrug resistance in Yersinia pestis mediated by a transferable plasmid. N. Engl J Med 1997;337(10):677-80

51.

Welch TJ, Fricke WF, McDermott PF, et al. Multiple Antimicrobial Resistance in Plague: an Emerging Public Health Risk. PLoS One 2007;2(3):e309

52.

Hinnebusch BJ, Rosso ML, Schwan TG, Carniel E. High-frequency conjugative transfer of antibiotic resistance genes to

human infection and colonization in Germany. PLoS ONE 2013;8(2):e55040 29.

Paterson GK, Harrison EM, Holmes MA. The emergence of mecC methicillin-resistant Staphylococcus aureus. Trends Microbiol 2014;22(1):42-7

30.

Petersen A, Stegger M, Heltberg O, et al. Epidemiology of methicillin-resistant Staphylococcus aureus carrying the novel mecC gene in Denmark corroborates a zoonotic reservoir with transmission to humans. Clin Microbiol Infect 2013;19(1): E16-22

31.

Harrison EM, Paterson GK, Holden TG, et al. Whole genome sequencing identifies zoonotic transmission of MRSA isolates with the novel mecA homologue mecC. EMBO Mol Med 2013;5:509-15

32.

Garcia-Alvarez L, Holden MT, Lindsay H, et al. Methicillin-resistant Staphylococcus aureus with a novel mecA homologue in human and bovine populations in the UK and Denmark: a descriptive study. Lancet Infect Dis 2011;11:595-603

Kamboj M, Cohen N, Gilhuley K, et al. Emergence of daptomycin-resistant VRE: experience of a single institution. Infect Control Hosp Epidemiol 2011;32(4):391-4 Kelesidis T, Humphries R, Uslan DZ, Pegues D. De novo daptomycin-nonsusceptible enterococcal infections. Emerg Infect Dis 2012;18(4): 674-6 van Hal SJ, Paterson DL, Gosbell IB. Emergence of daptomycin resistance following vancomycin-unresponsive Staphylococcus aureus bacteraemia in a daptomycin-naı¨ve patient–a review of the literature. Eur J Clin Microbiol Infect Dis 2011;30(5):603-10

33.

Leonard FC, Markey BK. Methicillin-resistant Staphylococcus aureus in animals: a review. Vet J 2008;175(1): 27-36 Stein RA. Methicillin-resistant Staphylococcus aureus–the new zoonosis. Int J Infect Dis 2009;13(3):299-301 Devriese LA, Van Damme LR, Fameree L. Methicillin (cloxacillin)-resistant Staphylococcus aureus strains isolated from bovine mastitis cases. Zentralbl Veterinarmed B 1972;19:598-605

26.

Vanderhaeghen W, Hermans K, Haesebrouck F, Butaye P. Methicillin-resistant Staphylococcus aureus (MRSA) in food production animals. Epidemiol Infect 2010;138(5):606-25

27.

Pantosti A, Venditti M. What is MRSA? Eur Respir J 2009;34:1190-6

28.

Ko¨ck R, Schaumburg F, Mellmann A, et al. Livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) as causes of


Review

36.

Bates J, Jordens Z, Selkon JB. Evidence for an animal origin of vancomycin-resistant enterococci. Lancet 1993;342(8869):490-1

37.

Nilsson O. Vancomycin resistant enterococci in farm animals - occurrence and importance. Infect Ecol Epidemiol 2012;2:16959

38.

39.

40.

Hammerum AM. Enterococci of animal origin and their significance for public health. Clin Microbiol Infect 2012;18(7): 619-25 Klare I, Konstabel C, Badstu¨bner D, et al. Occurrence and spread of antibiotic resistances in Enterococcus faecium. Int J Food Microbiol 2003;88(2-3):269-90 Kelesidis T. The Zoonotic Potential of Daptomycin Non-susceptible Enterococci. Zoonoses Public Health 2013. [Epub ahead of print]

1455

Review

Labro & Bryskier

Yersinia pestis in the flea midgut. Mol Microbiol 2002;46(2):349-54 53.


54.

55.

Urich SK, Chalcraft L, Schriefer ME, et al. Lack of antimicrobial resistance in Yersinia pestis isolates from 17 countries in the Americas, Africa, and Asia. Antimicrob Agents Chemother 2012;56(1):555-8 Verraes C, Van Boxstael S, Van Meervenne E, et al. Antimicrobial resistance in the food chain: a review. Int J Environ Res Public Health 2013;10(7): 2643-69 Aslam M, Diarra MS, Masson L. Characterization of antimicrobial resistance and virulence genotypes of Enterococcus faecalis recovered from a pork processing plant. J Food Prot 2012;75(8):1486-91

56.

Durso LM, Cook KL. Impacts of antibiotic use in agriculture: what are the benefits and risks? Curr Opin Microbiol 2014;19:37-44

57.

Eurosurveillance editorial team. European Union Summary Report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food 2012 published. Euro Surveill 2014;19(12): pii=20748

58.

Agnoletti F, Mazzolini E, Bacchin C, et al. First reporting of methicillin-resistant Staphylococcus aureus (MRSA) ST398 in an industrial rabbit holding and in farm-related people. Vet Microbiol 2014; 170(1-2):172-7

59.

EFSA (European Food Safety Authority) and ECDC (European Centre for Disease Prevention and Control), 2014. The European Union Summary Report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food in 2012. EFSA Journal 2014. 12(3):3590.336 pp

60.

61.

62.

Paterson GK, Larsen J, Harrison EM, et al. First detection of livestock-associated methicillin-resistant Staphylococcus aureus CC398 in bulk tank milk in the United Kingdom, January to July 2012. Euro Surveill 2012;17(50):pii: 20337 Bardiau M, Yamazaki K, Duprez JN, et al. Genotypic and phenotypic characterisation of methicillin-resistant Staphylococcus aureus (MRSA) isolated from milk of bovine mastitis. Lett Appl Microbiol 2013; 57(3):181-6 Buyukcangaz E, Velasco V, Sherwood JS, et al. Molecular Typing of Staphylococcus aureus and Methicillin-Resistant S. aureus (MRSA) Isolated from Animals and Retail Meat in North Dakota, United States. Foodborne Pathog Dis 2013;10(7):608-17

1456

63.

Wendlandt S, Kadlec K, Feßler AT, et al. Two different erm(C)-carrying plasmids in the same methicillin-resistant Staphylococcus aureus CC398 isolate from a broiler farm. Vet Microbiol 2014;171:382-7

74.

Fischer J, Rodriguez I, Schmoger S, et al. Escherichia coli producing VIM-1 carbapenemase isolated on a pig farm. J Antimicrob Chemother 2012;67: 1793-5

64.

Morgan M. Methicillin-resistant Staphylococcus aureus and animals: zoonosis or humanosis? J Antimicrob Chemother 2008;62(6):1181-7

75.

65.

Wendlandt S, Schwarz S, Silley P. Methicillin-Resistant Staphylococcus aureus: a Food-Borne Pathogen? Annu Rev Food Sci Technol 2013;4:117-39

Fischer J, Rodriguez I, Schmoger S, et al. Salmonella enterica subsp. Enterica producing VIM-1 carbapenemase isolated from livestock farms. J Antimicrob Chemother 2013;68:478-80

76.

Clemente L, Correia I, Themudo P, et al. Antimicrobial susceptibility of Salmonella enterica isolates from healthy breeder and broiler flocks in Portugal. Vet J 2014; 200(2):276-81

77.

Yang T, Zeng Z, Rao L, et al. The association between occurrence of plasmid-mediated quinolone resistance and ciprofloxacin resistance in Escherichia coli isolates of different origins. Vet Microbiol 2014;14:170(1-2)):89-96

78.

Kaesbohrer A, Schroeter A, Tenhagen BA, et al. Emerging antimicrobial resistance in commensal Escherichia coli with public health relevance. Zoonoses Public Health 2012;59 Suppl 2:158-65

66.

67.

Haenni M, Chaˆtre P, Me´tayer V, et al. Comparative prevalence and characterization of ESBL-producing Enterobacteriaceae in dominant versus subdominant enteric flora in veal calves at slaughterhouse, France. Vet Microbiol 2014;321-7 Timofte D, Maciuca IE, Evans NJ, et al. Detection and molecular characterization of Escherichia coli CTX-M-15 and Klebsiella pneumoniae SHV-12 b-lactamases from bovine mastitis isolates in the United Kingdom. Antimicrob Agents Chemother 2014;58(2):789-94

68.

Haenni M, Chaˆtre P, Madec JY. Emergence of Escherichia coli producing extended-spectrum AmpC b-lactamases (ESAC) in animals. Front Microbiol 2014;5:53

79.

Pyo¨ra¨la¨ S, Baptiste KE, Catry B, et al. Macrolides and lincosamides in cattle and pigs: use and development of antimicrobial resistance. Vet J 2014;pii: S1090-0233(14) 00082-3

69.

de Jong A, Smet A, Ludwig C, et al. Antimicrobial susceptibility of Salmonella isolates from healthy pigs and chickens (2008-2011). Vet Microbiol 2014;171: 298-306

80.

Heuer OE, Kruse H, Grave K, et al. Human health consequences of use of antimicrobial agents in aquaculture. Clin Infect Dis 2009;49(8):1248-53

81.

70.

Hammerum AM, Heuer OE. Human health hazards from antimicrobial-resistant Escherichia coli of animal origin. Clin Infect Dis 2009;48(7):916-21

Weir M, Rajic´ A, Dutil L, et al. Zoonotic bacteria and antimicrobial resistance in aquaculture: opportunities for surveillance in Canada. Can Vet J 2012;53(6):619-22

82.

71.

Woodford N, Wareham DW, Guerra B, Teale C. Carbapenemase-producing Enterobacteriaceae and non-Enterobacteriaceae from animals and the environment: an emerging public health risk of our own making? J Antimicrob Chemother 2014;69(2):287-91

Tusevljak N. MSc thesis. University of Guelph; 2011. Evaluating the importance of zoonotic bacteria, antimicrobial use and resistance in aquaculture and seafood. p. 269

83.

Saavedra MJ, Guedes-Novais S, Alves A, et al. Resistance to beta-lactam antibiotics in Aeromonas hydrophila isolated from rainbow trout (Oncorhynchus mykiss). Int Microbiol 2004;7(3):207-11

84.

Di Cesare A, Luna GM, Vignaroli C, et al. Aquaculture can promote the presence and spread of antibiotic-resistant Enterococci in marine sediments. PLoS ONE 2013;8(4): e62838

85.

Greig JD, Ravel A. Analysis of foodborne outbreak data reported internationally for source attribution. Int J Food Microbiol 2009;130:77-87

72.

73.

H Seiffert SN, Hilty M, Perreten V, Endimiani A. Extended-spectrum cephalosporin-resistant Gram-negative organisms in livestock: an emerging problem for human health? Drug Resist Updat 2013; 16(1-2):22-45 EFSA Panel on Biological Hazards (BIOHAZ). Scientific Opinion on Carbapenem resistance in food animal ecosystems. EFSA Journal 2013.11(12):3501 70pp




86.

Duran GM, Marshall DL. Ready-to-eat shrimp as an international vehicle of antibiotic-resistant bacteria. J Food Prot 2005;68:2395-401

87.

Rubin JE, Ekanayake S, Fernando C. Carbapenemase-producing organism in food. 2014. Emerg Infect Dis 2014;20(7): 1264-5

88.

Duquette RA, Nuttall TJ. Methicillin-resistant Staphylococcus aureus in dogs and cats: an emerging problem? J Small Anim Pract 2004;45(12):591-7

89.

Guardabassi L, Schwarz S, Lloyd DH. Pet animals as reservoirs of antimicrobial-resistant bacteria. J Antimicrob Chemother 2004;54(2):321-32

90.

Lloyd DH. Reservoirs of antimicrobial resistance in pet animals. Clin Infect Dis 2007;45(Suppl 2):S148-52

Weese JS. Antimicrobial resistance: time for action. Vet Rec 2011;169(5):122-3 ˇ eol B. 92. Mekic´ S, Matanovic´ K, S Antimicrobial susceptibility of Pseudomonas aeruginosa isolates from dogs with otitis externa. Vet Rec 2011;169(5):125 91.

93.

Cain CL. Antimicrobial resistance in staphylococci in small animals. Vet Clin North Am Small Anim Pract 2013;43(1): 19-40

94.

Ruscher C, Lu¨bke-Becker A, Wleklinski CG, et al. Prevalence of Methicillin-resistant Staphylococcus pseudintermedius isolated from clinical samples of companion animals and equidaes. Vet Microbiol 2009;136(1-2): 197-201

95.

96.

97.

Vincze S, Stamm I, Kopp PA, et al. Alarming proportions of methicillin-resistant Staphylococcus aureus (MRSA) in wound samples from companion animals, Germany 2010-2012. PLoS One 2014;9(1):e85656 Schmidt VM, Williams NJ, Pinchbeck G, et al. Antimicrobial resistance and characterisation of staphylococci isolated from healthy Labrador retrievers in the United Kingdom. BMC Vet Res 2014;10:17 Wedley AL, Dawson S, Maddox TW, et al. Carriage of Staphylococcus species in the veterinary visiting dog population in mainland UK: molecular characterisation of resistance and virulence. Vet Microbiol 2014;170(1-2):8

98.

Davis JA, Jackson CR, Fedorka-Cray PJ, et al. Carriage of methicillin-resistant staphylococci by healthy companion animals in the US. Lett Appl Microbiol 2014;59:1-8

99.

Epstein CR, Yam WC, Peiris JS, Epstein RJ. Methicillin-resistant commensal


Review

staphylococci in healthy dogs as a potential zoonotic reservoir for community-acquired antibiotic resistance. Infect Genet Evol 2009; 9(2):283-5

110.

Timofte D, Maciuca IE, Kemmett K, et al. Detection of the human-pandemic Escherichia coli B2-O25b-ST131 in UK dogs. Vet Rec 2014;174(14):352

100.

Hoet AE, van Balen J, Nava-Hoet RC, et al. Epidemiological Profiling of Methicillin-Resistant Staphylococcus aureus-Positive Dogs arriving at a Veterinary Teaching Hospital. Vector Borne Zoonotic Dis 2013;13(6):385-93

111.

101.

Nienhoff U, Kadlec K, Chaberny IF, et al. Methicillin-resistant Staphylococcus pseudintermedius among cats admitted to a veterinary teaching hospital. Vet Microbiol 2011;153(3-4):414-16

Albrechtova K, Dolejska M, Cizek A, et al. Dogs of nomadic pastoralists in northern Kenya are reservoirs of plasmid-mediated cephalosporin- and quinolone-resistant Escherichia coli, including pandemic clone B2-O25-ST131. Antimicrob Agents Chemother 2012;56(7):4013-17

112.

Ewers C, Bethe A, Stamm I, et al. CTX-M15-D-ST648 Escherichia coli from companion animals and horses: another pandemic clone combining multiresistance and extraintestinal virulence? J Antimicrob Chemother 2014;69(5):1224-30

113.

Abraham S, Wong HS, Turnidge J, et al. Carbapenemase-producing bacteria in companion animals: a public health concern on the horizon. J Antimicrob Chemother 2014;69(5):1155-7

114.

Gibson JS, Morton JM, Cobbold RN, et al. Multidrug-resistant E. coli and Enterobacter extraintestinal infection in 37 dogs. J Vet Intern Med 2008;22:844-50

115.

Park KM, Nam HS, Woo HM. Successful management of multidrug-resistant Pseudomonas aeruginosa pneumonia after kidney transplantation in a dog. J Vet Med Sci 2013;75(11):1529-33

116.

Pomba C, da Fonseca JD, Baptista BC, et al. Detection of the pandemic O25-ST131 human virulent Escherichia coli CTX-M-15-producing clone harboring the qnrB2 and aac(6’)-Ib-cr genes in a dog. Antimicrob Agents Chemother 2009;53(1): 327-8

Shaheen BW, Nayak R, Boothe DM. Emergence of a New Delhi metallo-b-lactamase (NDM-1)-encoding gene in clinical Escherichia coli isolates recovered from companion animals in the United States. Antimicrob Agents Chemother 2013;57(6):2902-3

117.

Nam EH, Ko S, Chae JS, Hwang CY. Characterization and zoonotic potential of uropathogenic Escherichia coli isolated from dogs. J Microbiol Biotechnol 2013;23(3): 422-9

Stolle I, Prenger-Berninghoff E, Stamm I, et al. Emergence of OXA-48 carbapenemase-producing Escherichia coli and Klebsiella pneumoniae in dogs. J Antimicrob Chemother 2013; 68(12):2802-8

118.

Ewers C, Bethe A, Wieler LH, et al. Companion animals: a relevant source of extended-spectrum b-lactamase-producing fluoroquinolone-resistant Citrobacter freundii. Int J Antimicrob Agents 2011; 37(1):86-7

119.

Endimiani A, Hujer KM, Hujer AM, et al. Acinetobacter baumannii isolates from pets and horses in Switzerland: molecular characterization and clinical data. J Antimicrob Chemother 2011;66(10): 2248-54

120.

So JH, Kim J, Bae IK, et al. Dissemination of multidrug-resistant Escherichia coli in

102.

103.

104.

105.

106.

107.

108.

109.

Muniz IM, Penna B, Lilenbaum W. Treating animal bites: susceptibility of Staphylococci from oral mucosa of cats. Zoonoses Public Health 2013;60(7):504-9 De Martino L, Lucido M, Mallardo K, et al. Methicillin-resistant staphylococci isolated from healthy horses and horse personnel in Italy. J Vet Diagn Invest 2010; 22(1):77-82 Moodley A, Damborg P, Nielsen SS. Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: literature review from 1980 to 2013. Vet Microbiol 2014;171(3-4):337-41 Rubin JE, Pitout JD. Extended-spectrum b-lactamase, carbapenemase and AmpC producing Enterobacteriaceae in companion animals. Vet Microbiol 2014;170(1-2): 10-18

Dahmen S, Haenni M, Chaˆtre P, Madec JY. Characterization of blaCTX-M IncFII plasmids and clones of Escherichia coli from pets in France. J Antimicrob Chemother 2013;68(12):2797-801 Ewers C, Grobbel M, Stamm I, et al. Emergence of human pandemic O25:H4ST131 CTX-M-15 extended-spectrum-betalactamase-producing Escherichia coli among companion animals. J Antimicrob Chemother 2010;65(4):651-60

1457

Review

Labro & Bryskier

Korean veterinary hospitals. Diagn Microbiol Infect Dis 2012;73(2):195-9


121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

Seiffert SN, Carattoli A, Tinguely R, et al. High Prevalence of Extended-Spectrum b-Lactamase, Plasmid-Mediated AmpC, and Carbapenemase Genes in Pet Food. Antimicrob Agents Chemother 2014;58(10): 6320-3

Diseased European Hedgehogs (Erinaceus europaeus) in Sweden. PLoS ONE 2013; 8(6):e66166 133.

Harrison EM, Paterson GK, Holden MT, et al. Whole genome sequencing identifies zoonotic transmission of MRSA isolates with the novel mecA homologue mecC. EMBO Mol Med 2013;5(4):509-15

Rose S, Hill R, Bermudez LE, Miller-Morgan T. Imported ornamental fish are colonized with antibiotic-resistant bacteria. J Fish Dis 2013;36(6):533-42

134.

Johnson AP. Methicillin-resistant Staphylococcus aureus: the European landscape. J Antimicrob Chemother 2011;66:Suppl 4 iv43-8

Dıáz MA, Cooper RK, Cloeckaert A, Siebeling RJ. Plasmid-mediated high-level gentamicin resistance among enteric bacteria isolated from pet turtles in Louisiana. Appl Environ Microbiol 2006;72(1):306-12

135.

Nakamura M, Fukazawa M, Yoshimura H, Koeda T. Drug resistance and R plasmids in Escherichia coli strains isolated from imported pet birds. Microbiol Immunol 1980;24(12):1131-8

136.

Weir M, Rajic´ A, Dutil L, et al. Zoonotic bacteria, antimicrobial use and antimicrobial resistance in ornamental fish: a systematic review of the existing research and survey of aquaculture-allied professionals. Epidemiol Infect 2012;140(2):192-206

137.

138.

Zaja˛c M, Wasyl D, Hoszowski A, et al. Genetic lineages of Salmonella enterica serovar Kentucky spreading in pet reptiles. Vet Microbiol 2013;166(3-4):686-9 Cinquepalmi V, Monno R, Fumarola L, et al. Environmental contamination by dog’s faeces: a public health problem? Int J Environ Res Public Health 2012;10(1): 72-84 Radhouani H, Silva N, Poeta P, et al. Potential impact of antimicrobial resistance in wildlife, environment and human health. Front Microbiol 2014;5:23 Sousa M, Silva N, Igrejas G, et al. Antimicrobial resistance determinants in Staphylococcus spp. recovered from birds of prey in Portugal. Vet Microbiol 2014;171: 436-40 Bonnedahl J, Drobni M, Gauthier-Clerc M, et al. Dissemination of Escherichia coli with CTX-M type ESBL between humans and yellow-legged gulls in the south of France. PLoS ONE 2009;4(6):e5958 Guenther S, Grobbel M, Lu¨bke-Becker A, et al. Antimicrobial resistance profiles of Escherichia coli from common European wild bird species. Vet Microbiol 2010; 144(1-2):219-25 Monecke S, Gavier-Widen D, Mattsson R, et al. Detection of mecC-Positive Staphylococcus aureus(CC130-MRSA-XI) in

1458

139.

140.

141.

142.

143.

van Duijkeren E, Catry B, Greko C, et al. Review on methicillin-resistant Staphylococcus pseudintermedius. J Antimicrob Chemother 2011;66(12): 2705-14 Bosch T, Verkade E, van Luit M, et al. High Resolution Typing by Whole Genome Mapping Enables Discrimination of LA-MRSA (CC398) Strains and Identification of Transmission Events. PLoS One 2013;8(6):e66493 Van den Eede A, Martens A, Flore´ K, et al. MRSA carriage in the equine community: an investigation of horse-caretaker couples. Vet Microbiol 2013;163(3-4):313-18 Lapierre L, Cornejo J, Borie C, et al. Genetic characterization of antibiotic resistance genes linked to class 1 and class 2 integrons in commensal strains of Escherichia coli isolated from poultry and swine. Microb Drug Resist 2008;14(4): 265-72 Oppliger A, Moreillon P, Charrie`re N, et al. Antimicrobial resistance of Staphylococcus aureus strains acquired by pig farmers from pigs. Appl Environ Microbiol 2012;78(22):8010-14 Fang HW, Chiang PH, Huang YC. Livestock-associated methicillin-resistant Staphylococcus aureus ST9 in pigs and related personnel in Taiwan. PLoS ONE 2014;9(2):e88826 Boost M, Ho J, Guardabassi L, O’Donoghue M. Colonization of butchers with livestock- -associated methicillin-resistant Staphylococcus aureus. Zoonoses Public Health 2013;60(8):572-6 Rinsky JL, Nadimpalli M, Wing S, et al. Livestock-associated methicillin and multidrug resistant I is present among industrial, not antibiotic-free livestock operation workers in North Carolina. PLoS ONE 2013;8(7):e67641 Spoor LE, McAdam PR, Weinert LA, et al. Livestock origin for a human pandemic clone of community-associated methicillin-

resistant Staphylococcus aureus. MBio 2013; 4(4):pii: e00356-13 144.

Rodriguez-Rivera LD, Wright EM, Siler JD, et al. Subtype analysis of Salmonella isolated from subclinically infected dairy cattle and dairy farm environments reveals the presence of both human- and bovine-associated subtypes. Vet Microbiol 2014;170(3-4):307-16

145.

Nienhoff U, Kadlec K, Chaberny IF, et al. Transmission of methicillin-resistant Staphylococcus aureus strains between humans and dogs: two case reports. J Antimicrob Chemother 2009;64(3):660-2

146.

Meyer E, Gastmeier P, Kola A, Schwab F. Pet animals and foreign travel are risk factors for colonisation with extended-spectrum b-lactamase-producing Escherichia coli. Infection 2012;40(6):685-7

147.

Huijbers PM, de Kraker M, Graat EA, et al. Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae in humans living in municipalities with high and low broiler density. Clin Microbiol Infect 2013;19(6):E256-E25

148.

Masclaux FG, Sakwinska O, Charrie`re N, et al. Concentration of Airborne Staphylococcus aureus (MRSA and MSSA), Total Bacteria, and Endotoxins in Pig Farms. Ann Occup Hyg 2013;57(5):550-7

149.

Fuller CC, Jawahir SL, Leano FT, et al. A multi-state Salmonella typhimurium outbreak associated with frozen vacuum-packed rodents used to feed snakes. Zoonoses Public Health 2008;55:481-7

150.

Wang N, Neilan AM, Klompas M. Staphylococcus intermedius infections: case report and literature review. Infect Dis Rep 2013;5(1):e3

151.

Smith JM. Staphylococcus aureus strains associated with the hedgehog, Erinaceus europaeus. J Hyg (Lond) 1965;63:285-91

152.

Smith JM, Marples MJ. Dermatophyte lesions in the hedgehog as a reservoir of penicillin-resistant staphylococci. J Hyg (Lond) 1965;63:293-303

153.

Moore PR, Evenson A, Luckey TD, et al. Use of sulfasuxidine, streptothricin, and streptomycin in nutritional studies with the chick. J Biol Chem 1946;165(2):437-41

154.

Manten A. The non-medical use of antibiotics and the risk of causing microbial drug-resistance. Bull World Health Organ 1963;29:387-400

155.

Thrower WR. Agriculture and the public health. Br Med J 1970;2(5701):69-74

156.

Cogliani C, Goosens H, Greko C. Restricting antimicrobial use in food




animals: lessons from Europe. Microbe 2011;6:274-9 157.

Hammerum AM. Enterococci of animal origin and their significance for public health. Clin Microbiol Infect 2012;18(7): 619-25

158.

Maron DF, Smith TJ, Nachman KE. Restrictions on antimicrobial use in food animal production: an international regulatory and economic survey. Global Health 2013;9:48

159.

FDA 2012. Available from: www.fda.gov/ downloads/animalveterinary/ guidancecomplianceenforcement/ guidanceforindustry/ucm216936.pdf

160.

Kuehn BM. FDA moves to curb antibiotic use in livestock. JAMA 2014;311(4):347-8

162.

Silley P, Simjee S, Schwarz S. Surveillance and monitoring of antimicrobial resistance and antibiotic consumption in humans and animals. Rev Sci Tech 2012;31(1):105-20

163.

Garcia-Migura L, Hendriksen RS, Fraile L, Aarestrup FM. Antimicrobial resistance of zoonotic and commensal bacteria in Europe: the missing link between consumption and resistance in veterinary medicine. Vet Microbiol 2014;170(1-2):1-9

164.

165.

166.

167.

168.

169.

Fraqueza MJ, Martins A, Borges AC, et al. Antimicrobial resistance among Campylobacter spp. strains isolated from different poultry production systems at slaughterhouse level. Poult Sci 2014;93(6): 1578-86

180.

170.

Scott L, Menzies P, Reid-Smith RJ, et al. Antimicrobial resistance in Campylobacter spp. isolated from Ontario sheep flock sand associations between antimicrobial use and antimicrobial resistance. Zoonoses Public Health 2012;59(4):294-301

Madoff L. Cooperation between animal and human health sectors is key to the detection, surveillance, and control of emerging disease: IMED 2007 meeting in Vienna, February 2007. Euro Surveill 2006. 11(51):pii=3101

181.

171.

Tadesse DA, Bahnson PB, Funk JA, et al. Prevalence and antimicrobial resistance profile of Campylobacter spp. isolated from conventional and antimicrobial-free swine production systems from different U.S. regions. Foodborne Pathog Dis 2011;8(3): 367-74

Lowder BV, Guinane CM, Ben Zakour NL, et al. Recent human-to-poultry host jump, adaptation, and pandemic spread of Staphylococcus aureus. Proc Natl Acad Sci U S A 2009;106:19545-50

182.

Lowder BV, Fitzgerald JR. Human origin for avian pathogenic Staphylococcus aureus. Virulence 2010;1(4):283-4

183.

Fitzgerald JR. Livestock-associated Staphylococcus aureus: origin, evolution and public health threat. Trends Microbiol 2012;20(4):192-8

184.

Cuny C, Friedrich A, Kozytska S, et al. Emergence of methicillin-resistant Staphylococcus aureus (MRSA) in different animal species. Int J Med Microbiol 2010; 300(2-3):109-17

185.

Lefebvre SL, Weese JS. Contamination of pet therapy dogs with MRSA and Clostridium difficile. J Hosp Infect 2009; 72(3):268-9

186.

Lefebvre SL, Reid-Smith RJ, Waltner-Toews D, Weese JS. Incidence of acquisition of methicillin-resistant Staphylococcus aureus, Clostridium difficile, and other health-care-associated pathogens by dogs that participate in animal-assisted interventions. J Am Vet Med Assoc 2009; 234(11):1404-17

187.

Haenni M, Saras E, Chaˆtre P, et al. A USA300 variant and other human-related methicillin-resistant Staphylococcus aureus strains infecting cats and dogs in France. J Antimicrob Chemother 2012;67(2):326-9

188.

Osadebe LU, Hanson B, Smith TC, Heimer R. Prevalence and Characteristics of Staphylococcus aureus in Connecticut Swine and Swine Farmers. Zoonoses Public Health 2013;60(3):234-43

189.

Synanthropization of animals in megapolis. Available from: http://awu.nauu.kiev.ua/ index.php/ebql/article/viewFile/70/49

190.

Navarro-Gonzalez N, Casas-Dıáz E, Porrero CM, et al. Food-borne zoonotic pathogens and antimicrobial resistance of indicator bacteria in urban wild boars in Barcelona. Spain Vet Microbiol 2013; 167(3-4):686-9

Mole B. MRSA: Farming up trouble. Nature 2013;499(7459):398-400

161.

Aarestrup FM, Jensen VF, Emborg HD, et al. Changes in the use of antimicrobials and the effects on productivity of swine farms in Denmark. Am J Vet Res 2010;71: 726-33 US Food and Drug Administration: 2009 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing Animals. 2010. Available from: www.fda.gov/downloads/ForIndustry/ UserFees/AnimalDrugUserFeeActADUFA/ UCM231851.pdf Mo SS, Norstro¨m M, Slettemea˚s JS, et al. Emergence of AmpC-producing Escherichia coli in the broiler production chain in a country with a low antimicrobial usage profile. Vet Microbiol 2014;171:315-20 Nilsson O, Bo¨rjesson S, Landeń A, Bengtsson B. Vertical transmission of Escherichia coli carrying plasmid-mediated AmpC (pAmpC) through the broiler production pyramid. J Antimicrob Chemother 2014;69(6):1497-500 Wondwossen A, Gebreyes WA, Thakur S, Morrow WE. Campylobacter coli: prevalence and antimicrobial resistance in antimicrobial-free (ABF) swine production systems. J Antimicrob Chemother 2005; 56(4):765-8


Review

172.

Smith TC, Gebreyes WA, Abley MJ, et al. Methicillin-resistant Staphylococcus aureus in pigs and farm workers on conventional and antibiotic-free swine farms in the USA. PLoS One 2013;8(5):e63704

173.

Go´mez-Sanz E, Kadlec K, Feßler AT, et al. Novel erm(T)-carrying multiresistance plasmids from porcine and human methicillin-resistant Staphylococcus aureus ST398 that also harbor cadmium and copper resistance determinants. Antimicrob Agents Chemother 2013;57(7):3275-82

174.

Nisanian M, Holladay SD, Karpuzoglu E, et al. Exposure of juvenile Leghorn chickens to lead acetate enhances antibiotic resistance in enteric bacterial flora. Poult Sci 2014; 93(4):891-7

175.

Davin-Regli A, Page`s JM. Cross-resistance between biocides and antimicrobials: an emerging question. Rev Sci Tech 2012; 31(1):89-104

176.

Schwaiger K, Harms KS, Bischoff M, et al. Insusceptibility to disinfectants in bacteria from animals, food and humans-is there a link to antimicrobial resistance? Front Microbiol 2014;5:88

177.

Fadli M, Chevalier J, Hassani L, et al. Natural extracts stimulate membrane-associated mechanisms of resistance in Gram-negative bacteria. Lett Appl Microbiol 2014;58(5):472-7

178.

Mishra NN, Bayer AS, Moise PA, et al. Reduced susceptibility to host-defense cationic peptides and daptomycin coemerge in methicillin-resistant Staphylococcus aureus from daptomycin-naive bacteremic patients. J Infect Dis 2012;206(8):1160-7

179.

Mishra NN, Yang SJ, Chen L, et al. Emergence of daptomycin resistance in daptomycin-naı¨ve rabbits with

methicillin-resistant Staphylococcus aureus prosthetic joint infection is associated with resistance to host defense cationic peptides and mprF polymorphisms. PLoS One 2013; 8(8):e71151

1459

Review 191.


192.

193.

Labro & Bryskier

Vieira-da-Motta O, Eckhardt-de-Pontes LA, Petrucci MP, et al. Microbiota and anthropic interference on antimicrobial resistance profile of bacteria isolated from Brazilian maned-wolf (Chrysocyon brachyurus). Braz J Microbiol 2014;44(4): 1321-6 Janatova M, Albrechtova K, Petrzelkova KJ, et al. Antimicrobial-resistant Enterobacteriaceae from humans and wildlife in Dzanga-Sangha Protected Area, Central African Republic. Vet Microbiol 2014;171(3-4):422-31 Walsh F, Duffy B. The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria. PLoS One 2013;8(6):e65567

194.

Finley RL, Collignon P, Larsson DG, et al. The scourge of antibiotic resistance: the important role of the environment. Clin Infect Dis 2013;57(5):704-10

195.

Bhullar KN, Waglechner A, Pawlowski et al. Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS One 2012;7:e34953

196.

Kelesidis T. The Zoonotic Potential of Daptomycin Non-susceptible Enterococci. Zoonoses Public Health 2013. [Epub ahead of print]

197.

Allen HK, Donato J, Wang HH, et al. Call of the wild: antibiotic resistance genes in natural environments. Nat Rev Microbiol 2010;8:251-9

198.

Larsson DG. Antibiotics in the environment. Ups J Med Sci 2014;119(2): 108-12

199.

Blaak H, de Kruijf P, Hamidjaja RA, et al. Prevalence and characteristics of ESBL-producing E. coli in Dutch recreational waters influenced by wastewater treatment plants. Vet Microbiol 2014;pii: S0378 1135(14)00157-6

200.

Hsu JT, Chen CY, Young CW, et al. Prevalence of sulfonamide-resistant bacteria, resistance genes and integron-associated horizontal gene transfer in natural water bodies and soils adjacent to a swine feedlot in northern Taiwan. J Hazard Mater 2014; pii: S0304-3894(14)00115-0

201.

Djordjevic SP, Stokes HW, Roy Chowdhury P. Mobile elements, zoonotic pathogens and commensal bacteria: conduits for the delivery of resistance genes into humans, production animals and soil microbiota. Front Microbiol 2013;4:86

202.

Colomer-Lluch M, Jofre J, Muniesa M. Quinolone resistance genes (qnrA and qnrS) in bacteriophage particles from wastewater samples and the effect of inducing agents on

1460

packaged antibiotic resistance genes. J Antimicrob Chemother 2014;69(5):1265-74 203.

204.

Veldman K, Kant A, Dierikx C, et al. Enterobacteriaceae resistant to third-generation cephalosporins and quinolones in fresh culinary herbs imported from Southeast Asia. Int J Food Microbiol 2014;177:72-7 van Overbeek LS, van Doorn J, Wichers JH, et al. The arable ecosystem as battleground for emergence of new human pathogens. Front Microbiol 2014;5:104

205.

McManus PS. Does a drop in the bucket make a splash? Assessing the impact of antibiotic use on plants. Curr Opin Microbiol 2014;19:76-82

206.

Zurek L, Ghosh A. Insects represent a link between food animal farms and the urban environment for antibiotic resistance traits. Appl Environ Microbiol 2014;80(12): 3562-7

207.

de Jong A, Thomas V, Klein U, et al. Pan-European resistance monitoring programmes encompassing food-borne bacteria and target pathogens of food-producing and companion animals. Int J Antimicrob Agents 2013;41(5):403-9

208.

209.

210.

Acar JF, Moulin G. Integrating animal health surveillance and food safety: the issue of antimicrobial resistance. Rev Sci Tech 2013;32(2):383-92 Moyaert H, de Jong A, Simjee S, Thomas V. Antimicrobial resistance monitoring projects for zoonotic and indicator bacteria of animal origin: common aspects and differences between EASSA and EFSA. Vet Microbiol 2014;279-83 Makarov V, Nedosekov V, Buchatskyu L, Polischiuk S. Synanthropization of animals in megapolis. Available from: http://www. who.int/gfn/supported/en/

211.

Teale CJ, Moulin G. Prudent use guidelines: a review of existing veterinary guidelines. Rev Sci Tech 2012;31(1):343-54

212.

Grave K, Torren-Edo J, Muller A, et al. Variations in the sales and sales patterns of veterinary antimicrobial agents in 25 European countries. J Antimicrob Chemother 2014;69(8):2284-91

213.

De Briyne N, Atkinson J, Pokludova´ L, et al. Factors influencing antibiotic prescribing habits and use of sensitivity testing amongst veterinarians in Europe. Vet Rec 2013;173(19):475

214.

WHO (World Health Organization). 2012 Antimicrobial Resistance. Available from: www.who.int/mediacentre/factsheets/ fs194/en/

215.

Pruden A, Larsson DG, Ame´zquita A, et al. Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment. Environ Health Perspect 2013;121(8): 878-85

216.

Suthar N, Roy S, Call DR, et al. An individual-based model of transmission of resistant bacteria in a veterinary teaching hospital. PLoS ONE 2014;9(6):e98589

217.

Redondo LM, Chacana PA, Dominguez JE, et al. Perspectives in the use of tannins as alternative to antimicrobial growth promoter factors in poultry. Front Microbiol 2014;5:118

218.

Bohez L, Ducatelle R, Pasmans F, et al. Long-term colonisation-inhibition studies to protect broilers against colonisation with Salmonella enteritidis, using Salmonella Pathogenicity Island 1 and 2 mutants. Vaccine 2007;25(21):4235-43

219.

Allen HK, Trachsel J, Looft T, Casey TA. Finding alternatives to antibiotics. Ann N Y Acad Sci 2014;1323(1):91-100

220.

Cheng G, Hao H, Xie S, et al. Antibiotic alternatives: the substitution of antibiotics in animal husbandry? Front Microbiol 2014;5:217

221.

Markestad A, Grave K. Reduction of antibacterial drug use in Norwegian fish farming due to vaccination. Dev Biol Stand 1997;90:365-9

222.

McGhee GC, Sundin GW. Evaluation of kasugamycin for fire blight management, effect on nontarget bacteria, and assessment of kasugamycin resistance potential in Erwinia amylovora. Phytopathology 2011;101:192-204

223.

Andersson DI, Hughes D. Microbiological effects of sublethal levels of antibiotics. Nat Rev Microbiol 2014;12(7):465-78

224.

Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol 2010; 8(4):260-71

225.

El-Halfawy OM, Valvano MA. Chemical communication of antibiotic resistance by a highly resistant subpopulation of bacterial cells. PLoS One 2013;8(7):e68874

226.

von Wintersdorff CJ, Penders J, Stobberingh EE, et al. High rates of antimicrobial drug resistance gene acquisition after international travel, the Netherlands. Emerg Infect Dis 2014;20(4): 649-57

227.

da Costa PM, Loureiro L, Matos AJ. Transfer of multidrug-resistant bacteria between intermingled ecological niches: the interface between humans, animals and the



environment. Int J Environ Res Public Health 2013;10(1):278-94


228.

Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009;48(1):1-12

229.

King AM, Reid-Yu SA, Wang W, et al. Aspergillomarasmine A overcomes metallo-b-lactamase antibiotic resistance. Nature 2014;510(7506):503-6

230.

Mandal SM, Roy A, Ghosh AK, et al. Challenges and future prospects of antibiotic therapy: from peptides to phages utilization. Front Pharmacol 2014;5:105


Review

231.

Golkar Z, Bagasra O, Pace DG. Bacteriophage therapy: a potential solution for the antibiotic resistance crisis. J Infect Dev Ctries 2014;8(2):129-36

234.

Zhang G, Sunkara LT. Avian antimicrobial host defense peptides: from biology to therapeutic applications. Pharmaceuticals (Basel) 2014;7(3):220-47

232.

Lie´vin-Le Moal V, Servin AL. Anti-infective activities of lactobacillus strains in the human intestinal microbiota: from probiotics to gastrointestinal anti-infectious biotherapeutic agents. Clin Microbiol Rev 2014;27(2):167-99

235.

Garcia-Alvarez L, Dawson S, Cookson B, Hawkey P. Working across the veterinary and human health sectors. J Antimicrob Chemother 2012;67(Suppl 1)):i37-49

233.

Keating TA, Lister T, Verheijen JC. New antibacterial agents: patent applications published in 2011. Pharm Pat Anal 2014; 3(1):87-112

1461

Armadillos: An emerging zoonosis in Florida.

Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis.

Molecular detection of Capillaria philippinensis: An emerging zoonosis in Egypt.

A rapidly emerging ocular zoonosis; Dirofilaria repens.

Multidrug resistance: an emerging crisis.

Echinocandin resistance: an emerging clinical problem?

[Ocular thelaziosis, an emergent zoonosis in Spain].

Laboratory systems as an antibacterial resistance containment tool in Africa.

Antibacterial resistance in sub-Saharan Africa: an underestimated emergency.

Antibiotic resistance in bacteria - an emerging public health problem.

Emerging resistance to fluoroquinolones in staphylococci: an alert.

Resistance to vancomycin and teicoplanin: an emerging clinical problem.

Tularaemia: a challenging zoonosis.

Aminoglycoside resistance emerging during therapy.

Tamoxifen Resistance: Emerging Molecular Targets.

Emerging quinolone resistance in campylobacters.

Hierarchical nested trial design (HNTD) for demonstrating treatment efficacy of new antibacterial drugs in patient populations with emerging bacterial resistance.

Emerging applications of riboswitches - from antibacterial targets to molecular tools.

The emerging role of mTOR signalling in antibacterial immunity.

Antibacterial mechanisms of polymyxin and bacterial resistance.

Antibacterial resistance leadership group: open for business.

Is Antimicrobial Resistance a Slowly Emerging Disaster?

FOXM1: an emerging master regulator of DNA damage response and genotoxic agent resistance.

Emerging Plasmodium vivax resistance to chloroquine in South America: an overview.