Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae* in Animal Production

*Carla Miranda, Gilberto Igrejas, Rosa Capita, Carlos Alonso-Calleja and Patrícia Poeta*

## **Abstract**

Colistin has been administrated for a long time in both human and veterinary medicine. Since the detection of the colistin resistance gene in animals, the increased concern about the impact on public health of colistin resistance has been evident, and several measures have been implemented. Some countries banned colistin use in foodproducing animals, however, other countries continue the animal administration of colistin without restrictions. Consequently, colistin resistance originated on animal production can be transmitted to humans through the food chain or the contaminated environment. Nowadays, this antibiotic was considered as the last resort for the treatment of multidrug-resistant Gram-negative infections or patients with fibrosis cystic. For these reasons, this review aimed to summarize the trend of antimicrobial use in livestock and aquaculture production, as well as, colistin-resistant bacteria in these animals, and the impact of its resistance on human health and the environment. In general, consumption and colistin use in livestock production have shown to decrease worldwide. In animal production, the detection of mcr genes, is well documented, demonstrating global dissemination of colistin resistance in *Enterobacteriaceae* isolates and the emergence of novel colistin-resistant genes. Moreover, identification of these genes has also been reported in animal food, humans and the environment.

**Keywords:** antibiotics, antimicrobial resistance, colistin resistance, *mcr*-1, *Enterobacteriaceae*, livestock, aquaculture

## **1. Introduction**

In veterinary medicine, colistin or polymyxin E has been administrated for a long time [1], mainly for therapeutic and prophylactic purposes in food animals. In pets, colistin is administered alone or in combination with other antibiotics for eye application and eardrops [2]. Colistin belongs to the antimicrobial class of polymyxins and currently was classified as the highest priority critically important antimicrobials for human medicine, according to WHO CIA list [3], and included in the category 2 (restrict), according to the EU antimicrobial advice ad hoc expert group (AMEG) classification. Polymyxins, as well as, fluoroquinolones and 3rd- or 4th-generation cephalosporins are considered the classes of antimicrobial agents that required the most urgent measures to tackle risks of the antimicrobial resistance (AMR) [4]. Therefore, this agent is used in both people and food animals for the treatment and prevention of *Enterobacteriaceae* infections, which include *Klebsiella* spp., *Escherichia coli*, *Acinetobacter* spp. and *Pseudomonas aeruginosa*. Colistin is highly used as the last resource in critical care settings or tackling multidrug-resistant (MDR) microorganisms, such as *Enterobacteriaceae*, in humans. Taking into account the increase of MDR *Enterobacteriaceae* prevalence in human infections, the amount of colistin administration can be considerable worldwide [1, 3]. In addition, this antimicrobial showed lower toxicity and more efficiency compared to beta-lactams and fluoroquinolones used as alternatives [5].

The detection of bacteria resistance to colistin has worried the scientific community, due to the presence of mobile-colistin-resistance (*mcr*) genes that are on plasmids and can be transferred among bacteria conferring resistance to colistin via the food chain and/or the environment through the contaminated manure, soil, air or water [1, 3, 6]. Furthermore, the scarce of alternatives against MDR Gramnegative bacteria infections can constitute an emerging threat to animal and human health. In addition, data regarding the presence of colistin resistance in livestock animals and animal products are dispersed. These factors, such as the detection of colistin-resistant genes in humans, animals and food, and the increase of colistin use to combat multi-resistant bacteria in human infections, implied international and national strategies to determine the risk and limit the colistin use in veterinary medicine [5]. For these reasons, this review summarizes to trend of antimicrobial use in food-producing animals, as well as, colistin-resistant bacteria in these animals, and the impact of its resistance on public health.

## **2. Colistin worldwide use in animal production**

Antibiotics, including colistin, are required in pets but mainly in aquaculture and livestock to maintain animal welfare, reproductive performance or as growth-promoting, and food security, although all antimicrobial growth promoters (AGPs) for food animal production are prohibited in Sweden, Denmark and Europe since 1986, 2000 and 2006, respectively (**Table 1**). Recently, China has banned colistin use and all AGPs in animal production in 2017 and 2020, respectively [6]. Of the 146 member countries, 86 (59%) have not authorized any antimicrobial drugs for growth promotion in animals since 2016, according to the World Organization for Animal Health (OIE) annual report [21]. In 2022, the EU will implement new legislation (Regulation (EU) 2019/6), prohibiting all forms of routine and prophylactic farm antibiotic use and banning the importation of all animal food produced with AGPs. Although some countries, such as the United States, Canada, Australia and New Zealand, have banned the antibiotic use classified as medically important, continue to administer other antibiotics as growth promoters like bacitracin [19, 20].

In animal production, estimates more than 57 million kilograms of antibiotics are annually used worldwide [22]. Antibiotic consumption in food-producing animals was globally estimated to increase by 67% between 2010 and 2030 [22], and 11.5% between 2017 and 2030 [23]. In parallel, a recent study reported the gap of register and control by the antibiotics sales online, showing the ease availability of veterinary antibiotics for purchase without a prescription, the factor that can raise the risk of resistant microorganisms [24].

*Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae *in Animal Production DOI: http://dx.doi.org/10.5772/intechopen.102722*


#### **Table 1.**

*The sales of antimicrobial agents and colistin for use in livestock animals.*

In veterinary medicine, colistin is mainly used to treat gastrointestinal infections caused by *Escherichia coli* in ruminants (cattle, sheep and goats), pigs, rabbits and poultry, and endotoxemia caused by other Gram-negative bacteria (**Figure 1**). In pig production, is often used as medicated premixes after weaning for the treatment and prevention of colibacillosis, diarrhea and septicemia caused by *E. coli* mainly in piglets [25, 26]. Colistin can be administrated via oral through the feed or drinking water, parental and intra-mammary in the form of colistin sulfate, for metaphylactic, prophylactic, growth promotion and therapeutic purposes [2].

#### **2.1 European countries**

In European countries, the total sales for veterinary antimicrobial agents, 99% were used for food-producing animals in 2016 and 2018 (approximately 8 and 6.4 tones, respectively), according to the annuals European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) report [4, 7]. The sales of polymyxins, including colistin only, for animal production, represented 5% in 2016, decreasing its sales by 40% in 25 countries of which three countries like Norway, Finland and Iceland not reported polymyxin sales from 2011 to 2018 [4]. In general, the antibiotic use between 2011 and 2018 in European animals has been declined at 34%, in particular the antimicrobial classes used in the treatment of severe human infections, such as

**Figure 1.**

*The possible pathways of the colistin administration into a food-producing animal (orange arrows) and consequently, the spreading of the colistin-resistant bacteria to humans, other animals and the environment (red arrows).*

polymyxins, 3rd- and 4th-generation cephalosporins and fluoroquinolones dropped by 70%, 24% and 4%, respectively [7]. However, antibiotic consumption is high and increasing in some countries because of the growing demands by consumers for animal proteins and depending on animal production composition and epidemiological situations of the production systems in each country [4, 22]. In Europe, the countries with the lowest antibiotic use were Norway, Iceland and Sweden, while Cyprus, Italy and Spain showed the highest farm antibiotic use in 2019 [7, 20].

In the United Kingdom (UK), the sold veterinary antibiotics for administration in food-producing animals showed a relevant reduction (45%) in 2015 but an increase (5%) in 2018 in comparison to 2019 (**Table 1**). Since 2015, sales of antimicrobial classes classified as a highest priority on the WHO CIA list decrease 74%, in particular, colistin showing a reduction of 99.9%. In 2019, colistin was sold 1.2 kg only for UK animal production and 8.8 kg was exported as medicated feed [8]. In the Netherlands, antibiotic sales decreased by 70% for farm animals including pigs, veal calves, broilers and dairy cattle, between 2009 and 2019, resulting from efforts of the veterinarians, livestock sectors and the authorities. Additionally, the polymyxins are considered as third choice agents and the use of colistin increased by 13% in 2019, mainly in weaned piglets and poultry (excepting broilers and turkey), although cattle farms not have prescriptions since 2015, according to the annual NethMap/MARAN 2020 report [9]. In Sweden, all antimicrobial classes showed a reduction notably in sales (32%) since 2010, leveled between 2014 and 2018, and in 2019 decreased 8% comparatively to 2018. The sales of polymyxins have decreased by 73%, between 2010 and 2019. In addition, no colistin is used in poultry [10]. In France, the sales of veterinary medicinal products showed a reduction by 48% between 2011 and 2018, in which for all species was observed a reduction of the administered antimicrobials. Taking into

*Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae *in Animal Production DOI: http://dx.doi.org/10.5772/intechopen.102722*

account the aim of the EcoAntibio 2017–2021 plan to reduce by 50% the colistin use in food-producing animals, in which for pigs has been achieved with a decreasing of 63%, while for cattle and poultry production only decreasing 48% and 49%, respectively, in 2018 [11].

In Denmark, the DANMAP program has allowed monitoring the use of antimicrobial agents in both animals and humans since 1995. Since then, the consumption of antimicrobial for animals has been reduced, due to the limits to its use to veterinarians and the national measures implemented of veterinary preventive medicine. Moreover, the total antimicrobial use for animals decreased by 5% in Denmark, between 2015 and 2016, in particular for pig (75%) and cattle (12%) production, and the aquaculture industry. Although the antimicrobial use classified as critically important remained low in food production, the colistin use that represented 1% for pigs in 2016, showing an increase (40 kg) mainly for the gastroenteritis treatment in weaners, between 2015 and 2016. This increase of the colistin use for pigs has been demonstrated since 2009, reporting a high increase, from 407 kg to 864 kg, between 2009 and 2016 respectively [5]. According to the annual BelVet-SAC report, the antimicrobial use in animals mainly veal calves, poultry and pigs, showed a relevant decrease by 40% and 8% in 2019 relative to 2011 and 2018, respectively, in Belgium. The polymyxin use also decreased by 66% and 11% in 2019 when compared to 2013 and 2018, respectively [12].

#### **2.2 Other countries**

In the United States (US), the total sales of medically important antibiotics approved for food-producing animals reduced by 21% and 38% from 2009 and 2015 through 2018, respectively, however, there was an increase by 9% from 2017, according to the report on antimicrobials sold or distributed for use in food-producing animals [15]. In 2018, these sales were estimated that 42%, 39%, 11% and 4% were intended for administration in cattle, swine, turkeys and chickens, respectively. In addition, colistin products have never been sold for animal use in the US, only products containing polymyxin B also belonging to the antimicrobial class of polymyxins were approved for ophthalmic infections in animals [2, 15]. In Canada, of which antimicrobials were distributed in 2014, 73% were in the same antimicrobial classes used in humans, and in 2017, 77% of distributed antimicrobials were intended for food-producing animals and 20% for humans. Moreover, antimicrobials sales showed a decrease by 12% mainly in pig and broiler chicken farms between 2016 and 2017, due to the implementation of measures for medically important antimicrobials banning them to use for growth promotion, according to the Canadian Animal Health Institute and the Public Health Agency of Canada. However, antibiotic sales for animal production increased by 6% between 2017 and 2018. Moreover, there are no colistin products approved for animal use and the predominant antimicrobial classes sold were tetracyclines and betalactams [17, 27]. The government of Brazil after the emergence of colistin resistance in animals and humans banned colistin use as AGPs in 2016 [18].

Australia showed one of the lowest levels of antibiotic resistance, although the Australian Pesticides and Veterinary Medicines Authority (APVMA) reported that 98% of the overall antibiotics sold for animal use between 2005 and 2010 were administered in food-producing animals, showing an increase of 11% in 2010 compared with 2008. Of which 43% were used for therapeutic purposes in poultry (49%), pigs (36%) and cattle (15%) mainly by feed (76%) and water (18%); and 6% were used as growth promoters. In addition, colistin was only reported for human use in

Australia [19]. In New Zealand, the antibiotic sold for farm animals increased by 4% and 3% between 2014 and 2017, and between 2016 and 2017, respectively [20].

The overall antimicrobial sales for animals in Japan showed a trend to decrease from 2001 to 2014 and since 2015 there was an upward trend until 2017, according to the Japanese Veterinary Antimicrobial Resistance Monitoring System (JVARM) that was implemented in 1999 [13]. From 2005 to 2010, the sales of polymyxins (colistin) for farm animals were 0.3–1.6%, with therapeutic use in beef cattle, pigs and broiler chickens [14]. China, the country that is expected to be the largest antimicrobial consumer worldwide in livestock animals in 2030, showed a reduction of 46% in antibiotic consumption from 2013 to 2017 [23]. With the emergence of colistin-resistant bacteria in China, colistin use was banned as a feed additive in animal production in 2016. Additionally, from the annual production of 12,000 tons of colistin in China, their use was estimated at 8000 tons per year in this country. The remains were exported to South Korea, Vietnam and India [28]. Similar to China, India is also one of the top antibiotic consumers for farm animals. However, the manufacture, sale and distribution of colistin, as well as, its formulations applied for food-producing animals, aquafarming and animal feed supplements were banned by the Indian Ministry of Health and Family welfare, since July 2019 [16].

## **3. Dissemination of colistin-resistant** *Enterobacteriaceae* **in animal production**

In food-producing animals, the widely antibiotic use constitutes a key factor to the development of resistant microorganisms in humans, these animals work as potential reservoirs of antibiotic-resistant bacteria transferable to them through food supply [29, 30]. The second joint interagency antimicrobial consumption and resistance analysis (JIACRA) report in bacteria from food-producing animals and humans produced by the European centre for disease prevention and control (ECDC), European food safety authority (EFSA) and European medicines agency (EMA) showed that the average antimicrobial consumption (AMC) was lower in humans (124 mg/kg) than in animals (152 mg/kg), however, the median AMC was higher in humans (118 and 67 mg/kg, respectively), in 2014. In addition, the results demonstrated statisticallysignificant associations between antimicrobial consumption and resistance for 3rdand 4th-generation cephalosporins and *Escherichia coli* in humans, for tetracyclines and polymyxins and *Escherichia coli* in animals, and fluoroquinolones and *Escherichia coli* in food-producing animals and humans. For carbapenems and polymyxins in *Klebsiella pneumoniae* from humans, there was also a significant association between AMC and AMR [30].

Colistin, an old antibiotic, used for the treatment of *E. coli* infections, was reintroduced as last resort for the treatment of emergent multi-resistant Gramnegative infections [26, 31]. In 2015, the *mcr*-1 gene responsible for the plasmidmediated (transferrable) colistin resistance was detected in *E. coli* isolates from animals, foods and patients in China [32]. With the emergence of a colistin resistance mechanism including the *mcr*-1 gene, first detected in China and remaining spreading worldwide (**Figure 2**); the concerns around colistin use in animals and humans have increased [32, 33]. Since then, several other countries worldwide have been reported the presence of colistin-resistant genes in Gram-negative bacteria isolated from food animals or products animals, even before 2015.

*Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae *in Animal Production DOI: http://dx.doi.org/10.5772/intechopen.102722*

**Figure 2.**

*Geographical distribution of the spreading colistin-resistant genes detected in worldwide animal production. Orange, presence of colistin-resistant genes in pigs; green, presence of colistin-resistant genes in poultry; yellow, presence of colistin-resistant genes in cattle; Purple, presence of colistin-resistant genes in fish.*

### **3.1 Colistin-resistant** *E. coli*

The occurrence of colistin resistance in indicator *E. coli* from poultry (turkeys and broilers) of 27 analyzed countries in 2014 and pigs for 18 countries in 2015, were significantly positive for the consumption of polymyxins [30]. Migura-Garcia et al. [34] reported the circulation of *mrc*-1 in *E. coli* isolated from Spanish pig farms since 2005 (**Table 2**). In Great Britain, one *E. coli* carrying the *mrc*-1 gene was also identified from a pig farm [41]. However, the UK reported that in 2015, 2017 and 2019, there was no resistance to colistin in *E. coli* from pigs and chickens [8]. In Denmark, *mcr*-1 gene was identified in *E. coli* from imported poultry meat [37]. In France, the presence of the *mcr*-1 gene from *E. coli* strains isolated from diseased pigs was confirmed by sequencing between 2009 and 2013 [42]. In this country, Perrin-Guyomard et al. [43] also reported the *mrc*-1 presence in 0.5% pigs analyzed in 2013, and in 6% turkeys and 2% broilers analyzed in 2014; and Haenni et al. [44] reported that the *mcr*-1 gene was present in 21% of the extended-spectrum-lactamase (ESBL)-producing *E. coli* isolates obtained from bovine calves in 2014 and the *mcr*-3 gene in 3% of ESBL-producing *E. coli* from cattle between 2011 and 2016 [45]. In Germany, also three ESBL-producing *E. coli* that originated from swine were positive for the *mcr*-1 gene during 2010–2011 [46]. In concordance, Roschanski et al. [67] reported the presence of the *mcr*-1 in *E. coli* collected from fecal samples of pig-fattening farms during 2011–2012; whilst *mcr*-2 was not detected in Germany (**Table 2**). In Portugal, two pig farms also showed *mcr*-1 positive *E. coli* isolates, in which this gene was identified on IncHI2, IncP, and IncX4 plasmids. This study

#### *The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions*


#### **Table 2.**

*Summary of the worldwide distribution of the mcr-positive Escherichia coli, resistance to colistin, from livestock animals.*

*Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae *in Animal Production DOI: http://dx.doi.org/10.5772/intechopen.102722*

reported that these food animals had received feed colistin as metaphylaxis during the 6 weeks before sample collection, suggesting a selective pressure. In addition, the presence of extended-spectrum beta-lactamases (ESBL)-encoding genes, such as *bla*CTX-M-2, *bla*TEM-1 and chloramphenicol gene, *flo*R, were also identified into same plasmids [51]. Similar results were also obtained by Manageiro et al. [68] and Fournier et al. [52].

In South Korea, the first detection of *mcr*-1 positive *E. coli* isolated from food animals was documented since 2013. Between 2013 and 2015, the *mcr*-1 gene was identified in 12 *E. coli* isolates collected from healthy chicken fecal samples and chicken carcasses at slaughterhouses, and a diseased pig. Additionally, all colistinresistant *E. coli* strains showed multidrug resistance (≥3 antimicrobial classes) and this gene was not detected in cattle samples [53]. Lima Barbieri et al. [35] reported the identification of the *mcr*-1 gene in diseased poultry fecal *E. coli* from Egypt and China and no *mcr*-1 or -2 gene was detected in the healthy birds. In the United States, two *E. coli* isolates from swine fecal samples at slaughter were positive for *mcr*-1 gene, however, fecal content samples from cattle, chickens and turkeys were negative to this resistance in 2016 [56]. The presence of *mcr*-1 gene was detected in food animals, such as healthy cattle, pigs and broilers since 2008 in Japan [58] and in pigs and chickens during 2013–2014 in Vietnam [59]. In Tunisia, three chicken farms were positive to colistin-resistant *E. coli* carrying the *mcr*-1 and *bla*CTX-M-1 genes, in which these animals were imported from France [60]. The *mcr*-1 gene was detected in *E. coli* obtained from swine samples in Venezuela [64], from chickens in South Africa [66] and swine and chickens samples collected in Brazil [63] and Ecuador [62]. In Argentina, *mcr*-1-positive and ESBL-producing *E. coli* isolates were identified from healthy fattening pigs and diarrheic piglets [65]. In Pakistan, *mcr*-1 positive *E. coli* were identified in healthy broilers during 2016–2017 [61] and in retail freshwater fish [69].

During 2011–2012, 12% of *E. coli* diarrhea strains originated Belgian calves and piglets were positive for *mcr*-1 [38]. Also, in Belgium, a novel plasmid-mediated colistin-resistant gene, *mcr*-2, was documented in porcine and bovine colistin-resistant *E. coli* in 2016, showing a higher prevalence of *mcr*-2 in porcine colistin-resistant *E. coli* in comparison to *mcr*-1 [39, 70]. In Bangladesh, the *mcr*-1 and *mcr*-2 genes were predominant in chicken gut *Enterobacteriaceae*, including *E. coli*, during 2017–2018 [57]. In China, a novel *mcr* gene, *mcr*-3, was identified in *E. coli* collected from health pigs in 2015 [36]. This gene, *mcr*-3 was also identified in porcine *E. coli* in South Korea [54] and Thailand [55]. Between 2015 and 2016, the *mcr*-4 gene was detected in *E. coli* isolates collected from piglets with diarrhea in Spain and Belgium [40]. In Italy, 72% of the *E. coli* isolates from pigs with post-weaning diarrhea were positive for *mcr*-1 from 2015 to 2016 [49]. Another Italian study identified *E. coli* carrying the *mcr*-1, -3 and -4 genes in fattening turkeys, broilers, pigs and bovines during 2014–2015 [50]. In the Netherlands, the *mcr*-1 gene was identified in *E. coli* from fecal samples obtained in slaughter pigs and white veal calves in 2019, representing less than 1%. Additionally, the *mcr*-4 was detected in white veal calves at a low level (2%). In turkey meat, colistin-resistant *E. coli* was identified (13%). However, *E. coli* isolated from broilers and chicken meat no *mcr* genes were identified [9]. Veldman et al. [47] also report *mcr*-1-positive *E. coli* from broilers, veal calves and turkeys from 2010 to 2013, in the Netherlands. In Poland, 62% of *E. coli* isolated from fecal samples of several food-producing animals, mainly turkeys, following broilers, laying hens, pig and bovine were present for *mcr*-1 gene, although no *mcr*-2 to -5 were detected during 2011–2016 [48].

## **3.2 Colistin-resistant** *Salmonella* **spp**

*Salmonella* Typhimurium carrying the *mrc*-1 gene was identified from a pig in Great Britain [41]. More recently, two *Salmonella* strains (serovars *S.* Dublin and *S.* Bovismorbificans) isolated from pig farm were resistant to colistin in 2019, although neither isolate had known transferable colistin resistance genes detected (**Table 3**). In ad dition, *S.* Dublin showed a degree of intrinsic colistin resistance and *S.* Bovismorbificans sequencing demonstrated the presence of chromosomal mutations conferring colistin resistance [8]. Four *S. enterica* (serovar Typhimurium and Rissen) collected from swine farms were positive for *mcr*-1 in Spain [71]. In Taiwan, the colistin resistance gene *mcr*-1 was identified in two *Salmonella* serovars (Typhimurium and Anatum) isolated from food animals with diarrhea, pigs and chickens, during 2012–2015. However, no gene was identified in all colistin-resistant strains tested phenotypically [75]. *Salmonella* Typhimurium carrying the *mrc*-1 gene, and *flo*R and *oqx*AB genes was identified from a pig in China, during 2013–2014 [76] and the *mcr*-1 gene in *S. enterica* from diseased chickens during 2014–2015 [77]. In Japan, *S. enterica* serovar Typhimurium carrying the *mcr*-1 gene was also detected in swine [78]. In Bangladeshi chicken, the *mcr*-1 and *mcr*-2 were isolated from *Salmonella* spp. [57].

A study that screened the *mcr*-1 positive *Salmonella* spp. in European food-producing animals, reported three isolates from pigs and cattle located in France and Germany from 2004 to 2014 [73]. During 2012–2015, 56% of the colistin-resistant *Salnomella* isolates from swine and 15% from poultry showed the presence of *mcr*-1 gene in Italy, as well as, in food samples of pork [72]. Another Italian study only identified *Salmonella* spp. carrying the *mcr*-1 gene in fattening turkeys in 2014 [50]. In 2013, a novel colistinresistant gene, *mcr*-4, was detected in *S. enterica* serovar Typhimurium obtained from the pig fecal sample at Italian slaughter [40]. German sample collection of *Salmonella* Paratyphi B isolated in 2012 from poultry, carried a novel colistin-resistant gene, *mcr*-5 [74].

## **3.3 Colistin-resistant** *Klebsiella pneumoniae*

In Portugal, *Klebsiella pneumoniae* isolated from swine farms were positive for *mcr*-1 gene (**Table 3**), carrying on IncHI2 and IncP plasmids, collected in 2016 [51, 52]. In Bangladesh, *Klebsiella* spp. isolated from chicken was positive to *mcr*-1 and *mcr*-2 [57]. In China, *K. pneumoniae* isolates harboring the *mcr*-1 gene were collected from pigs, cattle and chickens in 2016 [79] and harboring the *mcr*-3 gene were detected in chicken samples during 2016–2017 [80]. Other study reported the coexistence in *K. pneumoniae* isolates of the carbapenemase-encoding gene *bla*CTX-M-55 and *mcr*-7 from chickens [81], and the carbapenemase-encoding gene *bla*NDM and *mcr*-8 from pigs and chicken in China [82].

Recently, studies showed that the mechanism responsible for colistin resistance in *K. pneumoniae* resulted in inactivation of the *mgr*B gene through the upregulation of the PhoPQ system and consequently the overexpression of the *pmr*HFIJKLM operon [83, 89]. In France, the *mgr*B gene was identified in *K. pneumoniae* isolates from bovine mastitis [83].

## **3.4 Other colistin-resistant** *Enterobacteriaceae* **and non-***Enterobacteriaceae* **bacteria**

In China, the *mcr*-1 gene was detected in *Citrobacter freundii* isolates collected from pigs in 2012 (**Table 3**) [84] and *Citrobacter braakii* isolates collected from chickens in

**Animal specie Country Year of isolation Isolate strain Colistinresistant gene Reference** Pigs Spain 2010–2011 *S*. Typhimurium and *S*. Rissen *mcr*-1 [71] Pigs Great Britain 2016 *S*. Typhimurium *mcr*-1 [41] Pigs UK 2019 *S.* Dublin and *S.* Bovismorbificans *mcr*-1 [8] Pigs and poultry Italy 2012–2015 *Salmonella* spp. *mcr*-1 [72] Pigs Italy 2013 *S.* Typhimurium *mcr*-4 [40] Turkeys Italy 2014 *Salmonella* spp. *mcr*-1 [50] Pigs and cattle France 2005–2010 *Salmonella* spp. *mcr*-1 [73] Pigs Germany 2010 *Salmonella* spp. *mcr*-1 [73] Poultry Germany 2012 *Salmonella* Paratyphi B *mcr*-5 [74] Pigs and chickens Taiwan 2012–2015 *S*. Typhimurium and *S.* Anatum *mcr*-1 [75] Pigs China 2013–2014 *S.* Typhimurium *mcr*-1 [76] Chickens China 2014–2015 *S*. enterica *mcr*-1 [77] Pigs Japan 2013 *S.* Typhimurium *mcr*-1 [78] Chicken Bangladesh 2017–2018 *Salmonella* spp. *mcr*-1, *mcr*-2 [57] Pigs, chickens and cattle China 2016 *K. pneunomiae mcr*-1 [79] Chickens China 2016–2017 *K. pneunomiae mcr*-3 [80] Chickens China 2010–2015 *K. pneunomiae mcr*-7 [81] Pigs and chickens China 2015–2017 *K. pneunomiae mcr*-1, *mcr*-8 [82] Cattle France 2015 *K. pneunomiae mgr*B [83] Pigs Portugal 2016 *K. pneunomiae mcr*-1 [51, 52] Chicken Bangladesh 2017–2018 *Klebsiella* spp. *mcr*-1, *mcr*-2 [57] Chickens China 2012 *Citrobacter freundii mcr*-1 [84] Pigs China 2015 *Citrobacter braakii mcr*-1 [85] Chicken Bangladesh 2017–2018 *Proteus* spp. *mcr*-1, *mcr*-2 [57] Chicken Bangladesh 2017–2018 *Shigella* spp. *mcr*-1 [57] Chicken Bangladesh 2017–2018 *Enterobacter* spp. *mcr*-1 [57] Turkey German 2012 *Aeromonas media mcr*-3 [86] Pigs China 2018 *Acinetobacter baumannii mcr*-4 [87] Pigs Great Britain 2014–2015 *Moraxella mcr*-6 [88]

*Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae *in Animal Production DOI: http://dx.doi.org/10.5772/intechopen.102722*

#### **Table 3.**

*Summary of the worldwide distribution of the colistin-resistant Enterobacteriaceae (Salmonella, Klebsiella and Citrobacter) and non-Enterobacteriaceae (Aeromonas, Acinetobacter and Moraxella) in livestock animals.*

*pluranimalium*

2015 [85]. In Bangladeshi chicken, *mcr*-1 gene was identified from *Proteus* spp., *Shigella* spp. and *Enterobacter* spp., and the *mcr*-2 gene was detected in *Proteus* spp. [57].

Furthermore, an *Aeromonas media* carrying the *mcr*-3 was detected in German turkey in 2012 [86]. The *mcr*-4 gene was identified in *Acinetobacter baumannii* isolated from fecal pig samples at a Chinese slaughter in 2018 [87]. From healthy pigs in Great Britain, a novel mobile colistin resistance gene, *mcr*-6, was identified in *Moraxella pluranimalium* (**Table 3**) [88].

## **4. Colistin resistance in aquaculture production**

In aquaculture production, information about the presence of colistin resistance is scarce. This ecosystem is a possible reservoir of antibiotic resistance and it can contribute to the transfer of colistin-resistant genes to humans through the food chain and to aquatic environments [90, 91], requiring strict sanitary control by the public health authorities [92].

Hassan et al. [90] reported the identification of *E. coli* strains positive for *mcr*-1 isolated from Rainbow trout guts in Lebanon (**Table 4**). Moreover, isolates were multidrug-resistant to *bla*TEM-1, *tet*A and *str*A genes. In Vietnam, a AmpC-producing *E. coli* isolated from a fish sample was positive to *mcr*-1 in 2014 [93] and two ESBLproducing *E. coli* harboring *mcr*-1 and *sul* genes were detected from wild fish and striped catfish during 2014–2015 [94]. In China, *mcr*-1 gene was detected in seven *E. coli* from retail grass carp collected from fish markets in 2016 [69], and in two *E. coli* isolated from farmed fish in 2017 [96]. In same country, ESBL-producing *E. coli* strains carrying the *mcr*-1, *bla*CTX-Ms and *fos*A3 genes were isolated from shrimp purchased in markets and supermarkets during 2015–2016 [95].

*Salmonella enterica* serovar Rissen strains obtained from mussel samples carried the *mcr*-1 gene, in Spain from 2012 to 2016, and their genotypic profile showed other antibiotic resistance, such as *bla*TEM-1B, *aac*(6′)-Iaa, *tet*(A), *cml*A1, *aad*A1, *aad*A2, *dfr*A1, *sul*1 and *sul*3 [92].

An *Aeromonas* carrying the *mcr*-3 gene was isolated from a Chinese market sample in 2017 [96]. In Germany, three *Aeromonas* isolates were positive for *mcr*-3 genes recovered from ornamental fish, such as koi carp (*Aeromonas jandaei* and *Aeromonas hydrophila*) and golden orfe (*Aeromonas allosacharophila*), between 2005 and 2008, suggesting that the *mcr*-3 genes have circulated in European food-producing aquaculture animals at least 10 years before the first *mcr*-1-positive isolates from China [86].

Recently, two new no mobile genetic genes encoding phosphoethanolamine transferase, *ept*Av3 and *ept*Av7 were detected in *Aeromonas jandaei* strain isolated from retail fish in China. These genes demonstrated a high amino acid identity (80 and 79.9%) relative to *mcr*-3.1 and *mcr*-7.1 mobile genes, respectively. The strain demonstrated high-level colistin resistance, suggesting that *Aeromonas* can emerge and constitute as reservoir for *mcr*-3 and -7 genes [97]. Although the colistin-resistance prevalence in fish products is low, the antibiotic use in aquacultural activities can be a key factor for the rapid generation and dissemination of colistin-resistant bacteria in terrestrial and aquatic ecosystems [98]. In addition, antibiotic use for therapeutic and metaphylaxis purposes should be regulated and better assessed in aquaculture since there is antimicrobial consumption trend to increasing 33% between 2017 and 2030, suggesting that intensity use of antibiotics in some fish species can surpass the level of consumption in humans and terrestrial animals [98, 99].

*Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae *in Animal Production DOI: http://dx.doi.org/10.5772/intechopen.102722*


#### **Table 4.**

*Summary of the worldwide distribution of the colistin-resistant Enterobacteriaceae and non-Enterobacteriaceae in aquaculture production.*

## **5. Global impact of colistin-resistant** *Enterobacteriaceae* **to public health**

Inappropriate antibiotic use and its administration in food animals is a public health concern, contributing to the emergence of resistant bacteria in animals that can be transmitted to humans by ingestion of contaminated food or proximity with animals and their environment or other contaminated vehicles [5, 27]. In addition, characterization of colistin-resistance genes allows understanding of the molecular basis and evolution of colistin resistance, facilitating new interventions, such as the development of diagnostic tests [18]. Therefore, restriction of colistin use is essential to prevent the transmission of resistant genes, such as *mcr*-1, to other bacteria in the same or different animals, to the food supply and human community [53]. Moreover, the colistin-resistant genes have been identified in a variety of plasmids, such as IncHI2, IncP, Incl2 and IncX4, which are associated with the dissemination of other antibiotic resistance, in particular for β-lactams [34, 51].

In past years, the colistin administration in animal production has been decreasing. However, there is evidence that colistin resistance can increase due to the use of other antibiotics, in particular bacitracin, in animal production. Bacitracin is used in human medicine and veterinary medicine as a growth promoter in some countries, although the US is not marketed for food animals as a growth promoter for instance [20]. The bacitracin use in livestock production cans facilitate the transmission of bacitracin-resistant bacteria to agricultural ecosystems and humans by the food chain. Xu et al. [100] highlighted the extensive and imprudent usage of bacitracin in food animals to mitigate the spread of colistin resistance, since they observed that *mcr-1* gene confers cross-resistance to bacitracin, serving as a risk factor for the plasmid-mediated transmissible colistin resistance. This finding can explain the study performed by Lentz et al. [101] that reported the *mcr*-1 positive *E. coli* isolates from chickens that had not been fed with colistin antibiotic but had been fed with bacitracin and other antibiotics.

In some countries, high administration of colistin has been reported in food animals [2]. Touati et al. [102] demonstrated that farms are an important reservoir of colistin resistance genes, as well as, other antibiotic resistance genes. These genes are transferred from manure and slurry animal directly to soil and water used for irrigation, allowing their dissemination in the environment, which posture an emergent threat to public health. In Estonia, ESBL-producing *E. coli* isolates obtained from swine slurry samples carried the *mcr*-1 gene on a plasmid of the IncX4 group [103]. In Algeria, *E. coli* isolates carrying the *mcr*-1 and *mcr*-3 genes were isolated from bovine manure, agricultural soil and irrigation water [102]. In addition, the colistin resistance gene has also been identified in bacteria from other different environment niches and commodities, like vegetables, wells, rivers and lakes and coastal water or beaches and vegetables [104–106]. Moreover, wild animals can contribute to the dissemination of colistin resistance since these animals feed on landfills of urban household waste. Migura-Garcia et al. [34] reported colistin-resistant *E. coli* isolated from white storks (Ciconia ciconia) in Spain. Fernandes et al. [105] highlighted a potential new environmental reservoir in the case of public urban beaches, where colistin-resistant *E. coli* isolates carrying the *mcr*-1 and *bla*CTX-M genes were isolated and there is a high tourist turnover, facilitating the rapid spread of antimicrobial resistance. Zhao et al. [107] reported the presence of *mcr*-1 *K. pneumoniae* in hospital sewage.

Although there is a high rate of widespread dissemination of colistin-resistant bacteria in livestock, the rate of colistin resistance in healthy animals and animal products is low [53]. However, several studies have been reported the detection of *mcr-1* in food that originated from animals, confirming the risk of consuming these products colonized with resistant bacteria and one via transmission of colistin-resistant genes to humans [6]. For instance, *mcr*-1 positive *E. coli* isolates from lean ground beef, chicken meat samples and raw milk cheese were collected from markets of Canada, Brazil and Egypt, respectively [108–110]. Shen et al. [96] reported the aquaculture role as a reservoir for colistin resistance, suggesting the transmission of *mcr* genes via the aquatic food chain.

In humans, the administration of colistin in the hospital sector, mainly in patients in intensive care units and with cystic fibrosis, is increasing [30]. Most colistinresistant bacteria also showed resistance to several antimicrobial agents available for treatment, leading to antibiotic treatment failure, life-threatening illness and enormous clinical costs 5]\*\*\*. According to the ECDC report, countries with a high rate of carbapenem resistance also show a high rate of polymyxin-resistant isolates, suggesting loss of effect of antibiotic alternatives for the treatment of the infections caused by Gram-negative bacteria. In addition, colistin resistance was common in *K. pneumoniea*, *Acinetobacter* spp., *E. coli* and *Pseudomonas aeruginosa* [111, 112]. It is urgent to control the risk and rate of the spreading of colistin resistance worldwide, for this, it is necessary to work together in a One Health approach, according to Liu and Liu [112]. The data analysis of colistin resistance detecting in animals and humans is essential, as well as, motoring the epidemiological distribution of colistinresistant Gram-negative bacteria in animals [112].

## **6. Conclusions**

The immensely and novel diversity of colistin-resistant *Enterobacteriaceae* isolates is well documented in various ecosystems, where the occurrence of *mcr* genes with livestock, food, human and environmental origin have been detected. Here, this

*Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae *in Animal Production DOI: http://dx.doi.org/10.5772/intechopen.102722*

information was summarized to understand the global dissemination of colistin resistance, particular in food-producing animals, and to highlight the impact of colistin use in livestock and aquaculture production, and consequently public health. Although some countries had banned colistin use in food animals, in others colistin is administrated without restrictions. This review verified that the circulation of colistin-resistant genes started about 10 years before the first detection in 2015. Thereby, identification and continuous monitoring of colistin-resistance genes, as well as, prudent colistin use in both animals and humans are vital for tracking the colistin resistance threat and the associated socioeconomic costs.

## **Acknowledgements**

This work was supported by the Associate Laboratory for Green Chemistry— LAQV which is financed by national funds from FCT/MCTES (UIDB/50006/2020 and UIDP/50006/2020). This work was founded by the Ministerio de Ciencia, Innovación y Universidades (Spain, Project RTI2018-098267-R-C33) and the Junta de Castilla y León (Consejería de Educación, Spain, Project LE018P20). This work was supported by the project UIDB/CVT/00772/2020 funded by the Portuguese Foundation for Science and Technology (FCT).

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Carla Miranda1,2,3, †, Gilberto Igrejas3,4,5,†, Rosa Capita6,7, Carlos Alonso-Calleja6,7 and Patrícia Poeta1,3,8,9\*

1 Microbiology and Antibiotic Resistance Team (MicroART), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal

2 Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal

3 Associated Laboratory for Green Chemistry (LAQV-REQUIMTE), University NOVA of Lisboa, Lisboa, Caparica, Portugal

4 Department of Genetics and Biotechnology, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal

5 Functional Genomics and Proteomics Unit, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal

6 Department of Food Hygiene and Technology, Veterinary Faculty, University of León, León, Spain

7 Institute of Food Science and Technology, University of León, León, Spain

8 Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal

9 Veterinary and Animal Research Centre, Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal

\*Address all correspondence to: ppoeta@utad.pt

† These authors have contributed equally to this work.

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Worldwide Colistin Use and Spread of Resistant-*Enterobacteriaceae *in Animal Production DOI: http://dx.doi.org/10.5772/intechopen.102722*

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## **Chapter 7**
