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1 The Role of Socio-Cultural Developments for the Transmission of Multidrug-Resistant Bacteria Between Man and Companion Animals

The domestication of wild animals is regarded as a pivotal threshold in human evolution, a well-known fact that gives evidence for the prehistoric human relationships with companion animals (Zeder 2006). In this chapter we concentrate on the importance of three companion animals, i.e. dogs, cats and horses, as sources or targets of infections with four multidrug-resistant zoonotic bacterial pathogens. We consider the ongoing socio-cultural changes in the relationship between companion animals and humans as a highly important matter in this respect. Here we briefly describe the domestication of dogs as one example of this ongoing development. This is meant to just give a flavor of our vision in terms of the possibility of an exchange of zoonotic pathogens between companion animals and their owners. We envision that the ever closer relationship will increase the risk of exchange of microbiota, and thus also of pathogens.

Although the dog was the first domesticated animal the idea based on molecular clock estimates from mitochondrial DNA that domestication started about 135,000 years (Vilà et al. 1997) is not without controversy. More circumspect estimates of zooarcheologists lead to the conclusion that dog domestication began about 15,000 years ago. Since even a broad analysis of 49,024 autosomal SNPs in 1375 dogs (representing 35 breeds) and 19 wolves failed in unraveling the history of dog domestication, next-generation sequencing of modern and ancient dog genomes is needed to settle this debate (Larson et al. 2012). Nevertheless, DNA analysis revealed that American dogs were more similar to dogs from the Old World than to gray wolves of North America. This outcome supports the idea that dogs accompanied humans crossing the Bering Strait in the late Pleistocene (Leonard et al. 2002), who consequently availed from the dogs abilities in hunting, protection and as pack animals. Moreover, during the process of domestication, dogs have been selected for a set of social-cognitive abilities that enable them to communicate with humans in unique ways (Hare et al. 2002). The archeological finds of canine bones revealed distinctions against contemporary wolves that were pronounced in both skulls and dentition and could be interpreted as results of human intervention in natural selection or may be markers of an early commensal relationship with humans as so called “camp-follower scavengers” (Murugaiyan et al. 2014; Zeder 2006). Skull shape modifications were probably the result of changes in dogs’ brain morphology with a decrease of overall size relative to that of wolves and an increase in brain-to-body-size ratio (Schoenebeck and Ostrander 2013; Zeder et al. 2012).

In 2010, the estimated percentage of European households owning at least one dog or one cat was 27 and 24 %, respectively, a demonstration of the tight bond between mankind and domesticated animals, particularly canides, in postindustrial societies. Moreover, if it comes to numbers, 73.643.400 dogs and 84.705.500 cats were counted for European households (fediaf.org 2010). Since people are willing to spend a lot of money for their beloved companions not only for costly extensive medical treatments of seriously ill or elderly patients, but also for a wide range of unusual consumer products and services, pet animals contribute significantly to the economy (Walsh 2009). In 2010 the estimated combined annual turnover of pet food industry and related supply and services throughout Europe reached about € 24 billion (fediaf.org 2010).

It seems to be common knowledge that the human-animal interactions possess the potential to benefit human mental and physical health and wellbeing (O’Haire 2010). However, study results towards the association between pet ownership and human health were frequently found contradictory (McNicholas et al. 2005). Regarding the psychological part, the most important benefit of pet ownership was identified in terms of companionship (Duvall Antonacopoulos and Pychyl 2010). Nonetheless, a closer look at the complex psychological nature of human and companion animal relationships revealed that the degree of attachment (to the animal) is a stronger predictor of psychological distress than gender, marital status, age, and number of people within a household. However, the causal direction of this association remains unknown at present and needs to be further investigated (Peacock et al. 2012). Pet ownership in elderly people (≥ 65 years) is frequently discussed as a possibility to avoid loneliness and depression, a rising problem due to population aging in Western societies. Interestingly, only for those people who were both, divorced and living alone, pet ownership demonstrated the potential for being associated with greater satisfaction with life (Himsworth and Rock 2013). Thus, chronically disconnected people tend to substitute social contacts by companion animals (Serpell 2003; Zeder 2006). Moreover, a number of studies confirmed the positive impact of interactions with companion animals on physical health, particularly in patients with heart disease and chronic diseases like cancer (Friedmann and Thomas 1995; Johnson et al. 2003). Anderson et al. (1992) correlated pet ownership with cardiovascular benefits, e. g. lower systolic blood pressure, plasma cholesterol (men only) and triglyceride levels (Anderson et al. 1992).

The socio-cultural background including traditions seems to influence the orientation of companion animal owners towards their animal: Study results by Blouin et al. (2013) suggest that among dog owners, one group values mostly the usefulness of their dog (e.g. protection), another provide the status of surrogate humans, and the third group views the dogs as valuable companions including own (animal) interests (Blouin (2013). The second group uses anthropomorphism, a term which can be defined as the attribution of human mental states (thoughts, feelings, motivations and beliefs) to non-human creatures (Serpell 2003). Moreover, anthropomorphism induces a certain kind of evolutionary selection pressure and a variety of corresponding adaptations, which were not exclusively linked to animal welfare, resulting in a novel ecological niche (Serpell 2003). Beside the socio-cultural effects of this equalization of humans and companion animals, the transmission risk for pathogens rises as a result of offering certain human privileges to companion animals. This should be highlighted by the following study results: Of 102 dog owners, who attended a dog show event in 2009, 88.9 % reported to allow at least one dog in the house, 68.5 % allow the dog(s) to rest on the sofa, 39.8 % allow their dogs to come onto the bed, 93.5 % let them lick their hands and 52.8 % let them lick their face (Walther et al. 2012b). These exemplarily co-habitation and behavioral pattern give cause to concern with respect to the fact that 60 % of all human pathogens were generally regarded as zoonotic (Cleaveland et al. 2001; Woolhouse and Gowtage-Sequeria 2005) and a rising number of opportunistic bacteria exhibit multidrug resistance (Chuang et al. 2010; Stegmann et al. 2010; Wieler et al. 2011). Recent work published by Song et al. proving that family members share microbiota with their dogs, in particular regarding skin microbiota, gives further evidence on the extensive exchange of microbes (Song et al. 2013).

When new zoonotic pathogens emerge, a frequently chosen strategy is to search for the most important infections source, ignoring other species that might strongly influence transmission (Brisson et al. 2011). A considerable problem arises when scientists use the term “reservoir” in this context. Although “reservoir” is defined as the natural permanent infection source of a certain pathogen, some scientists assign rather deliberately any infection source identified as reservoir. This implies that eradication of the respective pathogen in this reservoir will be the key for intervention. This can be illustrated with the emergence of so-called “livestock-associated” (LA-) MRSA. The first report of colonized members of a farmer family and their pigs in the Netherlands in 2004 (Voss et al. 2005) was followed by a rush of scientists from different disciplines in stables, flocks and cages. Early focusing on a limited number of possible host species as infection source can delay biological understanding. This may cause misguiding public health interventions as the important host species of either amplifying or transmissing the pathogen are overlooked (Brisson et al. 2011; Walther et al. 2012a). In case of LA-MRSA, a broad spread took place since 2005, including infections of horses, dogs, cats and many other species. Similarly, the new MRSA variant harboring mecC, initially described for humans and ruminants, was subsequently also found in diseased companion animals (Walther et al. 2012a). The finding that particular genetic lineages of Staphylococci are able to infect several host species led to the introduction of the paradigma of extended host spectrum genotypes (EHSG) (Walther et al. 2009).

Knowledge concerning the risks associated with infections of companion animals with multidrug-resistance bacteria is rather limited (Stull et al. 2012). In consequence, interdisciplinary efforts are required to fulfill the demands of zoonotic disease information for both companion animal and non-owning households (Stull et al. 2012). We consider surveillance efforts in terms of a “One health” umbrella as the key starting point. Here we summarize knowledge on four multidrug-resistant bacterial species. We highlight the knowledge gaps of these increasing important in terms of disease burden in companion animals and their zoonotic potential.

2 Methicillin-Resistant Staphylococcus aureus in Companion Animals

The natural habitat of Staphylococcus (S.) aureus, a Gram-positive coccus, is the skin and the anterior nares of humans. Approximately 30 % of humans are permanently while up to 50 % are transiently colonized. Besides, various animals can be carriers. As an opportunistic pathogen, S. aureus plays an important role in both human and veterinary medicine, affecting a broad range of animals.

Methicillin-resistant S. aureus (MRSA) are resistant against all ß-lactam antibiotics mediated by the acquisition of the Penicillin-binding protein 2a (PBP2a) encoding mecA- or mecC-gene. PBP2 is expressed by all S. aureus and catalyzes two enzymatic reactions (transpeptidation and transglycosilation). By binding ß-lactam antibiotics, the transpeptidase of PBP2 loses its function which mediates the bactericidal effect. PBP2a acts as an additional transpeptidase and shows, unlike the native PBP2, a low affinity to ß-lactam antibiotics, thus it compensates the loss of function in PBP2 after therapy with ß-lactams.

Only a short time after the introduction of methicillin, MRSA-infections were reported with an increasing number in hospitals as well as other healthcare settings. This observed restriction led to the denomination of those genotypes as hospital-associated (HA-) MRSA. Along with methicillin-resistance, S. aureus frequently acquire resistance against various antimicrobials, leading to reduced therapeutic options. In human medicine, MRSA is one of the most important nosocomial pathogens that provides a significant burden to healthcare settings due to extended therapy, prolonged hospital stay and higher costs (Köck et al. 2010). During the 1990s the MRSA epidemiology changed, as MRSA-infections were no longer restricted to healthcare settings, but were increasingly observed in humans outside the hospital. In comparison to well-characterized HA-MRSA, these strains belonged to different genetic lineages and were termed as community-associated (CA-) MRSA (Chambers 2001). Nowadays, MRSA are important pathogens in both healthcare settings and surroundings without exposure to hospital environments (Köck et al. 2014).

It was not until the late 1990s that the awareness of MRSA as cause of infections in animals increased based on several case reports. In 2004, MRSA of a specific genetic lineage, namely CC398-MRSA, emerged as frequent colonizers of pigs and farmers in close contact. The initial assumed host restriction to swine and other livestock resulted in the denomination as Livestock-associated (LA-) MRSA. Since then, CC398-MRSA have been reported in humans and several other animal species (Köck et al. 2014).

Meanwhile, MRSA have been detected in a wide range of animals. In particular companion animals are regularly identified to be colonized and/or infected with MRSA. The main infection sites in dogs and cats include wounds, urogenital tract, skin and mucosa as well as ears (Walther et al. 2008). Data concerning colonization in dogs and cats are rare and difficult to compare due to heterogeneous study settings. However, these surveys describe colonization in dogs and cats with rates from zero to 4 % in healthy dogs and cats without clinical background and up to 9 % for dogs at a veterinary clinic (Weese 2010). Although there is a lack of knowledge concerning the colonization length, first evidence exists that MRSA-carriage is transient in dogs and cats (Loeffler et al. 2010b). The genotypes of canine and feline MRSA mirror predominant human HA-associated MRSA-lineages within the same geographic region like clonal complexes (CC)8 in France (Haenni et al. 2012), CC5 and CC22 in Germany (Vincze et al. 2013) and CC22 and CC30 in the United Kingdom (Loeffler et al. 2010a), indicating a spill-over from human hospitals to dogs and cats. In addition, CC398-MRSA can be detected in dogs and cats on a regular basis, underlining the potential of this lineage to colonize and infect not only livestock and humans but dogs and cats as well (Köck et al. 2014; Vincze et al. 2014).

In horses, MRSA-infections were described only occasionally after the first report in 1989 and it was not before the mid-1990s that an increasing number of equine MRSA-cases demonstrated the importance of this pathogen. Infections can be associated with both horses in clinical environments and without exposure to clinics. While nosocomial outbreaks in equine clinics occur on a regular basis resulting in a large number of surgical site infections, MRSA-infections also have a serious impact in sporadic outbreaks without clinical background. Common infections without hospital background include joint, incision, and skin or soft tissue infections (Weese 2010). Similar to colonization studies in dogs and cats, data for horses are difficult to compare and range, depending on the investigated population, from 0 to 5 % in horses from farms, up to 11 % in horses admitted to equine clinics (van Duijkeren et al. 2010). In contrast to strains from dogs and cats, equine MRSA-lineages do not mirror common regional human lineages. Instead, CC8-MRSA, a prior human epidemic clone with sparse occurrence currently in humans, was reported as most common lineage in horses, leading to speculations on putative advantages of this lineage in equine colonization and infection (Weese 2010). Only recently, CC398-MRSA were reported in several horses from different European countries like Belgium, France and The Netherlands (Van den Eede et al. 2009; van Duijkeren et al. 2010). Recent data point towards the microevolution of a horse-adapted sublineage of ST398 (Abdelbary et al. 2014).

Transmission events between companion animals and humans have been described regularly, showing either humans as infection or colonization source for dogs, cats and horses or vice versa (Faires et al. 2009; Ferreira et al. 2011; Köck et al. 2014; Manian 2003; Weese et al. 2005). Even though, there is evidence for zoonotic transmission between companion animals and humans, longitudinal studies that address the frequency and impact of these events are still missing. Since dogs and cats are regularly infected with MRSA-lineages similar to prevalent regional genotypes causing infections in humans, transmission might be an important factor for colonization and/or infection in both directions. These events need to be unraveled, therefore longitudinal studies as well as case-control studies are urgently needed. The above discussed changes in the socio-cultural relationship between humans and companion animals clearly provide more opportunities for transmission (Walther et al. 2012b). Consequently, owners of MRSA-infected dogs were found more often nasally colonized with MRSA than the average population in Great Britain. Thus, MRSA-infected dogs are already identified as a risk factor for human colonization (Loeffler et al. 2010a).

So far, genetic lineages that were recognized as cause of infections in dogs, cats and horses did not show specific restrictions to one or a limited number of hosts. In contrast, MRSA of these genotypes seem to possess the potential to infect and/or colonize humans as well. Genotypes with the ability to infect a broad host spectrum were termed as extended host spectrum genotypes (EHSG) (Köck et al. 2014; Walther et al. 2009). With the knowledge that (i) MRSA is an important pathogen in companion animal medicine, (ii) MRSA from companion animals are EHSG, (iii) ownership of an MRSA-infected companion animal results in a higher risk of human colonization, and (iv) epidemiology changes over time as proven for MRSA in horses, monitoring and surveillance utilizing molecular typing of MRSA in companion animals is crucial to understand dynamics and spread of MRSA in companion animals.

3 Extended-Spectrum Beta-Lactamase (ESBL)-Producing Enterobacteriaceae

Extended-spectrum beta-Lactamases (ESBL) are a diverse group of hydrolyzing enzymes produced by Gram-negative bacteria that inactivate a wide range of beta-lactam antibiotics including broad-spectrum penicillin and cephalosporin up to the 3rd generation. ESBL enzymes in general are encoded on plasmids. They can still be inhibited by clavulanic acid which separates ESBL from AmpC, another type group of beta-lactamases. The ampC genes are often chromosomally encoded and occur frequently in Enterobacteriaceae. Their overexpression due to mutations confers broad-spectrum beta-lactam resistance as well.

As carbapenems are not inactivated by ESBL-or AmpC producers, they often present the last treatment opportunity. This is due to the fact that ESBL-producing Enterobacteriaceae often display additional resistances to several other classes of antimicrobial substances, resulting in multidrug-resistant phenotypes. Therefore, ESBLs are a worrying global public health issue as infections caused by these multidrug-resistant organisms are associated with a higher morbidity and mortality and a greater fiscal burden (Dhillon and Clark 2012). Taking into account the increasing worldwide prevalence (central Europe approx. 10 % of clinical E. coli) and an ever diminishing supply in the antibiotic armamentarium, ESBLs represent a clear and present danger to public health (Dhillon and Clark 2012). Although ESBLs are often commensals, they represent primary or secondary pathogens in healthy individuals in a wide range of diseases such as urinary tract infections, wound infections, pneumonia and septicaemia (Canton and Coque 2006). Cephalosporins are among the most commonly used antimicrobial classes in companion animal medicine, therefore increasing resistance against this class also presents an emerging problem for veterinarians.

Initially ESBL-producing Enterobacteriaceae were only observed in clinical settings where the first nosocomial outbreaks were recorded in clinics in Central Europe in the late 1980s. Since then an explosive worldwide proliferation of ESBLs in human clinical settings has been observed (Ewers et al. 2012). Within the last decade a community-associated onset has taken place. In between ESBL-producing Enterobacteriaceae are isolated from a wide range of companion animals, livestock, environmental samples and wildlife all over the world (Guenther et al. 2011). These ESBL-producing Enterobacteriaceae of animal origin did not only present resistant commensals, but included strains relevant to human health underlining the zoonotic character of ESBL (Carattoli 2008; Ewers et al. 2011a; Hasman et al. 2005; Overdevest et al. 2011; Smet et al. 2010). Considering that horizontally acquired plasmids are encoding these resistances, it is obvious that these developments further enrich the resistome (Gaze et al. 2013).

ESBL-production in companion animals is primarily associated with Escherichia coli, but can also occur in other pathogenic Enterobacteriaceae such as Citrobacter, Proteus, Salmonella and Klebsiella (Ewers et al. 2011b). About a decade after the increased numbers of nosocomial infections in human medicine the numbers of ESBL involved in nosocomial infections of companion animals is also rising.

At present over 200 ESBL types are known and have been classified into three major classes: CTX-M, SHV and TEM. These ESBL-encoding genes are frequently located on plasmids, which harbour additional resistance genes and can be transmitted between different Enterobacteriaceae species. Amongst companion animals, ESBLs are mostly described in dogs, cats and horses, whereas their prevalence in other companion animals still remains unknown yet (Ewers et al. 2012). ESBL-producing Enterobacteriaceae are mostly spread by the faecal-oral route and transmission can occur either by direct contact or indirect by contaminated food and water.

As mentioned above different enzymes encode for ESBL-production and the ones present in companion animals are basically the same than the ones, which have been found in human isolates. The first descriptions in companion animals date back to the late 1990’s and these early studies reported the presence of mainly TEM and SHV genes in clinical isolates from dogs in Spain, Portugal and Italy (Feria et al. 2002; Teshager et al. 2000).

However, similar to the situation in humans also in companion animals a shift towards CTX-M-genes seems to have taken place over the last decade. These CTX-M-genes have been detected in 2.6–5.6 % of all reported clinical and commensal Enterobacteriaceae and overall this gene type accounts for about 25–76 % of all Extended-spectrum beta-lactamases originating from companion animals (Ewers et al. 2011b). Bla CTX-M-genes are particularly common in companion animal isolates from Europe, but can also often be found in isolates originating from America, Australia and Asia (Ewers et al. 2012). The most frequent CTX-M-types reported in companion animals are CTX-M-15 and CTX-M-1 (Damborg et al. 2011; Damborg et al. 2012; Dierikx et al. 2012, Dolejska et al. 2011; Ewers et al. 2010; Schink et al. 2011).

Extensive studies on risk factors concerning ESBL-carriage in companion animals are missing yet. However, risk factors identified in human medicine seem to be relevant in the veterinary context as well. Indeed, some studies showed that hospitalization and antimicrobial treatment—in particular with cephalosporins—appear to select for ESBL in horses and dogs (Damborg et al. 2011; Damborg et al. 2012; Dolejska et al. 2011; Maddox et al. 2012). Taking into account these main risk factors, general infection control measures and rational antibiotic use appear to be important steps in the prevention of an intra- and interspecies spread of ESBL-producing Enterobacteriaceae.

Regarding the zoonotic risk of ESBL-bacteria there is currently only limited evidence for a transmission between closely interacting humans and companion animals. One study reported the presence of the same E. coli clone harbouring a CTX-M-1 type beta-lactamase in a human and several horses in the same riding centre (Dolejska et al. 2011). Nevertheless, potentially zoonotic ESBL-strains exist in companion animals. One example is the pandemic multidrug-resistant and virulent E. coli lineage B2-O25b:H4-ST131-CTX-M15, which represents the dominant ESBL-isolate in most European countries and all over the world (Livermore et al. 2007). Recent studies have reported this lineage to be occurring in companion animals as well as—also in association with CTX-M-15– among E. coli isolates from dogs, cats and horses worldwide (Albrechtova et al. 2012; Ewers et al. 2010; Timofte et al. 2011).

This illustrates that besides the same genes, identical clonal lineages are also shared between humans and companion animals. Thus it seems that transmission of this recently evolved clone has taken place between humans and companion animals or vice versa, either directly or indirectly. Research is needed to assess and prevent the human health risk associated with the companion animals, especially in consideration of the frequent use of cephalosporins in small animal medicine.

Summing up the role of companion animals in human infections caused by ESBL-producing Enterobacteriaceae is currently impossible. There is strong evidence that a decade after these bacteria have established in human medicine we observe an identical epidemiology in companion animals. ESBLs in between have established in commensal and potentially pathogenic Enterobacteriaceae of companion animals. Undoubtedly, this could be a valuable source of human infections and vice versa.

4 Multidrug-Resistant Acinetobacter baumannii and Methicillin-Resistant Staphylococcus pseudintermedius (MRSP)

This chapter briefly summarizes trends in infections with two bacterial pathogens, as multidrug-resistant variants of these have only recently been detected in animals. Only initial evidence exists about their zoonotic potential. However, as multidrug-resistance is a potent driver towards bacteria successfully entering new habitats (Gaze et al. 2013; Guenther et al. 2011; Holt et al. 2012), we consider an increasing incidence of infections with multidrug-resistant variants of Acinetobacter (A.) baumannii as well as Staphylococcus (S.) pseudintermedius in the near future. S. pseudintermedius until recently was regarded as a non-zoonotic pathogen of dogs and horses. However, case reports in humans encouraged us to include this pathogen (Vincze et al. 2010). This even more as both pathogens display multidrug-resistant types which in the case of infections can hardly be treated by antibiotics. Furthermore, both species are of high tenacity, thus survive in the environment for considerable long time periods. Both form biofilms on abiotic surfaces. This leads to increased survival within human and veterinary clinics. These features are a prerequisite for both microbes to act as nosocomial agents, therefore large-scale desinfections are needed in case of nosocomial outbreaks.

A. baumannii is a facultative pathogen that is isolated both from humans and in animals from different diseases such as pneumonia, catheter-associated genital tract infections, septicemia, skin and soft tissues infections. It is mostly seen in immunocompromised patients (Karah et al. 2012; Kim et al. 2013; O’Shea 2012; Qiu et al. 2012; Renckens et al. 2006). As well-known nosocomial pathogen it is associated with increased morbidity and mortality in the medical field. Infections in companion animals have only recently been reported (Boerlin et al. 2001; Endimiani et al. 2011; Francey et al. 2000; Müller et al. 2014; Vaneechoutte 2000; Zordan et al. 2011). This is why crucial knowledge on the epidemiology is lacking.

Over the last 20 years multidrug-resistant Acinetobacter (A.) baumannii- strains are increasingly isolated from medical patients, mostly associated with infections in clinical settings. Mortalities of 40–75 % for ventilator-associated pneumonia and septicemia in 28–43 % have been reported for humans (McConnell et al. 2013; Qiu et al. 2012). Some 2–10 % of all nosocomial infections in intensive care units are caused by A. baumannii. The rate of multidrug-resistant A. baumannii isolates increased during 2002–2006 from 2.1 to 7.9 % (Wadl et al. 2010). In between increased isolation rates of multidrug-resistant A. baumannii are also observed in veterinary clinics. In cats and dogs A. baumannii has been reported to mainly cause wound and urinary tract infections. The latter ones are often associated with catheterized animals in veterinary hospitals therefore nosocomial origins are most probable (Zordan et al. 2011). An identical development is envisioned as already experienced with MRSA, namely the appearance of this multidrug-resistant pathogen first in human medicine and then with a decades’ time lag in veterinary settings (Ewers et al. 2012; Ewers et al. 2011b; Vincze et al. 2014; Wieler et al. 2011).

However, substantial epidemiological data are lacking. Even the reservoir of A. baumannii is still unknown, but most probably it is the environment as it can be isolated from soil, water and food. Although pathogenic A. baumannii are isolated from skin or surfaces or in stool samples, in general the ubiquitous apathogenic Acinetobacter spp. are isolated (Mortensen and Skaar 2012; Peleg et al. 2008). Acinetobacter may be part of the physiological microbiota of animals. However, still this hypothesis needs to be falsified. The question of the transmission direction between humans and animals is therefore also open and needs to be further ascertained (Hamouda et al. 2011; Müller et al. 2014; Peleg et al. 2008). As it is currently not possible to unequivocally identify A. baumannii by phenotypical or MALDI-TOF methods it is not always clear whether actually A. baumannii was identified or an isolate belonging to the Acinetobacter calcoaceticus-Acinetobacter baumannii complex (Acb complex) (Dijkshoorn et al. 2007; Peleg et al. 2008). Therefore molecular methods like analysis of the 16S-23S rRNA-gene spacer region, blaOXA-51-like gene, rpoB gene or whole genome sequence analysis are increasingly implemented (Chang et al. 2005). As each of the four species belonging to the Acb complex differ in clinical course and thus in different treatment options a correct species identification is of utmost importance (Espinal et al. 2012).

A. baumannii are naturally resistant against trimethoprim. In addition, they have a tendency to develop resistance extremely rapidly by up-regulation of efflux pumps or acquisition of resistant determinants. The intrinsic resistance mechanisms include the small number of porins, the AmpC cephalosporinase (Hamouda et al. 2011) and the multidrug efflux pump AbeABC. Different classes of antibiotics such as aminoglycosides, chloramphenicol, tetracyclines, fluoroquinolones, trimethoprim, and beta-lactams including Carbapenemene can be ejected as substrates (Gootz and Marra 2008; Müller et al. 2014). Resistance to fluoroquinolones is based primarily on mutations in the genes gyrA and parC, which encode a DNA gyrase and topoisomerase IV (Peleg et al. 2008). Genomic analysis of multidrug-resistant A. baumannii strains demonstrated that the genes that mediate resistance are usually encoded on so-called resistance islands. The 86-kb AbaR1 Island encoding 45 resistance genes is the largest island of resistance described (Fournier et al. 2006). A. baumannii has mechanisms that favor horizontal gene transfer and thus the rapid development of multidrug resistant (MDR=multidrug resistant) strains (Dijkshoorn et al. 2007; Giamarellou 2008; Müller et al. 2014; O’Shea 2012). This is why A. baumannii genomes harbor a large number of mobile genetic elements such as transposons, integrons class I or insertion sequences (Overdevest et al. 2011; Peleg et al. 2008). Thus in A. baumannii isolates ESBLs and Oxacillinases are seen, some even being carbapenemases (Gootz and Marra 2008; Peleg et al. 2008). Carbapenems are currently the most effective antibiotic in the treatment of A. baumannii infections. Resistance to these antibiotics significantly reduces therapeutic options. Meanwhile A. baumannii strains have been isolated that are resistant to all classes of commercially available antibiotics, which for both medical and veterinary doctors is a tremendous challenge (Dijkshoorn et al. 2007). Some authors argue that regarding A. baumannii we are closer to the end of the antibiotic era as with MRSA (Giamarellou et al. 2008; Müller et al. 2014).

Most infections in humans are caused by the so-called EU or international clones I-III. These are characterized by a high level of antibiotic resistance (Dijkshoorn et al. 2007; Giamarellou et al. 2008; Karah et al. 2012; Seifert et al. 2005). A. baumannii isolates belonging to these EU clones have also been responsible for outbreaks in German veterinary clinics and veterinary practices (Endimiani et al. 2011; Müller et al. 2014; Vaneechoutte et al. 2000; Zordan et al. 2011). It is clear that A. baumannii is a pathogen with zoonotic potential.

A totally different perspective is given by S. pseudintermedius. The bacterial species has previously been known as S. intermedius, one of the most important causes of pyodermia and otitis, particularly in dogs. In 2005, Devriese et al. described a novel coagulase positive staphylococcal (CPS) species, denominated as S. pseudintermedius (Devriese et al. 2005). In the following years, molecular taxonomic investigations revealed that S. pseudintermedius, S. delphini and S. intermedius are closely related CPS species referred to as staphylococci of the intermedius group (SIG). While S. intermedius seems to be commonly associated with pigeons, S. pseudintermedius is not only a common colonizer of the canine skin, but also an opportunistic pathogen frequently isolated from clinical specimens of dogs, and, to a lesser extent, of cats and various other host species (Bannoehr et al. 2007; Bannoehr and Guardabassi 2012; Kadlec et al. 2010; Ruscher et al. 2008; Sasaki et al. 2007; Solyman et al. 2013). These findings have led to the realization that most canine isolates previously identified as S. intermedius should have been classified as S. pseudintermedius (Bannoehr et al. 2009; Sasaki et al. 2007). While biochemical features seem to vary among isolates of the same SIG species, sequence based methods, analysis by MALDI-TOF (Matrix Assisted Laser Desorption Ionisation-Time Of Flight Mass Spectrometry) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) are considered as reliable identification tools for S. pseudintermedius (Bannoehr and Guardabassi 2012; Murugaiyan et al. 2014; Savini et al. 2012).

The first methicillin resistant variants of S. pseudintermedius were reported sporadically in the late 1990s (Gortel et al. 1999; Piriz et al. 1996). Only a few years later, a sudden rise of MRSP reports followed and meanwhile MRSP are among the most important therapeutic challenges due to their frequent multi-drug resistance phenotype world-wide (Bemis et al. 2009; Perreten et al. 2010; Ruscher et al. 2010). Moreover, MRSP are of particular concern with respect to the increase of nosocomial infections in veterinary medicine and their potential transferability to humans and other animals in the household (Perreten et al. 2010; Perreten et al. 2010; Wieler et al. 2011). Consequently, owners of dogs suffering from S. pseudintermedius-infections and veterinarians seem to be at higher risk for nasal colonization and/or contamination than other people. Dog owners who keep more than two dogs also have a significantly higher chance to harbor S. pseudintermedius in the nose cavity (Frank et al. 2009; Ishihara et al. 2010; Paul et al. 2011; Vincze et al. 2010; Walther et al. 2012b). A high level of domestic MRSP-contamination, probably mediated by loss of hair and epithelia cells of the infected animal patient, may lead to a higher risk of developing MRSP infections in case of surgical or non-surgical wounds for pet owners (van Duijkeren et al. 2011). A sudden increase of reports concerning cases of severe S. pseudintermedius-infection in humans is noticeable and seems to reflect these changes in infection ecology (Riegel et al. 2010; Savini et al. 2013; Stegmann et al. 2010; Van Hoovels et al. 2006). The public health impact of the sudden emergence of a multidrug resistant zoonotic pathogen frequently occurring in companion animals like MRSP needs to be the subject of more detailed molecular and epidemiological studies (Loeffler et al. 2010a).

5 Conclusions and Outlook

Human interventional therapeutic use and misuse of antimicrobial drugs both in veterinary and human medicine is a major driver for the enrichment of the bacterial resistome. The increasing isolation of multidrug-resistant bacteria from clinical infections, be they zoonotic or non-zoonotic, is a direct consequence of this recent development. While initially key multidrug-resistant bacteria like MRSA, ESBLs or A. baumannii have been isolated from medical clinics, their spread into the community was followed by infections in companion animals. In between, first cases of euthanasia due to failing therapy have been reported. These cases are vivid proof of a post-antibiotic era. Besides the clinical failure of antimicrobial drugs, multidrug-resistant bacteria show a change in habitat specificity in that they enable the bacteria to spread into previously unavailable habitats (Guenther et al. 2011; Holt et al. 2012). One particularly worrisome outcome of this development is the proven spread of MRSA into companion animals, leading not only to nosocomial infections in veterinary hospitals, but also to ongoing transmission between companion animals and their owners (Fig. 17.1). Similar trends are evidenced regarding ESBL-producing Enterobacteriaceae and multidrug-resistant A. baumannii. These worrisome developments have fostered the initiation of the EU-wide project CALLISTO to give ground on further scientific steps in developing strategies against these zoonotic agents (http://www.callistoproject.eu/joomla/). In the case of S. pseudintermedius a tendency is observed that this naturally species-specific facultative pathogen is able to infect humans by gaining multidrug resistance. The socio-cultural changes in the co-existence between humans and their companion animals foster these developments. The link between multidrug-resistance and increased zoonotic potential of bacterial pathogens is a key evolutionary challenge we have to tackle. The only way of success is a multi- and interdisciplinary approach, the start of which is a global molecular driven surveillance of multidrug-resistant bacteria. This can only be successful when implemented by a “One health” approach. Such a surveillance will unravel both the microevolution of these bacteria and the directionality of transmission. These data are needed as a base for future intervention studies. However, regardless of these larger research efforts—prudent use of antimicrobial drugs must be a prerequisite for each and everyone in the world of antimicrobial drug usage.

Fig. 17.1
figure 1

Transmission routes of multi-resistant bacteria between companion animals and humans

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There is a lack of knowledge on their prevalence in veterinary medicine based on the fact that no surveillance is in place. Clearly, effective preventive measures can only be installed based on unequivocal identification and representative epidemiological studies. Here the lack of knowledge is immense. As potential source of zoonotic transmission, data concerning colonization and infection should be determined and monitored continuously. Further, interdisciplinary studies are needed to determine the frequency of colonization and/or infection in owners and their animals with the same clone. These data can help to identify the impact of companion animals as source of human infection and/or colonization and could raise the owner’s awareness that companion animals can be a source of pathogen transmission in general, and in particular for MRSA.