Clostridioides difficile (formerly Clostridium difficile) is a large, gram-positive, anaerobic, spore-forming motile rod that is the major cause of antimicrobial-associated colitis in humans. Although C difficile infection is not generally considered a zoonosis, concern has been raised about the possibility of zoonotic disease transmission from animals to humans (1, 2).
C difficile–associated diarrhea and disease develop spontaneously in a variety of other species, especially horses and pigs. Gerbils, mice, hamsters, guinea pigs, rabbits, and other animals can also experience disease associated with this pathogen. C difficile has been isolated from the GI tract of a variety of other species, but the clinical relevance is unclear.
C difficile produces protein toxins A and B (TcdA and TcdB), and/or the binary toxin CDT in the intestine. TcdA and TcdB are exotoxins that increase permeability and inflammation in the intestinal tract. The mechanism of action of CDT is not known; however, studies in hamsters show that it likely increases the virulence of C difficile in the presence of TcdA and TcdB (3).
Exogenous and endogenous routes of C difficile infection (CDI) are both possible:
The exogenous route is more common. Infection occurs when spores are ingested (typically via the fecal-oral route of exposure, but airborne transmission is also possible). The spores germinate in the host's small intestine and then colonize the large intestine.
The endogenous route occurs less frequently. It involves the proliferation of toxigenic strains of C difficile that are already present in the GI tract of healthy animals. Infection typically occurs secondary to a disruption in the normal microbiota in the large intestine that is due to antimicrobial administration.
Diagnostic tests for C difficile toxins include cell cytotoxicity assays and ELISAs on intestinal contents or fecal samples. Anaerobic culture and PCR assays to detect C difficile can also be performed; however, without concurrent demonstration of toxin production they are not confirmatory for a diagnosis.
Clostridioides difficile Infection in Horses
Clostridioides difficile has been implicated in a range of diseases in horses, from mild self-limiting diarrhea to fatal hemorrhagic enterocolitis. It has also been proposed as a potential etiology of duodenitis–proximal jejunitis syndrome (also called anterior enteritis or proximal enteritis–jejunitis), the signs of which include colic, ileus, endotoxemia, and endogastric reflux.
Etiology of Clostridioides difficile Infection in Horses
C difficile can be found in low concentrations in the feces of healthy foals and adult horses, but actual prevalence within each population varies widely across studies. However, the studies do suggest that these C difficile populations can result in environmental contamination and exposure (2).
C difficile is also present in soil or the environment and can be carried on fomites associated with veterinarians and veterinary staff, including footwear and instruments.
Disease associated with C difficile in horses does not seem to depend on age. The exogenous fecal-oral route is the main mode of transmission. The factors that trigger disease are not well known; however, it is presumed that some alteration in the normal microbiota permits excessive multiplication of these bacteria, which produce toxins capable of causing intestinal damage and systemic effects. Although similar strains have been found in both humans and horses, the zoonotic disease risk of this organism remains unclear.
Predisposing factors for C difficile infection include dietary change and antimicrobial therapy. As with humans, recent antimicrobial therapy is common in the history of horses with C difficile–induced diarrhea.
Certain antimicrobials, notably macrolides and especially erythromycin, trimethoprim/sulfonamide, third-generation cephalosporins, clindamycin, and gentamycin, in combination with beta-lactam antimicrobials, are more likely than others to be associated with CDI. Mares with foals that are being treated with erythromycin ethylsuccinate appear to be at high risk of CDI.
Elimination of roughage from the diet before surgery is also reported to predispose horses to C difficile colitis (4). Acute diarrhea has been reproduced in healthy neonatal foals using C difficile spores and vegetative cell forms. Duodenitis–proximal jejunitis syndrome has also been associated with C difficile in a case control study of horses (5).
Clinical Findings of Clostridioides difficile Infection in Horses
Clinical signs of CDI in horses range from mild diarrhea to fatal hemorrhagic enterocolitis similar to the signs of infections with other enteric agents, including Salmonella spp, Clostridium perfringens type C, and Neorickettsia risticii. Associated signs of colic might be present, along with abdominal distention, hyperemic mucous membranes, fever, and signs of dehydration.
Adult horses with CDI can sometimes develop signs of abdominal discomfort or fever without diarrhea, but diarrhea is common. Foals might die even before clinical signs are detected; however, watery or hemorrhagic diarrhea and signs of toxemia are typically noted.
One or several animals on a farm can be affected by CDI. C difficile is proposed as one of the causes of proximal enteritis–jejunitis in horses, associated with severe, recurrent enterogastric reflux, fever, and malaise (5).
Lesions of Clostridioides difficile Infection in Horses
The characteristic CDI lesion is necrotizing enterocolitis-typhlitis; however, this finding is not specific. Foals < 1 month old often have lesions in the small intestine; older foals and adults tend to have lesions in the colon and cecum.
The CDI-affected intestine might have discolorations on the serosal surface due to congestion or hemorrhage. Foals might have hemorrhagic, fluid-filled small intestines. The affected large intestine, more common in adults, is often filled with gas or fluid, and the wall is edematous. Mucosal erosions or ulcerations might also be evident, and a pseudomembrane might be present.
Microscopically, CDI produces severe loss of colonic and cecal mucosal epithelial cells, necrotizing and sometimes hemorrhagic enteritis, colitis and typhlitis, and thrombosis in capillaries of the intestinal mucosa.
Diagnosis of Clostridioides difficile Infection in Horses
Fecal culture and toxin detection
Toxin gene identification by PCR ribotyping
The diagnosis of C difficile–caused diarrhea is based on history, clinical signs, and gross and/or microscopic lesions. Gold-standard confirmation of CDI relies on the detection of TcdA and/or TcdB in intestinal contents or feces, typically achieved with commercial ELISA.
Alternatively, cytotoxin assays are available; however, they are more technical and expensive. Detection of C difficile using PCR assay or anaerobic culture of intestinal contents, tissue, or feces enables a presumptive diagnosis, but confirmation relies on toxin detection because strains of C difficile that are not toxinogenic can be present in the GI tract of healthy horses.
Pearls & Pitfalls
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Control of Clostridioides difficile Infection in Horses
Adequate isolation procedures
Disease control in high-risk horses
Proper and judicious antimicrobial use
Steps can be taken to decrease the opportunity for CDI in horses. Proper isolation procedures and infectious disease control should be applied to high-risk horses being administered antimicrobials. The environmental load of C difficile spores can be decreased by surface disinfection with sporicidal disinfectants, and the transmission of infection can be decreased by handwashing and by isolation of infectious horses and foals.
Supportive care for CDI should focus on correcting dehydration and any related acid-base or electrolyte derangements. Specific treatment often includes administration of metronidazole, which has a longer half-life in foals, so the dose must be adjusted depending on the age of the animal:
To foals in the first 2 weeks of life, metronidazole can be administered at a dose of 10 mg/kg, PO or IV, every 12 hours (6).
For adult horses, the metronidazole dose ranges from 15 to 20 mg/kg, PO, every 8–12 hours up to 20 mg/kg, PO, every 6 hours (7).
Metronidazole can be administered rectally; however, doses higher than 20 mg/kg might be required (8, 9).
Di-tri-octahedral smectite can also be administered through a nasogastric tube to help neutralize the toxins.
Clostridioides difficile Infection in Swine
Etiology of Clostridioides difficile Infection in Swine
Clostridioides difficile has emerged as an important cause of diarrhea in neonatal swine. In some studies, it was identified as the second most frequent cause of diarrhea in pigs 1–7 days old (10, 11).
Although antimicrobial administration appears to be a risk factor for CDI in humans and horses, it does not appear to be a risk factor for piglets or foals. CDI can occur in older pigs, typically associated with antimicrobial administration for mastitis or metritis in postparturient sows.
Clinical Findings of Clostridioides difficile Infection in Swine
Piglets with CDI typically have nonhemorrhagic diarrhea, poor weight gain, respiratory distress, and scrotal edema. Rarely, death can occur before any evidence of diarrhea. When adult sows develop CDI, typical clinical signs are diarrhea and respiratory distress with a low mortality rate.
Lesions of Clostridioides difficile Infection in Swine
Mesocolonic edema is a characteristic feature of CDI in swine that occurs in almost all affected piglets; however, this lesion is not pathognomonic. Microscopic evidence of necrosuppurative typhlocolitis might be present.
Diagnosis of Clostridioides difficile Infection in Swine
Postmortem examination
Toxin detection
C difficile detection by anaerobic culture or by PCR assay
Diagnosis of CDI in pigs is complicated by the fact that C difficile and its TcdA and TcdB toxins have been detected in the GI tract of normal piglets. The diagnosis of CDI relies on the combination of gross and microscopic necropsy findings, along with toxin detection and C difficile detection (either by anaerobic culture or by PCR assay), as well as with additional testing to rule out other common causes of diarrhea.
As for horses, isolation of C difficile alone is not enough to confirm the diagnosis, because nontoxinogenic strains exist. Detection of the toxins or the genes that encode the toxins has better diagnostic value.
Toxinogenic C difficile strains that are virulent for humans have been identified in the intestinal tract of food animals and in some human food products (beef, pork, poultry, fish, and vegetables), raising the possibility for zoonotic disease transmission of C difficile.
Control of Clostridioides difficile Infection in Swine
Environmental decontamination
Antimicrobial therapy
Cleaning and disinfecting the environment is very important in the control of CDI and should begin as soon as possible after C difficile is detected on a farm.
Tylosin is frequently the antimicrobial of choice for treatment; however, some C difficile strains have demonstrated resistance. The tylosin dose for swine is 8.8 mg/kg, IM, every 12–24 hours (12). Beta-lactam antimicrobials and rifamycin can also be effective.
Clostridioides difficile Infection in Dogs
Etiology and epidemiology:Clostridioides difficile has not been established as a primary pathogen in dogs. Some studies demonstrate an association between the presence of C difficile toxins and enteric disease; others indicate a high prevalence of C difficile even with no signs of enteric disease (13). Dogs might act as a reservoir for zoonotic strains of C difficile, and humans might act as a reservoir for dogs; however transmission in either direction seems to be infrequent.
Diagnosis: Diagnosis of CDI in dogs follows the same principles as for pigs and horses described above, relying on compatible history, gross and microscopic findings, and detection of toxin in intestinal contents, along with culture of C difficile.
Clostridioides difficile Infection in Cattle and Sheep
Clostridioides difficile is capable of colonizing the intestinal tract of sheep and cattle; however, these animals appear mostly resistant to disease.
Some studies report an association between diarrhea in calves and the presence of C difficile toxins (14). C difficile itself has been isolated from calves with diarrhea, but often in association with other agents that are known to cause enteric disease.
Clostridioides difficile Infection in Laboratory Animals
Clostridioides difficile can cause enteric disease in Syrian hamsters, gerbils, guinea pigs, mice, rabbits and rats, making it possible for each of these species to serve as animal models for human CDI.
As with humans and horses, antimicrobial therapy for laboratory animals is a risk factor (but not a requirement) for CDI in gerbils, guinea pigs, and hamsters.
Key Points
Clostridioides difficile can colonize the intestinal tract of humans and animals, and it can produce extensive enteric disease in some instances.
Horses and swine are among the most susceptible animals to C difficile–associated diarrheal disease.
The best way to confirm a diagnosis of C difficile infection is by detecting the toxins produced by C difficile (TcdA and TcdB).
For More Information
Kachrimanidou M, Tzika E, Filioussis G. Clostridioides (Clostridium) difficile in food-producing animals, horses and household pets: a comprehensive review. Microorganisms. 2019;7(12):667.
Uzal FA, McClane BA, Gohari IM, Navarro MA, Popoff MR, eds. Clostridial Diseases of Animals. 2nd ed. John Wiley & Sons; 2026.
References
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