15 Santiago S. Diab, Francisco A. Uzal, and J. Glenn Songer Clostridium difficile-associated disease (CDAD) affects numerous species, especially humans and animals with expanded large bowels (gerbils, guinea pigs, hamsters, horses, rabbits, swine, and others). C. difficile has been isolated from the gastrointestinal tract of a wide variety of other animal species in which it is not associated with disease, its role in disease is not known, or only single case reports have been published. These include bears, camels, cats, cattle, dogs, donkeys, ducks, elephants, geese, goats, sheep, non-human primates, ostriches, poultry, pet birds, and even reptiles. In domesticated animals, CDAD is typically referred to as necrotizing enterotyphlocolitis and, with a few exceptions (notably pigs), is antibiotic-associated. In humans, the nature of the typical lesion gives rise to the common name of pseudomembranous colitis. C. difficile is a Gram-positive strict anaerobic rod, and its long-term survival, transmission, and, to an extent, the pathogenesis of its infections are mediated by the production of highly resistant spores, which are ubiquitous in the environment. C. difficile is well known for its widespread contamination of human and animal hospitals and other medical facilities, but can be found in surprisingly large numbers in any environment subject to fecal contamination. It is common in the large intestine and feces of domestic animals (particularly herbivores and swine) and, in consequence, can also be found in large numbers in manured soil. It is also common in meats and in vegetables that have been subjected to fecal contamination. C. difficile is in cluster XIa (“Peptostreptococcaceae”) (Chapter 1) and it appears morphologically as rods ~ 1.2 μm x 8 μm in size, occurring at times in short chains. Colonies are chartreuse under long-wave UV illumination. Solid media containing cefoxitin, cycloserine and fructose, often with taurocholate to initiate spore germination, are effective for isolation from feces and other contaminated environments. Spores are oval and subterminal. The vegetative forms of C. difficile do not survive for long periods of time in an aerobic environment; however, vegetative cells sporulate readily and the spores are highly resistant in air. The spores of C. difficile are resistant to most common disinfectants, making this microorganism a sturdy environmental contaminant. The pathogenesis of C. difficile infections is mediated by toxins A (TcdA) and B (TcdB), both members of the family of large clostridial toxins (LCTs); a role for a separate, ADP-ribosylating toxin (CDTa) also seems likely (Chapter 6). The genes for these toxins (tcdA, tcdB, and cdtA) are located chromosomally. The epidemiology of C. difficile varies among animal species. Abundant ongoing research on humans, animals, and the human–animal interface, including the environment and food supply, will likely significantly expand the current knowledge on this subject. The most comprehensive epidemiological studies have been done on the human population, where the field continues to evolve as the incidence of C. difficile infection (CDI) continues to grow. CDI has become the most common cause of human healthcare-associated infection in Europe, Canada, and the United States, exceeding even methicillin-resistant Staphylococcus aureus infections. In humans and pigs, but not in horses, the disease is age-dependent, affecting humans outside the neonatal period but contrarily piglets within the neonatal period, up to approximately 1 week of age. With the notable exception of piglets and neonatal foals, in most animals antibiotic administration is an important and critical risk factor. Hospitalization, a major risk factor for the human infection, is also important in horses. Hamsters and guinea pigs are often used as models for C. difficile infection in humans, since they readily develop C. difficile infection after colonization with spores and administration of antimicrobials. However, as in neonatal foals and piglets, disease may develop without prior antibiotic therapy. Direct transmission of C. difficile from animals and food to people has not been clearly documented, but there is increasing evidence that this occurs. Some C. difficile ribotypes that are virulent for humans, including the emerging ribotype 078, have been found in the intestinal tract of multiple food animals and in or on retail food (including beef, pork, poultry, fish, and vegetables) in the USA, Canada, and Europe. Colonization of the hamster intestinal tract by consumption of spore-contaminated food has been demonstrated experimentally, and exposure of humans through consumption of contaminated food may be more common than previously recognized. Thus, transmission may occur through direct contact with animals, from the environment, or by consumption of contaminated foods of animal or vegetable origin. C. difficile infection may be exogenous or endogenous. The exogenous route of infection is by far the most common and requires ingestion of C. difficile spores from a contaminated environment or from other animals. The fecal–oral route is the main source of exogenous infection, but C. difficile has also been found in air samples, air vents, and high horizontal surfaces from human hospitals and air samples from pig farms, suggesting that airborne transmission may also be possible. After ingestion, C. difficile spores resist the acidity of the stomach and germinate to the vegetative form in the small intestine and may subsequently colonize the large intestine. The endogenous form is less common and requires proliferation of endogenous C. difficile toxigenic strains carried in the intestinal tract of healthy animals, usually following destruction of the large bowel microflora by antibiotics that target anaerobic bacteria, resulting in bacterial multiplication, toxin production, and damage to the intestinal mucosa. This distinction between exogenous and endogenous infections is, however, somewhat artificial, as C. difficile is considered a ubiquitous opportunist that may be present in the environment and also in the intestinal tract of healthy animals. Differences in virulence between strains of C. difficile are well recognized (Chapter 6). C. difficile infection in horses is not age-dependent and the disease may develop in foals as young as 2 days of age, as well as in older foals and adults. The exogenous fecal–oral route is the main form of transmission, although the endogenous form of infection is also possible. Potential sources of C. difficile spores include, but are not limited to, feces of foals and adult horses with and without diarrhea, soil from stud farms, small and large animal hospitals, and the stalls, floors, medical equipment, and footwear of medical personnel in large animal clinics. It is common for human medical personnel to carry the organism on their hands and, although this has not been demonstrated in veterinary medical personnel, it is safe to assume that they may also do so. The two main risk factors for the development of CDAD in horses are antibiotic therapy with broad-spectrum antibiotics and hospitalization. Although all antibiotics appear to be capable of predisposing to CDAD in horses, erythromycin, trimethoprim/sulfonamides, third-generation cephalosporins, clindamycin and gentamicin in combination with β-lactams, are most often associated with the disease. In neonatal foals, and occasionally in older foals and adult horses, the disease may occur without prior antibiotic administration or hospitalization. Interestingly, a single study shows that only 26% of horses with C. difficile-associated disease had a history of antibiotic therapy prior to the onset of diarrhea, suggesting that antibiotic therapy may not be a significant factor in certain geographic regions or environments. In hospitalized horses, a potentially increased exposure to toxigenic C. difficile spores from a contaminated facility or contaminated medical instruments, the change to a hospital diet, pre- and post-surgical feed withdrawal, and antibiotic administration during hospitalization may all, alone or in combination, contribute to CDAD. Other, less clearly established risk factors, including stress, dietary changes, starvation, co-infections with other bacteria or parasites, colon impactions or torsions, transportation, surgical or medical treatment, and nasogastric intubation, have been proposed, but on the basis of anecdotal evidence rather than case-controlled reports. The prevalence of C. difficile in the feces of healthy foals ranges between 0 and 3% in most studies. However, one research group found a 29% prevalence in healthy foals less than 14 days of age and a 44% prevalence in foals without diarrhea treated with antibiotics, suggesting that foals may be an important source of infection. The prevalence of C. difficile infection in the feces of healthy adult horses is also considered low, ranging from 0 to 10%. However, the cumulative prevalence obtained in a 1-year longitudinal study in healthy adult horses was higher, since 40% of the horses were C. difficile culture-positive at least once throughout the year. This suggests both that C. difficile shedding from healthy horses is transient and dynamic and that exposure to C. difficile may be more common than thought based on data obtained from horizontal prevalence studies. The reported prevalence of C. difficile in foals and adult horses with diarrhea and enterocolitis has varied greatly between authors, ranging from 5% to 63%, likely reflecting not only geographic and other differences, but also variations in diagnostic approaches. The clinical signs and severity of CDAD in horses are very variable. Diarrhea is the main clinical manifestation and may be accompanied by colic, abdominal distension, hyperemic mucous membranes, fever, prolonged capillary refill time, tachycardia, tachypnea, and dehydration. Adult horses with CDAD may have abdominal discomfort or fever without diarrhea and sometimes small intestinal ileus and gas distention may be the primary complaint. Neonatal foals may develop enterocolitis with mild abdominal discomfort and colic with pasty feces or watery diarrhea, but death may occur without prior clinical signs or after a short period of depression, watery or hemorrhagic diarrhea, and toxemia. The clinical signs of CDAD are not specific, since other infectious enteropathogens such as Salmonella spp. or Neorickettsia risticii (equine ehrlichial colitis) may mimic CDAD. Type C or netF-associated type A C. perfringens-associated enterocolitis in foals may mimic CDAD, although both infections are more common in foals than in adult horses. The syndrome of duodenitis-proximal jejunitis of horses that is clinically characterized by abundant enterogastric reflux has been suggested to be associated with C. difficile infection. Although this association appears likely, definitive proof of causality is lacking. The lesions in the intestinal tract of foals and adult horses with CDAD are characteristic but not specific for this condition. Other known causes of enterocolitis, such as C. perfringens type C, Salmonella spp., Neorickettsia risticii, non-steroidal anti-inflammatory drugs, or even colitis of undetermined origin (formerly known as “Colitis X”) may cause similar or identical lesions. In naturally acquired CDAD, the distribution of the lesions in the intestinal tract is largely age-dependent, but occasional cases may present with a different distribution. Typically, foals under 1 month of age show lesions in the small intestine, whereas the colon and cecum may or may not be involved. In older foals and adult horses, the lesions are typically present in the colon and cecum, whereas the small intestine is usually spared. The serosal surface of affected small or large intestine may be normal or show grayish, bluish, or reddish discoloration as a consequence of severe mucosal and submucosal congestion or hemorrhage (Figure 15.1). The large intestine is often dilated by gas or fluid contents. In severe cases, the damage may extend through the intestinal wall, with multifocal patches of hemorrhage on the serosa. In foals, the intestinal content is often composed of hemorrhagic fluid (Figure 15.2). In older horses, the large intestinal content may be similar to that in foals but also may consist of abundant green fluid or a mix of green fluid and roughage (Figure 15.3). The intestinal wall, especially in the large intestine, is frequently moderately to markedly thickened by clear, gelatinous edema (Figure 15.4). The mucosa of both the small and large intestines may appear dull, opaque, brownish or greenish (Figure 15.5) or, if hemorrhagic, diffusely bright or dark red. There is frequently multifocal or regional mucosal erosion or ulceration and the mucosa can be multifocally covered by a tan, yellow, or greenish pseudomembrane composed of cellular and inflammatory debris admixed with intestinal contents (Figure 15.6). Figure 15.1 Clostridium difficile-associated disease; adult horse. The large colon and cecum show diffuse gray to bluish discoloration of the serosal surface due to mucosal and submucosal congestion and/or hemorrhage. Reproduced with permission from Diab et al. (2013) Vet. Pathol., 50: 1028–1036. Figure 15.2 Clostridium difficile-associated disease; foal. Abundant red (hemorrhagic) fluid in the small colon. Reproduced with permission from Diab et al. (2013) Vet. Pathol., 50: 1028–1036. Figure 15.3 Clostridium difficile-associated disease; adult horse. Abundant green fluid in the colon. Reproduced with permission from Diab et al. (2013) Vet. Microbiol., 167: 42–49. Figure 15.4 Clostridium difficile-associated disease; adult horse. The wall of the colon shows marked thickening by clear, gelatinous, submucosal edema. Reproduced with permission from Diab et al. (2013) Vet. Pathol., 50: 1028–1036. Figure 15.5 Clostridium difficile-associated disease; adult horse. Markedly edematous colon with dull, opaque, brownish to greenish discoloration of the mucosa. Reproduced with permission from Diab et al
Diseases produced by Clostridium difficile
Introduction
Etiology
General epidemiology and pathogenesis of Clostridium difficile infection
Animal diseases produced by Clostridium difficile
Enterocolitis of horses
Epidemiology
Clinical signs
Gross changes
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