203 REVIEW Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise ‘G. Caporale’, Campo Boario, 64100 Teramo, Italy * Corresponding author at: Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise ‘G. Caporale’, Campo Boario, 64100 Teramo, Italy. Tel.: +39 0861 332249, e-mail: f.iannino@izs.it. Parole chiave Campylobacter, Resistenza antimicrobica, Cani, Geni di resistenza. Riassunto La resistenza antimicrobica in medicina e in agricoltura è uno dei problemi emergenti più importanti di Sanità Pubblica. Dal 2005 la campilobacteriosi è tra le zonosi alimentari più diffuse in Europa. L’infezione può essere contratta consumando cibo o bevande contaminate o entrando in contatto con individui o animali infetti. I cani sono portatori di Campylobacter. Possono quindi essere fonte di infezione per l'uomo o svolgere un ruolo importante come reservoir di batteri resistenti o di geni di resistenza. L’uomo, a sua volta, può essere serbatoio di Campylobacter spp. per gli animali domestici. Questa review analizza la letteratura corrente relativa al rischio di resistenza antimicrobica di Campylobacter nell’interfaccia cane-uomo. Campylobacter e resistenza antibiotica nel cane e nell’uomo: uno studio “One Health” Keywords Campylobacter, Antimicrobial resistance, Dogs, Resistance genes. Summary Increasing antimicrobial resistance in both medicine and agriculture is recognised as a major emerging public health concern. Since 2005, campylobacteriosis has been the most zoonotic disease reported in humans in the European Union. Human infections due to Campylobacter  spp. primarily comes from food. However, the human-animal interface is a potential space for the bidirectional movement of zoonotic agents, including antimicrobial resistant strains. Dogs have been identified as carriers of the Campylobacter species and their role as a source of infection for humans has been demonstrated. Furthermore, dogs may play an important role as a reservoir of resistant bacteria or resistance genes. Human beings may also be a reservoir of Campylobacter spp. for their pets. This review analyses the current literature related to the risk of Campylobacter antimicrobial resistance at the dog-human interface. Filomena Iannino*, Stefania Salucci, Guido Di Donato, Pietro Badagliacca, Giacomo Vincifori and Elisabetta Di Giannatale Campylobacter and antimicrobial resistance in dogs and humans: “One Health” in practice Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 Accepted: 11.09.2017 | Available on line: 30.09.2019 extraintestinal infections, and post-infectious complications. Campylobacteriosis has been the most frequently reported zoonotic disease in humans in Europe since 2005, and the annual number of notified campylobacteriosis cases has increased in many European countries in recent years (EFSA 2015, Tam et al. 2003). Campylobacteriosis in humans is mainly caused by thermotolerant Campylobacter spp., however other species including the non-thermophilic C. fetus, are also known to cause human infection. Introduction Notes on Campylobacter infections and therapy in humans and dogs Campylobacteriosis is a collective description for infectious diseases caused by members of the genus Campylobacter which are ubiquitous bacteria. They are frequently found in the digestive tracts of mammals and wild and domestic birds. They commonly contaminate their surrounding environment, including water. Diseases are mainly characterized by acute enteritis, 204 Campylobacter and antimicrobial resistance Iannino et al. Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 that the organism is a commensal, while others reported an association between infection and clinical signs (Guest et al. 2007, Chaban et al. 2010), particularly in younger dogs (Parson et  al. 2010, Burnens et al. 1992). In immune-compromised or febrile dogs, or in dogs with evidence of hemorrhagic diarrhoea, antimicrobial treatment may be indicated. In these cases, macrolides or quinolones are the antibiotics most commonly used (Marks et al. 2011). Risk factors at the dog‑human interface Environment Poor hygiene conditions may be an important source of Campylobacter spp. These bacteria can survive on dry surfaces for at least 7 days (Ullman and Kischkel 1981), however in slurries and dirty water, Campylobacter can survive for up to 3 months (Nicholson et  al. 2005). Most surface water sources are contaminated by animal manure, which contains Campylobacter. Age Many studies demonstrated that younger dogs were more likely to act as carriers of Campylobacter  spp. and to shed the organism (Sandberg et al. 2002). This may suggest an age predisposition and immunity development (Sandberg et  al. 2002, Workman et  al. 2005, Acke et al. 2006, Parsons et al. 2010). In a study conducted in Barbados, over 70% of Campylobacter positive dogs were under 1-year-old, and of these, 32.8% were younger than 9 weeks old (Workman et al. 2005). Diarrhoea and enteric disease This topic is controversial. However, as a precautionary measure, diarrhoea should be included among the risk factors. High density housing The prevalence of Campylobacter spp. is higher in dogs living in groups (for example in kennels or shelter) than in households (Workman et  al. 2005, Acke et  al. 2006). This is probably due to stress, increased prevalence of gastrointestinal disease, close contact with other animals, and dietary variation (Table I). Contact with other animals Contact between dogs and other animal species could be an important risk factor. Natural reservoirs The species most commonly associated with human infection are C. jejuni, followed by C. coli, C. lari, and C.  upsaliensis (Wieland et  al. 2005, Leonard et  al. 2011, EFSA 2012). In most symptomatic cases, campylobacteriosis occurs as mild and self-limiting gastroenteritis characterised by 1-3 days of low fever, vomiting, myalgia, and headaches, followed by 3-7 days of abdominal pain with watery or bloody diarrhoea. Acute infection sometimes begins with a high fever, peaking during the first days of illness. Excretion ends within 10-14 days and severe complications are uncommon (Altekruse and Tollefson 2003, Blaser and Engberg 2008, Bolton 2015). Chronic infections or extra-intestinal infections can occur with fatal bacteraemia, hepatitis, pancreatitis, meningitis, recurrent colitis, acute cholecystitis and cystitis, cardiovascular complication, abscesses, and complications of the reproductive system (Goossens et  al. 1987, Manfredi et  al. 1999, Acke et  al. 2009, Keithlin et al. 2014). Antimicrobial therapy may be required in severe cases, in immune-compromised patients, or in prolonged disease. In humans, macrolides (primarily erythromycin, or alternatively one of the newer macrolides, such as clarithromycin or azithromycin) remain the frontline agents for treating culture-confirmed Campylobacter cases (Ge et al. 2013). Quinolones (e.g., ciprofloxacin) are also commonly used because of their common use in the empirical treatment of undiagnosed diarrheal illness such as travellers’ diarrhoea (Guerrant et  al. 2001). Tetracycline, doxycycline, and chloramphenicol are alternative treatments (Ge  et  al. 2013). Serious systemic infections should be treated with aminoglycosides such as gentamicin or beta-lactamases including carbapenem and imipenem (Okada et  al. 2008). Third-generation cephalosporins have not been proven effective for treating bacteremia due to the Campylobacter species other than C. fetus (Pacanowski et al. 2008). Dogs have been identified as asymptomatic carriers of some species of Campylobacter and their role as a source of infection for humans has been demonstrated (Skirrow 1991, Siemer et  al. 2004, Karenlampi et  al. 2007, Koene et  al. 2004). The high prevalence of Campylobacter infection in dogs is an important topic of public health, as shown in Table I. Approximately 6% of human cases of campylobacteriosis are due to contact with pets (Tenkate and Stafford 2001, Rossi et al. 2008). The role of Campylobacter as an enteric pathogen in dogs is unclear. Some studies did not find any significant relationship between diarrhoea and Campylobacter  spp. infection (Sandberg et  al. 2002, Workman et  al. 2005, Acke et  al. 2006), suggesting 205 Iannino et al. Campylobacter and antimicrobial resistance Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 Table I. Reported prevalence of dogs carrying Campylobacter spp. in relation to isolated species, type of sample, population sampled, geography, and detection methods. Bibliography Population Samples Total dogs Campylobacter spp. Detection Species Identification Method Geography López et al. 2002 Household dogs Faecal samples 380 17% Culture C. jejuni 12% Phenotypic test Argentina Workman et al. 2005 Household dogs Rectal swabs 130 46.9% Culture C. jejuni 26% PCR BarbadosC. coli 4% C. upsaliensis 2% Chaban et al. 2010 Healthy household dogs Faecal samples 70 56% PCR C. upsaliensis 43% PCR Canada C. hyointestinalis 13% C. jejuni 7% C. showae 6% C. coli 0% Diarrhoeic Household dogs Faecal samples 65 97% PCR C. upsaliensis 85% PCR C. jejuni 46% C. showae 28% C. coli 25% C. hyointestinalis 18% Leonard et al. 2011 Dogs from veterinary clinics Faecal swabs 240 22% Culture C. upsaliensis 19% PCR Canada C. jejuni 3% Hald & Madsen 1997 Healthy puppies aged between 11 and 17 weeks Rectal swabs 72 29% Culture C. jejuni 22.% Phenotypic test DenmarkC. upsaliensis 5% C. coli 1% Acke et al. 2009 Household dogs Rectal swabs 147 41% Culture C. upsaliensis 10% PCR IrelandC. jejuni 30% C. coli 1% Giacomelli et al. 2015 Household dogs Rectal swabs 100 11% Culture C. jejuni 5% PCR ItalyC. upsaliensis 5% C. coli 1% Shelter-housed dogs Rectal swabs 50 26% Culture C. jejuni 16% PCR Italy C. upsaliensis 2% C. hyointestinalis 6% C. lari 2% Mohan 2015 Faecal samples from walk way area Faecal samples 498 13% Culture C. jejuni 5% PCR New Zealand Salihu et al. 2010 Household dogs Rectal swabs 141 28% Culture C. upsaliensis 21% Phenotypic test Nigeria C. jejuni 6% Sandberg et al. 2002 Household dogs Rectal swabs 529 23% Culture C. upsaliensis 20% Phenotypic test Norway C. jejuni 3% Diarrhoeic household dogs Rectal swabs 66 27% Culture C. upsaliensis 23% Phenotypic test C. jejuni 3% Engvall et al. 2003 Household dogs Faecal samples 91 56% Culture C. upsaliensis 43% PCR Sweden C. jejuni 11% C. coli 2% C. helveticus 2% C. lari 1% Holmberg et al. 2015 Healthy dogs under the age of 2 Rectal swabs 180 37% Culture C. upsaliensis 29% PCR Sweden C. jejuni 4% Parson et al. 2010 Dogs from veterinary clinics Faecal samples 249 38% Culture C. upsaliensis 37% PCR UK Westgarth et al. 2009 Household dogs Faecal samples 183 26% Culture and direct PCR C. upsaliensis 25% PCR UK 206 Campylobacter and antimicrobial resistance Iannino et al. Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 determinants of ‘risk to human health’, towards a perspective of ‘shared risk’ between humans and animals (Rabinowitz et al. 2008). The ‘One Health’ approach recognises that the health of people is connected to the health of animals and the environment, and encourages physicians and veterinarians to work together. According to American Veterinary Medical Association (AVMA 2008) ‘One Health is the collaborative effort of multiple health science professions, together with their related disciplines and institutions (working locally, nationally, and globally) to attain optimal health for people, domestic animals, wildlife, plants, and our environment.’ Initially, ‘One Health’ research focused on zoonoses deriving from farm animals and wild animals. The enormous potential role of companion animals has been often disregarded. The growing number of household pets has given rise to new health issues. Among these, antimicrobial resistance is an important topic to consider within the ‘One Health’ approach. Notes on antimicrobial resistance Increasing antimicrobial resistance in both medicine and agriculture is recognised as a major emerging public health concern by various scholars and authorities, including the World Health Organization (Moore et  al. 2002, Di Giannatale et  al. 2014, Ozbey and Tasdemi 2014, Pezzotti et  al. 2003, Aarestrup and Engberg 2001, WHO 2004). This has made the clinical management of campylobacteriosis cases more complex. Antimicrobial resistant enteric infections are highest in the developing world, where the use of anti-microbial drugs in animals is largely unrestricted (Lengerh et al. 2013). Companion animals may play an important role as a reservoir of resistant bacteria or resistance genes. Furthermore, human beings may be a reservoir of pathogens for their pets (Rutland et al. 2009). Growing healthcare standards for an increasingly large population of household pets has led to a proliferation of geriatric animals that have extensive medical histories, which has included the administration of antimicrobial drugs. Large antimicrobial use exerts selective pressure on human and animal pathogens and is considered to be a major contributor to the development of antimicrobial resistance. Antimicrobial resistance can be classified into 3  groups: intrinsic, mutational, and acquired resistance. Intrinsic resistance refers to the inherent resistance to an antibiotic that is a naturally occurring feature of the micro-organism. for Campylobacter spp. include chicken and other poultry, wild birds, pigs, cats, sheep, cows (Workman et  al. 2005), and exotic pets such as turtles (Harvey and Greenwood 1985) and hamsters (Fox et al. 1983). The high prevalence (39.3%) reported by Workman and colleagues (Workman et  al. 2005) in wild birds is of particular interest, as dogs can easily encounter bird faeces in parks. Food Any form of homemade cooked food in a dog’s diet (or added to a dog’s diet) may increase the risk of dogs carrying Campylobacter spp. (Leonard et  al. 2011). Raw food, especially meat, is generally considered to be a source of Campylobacter  spp. (Westgarth et  al. 2009). A rapid change of diet can create a predisposition to enteric dismicrobism, which could in turn favour the onset of acute diarrhoea. In this condition, pathogens like silent Campylobacter spp., can take over, multiply, and exacerbate any gastroenteric symptoms. Season The season can affect both the patterns of infection in dogs and the way dogs shed Campylobacter spp. Some authors report a higher number of isolations during the summer and autumn months (López 2002, Mohan 2015). For example, in a study performed in Cordoba (Spain), Carbonero and colleagues (Carbonero et  al. 2012) reported that C.  upsaliensis peaked during the spring months, while C.  jejuni peaked during the summer months. This is consistent with other studies performed on other species, such as cattle and sheep, where the highest prevalence was also found during the spring and summer months (Grove White et al. 2010). Walking outdoors Housed dogs have less opportunity to become infected. Dogs that escape from their homes, or are free to access the external environment, have a higher risk of being positive for Campylobacter spp. (Westgarth et al. 2009). Note on the ‘One Health’ concept The ‘One Medicine’ concept as described by Schwabe (Schwabe 1964) has seen unprecedented revival in the last decade. The concept has evolved into a way of thinking about epidemiology and public health that is now known as ‘One Health’ (Zinsstag et  al. 2009). Rabinowitz suggested that, as humans, we should change the ‘us versus them’ paradigm, which implies thinking of animals as 207 Iannino et al. Campylobacter and antimicrobial resistance Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 on pathogenic bacteria and on commensal micro-organisms of the intestinal tract of humans and animals. Resistant commensal bacteria can constitute a reservoir of resistant genes for potentially pathogenic bacteria (Guardabassi et al. 2004). Antimicrobial resistance in Campylobacter spp. at the dog‑human interface Several studies have shown that antimicrobial use in food animals contributes to the selection of antimicrobial resistance. It furthermore poses risks to humans because of the transmission of resistant zoonotic bacteria via the food chain and the indirect transfer of resistance genes from animals to man. Antimicrobial resistance amongst companion animals, particularly dogs, is a complex area representing an increasing public health concern. At the crux of this critical issue is the fact that dogs often live in a close proximity to humans. Close physical contact through touching, petting, and licking occurs often as a result of the perception of household pets as family members. This creates opportunities for the interspecies transmission of Campylobacter  spp., including multidrug-resistant Campylobacter. However, it is difficult to ascertain how antimicrobial resistance in dogs is increasing because there is little useful data on antimicrobial drug use and resistance in companion animals. Furthermore, the heterogeneity of studies, different analytical methods employed for the isolation, identification, typing, and resistance assessment make the result comparison difficult. This indicates a need to harmonise and standardise diagnostic methods. In order to determine the real extent of antimicrobial resistance and to be able to compare data between laboratories monitoring resistance trends, standardised protocols for the determination of susceptibility to antibiotics should be used. Table II and Figure 1 summarises the relevant literature on antimicrobial resistance in human Campylobacter isolates. Among fluoroquinolones, the range of ciprofloxacin varies from 16% to 86%. A rapid increase in the proportion of Campylobacter strains resistant to fluoroquinolones has been reported in many countries worldwide (Luangtongkum et  al. 2009). These antibiotics are usually employed for the treatment of undiagnosed diarrheal illnesses. Among macrolides, the prevalence of erythromycin resistance varies from 1.5% to 28.5%. High erythromycin resistance levels were observed among strains isolated from Africa (Lengerh et  al. 2013). Macrolides are usually employed as frontline agents for treating culture-confirmed Campylobacter infection. Mutational resistance occurs due to a spontaneous chromosomal mutation that produces a genetically altered bacterial population that is resistant to a drug. Resistant bacteria transfer their resistance genes to a bacteria’s progeny during DNA replication. Acquired resistance refers to the horizontal acquisition of a genetic element that encodes antibiotic resistance from another micro-organism. This implies that genetic elements transfer from some outside source, such as other bacteria of the same species or even between different species (Soares et al. 2012). Horizontal transfer resistance genes can function through 3 main routes: conjugation, transformation, and transduction. Conjugation is the transfer of DNA fragments through a conjugative pilus or pore that forms a channel that facilitates the passage of plasmids (bacteria to bacteria). Transformation is the process whereby bacterial cells take-up free DNA from the environment and incorporate it into their genomes (‘free DNA transfer’). Transduction occurs when a bacteriophage that has previously replicated in another bacterial cell, packages a portion of the host genome (donor) into the phage head and transfers the genes to another (recipient) bacterial cell (‘bacteriophage-mediated transfer’) (Huddleston et al. 2014). Mobile genetic elements fall into 2 general types: elements that can move from one bacterial cell to another, which includes resistance plasmids and conjugative resistance transposons, and elements that can move from one genetic location to another in the same cell, which includes transposons and gene cassettes (Bennett 2005). Plasmids are the elements that move bacterial genes from one bacterial cell to another. Conjugative plasmids are able to promote their own transfer and the transfer of other plasmids from one bacterial cell to another. In general, they exist separately from the main bacterial chromosome, although the majority of replication functions are provided by the host cell and carry a considerable variety of genes, including those that confer antibiotic resistance (Bennett 2008). The spread of antimicrobial-resistant bacteria can occur through direct contact (petting, licking, etc.) or indirectly via the household environment, contamination of food, furnishings, etc. (Guardabassi et al. 2004). When they reach the new host, resistant bacteria can either colonise and infect, or remain for only a very short period of time. During this period, the resistant bacteria can not only spread their resistance genes to other bacteria residing in the new host (commensals or pathogens), but also accept resistance genes from other bacteria (da Costa et al. 2013). Antimicrobial drugs exert a selection pressure 208 Campylobacter and antimicrobial resistance Iannino et al. Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 Campylobacter  spp. isolates. The highest frequency of Campylobacter resistance has been recorded for ampi-cloxacillin (88.2%), clindamycin (73%), and azithromycin (64.7%). Resistance mechanisms A combination of endogenous and acquired genes underlies resistance mechanisms. In general, mechanisms of antibiotic resistance include: Among aminoglycosides, gentamicin resistance varies from 0% to 18%. Aminoglycosides are used for serious systemic Campylobacter infections in humans. The Campylobacter resistance to cephalosporins is very high (27%-100%). However, these antibiotics are limited to the treatment of C. fetus (Pacanowski et al. 2008). Table III and Figure 2 summarises the relevant literature on antimicrobial resistance in dog Table II. Humans. Relevant literature detailing Campylobacter antimicrobial resistance according to detection method, antimicrobial, species isolated, breakpoints, cut-off values, and geography. — cont’d Author Method Antimicrobial Species Resistant Breakpoints and cut-off values and notes Country Liao et al. 2012 Agar dilution Ampicillin- sulbactam Campylobacter spp. 5/24 (20.8%) Breakpoints in: CLSI guidelines (CLSI 2012) Taiwan Cefotaxime Campylobacter spp. 21/24 (87.5%) Ceftriaxone Campylobacter spp. 24/24 (100%) Ertapenem Campylobacter spp. 3/24 (12.5%) Imipenem Campylobacter spp. 0/24 (0%) Meropenem Campylobacter spp. 0/24 (0%) Doripenem Campylobacter spp. 0/24 (0%) Gemifloxacin Campylobacter spp. 15/24 (62.5%) Ciprofloxacin Campylobacter spp. 15/24 (62.5%) Levofloxacin Campylobacter spp. 14/24 (58.3%) Lengerh et al. 2013 Agar disc diffusion Erythromycin Campylobacter spp. 10/37 (27.7%) Concentration: Ampicillin 30 μg Amoxicillin-Clavulanic acid 30 μg Gentamicin 10 μg Tetracycline 30 μg Doxycycline 30 μg Chloramphenicol 30 μg Ciprofloxacin 5 μg Norfloxacin 5 μg Ceftriaxone 5 μg Erythromycin 15 μg Clindamycin 15 μg Trimethoprim- Sulphamethoxazole 25 μg Ethiopia Clindamycin Campylobacter spp. 18/44 (40,9%) Trimethoprim- Sulfamethoxazole Campylobacter spp. 24/44 (54.5%) Ciprofloxacin Campylobacter spp. 7/44 (16%) Ceftriaxone Campylobacter spp. 10/37 (27.7%) Chloramphenicol Campylobacter spp. 5/44 (11.4%) Nalidixic acid Campylobacter spp. 4/44 (9.1%) Cephalotin Campylobacter spp. 39/44 (88.6%) Gentamicin Campylobacter spp. 8/44 (18.2%) Amoxicillin- Clavulanic acid Campylobacter spp. 16/44 (36.4%) Ampicillin Campylobacter spp. 16/44 (36%) Tetracycline Campylobacter spp. 25/44 (56,8%) Doxycycline Campylobacter spp. 7/44 (15,9%) Norfloxacin Campylobacter spp. 6/44 (11.6 %) Abay et al. 2014 Disk diffusion and Etest Amoxicillin- Clavulanic acid C. jejuni 12/100 (12%) Disk diffusion test breakpoints: Amoxicillin Clavulanic acid 30 μg Ampicillin 10 μg Gentamicin 10 μg Nalidixic Acid 30 μg Streptomycin 10 μg Tetracycline 30 μg Etest breakpoints: Ciprofloxacin ≥ 4 Enrofloxacin ≥ 2 Erythromycin ≥ 32 Turkey Ampicillin C. jejuni 44/100 (44%) Gentamicin C. jejuni 0/100 (0%) Nalidixic acid C. jejuni 84/100 (84%) Streptomycin C. jejuni 3/100 (3%) Tetracycline C. jejuni 38/100 (38%) Ciprofloxacin C. jejuni 81/100 (81%) Enrofloxacin C. jejuni 85/100 (85%) Erythromycin C. jejuni 6/100 (6%) continued 209 Iannino et al. Campylobacter and antimicrobial resistance Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 agents out of bacterial cells. The best-described multi-drug efflux pump in Campylobacter is CmeABC, which consists of 3 components: an inner membrane transporter (encoded by cmeB), a periplasmic fusion protein (encoded by cmeA), and an outer membrane protein (encoded by cmeC). CmeABC extrudes a broad range of antibiotics, dyes, heavy metals, bile salts, and detergents. Other putative efflux pumps, including CmeDEF and CmeG, may also contribute to antibiotic resistance (Akiba et al. 2006, Iovine 2013, Lin et al. 2002). 1. The modification of the antibiotic’s target and/or its expression (i.e., DNA gyrase mutations); 2. The inability of the antibiotic to reach its target (i.e., expression of the major outer membrane protein, or MOMP); 3. The efflux of the antibiotic (i.e., multidrug efflux pumps such as CmeABC); 4. The modification or inactivation of the antibiotic (i.e., β-lactamase production) (Iovine 2013). Active efflux pump systems extrude antimicrobial Table II. Humans. Relevant literature detailing Campylobacter antimicrobial resistance according to detection method, antimicrobial, species isolated, breakpoints, cut-off values, and geography. — cont’d Author Method Antimicrobial Species Resistant Breakpoints and cut-off values and notes Country Gaudreau et al. 2014 Disk diffusion and Etest Erythromycin C. jejuni 16/440 (3.6%) Breakpoints in: CLSI guidelines (CLSI, 2010) susceptibilities were assessed initially by disk diffusion and later confirmed by Etest Canada C. coli 7/38 (18%) Ciprofloxacin C .jejuni 180/440 (41%) C. coli 19/38 (50%) Tetracycline C. jejuni 274/440 (62.3%) C. coli 20/38 (52.6%) Riley et al. 2015 Broth microdilution Ciprofloxacin C. jejuni 55/180 (30.5%) Breakpoints in: CLSI guidelines 2010 (Clinical and Laboratory Standards Institute, 2010) Canada C. coli 16/39 ( 41%) Erythromycin C. jejuni 7/180 (3.9%) C. coli 5/39 (12.8%) Tetracycline C. jejuni 116/180 (64.4%) C. coli 21/39 (53.8%) Stockdale et al. 2015 Disk diffusion Fluoroquinolone Campylobacter spp. 1,710/5,890 (29.0%) / UK Macrolides Campylobacter spp. 129/5,881 (2.2%) Thompson et al. 2015 Agar disk diffusion Amoxicillin- Clavulanic acid C. coli 0/20 (0%) Breakpoints in: CLSI guidelines Clinical and Laboratory Standards Institute, 2012 Vietnam C. jejuni 2/44 (4.5%) Ampicillin C. coli 5/20 (28%) C. jejuni 12/44 (26.5%) Ceftazidime C. coli 5/20 (25%) C. jejuni 5/44 (11.3%) Chloramphenicol C. coli 0/20 (0%) C. jejuni 1/44 (2,3%) Ciprofloxacin C. coli 20/20 (100%) C. jejuni 30/43 (69.7%) Erythromycin C. coli 5/20 (25%) C. jejuni 0/42 (0%) Gatifloxacin C. coli 2/20 (10%) C. jejuni 6/44 (13.6) Nalidixic acid C. coli 20/20 (100%) C. jejuni 34/44 (77.2) Ofloxacin C. coli 20/20 (100%) C. jejuni 32/44 (72.7) Trimethoprim C. coli 17/20 (85%) C. jejuni 32/43 (74.4%) continued 210 Campylobacter and antimicrobial resistance Iannino et al. Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 Table II. Humans. Relevant literature detailing Campylobacter antimicrobial resistance according to detection method, antimicrobial, species isolated, breakpoints, cut-off values, and geography. — cont’d Author Method Antimicrobial Species Resistant Breakpoints and cut-off values and notes Country Lapierre et al. 2016 Agar dilution Ciprofloxacin C. jejuni 20/66 (30.3%) Breakpoints: Ciprofloxacin ≥ 4 μg/ml Erythromycin ≥ 32 μg/ml Gentamicin ≥ 16 μg/ml Tetracycline ≥ 16 μg/ml Chile C. coli 4/7 (57.2%) Erythromycin C. jejuni 1/66 (1.5%) C. coli 2/7 (28.5%) Gentamicin C. jejuni 0/66 (0.0%) C. coli 0/7 (0.0%) Tetracycline C. jejuni 16/66 (24.3%) C. coli 2/7(28.5%) Olkkola et al. 2016 Broth microdilution Ciprofloxacin C. jejuni 8/95 (8.4%) Cut-off values: Ciprofloxacin 0.5 μg /l Erythromycin 4 μg /l Tetracycline 1 μg /l Streptomycin 4 μg /l Gentamicin 2 μg /l Nalidixic acid 16 μg /l Finland Erythromycin C. jejuni 0/95 (0%) Tetracycline C. jejuni 2/95 (2.1%) Streptomycin C. jejuni 1/95 (2.1%) Gentamicin C. jejuni 0/95 (0.0%) Nalidixic acid C. jejuni 8/95 (8.4%) Zhou et al. 2016 Agar dilution Ciprofloxacin C. jejuni 176/203 (86.7%) Breakpoints μg/ml: Ciprofloxacin ≥ 4 μg/ml Nalidixic acid ≥ 64 μg/ml Doxycycline ≥ 8 μg/ml Tetracycline ≥ 16 μg/ml Gentamicin ≥ 8 μg/ml Chloramphenicol ≥ 32 μg/ml Florfenicol ≥ 8 μg/ml Erythromycin ≥ 32 μg/ml. China Nalidixic acid (Nal) C. jejuni 176/203 (86.7%) Doxycycline (Dox) C. jejuni 162/203 (80.8%) Tetracycline (Tet) C. jejuni 186/203 (91.6%) Gentamicin (Gen) C. jejuni 15/203 (7.4%) Chloramphenicol (Chl) C. jejuni 25/203 (12.3%) Florfenicol (Ffc) C. jejuni 64/203 (31.5 %) Erythromycin C. jejuni 4/203 (2.0%) Cip-Nal-Dox-Tet C. jejuni 151/203 (74.4%) Ffc-Cip-Nal-Dox- Tet C. jejuni 61/203 (29.9%) Chl-Ffc-Cip-Nal- Dox-Tet C. jejuni 21/203 (9.9%) Gen-Ffc-Cip-Nal- Dox-Tet C. jejuni 12/203 (5.9%) 0 0.2 0.4 0.6 0.8 1 D o ri p en em Im ip en em M er o p en em St re p to m yc in M ac ro lid es G en ta m ic in Er yt h ro m yc in G en -F fc -C ip -N al -D o x- Te t C h lo ra m p h en ic o l C h l- Ff c- C ip -N al -D o x- Te t Er ta p en em N o r� o xa ci n A m o xi ci lli n C la vu la n ic a ci d C ef ta zi d im e A m p ic ill in -s u lb ac ta m G at i� o xa ci n Fl u o ro q u in o lo n e Ff c- C ip -N al -D o x- Te t Fl o rf en ic o l ( Ff c) A m p ic ill in C lin d am yc in C ip ro �o xa ci n Tr im et h o p ri m S u lfa m et h o xa zo le C ef tr ia xo n e Te tr ac yc lin e Le vo �o xa ci n N al d ix ic A ci d D o xy cy cl in e C ip -N al -D o x- Te t Tr im et h o p ri m O �o xa ci n En ro �o xa ci n C ef o ta xi m e C ep h lo ti n Figure 1. Humans. Literature detailing Campylobacter antimicrobial resistance. 211 Iannino et al. Campylobacter and antimicrobial resistance Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 Table III. Dogs. Relevant literature detailing Campylobacter antimicrobial resistance according to detection method, antimicrobial, species isolated, breakpoints, cut-off values, and geography. — cont’d Author Method Antimicrobial Species Resistant Breakpoints and cut-off values and notes Country Sandberg et al. 2002 E-test Ampicillin C. jejuni 0/22 (0,0%) Isolates from dogs and cats Breakpoints: Nalidixic acid ≥ 32 μg/mL Streptomycin ≥ 8 μg/mL The other breakpoints are not available Norway C. upsaliensis 0/20 (0,0%) Ciprofloxacin C. jejuni 0/22 (0,0%) C. upsaliensis 0/20 (0,0%) Chloramphenicol C. jejuni 0/22 (0,0%) C. upsaliensis 0/20 (0,0%) Erythromycin C. jejuni 0/22 (0,0%) C. upsaliensis 0/20 (0,0%) Gentamicin C. jejuni 0/22(0,0%) C. upsaliensis 0/20 (0.0%) Nalidixic acid C. jejuni 0/22(0,0%) C. upsaliensis 1/20 (5,0%) Streptomycin C. jejuni 1/22 (4,5%) C. upsaliensis 18/20 (90.0%) Tetracycline C. jejuni 0/22 (0.0%) C. upsaliensis 0/20(0.0%) Lee et al. 2004 E-test Gentamicin C. jejuni 0/11 (0.0%) Breakpoints Gentamicin 16 μg/mL Erythromycin 8 μg/mL Ciprofloxacin 4 μg/mL Tetracycline 16 μg/mL United States Erythromycin C. jejuni 0/11 (0.0%) Ciprofloxacin C. jejuni 1/11 (9.1%) Tetracycline C. jejuni 2/11 (18.2%) Tsai et al. 2007 E-test Azithromycin C. jejuni 32/33 (93.9%) Break point Azithromycin ≥ 2 μg/ml Chloramphenicol ≥ 32 μg/ml Ciprofloxacin ≥ 4 μg/ml Clindamycin ≥ 4 μg/ml Erythromycin ≥ 8 μg/ml Gentamicin ≥ 16 μg/ml Nalidixic acid ≥ 32 μg/ml Tetracycline ≥ 16 μg/ml Taiwan Chloramphenicol C. jejuni 23/33 (69.7%) Ciprofloxacin C. jejuni 6/33 (18.2%) Clindamycin C. jejuni 29/33 (87.9%) Erythromycin C. jejuni 27/33 (81.8%) Gentamicin C. jejuni 10/33 (33.3%) Nalidixic acid C. jejuni 17/33 (51.5%) Tetracycline C. jejuni 26/33 (78.8%) Rossi et al. 2008 Agar dilution Erythromycin C. jejuni 0/24 (0,0%) Isolates from dogs and cats Breakpoints: Erythromycin ≥ 8 μg/ml-1 Chloramphenicol ≥ 32 μg/ml-1 Gentamicin ≥ 16 μg/ml-1 Ampicillin ≥ 32 μg/ml-1 Tetracycline ≥ 16 μg/ml-1 Nalidixic acid ≥ 32 μg/ml-1 Ciprofloxacin ≥ 4 μg/ml-1 Enrofloxacin ≥ 4 μg/ml-1 One C. jejuni strain was multi-drug resistant to nalidixic acid, ciprofloxacin, tetracycline, and ampicillin, 5 were resistant to nalidixic acid, ciprofloxacin, and tetracycline. Italy C. upsaliensis 0/38(0,0%) C. helveticus 3/16 (18.7%). Chloramphenicol C. jejuni 1/24 (4.2%) C. upsaliensis 0/38 (0,0%) C. helveticus 0/16 (0,0%) Gentamicin C. jejuni 0/24 (0,0%) C. upsaliensis 0/38 (0,0%) C. helveticus 3/16 (18.7%) Ampicillin C. jejuni 3/24 (12.5%) C. upsaliensis 3/38 (7.8%) C. helveticus 0/16 (0,0%) Tetracycline C. jejuni 3/24 (12.5%) C. upsaliensis 0/38 (0,0%) C. helveticus 0/16 (0,0%) Nalidixic acid C. jejuni 15/24 (62.5%) C. upsaliensis 3/38 (7.9%) C. helveticus 1/16 (6.2%) Ciprofloxacin C. jejuni 15/24 (62.5%) C. upsaliensis 3/38 (7.9%) C. helveticus 1/16 (6.2%) Enrofloxacin C. jejuni 14/24 (58.3%) C. upsaliensis 3/38 (7.9%) C. helveticus 1/16 (6.2%) continued 212 Campylobacter and antimicrobial resistance Iannino et al. Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 Table III. Dogs. Relevant literature detailing Campylobacter antimicrobial resistance according to detection method, antimicrobial, species isolated, breakpoints, cut-off values, and geography. — cont’d Author Method Antimicrobial Species Resistant Breakpoints and cut-off values and notes Country Acke et al. 2009 E-test Nalidixic acid C. jejuni 19/51 (37.3%) Isolates from dogs and cats. Breakpoints not available Ireland Ciprofloxacin C. jejuni 10/51 (19.6%) Tetracycline C. jejuni 7/51 (13.7%) Ampicillin C. jejuni 7/51 (13.7%) Erythromycin C. jejuni 6/51 (11.8%) Chloramphenicol C. jejuni 3/51 (5.9%) Kurnar et al. 2012 Disk diffusion Amikacin Campylobacter spp. 0/51 (0.0%) Breakpoints: Amikacin 30 μg Amoxycillin-Clavulanic acid 20 μg Ampi-Cloxacillin 10 μg Ciprofloxacin 30 μg Chloramphenicol 30 μg Enrofloxacin 10 μg Erythromycin 15 μg Levofloxacin 5 μg Streptomycin 10 μg Tetracycline 30 μg India Amoxycillin- Clavulanic acid Campylobacter spp. 10/51 (19.6%) Apmpi-Cloxacillin Campylobacter spp. 45/51 (88.2) Ciprofloxacin Campylobacter spp. 41/51 (80.4%) Chloramphenicol Campylobacter spp. 0/51 (80.0%) Enrofloxacin Campylobacter spp. 35/51 (68.6%) Erythromycin Campylobacter spp. 46/51 (90.2%) Levofloxacin Campylobacter spp. 0/51 (0.0%) Streptomycin Campylobacter spp. 0/51 (0.0%) Tetracycline Campylobacter spp. 45/51 (88.2%) Andrzejewska et al. 2013 E-test Erythromycin C. jejuni 0/2 (0.0%) Erythromycin ≥ 32 μg/ml Azithromycin 32 μg/ml Ciprofloxacin 4 μg/ml ≥ Tetracycline 16 μg/ml Poland Azithromycin C. jejuni 0/2(0.0% Ciprofloxacin C. jejuni 2/2 (100%) Tetracycline C. jejuni 1/2(50.0%) Erythromycin C. coli 0/2(0.0%) Azithromycin C. coli 0/2(0.0%) Ciprofloxacin C. coli 1/2(50.0%) Tetracycline C. coli 1/2 (50.0%) Amar et al. 2014 Multi locus sequence typing (MLST) and fla-typing Quinolones C. jejuni 25/133 (20.9%) / Switzerland C. coli 3/6 (50%) Sahin et al. 2014 Broth microdilution Azithromycin C. jejuni 1/8 (12,2 %) Breakpoints: Azithromycin ≥ 8 μg/ml Ciprofloxacin≥ 4 μg/ml Clindamycin ≥ 8 μg/ml Erythromycin ≥ 32 μg/ml Florfenicol ≥ 16 μg/ml Gentamicin ≥ 8 μg/ml Nalidixic Acid ≥ 32 μg/ml Telithromycin ≥ 16, μg/ml Tetracycline ≥ 16 μg/ml United States Ciprofloxacin C. jejuni 1/8 (12,2 %) Clindamycin C. jejuni 1/8 (12,2 %) Erythromycin C. jejuni 1/8 (12,2 %) Florfenicol C. jejuni 0/8 (0,0 %) Gentamicin C. jejuni 0/8 (0,0 %) Nalidixic acid C. jejuni 0/8 (0,0 %) Telithromycin C. jejuni 1/8 (12,2 %) Tetracycline C. jejuni 1/8 (12,2 %) Olkkola et al. 2015 Broth microdilution and agar dilution method for Streptomycin Erythromycin C. jejuni 0/2 (0.0%) Erythromycin > 4 mg/l Tetracicline > 1 mg/l Streptomycin > 4 mg/l Gentamicin > 2 mg/l Ciprofloxacin > 0.5 mg/l Nalidixic acid > 16 mg/l Finland C. upsaliensis 0/24 (0.0%) Tetracycline C. jejuni 0/2 (0.0%) C. upsaliensis 0/24 (0.0%) Streptomycin C. jejuni 0/2 (0.0%) C. upsaliensis 19/24 (79.1%) Gentamicin C. jejuni 0/2 (0.0%) C. upsaliensis 0/24 (0.0%) Ciprofloxacin C. jejuni 0/2 (0.0%) C. upsaliensis 1/24 (0.2%) Nalidixic acid C. jejuni 0/2 (0.0%) C. upsaliensis 1/24 (0.2%) 213 Iannino et al. Campylobacter and antimicrobial resistance Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 A70T, Asp-203-Ser, Asp85Tyr, Asp90Asn, Pro104, and D90N, which are less common and do not play an important role in quinolone resistance as that which has been observed around the Thr86Ile mutation (Luo et  al. 2003, Payot et  al. 2006, Bachoual et  al. 2001). Multiple mechanisms for antibiotic resistance have also been reported, including active efflux pump systems and decreased outer membrane permeability (Charvalos et al. 1995, Taylor and Tracz 2005). In addition to the mutations in GyrA, the multi-drug efflux pump, CmeABC, also contributes to quinolone resistance by reducing the accumulation of the agents in Campylobacter cells. This efflux pump acts synergetically with DNA gyrase mutation to effect high-level quinolone resistance (Iovine 2013, Wieczorek and Osek 2013). Resistance to macrolides Macrolides, and particularly erythromycin, are drugs that are used when campylobacteriosis is strongly suspected (Guerrant et al. 2001). Macrolides interrupt protein synthesis in bacterial ribosome by targeting the 50S subunit and inhibit bacterial RNA-dependent protein synthesis. The main mechanisms of resistance to macrolides in Campylobacter are target modification, efflux, and altered membrane permeability. These mechanisms might act synergistically to confer high-level macrolide resistance (Iovine 2013, Cagliero et  al. 2006). Macrolide resistance in Campylobacter is mainly associated with point mutation(s) occurring in the peptidyl-encoding region in domain V of the 23S rRNA gene at positions 2074 and 2075, with the 2075 substitution being the more common position (Gibreel and Taylor 2006, Vacher et al. 2005, Multiple mechanisms of resistance can occur in a single isolate, leading to higher levels of resistance. Resistance to quinolones Quinolones and fluoroquinolones are broad-spectrum antibiotics used in both human and veterinary medicine and are generally considered the first choice to treat acute undiagnosed diarrhoeal illness. Campylobacteriosis in humans is clinically indistinguishable from other causes of bacterial diarrhoeal illness, and so, without evidence of Campylobacter infection, many cases are treated empirically with quinolones (Iovine 2013). These antibiotics inhibit the synthesis of bacterial DNA, causing cell death. Their targets are 2 bacterial enzymes, DNA gyrase and topoisomerase  IV, that act in bacterial DNA replication, transcription, recombination, and repairing (Wieczorek and Osek 2013). DNA gyrase is a tetrameric enzyme that catalyses negative DNA supercoiling and consists of 2 different subunits, GyrA and GyrB (encoded by the gyrA and gyrB genes). Campylobacter species lack topoisomerase IV, and resistance to quinolones is mainly due to amino acid(s) substitution(s) in the gyrA-encoding subunit of the DNA gyrase in a region identified as the quinolone-resistance determining region (QRDR) (Dionisi et al. 2004, Griggs et al. 2009). There are several different single GyrA modifications reported to be associated with quinolone resistance in Campylobacter species. The most frequently observed mutation resulting in the substitution of aminoacids is the C257T change in the gyrA gene, which leads to the Thr86Ile substitution, and confers high-level resistance. Other reported resistance-associated mutations include T86 K, 0 0.2 0.4 0.6 0.8 1 A m ik ac in A m o xy ci lli n -C la vu la n ic a ci d A m p ic ill in A m p i- C lo xa ci lli n A zi th ro m yc in C h lo ra m p h en ic o l C ip ro �o xa ci n C lin d am yc in En ro �o xa ci n Er yt h ro m yc in Fl o rf en ic o l G en ta m ic in Le vo �o xa ci n N al id ix ic A ci d Q u in o lo n es St re p to m yc in Te lit h ro m yc in Te tr ac yc lin e D Figure 2. Dogs. Literature detailing Campylobacter antimicrobial resistance. 214 Campylobacter and antimicrobial resistance Iannino et al. Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 is required for intrinsic and acquired β-lactam resistance in C. jejuni. Resistance to tetracyclines Tetracyclines are alternative agents for antimicrobial therapy in campylobacteriosis. These are lipophilic protein synthesis inhibitors. Their primary antimicrobial effect takes place by binding to the A site in the 30S subunit, thus hindering the movement of transfer RNA and inhibiting peptide elongation (Harms et  al. 2003). Resistance to tetracycline in Campylobacter principally involves a ribosomal protection protein termed Tet(O), which is widely present in Campylobacter isolates recovered from various animal species. This protein is part of a larger group of proteins called ribosomal protection proteins (RPPs), which includes Tet(M), Tet(Q), Tet(S), Tet(T), Tet(W), and OtrA (Chopra and Roberts 2001). Tetracycline resistance conferred by Tet(O) has become highly prevalent in Campylobacter worldwide. This gene is usually carried in a plasmid, although it can be chromosomally encoded (Wieczorek and Osek 2015, Connell 2003, Gibreel et  al. 2005). The gene, which encodes ribosomal protection proteins, is located on a self-transmissible plasmid, and is probably acquired through horizontal gene transfer from Streptomyces, Streptococcus, and Enterococcus  spp. (Batchelore et  al. 2004). Mutations in efflux pumps can also lead to resistance to tetracyclines. Resistance to aminoglycosides Aminoglycoside drugs are not a priority for treating Campylobacter infections but, in serious bacteremia, may be used by intravenous infusion. Their bactericidal activity is due to the inhibition of bacterial protein synthesis to binding 16S rRNA (Mingeot et  al. 1999). Aminoglicosydes exert antimicrobial activities in 2 ways: through alterations at the ribosomal binding sites, or through the production of aminoglycoside-modifying enzymes. Mutations at the site of aminoglycoside attachment may interfere with ribosomal binding. This can cause resistance to streptomycin, since this agent binds to a single site on the 30S subunit of the ribosome. Resistance to other aminoglycosides as a result of this mechanism are uncommon since they bind to multiple sites on both ribosomal subunits and high-level resistance cannot be selected through a single step. Enzymatic modification is the most common type of aminoglycoside resistance and mechanism is of clinical importance since the genes encoding aminoglycoside-modifying enzymes can be disseminated through plasmids or transposons. The enzymatic modification decreases affinity of Luangtongkum et al. 2009). These mutations confer a high-level resistance to macrolide antibiotics (erythromycin MIC >128 μg/ml) in C. jejuni and C. coli (Gibreel et al. 2005). These species carry 3 copies of 23s rRNA gene, all of which are usually mutated in macrolide-resistant strains. However, some strains with lower MICs to macrolides have been found to have only 2 mutated gene copies, suggesting a gene dosage effect (Iovine 2013, Vacher et al. 2005). Other mutations (usually insertions) in the ribosomal proteins L4 and L22 that have lead to macrolide resistance have been described (Cagliero et al. 2006). Efflux is another mechanism that causes macrolide resistance in Campylobacter. The CmeABC multi-drug efflux pump functions synergistically with 23S rRNA mutations to effect high-level macrolide resistance (Cagliero et al. 2006). In addition, the putative efflux pump CmeG may also contribute to macrolide resistance (Iovine et al. 2013). Other mutations (usually insertions) in the ribosomal proteins L4 and L22 that have lead to macrolide resistance have been described. These have been associated with a low level of macrolide resistance (Lehtopolku et  al. 2011). Macrolide resistance in C. jejuni and C. coli was conferred also from the synergy between the CmeABC efflux pump and mutations in the ribosomal proteins L4 (G74D) and L22 (insertions at position 86 or 98) (Caldwell 2008). Resistance to macrolides may also be caused by altered (decreased) membrane permeability that resulted from major outer membrane porin, which was chromosomally encoded by porA. (Pumbwe et al. 2004) Resistance to β‑lactam antibiotics β-lactam antibiotics are the most commercially available antibiotics. In 2009, beta-lactam antibiotics accounted for more than half of the total antibiotic sales globally (Hamad 2010). Although β-lactams are still not a drug of choice for treating Campylobacter infections, it has recently been proposed that an oral combination of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor, may provide an alternative therapy for Campylobacter infection (Elviss et al. 2009, Zeng et al. 2015). These antibiotics inhibit biosynthesis of the bacterial cell wall. Several β-lactam resistance mechanisms have been described, and the most widespread and threatening mechanisms are the production of β-lactamases (the enzymes that hydrolyse the β-lactam ring) and the CmeABC multi-drug efflux pump (Lin et  al. 2002, Alfredson and Korolik 2005). Another mechanism is the reduced uptake due to alteration in the outer membrane porine (Iovine 2013). Recently Zeng (Zeng et  al. 2015) described a putative lytic transglycosylase (LT) Cj0843c that 215 Iannino et al. Campylobacter and antimicrobial resistance Veterinaria Italiana 2019, 55 (3), 203-220. doi: 10.12834/VetIt.1161.6413.3 antimicrobial-resistant bacteria. This poses a new threat to urban hygiene. Campylobacter spp. continues to be a leading cause of bacterial diarrhoea illness throughout the world. Antimicrobial resistance to the drugs used to treat these illnesses can prolong the duration of illness and may compromise the treatment of patients with bacteraemia. The same antimicrobials used in dogs are used in humans. The major concern to both humans and animals is the resistance to macrolides, quinolones, and aminoglycosides such as gentamicin, which are the drugs used to treat serious campylobacteriosis. Drug-resistant Campylobacter can spread from humans to dogs and viceversa through direct contact or, indirectly, through the common environment. Thus, an integrated ‘One Health’ approach to surveillance and intervention is required. Antimicrobials are essential for the health of animals and humans, but it is extremely important to apply the principles of prudent use in order to contain the development of antimicrobial resistance. It is advised that veterinarians strictly observe the following instructions from the EU-COMMISSION NOTICE - Guidelines for the prudent use of antimicrobials in veterinary medicine (EU-COMMISSION NOTICE 2015): • The prescription and dispensation of antimicrobials must be justified by a veterinary diagnosis in accordance with the current status of scientific knowledge. • Where it is necessary to prescribe an antimicrobial, the prescription should be based on a diagnosis made following the clinical examination of the dog by the prescribing veterinarian. Where possible, antimicrobial susceptibility testing should be carried out to determine the choice of antimicrobial. • Routine prophylaxis must be avoided. • All information relating to the animals, the cause and the nature of the infection, and the range of available antimicrobial products must be taken into account when making a decision regarding antimicrobial treatment. • A narrow-spectrum antimicrobial should always be the first choice unless prior susceptibility testing – where appropriate supported by relevant epidemiological data – shows that this would be ineffective. The use of broad-spectrum antimicrobials and antimicrobial combinations should be avoided (with the exception of fixed combinations contained in authorized veterinary medicinal products). • The off-label use of the compounds in dogs aminoglycosides for the rRNA A-site (Wieczorek et  al. 2013, Llano-Sotelo et  al. 2002). Multiple aminoglycoside-modifying enzymes, including 3’-aminoglycoside phosphotransferase types I, III, IV, and VII, 3’,9-aminoglycoside adenyltransferase, and 6-aminoglycoside adenyltransferase, have been described in Campylobacter infection (Zhang et al. 2008). Aminoglycoside resistance was first detected in C.  coli and was mediated by a 3'-aminoglycoside phosphotransferase (encoded by aphA-3). This aphA-3 gene remains the most common source of aminoglycoside resistance in Campylobacter and is located in an insertioning sequence, IS607, or is found with genes encoding streptomycin resistance (encoded by aadE, a 6’-adenylyl transferase). The existence of a similar resistance cluster in Enterococcus suggests that Campylobacter acquired these genes through horizontal transfer (Gibreel et  al. 2005). Other genes that confer kanamicine resistence in C. jejuni are apha-1 and apha-7 (Iovine 2013). Moreover, 9 variants of gentamicin resistance genes have been identified: aph(2”)-Ib, Ic, Ig, If, If1, If3, Ih, aac(6’)-Ie/aph(2”)-Ia, and aac(6')-Ie/aph(2”)-If2. The aph(2”)-Ib, Ic, If1, If3, Ih, and aac(6’)-Ie/aph(2”)-If2 variants were identified for the first time in Campylobacter (Zhao et  al. 2015). The contribution of efflux to aminoglycoside resistance is less clear, but is less important than the plasmid-borne drug-modifying enzymes described previously (Iovine 2013). Antimicrobial susceptibility testing methods Several antimicrobial susceptibility testing (AST) methods such as disk diffusion, e- test, broth dilution, and agar dilution are available to test in vitro bacterial susceptibility to antimicrobials and to provide a reliable predictor of how an organism is likely to respond to antimicrobial therapy in the infected host. This type of information helps clinicians to select the appropriate antimicrobial agent. 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