J Antimicrob Chemother 2017; 72: 957–968 doi:10.1093/jac/dkw481 Advance Access publication 5 December 2016
Public health risk of antimicrobial resistance transfer from companion animals Constanc¸a Pomba1*, Merja Rantala2, Christina Greko3, Keith Edward Baptiste4, Boudewijn Catry5, € la € 2, Modestas Ruzauskas9, Pascal Sanders10, Engeline van Duijkeren6, Ana Mateus7, Miguel A. Moreno8, Satu Pyo¨ra 11 12 13 Christopher Teale , E. John Threlfall , Zoltan Kunsagi , Jordi Torren-Edo13,14, Helen Jukes15 and Karolina To¨rneke16 1
Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal; 2Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland; 3National Veterinary Institute, Uppsala, Sweden; 4Danish Health and Medicines Authority, Copenhagen, Denmark; 5Scientific Institute of Public Health, Brussels, Belgium; 6National Institute for Public Health and the Environment, Bilthoven, The Netherlands; 7 Royal Veterinary College, University of London, London, UK; 8Faculty of Veterinary Medicine, Complutense University, Madrid, Spain; 9 Veterinary Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania; 10Agence Nationale de Se´curite´ Sanitaire (ANSES), Fouge`res, France; 11Veterinary Laboratories Agency, New Haw, UK; 12Health Protection Agency, London, UK; 13European Medicines ria, UAB, Cerdanyola del Valle`s, Spain; 15Veterinary Medicines Directorate, Addlestone, UK; Agency, London, UK; 14Facultat de Veterina 16 €kemedelsverket, Uppsala, Sweden La *Corresponding author. Tel: þ351-213652837; Fax: þ351-213652897; E-mail:
[email protected]
Antimicrobials are important tools for the therapy of infectious bacterial diseases in companion animals. Loss of efficacy of antimicrobial substances can seriously compromise animal health and welfare. A need for the development of new antimicrobials for the therapy of multiresistant infections, particularly those caused by Gramnegative bacteria, has been acknowledged in human medicine and a future corresponding need in veterinary medicine is expected. A unique aspect related to antimicrobial resistance and risk of resistance transfer in companion animals is their close contact with humans. This creates opportunities for interspecies transmission of resistant bacteria. Yet, the current knowledge of this field is limited and no risk assessment is performed when approving new veterinary antimicrobials. The objective of this review is to summarize the current knowledge on the use and indications for antimicrobials in companion animals, drug-resistant bacteria of concern among companion animals, risk factors for colonization of companion animals with resistant bacteria and transmission of antimicrobial resistance (bacteria and/or resistance determinants) between animals and humans. The major antimicrobial resistance microbiological hazards originating from companion animals that directly or indirectly may cause adverse health effects in humans are MRSA, methicillin-resistant Staphylococcus pseudintermedius, VRE, ESBL- or carbapenemase-producing Enterobacteriaceae and Gram-negative bacteria. In the face of the previously recognized microbiological hazards, a risk assessment tool could be applied in applications for marketing authorization for medicinal products for companion animals. This would allow the approval of new veterinary medicinal antimicrobials for which risk levels are estimated as acceptable for public health.
Introduction During the last 50 years, the number of companion animals in modern society has substantially increased and a change in their social role has occurred. Attention to their welfare has increased as a consequence of the close contact between owners and their pets. Humans may acquire antimicrobial-resistant bacteria or the corresponding resistance genes not only from food-producing animals but also via contact with their companion animals. MRSA, methicillin-resistant Staphylococcus pseudintermedius (MRSP), ESBL/AmpC-producing Enterobacteriaceae and MDR non-fermenting Gram-negative bacteria have emerged in healthy and sick dogs and cats, implying a potential risk of transmission of
these bacteria to humans from infected or colonized companion animals.1–3 In addition, there is the possibility of transfer of resistance genes. In order to assess the risks within the context of applications for new veterinary antimicrobials for companion animals, there might be a need for additional data requirements with respect to antimicrobial resistance. The currently available guidance on pre-approval information for the registration of new veterinary medicinal products from the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products—VICH Topic GL27—is a guideline applicable to all new applications in the European, Japanese and
C The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. V
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US markets containing new active ingredients or existing substances for food-producing animals with respect to antimicrobial resistance (CVMP/VICH/644/01-FINAL).4 It does not provide guidance on this issue for companion animals. Issues related to risk from direct contact with companion animals are not covered by any guidance document of the EMA. In this review, the term ‘companion animals’ applies primarily to dogs, cats and horses not intended for human consumption. From a regulatory point of view, horses are classified as a food-producing species and data requirements of products for horses are covered by GL27. Horses are included herewith because they are commonly kept in close contact with people. In addition, advanced veterinary procedures involving extensive use of antimicrobials are performed in horses and MDR organisms have been recorded in this species. While it is acknowledged that emergence of MDR among animals also represents loss of effectiveness of antimicrobials, the main focus of this reflection paper is on the public health risk.
Use of antimicrobials Antimicrobials are used frequently in everyday practice for therapeutic and prophylactic purposes in companion animals. Antimicrobial consumption data, however, for these species are often incomplete and usually refer to drug manufacturer sales. Although sales data provide a rough estimate of the magnitude of antimicrobial consumption, data on the use of antimicrobials in different species are lacking. In the UK, there are examples of surveillance systems, such as VetCompass (http://www.rvc. ac.uk/VetCOMPASS/) and the Small Animal Veterinary Surveillance Network (SAVSNET) (http://www.liv.ac.uk/SA VSNET/), that may be used for monitoring of antimicrobial use in companion animals. In these systems, data are electronically collected from volunteering veterinary practices. The data allow monitoring at the prescription level. They could provide important insight into the patterns and trends of antimicrobial usage in different companion animal species as well as occurrence of common conditions, although total consumption cannot be derived from these systems. At present, these systems do not include horses. However, the VetCompass surveillance system is currently being developed for equine practice (http://www.rvc. ac.uk/vetcompass/projects/vetcompass-equine). The European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) project was launched in 2010 by the EMA. The fifth ESVAC report presents data on sales of veterinary antimicrobial agents from 26 EU/EEA countries according to a standardized protocol and template.5 Companion animal sales of antimicrobials is a fraction of the overall sales pattern of antimicrobial agents in animals. Some antimicrobial products authorized for human use are also used in companion animals, in application of the 0 cascade0 (Articles 10 and 11 of Directive 2001/82/EC of the European Parliament and of the Council). Additionally, injectable veterinary antimicrobial products used for companion animals are included in the sales for food-producing animals in the ESVAC report.5 In the ESVAC report, only the sales of tablets could be considered to reflect the use of antimicrobials in companion animals, since tablets are almost solely used for these species. Widespread use of broad-spectrum antimicrobials has been reported in small animal practice in Europe.5 The most commonly used antimicrobials for dogs and cats in Denmark, Finland, Italy,
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Sweden, Norway and the UK are b-lactams such as amoxicillin and amoxicillin combined with clavulanic acid.6–12 First-generation cephalosporins are also frequently used, especially in dogs.6,7,10,13,14 Increased use of the third-generation cephalosporin cefovecin in cats has been reported in the UK after the authorization of that product in Europe in 2006.10,15 Lincosamides (clindamycin), fluoroquinolones, macrolides, tetracyclines (doxycycline), nitroimidazoles and trimethoprim/sulphonamides have also been reported to be routinely used in small animal practice but on a smaller scale than b-lactams.7–11,16 Data on antimicrobial usage in horses are scarce. A recent study conducted in Finland reported that antimicrobials are used mainly to treat equine skin infections in this species. In that study, the most common antimicrobials used to treat horses were penicillins or trimethoprim/sulphonamides.14 In horses, combinations of benzylpenicillin with either gentamicin or trimethoprim/sulphonamides are often used in empirical antimicrobial therapy.14 In UK equine veterinary practice, 11% of prescriptions were for antimicrobial drugs not licensed for use in horses.17 Current EU Summary of Products Characteristics (SPC) guidance for the responsible use of antimicrobials in veterinary medicine recommends restriction of the use of fluoroquinolones and third- and fourth-generation cephalosporins to clinical cases and whenever possible supported by antimicrobial susceptibility testing (AST).18–20 In some countries, national prescribing guidance has been developed for companion animals.21–25 Additionally, the Federation of Veterinarians of Europe and the Federation of European Companion Animal Veterinary Associations (FECAVA) have produced guidance notes on prudent antimicrobial prescribing. Recently, the Heads of Medicines Agencies and FECAVA undertook a survey on antimicrobial prescribing habits by veterinarians.26 There were significant differences between the frequencies of performing susceptibility testing between the different types of practitioners and for the seven countries studied. Antimicrobial therapy was found to be mainly empirical rather than being based on AST (which was reserved for cases of poor response or complicated cases). The findings from a study in Italy revealed that only 5% of antimicrobial prescriptions in a veterinary teaching hospital were supported by results of microbiological culture and AST.9 Lack of confirmed diagnosis could lead to the misuse of antimicrobials. Antimicrobial administration has been reported for treatment of conditions in which efficacy has not been shown, such as diarrhoea in dogs and feline lower urinary tract disease, and for which antimicrobial treatment is usually not recommended.8,27 In the USA, a study in a canine ICU in a tertiary university referral hospital reported that the antimicrobial choices were appropriate in only 19% of the admitted patients.28 A cross-sectional study on antimicrobial prescribing patterns in the UK showed that 2% of prescriptions for dogs and cats were for products not authorized in those species.29 Dose regimens in excess of that recommended in the SPC were also found to be common in dogs and cats in Switzerland.30 In Switzerland, a study involving eight veterinary mixed practices reported that the dosage that corresponded to the manufacturer’s recommendation was employed in only 45% of the analysed prescriptions. Critically important antimicrobials, as defined by the WHO, e.g. fluoroquinolones, third- and fourth-generation cephalosporins and macrolides, were used in 9% of the prescriptions.30
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Drug-resistant bacteria of concern MDR organisms have been reported in companion animals, sometimes severely compromising the treatment outcome. Because of limited surveillance and awareness of the zoonotic transmission of antimicrobial resistance between companion animals and humans, the extent of transmission and importance for public health are poorly understood. In the following, the most relevant drug-resistant bacteria are reviewed as well as the evidence for their transmission between companion animals and humans.
Methicillin-resistant staphylococci MRSA MRSA is one of the most significant bacteria causing both hospitaland community-acquired infections in humans. MRSA has acquired the mecA gene, resulting in production of an altered PBP (PBP2a or PBP20 ), which confers resistance to all b-lactam antimicrobials used in animals. MRSA also occur in companion animals as reviewed by the Scientific Advisory Group on Antimicrobials (SAGAM).18,31 Since the first companion animal-related outbreak of MRSA in a rehabilitation geriatric ward was reported in 1988, infections and colonization with MRSA in companion animals have been described with increasing frequency.31–37 MRSA have been isolated from a variety of conditions in companion animals such as skin and soft-tissue infections, post-surgical wound infections, urinary tract infections and pneumonia.31 MRSA has also been associated with outbreaks in veterinary hospitals and other animal facilities.2 The majority of MRSA strains isolated from small animal patients are identical to human MRSA hospital-acquired strains belonging to certain genetic MRSA lineages such as ST254, ST8 and ST22 that are shared between animals and humans.1 Transmission of livestock-associated MRSA ST398 from companion animals (including horses) to humans has also been described.38,39 Animals may become colonized with MRSA, although the frequency and duration of colonization is unknown.36,40,41 To date, studies on the overall prevalence of MRSA colonization state that MRSA prevalence is low in dogs and cats.31,37 Prevalence estimates for MRSA range from 0% to 6% in different studies depending on the population, geographical location and methods used.42–47 MRSA have been frequently isolated from horses in Europe, Asia and North America from wound and surgical site infections and from healthy animals.31 Prevalence of MRSA in horses ranges from 0% to 7% and is higher in hospitalized horses compared with equine farms.48–50 There are also several reports concerning MRSA outbreaks in equine hospitals.31,51 MRSA can be passed between pet animals (dogs, cats and horses) and owners with the possibility for zoonotic infections.38,52–54 One case report described the same Panton– Valentine leucocidin toxin-positive MRSA strain in a dog and human in close contact.55 Another publication reports the transfer of MRSA ST225 and ST398 from humans to the family dog.56 In contrast to MRSA ST398, transmission of MRSA in these cases is usually considered to be predominantly from humans to animals. Although colonization of humans in contact with infected or colonized horses has been extensively documented, reports of clinical MRSA infections of humans associated with horse contact are rare and restricted to skin infection.1,31,39,57 Potential differences
between the human and animal epidemiology of MRSA may exist. The dynamics of MRSA colonization in animals and the risk factors involved are still inadequately documented.31 Veterinary staff and veterinary practitioners are at a higher risk of colonization with MRSA than the general population.31,40,58–61 A study from the UK observed that an important and globally disseminated MRSA clone, ST22, was shared between companion animals and humans with no apparent adaptation to animals.62 In Sweden, an MRSA strain, t032, spread in three veterinary clinics from different counties infecting seven dogs and colonizing several staff members.63 This evidence confirms that companion animals can serve as a reservoir of human MRSA.
MRSP Since 2006, MRSP has emerged as a significant health problem in canine and feline patients.64–69 In MRSP, the mecA gene, as in MRSA, mediates methicillin resistance. Evidence suggests that the origin of MRSP SCCmec elements is diverse and may be associated with Staphylococcus aureus as well as CoNS such as Staphylococcus epidermidis and Staphylococcus haemolyticus.70,71 Although methicillin-susceptible S. pseudintermedius isolates are genetically diverse, a limited number of MRSP clones have spread worldwide, resembling the worldwide MRSA dissemination.44,68,72,73 Compared with MRSA, the emergence of MRSP is of greater concern for veterinary patients as S. pseudintermedius is the primary staphylococcal species colonizing healthy dogs and cats. MRSP can cause a plethora of infections in dogs and cats such as skin and ear infections, surgical site infections, gingivitis, hepatitis, urinary tract infections, respiratory infections, arthritis, peritonitis and septicaemia.73 Also, a nosocomial outbreak has been described.73 In Europe and North America, the MDR profile of MRSP includes resistance to all oral and most parenteral antimicrobials approved for veterinary use.73 New MRSP clones have emerged in Asia and are also spreading.71 MRSP colonization is more common in dogs than in cats.74–76 The prevalence of MRSP colonization in various dog populations in different countries has been reported to be 0%–7% depending on the study population and methods, being highest in dogs suffering from chronic skin infections.1,44,76 While MRSA strains isolated from companion animals are mainly related to different human-associated MRSA clones, the scenario for MRSP is different. MRSP originates from an animal reservoir. Diverse SCCmec elements occur among the different MRSP genetic lineages, suggesting that the mecA gene has been acquired by different S. pseudintermedius strains on multiple occasions.1,76 Evidence suggests that the origin of the MRSP-specific SCCmec elements could be S. aureus.77 Transfer of SCCmec elements between different staphylococcal species is of concern. Although colonization or infection with MRSP is rare in humans, the potential transfer of new SCCmec elements and/or other antimicrobial resistance genes from MRSP to other staphylococcal species such as S. aureus is possible. Evidence on the zoonotic transmission of MRSP is limited, but is increasing. Veterinary hospitals and clinics play a role in the dissemination of MRSP between the animal patients and personnel at a veterinary practice as well as to the environment and society.76,78 Colonization of humans with MRSP seems to be uncommon and transient, as reported for methicillin-susceptible Staphylococcus intermedius (MSSP).73 Owners of infected pets and 959
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veterinarians in contact with infected animals seem to have a higher risk of being MRSP positive.73,76 Although there are low numbers of reports of MRSP colonization of veterinarians, it could be considered an occupational risk.66,79–86 Recently, a 4% MRSP carriage rate was found among small animal dermatologists.83 While reports on MRSP colonization of humans in daily contact with companion animals are rare,73,84 the number of case reports on MRSP infection in humans associated with a dog contact87–89 or even no apparent contact with dogs has increased.90–92 A cluster of infections in a tertiary hospital due to MRSP clone ST71 was described recently.93 In the light of this information, MRSP could be a more common pathogen in humans than previously recognized.94
Enterococci Enterococcus faecium and Enterococcus faecalis are the most common enterococci causing infections in people. They are generally considered to be commensals of limited virulence, but are capable of causing a wide range of infections including sepsis.95 VRE first appeared in human hospitals in the late 1980s in a few European countries.96 At present, six types of acquired vancomycin resistance genes in enterococci are known; however, only vanA and to a lesser extent vanB are wide, spread.96 Prior to the ban of avoparcin as a growth promoter in food animals in Europe (2006), high rates of VRE carriage in dogs (e.g. 48% VRE among canine enterococci in the Netherlands) were reported.97 A subsequent Dutch study, performed 5 years later and after the ban on avoparcin use in livestock, reported no VRE in a sample of 100 dogs.98 Healthy dogs and cats can be colonized by VRE99–101 and 13% of healthy dogs were found positive on faecal culture in a Spanish study.102 VRE carrying vanA have been described in healthy horses in Italy, Poland and Hungary.102 In Europe, acquired ampicillin resistance is a major phenotypic marker of hospital-acquired E. faecium and experience has shown that the appearance of such resistance often precedes increasing rates of VRE with a delay of several years.96 Ampicillin-resistant E. faecium were detected in 42 (23%) of 183 dogs screened in a cross-sectional study in the UK and in 19 (76%) of 25 dogs consecutively sampled in Denmark.103 In the latter longitudinal study, ampicillin-resistant E. faecium carriage was intermittent.103 Evidence of gene exchange between human and animal enterococci was described in the USA.104 A particular form of the Tn1546 transposon described in only human clinical VRE was found in a vancomycin-resistant E. faecium isolated from a dog’s urinary tract infection.104 This indicates that exchange of resistance determinants between human and canine enterococci can occur. In addition, VRE of dogs have been shown to be the same genetic lineages that cause hospital-acquired infections in humans.104–106 This applies also to ampicillin-resistant enterococci.104 Inclusion of dogs in surveillance programmes for VRE has been suggested.105
Enterobacteriaceae Members of the Enterobacteriaceae family include many species such as Escherichia coli, Klebsiella spp., Enterobacter spp. and Salmonella spp. Many organisms belonging to these species are commensals of the gastrointestinal tract. Increasing antimicrobial 960
resistance among Enterobacteriaceae is emerging as a significant public health concern in human medicine.107 Of particular note are the Enterobacteriaceae, which produce ESBLs, extendedspectrum cephalosporinases and plasmid-mediated AmpC b-lactamases (henceforth referred to as ESBLs). There are several reports of ESBL-producing bacteria in companion animals.108–117
E. coli FEC-1 (Fujisawa E. coli-1) was the first CTX-M-type ESBL enzyme, discovered in a cefotaxime-resistant E. coli strain isolated from the faeces of a laboratory dog in Japan in 1986.118 During the following decade, ESBLs disseminated in human clinical settings worldwide. The first report of an ESBL-producing uropathogenic E. coli from companion animals is from 1998 in Spain.119 This was followed by the detection of ESBL-producing E. coli in healthy dogs from Italy (mostly TEM and SHV derived) and dogs with urinary tract infection in Portugal (chromosomal AmpC hyperproduction).120,121 Since then, the number of reports concerning E. coli ESBLs in companion animals has increased rapidly.112–114,116,122 CTX-M enzymes have formed a rapidly growing family of ESBLs in bacteria from human infections.123,124 In companion animals both clinical and commensal isolates of E. coli often produce CTX-Mtype b-lactamases.125 MDR E. coli ST131 has recently emerged as a worldwide pandemic clone in humans.126 Reports of clinical infections in animals caused by ST131 are scant, which may be due to the fact that its detection requires genotypic methods.127 The first reported ST131 isolate of animal origin was from a Portuguese study in which 61 fluoroquinolone-resistant E. coli, isolated from 2004 to 2006 from dogs (n ¼ 41) and cats (n ¼ 20), were screened for ESBLs.117 Many clinical ST131 E. coli isolates from companion animals are similar to human clinical ST131 E. coli isolates based on their virulence genotype, resistance characteristics, plasmid content and PFGE profile.111,125 Recently, a study conducted in an Australian veterinary referral centre found fluoroquinolone-resistant extraintestinal pathogenic E. coli, including O25b-ST131, isolated from faeces of hospitalized dogs.128 Other ESBL-producing E. coli STs (ST156, ST405, ST410 and ST648) can also be found both in companion animals and humans.2,129 The detection of identical clones in humans and a number of non-human species (e.g. dogs, cats, horses and poultry) as well as in food may suggest their transmission through animal contact or food. Such transmission may also be a contributory factor to the rapid and successful dissemination of E. coli, although among humans the most important route of transmission is probably person to person.127 Recently, carbapenemase resistance in companion animals has emerged. NDM-1- and OXA-48-producing E. coli have been detected from companion animals’ infection samples in the USA and in Europe, respectively.130,131 In Finland, NDM-5 E. coli was observed recently in a specimen taken from a dog’s ear (M. Rantala, T. Gro¨nthal, M. € € senoja, K. Pekkanen and M. Osterblad, Eklund, J. Jalava, S. Nyka unpublished data). Very recently in China, the detection of mcr-1 in colistin-resistant CTX-M-15-producing E. coli strains isolated from companion animals and the possible transmission of mcr-1-harbouring E. coli between companion animals and a person was reported.132
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Other Enterobacteriaceae MDR Salmonella Typhimurium have been associated with outbreaks of gastrointestinal nosocomial infections in companion animals in veterinary clinics and an animal shelter.133 One such outbreak also involved veterinary staff and other persons in contact with animals.134 MDR Salmonella Typhimurium definitive phagetype 104 has been described to be a causative organism in some of these. Companion animal facilities may serve as foci of transmission for salmonellae between animals and humans if adequate control measures are not followed.133 As with E. coli, ESBL-producing strains of Salmonella are of concern. Ceftiofur resistance was identified in 9.8% of feline, 19.2% of equine and 20.8% of canine Salmonella isolates in one US study and CTX-M group III, SHV, TEM and CMY-2 b-lactamases were detected among these.130 Knowledge of ESBLs in other Enterobacteriaceae of companion animals is limited. The presence of different ESBL (CTX-M, SHV-12 or OXA-10) enzymes has been reported in Citrobacter isolates from dogs, cats and horses,122,136 Enterobacter isolates from dogs and cats137–139 and Klebsiella isolates from dogs, cats and horses.113– 114,138–141 Klebsiella pneumoniae from the ST11 human epidemic clone was isolated from dogs and cats in Spain. It was found to be highly resistant to aminoglycosides due to the ArmA methyltransferase.142 Very recently, the emergence and clonal spread of K. pneumoniae producing carbapenemase OXA-48 in dogs was first reported in Germany.131
Pseudomonas and Acinetobacter Pseudomonas aeruginosa is a Gram-negative bacterium that is ubiquitous in the environment. In veterinary medicine, P. aeruginosa is commonly related to otitis and pyoderma, but also nosocomial infections have been reported.143,144 Antimicrobial treatment generally involves combination protocols, although evidence on its efficacy is lacking.145 In veterinary medicine, multidrug resistance is a common problem in P. aeruginosa.145 Pan-resistant P. aeruginosa (resistant to all antimicrobials) has been reported in humans but not yet in animals.146 In a study of isolates from canine ear and skin infections, acquired resistance to gentamicin (7%) and amikacin (3%) was uncommon but resistance to fluoroquinolones was frequent with 16% of the isolates resistant to ciprofloxacin, 31% resistant to enrofloxacin and 52% resistant to orbifloxacin.147 Comparable antimicrobial resistance patterns were reported in other studies in Denmark and the USA.148,149 Recently, a study in Croatia showed a notable increase in gentamicin resistance in P. aeruginosa.150 Acinetobacter baumannii is a common species in hospitalacquired infections in humans. It can be found on the skin and in the oral cavity of healthy dogs, but is also ubiquitous in the environment.151 Only a few studies have described infections due to A. baumannii in animals.151–153 In 2000, Francey et al. described clinical characteristics of several pets with various A. baumannii infections (i.e. urinary, respiratory, wound and bloodstream infections), reporting an overall attributable mortality of 47%.151 A. baumannii isolates collected in 1998–2000 from pets and horses belonged to two main PFGE clones and the majority of A. baumannii infections were hospital acquired.151–153 Treatment options are often limited. A recent study showed that A. baumannii isolates from pets and horses shared common phenotypic and genotypic characteristics
with those described in humans.154 Recently, a case of urinary tract infection caused by a carbapenem-resistant A. baumannii was reported in a cat.155 The strains belonged to the same clonal lineages as those causing infections in humans. The spread of such A. baumannii strains in companion animals is concerning because of the multiple mechanisms of antimicrobial resistance, especially to carbapenems and colistin.156,157
Other bacteria Campylobacter spp Campylobacter spp. are frequent inhabitants of intestinal microbiota in many animal species including dogs. A longitudinal study of the excretion patterns of thermophilic Campylobacter spp. in young pet dogs in Denmark found that they excreted Campylobacter spp. during the majority of their early life and adolescent period. Campylobacter upsaliensis was excreted for months, with short-term interruptions by, or co-colonization with, other transitory Campylobacter spp., predominantly Campylobacter jejuni. C. jejuni was more prevalent in dogs between 3 months and 1 year of age than in dogs between 1 and 2 years of age.158 One study reports the occurrence of C. jejuni in pets living with human patients infected with C. jejuni. In this work, C. jejuni was recovered from four dogs (11%) and four cats (33%) living with Danish human patients infected with C. jejuni.159 There is evidence that pet ownership is a risk factor for Campylobacter infections in humans.160–163 In dogs, the role of Campylobacter as a cause of diarrhoea or other gastrointestinal infections is contradictory. Such organisms may have a role in diarrhoea in young dogs, but in cats they are not considered intestinal pathogens.164 Dogs and cats can be a source of infection for humans. Two studies have demonstrated C. jejuni dog–human transmission. One reported a case of neonatal C. jejuni sepsis in a 3-week-old infant who acquired the infection through transmission from a recently acquired household puppy.163 The second study revealed the occurrence of the same quinolone-resistant C. jejuni strain in a girl and her dog.159 Companion animals may play a role in the dissemination of this pathogen in the environment, particularly in urban areas, where direct pet-to-pet contact or exposure to faeces from other pets is likely to occur.
Clostridium difficile C. difficile infections have been described in many animal species including horses and dogs.164 The role of this organism as a pathogen in dogs is not clear, although in one report an association between the presence of diarrhoea and the detection of C. difficile toxins was observed.165 However, a small animal experiment using six dogs could not fulfil Koch’s postulates for C. difficile as a pathogen in dogs.165 Cats can also be colonized with C. difficile without any signs of diarrhoea.164 C. difficile colonization rates in healthy dogs and cats range from 1.4% to 21%.164 A higher prevalence of C. difficile has been reported—varying from 18% to 40%—in companion animals attending veterinary clinics.164 C. difficile can be found in the environment of veterinary practices.166 High rates of C. difficile colonization have been described in dogs that visit human hospitals.60 961
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Table 1. Examples of current off-label use and indications in companion animals of antimicrobials authorized for use only in human medicinea (adapted from EMA/AMEG, 2014188) Substance/class authorized only in human medicine
Target animal species
Carbapenems Mupirocin Nitrofurantoin Rifampicin Vancomycin
dog and cat dog and cat cat dog dog and cat
Indication/target pathogen undefined (declining) and E. coli infections infections caused by MRSA urinary tract infection infections caused by MRSP infections caused by MRSA and enterococci
a
European legislation (Articles 10 and 11 of Directive 2001/82/EC) allows for administration under certain conditions of products that are not authorized in veterinary medicine. The provisions (the so-called ‘cascade’) can be used only by way of exception, under the direct responsibility of a veterinarian and in particular to avoid causing unacceptable suffering to animals. Such administration is called off-label use.
Antibiotic-associated diarrhoea, colitis and pseudomembranous colitis caused by C. difficile are common nosocomial infections increasing in incidence and severity in humans worldwide.164 This is related to the emergence of certain hypervirulent strains of C. difficile, such as ribotypes 027 and 078. C. difficile often colonizes the gastrointestinal tract of many mammals, birds and reptiles. The organism is also common in the environment where it survives by forming spores. A zoonotic role of C. difficile has been suggested because animals often carry strains with the same ribotypes as strains that cause infections in humans.167
Factors associated with acquisition of drugresistant bacteria The administration of antimicrobials is a common risk factor for acquiring drug-resistant bacteria in humans.168,169 Antimicrobial use in small animals has also been identified as one of the risk factors for colonization or infection with resistant pathogens.170–172 Antimicrobial administration within 30 days before admission to a veterinary teaching hospital or ceftiofur or aminoglycoside administration during hospitalization was associated with MRSA colonization in horses.173,174 Many studies suggest that antimicrobial therapy is also a risk factor for MRSP infection or colonization in dogs.44,172,175 Recently, antimicrobial use was identified as a risk factor for colonization with ESBL- and AmpC-producing E. coli in dogs.176 Healthy dogs treated with oral enrofloxacin have been shown to be more effectively colonized with MDR E. coli than control dogs.177 Oral treatment of dogs with cefalexin has been proposed as a selector of CMY-2-producing E. coli among the faecal microbiota of dogs. The study design did not permit evaluation of the presence of CMY-2 producers before the treatment and their possible selection or persistence in intestinal microbiota thus remains to be elucidated.178 One study carried out in a veterinary ICU showed that the proportion of dogs carrying resistant E. coli increased with the duration of hospitalization and with the use of antimicrobial drugs.179 Other factors associated with antimicrobial resistance in humans are prolonged hospitalization, gastrointestinal surgery or transplantation, exposure to invasive devices of all types, especially central venous catheters, underlying diseases, severity of illness and advanced age.180 Studies concerning factors others than antimicrobials in companion animals are
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scarce.36,58 Risk factors for MRSA colonization of horses have been determined to be previous colonization, presence of colonized horses on the same farm, admission to the neonatal ICU and admission to a service other than the surgical service.174 Owners from MRSA-positive households, healthcare workers or veterinarians, exposure to medical hospitals, extensive wounds, prolonged hospitalization and immunosuppression also constitute possible risk factors.31,56 Apart from antimicrobial therapy and hospitalization,181 surgical interventions could also be a risk factor for acquiring MRSP in dogs.172 Concerning C. difficile, risk factors for colonization in dogs are as follows: living with an immunocompromised owner, antimicrobial administration to a dog or an owner, contact with children and visiting human hospitals.182 Pet animals as well as travelling have been reported as a risk factor for colonization with ESBL-producing E. coli in healthy infection control personnel.183
Discussion The available evidence shows that resistant bacteria emerge in companion animals and several MDR organisms are shared between companion animals and humans. These bacteria spread between animals and humans, although the direction of transfer is often difficult to prove. Nevertheless, the use of antimicrobials in companion animals implies selection as well as the potential to harbour and spread antimicrobial drug resistance, which constitutes a potential risk to public health. Of special concern is the situation when resistance against last-resort antimicrobials for human medicine is present. Table 1 gives examples of specific antimicrobials and indications for which human-only authorized antimicrobial classes have been used off-label in animals. Problems of resistance development and of infection control in companion animal hospitals are mimicking those in human hospitals.184 Hospitals in both scenarios are facilities of intensive use of antimicrobials and high density of patients and are therefore high-risk environments for the occurrence and spread of nosocomial infections and resistant bacteria.185,186 With increasing demand for advanced therapy coupled with the spread of MDR bacteria, one may foresee the need for new antimicrobials in the future in veterinary medicine. As part of the approval of new antimicrobial agents, there is a need to address concerns related to the spread of resistant
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Table 2. Selected microbiological hazards identified in this study Antimicrobial-resistant bacteria in companion animals
Type of hazard
Sources
MRSA MRSP VRE ESBL-producing Enterobacteriaceae Carbapenem-resistant Gram-negative bacteria Colistin-resistant E. coli
direct hazard direct hazarda indirect hazardb indirect hazard indirect hazardb indirect hazard
dogs, cats and horses dogs, cats and horses dogs and horses dogs, cats and horses dogs and cats dogs and cats
a
Low number of cases of human infections originating from companion animals. No human infections originating from companion animals have been reported.
b
bacteria and resistance genes to humans. The risk of transmission of resistance from companion animals to humans cannot be fully quantified. Overall, companion animal-derived antimicrobial resistance transmission to humans is complex and needs further investigation. Risk assessment methodology should be used to evaluate new antimicrobial treatment options for bacterial infections in companion animals. The new antimicrobial products would be those for which risk levels are estimated as acceptable. Microbiological hazards of concern may directly or indirectly cause adverse health effects in humans. Direct hazards for human health are defined as antimicrobial-resistant bacteria that are transmitted from animals to humans and cause disease in humans (zoonoses). Indirect hazards are the resistance genes that may be transmitted from companion animals to humans with consequences for public health. The most important microbiological hazards emerging from companion animals are summarized in Table 2. Based on available data, major foodborne zoonotic bacteria such as Salmonella and Campylobacter do not constitute a significant hazard in respect of antimicrobial resistance emerging from companion animals. The same rationale applies to C. difficile. It is not possible to evaluate the microbiological hazard created by P. aeruginosa or A. baumannii. In case of new applications for marketing authorization for medicinal products for companion animals the microbiological hazards identified in this document need to be characterized in relation to each new antimicrobial agent. Then, an abbreviated risk assessment model consistent with the principles of Codex187 and VICH GL274 could be applied. A predictable and transparent assessment should facilitate the process of approval for new veterinary medicine antimicrobials for use in companion animals. Availability of veterinary antimicrobials on the market would ensure use according to the SPC and reduce the need for the use of human products. This risk-based approach used for the approval of new veterinary medicinal products will guarantee that the marketing authorizations for medicinal products for companion animals are granted to antimicrobials for which risk levels are estimated as acceptable for public health.
Transparency declarations None to declare.
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