Clostridia-associated Enterocolitis in Horses
Clostridium difficile and C perfringens are common causes of enterocolitis in horses and foals. Antimicrobial administration has been associated with C difficile diarrhea. Some reports attribute 50% of cases of foal diarrhea to C perfringens. C difficile produces toxin A and/or toxin B, which cause fluid secretion and lead to intestinal inflammation. It is common for the GI tract of newborn foals to be rapidly colonized by C difficile, which can be cultured from feces using sensitive anaerobic techniques. Nontoxin-producing strains are considered commensals. C difficile can be isolated from various segments of the small and large intestine and rectum of a large proportion of healthy horses, and from fecal samples of as many as 8% of healthy horses. Approximately one-third of healthy broodmares and >90% of foals in the general population shed C perfringens in their feces; therefore, it is important to determine the presence of a toxin-producing strain.
Strains of C perfringens are classified by the toxins they produce. However, toxins and toxin-producing strains of C perfringens and C difficile can be detected in healthy as well as in diarrheic horses and foals. The most common type of C perfringens identified is type A, which can be detected in the feces of as many as 8% of healthy horses. Type C is rarely identified in the feces or environment of healthy broodmares and their foals but is associated with the highest mortality. Antimicrobial use, food deprivation, and other stressors have been suggested to predispose horses to the overgrowth of either or both C perfringens and C difficile, leading to GI disease. In one report, mares whose foals were being treated with erythromycin developed fatal enterocolitis associated with C difficile. Clostridial spores can persist in the environment and can be resistant to many disinfectants; therefore, nosocomial infection can occur in contaminated environments.
Clinical signs include sudden death, diarrhea with or without blood, colic, fever, reduced feed intake, and lethargy. Disease can range from subclinical to severe enterocolitis to peracute death before the development of diarrhea. With advanced diagnostic techniques, clostridial infections account for a large proportion of the previously undiagnosed cases known as “colitis-X.” Because of the loss of mucosal integrity, bacterial translocation across the GI tract can occur, resulting in bacteremia due to clostridial or other enteric bacterial species. Clinical signs of sepsis or systemic inflammatory response are often present and consistent with other causes of enterocolitis. Clostridiosis cannot be clinically distinguished from salmonellosis. Foals affected at <3 days of age with C perfringens–associated enterocolitis often have bloody diarrhea and colic. Fluid and gas-filled intestine is often identified on ultrasound or radiography. In severe cases, necrotizing enterocolitis occurs with thickening and even intramural gas evident within the wall of the intestine. Several foals on a particular farm may be affected, but the disease is typically sporadic.
The role of C perfringens type A in enterocolitis in neonatal foals is less clear; it has been reported that >90% of foals at 3 days of age shed this organism in their feces and that C perfringens type A is likely one of the first bacteria to colonize the intestinal tract of newborn foals, irrespective of hygiene protocols.
C difficile has been associated with enterocolitis in newborn foals as well as in adult horses. It has been identified as a nosocomial infection in people, and this may also be seen in horses.
The mortality rate associated with C difficile and C perfringens enterocolitis, especially type C, can be high, even with intensive medical treatment.
Diagnosis is based on identification of toxigenic clostridia from fresh fecal samples, reflux, intestinal contents, or tissue. Blood culture is indicated in foals and adults with severe enterocolitis. Fecal samples for culture and detection of toxins or toxin-producing genes should be delivered directly to the laboratory, or shipped overnight, chilled (not frozen) on ice. Samples for culture must be maintained in an anaerobic environment. Isolation of clostridial organisms requires anaerobic conditions and, depending on the organism, special growth media. C difficile is inherently difficult to culture, hence its name. Communicating to the laboratory that clostridial enterocolitis is a differential diagnosis is critical, because many veterinary laboratories do not routinely culture fecal samples anaerobically unless specifically requested to do so.
Because nonpathogenic serovars are common, a positive culture for C difficile or C perfringens must be confirmed by identification of toxins or their genes. A PCR test, available at selected laboratories, allows differentiation of C perfringens types A, B, C, D, and E based on combinations of α, β, ε, or ι toxins, as well as on identification of the gene coding for the β2 toxin. Commercially available tests for clostridial toxins include an ELISA for C difficile toxin A and C perfringens enterotoxin, and a latex agglutination test for C perfringens enterotoxin. Toxin tests can be performed in-house, are rapid, and for C difficile are both sensitive and specific. Diagnosis of clostridial enterocolitis is often made at necropsy and is based primarily on identification of intestinal necrosis associated with large gram-positive rods in intestinal smears. Tissue and fecal specimens must be taken immediately after death to avoid degradation of toxins or an overgrowth of clostridial organisms.
Treatment with metronidazole (15–20 mg/kg, PO, tid-qid) appears to be beneficial in treating enteric clostridial infections. Pharmacokinetic studies have not been performed in foals, but oral and even IV metronidazole appears generally safe. In some geographic regions, metronidazole-resistant C difficile strains have emerged that appear sensitive to vancomycin; however, metronidazole should be used whenever possible.
Supportive care is similar to that for other causes of equine enterocolitis, often requiring large volumes of IV polyionic fluids, with supplemental electrolytes (potassium, magnesium, and calcium), plasma or synthetic colloids for low oncotic pressure, anti-inflammatories such as flunixin meglumine, and broad-spectrum antibiotics if the horse is leukopenic and at risk of bacterial translocation across the compromised GI tract. Polymyxin B may aid in binding systemic endotoxin. Total or partial parenteral nutrition to provide nutritional support can be useful in foals if milk is withheld or decreased to allow gut rest. Foals with colic or profuse diarrhea often benefit from milk withdrawal. Continuous infusion of IV fluids and parenteral nutritional support is optimal but labor intensive and requires separation of the foal and mare. However, the course of diarrhea appears to be dramatically shortened, thus justifying the more intensive approach in some severe cases.
The yeast Saccharomyces boulardii has been shown to be protective in clostridial diarrhea in other species, and there is some evidence of beneficial effects in the treatment of horses with colitis. It produces a protease that specifically degrades C difficile toxins A and B. Orally administered DTO smectite powder also blinds clostridial toxins and may be useful in horses with diarrhea.
Specific antitoxin for C perfringens type C and D has also been used in foals; however, it is not approved for this use. The benefit of type C and D antitoxin in disease associated with type A or β2 toxin is unknown, but based on production methods, the α and β2 toxins are unlikely to be present in high levels in this toxoid.
No proven effective biologic products are available to immunize horses or foals against clostridial enterocolitis. When the disease is a problem in multiple foals on a farm, preventive measures have been implemented, but the efficacy and safety of these interventions have yet to be critically evaluated. These measures include vaccinating pregnant mares twice at 2- to 4-wk intervals at least 1 mo before foaling with C perfringens type C and D toxoid (bacterin products and those with oil adjuvants should be avoided); using C perfringens type C and D antitoxin prophylactically, PO, in newborn foals; and administering antimicrobials (eg, metronidazole) prophylactically to foals for the first 3–5 days of life. The C perfringens type C and D toxoid and antitoxin are not approved for use in horses; however, these products have been used by some owners because of the high mortality rate in foals with clostridial enterocolitis on problem farms. Adverse reactions to the C perfringens type C and D toxoid have been reported in broodmares.
The most important strategy for prevention is good farm hygiene. Clostridial spores are extremely resilient in the environment and resistant to many disinfectants. Keeping the foaling area and mare as clean as possible during the perinatal period and ensuring rapid ingestion (by stomach tube if necessary) of colostrum within 1 hr of birth have reduced incidence of disease on some contaminated farms. The mare’s hindlegs, tail, and udder can also be washed in soapy water immediately after foaling to decrease ingestion of fecal material by newborn foals. Affected animals should be isolated to limit cross-infection and contamination of pastures and stalls.