Gram-negative bacteria are known to cause severe infections in both humans and animals. Antimicrobial resistance (AMR) in Gram-negative bacteria is a major challenge in the treatment of clinical infections globally due to the propensity of these organisms to rapidly develop resistance against antimicrobials in use. In addition, Gram-negative bacteria possess highly efficient mechanisms through which the AMR can be disseminated between pathogenic and commensal bacteria of the same or different species. These unique traits of Gram-negative bacteria have resulted in evolution of Gram-negative bacterial strains demonstrating resistance to multiple classes of antimicrobials. The evergrowing resistance issue has not only resulted in limitation of treatment options but also led to increased treatment costs and mortality rates in humans and animals. With few or no new antimicrobials in production to combat severe life-threatening infections, AMR has been described as the one of the most severe, long-term threats to human health. Aside from overuse and misuse of antimicrobials in humans, another factor that has exacerbated the emergence of AMR in Gram-negative bacteria is the veterinary use of antimicrobials that belong to the same classes considered to be critically important for treating serious life-threatening infections in humans. Despite the fact that development of AMR dates back to before the introduction of antimicrobials, the recent surge in the resistance towards all available critically important antimicrobials has emerged as a major public health issue. This review thus focuses on discussing the development, transmission and public health impact of AMR in Gram-negative bacteria in animals.

Introduction

Gram-negative bacteria are a part of the commensal microflora of mammals and typically colonize the gastrointestinal tract of humans and animals. However, some of the species cause opportunistic infections in both humans and animals [1]. Enterobacteriaceae are a particularly important family of Gram-negative bacteria containing disease-causing species such as Escherichia coli, Salmonella spp., Shigella spp., Proteus spp., Enterobacter spp., Citrobacter spp. and Yersinia pestis. In addition, other Gram-negative species such as Pseudomonas aeruginosa, Klebsiella pneumoniae and Campylobacter spp. are commonly involved in disease and some environmental organisms such as Acinetobacter spp. can also cause serious infections in susceptible hosts [1,2]. The ability of Gram-negative bacteria to rapidly develop and disseminate resistance between the same as well as different strains contributes to these organisms emerging as a potential threat to human and animal health. Table 1 outlines many of the important diseases caused by Enterobacteriaceae, the majority of which are clinically managed with antimicrobial treatment.

Table 1
Major Enterobacteriaceae species responsible for human and animal infections1
Gram-negative bacteriaHuman infectionsAnimal infections
E. coli Hospital-acquired pneumonia, gastroenteritis, septicaemia, neonatal meningitis and urinary tract infection Young animals: enteric colibacillosis (pigs), neonatal diarrhoea, septicaemia or toxaemia. Adult animals: urinary tract infection (dogs), mastitis (cattle) and endometritis (horse) 
Enterobacter spp. Septicaemia, urinary tract infection Occasional mastitis in cows and sows 
K. pneumoniae Pneumonia, lung abscess, meningitis, otitis externa, urinary tract infection Occasional mastitis (with severe inflammatory response) 
Salmonella serotypes Typhoid, diarrhoea, gastroenteritis Enteritis, septicaemia and abortion in cattle, salpingitis in poultry, diarrhoea in chicks. Enterocolitis, septicaemia in pigs, horses, dogs and sheep 
Shigella spp. Shigellosis (bacillary dysentery) Not reported 
Gram-negative bacteriaHuman infectionsAnimal infections
E. coli Hospital-acquired pneumonia, gastroenteritis, septicaemia, neonatal meningitis and urinary tract infection Young animals: enteric colibacillosis (pigs), neonatal diarrhoea, septicaemia or toxaemia. Adult animals: urinary tract infection (dogs), mastitis (cattle) and endometritis (horse) 
Enterobacter spp. Septicaemia, urinary tract infection Occasional mastitis in cows and sows 
K. pneumoniae Pneumonia, lung abscess, meningitis, otitis externa, urinary tract infection Occasional mastitis (with severe inflammatory response) 
Salmonella serotypes Typhoid, diarrhoea, gastroenteritis Enteritis, septicaemia and abortion in cattle, salpingitis in poultry, diarrhoea in chicks. Enterocolitis, septicaemia in pigs, horses, dogs and sheep 
Shigella spp. Shigellosis (bacillary dysentery) Not reported 
1

Based on the data from references [13].

Antimicrobial treatment

The modern era of clinical use of antimicrobials began with Paul Ehrlich and Salvarsan in 1907 [4]. The discovery of penicillin by Sir Alexander Fleming and sulfonamides during the 1930s further accelerated the clinical use of antimicrobials [5]. The advent of antimicrobials enabled effective treatment of potentially fatal infections and revolutionized clinical treatment procedures in humans. The use of antimicrobials also led to emergence of AMR within the span of a few years and to overcome this issue, newer antimicrobial classes were introduced [6,7]. With the success of combating bacterial infections in humans, antimicrobials were then deployed to treat and control bacterial infections in animals. Table 2 lists the different antimicrobials available to treat Gram-negative bacterial infections in humans and animals. With the extensive use of antimicrobials in humans and animals, bacteria developed resistance to evade the effect of commonly used antimicrobials.

Table 2
Importance ratings and summary of use of common antimicrobials available to treat Gram-negative bacterial infections. Importance ratings are based on the WHO and Australian Antimicrobial Resistance Standing Committee ranking1
Antimicrobial classWHOAMRSCDrug nameUse in humansUse in animals in Australia (AVA)
Penicillin CI Low Amoxycillin, ampicillin Respiratory tract infections, surgical and endocarditis prophylaxis Used to treat a range of infections in pigs, poultry, cattle, sheep, horses, cats and dogs 
Penicillin and β-lactamase inhibitor CI Medium Amoxycillin–clavulanate Surgical prophylaxis, Gram-negative, aerobic and anaerobic infections Used in pigs, cattle, sheep, horses, dogs and cats 
  High Ticarcillin–clavulanate, piperacillin–tazobactum Treatment of Pseudomonas aeruginosa infections, mixed aerobic and anaerobic infections, skin and soft tissue infection Not registered 
Second generation cephalosporins and cephamycins HI Medium Cefaclor, cefuroxime–Axetil, cefoxitin Alternative for patients allergic to penicillin. Used for surgical prophylaxis and respiratory tract infection. Cephamycins have anti-anaerobe activity Cefuroxime is used as second line mastitis treatment in cattle 
Third and fourth generation cephalosporins CI High Ceftriaxone, cefotaxime ceftazidime cefepime Severe pneumonia, meningitis, pseudomonal infections, neutropenic sepsis Ceftiofur is registered for treatment of respiratory disease in cattle and it is used off-label in other livestock; cefovecin is used in companion animals 
Carbapenems CI High Imipenem, meropenem, doripenem ertapenem Treatment of multi-resistant, serious Gram-negative and mixed infections Not registered 
Monobactams CI High Aztreonam Resistant Gram-negative infections and also used as an alternative for patients with severe β-lactam allergy Not registered 
Tetracyclines HI Low Doxycycline, minocycline Minor respiratory tract infections and supportive in the treatment of pneumonia Used in livestock and companion animals 
Glycylcyclines CI High Tigecycline Mostly used for treating multi-resistant Gram-positive infections and some Gram-negative infections Not registered 
Aminoglycosides CI Medium Gentamicin In combination, used in the treatment of pseudomonal infection, endocarditis (gentamicin) Gentamicin is used in horses, cats and dogs – not registered for livestock 
  High Amikacin Treatment of Gram-negative organisms resistant to gentamicin, tobramycin Not registered 
Quinolones CI High Norfloxacin, ciprofloxacin, moxifloxacin Used in treating complicated urinary tract infections. Ciprofloxacin is an oral treatment for resistant Gram-negative bacteria. Moxifloxacin is used for managing serious respiratory tract infections in patients allergic to penicillin Not registered for livestock. Marbofloxacin, enrofloxacin registered for use in dogs and cats; enrofloxacin is used off-label in horses 
Polymyxins CI High Polymyxin B, colistin Topical application of polymyxin B helps to treat Gram-negative infections. Colistin is reserved for the treatment of multi-resistant Gram-negative infections Polymyxin B is used topically in cattle, sheep, horse, dogs and cats 
     Colistin is not registered 
Phenicols HI Low Chloramphenicol Used in topical-eye preparation and occasionally for treatment of bacterial meningitis Not registered for use in food producing animals 
Macrolides2 CI Low Erythromycin Treatment of minor Gram-positive infections Used in treating pigs, cattle, sheep 
Sulfonamides and DHFR inhibitors HI Medium Trimethoprime/ sulfamethoxazole Minor infections, treatment and prophylaxis of UTI Used in treating pigs, poultry, cattle, horse, dogs and cats 
Antimicrobial classWHOAMRSCDrug nameUse in humansUse in animals in Australia (AVA)
Penicillin CI Low Amoxycillin, ampicillin Respiratory tract infections, surgical and endocarditis prophylaxis Used to treat a range of infections in pigs, poultry, cattle, sheep, horses, cats and dogs 
Penicillin and β-lactamase inhibitor CI Medium Amoxycillin–clavulanate Surgical prophylaxis, Gram-negative, aerobic and anaerobic infections Used in pigs, cattle, sheep, horses, dogs and cats 
  High Ticarcillin–clavulanate, piperacillin–tazobactum Treatment of Pseudomonas aeruginosa infections, mixed aerobic and anaerobic infections, skin and soft tissue infection Not registered 
Second generation cephalosporins and cephamycins HI Medium Cefaclor, cefuroxime–Axetil, cefoxitin Alternative for patients allergic to penicillin. Used for surgical prophylaxis and respiratory tract infection. Cephamycins have anti-anaerobe activity Cefuroxime is used as second line mastitis treatment in cattle 
Third and fourth generation cephalosporins CI High Ceftriaxone, cefotaxime ceftazidime cefepime Severe pneumonia, meningitis, pseudomonal infections, neutropenic sepsis Ceftiofur is registered for treatment of respiratory disease in cattle and it is used off-label in other livestock; cefovecin is used in companion animals 
Carbapenems CI High Imipenem, meropenem, doripenem ertapenem Treatment of multi-resistant, serious Gram-negative and mixed infections Not registered 
Monobactams CI High Aztreonam Resistant Gram-negative infections and also used as an alternative for patients with severe β-lactam allergy Not registered 
Tetracyclines HI Low Doxycycline, minocycline Minor respiratory tract infections and supportive in the treatment of pneumonia Used in livestock and companion animals 
Glycylcyclines CI High Tigecycline Mostly used for treating multi-resistant Gram-positive infections and some Gram-negative infections Not registered 
Aminoglycosides CI Medium Gentamicin In combination, used in the treatment of pseudomonal infection, endocarditis (gentamicin) Gentamicin is used in horses, cats and dogs – not registered for livestock 
  High Amikacin Treatment of Gram-negative organisms resistant to gentamicin, tobramycin Not registered 
Quinolones CI High Norfloxacin, ciprofloxacin, moxifloxacin Used in treating complicated urinary tract infections. Ciprofloxacin is an oral treatment for resistant Gram-negative bacteria. Moxifloxacin is used for managing serious respiratory tract infections in patients allergic to penicillin Not registered for livestock. Marbofloxacin, enrofloxacin registered for use in dogs and cats; enrofloxacin is used off-label in horses 
Polymyxins CI High Polymyxin B, colistin Topical application of polymyxin B helps to treat Gram-negative infections. Colistin is reserved for the treatment of multi-resistant Gram-negative infections Polymyxin B is used topically in cattle, sheep, horse, dogs and cats 
     Colistin is not registered 
Phenicols HI Low Chloramphenicol Used in topical-eye preparation and occasionally for treatment of bacterial meningitis Not registered for use in food producing animals 
Macrolides2 CI Low Erythromycin Treatment of minor Gram-positive infections Used in treating pigs, cattle, sheep 
Sulfonamides and DHFR inhibitors HI Medium Trimethoprime/ sulfamethoxazole Minor infections, treatment and prophylaxis of UTI Used in treating pigs, poultry, cattle, horse, dogs and cats 

AMRSC, Australian Antimicrobial Resistance Standing Committee; AVA, Australian Veterinary Association Limited; CI, critically important; DHFR, dihydrofolate reductase; HI, highly important.

1

Based on the data from references [810].

2

Macrolides are classified under critically important category as per WHO rating due to their effectiveness against Campylobacter infections particularly in children.

Mechanisms of AMR in Gram-negative bacteria

Gram-negative bacteria, particularly within the Enterobacteriaceae family, have developed several mechanisms to evade the effects of antimicrobials. Some strains possess multiple mechanisms resulting in multidrug resistance (Figure 1). The mechanisms that can lead to resistance include:

  • Enzymatic degradation or modification: This mechanism involves the inactivation of antimicrobials with specific enzymes secreted by the bacteria, such as β-lactamase enzymes that hydrolyse the β-lactam ring thus inactivating penicillins and cephalosporins [11]. Examples of enzymes that lead to enzymatic degradation of cephalosporins are AmpC β-lactamases, extended-spectrum-β-lactamases (ESBLs) and carbapenemases [12].

  • Target modification: This mechanism of resistance occurs through alteration of the target site of the antimicrobial, which in turn prevents the binding of the antimicrobial to the bacterial cell thus disabling the antimicrobial activity [12]. Fluoroquinolone resistance as a result of modification to the gene that encodes the enzymes DNA gyrase and DNA topoisomerase IV, the two main targets of the antimicrobial, is an example of target modification and structural gene mutation (point mutation) [1214].

  • Reduction in cell permeability and expression of efflux pumps: Altering cell permeability or increasing the efflux action is another mechanism of resistance observed in Gram-negative bacteria. The outer membrane structure of Gram-negative bacteria is unique due to the presence of outer membrane proteins or porins, which are selective and help in regulating or restricting the entry of harmful substances into the cell. The antimicrobials have porin specificity and are required to pass through the water-filled channels to gain entry into the target sites [15]. Reduction or loss of porin changes the cell wall permeability and limits or prevents the entry of antimicrobials into the cell [12]. Due to this mechanism the antimicrobial agent cannot reach desirable concentrations within the bacterial cell and antimicrobial activity is inhibited. The efflux mechanism prevents the antimicrobial agent from achieving bactericidal concentration within the bacterial cell by removing the antimicrobial from the cell [12]. An increase in efflux activity can be due to chromosomally encoded efflux pumps such as resistance-nodulation division (RND) efflux pumps within the bacterial cell or by acquisition of specific genes (often plasmid encoded), an example being tetracycline resistance [16,17]. RND efflux systems ArcAB-TolC of E. coli and MexAB-OprM of Pseudomonas aeruginosa have been studied widely and are known to be effective against wide range of antimicrobials including cephalosporins, fluoroquinolones, penicillins and chloramphenicol [17,18].

  • Modification of metabolic pathway: Alterations or changes in the metabolic pathways (by secreting modified enzymes) within the bacterial cell can also result in resistance to an antimicrobial agent. Genes encoding such enzymes are often found on plasmids. Trimethoprim resistance is an example of this mechanism where the target site of trimethoprim is altered and bypassed by synthesis of the plasmid mediated additional trimethoprim-resistant DHFR [19,20].

Illustration of major antimicrobial resistance (AMR) mechanisms utilized by Gram-negative bacteria – enzymatic degradation (examples – penicillin and cephalosporins), target alteration (example – fluoroquinolones), porin specificity and efflux pumps (examples – tetracycline, cephalosporins, fluoroquinolones and penicillins)

Figure 1
Illustration of major antimicrobial resistance (AMR) mechanisms utilized by Gram-negative bacteria – enzymatic degradation (examples – penicillin and cephalosporins), target alteration (example – fluoroquinolones), porin specificity and efflux pumps (examples – tetracycline, cephalosporins, fluoroquinolones and penicillins)
Figure 1
Illustration of major antimicrobial resistance (AMR) mechanisms utilized by Gram-negative bacteria – enzymatic degradation (examples – penicillin and cephalosporins), target alteration (example – fluoroquinolones), porin specificity and efflux pumps (examples – tetracycline, cephalosporins, fluoroquinolones and penicillins)

Despite being accelerated by antimicrobial use, AMR is also a natural phenomenon in bacteria and resistance to antimicrobials in Gram-negative bacteria can either be an inherent characteristic or an acquired trait [21]. It is well documented that many resistance mechanisms emerged in bacteria long before antimicrobials were first used, for example bacterial penicillinase was identified before penicillin was introduced to the market [22]. It is worth noting that in studies of DNA extracted from 30000 years old permafrost cores, resistance genes to β-lactams, tetracycline and vancomycin (a last-line antimicrobial for treating multidrug-resistant, Gram-positive bacterial infections) were found [23]. Multidrug-resistant bacteria were also discovered in caves that had been isolated for millions of years [24]. The acquisition of AMR can be either through gene mutation or via horizontal gene transfer [21].

Horizontal gene transfer and mobile genetic elements

Horizontal gene transfer is the mechanism by which foreign DNA is acquired or transferred among bacteria and is one of the major mechanisms, by which bacteria acquire and transfer AMR. Horizontal gene transfer is facilitated by mobile genetic elements such as plasmids, transposons and integrons. The mobile genetic elements play a vital role in dissemination of AMR since these genetic structures have the ability to transfer multiple genes responsible for resistance to different classes of antimicrobials in a single event [5,12,25].

Plasmids

Plasmids are extrachromosomal, autonomous mobile genetic elements and are separate from bacterial chromosomes. Conjugative plasmids may serve as a carrier for several bacterial genes including resistance-conferring genes from one bacterial cell to other [25].

Transposons

Transposons, also referred to as jumping genes, are genes that can move within, attach to or detach from plasmids or bacterial chromosomes. Transposons can carry resistance genes that can ride on plasmids for transfer between bacterial cells thus disseminating resistance. Since, transposons generally do not have specific affinity or preference for a binding site on the plasmid or chromosome, this is a highly efficient and effective mechanism of resistance gene transfer [14].

Integrons

Integrons are another mobile genetic element that can capture AMR genes. Integrons are structures that integrate gene cassettes that are transcribed in the integron from a promoter [26]. An integron comprises an intI gene, attI recombination site and a Pc promoter (Figure 2). The gene cassettes responsible for conferring AMR are integrated at specific sites on the integron. The gene cassettes comprise a gene, a ribosome-binding site and an attC recombination site and retain a conserved region at their ends. Antimicrobial-resistant species can possess hundreds of such gene cassettes resulting in multi-resistance [27], for example the class 1 RI with gene cassette array dfrA 15-aadA1 in Shigella dysenteriae demonstrates resistance against streptomycin, spectinomycin and trimethoprim [28].

Diagrammatic representation of recently identified IncHl2 plasmid (pIMP4-SEM1) from Salmonella enterica Typhimurium in cat with multidrug-resistant region (red), class 1 integron (yellow) and insertion sequences (IS) (blue) adopted from [30]

Figure 2
Diagrammatic representation of recently identified IncHl2 plasmid (pIMP4-SEM1) from Salmonella enterica Typhimurium in cat with multidrug-resistant region (red), class 1 integron (yellow) and insertion sequences (IS) (blue) adopted from [30]
Figure 2
Diagrammatic representation of recently identified IncHl2 plasmid (pIMP4-SEM1) from Salmonella enterica Typhimurium in cat with multidrug-resistant region (red), class 1 integron (yellow) and insertion sequences (IS) (blue) adopted from [30]

Multidrug-resistance regions

Multi-resistant regions are collections of resistance genes that were originally located on the chromosomes of different and unrelated bacterial species merging in a single position on a chromosome or plasmid of the recipient bacterial cell [27]. The mobile genetic elements that transfer these resistance genes between DNA molecules such as IS, transposons, integrons and gene cassettes are known as integrative and mobile elements, an example being the SGI1 region in Salmonella spp. and AbaR in Acinetobacter baumannii [27]. The multidrug-resistance regions (MRRs) carry genes that confer resistance to multiple classes of antimicrobials including critically important antimicrobials and are a key factor in the rapid dissemination of AMR in both humans and animals [29] (Figure 2). A recently discovered plasmid isolated from S. enterica Typhimurium, pIMP4-SEM1, found in a cat in Australia is an example of a plasmid that includes a class I integron and several MRRs and heavy metal resistances. This IncHI2 plasmid (pIMP4-SEM1) carried resistance to nine antimicrobial classes including carbapenems (critically important antimicrobials). The carbapenem-resistance gene (blaIMP-4) was on a blaIMP-4-qacG-aacA4-catB3 cassette array (Figure 2) associated with class 1 integron [30].

Development and transmission of AMR in animals

In animals, antimicrobials are used for the treatment of specific bacterial infections, prophylaxis and growth promotion by minimizing bacterial infections or selecting certain species of gut bacteria, which increases weight gain. Some countries have banned the use of antimicrobial growth promotants, some allow a restricted range and others have limited or no controls over such use [32]. Many of the antimicrobials used for prophylaxis and therapeutic purposes in animals belong to the same classes used in human medicine. As a result, the AMR seen among bacterial isolates from animals becomes a public health concern as these antimicrobial-resistant bacteria can transfer easily from animal to human via direct contact or via the food chain [33].

Figure 3 shows the different routes of AMR transmission between human and animals. The major transmission routes of AMR between humans and animals are by direct contact or through the food chain. Antimicrobial resistant zoonotic bacteria such as Shiga-toxin producing E. coli (STEC), Salmonella spp. and Campylobacter spp. may transfer between hosts and cause infections [33]. In addition, non-pathogenic commensal E. coli that are resistant to antimicrobials may transfer and disperse AMR genes to human pathogens by horizontal gene transfer. Mobile genetic elements such as plasmids, transposons and integrons that carry AMR genes can move from humans to animals and vice versa via the environment [34].

Transmission of AMR between human and animals – (A) Direct transmission of antimicrobial-resistant bacteria between human and animals. (B) Transmission of resistant determinant genes encoded either on chromosomes or plasmids. (C) Mobile genetic elements (plasmids) carrying and disseminating resistance genes. (D) Transmission of resistance via transposons, IS, integrons assembled on gene cassettes and multi-resistant regions carrying array of gene cassettes resulting in multiple AMR in bacteria within same host or between animal and humans. Illustration adopted from [31]

Figure 3
Transmission of AMR between human and animals – (A) Direct transmission of antimicrobial-resistant bacteria between human and animals. (B) Transmission of resistant determinant genes encoded either on chromosomes or plasmids. (C) Mobile genetic elements (plasmids) carrying and disseminating resistance genes. (D) Transmission of resistance via transposons, IS, integrons assembled on gene cassettes and multi-resistant regions carrying array of gene cassettes resulting in multiple AMR in bacteria within same host or between animal and humans. Illustration adopted from [31]
Figure 3
Transmission of AMR between human and animals – (A) Direct transmission of antimicrobial-resistant bacteria between human and animals. (B) Transmission of resistant determinant genes encoded either on chromosomes or plasmids. (C) Mobile genetic elements (plasmids) carrying and disseminating resistance genes. (D) Transmission of resistance via transposons, IS, integrons assembled on gene cassettes and multi-resistant regions carrying array of gene cassettes resulting in multiple AMR in bacteria within same host or between animal and humans. Illustration adopted from [31]

The movement of food animals and animal products across continents further extends the spread of AMR thus making it an issue not just for an individual country but a worldwide concern [35]. Aside from routes such as international movement of people and food products, migratory birds are also considered to play a role in the transmission of antimicrobial-esistant bacteria among continents [36]. Another possible transmission route is the movement of AMR from humans to animals. There are reported cases where humans that work with animals are likely to have transferred resistant bacteria to animals, particularly wildlife but also possibly pets and food-producing animals. This has been demonstrated in a study where the isolation of multiresistance was found to be the highest in pets followed by farm animals and lowest in wild animals [37,38]. In animal production systems, antimicrobial-resistant bacteria can be amplified due to antimicrobial selection pressure from the various uses of antimicrobials. Once amplified, these antimicrobial-resistant bacteria can pose a potential public health risk to humans as indicated. In addition to food animals, use of antimicrobials in companion animals (dog, cat, horse) has also contributed to the movement of resistant bacteria to humans [39].

Resistance to critically important antimicrobials

One of the major concerns in the transmission of AMR between animals and humans is the transmission of resistance to critically important antimicrobials. Due to the emergence of multidrug-resistant bacteria that cannot be treated with first-line antimicrobials, the last-line drugs (critical) should be preserved to treat infections caused by resistant bacteria. As a result, ranking parameters for antimicrobials have been developed and are regularly revised by the World Health Organization (WHO) and other bodies [10]. The antimicrobial rankings have been developed from a human health perspective and require adherence to strict guidelines when used for infection management in food animals. According to the WHO guidelines [10], antimicrobials are rated as: (i) critically important when they are the only treatment option available for treating severe life-threatening infections in humans and do not have any alternatives or substitutes, (ii) highly important antimicrobials form the second line therapy and have limited but alternative options in case of resistant infections and (iii) important antimicrobials are the first-line therapy but due to their overuse have marked resistance issues [33].

The major critically important antimicrobials used to treat multidrug-resistant Gram-negative bacteria include fluoroquinolones, extended-spectrum cephalosporins, carbapenems and colistin [10]. The macrolide class of antimicrobials has also recently been classified as critically important by the WHO [10]. Although macrolides are predominantly used for treating infections caused by Gram-positive bacteria, they have also been found to be highly effective against certain Gram-negative bacteria such as Campylobacter spp. Macrolides are the preferred choice of treatment over fluoroquinolones for serious Campylobacter infections [10], especially in children. However, since it is generally accepted that macrolides have very limited use in treating infections caused by Gram-negative bacteria, further examination of resistance mechanisms against macrolides is not discussed in this review. Table 3 lists the different critically important antimicrobial classes and the corresponding bacterial genes conferring resistance to each class.

Table 3
Major critically important antimicrobials: targets, transmissible AMR genes and mechanisms
Critically important antimicrobialsTargetTransmissible AMR genes1Resistance mechanism
Third generation cephalosporins Peptidoglycan synthesis blaTEM, blaSHV, blaCTX-M, blaCMY Enzymatic degradation, altered target, efflux 
Carbapenem Peptidoglycan synthesis blaVEB, blaKPC, blaGES, blaOXA, blaIMP, blaVIM, blaNDM Enzymatic degradation, altered target, efflux 
Fluoroquinolones DNA replication qnrA, qnrB, qnrC, qnrD, qnrVC, aac(6′)-Ib-cr, qepA Target modification, efflux, inactivation 
Colistin Outer and cytoplasmic membrane mcr Target modification, efflux 
Critically important antimicrobialsTargetTransmissible AMR genes1Resistance mechanism
Third generation cephalosporins Peptidoglycan synthesis blaTEM, blaSHV, blaCTX-M, blaCMY Enzymatic degradation, altered target, efflux 
Carbapenem Peptidoglycan synthesis blaVEB, blaKPC, blaGES, blaOXA, blaIMP, blaVIM, blaNDM Enzymatic degradation, altered target, efflux 
Fluoroquinolones DNA replication qnrA, qnrB, qnrC, qnrD, qnrVC, aac(6′)-Ib-cr, qepA Target modification, efflux, inactivation 
Colistin Outer and cytoplasmic membrane mcr Target modification, efflux 
1

All resistance genes mentioned are plasmid-borne genes.

Fluoroquinolone resistance

Fluoroquinolones are used for the treatment of various infections including urinary tract, respiratory tract and gastrointestinal infections, but excessive use of this class of antimicrobials due to their safety and convenience of dosing has resulted in increased resistance issues. Enrofloxacin for animal treatment was first introduced in Europe and the United States of America in the late 1980s and resistance was first reported in veterinary isolates of Salmonella spp. in the mid 1990s [40]. A study of Campylobacter spp. isolated from humans and poultry showed increase in resistance to enrofloxacin from 0 to 11% and 0 to 14% respectively, between 1982 and 1989 [41]. Subsequent studies have reported a correlation between use of fluoroquinolones in food-producing animals and emergence of resistance in human infections [42,43]. Plasmid-borne fluoroquinolone resistance has now been found in animal isolates [44,45]. High-level fluoroquinolone resistance is conferred due to mutation in chromosomal quinolone resistance determining regions (QRDRs) DNA gyrase (gyrA, gyrB) and DNA topoisomerase IV genes (parC, parE) [46]. Studies have also demonstrated plasmid-mediated quinolone resistance by qnr genes [46]. Seven fluoroquinolone resistant genes have been identified and reported so far – qnrA, qnrB, qnrS, qnrC, qnrD and qnrVC. In addition to qnr genes, the presence of aminoglycoside resistance gene aac(6′)-Ib and also an efflux pump qepA also can result in quinolone resistance [47]. Importantly, it has been observed that the plasmids carrying qnr genes are often carriers of genes for ESBLs thus conferring multidrug resistance to two critically important antimicrobials to the members of the Enterobacteriaceae family [4850]. Human self-medication in developing countries and overuse of fluoroquinolones in food animals has led to further emergence and dissemination of resistance. One study evaluating the impact of fluoroquinolone use in swine, poultry, human and various environmental sources within farms in China reported very high prevalence of resistance [51].

Extended spectrum cephalosporin resistance

Third generation cephalosporins are classified as critically important antimicrobials and are often used to treat several life threatening infections in humans [10,52]. Apart from overuse of third generation cephalosporins in human medicine, another contributing factor that has led to further emergence and dissemination of resistance is the veterinary use of ceftiofur, an antimicrobial belonging to the same class. Ceftiofur was first introduced in the United States of America in 1998 following its earlier release in Europe. It has been demonstrated that ESBL producing human strains of E. coli and K. pneumoniae were resistant to ceftiofur and that there is a high correlation between resistance to ceftriaxone (a human third generation cephalosporin) and ceftiofur in these isolates [53]. Ceftiofur resistance was first detected in Salmonella isolates in Canada in the late 1990s [54] and in the United States of America at around the same time [55]. It was also recognized that ceftiofur resistant animal isolates produced AmpC (CMY-2) and ESBL enzymes [56,57]. The first gene reported to be responsible for ceftiofur resistance was blaCMY-2 [58]. Studies have reported that use of ceftiofur in food-producing animals not only exerts selection pressure for development of ceftiofur resistance but can also select for resistance to ceftriaxone, a critically important human antimicrobial in enteric E. coli and Salmonella spp. [59]. This is due to the fact that the genes that encode resistance to ceftiofur can also provide resistance to other third generation cephalosporins such as ceftriaxone (blaCMY-2, blaCTX-M). On the basis of Ambler classification, β-lactamases can be classified into four classes; class A serine β-lactamases (ESBLs, penicillinases), class B metallo-β-lactamases, class C AmpC-type-β-lactamases and class D OXA β-lactamases [60,61]. The most common and widespread β-lactamases are the ESBL cephalosporinases (CTX-M type enzymes), which confer resistance to nearly all penicillins and cephalosporins [62]. E. coli (ST131) is a highly virulent extraintestinal pathogen (ExPEC) belonging to a pathogenic subclone H30-Rx and has emerged as a major threat globally within a very short time span. The fluoroquinolone resistance and ESBL production resulting in multidrug resistance in E. coli (ST131) is attributed to a CTX-M-15 encoding mobile genetic element [63]. Other β-lactamases frequently encountered in Enterobacteriaceae can be chromosomal (AmpC) or plasmid mediated (pAmpCs) enzymes. CMY is the most frequently detected AmpC type β-lactamase among Gram-negative bacteria worldwide [6466].

Carbapenem resistance

Carbapenems are the last-line therapy for treatment of multidrug-resistant infections in humans. Failure of treatment with penicillin and cephalosporin has led to the extensive use of carbapenem in humans, which in turn has resulted in emergence of carbapenem resistance [67]. Although K. pneumoniae was the first pathogen detected to harbour the plasmid-encoded carbapenemases, there has been a steady surge of carbapenem resistance in E. coli and other members of the Enterobacteriaceae [68,69]. Apart from KPC, VIM, IMP and OXA-48 the most widely disseminated extensively drug resistant Gram-negative bacteria are the NDM-1 producing strains that are resistant to a number of other classes of antimicrobials. Resistance to carbapenems is more frequent in humans but previously several studies have reported detection of carbapenemase producing E. coli, Salmonella spp. and Acinetobacter spp. in food animals (poultry, cattle and pigs) and companion animals (dogs, cats and horses) [67,70]. It should be noted that carbapenems are not registered for use in animals although off-label use occurs in cats and dogs. The source of resistance in livestock isolates requires investigation. The diversity of carbapenemase enzymes allows them to confer resistance against all cephalosporins including carbapenems. The various categories of carbapenemases are class D enzymes (OXA family) found in Enterobacter and P. aeruginosa, metallo-β-lactamases (IMP, VIM family) observed predominantly in Klebsiella and Enterobacter spp. and non-metallo-carbapenemases (SME, IMI/NMC) in Serratia and Enterobacter spp. [64]. The KPC enzymes in K. pneumoniae and E. cloacae are of major concern as they confer broad-spectrum resistance against all β-lactams including cephalosporins, monobactams and carbapenems [11]. The rise in carbapenem resistance in Enterobacteriaceae is of major concern as the members of this family are most frequently encountered in healthcare and community infections thus increasing the chances of further dissemination of carbapenem resistance in the community [71]. The plasmid-mediated carbapenemases, MBLs (IMP, VIM), are more significant in the healthcare sector worldwide when compared with chromosomal carbapenemases (IMI, NMC-A and SME) due to their inherent mobility. Studies in the past have reported NDM-1 producing E. coli, OXA-48 producing E. coli and K. pneumoniae in companion animals [72,73]. Further, a recent study in Australia reported carbapenemase (IMP-4) producing S. enterica Typhimurium from cats [30]. These findings imply that companion animals serve as potential reservoirs to enable further dissemination of carbapenemase-producing Gram-negative bacteria within the community thus making it imperative that this critically important antimicrobial be used judicially in veterinary medicine [74].

Colistin resistance

Once seldom used for treating human infections due to side effects such as nephrotoxicity [75], increased resistance demonstrated by Gram-negative bacteria towards critically important antimicrobials has led to increased reliance on polymyxin antimicrobials, polymyxin B and polymyxin E (colistin), as a last resort [76]. Colistin is predominantly used in intensive care units in intravenous administrations. Colistin is also extensively used for treating E. coli and Salmonella in addition to use as a growth promotant in pigs and poultry in some countries [70, 71]. Colistin appears to have been used since the 1960s in pigs and poultry but the first resistance was reported in poultry in 2001 [77] and in pigs in 2005 [78]. It is reported to be chromosomally mediated by increased enzyme activity that results in modification of bacterial lipopolysaccharide (LPS) thus reducing the binding affinity of colistin [76]. A recent study identified and reported the plasmid mediated resistance gene mcr-1 in E. coli isolated from animals and humans [76]. Another study reported a different plasmid mediated resistance gene mcr-2 in porcine and bovine E. coli isolates [79]. Following the first detection of mcr-1 in isolates from food animals in China many countries have reported the presence of mcr-1 in isolates from human, animals and the environment [80]. In cases of human isolates, the resistance rates were highest in Asia followed by Europe and America [81]. Switzerland, China, Malaysia and France have reported mcr-1 in environmental samples, while 28 countries have reported presence of mcr-1 in isolates from food and other animals [80]. Since colistin is used as the last-line therapy for treating infections caused by carbapenemase-producing Enterobacteriaceae, the major implication of subsequent acquisition of mcr-1 and mcr-2 by these organisms is that it would make them potentially pan-drug resistant [76]. Studies have also reported coexistence of mcr-1 with blaNMD-1 in certain E. coli strains thus indicating that evolution of such strains can lead to resistance to all critically important antimicrobials [82].

Limiting critically important antimicrobial-resistant Gram-negative bacteria in livestock: a success story from Australia

Previous studies have suggested that the ecology of critically important AMR among Enterobacteriaceae isolated from Australian food-producing animals differs from that in other parts of the world [83,84]. This is attributed to Australia’s unique geography, quarantine restrictions (restrictions on importation of livestock and fresh meat from 1901) and more importantly, the tight regulations governing the use of critically important antimicrobials in livestock. In Australia, it is illegal to administer fluoroquinolones (which have never been registered) and carbapenems to any food-producing animals and ceftiofur use is registered only for treatment of bovine respiratory tract infections in individual animals although off-label use in pigs also occurs. This multifaceted approach has delivered promising results in minimizing the occurrence of critically important antimicrobial-resistant, Gram-negative bacteria from food producing animals.

So far in Australia, there are no reports of resistance to carbapenems among Enterobacteriaceae from livestock. A number of cross-sectional studies demonstrated absence of resistance to critically important antimicrobials among Gram-negative bacteria [85]. In addition, these studies reported extremely low levels of ceftiofur-resistant bacteria [85].

Some of the recent studies in Australia, however, have detected the carriage of carbapenem resistant S. enterica Typhimurium from cats and E. coli from seagulls [30,86]. Although the selection pressure for acquiring carbapenem resistance in these studies is highly unlikely to be due to carbapenem use as it is rarely used in treating companion animals and seagulls [74], the possibility of co-selection of carbapenem resistance due to use of other registered veterinary antimicrobials including β-lactam, fluoroquinolones and cephalosporins cannot be excluded. Studies have also reported the isolation of fluoroquinolone resistant E. coli ST354 from dogs, humans and chicken meat [8789]. These studies show that antimicrobial-resistant, Gram-negative bacteria do not have defined species boundaries and illustrates the complex nature of AMR within Gram-negative bacteria involving a cycle that encompasses humans, animals and the environment.

These findings also imply that regulation alone cannot prevent the emergence of bacterial resistance to critically important antimicrobials in animals. Besides regulating or limiting the use of antimicrobials, it is highly imperative to effectively control infection and maintain hygiene and biosecurity to limit the transmission of resistant bacteria from one individual to another within community and healthcare settings or from animal to human in animal production. Furthermore, prevention of infection and maintenance of water bodies and drinking water supplies that serve as a major source responsible for transmission of resistant bacteria, especially in developing countries, would play a vital role in restricting the dissemination of antimicrobial-resistant Gram-negative bacteria.

Conclusions

The emergence of resistance to critically important antimicrobials in Gram-negative bacteria in humans and animals has narrowed the available treatment options making it imperative to look for alternative treatment choices either independently or in combination with existing antimicrobials. The role of antimicrobials in preventing, controlling and treating infectious diseases in both humans and animals not only makes them indispensable but also necessitates their conservation. The current scenario thus demands further judicious use of antimicrobials in both veterinary and human medicine and development of viable alternative options. The consequences of AMR are presented by way of limitation in treatment options for bacterial infections, increase in treatment cost and higher mortality rates. This complex situation demands a multidisciplinary approach for successful control and management of AMR. Development of strategies for antimicrobial stewardship in human and veterinary medicine, reviving the process of developing newer antimicrobials for introduction in the market and appraising viable alternative options to antimicrobials are required as a combined approach to combat this global issue.

Summary

  • AMR is a natural phenomenon accelerated by antimicrobial use.

  • AMR is a serious threat to global public health.

  • Resistance is highly transferrable among different Gram-negative bacteria.

  • Antimicrobial-resistant bacteria can be transferred in either direction between humans and animals.

  • Gram-negative bacteria use a number of different mobile genetic elements to acquire or transfer AMR.

  • Emerging AMR in animals to critically important (last line) antimicrobials is a public health concern due to horizontal gene transfer of AMR genes.

We thank Mrs. Rebecca Jane Abraham (Murdoch University) and Dr. Stephen Page (Advanced Veterinary Therapeutics) for critical review of the manuscript and their valuable contribution

Competing interests

The author declares that there are no competing interests associated with the manuscript.

Abbreviations

     
  • AMR

    antimicrobial resistance

  •  
  • DHFR

    dihydrofolate reductase

  •  
  • ESBL

    extended-spectrum-β-lactamase

  •  
  • ExPEC

    Extraintestinal pathogenic E. coli

  •  
  • IS

    insertion sequences

  •  
  • MBL

    Metallo beta-lactamases

  •  
  • MRR

    multidrug-resistance region

  •  
  • RND

    resistance-nodulation division

  •  
  • ST

    Sequence Type

  •  
  • UTI

    Urinary Tract Infection

  •  
  • WHO

    World Health Organization

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