Clostridial and Clostridioides Infections

Diarrheal Syndromes

Clostridioides Difficile Infection

Definition

The hallmark of C. difficile infection is diarrhea, most commonly during or after (up to 3 months) a course of antibiotics. Most cases are defined by the presence of clinically significant diarrhea (three or more loose or unformed bowel movements per day) plus evidence of toxigenic C. difficile or its toxins A and/or B in stool. C. difficile infection can also be diagnosed by direct visualization of colonic pseudomembranes on endoscopy.

The Pathogen

C. difficile is a spore-forming, anaerobic, gram-positive bacilli that is ubiquitous in nature around the world. Production of toxin B is required for C. difficile to cause C. difficile infection (toxigenic strains), but not all strains of C. difficile have the gene for toxin B (nontoxigenic strains).

Epidemiology

C. difficile has a worldwide distribution. It has been isolated from soil, water, homes of otherwise healthy people, retail establishments, meat and vegetables purchased at grocery stores, and the feces of pets, livestock, and wild animals. Upwards of 50% of asymptomatic infants are colonized with C. difficile at any one point in time, as are 10 to 25% of toddlers. Approximately 3% of healthy, asymptomatic adults are colonized with C. difficile , but the colonization prevalence of toxigenic C. difficile in hospitalized adults can be as high as 20%. Although ambulatory adults are less likely than children to be colonized with C. difficile , clinical C. difficile infection is very uncommon in children, but the incidence increases with age, especially among people over age 60 years. For community-associated cases, new infections are mostly a result of the new acquisition of the organism followed by intestinal colonization. Most cases of health care–onset C. difficile infection are a result of a new acquisition of C. difficile after an antibiotic exposure, with a median of 3 to 7 days from the acquisition of C. difficile to the onset of infection.

The incidence and severity of C. difficile infection increased dramatically in the first decade of the 21st century, associated with a new predominant ribotype 027 strain, which was associated with dramatic outbreaks in North America and Europe. This strain, which is highly fluoroquinolone-resistant, produces a third toxin (binary toxin) and is readily transmissible in the health care setting. From 2011 to 2017, a 36% decline in the number of cases of health care–associated C. difficile infection ( Chapter 261 ; from about 305,000 to about 195,000) have been associated with declines in the proportion of cases due to the 027 strain, from nearly 35% in 2011 to only 15% by 2017. This decline was likely due to improved antimicrobial stewardship and a focus on preventing C. difficile transmission in hospitals. ^, Similar declines have been noted in community-associated C. difficile infection cases due to the 027 strain over the same time period, but cases of community-associated C. difficile infection have remained constant at about 170,000 per year, apparently because of the ubiquity of C. difficile in the community and the stable or even increased prescribing of outpatient antibiotics.

Pathobiology

As a strict anaerobe, vegetative C. difficile cells die after exposure to oxygen. Its spores, however, can survive for months in the external environment and lead to colonization. The normal adult gut microbiota provides the first line of defense against C. difficile colonization and infection, and the decline in colonization from infancy to adolescence mirrors the maturation of the gut microbiome. The metabolic activity of the healthy microbiome and competition for nutrients and binding sites determine whether C. difficile will colonize after an exposure and whether colonization will progress to clinical infection. For example, the microbiome converts primary bile salts, which are excreted into the bowel from the liver, into secondary bile salts that prevent C. difficile spores from germinating and growing. Primary bile salts, which can have the opposite effect, are more prevalent when their conversion to secondary bile salts is reduced by the effect of antibiotics on the microbiome.

For C. difficile to cause infection, it must produce toxins A and B, both of which cause glucosylation of GTPase proteins, which then lead to cytoskeletal disruption and cell death. The specific binding receptors for toxins A and B are primarily localized to the human adult colon, thereby explaining the lack of C. difficile infection in infants and the rarity of small bowel involvement. After the colonic mucosal cells die, toxins A and B induce acute neutrophilic inflammation, which can be visualized as pseudomembranes on endoscopy. An important secondary line of defense appears to be production of antibodies against toxins A and B, in particular toxin B, to protect against recurrent C. difficile infection.

Clinical Manifestations

C. difficile may colonize the colon without symptoms. In the face of toxin production, the clinical symptoms of C. difficile infection range from mild diarrhea to profuse but usually nonbloody diarrhea. More severe infection may be associated with fever, cramps, leukocytosis, and hypoalbuminemia, which is more common with advanced age. Life-threatening pseudomembranous colitis is characterized by major fluid losses, hypotension, toxic megacolon, and/or systemic complications.

Leukocytosis occurs in about 50% of cases. Severe infection is usually defined as a white blood cell count of >15,000/μL accompanied by a serum creatinine level of 1.5 times or more of the baseline level. Severe complicated infection is commonly defined as an extremely high white blood count (>50,000/μL), often with lactic acidosis, hypotension, shock, ileus, and/or toxic megacolon.

Diagnosis

Unexplained diarrhea (typically defined as three or more loose or unformed stools in ≤24 hours), especially when associated with recent or current antibiotic exposure, should raise a suspicion of possible C. difficile infection. However, the clinical suspicion of C. difficile infection is often incorrect given the many possible causes of diarrhea, especially in patients who have multiple comorbid illnesses.

No single laboratory test is adequate for the reliable diagnosis of C. difficile infection, The most specific test to establish a C. difficile infection is the detection of toxins A and/or B in stool. The most commonly used laboratory method to detect C. difficile toxins is an enzyme immunoassay, but its sensitivity ranges from only about 50 to 80%. Nucleic acid amplification tests (NAATs), most commonly polymerase chain reaction (PCR) testing, have a sensitivity of 90 to 95% (compared with the “gold standard” of culture for a toxigenic strain) but can lead to the overdiagnosis of infection because the diarrhea may be due to other causes in patients, especially in older individuals who have been frequently hospitalized, who have harmless carriage of a toxigenic strain of C. difficile . Stool culture for C. difficile also lacks specificity, given the potential for C. difficile colonization as opposed to infection. Testing of stools for glutamate dehydrogenase, or “common antigen,” is a rapid and sensitive screening test, but its specificity is only about 50%, so it requires confirmation with a toxin test.

Because of the limitations of each individual test, the optimal approach for the laboratory diagnosis of C. difficile infection is to use a combination of tests: PCR or glutamate dehydrogenase for screening, plus detection of free toxin in stools for confirmation. If patients have documented diarrhea (three or more loose or unformed stools in <24 hours) in the absence of other identifiable causes of diarrhea (e.g., laxative use and recent antibiotic use), PCR testing alone is usually adequate to make the diagnosis. For other patients, C. difficile infection can also be diagnosed by observing pseudomembranous colitis directly on sigmoidoscopy or colonoscopy, but this approach is best reserved for patients with a strong clinical suspicion of C. difficile infection despite negative laboratory testing.

Infectious diarrhea that persists for longer than 48 hours after hospital admission in an adult patient is almost always due to either C. difficile or norovirus ( Chapter 350 ) infection. Common noninfectious causes of persistent diarrhea ( Chapter 126 ) include laxatives, irritable bowel disease ( Chapter 123 ), ischemic colitis ( Chapter 129 ), and inflammatory bowel disease ( Chapter 127 ). Of note, ischemic colitis can also cause pseudomembranes, which can be confused with C. difficile infection. For antibiotic-associated diarrhea with a negative C. difficile toxin assay, the cause is usually not identified. Since a negative toxin test result does not exclude a diagnosis of C. difficile infection, empiric treatment of C. difficile infection may still be considered in patients who have clinical symptoms highly suggestive of C. difficile infection after alternative diagnoses are excluded.

Treatment

When diarrhea is mild, the discontinuation of antibiotics and supportive care may be sufficient to effect cure. However, it is not possible to identify prospectively with confidence who will respond to such management, and most patients will require specific treatment. Nevertheless, the offending antibiotic(s) should be discontinued because continuing them results in lower cure rates and higher rates of reinfection.

For patients with mild/moderate or severe C. difficile infection (variously defined as a white blood cell count >15,000/µL or a creatinine increase to >1.5-fold above baseline), fidaxomicin (200 mg orally twice a day for 10 days) is preferred over vancomycin (125 mg orally four times a day for 10 days) because it is equally efficacious for the acute infection and better for reducing the risk of recurrent infection. A clinical response typically occurs over several days (mean time to resolution of diarrhea is about 3 days). A failure to resolve by day 5 or 6 often indicates either that C. difficile is not the cause of the symptoms or, less commonly, that the disease has progressed too far. For fulminant C. difficile infection with an ileus, vancomycin (500 mg four times a day orally or by nasogastric tube) plus metronidazole (500 mg IV every 8 hours) is recommended, with vancomycin also potentially administered by enema. If symptoms progress despite this therapy, life-saving colectomy or a colon-sparing loop ileostomy should be considered before the white blood cell count reaches 50,000/μL or the lactate concentration exceeds 5.0 mmol/L.

Approximately 15% of patients treated with fidaxomicin (as compared with about 25% after treatment with vancomycin) have a recurrence of C. difficile infection within 4 weeks after treatment is completed, either because of a relapse (about 80% of cases) if C. difficile spores are not completely eradicated or reinfection (about 20% of cases) with a new strain. Patients with multiple recurrences of C. difficile infection are extremely difficult to treat and may benefit from consultation with an infectious disease specialist or gastroenterologist. For such recurrences, guidelines recommend fidaxomicin (standard dosing or dosing twice daily for 5 days and then every other day for 20 days under expert guidance). in preference to a standard course of vancomycin. In patients who are receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab (a human monoclonal antibody against C . difficile toxin B infused at a dose of 10 mg per kilogram of body weight) is associated with a substantially lower rate of recurrent infection than placebo and has a safety profile similar to that of placebo. Guidelines recommend using bezlotoxumab plus antibiotics for patients who have a recurrent C. difficile infection within 6 months.

For three or more confirmed episodes of C. difficile infection, fecal microbiota transplantation, using fresh or frozen donor material administered via enema, colonoscopy, or oral capsules, is safe and efficacious to prevent recurrent C. difficile infection, with about a 70% cure rate. Some data also support fecal microbiota transplantation over vancomycin for a first or second infection. Fecal transplantation is also superior to fidaxomicin for the treatment of recurrent C. difficile infection, and it has been shown to be safe for at least 3 to 4 years after transplantation. RBX2660, a fecal microbiota-based product administered by enema, was recently approved by the U.S. Food and Drug Administration (FDA), and SER109, a capsule formulation, appears promising as well. Therapies under investigation to prevent recurrent C. difficile infection include oral administration of spores of a nontoxigenic C. difficile strain, which in one trial reduced C. difficile infection by about 75%.

Prevention

The key to preventing C. difficile infection focuses on preventing the transmission of C. difficile and to decrease the risk of infection if transmission occurs. The former is accomplished by contact precautions and the latter by antimicrobial stewardship ( Chapter 261 ). Contact precautions involve placing patients with C. difficile infection into private rooms, when available, using dedicated equipment (e.g., isolation stethoscopes), and having health care personnel wear gowns and gloves whenever entering the patient’s room. Proper and consistent use of gowns and gloves is key to preventing contamination of health care workers’ hands. Alcohol hand hygiene products do not kill or remove C. difficile spores, but handwashing with soap and water removes, at best, 1 log of spores, even under experimental conditions where proper handwashing technique is ensured. Thorough cleaning of the environment is essential to eliminate spores. Although not necessary if thorough environmental cleaning is accomplished, a sporicidal agent (e.g., sodium hypochlorite) is often used as well. Preventing unnecessary antibiotic use and avoiding high-risk antibiotics (e.g., clindamycin, fluoroquinolones, and extended-spectrum cephalosporins) decreases the risk of colonization and infection by preserving the microbiome, and it is likely the most effective means at preventing C. difficile infection.

A concerning trend is the increasing concomitant use of oral vancomycin (125 mg daily) to prevent C. difficile infection while patients are receiving other antibiotics in the absence of well-done trials with adequate follow-up. Oral vancomycin is highly disruptive to the microbiome and leads to a greater alteration of the microbiome and a higher risk for C. difficile infection once it is stopped. Probiotics are not effective for preventing C. difficile infection. Research is ongoing to assess interventions aimed at asymptomatic C. difficile carriers. C. difficile toxoid vaccine is currently in phase III trials.

Prognosis

The vast majority (about 80 to 85%) of symptomatic cases resolve after the implicated antibiotic is discontinued and a 10-day course of fidaxomicin or vancomycin is completed, but patients with refractory, fulminant disease eventually require colectomy. The incremented mortality rate of C. difficile infection for hospitalized patients may be as high as 7%, with the majority of fatalities occurring in patients over age 65 years, but the overall 30-day mortality appears to be about 15% because of patients’ ages and comorbid conditions. For patients who have recurrences, the risk of death is 33% higher than for patients with a single episode.

Clostridium Perfringens Type A Diarrhea

C. perfringens type A causes food poisoning after the ingestion of food, usually meat, that is heavily contaminated with enterotoxin-producing strains. Storage at room temperature rather than refrigeration is typically the underlying cause. The ingested vegetative bacteria sporulate and produce enterotoxin in the small intestine. After an incubation period of 7 to 15 hours, patients develop usually mild and self-limited diarrhea and abdominal pain.

In hospitalized or institutionalized patients, this bacterium can cause severe and protracted infectious diarrhea, often in the setting of prior or concomitant use of antibiotics. In institutionalized mentally ill patients, use of antidiarrheal agents has been associated with necrotizing colitis. Diagnostic confirmation relies on detection of C. perfringens enterotoxin in the stool or a count of 10 ⁶ or more C. perfringens organisms per gram of stool within 48 hours after the onset of a typical illness.

Treatment

Most cases are self-limited and do not need treatment. Metronidazole (e.g., 500 mg four times daily for 7 to 14 days) is recommended for patients who have protracted diarrhea. As with C. difficile infection, however, diarrhea may recur after successful treatment.

Clostridium Perfringens Type C Enteritis

C. perfringens type C enteritis, also called enteritis necroticans, is a necrotizing proximal small intestinal infection caused by strains of C. perfringens that produce β-toxin. Enteritis necroticans can occur sporadically or in outbreaks, most often in developing countries, where it primarily affects children with severe protein malnutrition ( Chapter 197 ). Enteritis necroticans also occurs sporadically in the developed world, particularly among patients with diabetes. Histopathologic findings include deep small intestinal necrosis with vascular necrosis and hemorrhage in the lamina propria.

Affected patients usually develop severe abdominal pain 12 hours to several days after eating contaminated food. Vomiting and bloody diarrhea are frequent, and the abdomen becomes distended with thickened bowel loops. The diagnosis is usually clinical. Culture to identify specific β-toxin–producing strains of C. perfringens remains a research tool.

Treatment and Prognosis

Treatment is primarily supportive, including nasogastric suction and rehydration. Surgical resection of the infected bowel is often required in patients who do not initially respond to supportive measures. Empirical antibiotics (e.g., penicillin, chloramphenicol, metronidazole) are typically prescribed under expert guidance, but their efficacy is unknown. Prognosis, which depends on the extent of disease and the availability of surgery, ranges from spontaneous recovery to death.

Necrotizing Clostridial Tissue Infection

Clostridial Myonecrosis (Gas Gangrene)

Clostridial myonecrosis, or gas gangrene, is a life-threatening infection that can be cause by several Clostridium species. Traumatic gas gangrene is typically caused by Clostridium perfringens . Clostridium septicum is associated with spontaneous gangrene, believed to be related to translocation of the bacterium from the gut associated with an occult neoplasm.

Epidemiology

Traumatic gas gangrene is typically seen after traumatic injury (e.g., motor vehicle accidents, gunshot and knife wounds, crush injuries, and subcutaneous injections), particularly if treatment is delayed. The vast majority of post-traumatic cases are due to C. perfringens , but cases also can be associated with C. septicum , C. novyi , C. histolyticum , C. bifermentans , C. tertium , and C. fallax . Approximately 30% of cases occur after bowel or biliary tract surgery because of translocation of bacteria across the gut wall, often in association with adenocarcinoma of the colon. Infection can also occur in the setting of neutropenic enterocolitis after intense chemotherapy for treatment of acute leukemia.

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