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Curr Clin Micro Rpt
DOI 10.1007/s40588-016-0029-3
BACTERIOLOGY (N BOREL, SECTION EDITOR)
Epidemiology and Antimicrobial Resistance in Clostridium
difficile With Special Reference to the Horse
Angelika Schoster 1 & Henry Staempfli 2
# Springer International Publishing AG 2016
Abstract Clostridium difficile is an important gastrointestinal
pathogen in humans and animals. Disease occurs after intes-
tinal colonization with toxigenic strains of C. difficile and
subsequent proliferation due to disturbances of the microbiota.
Several animal species can be affected, but mainly pigs and
horses, and occasionally dogs, develop clinical disease. Path-
ogenesis appears to be similar in animals and humans. Initial-
ly, this disease was mainly considered to be a nosocomial
infection after antimicrobial exposure; now, it often has a com-
munity onset without prior antimicrobial exposure. Therefore,
reservoirs of C. difficile including animal feces, food, and the
environment have recently been investigated. The bacterium
has been isolated from the feces of healthy individuals from
several species, including domestic and wild animals. Molec-
ular types isolated from animals correlate with human ones,
suggesting that animals could serve as an important reservoir.
The use of antimicrobials appears associated with infection
patterns and resistance profiles of C. difficile.
This article is part of the Topical Collection on Bacteriology
* Angelika Schoster
aschoster@vetclinics.uzh.ch
Henry Staempfli
hstaempf@uoguelph.ca
1
Vetsuisse Faculty, Equine Department, University of Zurich,
Winterthurerstrasse 260, 8057 Zurich, Switzerland
2
Ontario Veterinary College, Department of Clinical Studies,
University of Guelph, Guelph, ON N1G2W1, Canada
Keywords Equine colitis . Clostridial enteric disease .
Metronidazole resistance . Antimicrobial-associated disease
Introduction
Clostridium difficile is a Gram-positive, spore-forming obli-
gate anaerobe, which was first isolated from the meconium
of a human infant [1]. Originally named Bacillus difficilis
due to its difficult culture requirements, it was later re-
classified as C. difficile. Early on, it was thought that the
bacterium was a commensal of the gastrointestinal tract, as it
could be isolated from the feces of non-diarrheic human
infants [1]. C. difficile was determined to be a human gas-
trointestinal pathogen in the 1970s [2, 3•, 4]. Initially,
C. difficile infection (CDI) was regarded as a nosocomial
infection among hospitalized humans with particular risk
factors, such as age and antimicrobial treatment [5]. Over
the past three decades, the incidence of CDI has steadily
increased and over time the epidemiology of the disease
has changed. Since the mid-2000s, community-acquired in-
fections in humans have been more frequently reported, sug-
gesting that additional reservoirs of the bacterium exist [6].
It was also in the early 2000s when the association with
enteric disease in animals was confirmed. While enteric dis-
ease due to C. difficile is uncommon in animals aside from
horses and pigs, carriage of C. difficile by food-producing
animals and household pets might serve as a reservoir for
human infection [7]. Molecular fingerprinting methods com-
paring strains isolated from humans and animals indicate the
potential of a shared habitat of C. difficile between humans
and animals [8]. Recent studies report the occurrence of
C. difficile in a variety of food-producing animals, particu-
larly endemic strains such as 027 and 078 [8–10]. The wide-
spread dissemination of toxigenic C. difficile in animals and

the considerable overlap in strain distribution between spe-
cies furthers raise concerns about interspecies transmission
of this pathogen [11, 12].
Virulence Factors
The two main virulence factors of C. difficile are toxin A, an
enterotoxin, and toxin B, a cytotoxin, produced by vegetative
forms of the bacterium [13]. Both toxins act synergistically
and disrupt the enzymatic activity of Rho GTPase, which
regulates actin polymerization. This leads to a disruption of
the cytoskeleton and cell death [14]. A+B+ strains are desig-
nated as toxigenic with the potential of causing disease while
non-toxigenic strains are avirulent. A−B+ strains have recently
been identified in the feces of 3–12 % of normal humans [15,
16] and 4–18 % of horses [17–19]. These strains have been
associated with outbreaks in humans [20–23] and horses [17,
18] and appear to be more problematic and endemic compared
to before 1999. However, their clinical significance is still not
fully understood [24]. Some C. difficile isolates produce an
actin-specific ADP-ribosyltransferase (binary toxin, CDT) be-
lieved to act as an additional virulence factor in synergy with
toxin A and B [25, 26]. The role of CDT is still under inves-
tigation and much debated although most hypervirulent strains
express this toxin [27]. Certain strains produce larger quanti-
ties of toxin than others, and this is likely linked to a genome
mutation in the tcdC region, a region which downregulates
toxin production in wild-type strains. Strains with this muta-
tion are termed Bhypervirulent,^ but their clinical effect is
controversial, and a corresponding in vivo hypervirulence
has so far not been proven [28].
Epidemiology of C. difficile
C. difficile exist as vegetative cells and spores. Vegetative cells
are the active growing forms, causing disease, but cannot sur-
vive prolonged periods of oxygen exposure. Spores are fastid-
ious and are the infectious form that is acquired via feco-oral
route [29]. Infected patients and contaminated environments
were initially thought to play the main role in C. difficile trans-
mission between humans [30]. C. difficile has now been iso-
lated from several environments including soil, water, and the
digestive tract of healthy and diseased animals and humans
[5]. Portable sequencing technologies have shown that spread
of hospital clones is not the main source of consecutive infec-
tions, instead consecutive CDI is often due to different strains
[31••]. This suggests that person-to-person transmission with-
in hospitals is not as high as was initially suspected and that
C. difficile is likely to be transmitted also through incoming
patients, personnel, visitors, or visitation animals. The change
in disease epidemiology patterns led to the discovery of
Curr Clin Micro Rpt
additional reservoirs of C. difficile and the suggestion that
CDI might be a zoonosis or food-borne disease with food-
producing animals as an important reservoir [5].
To date, a total of 190 molecularly distinct strains of
C. difficile have been found in humans and 30–50 types
have been reported in animals [32]. Some of these strains
appear host species specific, but others have been isolated
from both humans and animals, and now there is concern
regarding zoonotic transmission from animals to humans or
vice versa [33, 34•]. Some strains of C. difficile appear to
be endemic causing more severe disease compared to
others. In North America, the current endemic strain of
C. difficile in humans has been identified as BI/NAP1/
027/III (REA/PFGE/ribotype/toxinotype) [35] and more re-
cently BK/NAP7/078/V in North America and Europe [28,
36]. This latest strain is of concern due to high-level fluo-
roquinolone resistance and hypervirulence causing higher
morbidity and mortality [36, 37].
C. difficile in Horses
Depending on geographical region, horses appear to be
more important reservoirs of C. difficile in comparison to
other animals studied to date [38]. The epidemiology and
pathophysiology of CDI in horses is incompletely under-
stood. While C. difficile is an important cause of equine
enterocolitis, it can also be isolated from feces of healthy
horses [39]. In adult healthy horses, the carrier rates in
fecal samples vary from 0 to 33 % and are related to
geographical location and horse population studied, with
most studies reporting shedding rates of less than 10 %
[4–19, 40–43]. Shedding is transient and multiple molecular
types can be cultured from horses over time, indicating that
horses are transiently colonized by one strain and subse-
quently can become carriers of a different strain [44]. Shed-
ding rates are likely underestimated, as it appears that in-
termittent shedding is common. When horses were sampled
monthly over the course of one year, incidence of
C. difficile carriage was 5.5 %, but when cumulative pre-
valence was calculated, 40 % of horses harbored C. difficile
at some point during the year, indicating that point preva-
lence rates likely underestimate carriage status [44]. Fecal
samples are a poor proxy of other compartments of the
gastrointestinal tract, and therefore carriage rates are likely
underestimated further [43, 45, 46]. As in other species,
carrier rates are much higher in young healthy foals com-
pared to those in older foals and adults, ranging from 16–
29 % in foals less than 14 days [19, 40–47] to 0.6 % in
foals between 14 and 29 days of age [40, 47]. Since horses
appear to be frequently exposed to C. difficile, risk factors
and individual susceptibility might account for why some
horses develop disease and others do not.
Curr Clin Micro Rpt
Data on molecular strains in horses are currently limited.
Early studies in healthy adult horses have shown marked di-
versity in ribotypes [8, 19] whereas more recent studies have
shown a high prevalence of ribotype 078 and 027, thus poten-
tially linking disease in horses to humans [18, 42, 47]. There
are no recorded proven reports of potential transmission of
C. difficile from horses to humans and vice versa and no stud-
ies evaluating the similarities in molecular strains between
horses and their caretakers.
C. difficile in Food-Producing Animals
C. difficile has been isolated from the feces of food-producing
animals including calves, poultry, and pigs [9, 48]. The role of
the horse in food production systems has so far not been eval-
uated. Carrier rates in food-producing animals depend on age
and season. Carriage rates are generally higher in younger
animals and decrease over time in poultry, cattle, and pigs
[49, 50].
In cattle, it has been shown that carrier rates generally de-
crease with age and are approximately 7 % at the time of
slaughter [51•]. An increase at the time of entry into feedlots
associated with antimicrobial treatment has also been shown,
supporting an association between C. difficile and antimicro-
bial use [9]. Around finishing time, shedding rates are not
affected by antimicrobial administration [11]. Not all animals
are carriers and it cannot be predicted which ones are [11]. Up
to 100 % of healthy pigs less than 2 weeks of age have been
shown to carry C. difficile [52], decreasing to 2.5 % around the
time of harvest. Recently, C. difficile was isolated from lym-
phatics from 1 % of pigs at slaughter, indicating that dissem-
ination through the circulatory system occurs. Contamination
during slaughter processing might therefore not be the only
reason for the presence of this bacterium in meat [53]. In
poultry, C. difficile can be isolated from up to 60 % of chicken
during early production cycle, but carriage rate decreases to
<5 % around the time of harvesting [54, 55]
Studies of isolates from food-producing animals show
ribotype 078 to be the most prevalent (up to 80 %) in
pigs with calves demonstrating a larger diversity of
strains [9, 56, 57]. Most recently, almost identical strains
were isolated from pig farmers and their pigs, strength-
ening a suggestion that C. difficile could be transmitted
from animals to humans or vice versa, but to date, a
common environmental source could not be entirely
ruled out [58••].
C. difficile, including ribotype 027 and 078, has been iso-
lated from a variety of food sources, including meat, water,
and vegetables in North America, Europe, and Asia. This
reinforces the hypothesis of the potential risk of foodborne
infections linked to C. difficile. [59–65].
C. difficile in Companion Animals
In household pets, C. difficile carriage of up to 10 % is report-
ed and appears to be mainly asymptomatic. Nevertheless,
there are a few reports where pets developed disease when
the typical risk factors including antimicrobial treatment and
hospitalization were present [66, 67]. While strains isolated
from dogs differed from strains isolated from the correspond-
ing households, there are striking similarities between the
ribotypes of pets and human strains from patients in the same
geographical region, particularly concerning ribotype 027
[66]. Ribotype 027 has also been isolated from therapy dogs,
and these could be a potential reservoir for hospital patients
[68]. To date, there has been no confirmed direct transmission
from animal to humans, but one current recommendation in-
cludes to withdraw raw meat from the diet of household pets
to the exposure risk [69]. There is currently no data about the
role of companion animals used and held in livestock settings.
C. difficile Infection in Humans and Animals
Development of CDI depends on three major factors. Expo-
sure to spores or vegetative forms of C. difficile, followed by
proliferation and production of toxins in an immunologically
susceptible host with an abnormal gastrointestinal microbiota
allowing overgrowth of C. difficile (Fig. 1) [27].
Disease is usually restricted to adults, and the spectrum of
clinical manifestations ranges from healthy carriers to patients
with fulminant pseudomembranous colitis [27]. Not every hu-
man colonized by C. difficile will develop disease. This is
likely due the immune response and colonization resistance
in the form of microbe–microbe interaction, production of
antimicrobial substances by the resident microbiota, and com-
petition for nutrients and niches [27, 70]. When disruption of
the resident microbiota occurs, classically due to antimicrobial
treatment, toxigenic C. difficile proliferate and produce toxins
[71]. It is currently unknown which specific components of
microbiota confer protection against C. difficile infection, but
likely the phyla Firmicutes and Bacteriodetes play an impor-
tant role. Ampicillin, amoxicillin, cephalosporins,
clindamycin, and fluorquinolones are the antibiotics most fre-
quently associated with the disease [72]. There are many ad-
ditional risk factors for CDI, many associated with hospitali-
zation and concurrent illness (Fig. 1). Recently, CDI has in-
creasingly been described as a community-acquired disease
and linked to prior antimicrobial treatment, particularly with
fluoroquinolone [6]. Transmission from animals and food
sources is now being debated as a cause for these forms of
CDI [33].
In horses, CDI appears to be predominantly community-
associated rather than nosocomial in origin [4, 39, 73–75].
Horses are susceptible as adults or as foals and may develop

Fig. 1 Epidemiology and pathogenesis of C. difficile in horses. Purple:
Spores of Clostridium difficile; red, vegetative form of C. difficile. Horses
ingest spores of C. difficile from a variety of sources. Depending on risk
factors, protective factors, and strain, horses develop disease or remain
healthy. Disturbances of the microbiota through a variety or risk factors
disease as early as the first few days of life [73, 76, 77]. Cases
can occur sporadically or during outbreaks [73, 77, 78]. Trans-
mission occurs via feco-oral route by ingestion of vegetative
forms of C. difficile present in soil or fecal samples from
healthy carriers [79]. Alternatively, C. difficile might prolifer-
ate in subclinical carriers when predisposing factors appear
[80]. C. difficile is considered one of the most important
causes of acute enterocolitis in horses and can be isolated from
10 to 40 % of adult horses and 5 to 60 % of foals with diarrhea
[4–30, 31••, 32, 33, 34•, 35–40, 73, 81–84]. The various man-
ifestations of CDI in horses range from carrier status without
clinical signs to horses with fulminant enterocolitis [39].
Koch’s postulates of transmissible infection have been ful-
filled for CDI in foals [85]. In one experimental study, ten
horses were infected with oral C. difficile broth with and with-
out pre-treatment with low-dose penicillin. While C. difficile
was cultured from all horses, none developed diarrhea [86].
The final proof of causal relationship between C. difficile and
diarrhea in adult horses awaits confirmation.
The main risk factors for CDI in horses are antimicrobial
treatment and hospitalization (Fig. 1) [39, 40, 75, 81–87].
While all antimicrobials can be associated with CDI in horses,
beta-lactams, trimethoprim sulfonamides, clindamycin, eryth-
romycin, rifampicin, and gentamicin have been implicated
most often [40–50, 51•, 52–57, 58••, 59–78, 85, 88, 89].
Curr Clin Micro Rpt
leads to proliferation and toxin production of toxigenic C. difficile strains
and development of disease. Non-toxigenic strains do not cause disease.
If protective factors outweigh risk factors, horses can remain healthy
despite ingestion of toxigenic C. difficile strains
The association of antimicrobials with CDI is further support-
ed by reports from Sweden, where an association of erythro-
mycin succinate administration to foals was linked to fatal
C. difficile colitis in mares. Mares, whose foals were treated
with erythromycin succinate for Rhodococcus equi pneumo-
nia, developed diarrhea; 45 % were positive for C. difficile.
Foals whose mares developed diarrhea had higher amounts of
erythromycin succinate measured in their feces compared to
foals of healthy mares, indicating that there might have been
intake of erythromycin succinate by the mares [75]. Interest-
ingly, the recovered C. difficile isolates were resistant to eryth-
romycin and rifampin, which could have contributed to dis-
ease pathogenesis [75]. This was further supported in an ex-
perimental study when six mares were given low doses of
erythromycin succinate; two developed fatal colitis due to
CDI [88]. In vitro data has shown that some antimicrobials
might upregulate expression of adhesion genes [90]. Howev-
er, CDI can occur in adult horses without prior antimicrobial
treatment and antimicrobial treatment does not create a higher
risk of CDI versus colitis due to other etiologies [39]. There is
currently no proven association of isolated ribotypes with in-
cidence or severity of disease in horses.
In foals less than 7 days and a small proportion of older
animals, CDI is not associated with antimicrobial treatment or
hospitalization [39, 91]. The predisposing factors in these
Curr Clin Micro Rpt
animals are unclear, but stress factors such as transportation,
administration of proton pump inhibitors, change of diet, and
surgical or medical treatment have been discussed [81, 91].
The role of the gastrointestinal microbiota in disease preven-
tion and colonization has only recently been investigated, and
little information is available in horses. Decreased bacterial
richness was shown in two horses colonized with C. difficile;
however, none of the horses developed clinical disease [92••].
In humans, C. difficile is thought to be mainly a colonic
pathogen but cases of small intestinal enteritis have been re-
ported occasionally [93]. While lesion distribution in colitis-
affected adult horses is usually restricted to the cecum and
ascending colon [77–91, 92••, 93–95], foals suffering from
naturally occurring or experimental C. difficile enterocolitis
have severe small intestinal mucosal lesions with variable in-
volvement of the colon and cecum [77, 89]. C. difficile has
been recovered from the reflux of horses diagnosed with
duodenitis proximal jejunitis (anterior enteritis) [96] and small
intestinal segments of healthy horses [43] as well as from the
feces of horses affected by other small intestinal disorders
[97], but a causal relationship has not yet been proven.
Several other animal species have been shown to suffer
from CDI; however, the pathogenicity of C. difficile in many
of these species is still controversial. Aside from laboratory
animals which serve as animal models for human disease,
naturally occurring C. difficile-associated enteritis has been
seen in food-producing animals such as pigs and cattle, in
companion animals such as dogs and cats, and in wildlife in
captivity [32]. Lesion distribution depends on animal spe-
cies, and both small and large intestines can be affected
depending on age and species [94]. Among pigs, young
piglets have the highest risk of developing disease; up to
100 % of a litter can be affected in infected farrowing facil-
ities [98]. In such animals, disease can be fatal or result in
decreased weight gain. There is also one report of increased
mortality in CDI-affected sows associated with antimicrobial
treatment [99]. The role of C. difficile in calf enteritis is
controversial. While it was shown that calves suffering from
diarrhea shed C. difficile in higher amounts than controls
[49], experimental infection of colostrum deprived suckling
calves failed to establish a causal relationship [100].
Antimicrobial Resistance in C. difficile
In humans, metronidazole and vancomycin are the current
pillars of treatment for CDI. Despite the use in millions of
patients, clinically relevant resistance to metronidazole or van-
comycin has so far not been reported [72]. Since 2011,
fidaxomicin, a poorly absorbed bactericidal marcocyclic anti-
biotic, has been approved for humans. Despite its superiority
to vancomycin to prevent recurrent infection, its high cost has
limited its use [101]. In horses, fidaxomicin has not been
studied and vancomycin is mostly cost prohibitive and should
be handled as a protected antimicrobial; therefore, metronida-
zole is currently commonly used. Zinc bacitracin has been
evaluated for treatment of colitis in horses; however, there is
almost universal resistance among C. difficile isolates [102].
While clinically not yet important, metronidazole resis-
tance has been reported in C. difficile isolates. Generally,
metronidazole-resistant strains are considered more virulent
and cause more severe disease compared to metronidazole-
sensitive C. difficile. Metronidazol resistance in equine iso-
lates is uncommon [4, 103–105] but has been described in
North America [17, 106].
In vitro resistance to antimicrobials is common among
C. difficile isolates and depending on the ribotype and species
it is isolated from (Table 1). In vitro resistance to more than
one antimicrobial has been found in several equine studies,
with most isolates being resistant to ceftiofur and gentamicin,
not surprising as these represent commonly used antimicro-
bials in equine practice [103, 104, 107]. Resistance to peni-
cillin in horses varies [105] while resistance to oxytetracy-
cline is reported as uncommon in equine isolates [105] but
also in human and swine isolates [108, 109]. Resistance to
erythromycin is common in humans and has also been report-
ed in equines [105]. No association of antimicrobial resis-
tance and molecular strains has been determined so far in
horses [103, 110].
Resistance to antimicrobials is linked to clinical disease in
humans and horses. Antimicrobial treatment is a major risk
factor of developing clinical CDI, as resistant C. difficile
strains overgrow the microbiota which is hampered by anti-
microbial treatment [72]. Recently, CDI has mostly been as-
sociated with prior fluoroquinolone treatment, and fluoroquin-
olone resistance in C. difficile is increasing corresponding to
fluoroquinolone use [72]. In horses, erythromycin succinate
and rifampin given to foals resulted in fatal CDI in the mares
due to erythromycin succinate–resistant strains [75]. In human
medicine, it has been shown that reduction of antimicrobial
use leads to a reduction in CDI cases associated with the
respective antimicrobial [111].
Other Treatment Options
Several adjunctive treatment options for primary and recurrent
CDI have been evaluated in humans. Probiotic treatment has
been evaluated in many studies, with evidence currently not
being strong enough to support their use as either preventative
or therapeutic measure [112]. In the early 2000s, an old meth-
od for therapy of gastrointestinal disease was revisited—fecal
microbial transplantation, also called fecal bacteriotherapy.
Fecal microbial transplantation has since been evaluated for
treatment of recurrent CDI in human patients. With this meth-
od, the microbiota of a healthy donor is transferred to the
 Curr Clin Micro Rpt

Table 1 In vitro antimicrobial

resistance in Clostridium difficile Antimicrobial Human Horse
isolates from humans and horses
Antimicrobial Association Antimicrobial Association
resistance with resistance with
CDI CDI
Ampicillin Uncommon Very common Uncommon Common
Amoxicillin Uncommon Very common Uncommon Common
Penicillin Uncommon Common Uncommon Very common
Cephalosporins Common Very common Common Very common
Sulfonamides Very common Common Very common Very common
Aminoglycosides
Clindamycin Common Common Common Very commona
Gentamicin Common Uncommon Common Very common
Tetracycline Uncommon Uncommon Uncommon Uncommon
Macrolides Common Common Uncommon Uncommon
Metronidazol Uncommon Uncommon Uncommon Uncommon
Vancomycin Uncommon Uncommon Uncommon Uncommonb
Fluorquinolone
Ciprofloxacin Very common Very common Common Very commona
Moxifloxacin Uncommon Common Uncommon Uncommonb
Rifampin Uncommon Uncommon Uncommon Very common
Chloramphenicol Uncommon Uncommon Uncommon Uncommonb
a
Antimicrobials not recommended for use in horses due to severe side effects
b
Antimicrobials rarely used in horses

gastrointestinal tract of the affected patient through colonic or
duodenal infusion of a fecal slurry. Cure rates of up to 90 % of
recurrent C. difficile infection have been reported, and the
method is currently also being investigated as a treatment
option for primary CDI [113].
present in either humans or horses, supporting its use as
first-line antimicrobial against CDI in horses, but resistant
strains have been reported in recent years. Antimicrobial re-
sistance in C. difficile isolates is common and corresponds to
the classes most commonly used in that species.

Compliance with Ethical Standards

Conclusions Conflict of Interest The authors have no conflict of interest.

C. difficile is an important pathogen in human and animals,
and potentially a zoonotic agent. Similar to humans, newborn
animals tend to shed C. difficile in higher rates compared to
adults. However, unlike humans, neonatal animals are at risk
of developing disease due to C. difficile. Strains shed by ani-
mals are similar to human strains, including two hypervirulent
ribotypes, 078 and 027. Animal to human transmission has
not been proven, but animals could be an important reservoir
for human CDI. The epidemiology and pathophysiology of
the disease are incompletely understood but linked to distur-
bance of the microbiota and subsequent proliferation of
C. difficile with toxin production. Antimicrobial use is the
biggest risk factor for human and likely also equine disease,
with fluorquinolones currently being the most important anti-
microbial associated with CDI. Treatment of CDI is currently
mainly based on metronidazole in horses, with vancomycin
and fidaxomicin being alternatives in human medicine. Clin-
ically relevant metronidazole resistance is currently not
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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