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Systematic Review

Mobile Colistin Resistance (mcr) Genes in Cats and Dogs and Their Zoonotic Transmission Risks

Faculté de Pharmacie, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille University, 19-21 Boulevard Jean Moulin, CEDEX 05, 13385 Marseille, France
IHU-Méditerranée Infection, 19-21 Boulevard Jean Moulin, CEDEX 05, 13385 Marseille, France
Faculté des Sciences de la Nature et de la Vie, Université Batna-2, Route de Constantine, Fésdis, Batna 05078, Algeria
Authors to whom correspondence should be addressed.
Pathogens 2022, 11(6), 698;
Submission received: 13 April 2022 / Revised: 14 June 2022 / Accepted: 15 June 2022 / Published: 17 June 2022


Background: Pets, especially cats and dogs, represent a great potential for zoonotic transmission, leading to major health problems. The purpose of this systematic review was to present the latest developments concerning colistin resistance through mcr genes in pets. The current study also highlights the health risks of the transmission of colistin resistance between pets and humans. Methods: We conducted a systematic review on mcr-positive bacteria in pets and studies reporting their zoonotic transmission to humans. Bibliographic research queries were performed on the following databases: Google Scholar, PubMed, Scopus, Microsoft Academic, and Web of Science. Articles of interest were selected using the PRISMA guideline principles. Results: The analyzed articles from the investigated databases described the presence of mcr gene variants in pets including mcr-1, mcr-2, mcr-3, mcr-4, mcr-5, mcr-8, mcr-9, and mcr-10. Among these articles, four studies reported potential zoonotic transmission of mcr genes between pets and humans. The epidemiological analysis revealed that dogs and cats can be colonized by mcr genes that are beginning to spread in different countries worldwide. Overall, reported articles on this subject highlight the high risk of zoonotic transmission of colistin resistance genes between pets and their owners. Conclusions: This review demonstrated the spread of mcr genes in pets and their transmission to humans, indicating the need for further measures to control this significant threat to public health. Therefore, we suggest here some strategies against this threat such as avoiding zoonotic transmission.

1. Introduction

Across history, humans have cared for certain animals and continue to share their daily lives with pets, especially cats and dogs. Approximately 223 million pets are owned worldwide today [1]. These animals provide psychological support, and they are faithful and enjoyable companions [2]. However, owners are frequently exposed to pathogenic and zoonotic bacteria harbored by their pets [3,4]. Considerable care is often given to companion animals in order to prevent them from catching infections. For this purpose, several antibiotics including polymyxin are regularly administered as prophylaxis to pets, including those that are also authorized for human use [5]. Antibiotics are widely considered to be the most effective treatment for bacterial infections in pets; hence, their loss of efficacy can result in serious therapeutic difficulties for animals and humans [6]. Colistin (polymyxin E) is a cationic antimicrobial peptide that was first discovered in 1947 and was first used in human medicine in 1959 but abandoned in the 1980s because of its nephrotoxic and neurotoxic effects [7]. However, colistin, which is a powerful molecule, was reintroduced because of the emergence of multidrug-resistant Gram-negative bacteria (GNB), especially those resistant to carbapenems [8]. Polymyxin has been commonly used in veterinary medicine for both pets and food animals for several years. On the other hand, polymyxin E is a last-resort antibiotic against certain multidrug-resistant bacterial infections [7]. Alongside colistin use, colistin-resistant bacteria emerge through two mechanisms: (i) via chromosomal gene mutations such as mutations of the two-component system (TCS) phoP/phoQ and mgrB regulator leading to the modification or the complete loss of the membrane lipopolysaccharide layer, and in addition, several mutations that activate the pmrA/pmrB (TCS) are characterized as polymyxin resistance mediators [9,10]; (ii) via a mobile colistin resistance gene (mcr) on a conjugative plasmid discovered in 2015 by Liu et al. in Escherichia coli isolated from pigs in China, thus generating a global health interest [11]. Currently, a total of ten mcr variants (mcr-1 to mcr-10) have been reported in the literature [12,13,14,15,16,17,18,19,20]. A few years after the discovery of mcr genes, this mechanism has been disseminated worldwide and reported in humans, animals, food, and the environment, with some of them in zoonotic cases [21,22,23,24]. Colistin resistance genes have been evidenced in animals more than in humans [25]. Thus, animals may play a crucial role in the transmission of mobile colistin resistance genes (mcr) [26,27]. The close contact between humans and pets increases favorable conditions for the transmission of antibiotic-resistant bacteria through their tight behavior [28]. Previously, several antibiotic resistance genes (ARGs) that were discovered in dogs, cats, and birds were shared with their owners [28,29,30]. Colistin resistance genes (mcr) are usually located on mobile genetic elements (i.e., transposons) mainly vehiculated by conjugative plasmids which facilitate the dissemination of mcr genes among bacteria [31,32]. Humans and animals can exchange diverse bacterial antibiotic resistance genes (ARGs) via physical contact. The zoonotic transmission of bacteria harboring ARGs is more frequent when it covers food animals or animals in direct contact with humans such as pets [33]. Exchanging plasmids carrying ARGs accentuates the risk of zoonotic transmissions leading to infectious diseases difficult to treat [34,35,36,37,38,39]. In the present review, we report colistin-resistant bacteria in pets (i.e., dogs and cats) and discuss the risk of zoonotic transmission of such bacteria from these animals to their owners.

2. Material and Methods

2.1. Design and Collection of Articles

This systematic review was conducted according to meta-analysis guidelines (PRISMA) [40]. Harzing’s Publish software, Version 3, Anne-Wil Harzing (Middlesex University, London, UK) was used to improve the search fields and to scan all published studies [41]. The databases used to perform a global bibliography search were as follows: Google Scholar, Web of Science, PubMed, Scopus, and Microsoft Academic. The keywords used in the systematic search were “colistin resistance”, “polymyxin resistance”, “mcr genes”, “pets”, “companion animal”, “dog”, “cat”, and “zoonotic transmission”. An additional online research for discussion results was performed using Z-library [42].

2.2. Inclusion and Exclusion Criteria

From all the selected articles, the titles and abstracts were principally extracted and analyzed. Articles that were duplicates, were lacking the full text, featured language constraints, or were off-topic were excluded.

2.3. Extraction of the Dataset

All articles reporting colistin-resistant bacteria in pets and zoonotic transmission were thoroughly analyzed. The extracted criteria contained all the information about strains harboring mcr genes in dogs and cats. The criteria corresponded to (i) the total number of strains screened, (ii) bacterial species, (iii) sequence type (ST), (iv) geographical location where strains were isolated, (v) sample origin, (vi) year of sampling, (vii) plasmids, (viii) zoonotic transmission, (ix) colistin resistance mechanisms, (x) resistance genes, and (xi) associated diseases. The extracted dataset was used to develop a comparative analysis of the emergence of mcr genes in cats and dogs to highlight the human risk of zoonotic transmission.

3. Results and Discussion

3.1. Bibliographic Research

The bibliographic research resulted in a total of 1231 articles from the interrogated databases such as Google Scholar, PubMed, Scopus, Microsoft Academic, and Web of Science. The flowchart shown in Figure 1 presents the process via which studies were selected. The first screening led to the removal of 84% (n = 1033) of the total selected studies because they corresponded to duplicated articles (n = 198; 16%) or off-topic articles (n = 835; 68%). Other studies were included from the Z-library search (n = 56). All the selected studies (n = 254) were screened for a second time. During the second screening, 41% (n = 104) of studies were excluded due to the following reasons: off-topic, language problems, duplicates, uninteresting studies, and studies concerning pet diseases. Among the final 150 selected studies, 12% (n = 18) reported bacteria harboring mcr genes in dogs, 1% (n = 2) reported bacteria harboring mcr genes in cats, and 5% (n = 7) reported bacteria harboring mcr genes in both cats and dogs. Only four studies reported the zoonotic transmission of colistin-resistant bacteria from dogs and cats to their owners. The characteristics of the selected articles were explored using the statistical parameters presented in Table 1.

3.2. Colistin Resistance Mechanisms

3.2.1. Chromosomic Colistin Resistance

Bacteria are exposed to several antimicrobials or environmental stimuli such as colistin, which is a cationic antimicrobial peptide (CAMP) that leads bacteria to develop strategies to protect themselves [43,44]. One of the described mechanisms of resistance to colistin is mutations, which are the first protection means against the alteration of the bacterial membrane [31,45,46]. Figure 2 schematically illustrates the mechanism of colistin resistance induced by chromosomal mutations. Activation of the two-component system (TCS) PmrA/PmrB generates the upregulation of the operons pmrCAB and arnBCADTEF-pmrE (pmrHFIJKLM). The last cascade of activation stimulates the synthesis and transfer of phosphoethanolamine (PetN) and l-Ara4N to the 4′-phosphate group to lipid A in the membrane lipopolysaccharide (LPS). It should be noted that LPS is the primary target of colistin. The addition of cationic groups to the surface of LPS increases its positive charge and decreases the affinity to polymyxin [47,48]. The PhoP/PhoQ TCS can directly activate the PmrA/PmrB TCS via the PmrD regulator [49,50]. However, direct activation of the operon arnBCADTEF can be managed by PhoP independently of pmrD [51]. In addition, the mgrB and micA genes have negative feedback on TCSs (PhoP/PhoQ). This feedback is monitored by inhibition of the kinase activity on PhoQ and/or by stimulating its phosphatase activity. Any mutations in this system, therefore, lead to the overexpression of PhoP/PhoQ that activates the pmrD activator (pmrA activation) and pagL lipid A deacylation [52,53]. Moreover, other colistin resistance mechanisms have been reported such as (i) the phosphorylation of pmrE or Ugd by Etk (tyrosine kinase) leading to alteration of the LPS structure, (ii) the alterations in Kdo (3-deoxy-d-manno-octulosonic acid), residues of LPS which can induce colistin resistance in E. coli, or (iii) mutations in mgrR which increase colistin resistance in E. coli [54,55].

3.2.2. Plasmid-Mediated Colistin Resistance

Until late 2015, colistin resistance was related to chromosomic mutations without any proven horizontal transfer. Later, Chinese researchers discovered an IncI2-type plasmid carrying a new colistin resistance gene mcr-1 (for mobile colistin resistance) in E. coli strains from pigs [11]. A few months later, researchers began to screen for the presence of these genes in various samples from different countries around the world [56]. The recent discovery of mcr-1 does not exclude its prior existence, as proven by its detection in E. coli in a collection dating from the 1980s [57]. Researchers then began to look for genes similar to mcr-1 which were classified as mcr variants ranging from mcr-2 to mcr-10 (mcr-10 is the most recently discovered gene) [20,58]. The mcr genes encode phosphoethanolamine transferase enzymes that decrease the affinity of colistin to the bacterial external membrane through the addition of a phosphoethanolamine moiety to lipid A [59]. The colistin resistance mechanism usually confers a low level of colistin resistance with low minimum inhibitory concentrations [60]. Colistin resistance is of great interest due to its ability to be transferred via horizontal gene transfer mechanisms [61]. The significant spread of mcr genes is due to the association of mcr genes with a large variety of mobile genetic elements [62,63,64]. It is also possible for colistin resistance genes to coexist in the same bacterial isolate via different mobile genetic elements as recently described in the co-occurrence of mcr genes in E. coli harboring the mcr-3 gene on an IncFII plasmid and a transposon carrying the mcr-1 gene in the chromosome [65].

3.3. Antimicrobial Uses

3.3.1. Antimicrobials and Colistin Treatment for Pets

In this section, we report colistin use in companion animals around the world. In Europe, 62% of cats with urinary pathologies and 36% of dogs with dental disease are treated with critically important antibiotics (CIAs) including colistin [66]. Colistin use in animals is for therapeutic purposes, as a feed additive, or as metaphylactic treatment [67]. Less stringent standards are imposed upon the use of colistin in companion animals compared to those imposed on humans and food-producing animals [68]. The use of antimicrobials in Europe was investigated in animals, including cats and dogs, indicating that cats receive antimicrobial treatment (13%) less frequently than dogs (25%) [69]. The most commonly used antimicrobials were β-lactams such as amoxicillin–clavulanate (cats: 28%; dogs: 27%). Concerning cats, the second most widely used active compound as an antibiotic was cefovecin (third-generation cephalosporin) [69]. Currently, polymyxin B sulfate represents 6% of the treatments used in companion animals. Moreover, polymyxin B sulfate is classified by the World Health Organization (WHO) as a critically important antimicrobial of the highest priority [69]. Further German studies identified the total amount of polymyxin used in dogs and cats in 2017 and 2018 in one veterinary hospital to be 0.06% and 0.13%, respectively [70]. In recent research carried out in 2019 in Australia on a cohort of cats and dogs using the VetCompass software, the most frequently used antibiotics were cefovecin and amoxicillin–clavulanate, respectively [71]. In 2014, very restricted use of antibiotics in pets (1% of 1.4 million kg of antibiotics sold) was reported in Canada [72]. In Japan, the extent of antibiotics used in domestic animals remains unknown since human antimicrobials are used for companion animals rather than humans [73]. In total, an estimated 29.9 tons of antimicrobial drugs were used in companion animal clinics between 2017 and 2018. Less than 1% of this total represents the annual consumption of polypeptides (colistin) [74].

3.3.2. Antimicrobial Use and Antimicrobial Resistance

Many studies have reported that the increase in AMR results from uncontrolled AMU [75]. The quantitative use and the qualitative use of antibiotics in pets are very significant in the veterinary field. AMU is based on information collected from veterinary centers and pharmaceutical companies. Some studies are not representative due to the lack of information regarding the quantification of AMU [76]. The most commonly used antibiotics in animal medicine are also used in human medicine. Furthermore, the use of some antibiotics is restricted due to their unfavorable and toxic side effects (glycopeptides and streptogramins) [77]. Due to the rapid spread of AMR and the excessive use of antibiotics in pets, restrictions on antimicrobial use were required. Such restrictions were applied to antibiotics that are critical to human health, such as colistin [78]. Colistin was used for more than 70 years before being banned due to its high nephrotoxicity [38]. Although colistin use was prohibited for several years, its resistance continues to emerge. The spread of multidrug-resistant bacteria and especially carbapenem-resistant bacteria has led to the reuse of colistin [68]. Furthermore, in some cases, there are no convenient alternatives to colistin, which is an effective antibiotic. Few drugs are available against certain urogenital infections and respiratory infections in pets [79].

3.3.3. Approaches Aimed at Reducing Antimicrobial Use

Several attempts have been developed in South Africa to optimize antimicrobial use (AMU) and reduce antimicrobial resistance (AMR) in domestic animals. These approaches were based on questionnaires about current knowledge and attitudes toward antibiotics and strategies to restrict their use. According to the survey results, the majority of respondents (79.4%; n = 81) believed that antibiotics were sometimes prescribed for unconfirmed infections; on the other hand, 75.5% of respondents (n = 77) rarely took antibiotics to treat infections, while 18.7% of respondents (n = 19) often used antibiotics for treatment [80]. Other therapeutic approaches have also been used, including strategies to combine colistin with other antibiotics. Antibiotics are combined to increase antibacterial efficacy and reduce the emergence of AMR [81]. Recent extensive research concerning AMU in veterinary medicine has been greatly extended. AMR is highly increasing in human medicine, leading to doubt about all antimicrobial usage, particularly in food animals in which these antibiotics have long been used in centralized management to promote growth and prevent diseases [82]. AMU in dogs and cats has also been investigated in three European countries (Belgium, Italy, and the Netherlands), and no association between AMU and AMR was found in the investigated samples [69]. However, other researchers have reported a direct crosslink between the use of colistin in the European Union and the development of resistance in animals [83]. The principal causes of AMR in companion animals were purported to be related to the quality of use, rather than the quantity [50]. Many aspects of reducing AMU in animals and infection control can be improved in order to reduce the spread of AMR and to preserve antibiotics for future use [68].

3.4. mcr Genes in Companion Animals

Among the analyzed articles here, 18 of them reported the detection of mcr genes in dogs, while 2 studies reported their detection in cats. Seven studies described the detection of mcr genes in both dogs and cats.

3.4.1. mcr Genes in Dogs

As presented in Table 2, mcr genes were found in dogs in several countries around the world from diverse dog samples. For example, in 2016, one study reported the detection of transferable plasmids harboring mcr genes in dogs. This concerned the isolation of four E. coli strains belonging to the sequence type ST354 and harboring the mcr-1 gene on a conjugative replicon. The study was conducted on 39 fecal samples taken from a pet shop in China. Interestingly, one of the isolates carried IMP-4 carbapenemase [84]. Thereafter, three Chinese studies published in 2017 reported the isolation of mcr-1-positive E. coli and Klebsiella pneumoniae from fecal samples, nasal samples, and rectal swabs [85,86,87]. Fecal samples were sampled from dogs living in pig and poultry farms. The swine farm isolates belonged to ST10 and harbored the mcr-1 gene on an IncX4 plasmid [86]. In 2018, Wang and his colleagues reported the isolation of seven mcr-1-producing E. coli from clinical samples (urine, nasal secretions, feces, and diarrhea); the strains belonged to ST93, ST1011, ST3285, and a new strain [35]. In 2019, an mcr-1-positive E. coli ST770 isolate was obtained from a urinary tract infection in Argentina. The mcr-1 gene was harbored by the conjugative IncI2 plasmid, and the strain co-expressed the blaCTX-M-2 extended-spectrum β-lactamase (ESBL) [88]. In addition, two Chinese studies reported the isolation of mcr-producing E. coli ST6316, ST405, ST46, and ST162 from clinical samples [89,90]. In Ecuador, Ortega-Paredes and his colleagues described the isolation of an mcr-1-positive E. coli strain co-expressing blaCTX-M-65 ESBL from disposed feces in a public park [91]. Furthermore, mcr-1 was detected in K. pneumoniae ST307 and Enterobacter cloacae ST1005 from clinical samples [92]. In 2020, a Brazilian study described the isolation of mcr-1-positive E. coli, Enterobacter sp., and Klebsiella sp. from clinical samples [93]. Furthermore, mcr-1 and mcr-3.7 were detected in a single E. coli ST132 isolated from a fecal sample in China. The mcr-1 and mcr-3.7 genes were located on two different transferable (together and separately) plasmids, namely, IncX4 and IncP2, respectively, and the isolate co-produced blaCTX-M-14 ESBL [94]. In addition, two studies from Ecuador reported the isolation of mcr-1-producing E. coli ST1630 and ST2170 (from rectal swabs) and ST162, ST1196, and ST744 (fecal samples). The rectal swab isolates harbored the gene on a transferable IncI2 plasmid [95], and fecal isolates co-expressed blaCTX-M-55 and blaCTX-M-65 ESBLs [96]. In South Korea, mcr-1-positive E. coli ST162 was isolated from diarrhea. Like the previous study, the mcr-1 gene was located on an IncI2 transferable plasmid [97]. In 2021, we noted the detection of other mcr genes in samples from dogs. Among seven studies reporting the detection of mcr genes in dogs, only three studies from China reported detection of the mcr-1 gene. This was in relation to the detection of several strains of mcr-1-producing K. pneumoniae and E. coli from fecal samples, rectal swabs, and clinical samples [98,99,100]. The mcr-1 gene was harbored by the IncI2, IncX4, and IncHI2 plasmids [98]. Except for mcr-6 and mcr-7, all the other mcr genes have been reported from dogs. Wang et al. (2021) reported the detection of mcr-2, mcr-3, mcr-4, mcr-5, mcr-9, and mcr-10 in K. pneumoniae isolates from fecal samples in China. Interestingly, associations between mcr-1 and mcr-3 or mcr-5 were reported [100]. The mcr-3 gene was also reported in E. coli ST10 co-expressing blaCTX-M-55 isolated from clinical samples in Thailand [101]. The mcr-8 gene was detected in K. pneumoniae ST3410 co-harboring the blaCTX-M ESBL gene obtained from a nasal swab in China [99]. The mcr-9 gene was also detected in Egypt and the United Kingdom. An Egyptian study reported the detection of mcr-9-positive Enterobacter hormaechei ST493 isolated from clinical samples [102]. A British study described the isolation of mcr-9-positive E. coli ST372 co-expressing the blaCTX-M-9 ESBL obtained from clinical samples [103]. Lastly, Enterobacter roggenkampii positive for the mcr-10 gene on an IncFIB plasmid was isolated in Japan from a pus sample [104]. In France, although the use of colistin in dogs is highly monitored, mcr-1 genes were detected in dogs in our recent work [105].

3.4.2. mcr Genes in Cats

Compared with dogs, few data are available regarding the detection of the mcr gene in cats (Table 3). A total of six studies reported the isolation of mcr-producers from cats. The first one was from China in 2016, where the authors described the detection of mcr-1-positive E. coli belonging to ST93 and another previously undescribed strain in fecal samples [84]. The second study reported the detection of the mcr-1 gene in E. coli isolated from nasal and rectal swabs from cats in China in 2017 [87]. The third study was also conducted in China and reported the detection of mcr-1 E. coli ST93 isolated from a diarrheic cat in 2018 [35]. The fourth study was from Brazil and reported on the isolation of mcr-1-positive K. pneumoniae ST307 causing urinary tract infection in 2021 [106]. The other mcr gene detected in cats was mcr-9 in Enterobacter hormaechei ST493 and ST182 and Enterobacter asburiae from clinical samples in Egypt and from nasal swabs in Japan, respectively [102,107]. In the Japanese isolates, the mcr-9 gene was located on the IncHI2 plasmid [107].
In addition to the isolation of mcr-producers, the direct detection of mcr genes in fecal samples from dogs and cats was also reported in China in 2017 and more recently in 2022 [108,109]. Another recent study in France showed that cats host bacteria harboring the colistin resistance mcr-1 gene [105].

3.4.3. Source of mcr Genes in Pets

Colistin-resistant Enterobacteriaceae in dogs are managed by diverse epidemiological factors [110]. Flies with several resistance genes against cephalosporins (bla) and colistin can be a contamination source of mcr genes between dogs and their owners [111]. As reported, humans may not be the origin of mcr genes in domestic animals. In Beijing, characteristics of K. pneumoniae in humans and companion animals were largely different, and mcr genes and blaNDM were not present in the genomes of K. pneumoniae isolated from humans [99]. In another study, researchers suspected that farm animals were the source of mcr genes in diseased dogs and cats (without colistin treatment) [100]. The environment is also an important factor in the spread of mcr genes such as mcr-1, mcr-3, and mcr-7.1, as well as other ARGs [112]. Many methods were performed to review the spread and evolution of ARG transmission from food animals, humans, and the environment [113]. Furthermore, as reported in China, pet food was also identified as a source of intestinal colistin resistance genes in pets [87]. In addition, in Vietnam and Japan, wastewater is a source of mcr-1 in urban sewage. The health of city dwellers and pets is generally reflected in domestic sewage [114]. The spread of mobile genetic elements is responsible for the high emergence of mcr genes across countries and continents. As a result, colistin resistance genes can easily be transferred from humans to animals [115]. To date, mobile genetic elements have played a crucial role in the dissemination of mcr genes around the world [32,116]. As shown in Figure 3, the mcr genes in dogs and cats have begun to spread around the world.

3.5. Zoonotic Transmission

3.5.1. Zoonotic Transmission of mcr Genes between Pets and Humans

The zoonotic transmission of mcr-carrying enterobacteria was previously suggested in four studies from China and Ecuador. Zhang et al. (2016) suggested a potential transmission of mcr-1-positive E. coli between dogs and humans. This suggestion was based on the isolation of clonally related mcr-1-producing strains (by multilocus sequence typing and pulsed-field gel electrophoresis profiles (PFGE)) from dogs and a pet shop worker in China [84]. Following this study, Lei and his colleagues reinforced this suggestion when they investigated the prevalence of mcr-producers in companion animals in Beijing. They observed clonal relatedness (the same PFGE patterns) between mcr-1-positive E. coli isolated from dogs, cats, and one pet owner. In the same study, pet food samples were positive for the mcr-1 gene, suggesting that several factors may contribute to the emergence of mcr-1 in pets [87]. In addition, another Chinese study reported significant mcr-1 carriage between dogs and their owners, where the carriage of this gene by owners was a risk factor for its presence in dogs [98]. Lastly, the owner of a dog who was tested positive for intestinal carriage of mcr-1-producing E. coli was reported as the first case of mcr-1 carriage in Ecuador [95]. Furthermore, pets harbor bacteria that require the use of polymyxin for treatment, including methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus spp., vancomycin-resistant Enterococcus, and ESBL- or carbapenemase-producing Enterobacteriaceae and Gram-negative bacteria [117]. The mcr-1 and mcr-2 colistin resistance genes, in particular, have a high potential for zoonotic transmission (being predominant in animals rather than in humans) [57]. According to one study on 229 Chinese families, there was a significant co-occurrence of mcr and β-lactamase genes in dogs and their owners. The mcr-1 and blaCTX-M genes were found to be present in 2.7% and 5.3% of the population, respectively [98]. In Egypt, researchers reported a high potential of animal–human transmission of blaVIM-4-, blaOXA-244-, and mcr-9-producing E. hormaechei. The transmission was associated with respiratory infections. These bacteria also harbored β-lactam and carbapenem resistance genes; this was the first report to confirm their potential animal-to-human transmission [102]. According to another study conducted in Argentina, dogs can carry mcr genes and blaCTX-M-2 co-producing E. coli (ST770) previously reported in humans [88]. Due to the close relationship between pets and their owners, the microbiota of pets and humans share a diversity of bacteria and ARGs [118]. Dogs and cats host zoonotic microorganisms due to their close physical contact with humans (licking, petting, and contact with furnishings) including around pets’ spaces (carpets and beds) [119]. The exchange of pathogenic microorganisms and resistance genes between animals and their owners has frequently been reported [120,121]. In some cases, ARGs found in hospital patients were similar to those found in pets. As a result, vigilance is required against the zoonotic transmission of resistant bacteria, which are shared between pets and their owners [122].

3.5.2. Health Risks Associated with Colistin-Resistant Bacteria in Pets

People who bring pets into their homes are the most exposed to the emergence of pathogenic organisms. These individuals are exposed to bacteria that carry the mcr gene or bacteria that are naturally colistin-resistant, especially those linked to human diseases. Vancomycin-resistant enterococci (VREs) are naturally colistin-resistant bacteria, and the zoonotic transmission of VREs from pets to their owners is a public health problem [123]. In Guangzhou, China, and South Korea, researchers have reported diarrhea in dogs caused by E. coli with mcr genes (ST93, ST3285, and ST160) [35,97]. Urinary tract infections have also been diagnosed featuring colistin-resistant bacteria in pets from Europe (France, Spain, and Portugal) and Argentina. Bacterial culture revealed the presence of the multidrug-resistant bacteria Acinetobacter spp. and E. coli carrying the mcr-1 gene associated with other genes, namely, blaCTX-M-2, aadA1, and sul1 [88,124,125]. In China, the UK, and Egypt, pneumonia and respiratory diseases have been diagnosed in canines and their owners. The pneumopathy was associated with the presence of the following colistin-resistant strains: K. pneumoniae, E. coli, P. aeruginosa, and E. hormaechei carrying mcr-1 or mcr-9 [35,102,126]. Further enteropathogenic and gastrointestinal diseases revealed the presence of E. coli (ST372) harboring mcr-1 isolated from dogs and humans in Spain [108,124]. Other colistin-resistant bacteria linked to infections or nosocomial diseases have also been found in Spain, the United Kingdom, Lebanon, Taiwan, and China [84,92,98,126,127]. The co-occurrence of mcr genes with other resistance genes increases the potential of the bacterium to exhibit multiple resistance to antibiotics, which is a major public health problem. Colistin-resistant isolates described in humans and their pets can be associated with β-lactam resistance genes. Genome analysis revealed mcr genes associated with these β-lactamases, namely, blaTEM, blaCTX-M, and blaSHV [87,128,129,130,131,132,133]. Furthermore, carbapenem resistance genes can be adequately supplied with mcr genes produced in clinical bacteria such as blaNDM-1 [134]. The coexistence of mcr and carbapenemases indicates the crossover of resistance between pets and their owners. Multidrug-resistant bacteria with EptA and β-lactamase genes are considered to be the strains for which it is complicated to find an effective therapeutic solution [128,135].

3.5.3. Strategies to Control the Zoonotic Transmission of Colistin Resistance from Pets

Zoonotic transmission is managed by different bacterial species that can harbor a variety of ARGs through recombinant plasmids. Systematically, this increases the therapeutic difficulty to treat infectious diseases caused by these bacteria [136,137]. The significant spread and horizontal transmission of colistin resistance highlight the need to adopt restriction protocols on colistin use using the One Health approach [138]. Mobile genetic elements (MGEs) play a major role in zoonotic transmission [139]. Figure 4 shows a graphic representation of zoonotic transmission and MGEs that monitor the spread of mcr genes.
In this section of the review, we suggest some approaches to reduce zoonotic transmission. Reducing the use of all antibiotics, particularly colistin, would reduce the emergence of colistin resistance. Colistin resistance is usually mediated by chromosomic mutations, mcr genes, or the selection pressure of bacteria resistant to colistin [140,141]. Livestock is the first source of ARGs for human beings due to the excessive use of antibiotics as a growth factor or in the form of subtherapeutic treatment. Antibiotic concentrations, on the other hand, should be investigated in relation to the spread of ARGs in order to assess the risk of zoonotic transmission from pets [141]. The lack of daily hygiene and cleanliness is one of the major reasons for the emergence of pathogens and resistance genes [142,143,144]. In order to reduce antibiotic use and gastrointestinal infections, strict hygiene conditions must be observed to ensure uncontaminated food and clean drinking water. Furthermore, global access to vaccination can also play an important role in protecting pets from bacterial and viral infections that require antibiotics and the use of colistin [145]. Pets such as cats and dogs are in direct contact with human beings, and immediate vigilance is required regarding the pet–human mode of transmission [146]. Considering the fact that pets are in close physical contact with humans and frequently share their living quarters, the use of cleaning and disinfection tools is necessary [142,147]. The evacuation of waste from pharmaceutical and manufacturing plants, pet shops, and hospitals must be rigorously monitored. The waste ends up in waterways and can contribute to the emergence of ARGs such as mcr genes in soil and water [148]. To reduce the transmission of zoonotic organisms that are pathogenic in Germany, researchers investigated the potential collection of samples from pets and their owners. The current method has proven to be a very useful tool for investigating zoonoses in population-based studies [149]. Moreover, AMR and AMU in pets must be translated into an accessible shared public data system [150].

4. Conclusions

The number of adopted pets by humans has increased, and due to the close contact between these pets and their owners, more attention is being given to their welfare. This review confirms the dissemination of plasmid-mediated colistin resistance in this kind of companion animal, where 8 out of the 10 currently described mcr genes have been detected in samples obtained from these animals. This concerning resistance mechanism has been detected in both diseased and healthy animals, thus presenting an important reservoir for these genes. Considering that some studies have highlighted the potential zoonotic transmission of mcr-producers between pets and their owners, greater emphasis should be given to screening and reducing colistin resistance, especially regarding mcr genes in companion animals. Certain behaviors can be adopted to avoid zoonotic transmission. The most important is daily hygiene at home or outside during any contact with pets. The zoonotic transmission of mcr genes should be further investigated in order to minimize the consequences of colistin resistance for human health.

Author Contributions

Conceptualization, A.H., J.-M.R. and S.M.D.; methodology, A.H.; software, S.M.D.; validation, J.-M.R. and S.M.D.; formal analysis, A.H. and B.D.; investigation, A.H. and Z.C.; resources, S.M.D.; data curation, J.-M.R.; writing—original draft preparation, A.H. and Z.C.; writing—review and editing, S.M.D.; supervision, J.-M.R., B.D. and S.M.D. All authors have read and agreed to the published version of the manuscript.


The IHU-Méditerranée Infection supported this work (reference: Méditerranée Infection 10-IAHU-03).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Beetz, A.; Uvnäs-Moberg, K.; Julius, H.; Kotrschal, K. Psychosocial and psychophysiological effects of human-animal interactions: The possible role of oxytocin. Front. Psychol. 2012, 3, 234. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. New Perspectives on Human-Animal Interactions: Theory, Policy, and Research—Google Livres. Available online: (accessed on 17 January 2022).
  3. Szwabe, K.; Błaszkowska, J. Stray dogs and cats as potential sources of soil contamination with zoonotic parasites. Ann. Agric. Environ. Med. 2017, 24, 39–43. [Google Scholar] [CrossRef] [PubMed]
  4. Belas, A. Extended-spectrum–beta-lactamases, cephalosporinases, and carbapenemase-producing Escherichia coli in the human-dog interface. Ph.D. Thesis, Universidade de Lisboa, Lisboa, Portugal, 2021. [Google Scholar]
  5. DeVincent, S.J.; Viola, C. Introduction to animal antimicrobial use data collection in the United States: Methodological options. Prev. Vet. Med. 2006, 73, 105–109. [Google Scholar] [CrossRef] [PubMed]
  6. Rice, L.B. Unmet medical needs in antibacterial therapy. Biochem. Pharmacol. 2006, 71, 991–995. [Google Scholar] [CrossRef]
  7. Berlana, D.; Llop, J.M.; Fort, E.; Badia, M.B.; Jódar, R. Use of colistin in the treatment of multiple-drug-resistant gram-negative infections. Am. J. Health Pharm. 2005, 62, 39–47. [Google Scholar] [CrossRef]
  8. Nation, R.L.; Li, J. Colistin in the 21st Century. Curr. Opin. Infect. Dis. 2009, 22, 535. [Google Scholar] [CrossRef]
  9. Rozenberg-Arska, M.; Dekker, A.W.; Verhoef, J. Colistin and trimethoprim-sulfamethoxazole for the prevention of infection in patients with acute non-lymphocytic leukaemia. Decrease in the emergence of resistant bacteria. Infection 1983, 11, 167–169. [Google Scholar] [CrossRef]
  10. Aghapour, Z.; Gholizadeh, P.; Ganbarov, K.; Bialvaei, A.Z.; Mahmood, S.S.; Tanomand, A.; Yousefi, M.; Asgharzadeh, M.; Yousefi, B.; Kafil, H.S. Molecular mechanisms related to colistin resistance in Enterobacteriaceae. Infect. Drug Resist. 2019, 12, 965. [Google Scholar] [CrossRef] [Green Version]
  11. Liu, Y.Y.; Wang, Y.; Walsh, T.R.; Yi, L.X.; Zhang, R.; Spencer, J.; Doi, Y.; Tian, G.; Dong, B.; Huang, X.; et al. Emergence of plasmid-mediated colistin resistance mechanism mcr-1 in animals and human beings in China: A microbiological and molecular biological study. Lancet Infect. Dis. 2016, 16, 161–168. [Google Scholar] [CrossRef]
  12. Xavier, B.B.; Lammens, C.; Ruhal, R.; Malhotra-Kumar, S.; Butaye, P.; Goossens, H.; Malhotra-Kumar, S. Identification of a novel plasmid-mediated colistinresistance gene, mcr-2, in Escherichia coli, Belgium, June 2016. Eurosurveillance 2016, 21, 30280. [Google Scholar] [CrossRef]
  13. Eichhorn, I.; Feudi, C.; Wang, Y.; Kaspar, H.; Feßler, A.T.; Lübke-Becker, A.; Michael, G.B.; Shen, J.; Schwarz, S. Identification of novel variants of the colistin resistance gene mcr-3 in Aeromonas spp. from the national resistance monitoring programme GERM-Vet and from diagnostic submissions. J. Antimicrob. Chemother. 2018, 73, 1217–1221. [Google Scholar] [CrossRef]
  14. Carattoli, A.; Villa, L.; Feudi, C.; Curcio, L.; Orsini, S.; Luppi, A.; Pezzotti, G.; Magistrali, C.F. Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016. Eurosurveillance 2017, 22, 30589. [Google Scholar] [CrossRef] [Green Version]
  15. Borowiak, M.; Fischer, J.; Hammerl, J.A.; Hendriksen, R.S.; Szabo, I.; Malorny, B. Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. Enterica serovar Paratyphi B. J. Antimicrob. Chemother. 2017, 72, 3317–3324. [Google Scholar] [CrossRef] [Green Version]
  16. AbuOun, M.; Stubberfield, E.J.; Duggett, N.A.; Kirchner, M.; Dormer, L.; Nunez-Garcia, J.; Randall, L.P.; Lemma, F.; Crook, D.W.; Teale, C.; et al. mcr-1 and mcr-2 (mcr-6.1) variant genes identified in Moraxella species isolated from pigs in Great Britain from 2014 to 2015. J. Antimicrob. Chemother. 2017, 72, 2745–2749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Yang, Y.Q.; Li, Y.X.; Lei, C.W.; Zhang, A.Y.; Wang, H.N. Novel plasmid-mediated colistin resistance gene mcr-7.1 in Klebsiella pneumoniae. J. Antimicrob. Chemother. 2018, 73, 1791–1795. [Google Scholar] [CrossRef] [Green Version]
  18. Wang, X.; Wang, Y.; Zhou, Y.; Wang, Z.; Wang, Y.; Zhang, S.; Shen, Z. Emergence of colistin resistance gene mcr-8 and its variant in Raoultella ornithinolytica. Front. Microbiol. 2019, 10, 228. [Google Scholar] [CrossRef] [Green Version]
  19. Carroll, L.M.; Gaballa, A.; Guldimann, C.; Sullivan, G.; Henderson, L.O.; Wiedmann, M. Identification of novel mobilized colistin resistance gene mcr-9 in a multidrug-resistant, colistin-susceptible Salmonella enterica serotype typhimurium isolate. MBio 2019, 10, e00853-19. [Google Scholar] [CrossRef] [Green Version]
  20. Wang, C.; Feng, Y.; Liu, L.; Wei, L.; Kang, M.; Zong, Z. Identification of novel mobile colistin resistance gene mcr-10. Emerg. Microbes Infect. 2020, 9, 508–516. [Google Scholar] [CrossRef] [Green Version]
  21. Jayol, A.; Poirel, L.; Dortet, L.; Nordmann, P. National survey of colistin resistance among carbapenemase-producing Enterobacteriaceae and outbreak caused by colistin-resistant blaOXA-48-producing Klebsiella pneumoniae, France, 2014. Eurosurveillance 2016, 21, 30339. [Google Scholar] [CrossRef] [Green Version]
  22. Dandachi, I.; Chabou, S.; Daoud, Z.; Rolain, J.M. Prevalence and emergence of extended-spectrum cephalosporin-, carbapenem- and colistin-resistant gram negative bacteria of animal origin in the Mediterranean basin. Front. Microbiol. 2018, 9, 2299. [Google Scholar] [CrossRef]
  23. Grami, R.; Mansour, W.; Mehri, W.; Bouallègue, O.; Boujaâfar, N.; Madec, J.; Haenni, M. Impact of food animal trade on the spread of mcr-1-mediated colistin resistance, tunisia, July 2015. Eurosurveillance 2016, 21, 30144. [Google Scholar] [CrossRef] [PubMed]
  24. Dandachi, I.; Fayad, E.; Sleiman, A.; Daoud, Z.; Rolain, J.M. Dissemination of Multidrug-Resistant and mcr-1 Gram-Negative Bacilli in Broilers, Farm Workers, and the Surrounding Environment in Lebanon. Microb. Drug Resist. 2020, 26, 368–377. [Google Scholar] [CrossRef] [PubMed]
  25. Algammal, A.M.; Hetta, H.F.; Elkelish, A.; Alkhalifah, D.H.H.; Hozzein, W.N.; Batiha, G.E.S.; El Nahhas, N.; Mabrok, M.A. Methicillin-Resistant Staphylococcus aureus (MRSA): One Health Perspective Approach to the Bacterium Epidemiology, Virulence Factors, Antibiotic-Resistance, and Zoonotic Impact. Infect. Drug Resist. 2020, 13, 3255. [Google Scholar] [CrossRef]
  26. Ben Khedher, M.; Baron, S.A.; Riziki, T.; Ruimy, R.; Raoult, D.; Diene, S.M.; Rolain, J.M. Massive analysis of 64,628 bacterial genomes to decipher water reservoir and origin of mobile colistin resistance genes: Is there another role for these enzymes? Sci. Rep. 2020, 10, 5970. [Google Scholar] [CrossRef] [Green Version]
  27. Elbediwi, M.; Li, Y.; Paudyal, N.; Pan, H.; Li, X.; Xie, S.; Rajkovic, A.; Feng, Y.; Fang, W.; Rankin, S.C.; et al. Global Burden of Colistin-Resistant Bacteria: Mobilized Colistin Resistance Genes Study (1980–2018). Microorganisms 2019, 7, 461. [Google Scholar] [CrossRef] [Green Version]
  28. Bhat, A.H. Bacterial zoonoses transmitted by household pets and as reservoirs of antimicrobial resistant bacteria. Microb. Pathog. 2021, 155, 104891. [Google Scholar] [CrossRef]
  29. Skarżyńska, M.; Zaja̧c, M.; Bomba, A.; Bocian, Ł.; Kozdruń, W.; Polak, M.; Wia̧cek, J.; Wasyl, D. Antimicrobial Resistance Glides in the Sky—Free-Living Birds as a Reservoir of Resistant Escherichia coli With Zoonotic Potential. Front. Microbiol. 2021, 12, 673. [Google Scholar] [CrossRef]
  30. Ahmed, Z.S.; Elshafiee, E.A.; Khalefa, H.S.; Kadry, M.; Hamza, D.A. Evidence of colistin resistance genes (mcr-1 and mcr-2) in wild birds and its public health implication in Egypt. Antimicrob. Resist. Infect. Control 2019, 8, 197. [Google Scholar] [CrossRef]
  31. Olaitan, A.O.; Morand, S.; Rolain, J.M. Mechanisms of Polymyxin resistance: Acquired and intrinsic resistance in bacteria. Front. Microbiol. 2014, 5, 643. [Google Scholar] [CrossRef] [Green Version]
  32. Dénervaud Tendon, V.; Poirel, L.; Nordmann, P. Transferability of the mcr-1 Colistin Resistance Gene. Microb. Drug Resist. 2017, 23, 813–814. [Google Scholar] [CrossRef] [Green Version]
  33. Kaye, K.S.; Pogue, J.M.; Tran, T.B.; Nation, R.L.; Li, J. Agents of Last Resort: Polymyxin Resistance. Infect. Dis. Clin. 2016, 30, 391–414. [Google Scholar] [CrossRef] [PubMed]
  34. Wang, Y.; Liu, F.; Zhu, B.; Gao, G.F. Metagenomic data screening reveals the distribution of mobilized resistance genes tet(X), mcr and carbapenemase in animals and humans. J. Infect. 2020, 80, 121–142. [Google Scholar] [CrossRef] [PubMed]
  35. Wang, J.; Huang, X.-Y.; Xia, Y.-B.; Guo, Z.-W.; Ma, Z.-B.; Yi, M.-Y.; Lv, L.-C.; Lu, P.-L.; Yan, J.-C.; Huang, J.-W.; et al. Clonal Spread of Escherichia coli ST93 Carrying mcr-1-Harboring IncN1-IncHI2/ST3 Plasmid Among Companion Animals, China. Front. Microbiol. 2018, 9, 2989. [Google Scholar] [CrossRef] [PubMed]
  36. Stein, A.; Raoult, D. Colistin: An Antimicrobial for the 21st Century? Clin. Infect. Dis. 2002, 35, 901–902. [Google Scholar] [CrossRef] [Green Version]
  37. Levin, A.S.; Barone, A.A.; Penço, J.; Santos, M.V.; Marinho, I.S.; Arruda, E.A.G.; Manrique, E.I.; Costa, S.F. Intravenous Colistin as Therapy for Nosocomial Infections Caused by Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin. Infect. Dis. 1999, 28, 1008–1011. [Google Scholar] [CrossRef] [Green Version]
  38. Lim, L.M.; Ly, N.; Anderson, D.; Yang, J.C.; Macander, L.; Jarkowski, A.; Forrest, A.; Bulitta, J.B.; Tsuji, B.T. Resurgence of Colistin: A review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2010, 30, 1279–1291. [Google Scholar] [CrossRef]
  39. Kempf, I.; Fleury, M.A.; Drider, D.; Bruneau, M.; Sanders, P.; Chauvin, C.; Madec, J.Y.; Jouy, E. What do we know about resistance to colistin in Enterobacteriaceae in avian and pig production in Europe? Int. J. Antimicrob. Agents 2013, 42, 379–383. [Google Scholar] [CrossRef]
  40. Shamseer, L.; Moher, D.; Clarke, M.; Ghersi, D.; Liberati, A.; Petticrew, M.; Shekelle, P.; Stewart, L.A.; Altman, D.G.; Booth, A.; et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation. BMJ 2015, 349, g7647. [Google Scholar] [CrossRef] [Green Version]
  41. Publish or Perish. Available online: (accessed on 17 January 2022).
  42. Z-Library. The World’s Largest Ebook Library. Available online: (accessed on 17 January 2022).
  43. Moffatt, J.H.; Harper, M.; Harrison, P.; Hale, J.D.F.; Vinogradov, E.; Seemann, T.; Henry, R.; Crane, B.; St. Michael, F.; Cox, A.D.; et al. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob. Agents Chemother. 2010, 54, 4971–4977. [Google Scholar] [CrossRef] [Green Version]
  44. Hussein, A.H.M.; Ghanem, I.A.I.; Eid, A.A.M.; Ali, M.A.; Sherwood, J.S.; Li, G.; Nolan, L.K.; Logue, C.M. Molecular and phenotypic characterization of Escherichia coli isolated from broiler chicken flocks in Egypt. Avian Dis. 2013, 57, 602–611. [Google Scholar] [CrossRef]
  45. Biswas, S.; Brunel, J.M.; Dubus, J.C.; Reynaud-Gaubert, M.; Rolain, J.M. Colistin: An update on the antibiotic of the 21st century. Expert Rev. Anti-Infect. Ther. 2014, 10, 917–934. [Google Scholar] [CrossRef]
  46. Sun, S.; Negrea, A.; Rhen, M.; Andersson, D.I. Genetic analysis of colistin resistance in Salmonella enterica serovar typhimurium. Antimicrob. Agents Chemother. 2009, 53, 2298–2305. [Google Scholar] [CrossRef] [Green Version]
  47. Gunn, J.S. Bacterial modification of LPS and resistance to antimicrobial peptides. J. Endotoxin Res. 2001, 7, 57–62. [Google Scholar] [CrossRef]
  48. Raetz, C.R.H.; Reynolds, C.M.; Trent, M.S.; Bishop, R.E. Lipid A Modification Systems in Gram-Negative Bacteria. Annu. Rev. Biochem. 2007, 76, 295–329. [Google Scholar] [CrossRef] [Green Version]
  49. Kox, L.F.F.; Wösten, M.M.S.M.; Groisman, E.A. A small protein that mediates the activation of a two-component system by another two-component system. EMBO J. 2000, 19, 1861–1872. [Google Scholar] [CrossRef] [Green Version]
  50. Kato, A.; Latifi, T.; Groisman, E.A. Closing the loop: The PmrA/PmrB two-component system negatively controls expression of its posttranscriptional activator PmrD. Proc. Natl. Acad. Sci. USA 2003, 100, 4706–4711. [Google Scholar] [CrossRef] [Green Version]
  51. Mitrophanov, A.Y.; Jewett, M.W.; Hadley, T.J.; Groisman, E.A. Evolution and Dynamics of Regulatory Architectures Controlling Polymyxin B Resistance in Enteric Bacteria. PLOS Genet. 2008, 4, e1000233. [Google Scholar] [CrossRef] [Green Version]
  52. Trent, M.S.; Pabich, W.; Raetz, C.R.H.; Miller, S.I. A PhoP/PhoQ-induced Lipase (PagL) that catalyzes 3-O-deacylation of lipid A precursors in membranes of Salmonella typhimurium. J. Biol. Chem. 2001, 276, 9083–9092. [Google Scholar] [CrossRef] [Green Version]
  53. Falagas, M.E.; Rafailidis, P.I.; Matthaiou, D.K. Resistance to Polymyxins: Mechanisms, frequency and treatment options. Drug Resist. Updat. 2010, 13, 132–138. [Google Scholar] [CrossRef]
  54. Lacour, S.; Doublet, P.; Obadia, B.; Cozzone, A.J.; Grangeasse, C. A novel role for protein-tyrosine kinase Etk from Escherichia coli K-12 related to Polymyxin resistance. Res. Microbiol. 2006, 157, 637–641. [Google Scholar] [CrossRef]
  55. Moon, K.; Gottesman, S. A PhoQ/P-regulated small RNA regulates sensitivity of Escherichia coli to antimicrobial peptides. Mol. Microbiol. 2009, 74, 1314–1330. [Google Scholar] [CrossRef] [Green Version]
  56. Baron, S.; Hadjadj, L.; Rolain, J.M.; Olaitan, A.O. Molecular mechanisms of Polymyxin resistance: Knowns and unknowns. Int. J. Antimicrob. Agents 2016, 48, 583–591. [Google Scholar] [CrossRef]
  57. Skov, R.L.; Monnet, D.L. Plasmid-mediated colistin resistance (mcr-1 gene): Three months later, the story unfolds. Eurosurveillance 2016, 21, 30155. [Google Scholar] [CrossRef] [Green Version]
  58. Ling, Z.; Yin, W.; Shen, Z.; Wang, Y.; Shen, J.; Walsh, T.R. Epidemiology of mobile colistin resistance genes mcr-1 to mcr-9. J. Antimicrob. Chemother. 2020, 75, 3087–3095. [Google Scholar] [CrossRef] [PubMed]
  59. Hu, M.; Guo, J.; Cheng, Q.; Yang, Z.; Chan, E.W.C.; Chen, S.; Hao, Q. Crystal Structure of Escherichia coli originated mcr-1, a phosphoethanolamine transferase for Colistin resistance. Sci. Rep. 2016, 6, 38793. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Islam, S.; Urmi, U.L.; Rana, M.; Sultana, F.; Jahan, N.; Hossain, B.; Iqbal, S.; Hossain, M.M.; Mosaddek, A.S.M.; Nahar, S. High abundance of the colistin resistance gene mcr-1 in chicken gut-bacteria in Bangladesh. Sci. Rep. 2020, 10, 17292. [Google Scholar] [CrossRef] [PubMed]
  61. Lin, Y.; Dong, X.; Wu, J.; Rao, D.; Zhang, L.; Faraj, Y.; Yang, K. Metadata Analysis of mcr-1-Bearing plasmids inspired by the sequencing evidence for horizontal transfer of antibiotic resistance genes between polluted river and wild birds. Front. Microbiol. 2020, 11, 352. [Google Scholar] [CrossRef] [PubMed]
  62. Snesrud, E.; He, S.; Chandler, M.; Dekker, J.P.; Hickman, A.B.; McGann, P.; Dyda, F. A model for transposition of the colistin resistance gene mcr-1 by ISApl1. Antimicrob. Agents Chemother. 2016, 60, 6973–6976. [Google Scholar] [CrossRef] [Green Version]
  63. Nang, S.C.; Li, J.; Velkov, T. The rise and spread of mcr plasmid-mediated Polymyxin resistance. Crit. Rev. Microbiol. 2019, 45, 131–161. [Google Scholar] [CrossRef]
  64. Liu, G.; Ali, T.; Gao, J.; Ur Rahman, S.; Yu, D.; Barkema, H.W.; Huo, W.; Xu, S.; Shi, Y.; Kastelic, J.P.; et al. Co-Occurrence of plasmid-mediated colistin resistance (mcr-1) and extended-spectrum β-lactamase encoding genes in Escherichia coli from Bovine Mastitic Milk in China. Microb. Drug Resist. 2020, 26, 685–696. [Google Scholar] [CrossRef]
  65. Hamame, A.; Davoust, B.; Rolain, J.-M.; Diene, S.M. Genomic characterisation of an mcr-1 and mcr-3-producing Escherichia coli strain isolated from pigs in France. J. Glob. Antimicrob. Resist. 2022, 28, 174–179. [Google Scholar] [CrossRef]
  66. De Briyne, N.; Atkinson, J.; Borriello, S.P.; Pokludová, L. Antibiotics used most commonly to treat animals in Europe. Vet. Rec. 2014, 175, 325. [Google Scholar] [CrossRef] [Green Version]
  67. Coetzee, J.; Corcoran, C.; Prentice, E.; Moodley, M.; Mendelson, M.; Poirel, L.; Nordmann, P.; Brink, A.J. Emergence of plasmid-mediated colistin resistance (mcr-1) among Escherichia coli isolated from South African patients. S. Afr. Med. J. 2016, 106, 449–450. [Google Scholar] [CrossRef]
  68. Prescott, J.F. Antimicrobial use in food and companion animals. Anim. Health Res. Rev. 2008, 9, 127–133. [Google Scholar] [CrossRef]
  69. Joosten, P.; Ceccarelli, D.; Odent, E.; Sarrazin, S.; Graveland, H.; Van Gompel, L.; Battisti, A.; Caprioli, A.; Franco, A.; Wagenaar, J.A.; et al. Antimicrobial usage and resistance in companion animals: A cross-sectional study in three european countries. Antibiotics 2020, 9, 87. [Google Scholar] [CrossRef] [Green Version]
  70. Schnepf, A.; Kramer, S.; Wagels, R.; Volk, H.A.; Kreienbrock, L. Evaluation of Antimicrobial Usage in Dogs and Cats at a Veterinary Teaching Hospital in Germany in 2017 and 2018. Front. Vet. Sci. 2021, 8, 689018. [Google Scholar] [CrossRef]
  71. Hur, B.; Hardefeldt, L.Y.; Verspoor, K.; Baldwin, T.; Gilkerson, J.R. Using natural language processing and VetCompass to understand antimicrobial usage patterns in Australia. Aust. Vet. J. 2019, 97, 298–300. [Google Scholar] [CrossRef]
  72. Ebrahim, M.; Gravel, D.; Thabet, C.; Abdesselam, K.; Paramalingam, S.; Hyson, C. Anitmicrobial Resistance (AMR): Antimicrobial use and antimicrobial resistance trends in Canada: 2014. Canada Commun. Dis. Rep. 2016, 42, 227. [Google Scholar] [CrossRef]
  73. Kumazawa, J.; Yagisawa, M. The history of antibiotics: The Japanese story. J. Infect. Chemother. 2002, 8, 125–133. [Google Scholar] [CrossRef]
  74. Makita, K.; Sugahara, N.; Nakamura, K.; Matsuoka, T.; Sakai, M.; Tamura, Y. Current status of antimicrobial drug use in japanese companion animal clinics and the factors associated with their use. Front. Vet. Sci. 2021, 8, 1119. [Google Scholar] [CrossRef]
  75. Wassenaar, T.M.; Silley, P. Antimicrobial resistance in zoonotic bacteria: Lessons learned from host-specific pathogens. Anim. Health Res. Rev. 2008, 9, 177–186. [Google Scholar] [CrossRef] [PubMed]
  76. Kempf, I.; Jouy, E.; Chauvin, C. Colistin use and colistin resistance in bacteria from animals. Int. J. Antimicrob. Agents 2016, 48, 598–606. [Google Scholar] [CrossRef] [PubMed]
  77. Phillips, I.; Casewell, M.; Cox, T.; De Groot, B.; Friis, C.; Jones, R.; Nightingale, C.; Preston, R.; Waddell, J. Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data. J. Antimicrob. Chemother. 2004, 53, 28–52. [Google Scholar] [CrossRef] [PubMed]
  78. Buckland, E.L.; O’Neill, D.; Summers, J.; Mateus, A.; Church, D.; Redmond, L.; Brodbelt, D. Characterisation of antimicrobial usage in cats and dogs attending UK primary care companion animal veterinary practices. Vet. Rec. 2016, 179, 489. [Google Scholar] [CrossRef] [Green Version]
  79. Lhermie, G.; La Ragione, R.M.; Weese, J.S.; Olsen, J.E.; Christensen, J.P.; Guardabassi, L. Indications for the use of highest priority critically important antimicrobials in the veterinary sector. J. Antimicrob. Chemother. 2020, 75, 1671–1680. [Google Scholar] [CrossRef]
  80. Maruve, S.A. Knowledge, Attitudes and Practices of Veterinarians on Antibiotic Use, Resistance and Its Containment in South Africa. Available online: (accessed on 10 February 2022).
  81. Armengol, E.; Domenech, O.; Fusté, E.; Pérez-Guillén, I.; Borrell, J.H.; Sierra, J.M.; Vinas, M. Efficacy of combinations of colistin with other antimicrobials involves membrane fluidity and efflux machinery. Infect. Drug Resist. 2019, 12, 2031. [Google Scholar] [CrossRef] [Green Version]
  82. Van Boeckel, T.P.; Brower, C.; Gilbert, M.; Grenfell, B.T.; Levin, S.A.; Robinson, T.P.; Teillant, A.; Laxminarayan, R. Global trends in antimicrobial use in food animals. Proc. Natl. Acad. Sci. USA 2015, 112, 5649–5654. [Google Scholar] [CrossRef] [Green Version]
  83. Catry, B.; Cavaleri, M.; Baptiste, K.; Grave, K.; Grein, K.; Holm, A.; Jukes, H.; Liebana, E.; Navas, A.L.; Mackay, D.; et al. Use of colistin-containing products within the European Union and European Economic Area (EU/EEA): Development of resistance in animals and possible impact on human and animal health. Int. J. Antimicrob. Agents 2015, 46, 297–306. [Google Scholar] [CrossRef]
  84. Zhang, X.-F.; Doi, Y.; Huang, X.; Li, H.-Y.; Zhong, L.-L.; Zeng, K.-J.; Zhang, Y.-F.; Patil, S.; Tian, G.-B. Possible Transmission of mcr-1–Harboring Escherichia coli between Companion Animals and Human. Emerg. Infect. Dis. 2016, 22, 1679. [Google Scholar] [CrossRef] [Green Version]
  85. Wang, Y.; Zhang, R.; Li, J.; Wu, Z.; Yin, W.; Schwarz, S.; Tyrrell, J.M.; Zheng, Y.; Wang, S.; Shen, Z.; et al. Comprehensive resistome analysis reveals the prevalence of NDM and mcr-1 in Chinese poultry production. Nat. Microbiol. 2017 24 2017, 2, 16260. [Google Scholar] [CrossRef]
  86. Guenther, S.; Falgenhauer, L.; Semmler, T.; Imirzalioglu, C.; Chakraborty, T.; Roesler, U.; Roschanski, N. Environmental emission of multiresistant Escherichia coli carrying the colistin resistance gene mcr-1 from German swine farms. J. Antimicrob. Chemother. 2017, 72, 1289–1292. [Google Scholar] [CrossRef] [Green Version]
  87. Lei, L.; Wang, Y.; Schwarz, S.; Walsh, T.R.; Ou, Y.; Wu, Y.; Li, M.; Shen, Z. mcr-1 in Enterobacteriaceae from Companion Animals, Beijing, China, 2012–2016. Emerg. Infect. Dis. 2017, 23, 710. [Google Scholar] [CrossRef]
  88. Rumi, M.V.; Mas, J.; Elena, A.; Cerdeira, L.; Muñoz, M.E.; Lincopan, N.; Gentilini, É.R.; Di Conza, J.; Gutkind, G. Co-occurrence of clinically relevant β-lactamases and mcr-1 encoding genes in Escherichia coli from companion animals in Argentina. Vet. Microbiol. 2019, 230, 228–234. [Google Scholar] [CrossRef]
  89. Chen, Y.; Liu, Z.; Zhang, Y.; Zhang, Z.; Lei, L.; Xia, Z. Increasing Prevalence of ESBL-Producing Multidrug Resistance Escherichia coli From Diseased Pets in Beijing, China From 2012 to 2017. Front. Microbiol. 2019, 10, 2852. [Google Scholar] [CrossRef]
  90. Zhang, P.; Wang, J.; Wang, X.; Bai, X.; Ma, J.; Dang, R.; Xiong, Y.; Fanning, S.; Bai, L.; Yang, Z. Characterization of five Escherichia coli isolates co-expressing ESBL and mcr-1 resistance mechanisms from different origins in China. Front. Microbiol. 2019, 10, 1994. [Google Scholar] [CrossRef] [Green Version]
  91. Ortega-Paredes, D.; Haro, M.; Leoro-Garzón, P.; Barba, P.; Loaiza, K.; Mora, F.; Fors, M.; Vinueza-Burgos, C.; Fernández-Moreira, E. Multidrug-resistant Escherichia coli isolated from canine faeces in a public park in Quito, Ecuador. J. Glob. Antimicrob. Resist. 2019, 18, 263–268. [Google Scholar] [CrossRef]
  92. Chang, M.-H.; Chen, G.-J.; Lo, D.-Y. CHROMOSOMAL LOCATIONS OF mcr-1 IN Klebsiella pneumoniae AND Enterobacter cloacae FROM DOGS. Taiwan Veter. J. 2019, 45, 79–84. [Google Scholar] [CrossRef] [Green Version]
  93. Kobs, V.C.; Valdez, R.E.; de Medeiros, F.; Fernandes, P.P.; Deglmann, R.C.; Gern, R.M.M.; França, P.H.C. mcr-1-carrying Enterobacteriaceae isolated from companion animals in Brazil. Pesqui. Veterinária Bras. 2020, 40, 690–695. [Google Scholar] [CrossRef]
  94. Du, C.; Feng, Y.; Wang, G.; Zhang, Z.; Hu, H.; Yu, Y.; Liu, J.; Qiu, L.; Liu, H.; Guo, Z.; et al. Co-occurrence of the mcr-1.1 and mcr-3.7 genes in a multidrug-resistant Escherichia coli isolate from China. Infect. Drug Resist. 2020, 13, 3649–3655. [Google Scholar] [CrossRef]
  95. Loayza-Villa, F.; Salinas, L.; Tijet, N.; Villavicencio, F.; Tamayo, R.; Salas, S.; Rivera, R.; Villacis, J.; Satan, C.; Ushiña, L.; et al. Diverse Escherichia coli lineages from domestic animals carrying colistin resistance gene mcr-1 in an Ecuadorian household. J. Glob. Antimicrob. Resist. 2020, 22, 63–67. [Google Scholar] [CrossRef]
  96. Albán, M.V.; Núñez, E.J.; Zurita, J.; Villacís, J.E.; Tamayo, R.; Sevillano, G.; Villavicencio, F.X.; Calero-Cáceres, W. Canines with different pathologies as carriers of diverse lineages of Escherichia coli harboring mcr-1 and clinically relevant β-lactamases in central Ecuador. J. Glob. Antimicrob. Resist. 2020, 22, 182–183. [Google Scholar] [CrossRef] [PubMed]
  97. Moon, D.C.; Mechesso, A.F.; Kang, H.Y.; Kim, S.-J.; Choi, J.-H.; Kim, M.H.; Song, H.-J.; Yoon, S.-S.; Lim, S.-K. First Report of an Escherichia coli Strain Carrying the Colistin Resistance Determinant mcr-1 from a Dog in South Korea. Antibiotics 2020, 9, 768. [Google Scholar] [CrossRef] [PubMed]
  98. Lei, L.; Wang, Y.Y.; He, J.; Cai, C.; Liu, Q.; Yang, D.; Zou, Z.; Shi, L.; Jia, J.; Wang, Y.Y.; et al. Prevalence and risk analysis of mobile colistin resistance and extended-spectrum β-lactamase genes carriage in pet dogs and their owners: A population based cross-sectional study. Emerg. Microbes Infect. 2021, 10, 242–251. [Google Scholar] [CrossRef] [PubMed]
  99. Zhang, Z.; Lei, L.; Zhang, H.; Dai, H.; Song, Y.; Li, L.; Wang, Y.; Xia, Z. Molecular Investigation of Klebsiella pneumoniae from Clinical Companion Animals in Beijing, China, 2017–2019. Pathogens 2021, 10, 271. [Google Scholar] [CrossRef]
  100. Wang, G.; Liu, H.; Feng, Y.; Zhang, Z.; Hu, H.; Liu, J.; Qiu, L.; Guo, Z.; Huang, J.; Qiu, J.; et al. Colistin-resistance mcr genes in Klebsiella pneumoniae from companion animals. J. Glob. Antimicrob. Resist. 2021, 25, 35–36. [Google Scholar] [CrossRef]
  101. Nittayasut, N.; Yindee, J.; Boonkham, P.; Yata, T.; Suanpairintr, N.; Chanchaithong, P. Multiple and High-Risk Clones of Extended-Spectrum Cephalosporin-Resistant and blaNDM-5-Harboring Uropathogenic Escherichia coli from cats and dogs in Thailand. Antibiotics 2021, 10, 1374. [Google Scholar] [CrossRef]
  102. Khalifa, H.O.; Oreiby, A.F.; El-Hafeez, A.A.A.; Okanda, T.; Haque, A.; Anwar, K.S.; Tanaka, M.; Miyako, K.; Tsuji, S.; Kato, Y.; et al. First report of multidrug-resistant carbapenemase-producing bacteria coharboring mcr-9 associated with respiratory disease complex in pets: Potential of animal-human transmission. Antimicrob. Agents Chemother. 2021, 65, 633. [Google Scholar] [CrossRef]
  103. Singleton, D.A.; Pongchaikul, P.; Smith, S.; Bengtsson, R.J.; Baker, K.; Timofte, D.; Steen, S.; Jones, M.; Roberts, L.; Sánchez-Vizcaíno, F.; et al. Temporal, Spatial, and Genomic Analysis of Enterobacteriaceae Clinical Antimicrobial Resistance in Companion Animals Reveals Phenotypes and Genotypes of One Health Concern. Front. Microbiol. 2021, 12, 2160. [Google Scholar] [CrossRef]
  104. Sato, T.; Usui, M.; Harada, K.; Fukushima, Y.; Nakajima, C.; Suzuki, Y.; Yokota, S. Complete Genome Sequence of an mcr-10-Possessing Enterobacter roggenkampii Strain Isolated from a dog in Japan. Microbiol. Resour. Announc. 2021, 10, e0042621. [Google Scholar] [CrossRef]
  105. Hamame, A.; Davoust, B.; Rolain, J.M.; Diene, S.M. Screening of colistin-resistant bacteria in domestic pets from France. Animals 2022, 12, 633. [Google Scholar] [CrossRef]
  106. Hayakawa Ito de Sousa, A.T.; dos Santos Costa, M.T.; Makino, H.; Cândido, S.L.; de Godoy Menezes, I.; Lincopan, N.; Nakazato, L.; Dutra, V. Multidrug-resistant mcr-1 gene-positive Klebsiella pneumoniae ST307 causing urinary tract infection in a cat. Braz. J. Microbiol. 2021, 52, 1043–1046. [Google Scholar] [CrossRef]
  107. Sato, T.; Usui, M.; Harada, K.; Fukushima, Y.; Nakajima, C.; Suzuki, Y.; Yokota, S. Complete Genome Sequence of an mcr-9-Possessing Enterobacter asburiae Strain Isolated from a Cat in Japan. Microbiol. Resour. Announc. 2021, 10, e0028121. [Google Scholar] [CrossRef]
  108. Chen, X.; Zhao, X.; Che, J.; Xiong, Y.; Xu, Y.; Zhang, L.; Lan, R.; Xia, L.; Walsh, T.R.; Xu, J.; et al. Detection and dissemination of the colistin resistance gene, mcr-1, from isolates and Fecal samples in China. J. Med. Microbiol. 2017, 66, 119–125. [Google Scholar] [CrossRef]
  109. Yang, Y.; Hu, X.; Li, W.; Li, L.; Liao, X.; Xing, S. Abundance, diversity and diffusion of antibiotic resistance genes in cat feces and dog feces. Environ. Pollut. 2022, 292, 118364. [Google Scholar] [CrossRef]
  110. Saraf, A. Epidemiology of Colistin Resistance in Enterobacteriaceae Isolates from Perianal Region of Pet Dogs. Master’s Thesis, ICAR-Indian Veterinary Research Institute, Uttar Pradesh, India, July 2017. Available online: (accessed on 15 February 2022).
  111. Fukuda, A.; Usui, M.; Okubo, T.; Tagaki, C.; Sukpanyatham, N.; Tamura, Y. Co-harboring of cephalosporin (bla)/colistin (mcr) resistance genes among Enterobacteriaceae from flies in Thailand. FEMS Microbiol. Lett. 2018, 365, 178. [Google Scholar] [CrossRef]
  112. dos Santos, L.D.R.; Furlan, J.P.R.; Ramos, M.S.; Gallo, I.F.L.; de Freitas, L.V.P.; Stehling, E.G. Co-occurrence of mcr-1, mcr-3, mcr-7 and clinically relevant antimicrobial resistance genes in environmental and fecal samples. Arch. Microbiol. 2020, 202, 1795–1800. [Google Scholar] [CrossRef]
  113. Tolosi, R.; Apostolakos, I.; Laconi, A.; Carraro, L.; Grilli, G.; Cagnardi, P.; Piccirillo, A. Rapid detection and quantification of plasmid-mediated colistin resistance genes (mcr-1 to mcr-5) by real-time PCR in bacterial and environmental samples. J. Appl. Microbiol. 2020, 129, 1523–1529. [Google Scholar] [CrossRef]
  114. Vu, T.M.H.; Kasuga, I. Prevalence of plasmid-mediated colistin resistance gene mcr-1 in domestic wastewater. IOP Conf. Ser. Earth Environ. Sci. 2020, 496, 012015. [Google Scholar] [CrossRef]
  115. Hadjadj, L.; Riziki, T.; Zhu, Y.; Li, J.; Diene, S.M.; Rolain, J.M. Study of mcr-1 Gene-Mediated Colistin Resistance in Enterobacteriaceae Isolated from humans and animals in different countries. Genes 2017, 8, 394. [Google Scholar] [CrossRef] [Green Version]
  116. Teo, J.W.P.; Chew, K.L.; Lin, R.T.P. Transmissible colistin resistance encoded by mcr-1 detected in clinical Enterobacteriaceae isolates in Singapore. Emerg. Microbes Infect. 2016, 5, e87. [Google Scholar] [CrossRef]
  117. Pomba, C.; Rantala, M.; Greko, C.; Baptiste, K.E.; Catry, B.; van Duijkeren, E.; Mateus, A.; Moreno, M.A.; Pyörälä, S.; Ružauskas, M.; et al. Public health risk of antimicrobial resistance transfer from companion animals. J. Antimicrob. Chemother. 2017, 72, 957–968. [Google Scholar] [CrossRef]
  118. Wipler, J.; Čermáková, Z.; Hanzálek, T.; Horáková, H.; Žemličková, H. [Sharing bacterial microbiota between owners and their pets (dogs, cats)]. Klin. Mikrobiol. Infekc. Lek. 2017, 23, 48–57. [Google Scholar]
  119. Faires, M.C.; Tater, K.C.; Weese, J.S. An investigation of methicillin-resistant Staphylococcus aureus colonization in people and pets in the same household with an infected person or infected pet. J. Am. Vet. Med. Assoc. 2009, 235, 540–543. [Google Scholar] [CrossRef] [Green Version]
  120. Effelsberg, N.; Kobusch, I.; Linnemann, S.; Hofmann, F.; Schollenbruch, H.; Mellmann, A.; Boelhauve, M.; Köck, R.; Cuny, C. Prevalence and zoonotic transmission of colistin-resistant and carbapenemase-producing Enterobacterales on German pig farms. One Health 2021, 13, 100354. [Google Scholar] [CrossRef]
  121. Trung, N.V.; Matamoros, S.; Carrique-Mas, J.J.; Nghia, N.H.; Nhung, N.T.; Chieu, T.T.B.; Mai, H.H.; van Rooijen, W.; Campbell, J.; Wagenaar, J.A.; et al. Zoonotic transmission of mcr-1 colistin resistance gene from small-scale poultry farms, Vietnam. Emerg. Infect. Dis. 2017, 23, 529. [Google Scholar] [CrossRef] [Green Version]
  122. Pomba, C.; Belas, A.; Menezes, J.; Marques, C. The public health risk of companion animal to human transmission of antimicrobial resistance during different types of animal infection. Adv. Anim. Health Med. Prod. 2020, 265–278. [Google Scholar] [CrossRef]
  123. Werner, G.; Coque, T.M.; Franz, C.M.A.P.; Grohmann, E.; Hegstad, K.; Jensen, L.; van Schaik, W.; Weaver, K. Antibiotic resistant enterococci—Tales of a drug resistance gene trafficker. Int. J. Med. Microbiol. 2013, 303, 360–379. [Google Scholar] [CrossRef] [PubMed]
  124. Flament-simon, S.C.; de Toro, M.; García, V.; Blanco, J.E.; Blanco, M.; Alonso, M.P.; Goicoa, A.; Díaz-gonzález, J.; Nicolas-chanoine, M.H.; Blanco, J. Molecular Characteristics of Extraintestinal Pathogenic E. coli (ExPEC), Uropathogenic E. coli (UPEC), and Multidrug Resistant E. coli Isolated from Healthy Dogs in Spain. Whole Genome Sequencing of Canine ST372 Isolates and Comparison with Human Isolates Causing Extraintestinal Infections. Microorganisms 2020, 8, 1712. [Google Scholar] [CrossRef]
  125. Pomba, C.; Endimiani, A.; Rossano, A.; Saial, D.; Couto, N.; Perreten, V. First report of blaOXA-23-mediated carbapenem resistance in sequence type 2 multidrug-resistant Acinetobacter baumannii associated with urinary tract infection in a cat. Antimicrob. Agents Chemother. 2014, 58, 1267–1268. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Scott, A.; Pottenger, S.; Timofte, D.; Moore, M.; Wright, L.; Kukavica-Ibrulj, I.; Jeukens, J.; Levesque, R.C.; Freschi, L.; Pinchbeck, G.L.; et al. Reservoirs of resistance: Polymyxin resistance in veterinary-associated companion animal isolates of Pseudomonas aeruginosa. Vet. Rec. 2019, 185, 206. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Gharaibeh, M.H.; Shatnawi, S.Q. An overview of colistin resistance, mobilized colistin resistance genes dissemination, global responses, and the alternatives to colistin: A review. Veter. World 2019, 12, 1735–1746. [Google Scholar] [CrossRef] [Green Version]
  128. Ngbede, E.O.; Poudel, A.; Kalalah, A.; Yang, Y.; Adekanmbi, F.; Adikwu, A.A.; Adamu, A.M.; Mamfe, L.M.; Daniel, S.T.; Useh, N.M.; et al. Identification of mobile colistin resistance genes (mcr-1.1, mcr-5 and mcr-8.1) in Enterobacteriaceae and Alcaligenes fecalis of human and animal origin, Nigeria. Int. J. Antimicrob. Agents 2020, 56, 106108. [Google Scholar] [CrossRef]
  129. Rapoport, M.; Faccone, D.; Pasteran, F.; Ceriana, P.; Albornoz, E.; Petroni, A.; Group, the M.; Corso, A. First Description of mcr-1-Mediated Colistin Resistance in Human Infections Caused by Escherichia coli in Latin America. Antimicrob. Agents Chemother. 2016, 60, 4412–4413. [Google Scholar] [CrossRef] [Green Version]
  130. Stoesser, N.; Mathers, A.J.; Moore, C.E.; Day, N.P.J.; Crook, D.W. Colistin resistance gene mcr-1 and pHNSHP45 plasmid in human isolates of Escherichia coli and Klebsiella pneumoniae. Lancet Infect. Dis. 2016, 16, 285–286. [Google Scholar] [CrossRef] [Green Version]
  131. Payne, M.; Croxen, M.A.; Lee, T.D.; Mayson, B.; Champagne, S.; Leung, V.; Bariso, S.; Hoang, L.; Lowe, C. mcr-1–Positive Colistin-Resistant Escherichia coli in Traveler Returning to Canada from China—Volume 22, Number 9—September 2016—Emerging Infectious Diseases journal—CDC. Emerg. Infect. Dis. 2016, 22, 1673–1675. [Google Scholar] [CrossRef] [Green Version]
  132. Hasman, H.; Hammerum, A.M.; Hansen, F.; Hendriksen, R.S.; Olesen, B.; Agersø, Y.; Zankari, E.; Leekitcharoenphon, P.; Stegger, M.; Kaas, R.S.; et al. Detection of mcr-1 encoding plasmid-mediated colistin-resistant Escherichia coli isolates from human bloodstream infection and imported chicken meat, denmark 2015. Eurosurveillance 2015, 20, 1–5. [Google Scholar] [CrossRef] [Green Version]
  133. Papa-Ezdra, R.; Grill Diaz, F.; Vieytes, M.; García-Fulgueiras, V.; Caiata, L.; Ávila, P.; Brasesco, M.; Christophersen, I.; Cordeiro, N.F.; Algorta, G.; et al. First three Escherichia coli isolates harboring mcr-1 in Uruguay. J. Glob. Antimicrob. Resist. 2020, 20, 187–190. [Google Scholar] [CrossRef]
  134. Pathak, A.; Singh, S.; Kumar, A.; Prasad, K.N. Emergence of chromosome borne colistin resistance gene, mcr-1 in clinical isolates of Pseudomonas aeruginosa. Int. J. Infect. Dis. 2020, 101, 22. [Google Scholar] [CrossRef]
  135. Mulvey, M.R.; Mataseje, L.F.; Robertson, J.; Nash, J.H.E.; Boerlin, P.; Toye, B.; Irwin, R.; Melano, R.G. Dissemination of the mcr-1 colistin resistance gene. Lancet Infect. Dis. 2016, 16, 289–290. [Google Scholar] [CrossRef] [Green Version]
  136. Holmes, A.H.; Moore, L.S.P.; Sundsfjord, A.; Steinbakk, M.; Regmi, S.; Karkey, A.; Guerin, P.J.; Piddock, L.J.V. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet 2016, 387, 176–187. [Google Scholar] [CrossRef]
  137. Dafale, N.A.; Srivastava, S.; Purohit, H.J. Zoonosis: An Emerging Link to Antibiotic Resistance Under “One Health Approach”. Indian J. Microbiol. 2020, 60, 139–152. [Google Scholar] [CrossRef] [PubMed]
  138. Norris, J.M.; Zhuo, A.; Govendir, M.; Rowbotham, S.J.; Labbate, M.; Degeling, C.; Gilbert, G.L.; Dominey-Howes, D.; Ward, M.P. Factors influencing the behaviour and perceptions of Australian veterinarians towards antibiotic use and antimicrobial resistance. PLoS ONE 2019, 14, e0223534. [Google Scholar] [CrossRef]
  139. Davies, M.; Stewart, P.R. Transferable drug resistance in man and animals: Genetic relationship between r-plasmids in enteric bacteria from man and domestic pets. Aust. Vet. J. 1978, 54, 507–512. [Google Scholar] [CrossRef] [PubMed]
  140. Al-Tawfiq, J.A.; Laxminarayan, R.; Mendelson, M. How should we respond to the emergence of plasmid-mediated colistin resistance in humans and animals? Int. J. Infect. Dis. 2017, 54, 77–84. [Google Scholar] [CrossRef] [Green Version]
  141. Hao, H.; Cheng, G.; Iqbal, Z.; Ai, X.; Hussain, H.I.; Huang, L.; Dai, M.; Wang, Y.; Liu, Z.; Yuan, Z. Benefits and risks of antimicrobial use in food-producing animals. Front. Microbiol. 2014, 5, 288. [Google Scholar] [CrossRef] [Green Version]
  142. Damborg, P.; Broens, E.M.; Chomel, B.B.; Guenther, S.; Pasmans, F.; Wagenaar, J.A.; Weese, J.S.; Wieler, L.H.; Windahl, U.; Vanrompay, D.; et al. Bacterial Zoonoses Transmitted by Household Pets: State-of-the-Art and Future Perspectives for Targeted Research and Policy Actions. J. Comp. Pathol. 2016, 155, S27–S40. [Google Scholar] [CrossRef] [Green Version]
  143. Larson, E. Community Factors in the Development of Antibiotic Resistance. Annu. Rev. Public Health 2007, 28, 435–447. [Google Scholar] [CrossRef] [Green Version]
  144. Wall, S. Prevention of antibiotic resistance—An epidemiological scoping review to identify research categories and knowledge gaps. Glob. Health Action 2020, 12, 1756191. [Google Scholar] [CrossRef]
  145. Lipsitch, M.; Siber, G.R. How can vaccines contribute to solving the antimicrobial resistance problem? MBio 2016, 7. [Google Scholar] [CrossRef] [Green Version]
  146. Bloomfield, S.F. Home hygiene: A risk approach. Int. J. Hyg. Environ. Health 2003, 206, 1–8. [Google Scholar] [CrossRef]
  147. Umber, J.K.; Bender, J.B. Pets and Antimicrobial Resistance. Vet. Clin. N. Am. Small Anim. Pract. 2009, 39, 279–292. [Google Scholar] [CrossRef]
  148. Hembach, N.; Schmid, F.; Alexander, J.; Hiller, C.; Rogall, E.T.; Schwartz, T. Occurrence of the mcr-1 colistin resistance gene and other clinically relevant antibiotic resistance genes in microbial populations at different municipal wastewater treatment plants in Germany. Front. Microbiol. 2017, 8, 1282. [Google Scholar] [CrossRef]
  149. Hille, K.; Möbius, N.; Akmatov, M.K.; Verspohl, J.; Rabold, D.; Hartmann, M.; Günther, K.; Obi, N.; Kreienbrock, L. Zoonoses research in the German National Cohort: Feasibility of parallel sampling of pets and owners. Bundesgesundheitsblatt. Gesundheitsforsch. Gesundheitsschutz 2014, 57, 1277–1282. [Google Scholar] [CrossRef]
  150. Laxminarayan, R.; Matsoso, P.; Pant, S.; Brower, C.; Røttingen, J.A.; Klugman, K.; Davies, S. Access to effective antimicrobials: A worldwide challenge. Lancet 2016, 387, 168–175. [Google Scholar] [CrossRef]
Figure 1. Identification of included studies in this review using PRISMA guidelines (meta-analysis).
Figure 1. Identification of included studies in this review using PRISMA guidelines (meta-analysis).
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Figure 2. Signaling regulation involved in the colistin resistance mechanism. The gene mgrB exerts negative feedback on the two-component system (TCS) phoP/phoQ. A mutation of the mgrB gene (indicated by red-colored star symbols) induces a constitutive induction of the phoP/phoQ system. Activation of phoP/phoQ activates pmrD and the arnBCADTEF operon; pmrD in turn activates pmrA. The pmrA/pmrB TCS can also be activated by a mutation in the pmrA/pmrB genes; this activation activates both arnBCADTED and pmrC, which collectively modify lipopolysaccharides (LPSs) via the addition of 4-amino-deoxy-l-arabinose (L-Ara4N) or phosphoethanolamine (PetN). PetN can also be added to LPSs by phosphoethanolamine transferase expressed by the mcr genes. Amino acid substitutions in CrrB/CrrA induce crrC expression by inducing elevated expression of pmrC via the activation of pmrA. On the other hand, the efflux pumps (AcrAB/TolC, SoxS/R, and KpnEF) allow rejecting colistin outside the bacteria.
Figure 2. Signaling regulation involved in the colistin resistance mechanism. The gene mgrB exerts negative feedback on the two-component system (TCS) phoP/phoQ. A mutation of the mgrB gene (indicated by red-colored star symbols) induces a constitutive induction of the phoP/phoQ system. Activation of phoP/phoQ activates pmrD and the arnBCADTEF operon; pmrD in turn activates pmrA. The pmrA/pmrB TCS can also be activated by a mutation in the pmrA/pmrB genes; this activation activates both arnBCADTED and pmrC, which collectively modify lipopolysaccharides (LPSs) via the addition of 4-amino-deoxy-l-arabinose (L-Ara4N) or phosphoethanolamine (PetN). PetN can also be added to LPSs by phosphoethanolamine transferase expressed by the mcr genes. Amino acid substitutions in CrrB/CrrA induce crrC expression by inducing elevated expression of pmrC via the activation of pmrA. On the other hand, the efflux pumps (AcrAB/TolC, SoxS/R, and KpnEF) allow rejecting colistin outside the bacteria.
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Figure 3. Global distribution of bacteria harboring mcr genes isolated from dogs, cats, and zoonotic transmission around the world.
Figure 3. Global distribution of bacteria harboring mcr genes isolated from dogs, cats, and zoonotic transmission around the world.
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Figure 4. Transfer of colistin resistance from pets to their owners. (A): Animals carry in their guts various bacteria in which colistin resistant bacteria have a high prevalence. Those bacteria are found in stools of pets. (B): The close contact between pets and their owners exposes human to the zoonotic transmission of colistin resistance via MGEs. (C): Zoonotic transmission of MDR bacteria is a public health problem. Small red lines represent the transfer of colistin-resistant bacteria via mobile genetic elements. Red and green bacilli represent bacteria which are resistant and sensitive to colistin, respectively.
Figure 4. Transfer of colistin resistance from pets to their owners. (A): Animals carry in their guts various bacteria in which colistin resistant bacteria have a high prevalence. Those bacteria are found in stools of pets. (B): The close contact between pets and their owners exposes human to the zoonotic transmission of colistin resistance via MGEs. (C): Zoonotic transmission of MDR bacteria is a public health problem. Small red lines represent the transfer of colistin-resistant bacteria via mobile genetic elements. Red and green bacilli represent bacteria which are resistant and sensitive to colistin, respectively.
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Table 1. Characteristics and limitations of the citation metrics and underlying sources that Publish or Perish used for all reporting items obtained during the literature search. The keywords used for the research were as follows: polymyxin resistance, colistin resistance, pets, companion animal, dog, cat, mcr genes, and zoonotic transmission.
Table 1. Characteristics and limitations of the citation metrics and underlying sources that Publish or Perish used for all reporting items obtained during the literature search. The keywords used for the research were as follows: polymyxin resistance, colistin resistance, pets, companion animal, dog, cat, mcr genes, and zoonotic transmission.
SourcePapersH IndexG IndexAWCRE IndexH CoverageG CoverageYear FirstYear Last
Web of Science8593967231946.9736.7353.3419052022
h_index: quantification of an individual’s scientific research output; g-index: the (unique) largest number of the top g articles received (together) with at least g2 citations; AWCR: the number of citations of an entire body of work, adjusted for the age of the paper; e-index: the square root of the surplus citations in the h-set; h_coverage and g_coverage: coverage data for citations.
Table 2. The mcr-positive isolates detected in dogs.
Table 2. The mcr-positive isolates detected in dogs.
mcr GenesBacterial SpeciesSequence TypeNumber
Isolation SourceYearCountryReference
mcr-1E. coliST3544Fecal sample2016China[84]
mcr-1E. coli/5Fecal sample2017China[85]
mcr-1E. coliST101Fecal sample2017China[86]
mcr-1E. coli/45Nasal and rectal swabs2017China[87]
K. pneumoniae/2
mcr-1E. coliST934Urine, nasal secretion,
fecal sample, diarrhea
New ST1
mcr-1E. coliST7701Urinary tract infection2019Argentina[88]
mcr-1E. coliST63161Uterus2019China[89]
mcr-1E. coliST1621Clinical sample2019China[90]
mcr-1E. coli/1Fecal sample2019Ecuador[91]
mcr-1K. pneumoniaeST3072Urine, pyometra2019Taiwan[92]
E. cloacaeST10052Urine
mcr-1E. coli/1Urine2020Brazil[93]
Klebsiella sp. /1Abdominal seroma
Enterobacter. sp. /1Nasal secretion
mcr-1/mcr-3.7E. coliST1321Fecal sample2020China[94]
mcr-1E. coliST16301Rectal swabs2020Ecuador[95]
mcr-1E. coliST1621Fecal sample2020Ecuador[96]
mcr-1E. coliST1621Diarrhea2020South Korea[97]
mcr-1K. pneumoniae/149Fecal sample2021China[100]
mcr-1E. coliST6483Rectal swabs2021China[98]
mcr-1K. pneumoniaeST6561Urine2021China[99]
mcr-2K. pneumoniae/11Fecal sample2021China[100]
mcr-3K. pneumoniae/15Fecal sample2021China[100]
mcr-3E. coliST101Clinical sample2021Taiwan[101]
mcr-4K. pneumoniae/6Fecal sample2021China[100]
mcr-5K. pneumoniae/18Fecal sample2021China[100]
mcr-8K. pneumoniaeST34101Nasal swabs2021China[99]
mcr-9K. pneumoniae/5Fecal sample2021China[100]
mcr-9E. hormaecheiST4932Clinical sample2021Egypt[102]
mcr-9E. coliST3721Clinical sample2021United Kingdom[103]
mcr-10K. pneumoniae/4Fecal sample2021China[100]
mcr-10E. roggenkampii/1Pus2021Japan[104]
mcr_1E. coli 10Fecal sample2020France[105]
Table 3. The mcr-positive isolates detected in cats.
Table 3. The mcr-positive isolates detected in cats.
mcr GenesSpeciesSTNumber of
mcr-1E. coliST931Fecal sample2016China[84]
New ST1
mcr-1E. coli/1Nasal and rectal swabs2017China[87]
mcr-1E. coliST931Diarrhea2018China[35]
mcr-1K. pneumoniaeST3071Urinary tract infection2021Brazil[106]
mcr-9E. hormaecheiST4931Clinical samples2021Egypt[102]
mcr-9E. asburiae/1Nasal swab2021Japan[107]
mcr-1E. coli 4Fecal sample2020France[105]
mcr-1Rahnella aquatili 1Fecal sample2020France[105]
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Hamame, A.; Davoust, B.; Cherak, Z.; Rolain, J.-M.; Diene, S.M. Mobile Colistin Resistance (mcr) Genes in Cats and Dogs and Their Zoonotic Transmission Risks. Pathogens 2022, 11, 698.

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Hamame A, Davoust B, Cherak Z, Rolain J-M, Diene SM. Mobile Colistin Resistance (mcr) Genes in Cats and Dogs and Their Zoonotic Transmission Risks. Pathogens. 2022; 11(6):698.

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Hamame, Afaf, Bernard Davoust, Zineb Cherak, Jean-Marc Rolain, and Seydina M. Diene. 2022. "Mobile Colistin Resistance (mcr) Genes in Cats and Dogs and Their Zoonotic Transmission Risks" Pathogens 11, no. 6: 698.

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