Download Antimicrobial resistance in bacteria from horses

Equine Veterinary Journal ISSN 0425-1644
DOI: 10.1111/evj.12471
Review Article
Antimicrobial resistance in bacteria from horses: Epidemiology of
antimicrobial resistance
T. W. MADDOX*†, P. D. CLEGG†, N. J. WILLIAMS and G. L. PINCHBECK‡
National Consortium for Zoonosis Research, School of Veterinary Sciences, Neston, UK
†
Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, Neston, UK
‡
Department of Epidemiology and Population Health, Institute of Infection and Global Health, School of Veterinary Sciences, Leahurst Campus, University
of Liverpool, Neston, UK.
*Correspondence email: [email protected]; Received: 02.12.14; Accepted: 14.06.15
Summary
Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.
While the epidemiology of antimicrobial resistance in bacteria from man has been studied extensively, less work has been undertaken in
companion animals, particularly horses. Methicillin-resistant Staphylococcus aureus has been identified as a cause of infections, with a low
prevalence of nasal carriage by horses in the community but higher for hospitalised horses. Molecular characterisation has shown methicillinresistant Staphylococcus aureus strains either to be predominantly of types associated with horses or of sequence type ST398. Antimicrobialresistant Escherichia coli (including multidrug-resistant and extended spectrum b-lactamase-producing isolates) have caused infections and been
documented in faecal carriage by horses, with many significant resistance mechanisms identified. More sporadic reports and molecular
characterisation exist for resistance in other bacteria such as enterococci, Salmonella, Acinetobacter and Pseudomonas species. Limited work has
been undertaken evaluating risk factors and much of the epidemiology of antimicrobial resistance in bacteria from horses remains to be
determined.
Keywords: horse; antimicrobial resistance; epidemiology; Escherichia coli; extended spectrum b-lactamase; methicillin-resistant Staphylococcus aureus
Introduction
Bacterial resistance to antimicrobial agents represents a significant
challenge for both human and veterinary medicine [1,2]. While
acknowledged as an emerging problem in companion animals, the carriage
of antimicrobial resistance bacteria by horses has only comparatively
recently started to receive attention [3]. Much research has focused on
methicillin-resistant Staphylococcus aureus (MRSA), but clinically significant
antimicrobial resistance is encountered in many other bacterial species,
notably in Gram-negative members of the Enterobacteriaceae, such as
Escherichia coli.
Antimicrobials agents function by interrupting specific metabolic
functions within bacterial cells. There are 4 primary targets for antimicrobial
action; disruption of cell wall synthesis, inhibition of DNA/RNA synthesis,
inhibition of protein biosynthesis or interference with a crucial metabolic
pathway [4]. Antimicrobial resistance can be defined as the ability of a
microbe to survive and reproduce in the highest concentrations of an
antimicrobial that can be achieved in body tissues [5]. The mechanisms
through which bacteria can achieve resistance to antimicrobials have been
reviewed [6] and are summarised in Fig 1. Such mechanisms group into 3
major categories: protection or modification of the antimicrobial target site;
exclusion of the antimicrobial agent from the cell interior (via reduced cell
permeability or efflux pump expulsion); and production of antimicrobial
inactivating enzymes [7]. Resistance mechanisms can be either intrinsic to
the bacteria (arising from a particular trait common to all bacteria of that
group) or represent acquired mechanisms found only in some members of
a genus or species (as a consequence of some alteration to the bacterial
genome).
Acquired resistance can arise through endogenous means via mutations
in chromosomal genes, but is often achieved exogenously by horizontal
acquisition of foreign genetic elements. The transferable genetic material
involved in exogenous resistance can comprise resistance genes encoded
on plasmids, gene cassettes linked to integrons, transposons and other
mobile genetic components [8,9]. Pumps for drug efflux, enzymes for
antimicrobial inactivation, alternative versions of the antimicrobial target
site and sometimes factors providing protection for the molecular target
756
can be encoded by these genetic elements [10–14]. Exogenous exchange
of genetic material may take place between differing strains of the same
species or even across genera, and can occur via bacterial transformation
(incorporation of exogenous DNA from dead bacteria), conjugation
(transfer of plasmids) or transduction (DNA transferred by viral
bacteriophages that infect bacteria). Irrespective of their specific origin,
acquired antimicrobial resistance mechanisms are of particular concern, as
they allow both the emergence and rapid dissemination of resistance in
previously susceptible bacterial populations. The majority of recognised
antimicrobial resistance mechanisms have been documented in equine
bacterial isolates. However, an appreciation of the epidemiology of such
bacteria in horses is required.
Epidemiology of antimicrobial resistance in
horses
Antimicrobial resistance in bacteria recovered from horses has been
recognised since the 1970s [15] but in most cases the epidemiology of such
resistance in horses has not been assessed. Many reports have concerned
pathogenic bacterial isolates submitted for diagnostic bacteriology [16–24],
with fewer studies monitoring resistance in commensal strains [25,26].
Exactly what constitutes antimicrobial resistance varies between
studies; for the purposes of this review resistance was considered present
if there was demonstration of phenotypic resistance (on the basis of
antimicrobial susceptibility testing). In reports describing clinical infection
this may also equate to demonstrated clinical resistance/treatment failure,
but this will not apply to epidemiological studies surveying for prevalence.
Detection of a resistance gene (genotypic resistance) was not considered
indicative of resistance unless supported by susceptibility testing.
To date, most epidemiological studies of antimicrobial resistant bacteria
from horses have focused on resistance in staphylococci and
Escherichia coli. In particular, organisms such as MRSA and extended
spectrum b-lactamase (ESBL)-producing E. coli have attracted much
attention due to their often significant multidrug resistance. Additionally,
this reflects the pathogenic potential of these bacteria, their prevalence
Equine Veterinary Journal 47 (2015) 756–765 © 2015 EVJ Ltd
Antimicrobial resistance in bacteria from horses
T. W. Maddox et al.
Antimicrobial
mechanism of action
Disruption of bacterial
Antimicrobial target
within bacteria
Penicillin binding
protein (PBP)
Cell wall
peptidoglycans
synthesis
Type of acquired
resistance mechanism
Penicillins,
other β-lactams
Extended-spectrum
β-lactams
cell wall synthesis
Inhibition of DNA
Antimicrobial
class
DNA topoisomerase
enzymes
Glycopeptides
Quinolones
and
Fluoroquinolones
Target modification
Inactivating enzymes
Macrolides
and
Lincosamides
50S ribosomal
subunit
metabolic pathway
(folic acid synthesis)
Dihydrofolate
reductase
Dihydropteroic acid
synthase
blaCTX-M, blaOXA
Altered QRDR of
topoisomerase enzymes
Chromosomal mutations of
gyrA and parC
Target protection
Pentapeptide molecule
(protection factor)
qnrA, qnrB, qnrS
Inactivating enzymes
Acetyltransferase
enzymes
AAC(6’)-Ib-cr
Antimicrobial efflux
Efflux pumps
qepA
Antimicrobial efflux
Efflux pumps
tet(A), tet(B), tet(C)
Target protection
Ribosomal protection
factor
tet(M)
Adenylyltransferase/
acetyltransferase enzymes
vanA, vanB
aadA1, aadA2, aadA4,
aac(3)-I, aac(6’)-Ib
Target modification
Methylase enzymes
armA, rtmB
Target modification
Altered ribosomal
binding site
ermA, ermB
Antimicrobial efflux
Efflux pumps
mef(A), msr(D)
Esterase, acetyltransferase
enzymes
mph(C)
Chloramphenicol
Acetyltransferase
enzyme
cat
Trimethoprim
Alternative dihydrofolate
reductase (DHFR)
dfrA1
Alternative dihydropteroic
acid synthase (DHPS)
sul1, sul2
Inactivating enzymes
Interference with
Extended-spectrum
β-lactamases (ESBLs)
blaTEM, blaSHV, blaCMY blaZ
Target modification
Aminoglycosides
biosynthesis
β-lactamase enzymes
(including AmpC enzymes)
mecA
Alternative peptidoglycan
precursors
Inactivating enzymes
Inhibition of protein
Alternative PBP with
reduced affinity (PBP2a)
Common encoding
genes
Target modification
Tetracyclines
30S ribosomal
subunit
Specific resistance
mechanism
Target modification
Sulfonamides
Fig 1: Antimicrobial mechanisms of action, common acquired antimicrobial resistance mechanisms and their encoding genes.
and significance in human medicine, and possible zoonotic nature. The
occurrence, mechanisms and, where available, epidemiology of
antimicrobial resistance in these and other bacteria relevant to equine
medicine will be considered.
Staphylococcal species
Methicillin-resistant S. aureus remains the best characterised of all
antimicrobial resistant bacteria from horses, most likely reflecting its
potentially pathogenic nature and the possible implications of zoonotic
spread. However, significant resistance is seen in other staphylococcal
species and may be clinically relevant. Staphylococci are considered
among the most important Gram-positive pathogens in human and
veterinary medicine [27,28]. Many of the genus are part of the
commensal flora of the skin and mucous membranes of most mammals,
with over 40 different species and subspecies described. S. aureus and
Staphylococcus pseudintermedius are among the more frequent
pathogenic staphylococci encountered in animals. These species and
some strains of Staphylococcus hyicus are characterised by their ability
to coagulate rabbit serum and are consequently named coagulasepositive, with the remainder of the genus (including species such as
Equine Veterinary Journal 47 (2015) 756–765 © 2015 EVJ Ltd
Staphylococcus epidermidis and Staphylococcus sciuri) termed
coagulase-negative staphylococci (CNS). The CNS have been considered
largely nonpathogenic, but some are recognised as causing opportunistic
infections [29–31]. Coagulase-negative species are the predominant
commensal staphylococci found in horses, with several species
colonising their mucous membranes. Coagulase-positive staphylococci
carriage appears less common, with a lower prevalence for S. aureus
[32–34] and S. pseudintermedius only very rarely reported in horses [35].
Resistance to a variety of antimicrobial agents is common within the
genus. However, resistance to the narrow spectrum b-lactam methicillin is
considered of particular significance as it generally signifies resistance to all
b-lactams drugs [36].
Methicillin-resistant staphylococcal carriage in horses
In common with nonresistant members of the genus, methicillin-resistant
staphylococci largely reside commensally on the mucous membranes,
particularly within the nasal chambers [37–39]. Persistent recovery of the
organisms from such sites indicates true commensal colonisation, whereas
isolated or intermittent detection may simply reflect transient carriage.
Carriage of MRSA has also been documented on the skin of horses
hospitalised for prolonged periods [40]. Most MRSA colonised animals do
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Antimicrobial resistance in bacteria from horses
not develop clinical infections, but colonisation is recognised as a risk
factor for infection under some circumstances [41].
Various studies have evaluated equine carriage of MRSA for different
horse populations (Supplementary Item 1). The prevalence appears highest
for hospitalised horses, 2.3–16.4% under normal circumstances [41,42], and
may be considerably higher during outbreaks of clinical infection [43].
Generally, lower prevalences from 1.9 to 10.9% have been found for horses
at admission to equine hospitals. Studies of horses in the wider community
from a number of countries have consistently identified a low prevalence
of carriage of <2%. While a higher community prevalence has been
identified by some in the USA and Canada [44,45], these studies used
targeted or small convenience samples, and showed that prevalence can
vary considerably between premises (with carriage ranging from 0 to 61%
on individual yards). There has been more limited evaluation of methicillinresistant CNS carriage in horses, but studies undertaken have generally
reported much higher figures for prevalence of up to 42% [34,37,46].
T. W. Maddox et al.
admission to equine hospitals [43,61] and clusters of clinical infection have
been reported [62,63]. This may be particularly significant; ST398 has been
the cause of outbreaks of clinical infection in people working with animals
[64,65] and carriage by a recently hospitalised foal has resulted in
documented zoonotic human infection [66]. Healthy horse-owners and
workers have also been identified as carrying the same ST398 MRSA types
as their animals [67].
Strains in both clonal complexes 8 and 398 typically carry variants of
SCCmec IV and this SCCmec type has consistently predominated among
MRSA isolates recovered from horses. Isolates from horses harbouring
other SCCmec types are unusual and there are only sporadic reports of
equine MRSA possessing SCCmec types V and VI in Europe and the USA
[61,68–72]. Interestingly, all of these SCCmec types represent the smaller
versions of this gene cassette. It is suggested that such strains are better
adapted for survival outside of situations of high antimicrobial selection
pressure, as the carriage of a smaller SCCmec unit results in a lesser fitness
cost to the organism [73].
Molecular epidemiology of MRSA in horses
Methicillin-resistance in MRSA and other staphylocci generally results from
carriage of one of a number of SCCmec gene cassettes. This large but
variably-sized DNA fragment incorporates the mecA gene that encodes a
modified alternative penicillin-binding protein (designated PBP2a), a key
enzyme required for cell wall synthesis. PBP2a provides a substitute for
conventional penicillin binding proteins and its reduced affinity for b-lactam
antimicrobials affords resistance to methicillin and most other b-lactam
agents [47]. Resistance to b-lactam can also be mediated through
staphylococcal production of a penicillinase enzyme (encoded by the blaZ
b-lactamase gene) and although widespread and encountered in
staphylococci from horses [48,49], only a narrow spectrum of resistance is
conferred. A range of other genes can be included within the SCCmec unit
and results in its variable size; in some cases these incorporated
genes confer resistance to other unrelated antimicrobials [50]. SCCmec
cassettes can be assigned to groups based on their integrated genes,
with at least 8 major types (SCCmec types I to VIII) and several subtypes
defined [51].
Identification of the specific SCCmec type carried by an isolate forms the
basis of one of several typing systems used for molecular characterisation
of MRSA strains, although the limited number of identifiable types means
it is not a highly discriminatory technique [52]. Other typing schemes
involve gene sequencing of a single chromosomal gene locus encoding
staphylococcal protein A (spa gene typing) or sequencing fragments of 7
well-conserved chromosomal housing-keeping genes (multilocus sequence
typing [MLST]) [53,54]. Multilocus sequence typing analysis assigns an
isolate a sequence type (ST) based on alleic profiles and these can be
grouped together in related clonal complexes (CC). Good correlation is
seen between MLST and spa-gene typing, and their high discrimination
makes both suitable tools for investigating the molecular epidemiology of
MRSA [55].
Over 25 different spa-types have been recovered from horses, the most
frequent types encountered being t011, t064 and t451 (Supplementary
Item 2). Most isolates are assigned by MLST to CC398 or CC8, with over
two-thirds of studies identifying equine isolates as belonging to these 2 CC.
However, the molecular epidemiology of MRSA in horses may be
changing. Prior to 2007, MRSA strain types from horses appeared largely
restricted to the species. In contrast, many of the MRSA types recovered
from dogs are highly similar or identical to the most commonly identified
human strains [56,57]. Equine MRSA isolates typically represented rarer
human types or equine-specific strains, mainly sequence types ST8 or
ST254 (both CC8) carrying SCCmec IV cassette types [56–58]. However,
following the identification of the first equine isolate of the livestockassociated clone ST398 (belonging to CC398) [59], spa-types of this
sequence type (mostly t011 and occasionally t034) now predominate
among reports of both carriage and infection. In contrast to most other
MRSA types, this sequence type appears to have a high prevalence of
colonisation in large animals, especially pigs [60]. This has led to the
suggestion that ST398 may represent the first truly animal adapted strain
of MRSA. Most studies involving horses from European countries have
now recognised ST398 among equine MRSA isolates (Supplementary Item
2). High prevalences for ST398 of 9–11% have been detected in horses at
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MRSA infection and risk factors
Although studies determining the true prevalence of equine MRSA
infections are lacking, cases of MRSA seen in horses appear relatively
infrequent in comparison with human infections. Most reported equine
cases have been infections of soft tissues; mainly traumatic wounds and
post surgical incisions, but cases of osteomyelitis and joint sepsis are also
repeatedly identified (clinical cases are summarised in Supplementary Item
3). The incidence of infection in equine hospitals appears to be low, with
reported infection rates of 1.8 [41] and 4.8 cases [58] per 1000 hospital
admissions. However, there have also been clusters or outbreaks of
infection reported in equine clinics [43,74]. In contrast, methicillin-resistant
CNS have only very rarely been implicated as the cause of clinical infection
[75].
The low prevalence of clinical disease has hampered determination of
risk factors for MRSA infections in horses. However, a large study identified
horses with nasal colonisation detected on hospital admission as being
more likely to develop nosocomial clinical MRSA infections during
hospitalisation [41]. Another multicentre study evaluated factors associated
with community- vs. hospital-acquired infection and clinical outcome in 115
infected horses [76]. The majority of MRSA infected horses (83.8%) survived
to discharge, similar to those with methicillin-susceptible S. aureus
infections. However, prior i.v. catheterisation, a community-acquired
infection and dissemination of infection to other body sites were
significantly associated with nonsurvival. The only risk factor identified for
hospital-acquired infection was incisional sepsis and the large number of
post surgical infections reported in horses [62,74,76–78] would seem to
support invasive surgery as a likely risk factor.
Risk factors for nasal carriage or colonisation with MRSA (as opposed to
infection) have also been assessed. Prior antimicrobial treatment (with
penicillin and trimethoprim), originating from an MRSA-positive premises,
previously documented MRSA colonisation and admission for neonatal
care were recognised as risk factors for carriage detected at hospital
admission [79]. Similarly, antimicrobial administration has been associated
with development of nosocomial MRSA colonisation during hospitalisation
[41]. For horses in the community, residing on a stable yard premises with
more than 20 horses was the only risk factor identified for MRSA nasal
colonisation in a further study [44]. Conversely, no risk factors were
identified for MRSA carriage by another study [80], leading to the
suggestion that horses may function more as contaminated vectors rather
than truly colonised animals. Some support for this is provided by the
demonstration of spontaneous loss of MRSA carriage in untreated horses
followed longitudinally [81]. However, horses with previous clinical
infections of other sites have shown persistent nasal carriage for up to
711 days, with a median of 143 days [82].
Escherichia coli
Escherichia coli is considered part of the normal gastrointestinal tract of
most mammals, with an almost universal prevalence in horses [83]. Despite
a predominantly commensal nature, many strains of E. coli are capable of
Equine Veterinary Journal 47 (2015) 756–765 © 2015 EVJ Ltd
Antimicrobial resistance in bacteria from horses
T. W. Maddox et al.
causing disease of both the gastrointestinal tract and extraintestinal sites
[84].
Antimicrobial resistance in E. coli
Antimicrobial resistance is commonly encountered in this species, with
b-lactam resistance representing a particular concern. E. coli are
intrinsically resistant to penicillin as it is unable to penetrate their outer
membrane [85] and there is widespread acquired resistance to other
b-lactams, mostly through the production of inactivating b-lactamase
enzymes such as TEM-1, TEM-2 and SHV-1, or AmpC b-lactamases, all
encoded by various bla resistance genes [13,86,87]. The extended
spectrum b-lactam antimicrobials (including cefotaxime, ceftiofur and
cefquinome), were developed in response to resistance seen to the early
b-lactams. Resistance to these agents is conferred by bacterial production
of ESBL enzymes, of which there are many types [88]. Many ESBL enzymes
are simple mutations of the original TEM/SHV b-lactamases; only a small
number of amino acid substitutions are necessary to extend their spectrum
of activity to include the newer compounds [89]. However, the last 2
decades have seen the emergence of a family of ESBL enzymes that are
distinct from SHV and TEM-types and have become prominent within E. coli
[90]. These enzymes are able to hydrolyse the ESBL cefotaxime and are
consequently named cefotaximases (CTX-M). They have been identified in
E. coli recovered from man and animals, with a large number of subtypes
identified [91–93].
Prevalence of antimicrobial resistant E. coli
Resistance to all groups of antimicrobial agents available to equine
practitioners (penicillins, cephalosporins, aminoglycosides, tetracyclines,
fluoroquinolones and potentiated sulphonamides) has been described for
E. coli from horses [17,18,20,22,26,94]. Studies have examined E. coli
recovered from the faeces of horses without disease (both hospitalised
and non-hospitalised horses) and clinical isolates causing disease. The
prevalence of faecal carriage of E. coli with resistance to at least one
antimicrobial is generally higher for hospitalised horses compared with
nonhospitalised horses in the community. Prevalence of 60.5–81.7% has
been identified for hospitalised horses [95–97], whereas a lower
prevalence of 13.4–24.5% has been reported for community horses
[96,98,99], although a prevalence of 69.5% was identified by one large
study [34]. For resistance to specific antimicrobial agents, some broad
similarities are apparent for both hospitalised and nonhospitalised
horses, with a higher prevalence of resistance to trimethoprim/
sulphamethoxazole, tetracyclines and the nonextended spectrum blactams, and somewhat lower prevalence for aminoglycoside and
fluoroquinolone resistance. However, this difference is less marked for
hospitalised horses, where resistance to aminoglycosides and
fluoroquinolones is more frequently encountered [26,34,97–100]. The
estimated prevalence of carriage of multidrug resistant isolates with
considerably lower for horses in the community (2.6–37.6%) compared
with hospitalised horses (13–53.5%) [34,96–100]. The prevalence of faecal
ESBL-producing E. coli appears low among horses in the community;
identified as 6.7% by one study [34], but may be as high as 27.3% in
hospitalised horses [96,97].
For clinically derived isolates of E. coli, resistance to b-lactams and
trimethoprim/sulphamethoxazole has also tended to predominate
[21,101,102]. However, multidrug-resistant and ESBL-producing E. coli
isolates have been identified as the cause of infections in horses on
multiple occasions. Most of these infections have been of soft tissues or
wounds, but involvement in uterine and synovial infections have also been
reported [16,22,103,104].
Molecular characterisation of resistance in E. coli
Many antimicrobial resistance determinants or their encoding genes have
been recovered from both clinically derived and faecal commensal E. coli
from horses (summarised in Supplementary Item 4). Multidrug resistant,
and more recently ESBL-producing isolates, have been recovered from
faecal samples of clinically normal horses, as well as from soft tissue and
wound infections [22,95,105]. Of particular note is the frequent occurrence
of CTX-M-type ESBL-producing E. coli from horses, and especially the
Equine Veterinary Journal 47 (2015) 756–765 © 2015 EVJ Ltd
recent emergence of E. coli of sequence type (ST) ST131 producing CTX-M15 [16]. The ST131 sequence type has rapidly become globally
disseminated and is a significant cause of human disease [106]. Also
relatively recently, there has been identification of the aminoglycoside
modifying acetyltransferase enzyme (AAC(60 )-Ib-cr), conveying low level
ciprofloxacin resistance [16], and several qnr genes encoding efflux pumps
for quinolone (fluoroquinolone) resistance [107].
Epidemiology of antimicrobial resistant E. coli
Some epidemiological aspects of antimicrobial-resistant E. coli in horses
have been examined. As noted previously, the prevalence in hospitalised
animals is higher than for those in the community. Moreover, this
prevalence has been shown to increase significantly during hospitalisation,
with this effect being particularly profound for multidrug-resistant and
ESBL-producing E. coli [97,108,109]. Some studies including hospitalised
horses have noted a somewhat consistent effect of antimicrobial exposure
being associated with increased risk of resistance in faecal E. coli
[26,95,97], although this does not appear true for all antimicrobial types or
all resistance types. One study also associated overall hospital-level
treatment with antimicrobials with increased prevalence of resistance,
even in animals not actually being treated [97]. Other studies have not
identified significant effects for antimicrobial exposure in hospitalised
horses [100,109], suggesting hospitalisation even without treatment as a
likely further risk factor. Two studies identified hospitalisation for
gastrointestinal disease as a risk factor [97,110] and a further study found
increased risk of resistance in horses with gastrointestinal disease
treated with antimicrobials compared with those treated similarly for
nongastrointestinal disease [95].
Outside of the hospital setting, fewer studies have evaluated risk factors
for carriage of antimicrobial-resistant E. coli. Recent hospitalisation, recent
antimicrobial treatment, contact with nonequid animals and some specific
premise types were associated with various antimicrobial resistances by
some studies [95,111]. Prevalence of carriage of ESBL-producing E. coli
appears low (<7%) among horses in the community [34,95], but similar risk
factors have been recognised for carriage of such bacteria. However,
interestingly being stabled on the same yard as a recently hospitalised
horse was identified as a further risk factor for ESBL-producing E. coli
carriage [111]. Supportive of this finding has been the identification of
continued carriage of multidrug resistant bacteria by horses discharged
from hospital on returning to the community [95].
Enterococci
Enterococci are Gram-positive members of the commensal flora of the
gastrointestinal tract of many mammals, including man and horses [112].
However, they are also capable of causing disease and represent a serious
cause of nosocomial infections in people [113], with the most significant
species being Enterococcus faecalis and Enterococcus faecium. All
enterococci are intrinsically resistant to cephalosprins and
aminoglycosides, limiting treatment options, which is complicated further
by the increasing prevalence of transferable resistance to other
antimicrobials (most critically to vancomycin) in some species [113]. Most
vancomycin resistant enterococci (VRE) are E. faecalis and E. faecium, but
resistance is occasionally seen in other members of the genus such as
Enterococcus gallinarum, Enterococcus durans and Enterococcus
casseliflavus [114,115].
Epidemiological studies regarding enterococci in horses are lacking.
Transferable van genes for resistance to vancomycin have been
documented in enterococcal isolates of several species from horses, with
vanA and vanB genes detected, and sample prevalences of 6.7–9.6%
[112,115,116]. Other resistance genes have also been identified, including
for macrolides (erm(B)) and tetracycline (tet(L)) [112]. The equine situation
somewhat parallels human medicine: a significant increase in both the
prevalence and breadth of resistance has been seen in clinical
enterococcal isolates over the last 2 decades [117]. Enterococcus faecalis
and E. gallinarum isolates with extensive multidrug resistance have been
the cause of infection in horses, but only currently in limited reports or as
isolated cases [114].
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Antimicrobial resistance in bacteria from horses
Pseudomonas
Multidrug resistance is commonly encountered in Pseudomonas species,
partly due to widespread intrinsic resistance to agents such as b-lactams
and also the high prevalence of multidrug efflux pumps observed.
Pseudomonas aeruginosa provides a prime example of this as it can host 4
major efflux systems known as MexAB-OprM, MexXY-OprM, MexCD-OprJ
and MexEF-OprN [118]. MexABOprM and MexXY-OprM are expressed
constitutively in wild type cells and provide intrinsic multidrug resistance.
However, MexCD-OprJ and MexEF-OprN are hyperexpressed only in
mutant strains and represent acquired multidrug resistance mechanisms.
Other members of the genus, such as Pseudomonas fluorescens, less
frequently demonstrate multidrug resistance.
Extensive multidrug resistance has been seen in Pseudomonas isolates
recovered from foals with sepsis, with resistance to most of the
antimicrobials tested and only amikacin, ticarcillin/clavulanic acid and
imipenem remaining active against the majority of isolates [117]. With
carbapenems such as imipenem considered critically important
antimicrobials and largely reserved for human medicine [2], treatment
options can be limited for horses. Pseudomonas species (particularly
P. aeruginosa) are often involved in ulcerative keratitis, and extensive
multidrug resistance has been seen in isolates from such cases, with
increased prevalence of resistance seen over time [119]. The genes and
mechanisms involved in antimicrobial resistance in equine Pseudomonas
have not been well characterised. An outbreak of endometritits associated
with P. aeruginosa with limited antimicrobial resistance showed the
isolates involved to be genotypically identical [120], but few studies have
examined the epidemiology of resistant Pseudomonas in horses.
Salmonella
Salmonellosis is a significant cause of clinical disease in horses in some
situations, with several of the over 2500 serotypes of Salmonella enterica
having been associated with outbreaks of nosocomial disease in equine
hospitals [121–123]. Antimicrobial-resistant serotypes have been recovered
from horse faeces, such as Heidelberg, Newport and Typhimurium,
(including the often multidrug-resistant definitive phage type DT104) [124–
128]. Several of the more significant resistance mechanisms have been
identified in equine Salmonella isolates. Extended spectrum b-lactamasegenes such as blaCTX-M-1, blaCTX-M-15, blaSHV-12 and the plasmid-mediated
ampC gene blaCMY-2 have been identified [128–131]. Antimicrobial
resistance genes associated with integrons are prevalent within
Salmonella, particularly DT104 [127]. Several examples have been identified
in Salmonella from horses including aminoglycoside-modifying
adenylyltransferase enzymes such as aadA1, aadA2, aadB, sul1 for
sulfonamide resistance and multiple alternative dihydrofolate reductase dfr
genes providing trimethoprim resistance [126,132].
Although risk factors for shedding of Salmonella have received some
attention [133], the specific epidemiology of antimicrobial-resistant
Salmonella has not been characterised. However, over a 20 year period, a
significant increase in minimum inhibitory concentration values for
ceftizoxime (a third generation cephalosporin) and decrease in proportion
of isolates susceptible to gentamicin has been noted for Salmonella
recovered from foals with sepsis [117]. Salmonella isolates have also been
implicated as causal agents in some cases of diarrhoea associated with
antimicrobial treatment [134]. Salmonella can be recovered from the
faeces of horses without disease, but the shedding of antimicrobial
resistant Salmonella in the general horse population appears to be very
low [135].
Acinetobacter
Acinetobacter species are Gram-negative coccobacilli, and are considered
opportunistic pathogens that are often associated with nosocomial
infections in man [136]. One species in particular, Acinetobacter baumannii,
frequently exhibits high-level resistance to a wide range of antimicrobials
including
aminoglycosides,
cephalosporins,
fluroquinolone
and
tetracyclines [136], with less resistance seen in other members of the
760
T. W. Maddox et al.
genus. Despite their significance in human medicine, they have received
limited attention in veterinary species, particularly horses. Multidrugresistant isolates of A. baumannii have been sporadically reported as
causes of wound infections and bronchopneumonia [137,138], with
sensitivity restricted to trimethoprim-sulfonamide and marbofloxacin in
some cases.
Specific resistance mechanisms have been documented in some equine
cases; class 1 integrons containing multiple aminoglycoside resistance
genes have been found in A. baumannii [137] and the carbapenemase
OXA-23 has been documented in an equine Acinetobacter isolate [139].
Conclusions
Antimicrobial resistance is prevalent in bacteria from horses, particularly
E. coli, and many of the most significant resistance mechanisms have been
identified in equine isolates. For some bacteria, a relatively high prevalence
of multidrug resistance has been identified and such bacteria have been
the cause of infections in horses. Methicillin-resistant S. aureus has
predominated as a concern, and while its prevalence in hospitalised horses
can be high, it is less frequently present in the general equine population.
However, the emergence of multidrug resistance in many other bacterial
species, particularly the increasing prevalence of ESBL-producing bacteria,
represents a huge challenge for society. For horses, little work has
examined either the prevalence or mechanisms of resistance encountered
in many of the significant bacterial species and the need for increased
surveillance is clear. There has been limited evaluation of risk factors
associated with either carriage or infection for some antimicrobial-resistant
bacteria, with some consistent effects of antimicrobial treatment noted.
However, antimicrobial exposure has not been the sole reason identified
for resistance and many risk factors are currently undetermined. It is clear
that these aspects will need to be more fully addressed if successful
attempts are to be made to limit the problems associated with such
organisms in the future.
Authors’ declaration of interests
No competing interests have been declared.
Ethical animal research
Not applicable for this review article.
Source of funding
None.
Authorship
T.W. Maddox was the primary author and all authors contributed
substantially to writing and editing of the manuscript.
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Supporting Information
Additional Supporting Information may be found in the online version
of this article at the publisher’s website:
Supplementary Item 1: Estimates of carriage of methicillin-resistant
Staphylococcus aureus by horses in various equine populations.
Supplementary Item 2: Molecular characterisation of methicillinresistant Staphylococcus aureus isolates recovered from horses.
(Additionally many CC398 isolates were recovered from several countries
of mainland Europe; the majority of these (over 80%) were characterised
as spa type t011 carrying SCCmec IV [154].)
Supplementary Item 3: Frequency and characteristics of reported
clinical methicillin-resistant Staphylococcus aureus infections in horses.
Supplementary Item 4: Antimicrobial resistance genes identified in
Escherichia coli recovered from horses.
765