D i a g n o s i s an d Tre a t m e n t o f

U n d i ff e re n t i a t e d a n d
I n f e c t i o u s A c u t e Di a r r h e a i n t h e
Adult Horse
a,b,1 b,
Sarah D. Shaw, DVM , Henry Stämpfli, DVM, Dr Med Vet *

KEYWORDS
 Equine  Colitis  Typhlocolitis  Infectious diarrhea  Intravenous fluid therapy

KEY POINTS
 Strict biosecurity measures should be enforced for all cases of acute diarrhea in adult
horses.
 Diagnostic tests for salmonellosis, clostridiosis, coronavirus, and Potomac horse fever are
evolving.
 Aims of treatment of acute diarrhea include fluid resuscitation, correction of electrolyte ab-
normalities, and limiting the systemic inflammatory response.
 Limited evidence exists to support many of the medications used to treat acute diarrhea
and the judicious use of therapeutics is warranted.

INTRODUCTION

Acute diarrhea associated with colitis or typhlocolitis is a major cause of morbidity in

horses and is life-threatening. Clinical signs of colic, hypovolemia, and endotoxemia
result from altered motility, hypersecretion of fluid, and disruption of the mucosal
barrier secondary to intestinal inflammation.
Undifferentiated and infectious acute diarrhea is a diagnostic and therapeutic
challenge. Differential diagnoses for the acutely diarrheic horse share similar clinical
and clinicopathologic features. Determination of causation is rarely possible. The
fundamental diagnostic approach includes assessment of hydration, electrolyte and

a
Rotenberg Veterinary P.C., Palgrave, Ontario LOG 1WO, Canada; b Large Animal Medicine,
Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph,
Ontario N1G 2W1, Canada
1
Present address: PO Box 1015, Tottenham, Ontario L0G 1W0, Canada.
* Corresponding author. Department of Clinical Studies, Ontario Veterinary College, University
of Guelph, 50 Stoneroad, Guelph, Ontario N1G 2W1, Canada.
E-mail address: [email protected]

Vet Clin Equine 34 (2018) 39–53

https://doi.org/10.1016/j.cveq.2017.11.002 vetequine.theclinics.com
0749-0739/18/ª 2017 Elsevier Inc. All rights reserved.
40 Shaw & Stämpfli

acid-base abnormalities, mucosal integrity, organ function, and the inflammatory

response. Immediate therapeutic intervention, often in the absence of a definitive
diagnosis, reduces comorbidities and mortality.

INITIAL DIAGNOSTICS
Bloodwork
Hematologic abnormalities seen early in the course of gastrointestinal disease reflect
stress and endotoxemia. Leukopenia may be characterized by lymphopenia,
neutropenia with or without a left shift, and toxic changes in neutrophils. A neutrophilic
leukocytosis may be seen later. Degenerative left shifts and the presence of metamye-
locytes and myelocytes are poor prognostic indicators.1 Hemoconcentration and
thrombocytopenia are common. Horses with a packed cell volume greater than
45% were 3.5 times less likely to survive.2 Hyperfibrinogenemia and elevated serum
amyloid A may be seen in acute, severe, colitis3
Diarrhea in horses is associated with hemodynamic and electrolyte changes caused
by intraluminal sequestration of fluid. Serum biochemistry often reveals renal or prerenal
azotemia and electrolyte abnormalities including hyponatremia, hypochloremia, hypo-
kalemia, and hypocalcemia. In one retrospective, negative base excess was the best
prognostic indicator.4 In a study of 101 horses, plasma lactate at admission was not
associated with survival status. However, reduction in serial lactate concentration by
greater than or equal to 30% 4 to 8 hours and by greater than or equal to 50% 24 hours
after admission was significantly associated with survival.5 A creatinine concentration
greater than 2.0 mg/dL (176.8 mmol/L) was also associated with a lower likelihood of sur-
vival.2 Hyperproteinemia may be present with severe dehydration, although mild to se-
vere hypoproteinemia is also seen as a result of gastrointestinal protein loss.

Ultrasonography
Abdominal ultrasonography is an important diagnostic aid in cases of acute diarrhea
and should be performed to assess large and small intestinal wall thickness and peri-
toneal fluid volume and character. See Nicola C. Cribb, Luis G. Arroyo’s article,
“Techniques and Accuracy of Abdominal Ultrasound in Gastro-Intestinal Diseases
of Horses and Foals,” in this issue for more details.

Pathogen-Specific Serologic and Fecal Diagnostics

Commercial laboratories frequently offer diarrhea panels, which are helpful for
screening for numerous pathogens. However, like any screening test, specificity
may be compromised and results should be interpreted with caution. Furthermore,
some diagnostic laboratories include tests that are unnecessary or not clinically rele-
vant in the adult horse. Table 1 provides a summary of commercially available fecal
and serologic diagnostics and their limitations.

DIFFERENTIAL DIAGNOSES
Salmonellosis
Salmonellosis is a well-recognized cause of acute diarrhea in the horse. It is reported
as a result of infection with Salmonella enterica subsp. enterica, a G , facultative
anaerobic bacterium. Numerous serovars are associated with clinical disease but
Salmonella typhimurium is commonly isolated from diarrheic horses and associated
with high pathogenicity.6 Salmonella infection in adult horses ranges from the
inapparent carrier state, to pyrexia, anorexia, leukopenia, and depression without
diarrhea, to acute, severe, enterocolitis with diarrhea.
 Infectious Acute Diarrhea in the Adult Horse 41

Table 1
Diagnostic tests for acute diarrhea in the adult horse

Pathogen Diagnostic Tests Comments

Salmonella spp Fecal PCR Potentially highly sensitive and specific. Fast
turnaround time. Serial samples needed.
Fecal culture Slower but provides isolates for susceptibility
testing and typing. Serial samples needed.
Sensitivity is impacted greatly by laboratory
methods, such as enrichment culture, and
laboratory experience.
Clostridium Culture (isolation Extra testing required to determine if isolates
difficile with selective media) are toxigenic.
Antigen ELISA Quick and inexpensive. Very sensitive but lower
specificity. Will detect toxigenic and
nontoxigenic strains. Most often used as in
initial screening test because of high negative
predictive value, with positives tested by ELISA
or PCR.
Toxin A/B II ELISA, Performance of different commercial assays on
(or cytopathic effect horse feces is likely highly variable. Has been
cell culture) clinical standard for diagnosis.
PCR for TcdA and TcdB Can be quick and highly sensitive. False-positives
can occur because of detection of carriers,
which is common in some populations.
Clostridium Culture Low diagnostic yield because of common
perfringens shedding by healthy horses.
Culture 1 PCR PCR to detect selected toxin genes can increase
diagnostic relevance, particularly with genes
more commonly associated with disease
(eg, NetF, beta2).
Toxin-ELISA Currently restricted to enterotoxin. Positive
results are suggestive but enterotoxin is
detected in some healthy horses.
PCR Genotyping is available in specialized
laboratories.
Coronavirus Fecal PCR Epidemiology of ECoV is not well established but
positive results in horses with disease
consistent with ECoV infection provides a
presumptive diagnosis.
Neorickettsia Fecal and blood PCR Detection in blood may be more sensitive early
risticii in the course of disease; horses become PCR
positive on feces later.
Serology (IFA) Single serum samples are not diagnostic.

Abbreviations: ECoV, equine coronavirus; ELISA, enzyme-linked immunosorbent assay; IFA, indirect
fluorescent antibody; PCR, polymerase chain reaction; TcdA, C difficile toxin A; TcdB, C difficile are
toxin B.

Clinically apparent salmonellosis in adult horses most commonly manifests as

enterocolitis with large-volume, watery diarrhea with subsequent bacteremia.7 Pro-
found neutropenia is characteristic in Salmonella infections and results from neutrophil
margination, invasion into the intestinal villi, and loss in the intestinal lumen.8 Intestinal
mucosal damage permits bacterial entry into the portal circulation, potentially
damaging hepatocytes and increasing serum levels of sorbitol dehydrogenase and
aspartate transaminase.8 Dehydration is severe and is associated with prerenal
42 Shaw & Stämpfli

azotemia and decreased blood pH. Clinical signs of pyrexia, inappetance, diarrhea,
and colic are largely a result of the host inflammatory response.
Risk factors for infection include recent abdominal surgery, antimicrobial adminis-
tration, transportation, gastrointestinal disease, immunosuppression, diet changes,
respiratory disease, high ambient temperature, and general anesthesia.9–11 Historical-
ly, a diagnosis of Salmonella colitis was made through identification of the organism on
fecal culture, but it is only intermittently shed. Real-time quantitative polymerase chain
reaction (qPCR) has largely replaced culture based on shorter time to results,
increased relative sensitivity, and potentially fewer serial samples required to detect
Salmonella.7,12 Between three and five serial fecal samples (for PCR or culture),
depending on laboratory methods, are recommended to determine negative
Salmonella status.
Treatment in early disease is mainly supportive with intravenous, isotonic fluids
directed at volume replacement and to buy time for tissue recovery. Acid-base and
electrolyte abnormalities should be corrected and inflammation controlled. Severe
leukopenia frequently occurs in cases of Salmonella infection and warrants consider-
ation of antimicrobial therapy with aminoglycosides, fluoroquinolones, or cephalospo-
rins. Given the propensity for this organism to cause microthrombosis and infarction,
anticoagulant therapy may be considered. Nosocomial Salmonella infections and
hospital biosecurity have been the focus of recent literature. Outbreaks in teaching
hospitals have resulted in prolonged closures, significant economic losses, and
decreased clinic time for veterinary students. Strict biosecurity measures should
be enforced in cases of acute diarrhea to prevent the potential nosocomial spread
of Salmonella spp and other highly infectious organisms.

Clostridiosis
Colitis as a result of Clostridium difficile infection (CDI) was first described in horses in
1987. Clostridium perfringens and C difficile are the clostridial species most commonly
associated with diarrhea, with sporadic cases attributed to Clostridium septicum,
Clostridium sordelli, and Clostridium cadaveris.

Clostridium difficile
C difficile is a common isolate in cases of colitis in adult horses. CDI has received
recent attention in the human literature, although the most prevalent ribotypes respon-
sible for disease differ between humans and animals. C difficile is isolated from the
manure of healthy horses and prevalence rates range from 0% to 33%.13,14 Thus,
the carrier state in horses and livestock has been suggested as a reservoir for human
CDI.
The most important risk factors for CDI in adult horses are antimicrobial administra-
tion and hospitalization. Isolation of toxigenic C difficile has been associated with the
administration of all antimicrobials, most notably b-lactams, gentamicin, trimethoprim
sulfonamides, clindamycin, erythromycin, and rifampicin.14 Proton pump inhibitors
and H2 antagonists have been implicated in the development of CDI in horses, but
strong evidence is lacking.
The most important virulence factors of C difficile are toxin A (TcdA, an enterotoxin)
and toxin B (TcdB, a cytotoxin). Clinical disease, however, only occurs when the
normal gastrointestinal flora is disrupted and toxigenic strains of C difficile proliferate.
In humans CDI is acute or chronic, whereas chronic CDI in horses has not been
described.
C difficile colitis varies from peracute colitis with a rapid decline to a milder, more
prolonged course. Horses may be pyrexic, depressed, and anorexic before
 Infectious Acute Diarrhea in the Adult Horse 43

developing diarrhea and gastrointestinal signs. Neutropenia, hypoproteinemia, dehy-

dration, hemoconcentration, and electrolyte and acid-base abnormalities may all be
appreciated. C difficile is challenging to culture so false-negative test results are
possible and CDI is therefore likely underdiagnosed. Enzyme immunoassays have
been developed for the identification of TcdA and TcdB, although their performance
is highly variable. More recently, molecular detection methods following bacterial cul-
ture have been used to identify genes for TcdA and TcdB in the feces of horses.15,16
Aside from supportive care, specific treatments for CDI remain controversial. Evi-
dence exists that Saccharomyces boulardii, a nonpathogenic yeast, can destroy
TcdA.17 Di-tri-octahedral smectite binds TcdA and TcdB in a dose-dependent manner
in vitro and may be useful to limit the toxemic effects of these toxins. Metronidazole is
commonly used to treat C difficile colitis in horses to reduce the C difficile population,
whereas the normal flora is restored. Although metronidazole resistance has been
documented in cases of human infection, it is not a prevalent feature in equine
CDI.14 However, even targeted antimicrobial therapy can have deleterious effects
on the microbiota and may disrupt or delay recolonization with beneficial bacteria.
Recently, fecal transfaunation, also known as fecal microbial transplantation or fecal
bacteriotherapy, has re-emerged as a treatment of CDI in humans and horses. Prox-
imal duodenal infusion with donor feces was significantly more effective than standard
vancomycin therapy in humans with recurrent CDI.18 Anecdotal evidence supports the
use of fecal microbial slurries via nasogastric intubation for treatment of acute cases of
equine CDI.19 Further investigation is needed to provide evidence-based support.

Clostridium perfringens
C perfringens is associated with occasional cases of acute diarrhea in adult horses. It
has been isolated from the gastrointestinal flora of normal horses, although reported
prevalence rates are low, ranging from 0% to 8% in healthy adult horses.13 It is clas-
sified into five types (A to E) based on exotoxin production. C perfringens type A is the
isolate most commonly cultured from healthy and diarrheic adult horses. b2 toxin, sus-
pected to be produced by a subtype of C perfringens type A, has been associated with
clinical C perfringens infections in horses with colitis.20,21 b-toxin produced by types B
and C has direct cytotoxic effects resulting in enterocyte necrosis, mucosal ulceration,
and hemorrhagic diarrhea. Enterotoxin, produced by both type A and type C strains,
creates pores and alters membrane permeability, leading to cell necrosis. The pore-
forming toxin NetF has also been recently identified as a major virulence determinant
and has been associated with necrotizing enteritis in foals and dogs.
Clinical signs of C perfringens vary from peracute fatal colitis to a milder presenta-
tion with anorexia, depression, and pyrexia. Gastrointestinal signs include profuse,
watery diarrhea that may be hemorrhagic. Affected horses demonstrate nonspecific
signs of colic, endotoxemia, and dehydration. Given its presence in the feces of
normal horses, the diagnosis of C perfringens colitis is challenging. Quantitative fecal
culture no longer supports a diagnosis of C perfringens colitis. Enzyme immunoassays
for the C perfringens enterotoxin detect its presence in healthy and clinically affected
horses. More recently, PCR has been used to detect toxin genes, although not proving
a causal relation.15 Therapy is mainly supportive. Specific therapy aimed at binding
exotoxins includes treatment with di-tri-octahedral smectite.22,23 There is limited evi-
dence of the benefits of metronidazole therapy in cases of C perfringens colitis.

Coronavirus
Equine coronavirus (ECoV) has recently emerged as a significant enteric pathogen in
adult horses.24,25 Although coronaviruses have been long identified in the feces of
44 Shaw & Stämpfli

adult horses and foals, their role in the pathogenesis of enteric fever and diarrhea was
only recently elucidated after outbreaks of clinical disease. ECoV is an enveloped,
positive-stranded RNA virus belonging to the Betacoronavirus-1 genus. Transmission
is believed to be via the fecal-oral route. Infection begins in the small intestine. Lesions
include necrosis and sloughing of enterocytes in the intestinal villi, dilated crypts filled
with necrotic debris, and mucosal inflammation.25,26
Hematologic abnormalities include leukopenia, characterized by neutropenia and/
or lymphopenia.25 The most common clinical manifestations of ECoV infection include
anorexia, lethargy, and fever.22,25 In a report of 59 clinical cases, diarrhea and colic
were only seen 20% and 7% of affected horses, respectively.25 Neurologic signs
associated with ECoV infection have been described and seem to be associated
with hyperammonemic encephalopathy with Alzheimer type II astrocytosis in the
cerebral cortex.26
Diagnosis of ECoV colitis is currently based on PCR of feces, gastrointestinal con-
tents, or tissue samples. In one study there was no significant statistical difference in
absolute ECoV quantification between positive sick and positive healthy horses. How-
ever, the overall agreement between clinical status (horses demonstrating clinical
signs of ECoV infection) and ECoV-positive status on PCR was 91%.25 Therapy is
directed at supportive care and prevention of hyperammonemic encephalopathy.

Potomac Horse Fever

Potomac horse fever (PHF), or equine neorickettsiosis, was first recognized as a cause
of acute typhlocolitis in horses in the United States in 1984 along the Potomac River
area and has since been described in Canada, Uruguay, Brazil, and Europe. This
acute, potentially fatal disease is an infection with the gram-negative, obligate, intra-
cellular, bacterial endosymbiont Neorickettsia risticii.27 The bacterium survives in
digenic trematodes, such as Acanthatrium and Lecithodendrium spp.28 Trematodes
use freshwater and lymnaeid snails as first intermediate hosts and aquatic insects
(mayflies, caddisflies, damselflies, dragonflies, and stoneflies) as second intermediate
hosts.29,30 The definitive hosts of these trematodes are brown bats (Eptesicus fuscus
and Myotis lucifugus). Horses become accidental hosts of digenic trematodes when
they inadvertently ingest infected intermediate hosts. N risticii is released from the
trematode and once inside the equine gastrointestinal tract it invades and replicates
within the colonic epithelial cells. It also translocates into blood monocytes (equine
monocytic ehrlichiosis), mast cells, and tissue macrophages. A seasonal rise in dis-
ease incidence is seen during warmer months.
The most common clinical signs of PHF are diarrhea, fever, anorexia, depres-
sion, and colic.30 Abortions may also occur as a result of N risticii infection. In
one retrospective of 44 horses with PHF, laminitis was identified in 36%, of which
88% were affected in all four feet.30 Horses present with clinicopathologic abnor-
malities typically seen in equine colitis. The same study identified that serum creat-
inine and urea nitrogen concentrations, hematocrit, red blood count, blood
hemoglobin concentration, band neutrophils, serum aspartate transaminase,
serum CK, and anion gap were significantly higher in nonsurvivors. Further, serum
chloride, serum sodium, and duration of hospitalization were significantly lower in
nonsurvivors.30
Diagnostics for PHF include serum indirect fluorescent antibody testing, enzyme-
linked immunosorbent assay, culture of N risticii from buffy coat or feces, and PCR
on whole blood or feces. Both exposure and vaccination lead to many false positives
with antibody testing and in one study 16% of healthy horses had a rise in paired in-
direct fluorescent antibody titers,31 so antigen testing is recommended. Culture of N
 Infectious Acute Diarrhea in the Adult Horse 45

risticii remains the gold standard of diagnosis, although PCR was reported to identify
81% of culture-positive, naturally infected horses.32
Tetracycline antibiotics effectively kill N risticii and oxytetracycline administration to
horses with clinical signs of disease has been positively associated with survival.30
Additional therapy is supportive and includes fluid replacement and laminitis preven-
tion. Particular attention should be paid to fluid resuscitation in hypovolemic horses
either before, or in conjunction with, administration of nephrotoxic drugs (oxytetracy-
cline and nonsteroidal anti-inflammatory drugs [NSAIDs]). Several killed and adjuvants
vaccines have been marketed. However, vaccine failure rates are high,33,34 likely
caused by the antigenic differences present among greater than 14 N rickettsia strains
isolated from clinical cases.27

TREATMENT AND SUPPORTIVE CARE

Fluid Therapy
Fluid therapy in gastrointestinal disease has been covered in depth.35 Fluid plans
should be based on clinical and clinicopathologic assessment. Fluid deficits are based
on the formula:

Volume deficit (L) 5 Bwt (kg) * % dehydration

A generally accepted approach is replacement of the volume deficit at a rate of 10 to

20 mL/kg/h.35 The patient should be reassessed every 4 to 6 hours and changes to the
fluid plan made according to changes in hydration status. Maintenance requirements
and ongoing fluid losses should also be calculated to administer fluids at an appro-
priate rate:

Maintenance fluid volume 5 50 to 100 mL/kg per 24 hours

The goal of fluid therapy is volume resuscitation and correction of lactic acidosis;
commercially available, balanced, isotonic fluids should be administered. Fluid sup-
plementation decisions should be made based on serum electrolytes and acid-base
status. Lactic acidosis caused by dehydration is common. Hypokalemia is common
in anorectic horses with gastrointestinal disease and should be addressed when
serum potassium is less than 3 mEq/L. Sodium bicarbonate supplementation is
considered if the base deficit is greater than 10 mEq/L or the pH is less than 7.2.
The required amount of sodium bicarbonate should be administered as an isotonic so-
lution over a period of 24 hours.35 It is important to remember that the administration of
sodium bicarbonate does not correct a metabolic acidosis (lactic acidosis) secondary
to dehydration. Therefore, sodium bicarbonate should be used as adjunct therapy to
balanced isotonic fluids, and only if metabolic acidosis is severe. The amount of so-
dium bicarbonate required is estimated using the following formula:

Na-HCO3 (mmoL/L) 5 BE x BW x 0.3

An ionized calcium level of less than 1.4 mg/dL (0.3493 mmol/L)35 and decreased
intestinal motility are indications for calcium supplementation.
Colloid Oncotic Support
The general indications for the use of colloids include hypovolemia, hyproteinemia,
and decreased osmotic pressure. Because hypoproteinemia is common in horses
with diarrhea, synthetic colloids and commercial equine plasma are often
administered.
46 Shaw & Stämpfli

The literature evaluating the use of synthetic colloids in horses is limited to experi-
mental studies and small population clinical evaluations. Hydroxyethyl starch (HES)
increased colloid osmotic pressure (COP) in normal ponies but had dose-
dependent effects on hemostatic variables, leading a trend in prolongation of bleeding
times.36 In hypoproteinemic horses, HES had a modest effect on COP but adminis-
tering typical doses did not restore COP to normal.37,38 In an experimental endotox-
emia, the use of HES with hypertonic saline solution exerted no benefit on cardiac
output or systemic vascular resistance compared with isotonic fluid resuscitation.39
Furthermore, no significant differences in coagulation measures were noted between
horses treated with HES versus isotonic fluids.40 However, HES has been shown to
adversely affect platelet function in vitro and in healthy horses.41,42
The use of synthetic colloids over crystalloids in human patients with sepsis has
been questioned. Colloid administration has been associated with acute kidney injury,
osmotic nephrosis, hemorrhage, anaphylactoid reactions, tissue accumulation,
hepatic organ failure, and pruritus. Despite numerous randomized clinical trials and
meta-analyses, there is conflicting evidence correlating colloid administration with
increased mortality rates and increased need for renal-replacement therapy. Howev-
er, the 2012 Surviving Sepsis Campaign recommended against the use of HES in
sepsis.43 As a result, the European Medicine Agency concluded that HES solutions
should not be used in patients with sepsis or critically ill patients and the Food and
Drug Administration placed a boxed warning on HES for increased mortality and
renal-replacement therapy in 2013.
A recent study comparing the effects of HES versus commercial equine plasma on
clinicopathologic values and COP in healthy horses revealed both products produced
equivalent, although modest, increases in plasma COP. Meanwhile, plasma had a less
profound and less prolonged dilutional effect on hematocrit, blood hemoglobin, serum
total protein, and albumin concentration compared with HES.44
The benefits of HES over plasma include lower cost, easier storage, higher oncotic
pressure, and no risk of infectious disease transmission.44 However, equine plasma
provides immunoglobulins, coagulation factors, and antithrombin. Plasma may also
be less likely to result in acute kidney injury or coagulation abnormalities in critically
ill patients. Although evidence from the human literature cannot be applied to equine
medicine, there is a need for further evaluation of HES use in critically ill and septic
horses. In the meantime, judicious use of colloids in these patients is recommended.

Antimicrobial Therapy
The advantages and disadvantages of antimicrobial administration should be consid-
ered before use in cases of acute diarrhea. In one retrospective, horses presenting
with colitis that were previously treated with antimicrobials were 4.5 times less likely
to survive than those not treated.2 Antimicrobial use affects the fecal microbiota,45,46
which is likely already disturbed.47 Procaine penicillin, ceftiofur sodium, and trimetho-
prim sulfadiazine administration all impacted the fecal microbiota in healthy horses,
and changes often persisted for 25 days.46
The identification or clinical suspicion of the presence of certain pathogens warrants
targeted antimicrobial use. Oxytetracycline is considered the treatment of choice for
horses with PHF.30 Metronidazole is recommended for the treatment of C difficile–
associated diarrhea (CDAD) in humans and is often used to treat horses with
confirmed or presumed CDAD. However, Magdesian and colleagues15 demonstrated
an association between metronidazole administration and identification of
metronidazole-resistant C difficile strains. Although metronidazole resistance in hors-
es with CDIs is not considered clinically important at this time, these strains are
 Infectious Acute Diarrhea in the Adult Horse 47

suspected to be more virulent.14 To this effect, horses with metronidazole-resistant

strains of C difficile had an increased risk of mortality compared with horses infected
with metronidazole-susceptible strains.15
Antimicrobial therapy may be warranted in acute diarrhea cases demonstrating
severe neutropenia and/or evidence of septic foci, such as in the lungs, liver, or jugular
veins. Antimicrobial drug selection should be based on culture and susceptibility pat-
terns of the causative agents whenever possible. However, in cases of acute undiffer-
entiated diarrhea in horses, antibiotics may be contraindicated because of further
disruption of the microbiota. Furthermore, increased shedding of Salmonella was
associated with the administration of antimicrobials48 and multidrug resistance in
Salmonella spp is an emerging threat. Therefore, judicious use of systemic antimicro-
bials is strongly recommended.

Limiting the Effects of Endotoxemia

Efforts should be made to limit endotoxin entry into circulation, reduce the release of
inflammatory mediators, neutralize circulating endotoxin, and provide supportive
care.49 NSAIDs inhibit cyclooxygenase enzymes associated with early hemodynamic
responses to endotoxin. Both flunixin meglumine and ketoprofen significantly
decreased the production of thromboxane B2 production by blood monocytes
in vitro.50 Low doses of flunixin meglumine (0.25 mg/kg) suppressed thromboxane
and prostaglandin production in horses challenged with endotoxin.51 Although a
dose of 1.1 mg/kg is also antiendotoxic, the lower dose may be associated with fewer
side effects, especially in cases with renal insufficiency. Administration of NSAIDs to
horses with endotoxemia is a mainstay of treatment. Albeit in practice, treatment is
initiated following challenge with endogenous endotoxins, whereas experimentally,
benefits were noted when NSAIDs were administered before endotoxin exposure. Cli-
nicians often administer flunixin meglumine every 8 hours to control the clinical signs
of endotoxemia while limiting adverse side effects, such as renal papillary necrosis
and gastrointestinal ulceration.49
Polymyxin B is a cationic polypeptide antibiotic that forms a stable complex with the
lipid A component of lipopolysaccharide. Once bound, lipopolysaccharide does not
interact with equine inflammatory cells, thus preventing initiation of the proinflamma-
tory cascade.49,52 Initial high doses reportedly produced signs of neurotoxicity and
nephrotoxicity. When administered to healthy horses at doses between 1000 and
5000 IU/kg, polymyxin B inhibited 75% of endotoxin-induced tumor necrosis factor
activity53 and no alterations in either creatinine53 nor urine g-glutamyltransferase-to-
creatinine ratios52 were noted. However, polymyxin B should be used with caution
in hypovolemic and azotemic animals and should always be administered diluted in
isotonic fluids. If side effects of neuromuscular blockage or other neurologic side ef-
fects occur, administration should be discontinued.
Hyperimmune plasma or serum, derived from horses immunized against G-bacteria
and endotoxin, has the proposed benefits of neutralizing endotoxin and modulating
leukocyte activation. However, there is conflicting evidence of the benefits of admin-
istration of hyperimmune plasma in experimental models of endotoxemia in horses.49
A recent study54 revealed that pretreatment with hyperimmune equine plasma failed to
modify clinical signs of experimentally induced endotoxemia and had no impact on
leukocyte activation, but reduced the bioactivity of tumor necrosis factor-a. Further
studies are needed to evaluate the clinical benefits of hyperimmune plasma or serum
in endotoxemic horses.
Pentoxifylline is a methyxanthine derivative that increases the deformability of red
blood cells, suppresses production of proinflammatory cytokines, and can inhibit
48 Shaw & Stämpfli

the activation of B and T cells.55 Experimentally, pentoxifylline administration had

limited beneficial effects in endotoxemic horses56 and slight benefits in combination
therapy with flunixin meglumine.57 Pentoxifylline is most commonly used in horses
with laminitis and placentitis to increase microvascular blood flow, but there are
currently no published controlled clinical trials supporting its use.

Intraluminal Intestinal Binding Agents

In theory, binding exotoxins and endotoxin within the gut lumen may decrease sys-
temic absorption in horses with colitis. Di-tri-octaheadral smectite is a negatively
charged, hydrated, aluminomagnesium that binds positively charged organic cations.
Dose-dependent binding of Di-tri-octaheadral smectite with C difficile toxins A and B,
C perfringens enterotoxin, and endotoxin has been demonstrated in vitro.23,24 The rec-
ommended dose is a 1.4-kg loading dose followed by 454 g every 6 to 12 hours,
necessitating frequent nasogastric intubation. Activated charcoal is a nonspecific
binding agent used in many monogastric species. A recent in vitro study demon-
strated no significant effects of activated charcoal on the microbial population, major
metabolites produced, rate of gas production, or pH values.58 These findings suggest
that the impact of activated charcoal on the equine hindgut, and binding of toxic sub-
stances, may be minimal. Further in vivo studies are needed to elucidate the benefits
of these binding agents.

Probiotics
Probiotics are discussed elsewhere in this issue. In one study of 14 horses with diar-
rhea, administration of S boulardii decreased the duration of diarrhea from 7 to 5 days,
compared with control horses.59 In contrast, there was no significant difference in re-
turn to normal manure, return to normal heart rate, appetite improvement, or any other
clinical variables measured between Saccharomyces-treated and control horses in a
randomized prospective study.60
The administration of Lactobacillillus spp and Bifidobacterium animalis lactis had no
impact on clostridial shedding and minimal impact on the composition of the fecal
microbiota in foals when administered for 3 weeks.61 Recent literature suggests that
orally administered probiotics (Pediococcus acidilactici and S boulardii) may have
immunomodulatory effects in horses.62 At this time, there is conflicting evidence
regarding the clinical benefit of probiotic administration. Furthermore, label claims
on veterinary probiotic preparations often contain gross inaccuracies and quality con-
trol of products is lacking.63,64

Additional Supportive Care Measures

Gastroprotectants such as omeprazole and H2 antagonists, are often used prophylac-
tically to prevent gastric ulceration in anorectic horses with acute diarrhea. Proton
pump inhibitor administration has long been suspected to be a risk factor for CDAD
in humans, although high-quality evidence of a cause-effect relationship is lacking.65
Foals treated with antiulcer medication were two times more likely to develop diarrhea
than those left untreated, but this was not associated with CDI.66 The relationship be-
tween antiulcer medications, diarrhea, and CDAD in adult horses is unknown, but
increasing gastric pH may eliminate a defense against C difficile and other pathogens.
Laminitis is commonly encountered in cases of sepsis. Currently, distal limb cryo-
therapy (applied from hoof to carpus for 72 hours continuously) is the only method
of prevention of laminitis in horses with systemic inflammation that has been vali-
dated.67 Other feasible laminitis prevention techniques include treating the primary
disease process, anti-inflammatory therapy (NSAIDs, pentoxifylline), inhibition of
 Infectious Acute Diarrhea in the Adult Horse 49

neutrophil and platelet margination (low-molecular-weight heparin, pentoxifylline,

aspirin, and possibly corticosteroids), antioxidant therapy (dimethyl sulfoxide), and
physical support of the sole with easing of breakover.68
Bacterial sepsis has the potential to lead to disseminated intravascular coagulation
secondary to widespread inflammation. Salmonellosis has been associated with
thrombotic events in ewes and disseminated intravascular coagulation in horses.8 In
a controlled clinical trial in humans with sepsis, heparin improved hypercoagulable
states, reduced time in the intensive care unit, and decreased days on mechanical
ventilation.69 In a retrospective study of 360 horses that underwent colic surgery,
the prevalence and grade of laminitis was lower in horses treated with low-
molecular-weight heparin.70 Although unfractioned heparin is often used for prophy-
laxis of coagulation disorders, low-molecular-weight heparin was associated with
fewer side effects, such as decreased packed cell volume (PCV), catheter-site com-
plications, and decreased platelet counts.71 Based on limited data, heparin therapy
may be indicated in as a prophylactic measure in horses with severe sepsis.
Nutritional support improves outcomes in critically ill humans and small animal pa-
tients. Horses with acute colitis or typhlocolitis are often partially or completely
anorexic as a result of ileus, dysmotility, hypoperfusion, and the systemic inflamma-
tory response. A low-bulk diet, such as a complete pelleted feed, good-quality
grass hay, or alfalfa, is recommended for horses with acute colitis.72 Offering fresh
grass may stimulate the appetites of anorectic horses, although large amounts
of grass may contribute to the development of laminitis or colic signs. Parenteral nutri-
tion is beneficial in severely catabolic cases of acute colitis that do not tolerate enteral
feeding. Parenteral nutrition is indicated in diarrheic patients with anorexia persisting
more than 48 to 72 hours and in pregnant and lactating mares.

SUMMARY

The cause of acute, infectious, diarrhea in adult horses is often difficult to define. How-
ever, aims of therapy are universal and prompt intervention decreases morbidity and
mortality. Furthermore, strong evidence to support many common therapeutic options
is lacking, and this should be considered when constructing treatment plans.

REFERENCES

1. Sanchez LC. Pathophysiology of Diarrhea. In: Reed SM, Bayly WM, Sellon DC,
editors. Equine internal medicine. vol. 3rd edition. St. Louis(MO): Saunders;
2010. p. 793–866.
2. Cohen ND, Woods AW. Characteristics and risk factors for failure of horses with
acute diarrhea to survive: 122 cases (1990-1996). J Am Vet Med Assoc 1999;
214(3):382–90.
3. Belgrave RL, Dickey MM, Arheart KL, et al. Assessment of serum amyloid A
testing of horses and its clinical application in a specialized equine practice.
J Am Vet Med Assoc 2013;243(1):113–9.
4. Staempfli HR, Townsend HGG, Prescott JF. Prognostic features and clinical pre-
sentation of acute idiopathic enterocolitis in horses. Can Vet J 1991;32(2):232–7.
5. Hashimoto-Hill S, Magdesian KG, Kass PH. Serial measurement of lactate con-
centration in horses with acute colitis. J Vet Intern Med 2011;25(6):1414–9.
6. Weese JS, Baird JD, Poppe C, et al. Emergence of Salmonella typhimurium defin-
itive type 104 (DT104) as an important cause of salmonellosis in horses in On-
tario. Can Vet J 2001;42(10):788–92.
50 Shaw & Stämpfli

7. Kurowski B, Traub-dargatz JL, Morley PS, et al. Detection of Salmonella spp in

fecal specimens by use of real-time polymerase chain reaction assay. Am J Vet
Res 2002;63(9):1256–68.
8. Timoney J. Salmonella infections in horses. In: Barrow PA, Methner U, editors.
Salmonella in domestic animals. 2nd edition. Oxfordshire(UK): CABI; 2013.
p. 305–17.
9. Ekiri AB, MacKay RJ, Gaskin JM, et al. Epidemiologic analysis of nosocomial sal-
monella infections in hospitalized horses. J Am Vet Med Assoc 2009;234(1):
108–19.
10. Ernst NS, Hernandez JA, MacKay RJ, et al. Risk factors associated with fecal sal-
monella shedding among hospitalized horses with signs of gastrointestinal tract
disease. J Am Vet Med Assoc 2004;225(2):275–81.
11. Alinovi CA, Ward MP, Couëtil LL, et al. Risk factors for fecal shedding of Salmo-
nella from horses in a veterinary teaching hospital. Prev Vet Med 2003;60(4):
307–17.
12. Cohen ND, Martin LJ, Simpson RB, et al. Comparison of polymerase chain reac-
tion and microbiological culture for detection of salmonellae in equine feces and
environmental samples. Am J Vet Res 1996;57(6):780–6.
13. Schoster A, Arroyo LG, Staempfli HR, et al. Presence and molecular characteriza-
tion of Clostridium difficile and Clostridium perfringens in intestinal compartments
of healthy horses. BMC Vet Res 2012;8(94):1–6.
14. Schoster A, Staempfli H. Epidemiology and antimicrobial resistance in Clos-
tridium difficile with special reference to the horse. Curr Clin Microbiol Rep
2016;3(1):32–41.
15. Magdesian KG, Dujowich M, Madigan JE, et al. Molecular characterization of
Clostridium difficile isolates from horses in an intensive care unit and association
of disease severity with strain type. J Am Vet Med Assoc 2006;228(5):751–5.
16. Magdesian KG, Leutenegger CM. Real-time PCR and typing of Clostridium diffi-
cile isolates colonizing mare-foal pairs. Vet J 2011;190(1):119–23.
17. Elmer GW, McFarland LV. Biotherapeutic agents in the treatment of infectious
diarrhea. Gastroenterol Clin North Am 2001;30(3):837–54.
18. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for
recurrent Clostridium difficile. N Engl J Med 2013;368(5):407–15.
19. Mullen KR, Yasuda K, Divers TJ, et al. Equine faecal microbiota transplant: cur-
rent knowledge, proposed guidelines and future directions. Equine Vet Educ
2016;1–10.
20. Waters M, Raju D, Garmory HS, et al. Regulated expression of the beta2-toxin
gene (cpb2) in Clostridium perfringens type A isolates from horses with gastroin-
testinal diseases. J Clin Microbiol 2005;43(8):4002–9.
21. Gohari IM, Arroyo L, MacInnes JI, et al. Characterization of Clostridium perfrin-
gens in the feces of adult horses and foals with acute enterocolitis. Can J Vet
Res 2014;78(1):1–7.
22. Lawler JB, Hassel DM, Magnuson RJ, et al. Absorptive effects of di-tri-octahedral
smectite on Clostridium perfringens alpha, beta, and beta-2 exotoxins and
equine colostral antibodies. Am J Vet Res 2008;69(2):233–9.
23. Weese JS, Cote NM, deGannes RVG. Evaluation of in vitro properties of di-tri-
octahedral smectite on clostridial toxins and growth. Equine Vet J 2003;35(7):
638–41.
24. Oue Y, Ishihara R, Edamatsu H, et al. Isolation of an equine coronavirus from
adult horses with pyrogenic and enteric disease and its antigenic and genomic
 Infectious Acute Diarrhea in the Adult Horse 51

characterization in comparison with the NC99 strain. Vet Microbiol 2011;150:

41–8.
25. Pusterla N, Mapes S, Wademan C, et al. Emerging outbreaks associated with
equine coronavirus in adult horses. Vet Microbiol 2013;162(1):228–31.
26. Giannitti F, Diab S, Mete A, et al. Necrotizing enteritis and hyperammonemic en-
cephalopathy associated with equine coronavirus infection in equids. Vet Pathol
2015;52(6):1148–56.
27. Xiong Q, Bekebrede H, Sharma P, et al. An ecotype of Neorickettsia risticii
causing Potomac horse fever in Canada. Appl Environ Microbiol 2016;82(19):
6030–6.
28. Pusterla N, Johnson EM, Chae JS, et al. Digenetic trematodes, Acanthatrium sp.
and Lecithodendrium sp., as vectors of Neorickettsia risticii, the agent of Poto-
mac horse fever. J Helminthol 2003;77(4):335–9.
29. Mott J, Muramatsu Y, Seaton E, et al. Molecular analysis of Neorickettsia risticii in
adult aquatic insects in Pennsylvania, in horses infected by ingestion of insects,
and isolated in cell culture. J Clin Microbiol 2002;40(2):690–3.
30. Bertin FR, Reising A, Slovis NM, et al. Clinical and clinicopathological factors
associated with survival in 44 horses with equine neorickettsiosis (Potomac horse
fever). J Vet Intern Med 2013;27(6):1528–34.
31. Madigan JE, Rikihisa Y, Palmer JE, et al. Evidence for a high rate of false-positive
results with the indirect fluorescent antibody test for Ehrlichia risticii antibody in
horses. J Am Vet Med Assoc 1995;207(11):1448–53.
32. Mott J, Rikihisa Y, Zhang Y, et al. Comparison of PCR and culture to the indirect
fluorescent-antibody test for diagnosis of Potomac horse fever. J Clin Microbiol
1997;35(9):2215–9.
33. Atwill ER, Mohammed HO. Evaluation of vaccination of horses as a strategy to
control equine monocytic ehrlichiosis. J Am Vet Med Assoc 1996;208(8):1290–4.
34. Dutta SK, Vemulapalli R, Biswas B. Association of deficiency in antibody
response to vaccine and heterogeneity of Ehrlichia risticii strains with Potomac
horse fever vaccine failure in horses. J Clin Microbiol 1998;36(2):506–12.
35. Seahorn JL, Seahorn TL. Fluid therapy in horses with gastrointestinal disease. Vet
Clin North Am Equine Pract 2003;19(3):665–79.
36. Jones PA, Tomasic M, Gentry PA. Oncotic, hemodilutional, and hemostatic effects
of isotonic saline and hydroxyethyl starch solutions in clinically normal ponies. Am
J Vet Res 1997;58(5):541–8.
37. Jones PA, Bain FT, Byars TD, et al. Effect of hydroxyethyl starch infusion on
colloid oncotic pressure in hypoproteinemic horses. J Am Vet Med Assoc
2001;218(7):1130–5.
38. Bellezzo F, Kuhnmuench T, Hackett ES. The effect of colloid formulation on colloid
osmotic pressure in horses with naturally occurring gastrointestinal disease. BMC
Vet Res 2014;10(Suppl S8):1–5.
39. Pantaleon LG, Furr MO, McKenzie HC, et al. Cardiovascular and pulmonary ef-
fects of hetastarch plus hypertonic saline solutions during experimental endotox-
emia in anesthetized horses. J Vet Intern Med 2006;20(6):1422–8.
40. Pantaleon LG, Furr MO, McKenzie HC, et al. Effects of small- and large-volume
resuscitation on coagulation and electrolytes during experimental endotoxemia
in anesthetized horses. J Vet Intern Med 2007;21(6):1374–9.
41. Blong AE, Epstein KL, Brainard BM. In vitro effects of three formulations of hy-
droxyethyl starch solutions on coagulation and platelet function in horses. Am J
Vet Res 2013;74(5):712–20.
52 Shaw & Stämpfli

42. Epstein KL, Bergren A, Giguère S, et al. Cardiovascular, colloid osmotic pressure,
and hemostatic effects of 2 formulations of hydroxyethyl starch in healthy horses.
J Vet Intern Med 2014;28(1):223–33.
43. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: International
guidelines for management of severe sepsis and septic shock, 2012. Intensive
Care Med 2013;39(2):165–228.
44. McKenzie EC, Esser MM, McNitt SE, et al. Effect of infusion of equine plasma or
6% hydroxyethyl starch (600/0.75) solution on plasma colloid osmotic pressure in
healthy horses. Am J Vet Res 2016;77(7):708–14.
45. Grønvold AMR, L’Abée-Lund TM, Strand E, et al. Fecal microbiota of horses in the
clinical setting: potential effects of penicillin and general anesthesia. Vet Micro-
biol 2010;145(3–4):366–72.
46. Costa MC, Stämpfli HR, Arroyo LG, et al. Changes in the equine fecal microbiota
associated with the use of systemic antimicrobial drugs. BMC Vet Res 2015;
11(19):1–12.
47. Costa MC, Arroyo LG, Allen-Vercoe E, et al. Comparison of the fecal microbiota of
healthy horses and horses with colitis by high throughput sequencing of the V3-
V5 region of the 16s rRNA gene. PLoS One 2012;7(7):1–12.
48. House JK, Mainar-Jaime RC, Smith BP, et al. Risk factors for nosocomial salmo-
nella infection among hospitalized horses. J Am Vet Med Assoc 1999;214(10):
1511–6.
49. Moore JN, Barton MH. Treatment of endotoxemia. Vet Clin North Am Equine Pract
2003;19(3):681–95.
50. Jackman BR, Moore JN, Barton MH, et al. Comparison of the effects of ketoprofen
and flunixin meglumine on the in vitro response of equine peripheral blood mono-
cytes to bacterial endotoxin. Can J Vet Res 1994;58(2):138–43.
51. Semrad SD, Hardee GE, Hardee MM, et al. Low dose flunixin meglumine: effects
on eicosanoid production and clinical signs induced by experimental endotoxae-
mia in horses. Equine Vet J 1987;19(3):201–6.
52. Morresey PR, MacKay RJ. Endotoxin-neutralizing activity of polymyxin B in blood
after IV administration in horses. Am J Vet Res 2006;67(4):642–7.
53. Parviainen AK, Barton MH, Norton NN. Evaluation of polymyxin B in an ex vivo of
endotoxemia in horses. Am J Vet Res 2001;62(1):72–6.
54. Forbes G, Church S, Savage CJ, et al. Effects of hyperimmune equine plasma on
clinical and cellular responses in a low-dose endotoxaemia model in horses. Res
Vet Sci 2012;92(1):40–4.
55. Liska DA, Akucewich LH, Marsella R, et al. Pharmacokinetics of pentoxifylline and
its 5-hydroxyhexyl metabolite after oral and intravenous administration of pentox-
ifylline to healthy adult horses. Am J Vet Res 2006;67(9):1621–7.
56. Barton MH, Moore JN, Norton N. Effects of pentoxifylline infusion on response of
horses to in vivo challenge exposure with endotoxin. Am J Vet Res 1997;58(11):
1300–7.
57. Baskett A, Barton MH, Norton N, et al. Effect of pentoxifylline, flunixin meglumine,
and their combination on a model of endotoxemia in horses. Am J Vet Res 1997;
58(11):1291–9.
58. Edmunds JL, Worgan HJ, Dougal K, et al. In vitro analysis of the effect of supple-
mentation with activated charcoal on the equine hindgut. J Equine Sci 2016;
27(2):49–55.
59. Desrochers AM, Dolente BA, Roy M-F, et al. Efficacy of Saccharomyces boulardii
for treatment of horses with acute enterocolitis. J Am Vet Med Assoc 2005;227:
954–9.
 Infectious Acute Diarrhea in the Adult Horse 53

60. Boyle AG, Magdesian KG, Durando MM, et al. Saccharomyces boulardii
viability and efficacy in horses with antimicrobial-induced diarrhoea. Vet Rec
2013;172:128.
61. Schoster A, Staempfli HR, Abrahams M, et al. Effect of a probiotic on prevention
of diarrhea and Clostridium difficile and Clostridium perfringens shedding in
foals. J Vet Intern Med 2015;29(3):925–31.
62. Furr M. Orally administered Pediococcus acidilactici and Saccharomyces boular-
dii-based probiotics alter select equine immune function parameters. J Equine
Vet Sci 2014;34(10):1156–63.
63. Weese JS. Microbiologic evaluation of commercial probiotics. J Am Vet Med As-
soc 2002;220(6):794–7.
64. Scott Weese J, Martin H. Assessment of commercial probiotic bacterial contents
and label accuracy. Can Vet J 2011;52(1):43–6.
65. Tleyjeh IM, Bin Abdulhak AA, Riaz M, et al. Association between proton pump in-
hibitor therapy and Clostridium difficile infection: a contemporary systematic re-
view and meta-analysis. PLoS One 2012;7:e50836.
66. Furr M, Cohen ND, Axon JE, et al. Treatment with histamine-type 2 receptor an-
tagonists and omeprazole increase the risk of diarrhoea in neonatal foals treated
in intensive care units. Equine Vet J 2012;44(Suppl. 41):80–6.
67. Van Eps AW, Pollitt CC. Equine laminitis model: lamellar histopathology seven
days after induction with oligofructose. Equine Vet J 2009;41(8):735–40.
68. Divers TJ. Clinical application of current research findings toward the prevention
and treatment of acute laminitis in horses with systemic inflammatory diseases:
an internist’s perspective. J Equine Vet Sci 2010;30(9):517–24.
69. Liu X-L, Want X-Z, Liu X-X, et al. Low-dose heparin as treatment for early dissem-
inated intravascular coagulation during sepsis: a prospective clinical study. Exp
Ther Med 2014;7:604–8.
70. De La Rebière Pouyade G, Grulke S, Detilleux J, et al. Evaluation of low-
molecular-weight heparin for the prevention of equine laminitis after colic surgery:
retrospective study. J Vet Emerg Crit Care (San Antonio) 2009;19(1):113–9.
71. Feige K, Schwarzwald CC, Bombeli T. Comparison of unfractioned and low mo-
lecular weight heparin for prophylaxis of coagulopathies in 52 horses with colic: a
randomised double-blind clinical trial. Equine Vet J 2003;35(5):506–13.
72. Gary Magdesian K. Nutrition for critical gastrointestinal illness: feeding horses
with diarrhea or colic. Vet Clin North Am Equine Pract 2003;19(3):617–44.