Clostridioides (Clostridium) Difficile Colitis

C difficile is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C difficile infection (CDI) commonly manifests as mild to moderate diarrhea, occasionally with abdominal cramping. Pseudomembranes (adherent, yellowish white plaques on the intestinal mucosa) are occasionally observed (see the images below). In rare cases, patients with C difficile infection can present with an acute abdomen and fulminant, life-threatening colitis. (See Presentation.)

Clostridioides (Clostridium) Difficile Colitis. Endoscopic visualization of pseudomembranous colitis, a characteristic manifestation of full-blown <i>C difficile</i> colitis. Classic pseudomembranes are visible as raised, yellow plaques ranging from 2 to 10 mm in diameter and scattered over the colorectal mucosa. Courtesy of Gregory Ginsberg, MD, University of Pennsylvania.

Clostridioides (Clostridium) Difficile Colitis. Barium enema demonstrating the typical serrated appearance of the barium column (resulting from trapped barium between the edematous mucosal folds and the plaquelike membranes of pseudomembranous colitis).

Approximately 20% of individuals who are hospitalized become colonized with C difficile during hospitalization, and more than 30% of these patients develop diarrhea. Thus, C difficile colitis is currently one of the most common nosocomial infections. (See Pathophysiology and Etiology.)

The diagnosis of C difficile colitis should be suspected in any patient with diarrhea who has received antibiotics within the previous 3 months, has been recently hospitalized, and/or has an occurrence of diarrhea 48 hours or more after hospitalization.[1] However, more recent studies have shown that C difficile can be the cause of diarrhea in community dwellers without previous hospitalization or antibiotic exposure[2] ; therefore, the diagnosis should be suspected in this population as well. (See Presentation and Workup.)

Once infected with C difficile, the rate of disease recurrence is 20-40%, especially when first-line agents such as metronidazole and vancomycin are not successful.[9] In patients with CDI who develop fulminant colitis, early surgical intervention is crucial. Note that although intravenous immunoglobulin (IVIG) and tigecycline have been used in patients with severe refractory disease, delaying surgery may lead to worse outcomes. (See Treatment and Medication.)[9] In addition, the use of tigecycline in oncology patients with CDI has been reported with breakthrough CDIs in those who received it for non-CDI indications.[10]

C difficile colitis results from a disturbance of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation and damage. Colonization occurs by the fecal-oral route. Hospitalized patients are the primary targets of C difficile infection (CDI), although C difficile is present as a colonizer in 2-3% of healthy adults and in as many as 70% of healthy infants.[11] (Treatment of asymptomatic carriers is not recommended.)

C difficile forms heat-resistant spores that can persist in the environment for several months to years. Outbreaks of C difficile diarrhea may occur in hospitals and outpatient facilities where contamination with spores is prevalent. Although the normal gut flora resists colonization and overgrowth with C difficile, the use of antibiotics, which alter and suppress the normal flora, allows proliferation of C difficile, toxin production, and diarrhea.

Pathogenic strains of C difficile produce 2 distinct toxins. Toxin A is an enterotoxin, and toxin B is a cytotoxin; both are high–molecular weight proteins capable of binding to specific receptors on the intestinal mucosal cells. Receptor-bound toxins gain intracellular entry by catalyzing a specific alteration of Rho proteins—small glutamyl transpeptidase (GTP)–binding proteins that assist in actin polymerization, cytoskeletal architecture, and cell movement. Both toxin A and toxin B appear to play a role in the pathogenesis of C difficile colitis in humans.

More recently, rat studies suggest that C difficile toxin B induces senescence in enteric glial cells (ECGs); investigators hypothesize that EGCs that survive toxin B and acquire senescence potentially cause the development of irritable bowel syndrome and inflammatory bowel disease via persistent inflammation, transfer of senescence status, and stimulation of preneoplastic cells.[12]

The NAP1 hypervirulent strain of C difficile is associated with the most serious sequelae of CDI, causing severe and fulminant colitis that is characterized by leukocytosis, renal failure, and toxic megacolon.[13] The widespread use of fluoroquinolone antibiotics may have played a role in the proliferation of the NAP1 strain. Once rising white blood cell count or hemodynamic instability occurs and fulminant colitis is imminent, subtotal colectomy with end ileostomy is often necessary. Fecal bacteriotherapy and immunotherapy are investigative treatment strategies that have potential for managing patients with severe CDI.[13]

C difficile colitis results from a disruption of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation, mucosal damage, and diarrhea.

Risk factors

Antibiotic exposure

The primary risk factor for C difficile colitis is previous exposure to antibiotics; the most commonly implicated agents include the cephalosporins (especially second and third generation), the fluoroquinolones, ampicillin/amoxicillin, and clindamycin. Less commonly implicated antibiotics are the macrolides (ie, erythromycin, clarithromycin, azithromycin) and other penicillins. Agents occasionally reported to cause the disease include aminoglycosides, trimethoprim-sulfamethoxazole, metronidazole, chloramphenicol, tetracycline, imipenem, and meropenem.

Even brief exposure to any single antibiotic can cause C difficile colitis. A prolonged antibiotic course or the use of two or more antibiotics increases the risk of disease. Moreover, antibiotics traditionally used to treat C difficile, vancomycin and metronidazole, have also been shown to cause disease.[14]

Hospitalized patients who occupy a bed whose previous occupant received antibiotics appear to have an increased risk of C difficile infection (CDI).[15] A multicenter retrospective (2010-2015) study of 100,615 pairs of patients who sequentially occupied a given hospital bed found that less than 1% (576 pairs; 0.57%) of subsequent patients developed CDI, regardless of whether they themselves received antibiotics or not.[15] The association was statistically significant (log-rank P< 0.01).

Proton pump inhibitors

A US Food and Drug Administration (FDA) safety communication on February 8, 2012, described a possible association between the use of proton pump inhibitors (PPIs) and the development of Clostridium difficile –associated diarrhea (CDAD).[16] Data were collected from the US Food and Drug Administration’s (FDA's) Adverse Event Reporting System (AERS) and the medical literature for cases of CDAD in patients undergoing treatment with PPIs.

Many of the adverse event reports involved patients who were elderly, had chronic and/or concomitant underlying medical conditions, or were taking broad-spectrum antibiotics that could have predisposed them to developing CDAD.[16] The FDA also reviewed a total of 28 observational studies described in 26 publications. Of these studies, 23 showed a higher risk of C difficile infection or disease, including CDAD, associated with PPI exposure, compared with no PPI exposure.

Antidepressants

Two related studies documented an increased risk of CDI in adults taking the antidepressants mirtazapine and fluoxetine.[17, 18] In a longitudinal study of 16,781 older adults (mean age, 67.9 y), 404 of whom had been diagnosed with CDI at least once, major depression was associated with a 36% increase in the odds of developing an infection with C difficile.

In the second study, in which 4047 adult patients had their stools tested for C difficile while they were hospitalized, the odds of testing positive for the bacterium were twice as high in patients who received mirtazapine or fluoxetine as in those who did not.[17, 18] None of the other 10 antidepressants that were tested in the study increased the risk of CDI.

Other risk factors

Advanced age (>60 y) and hospitalization (particularly sharing a hospital room with an infected patient, intensive care unit stays, and prolonged hospital stays) are known risk factors for infection with C difficile. Severe illnesses, immune suppression, and gastric acid suppression[19] (or bypassing gastric acid via enteral feeds) are also well-established risk factors. In addition, in recent years, inflammatory bowel disease (IBD) has been implicated as a strong risk factor for C difficile infection (CDI).[9, 20] Early emergency general surgery has also been associated with a high incidence of CDI, particularly in patients who receive 3 or more postoperative antibiotics and those who undergo bowel resections.[21]

Rarer associations include the following:

• Antineoplastic agents, principally methotrexate

• Hemolytic-uremic syndrome

• Malignancies

• Intestinal ischemia

• Chronic kidney disease

• Necrotizing enterocolitis

• Hirschsprung disease

• Nonsurgical gastrointestinal procedures, including placement of nasogastric tubes

Genetics/genomics

Two genome-wide association studies (GWAS) found an association between a common polymorphism in the upstream promoter of the interleukin (IL)-8 gene and an increased risk for both the initial occurrence and the recurrence of CDI.[22, 23] Neutrophil recruitment to the intestine is thought to be coordinated by IL-8, and the polymorphism in the IL-8 promoter is thought to influence the manner in which neutrophils are recruited to the intestines when CDI is present.[22, 23]

An additional study looked more specifically at the regulation of the regenerating islet-derived genes (REG) in IBD. Interestingly, the study found that the activities of all REG genes were upregulated not only in IBD but also in patients with pseudomembranous colitis.[24] The implication from this study is that the function of the REG family of genes is more generalized in response to inflammation. These proteins are involved in injury, repair, and growth in the intestine. Also of interest is that REG proteins in the gut appear to be antimicrobial, with a function similar to lectin.[24]

Toxin A is an enterotoxin that is responsible for the major manifestations of colitis in humans. In a murine model deficient in the neurokinin-1 receptor, protection against inflammation from toxin A was demonstrated.[25] This protein, which is encoded by the NK1R gene, functions as the receptor for substance P. Downstream effects from this protective effect included decreased intestinal levels of tumor necrosis factor (TNF)-alpha and leukocyte myeloperoxidase. The overall suggestion from this study is that the substance P receptor is very important in the pathogenesis of inflammatory diarrhea.[25]

Further insight into the genetics of C difficile toxin A reveals that the main binding protein is gp96.[26] In addition, it has been found that C difficile has potent stimulatory activity for the Nod1 gene, and mice who were homozygous knockouts for Nod1 had increased lethality to CDI despite similar levels of intestinal damage relative to control the mice.[27] Those mice also had impaired clearance of bacteria and increased translocation of the bacteria. The implication of this study is that Nod1 regulates the susceptibility to C difficile.[27]

Ultimately, many of the genetic influences on CDI and the clinical course of C difficile colitis likely remain unknown. At this point, it is understood that subtle differences in the immune system may significantly influence the natural history of C difficile disease.

Occurrence in the United States

In the United States, C difficile infection (CDI) occurs primarily in hospitalized patients, causing as many as 3 million cases of diarrhea and colitis per year. Cancer patients are significantly affected by CDI healthcare-associated diarrhea.[28] Diarrhea caused by C difficile is also linked to 14,000 American deaths annually.[29]

The incidence of reported CDI infection continues to increase. In the 1980s, McFarland et al reported that 7% of patients admitted to a hospital and 28% of patients who were hospitalized had positive cultures for the organism. By the 1990s, the incidence of C difficile in hospitalized patients had risen to 30-40 per 100,000 population, and by 2005, to 84 per 100,000 population.

Indeed, in contrast to the incidence rates of other nosocomial infections, which declined from 2000 to 2009, the number of hospitalized patients with any CDI as a discharge diagnosis more than doubled in the same period, from approximately 139,000 to 336,600. Furthermore, the number of patients with a primary diagnosis of CDI more than tripled, from 33,000 to 111,000.[30]

New CDI populations have emerged, and studies have challenged the notion that C difficile is primarily a hospital infection, as more cases are being seen in the community.[2, 31, 32] These cases include patients with community-acquired infection and no previous antibiotic exposure, pregnant women, and patients with inflammatory bowel disease (IBD).[9, 20]

A population-based study from Olmsted County, Minnesota, demonstrated that 41% of the cases of C difficile infection were community acquired and that the incidence of both community- and hospital-acquired C difficile increased significantly from 1991 to 2005.[2]

International occurrence

The incidence of CDI, as well as deaths attributable to C difficile, has also risen in Europe and Canada. In Canada's Estrie region of Quebec, the incidence quadrupled in 2003 to 92.2 cases per 100,000 population. In a survey of 97 hospitals across 34 European countries, the incidence of C difficile in hospitalized patients was 41 per 100,000 patient-days.[33]

The worldwide increased incidence of CDI has been attributed to a variety of risk factors, including more elderly patients in the population, treatment resistance to fluoroquinolones, and the emergence of a newly discovered, more virulent strain of C difficile (BI/NAP1/027).[34] Additional risk factors toward increasing CDIs include the use of penicillins and clindamycin, as well as an increased use in the total number of antibiotics in the community.[34]

Age-related demographics

CDI is more common in elderly people, and old age may promote susceptibility to colonization and disease. Cross-infection by C difficile is common in neonatal units, but neonates do not seem to develop C difficile –associated diarrhea. More recently, there have been specific populations affected by C difficile that were previously believed to be at low risk, such as young, healthy persons not exposed to a hospital environment or antimicrobial therapy and young women in a peripartum setting.

A study by Nylund et al suggested an increase in CDI among hospitalized children, especially in those with medical conditions such as IBD and immunosuppression.[35] Also at risk are individuals hospitalized with conditions that require antibiotic administration.

Some patients with C difficile colitis with mild disease may recover without specific therapy; however, persistent diarrhea may be debilitating and can last for several weeks; therefore, treatment is recommended even in mild disease

The use of oral metronidazole or vancomycin produces response rates of greater than 95% in mild to moderate cases, with symptomatic improvement (diarrhea) in as little as 3-4 days and complete resolution in 7-10 days

Approximately 20-27% of patients treated for a first episode of C difficile colitis relapse after successfully completing therapy, typically 3 days to 3 weeks after treatment has ended.

Patients who relapse once are at an even greater risk for further relapses; the relapse rate for patients with 2 or more relapses is 65%.[36]

Adverse outcomes from C difficile infection (CDI) include treatment failure, development of severe or severe-complicated infection, sepsis and the need for admission to the intensive care unit, need for colectomy, increased length of hospital stay, need for hospital admission in patients with community-acquired CDI, and mortality.[37] (Mortality rates from C difficile –associated diarrhea as high as 4.2-6.9% were found in several centers in North America; in a multicenter study from Quebec, mortality rates increased with age.[38] )

However, there is evidence that reliance primarily on hospital-based studies of CDI, with relatively few studies having been made of community-acquired cases, may have led researchers to underestimate the burden, but overestimate the severity, of the condition.[2] Patients with community-acquired CDI are generally younger, with less severe infection relative to hospitalized patients with CDI.[2]

Severe strains

Several outbreaks have been caused by the North American Pulsed Field type 1 and polymerase chain reaction (PCR) ribotype 027 (NAP1/027) strain. This virulent strain has been associated with increased production of toxins A and B, fluoroquinolone resistance, and the production of a binary toxin. The role of the binary toxin is not clear, but it may synergistically increase the virulence of toxins A and B.

Based on the data from the Centers of Disease Control and Prevention (CDC), the virulent strain NAP1/027 has been reported in most US states and in several countries in Europe.

PCR ribotypes 018 and 056, identified in Europe, have been associated with more severe Cdifficile colitis.[33]

Predictors of severe outcomes in IBD and ulcerative colitis

Patients with IBD are well known to be at an increased risk for CDI. A study identified 3 independent predictors for severe outcomes in hospitalized IBD patients with CDI: (1) serum albumin less than 3 g/dL, (2) hemoglobin level below 9 g/dL, and (3) elevated serum creatinine above 1.5 mg/dL.[39]

In another study, investigators found that CDI is associated with a worse long-term outcome in patients with ulcerative colitis.[40] In the year following treatment for CDI in these patients, an escalation in medical management was noted. In addition, independent predictors for colectomy within 1 year were infection with C difficile and endoscopically proven severe disease.[40]

Complications

Fulminant colitis

Fulminant colitis is a rare form of CDI, occurring in only 3% of patients but accounting for most of the serious complications. These include toxic megacolon, colonic perforation, and death. Surgical intervention is usually required in patients who develop fulminant colitis.

Sailhamer et al conducted a retrospective review of 4796 patients with C difficile colitis, 199 (4.1%) of whom had the fulminant form, as defined by the need for colectomy or admission to the intensive care unit.[41] The in-hospital mortality rate for fulminant C difficile colitis was 34.7%. The investigators determined that independent predictors of mortality included the following:

• Age of 70 years or older

• Severe leukocytosis or leukopenia or bandemia

• Cardiorespiratory failure

The presence of all 3 factors resulted in a 57.1% mortality rate; in the absence of all 3, the mortality rate was 0%.[41] The investigators concluded that despite awareness and treatment of fulminant C difficile colitis, this condition remains highly lethal. Thus, reliable predictors of mortality should be used to prompt aggressive surgical intervention.[41]

To determine the long-term survival rate, rate of gastrointestinal continuity restoration, and rate of recurrence following an attack of fulminant C difficile colitis, Miller et al searched a pathologic database for patients with this condition, defined as those who had a bout of C difficile colitis and whose disease required surgical intervention after failure of medical therapy.[42]

Of the 49 patients who fit the criteria, the investigators found a 30-day mortality rate of 57% (28/49), with an in-hospital mortality rate of 49%. Moreover, the 5-year survival rate for the long-term survival group was poor, at 38% (16.3% for all patients). Twenty percent of patients had restored gastrointestinal continuity. One case of recurrence of C difficile colitis was reported.[42]

Toxic megacolon

Toxic megacolon is an acute toxic colitis with dilatation of the colon. This condition is diagnosed clinically in a patient with signs and symptoms of severe toxicity, the presence of a tender abdomen, and a dilated colon on plain radiograph of the abdomen.

Colonic perforation

Colonic perforation is usually accompanied by abdominal rigidity, involuntary guarding, rebound tenderness, and absent bowel sounds. Free air may be revealed on abdominal radiographs. Any suspicion of perforation in this setting should prompt immediate surgical consultation.

C difficile colonization results in a wide spectrum of clinical conditions, including an asymptomatic carrier state; mild, self-limited diarrhea; pseudomembranous colitis; and fulminant colitis. Most patients develop diarrhea during or shortly after starting antibiotics. However, 25-40% of patients may not become symptomatic for as many as 10 weeks after completing antibiotic therapy.

Symptoms often include the following:

• Mild to moderate watery diarrhea that is rarely bloody

• Cramping abdominal pain

• Anorexia

• Malaise

• Fever, especially in more severe cases

Physical examination is generally nonspecific in patients with mild C difficile infection. Fever, signs of dehydration, lower abdominal tenderness, and/or rebound tenderness (raising the possibility of colonic perforation and peritonitis) may be present.

More concerning signs include marked dehydration, marked abdominal tenderness, and distention, as well as marked rigidity and decreased bowel sounds. These may indicate the presence of complications such as toxic megacolon, and bowel perforation.

Leukocytosis is common in C difficile infection (CDI) and the white blood cell (WBC) count levels may be quite elevated, a finding that portends a worse prognosis. Patients with C difficile are also prone to acute kidney injury. Therefore, white blood cell counts and serum creatinine should be measured in patients with C difficile. Because the presence of leukocytosis and renal impairment are indicators of severe infection, patients with these findings should be treated initially with oral vancomycin instead of metronidazole.[5]

In severe disease, electrolyte imbalance, dehydration, hypoalbuminemia, and anasarca may occur, and patients should be monitored periodically. If surgical intervention is being considered, serum lactate levels and white blood cell counts may aid clinicians in their decision making.

The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommend testing for C difficile and its toxins in symptomatic patients only on diarrheal stool, unless there is suspicion of ileus due to C difficile.[5, 43] When individuals are asymptomatic, stool testing is not recommended unless for epidemiologic studies, in which case stool cultures are the most sensitive studies.[5, 43]

C difficile testing is not recommended in asymptomatic patients due to the difficulty in distinguishing asymptomatic carriage from infection in this setting. In addition, repeat testing for C difficile is not recommended following successful treatment in a patient recently treated for CDI.[5, 43]

Retesting for C difficile is not recommended, particularly for molecular studies, as detection rates and results do not improve, and there is an associated increase in healthcare costs and the likelihood of false-positive findings.[43]

In symptomatic patients, stool testing for C difficile should be performed only on diarrheal samples,[5, 43] and perirectal swabs are not accepted for testing, unless there is suspicion for ileus due to this organism. Stool testing is not recommended for asymptomatic patients, as the results are not clinically useful; if such testing is used for epidemiologic purposes, stool culture is required.[5, 43]

Stool may be positive for blood in the presence of severe colitis, but grossly bloody stools are unusual. Fecal leukocytes are present in about half of the C difficile colitis cases.

Stool cultures are the most sensitive tests for detecting C difficile and its toxins.[5] Moreover, results of the stool cultures followed by the identification of a toxigenic culture from an experienced laboratory are the standard used for comparison with other diagnostic testing.[5] However, despite their role as the gold standard test in patients with suspected C difficile infection (CDI), stool cultures have a long turnaround time and are resource intensive. Such factors make them too slow for practical clinical decision making (to treat or not to treat) in affected patients. Consequently, in clinical practice, enzyme immunoassay (EIA) for C difficile toxin A and B is used more often.

However, although EIA is a rapid test for C difficile toxin A and B, it is not an ideal alternative test for diagnosing CDI, due to it having a lesser sensitivity than the cell cytotoxin assay (see below). Nonetheless, the poor sensitivity of EIA can be overcome by obtaining repeat stool specimens or by combining EIA with polymerase chain reaction (PCR) assay or C difficile antigen (glutamate dehydrogenase [GDH]) EIA.

The following are stool assays for C difficile, from the most sensitive to the least sensitive:

• Stool culture is the most sensitive (sensitivity 90-100% and specificity 84-100%), but results are slow and may lead to delay in diagnosis if used alone

• GDH EIA is very sensitive (sensitivity 85-100% and specificity 87-98%); this test detects the presence of GDH produced by C difficile; positive test results need to be rerun by another assay to verify

• Real-time PCR assay may be used to detect C difficile gene toxin as an alternative “gold standard” to stool culture, with some studies demonstrating excellent sensitivity and specificity, as well as test-retest reliability[3, 44] ; in a study that used toxigenic culture as the gold standard, the sensitivity was 86%, the specificity was 97%, the positive predictive value (PPV) was 90%, and the negative predictive value (NPV) was 96%, for C difficile[3] (the PCR test is also inexpensive and has a fast turnaround time)

• The stool cytotoxin test has a sensitivity of 70-100% and a specificity of 90-100%; the diarrheal stool is filtered and then added to cultured fibroblasts; a positive test result is the demonstration of a cytopathic effect that is neutralized by specific antiserum; however, this test result is reported only as positive or negative, it is expensive, and it requires overnight incubation and a tissue culture facility

• EIA for detecting toxins A and B is used in most laboratories; it has moderate sensitivity (79-80%) but excellent specificity (98%); repeat testing is needed if the initial test is negative; EIA for toxin A is available, but it has come to be used less frequently because of the availability of EIA for toxins A and B

• Latex agglutination technique can also be used to detect GDH; however, the sensitivity of this test is poor (48-59%), although the specificity is 95-96%

Toxin testing has the most important clinical relevance, but its lack of sensitivity is an issue. The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) suggest an interim strategy; ie, a 2-step method that has the potential to overcome the sensitivity concern.[5] It would be carried out as follows:

• For the initial screening, use EIA detection of GDH

• This would be followed by a confirmatory test only for GDH-positive stool specimens by cell cytotoxic assay or toxigenic culture

In addition, the SHEA and IDSA note that although PCR assay testing appears to be rapid, sensitive, and specific, further research is needed before it can be recommended for routine testing in cases of suspected CDI.[5]

Biomarkers

A study by El Feghaly et al indicated that fecal inflammatory cytokines may be useful as biomarkers for distinguishing between C difficile colonization and actual disease. They may also be helpful in determining whether a child with C difficile infection is at a high risk for prolonged diarrhea. The study involved 65 children who were known to be C difficile positive, as well as symptomatic and asymptomatic controls. Results included the following[45] :

• Fecal cytokines: Elevated in symptomatic children (cases and controls); also elevated at diagnosis in patients with a significantly greater time to resolution of diarrhea (TTROD)

• Fecal chemokine ligand (CXCL)–5 messenger ribonucleic acid (mRNA): Correlation found between abundance at diagnosis and persistent diarrhea

• Phosphorylated p38: Lacks sensitivity, although specific for C difficile infection

Although endoscopy is not routinely recommended for the diagnosis or management of C difficile infection (CDI), this procedure may demonstrate the presence of raised, yellowish white, 2- to 10-mm plaques overlying an erythematous, edematous mucosa. These plaques are termed pseudomembranes (see the following images). Pseudomembranes are observed in 14-25% of patients with mild C difficile disease and 87% of patients with fulminant disease.

Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis revealing the characteristic yellowish plaques.

Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis, again demonstrating the characteristic yellowish plaques.

Clostridioides (Clostridium) Difficile Colitis. Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M. Osgard, MD.

Histologic findings

Biopsy of pseudomembranous plaques reveals an inflammatory exudate composed of mucinous debris, fibrin, necrotic epithelial cells and polymorphonuclear cells. The underlying crypts show disruption by mucous and inflammatory debris. The intervening mucosa shows edema but is otherwise unremarkable.

Things to consider

Most patients have disease throughout the colon. However, sigmoidoscopy alone may not reveal any abnormality if the disease is confined to the right colon. Typical pseudomembranes are beyond the limit of flexible sigmoidoscopy in 10% of patients. Therefore, colonoscopy is more useful.

Endoscopic examination findings may be normal in patients with mild disease or may demonstrate nonspecific colitis in moderate cases. Endoscopy is the least sensitive means of diagnosing C difficile relative to stool assays.

Sigmoidoscopy and colonoscopy in patients with fulminant colitis may be contraindicated because of the risk of perforation. Limited proctoscopy, with minimal air insufflation, may be a useful diagnostic tool in case of a diagnostic dilemma.

The American College of Radiology (ACR) recommends abdominal computed tomography (CT) scanning as the imaging modality of choice for C difficile colitis when pseudomembranous colitis, other complications of C difficile infection (CDI), or other intra-abdominal pathology is suspected.[4] Marked colonic wall thickening is the most common finding (see the following images). Other features may include ascites, irregularity of the bowel wall, and pericolonic stranding. In patients with sepsis due to suspected megacolon, abdominal radiography may be performed instead of CT scanning to establish the presence of megacolon in a timely manner.

Clostridioides (Clostridium) Difficile Colitis. Axial computed tomography scan of pseudomembranous colitis.

Clostridioides (Clostridium) Difficile Colitis. Computed tomography scan depicting pseudomembranous colitis.

The decision to treat C difficile infection (CDI) and the type of therapy administered depend on the severity of infection, as well as the local epidemiology and type of C difficile strains present. Except for perioperative prophylaxis, it is recommended that the use of cephalosporin and clindamycin be restricted for infection prevention.[5] No treatment is necessary for asymptomatic carriers.

Guidelines recommend administering fixaxomicin for initial and recurrent infections, with oral vancomycin as an alternative.[46, 47, 48, 49, 50] Rifaximin, bezlotoxumab, and fecal microbiota transplantation (FMT) are other treatment options.

In patients with severe or complicated CDI, oral vancomycin is recommended as first-line therapy due to faster symptom resolution and fewer treatment failures than when metronidazole is used.

FMT is recommended for patients with multiple recurrences of CDI whose conditions persist despite appropriate antibiotic treatments.[51, 52] A 2018 systematic review and meta-analysis comprising 7 studies with 543 patients with recurrent CDI that compared FMT to standard-of-care management found FMT to hold promise as a treatment modality in this setting relative to medical therapy alone.[53] There was no significant difference regarding different forms (fresh vs frozen) and routes (upper vs lower) of FMT administration.

New approaches to the prevention and management of CDI continue to undergo development and investigation.[54] See the Guidelines section for recent treatment recommendations.

CDC promotes improving inpatient antibiotic prescribing to reduce drug resistance and increase patient safety

In a CDC analysis of data regarding antibiotic prescribing in hospitalized patients, Fridkin and colleagues estimated that a 30% reduction in the use of broad-spectrum antibiotics would result in a 26% reduction in CDIs.[55, 56] In addition, improvement in physician antibiotic prescribing habits from overuse and incorrect use would also help to reduce antibiotic resistance.

The authors recommended the following measures[56] :

• Promptly initiate antibiotics for a presumed infection, but first obtain any recommended cultures.

• Document and specify the drug's indication, dose, and expected duration of use in the patient's medical chart.

• Reassess the patient within 48 hours based on test results and patient examination; adjust the antibiotic regimen (dose, duration) and/or the agent, or end the antibiotic treatment, as needed.

Surgical intervention

A systematic review and meta-analysis of 12 observational studies with at least moderate quality that comprised 35,057 patients with inflammatory bowel disease (IBD) with CDI and 929,259 patients without CDI found that although CDI did not appear to increase the risk of colectomy in the short term in IBD patients, over the long term, it appeared to increase the colectomy risk in those with IBD overall and in those with ulcerative colitis.[57]

Patients with fulminant colitis and toxic megacolon may require operative intervention, such as colectomy with preservation of the rectum. These patients’ serum lactate levels and peripheral leukocyte counts may aid in the decision to operate; there is a significant risk for perioperative mortality with elevated serum lactate levels (5 mmol/L) and leukocytosis (50,000 cells/µL).[5]

Lee and colleagues evaluated clinical factors associated with mortality in emergency colectomies performed for C difficile colitis. They used the ACS-NSQIP database from 2005 to 2010 to study emergently performed open colectomies for a primary diagnosis of C difficile colitis on the International Classification of Diseases, Ninth Revision. They compared the preoperative, intraoperative, and postoperative factors between survivors and nonsurvivors. To study clinical factors that may be associated with 30-day mortality, they performed multivariate stepwise binomial logistic regression analyses. The overall mortality for this cohort was 33% (111/335) with a median time to death of 8 days. Survivors were discharged, on average, on postoperative day 24.[58]

On multivariate analysis, those aged 80 years or older were associated with a ninefold increase in the odds of mortality. Other factors associated with increased mortality were preoperative shock, preoperative dialysis dependence, chronic obstructive pulmonary disease, and wound class III. In addition, thrombocytopenia, coagulopathy, and renal insufficiency were associated with a higher mortality. This is the largest series of colectomies performed for C difficile colitis in the literature. The investigators’ findings may be useful in selecting appropriate patients for surgical intervention and may help to define a population where surgery may not be beneficial.[58]

For more information, see the Medscape Drugs & Diseases articles Toxic Megacolon and Pseudomembranous Colitis Surgery.

Consultations

In patients with complicated CDI, a gastroenterologic consultation may be useful for consideration of a colonoscopic evaluation. Surgical consultation is recommended in patients with suspected fulminant colitis, toxic megacolon, or peritonitis.

Cessation of the causative antibiotic is essential when possible, as this may affect the risk of recurrence of infection with C difficile.[5] Avoid antidiarrheal agents (eg, diphenoxylate with atropine); they have been reported to increase the duration and severity of symptoms.

See the Guidelines section for recent treatment recommendations.

Mild to moderate infection

Discontinuing antibiotic therapy may be the only treatment necessary for those with mild antibiotic-associated diarrhea without fever, abdominal pain, or leukocytosis. This conservative approach allows for the reconstitution of the normal colonic microflora and markedly reduces the risk of relapse. If ongoing antibiotic therapy is necessary, a treatment can be chosen that is less frequently associated with CDI, such as intravenous aminoglycosides, sulfonamides, macrolides, tetracycline, or vancomycin.

Patients with mild to moderate diarrhea or colitis, as defined by the absence of leukocytosis, acute kidney injury, fever, sepsis, or megacolon, should receive antibiotic therapy with oral metronidazole or oral vancomycin (in those who are intolerant to metronidazole) for 10-14 days. The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) indicate that metronidazole (500 mg PO TID for 10-14 days) is the drug of choice in these patients.[5]

In a retrospective study of 300 patients, a low-dose regimen of oral vancomycin (< 500 mg/day) was as effective as a high-dose regimen (>500 mg/day) for the treatment of CDIs. Clinical improvement rates for the low- and high-dose regimens were 85% and 86%, respectively, at 72 hours and 93% and 96%, respectively, at the end of therapy/hospital discharge. Patients on the low vancomycin dose had lower in-hospital mortality rates (15% versus 23%) but higher C difficile –related hospital readmission rates (12% vs 5%).[59]

Severe or severe-complicated infection

In patients with suspected severe or complicated CDI, initiate early empirical therapy while the stool tests are pending.[5] Oral vancomycin (125 mg PO QID for 10-14 days)[5] is recommended as first-line therapy in these cases due to faster symptom resolution and fewer treatment failures than when metronidazole is used. Vancomycin is not absorbed and acts directly at the infection site. Symptomatic improvement can be expected within 2-3 days.

Patients with inflammatory bowel disease (IBD) represent a unique population in whom treatment with vancomycin is recommended regardless of disease severity, owing to the high rate of recurrence of CDI in this population, as well as the association between CDI and adverse health outcomes, such as surgery and mortality.

In fulminant cases, combined therapy with intravenous metronidazole and vancomycin (PO or PR) is the treatment of choice.[5] Intravenous vancomycin is ineffective and should not be used for C difficile. The SHEA and IDSA recommend intravenous metronidazole 500 mg every 8 hours with oral vancomycin 500 mg 4 times per day (and/or 500 mg PR q6h in 100 mL normal saline as a retention enema).[5]

In several clinical trials, 200 mg of oral fidaxomicin administered every 12 hours for 10 days was found to be noninferior to 125 mg of oral vancomycin administered every 6 hours for 10 days for the treatment of C difficile in adults.[60] There was no difference in cure rates based on C difficile disease severity. Symptomatic improvement is generally expected within 2-3 days.

The FDA approved fidaxomicin for children aged 6 months or older in January 2020 for treatment of C difficile-associated diarrhea (CDAD). Approval was based on the phase 3 SUNSHINE clinical trial that included 148 randomized patients younger than 18 years with confirmed CDI, of whom 142 received either fidaxomicin or vancomycin in a 2:1 ratio.[61] Clinical response assessed through 2 days following 10 days of treatment was similar between the fidaxomicin and vancomycin groups (77.6% vs 70.5%), respectively). Sustained clinical response through 30 days after the end of treatment was higher for fidaxomicin than for vancomycin (68.4% vs 50.0%).[61]

In a multicenter retrospective (2013-2014) study of CDI in 72 Spanish patients, fidaxomicin treatment was effective and well tolerated in patients with severe CDI as well as those at high risk of recurrent disease.[62] The clinical cure rate was 90.3%, with a 16.7% recurrence rate and a 72.2% sustained cure rate. The investigators found that factors that adversely affected the sustained cure rate included the presence of cardiovascular disease, acute renal failure, and systemic antibiotic treatment, as well as the C-reactive protein level measured at the time of the diagnosis.[62]

Relapse

Relapse is generally common, occurring in up to 20-27% of cases. Relapse typically occurs 3 days to 3 weeks after the treatment is discontinued. Possible reasons for relapse include ongoing risk factors such as antibiotic exposure, failure to eradicate the organism from the colon, and reinfection from the environment.

In October 2016, the FDA approved bezlotoxumab, a human monoclonal antibody that binds to C difficile toxin B and neutralizes its effects.[63] It is used with standard-of-care antibiotics to reduce the recurrence of CDI in adults who have a high risk of recurrence. Approval was based on the results from the global Monocolonal Antibodies For C Difficile Therapy (MODIFY) I and MODIFY II studies, which showed a single dose of bezlotoxumab (in conjunction with antibiotics) is superior to placebo in prevention of CDI recurrence through 12 weeks (P= 0.0003 for both trials).[63, 64] High risk in these studies was defined as age 65 years and older, recent CDI (within 6 months), prior recurrent CDI, compromised immunity, severe CDI (Zar score >1), or infection with a hypervirulent, binary toxin–positive strain.

In general, management of the first recurrence of CDI is the same as that for the initial episode, including stratification according to disease severity.[5] However, although metronidazole can be used for the first recurrence of CDI (if it is not severe), the drug should not be used for subsequent recurrences or for long-term, chronic therapy (risk of cumulative neurotoxicity). Rather, a second or later recurrences should be managed with vancomycin therapy using a tapered and/or pulse regimen.[5]

The SHEA and IDSA have made no recommendations for preventing recurrent CDI in patients with an underlying infection requiring continued antimicrobial management.[5]

Probiotics

In adults and children on antibiotic treatment, the AGA recommends the use of S boulardii; or the 2-strain combination of i>L acidophilus CL1285 and Lactobacillus casei LBC80R; or the 3-strain combination of L acidophi ;L acidophilus, L delbrueckii subsp bulgaricus, B bifidum, and Streptococcus salivarius subsp thermophilus over no or other probiotics for prevention of CDI.[47] ​

Probiotics are generally not recommended for the treatment of active CDI owing to limited data supporting their benefits and a potential risk for septicemia.[5] However, a meta-analysis that evaluated 34 studies and 4138 patients supported earlier studies indicating that probiotics can prevent the diarrhea that is associated with antibiotic use.[65]

Fecal microbiota transplantation (FMT) is a novel therapy that involves the transfer of stool from a healthy donor to a patient with C difficile infection (CDI) in order to reconstitute the normal colonic microbial flora.[66] FMT has been reported to repopulate the colonic flora, with efficacy rates of greater than 90% demonstrated even in cases refractory to antibiotic therapy.[67] Several studies have shown that FMT by colonoscopy or enema is an effective approach for patients with recurrent C difficile colitis, with clinical success rates of up to 95%.[68, 69]

In November 2022, the FDA approve microbiota via rectal administration for prevention of recurrence of CDI in adults following antibiotic treatment for CD recurrence. Approval was based on the PUNCH CD3 phase 3 clinical trial.[70] Adults who had at least one CDI recurrence with a positive stool assay for C difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of microbiota or placebo. The primary endpoint was treatment success, defined as the absence of CDI diarrhea within 8 weeks of study treatment. Among 267 patients who received blinded treatment (n = 180, microbiota; n = 87, placebo), successful treatment was 70.6% versus 57.5% with microbiota and placebo, respectively. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the microbiota and the placebo groups.[70]

Data regarding fetal microbiota transplantation (FMT) in children with recurrent Clostridium difficile colitis are limited and focus on colonoscopic administration of FMT. Kronman et al describe 10 consecutive children who received FMT via nasogastric tube for the treatment of recurrent CDI. The children’s median age was 5.4 years, and 30% were receiving simultaneous immunosuppression. Median follow-up was 44 days, and 90% of patients resolved their CDI. The authors conclude that FMT via nasogastric tube appears to be safe, well tolerated, and effective in treating recurrent C difficile colitis in pediatric patients.[71]

Long-term data from a fecal transplantation clinical trial (≥3 mo from the time of fecal transplantation) revealed that of the 77 of 98 patients who could be contacted, 91% did not have a relapse.[6] Of the patients who did relapse, all but 1 were treated successfully with vancomycin or additional fecal transplantation.[6]

In the first randomized, controlled trial of fecal transplantation, investigators in the Netherlands found fecal transfer to be 3 times more effective than antibiotics in curing recurrent CDI, leading to the study’s early termination.[7, 8] The study compared 3 treatments: (1) standard vancomycin therapy (500 mg PO QID for 14 days), (2) standard vancomycin therapy plus bowel lavage, and (3) 4 days of vancomycin therapy (500 mg PO QID) followed by bowel lavage and infusion of donor feces through a nasoduodenal tube.[7, 8]

In a retrospective study of 83 immunocompromised patients who underwent fecal transplantation for recurrent (12%), refractory (54%), or severe (34%) CDI, the cure rate after a single transplant was 79% (52 of the 66 patients with at least 12 weeks of follow-up). Seven of the 9 patients who underwent a second transplant were also cured. Mean follow-up was 12 months. Serious adverse events, including 2 deaths, occurred within 12 weeks of the transplant in 10 patients (15%).[72]

Of the patients treated with fecal transplantation, 13 of 16 (81%) had resolution of C difficile –associated diarrhea after the first infusion, and 2 of the 3 remaining patients experienced resolution after receiving a second infusion with feces from a different donor.[7, 8] By contrast, CDI resolved in only 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage.[7, 8]

However, it should be noted that FMT carries the risk of infection transmission (human immunodeficiency virus [HIV], hepatitis, and retrovirus). Administration of other bacterial preparations is under investigation.

A meta-analysis of intestinal microbiota transplantation (IMT) in which intestinal microorganisms in a suspension of healthy donor stool were infused into the intestines of patients with recurrent CDI and pseudomembranous colitis found that out of 317 patients across 27 case series and reports, 92% were successfully treated with this therapy.[73] Adverse effects were uncommon. Although further study is required, this review supports use of the IMT as a promising treatment for recurrent CDI.[73]

See the Guidelines section for recent FMT guidelines recommendations.

C difficile is now recognized as a major nosocomial pathogen, and universal precautions against it should be implemented. The following guidelines are recommended when dealing with patients with C difficile colitis[5, 30] :

• Use disposable gloves, laboratory coats, and proper washing techniques

• Educate the medical and nursing staff, as well as family and visitors, regarding the disease and its epidemiology, and emphasize compliance with hand hygiene practices (such as washing with soap or antimicrobial soap and water)

• Hospital transmission is likely associated with the survival of spores on inanimate objects; therefore, close attention to cleanliness and disinfective measures are important (eg, use of contact precautions for 48 hours or longer following resolution of diarrhea, disposable electronic rectal thermometers, chlorine-containing cleansers or other sporicidal agents), particularly during the patient’s diarrheal period

• Isolation of patients who are infected is strongly recommended but often impractical at most hospitals; in such situations, a dedicated commode for each patient should be provided

The most important preventive measure is the judicious use of antimicrobial agents. Principal CDI prevention recommendations from the Centers for Disease Control and Prevention (CDC), as well as the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA), include improved antibiotic therapy, early and accurate CDI detection, isolation of symptomatic patients, and reduction of C difficile contamination on environmental surfaces in healthcare settings.[5, 30]

CDI risk is increased 7- to 10-fold during antibiotic use and for 1 month after the drug is discontinued; the risk is approximately 3-fold during the second and third month after discontinuation.[30]

A systematic review and meta-analyses of observational studies have shown evidence of an increased risk for recurrent CDI among patients who use gastric acid suppressants; the investigators suggest it may be reasonable for clinicians to reassess whether their patients with CDI need to take these agents.[19]

Guidelines for the management of Clostridioides difficile infection (CDI) were published in June 2021 by the American Society of Colon and Rectal Surgeons (ASCRS) in Diseases of the Colon and Rectum.[48]

Evaluation

When Clostridioides difficile infection (CDI) is suspected, perform a disease-specific history emphasizing risk factors, symptoms, comorbidities, and signs of severe or fulminant disease.

Evaluate patients to determine severity of CDI and presence of peritonitis or multisystem organ failure.

Diagnosis of CDI should include two-step laboratory stool testing to increase accuracy.

Routine endoscopic evaluation to diagnose or determine the extent of CDI is not recommended.

Management

Oral vancomycin or fidaxomicin is first-line treatment for an initial CDI.

Metronidazole alone is no longer considered appropriate first-line treatment for CDI.

Surgery

Reserve surgery for C difficile colitis for patients with colonic perforation or severe colitis who do not improve with medical therapy.

Subtotal colectomy with end ileostomy is recommended for severe-complicated or fulminant C difficile colitis.

A diverting loop ileostomy with antegrade colonic lavage may be an alternative to subtotal colectomy for the treatment of severe-complicated or fulminant CDI.

Recurrent and Refractory CDI

A prolonged course of vancomycin, adding bezlotoxumab or using fidaxomicin, is an acceptable therapy for recurrent or refractory CDI in stable patients.

Patients with recurrent or refractory CDI should be considered for fecal bacteriotherapy if conventional measures have failed.

2021 Updated ISDA/SHEA guidelines

The following selected updated recommendations on Clostridium difficile infection (CDI) were released in September 2021 by the Infectious Diseases Society of America (ISDA) and Society for Healthcare Epidemiology of America (SHEA).[49]

In patients with a first CDI episode, fidaxomicin is recommended instead of a standard course of vancomycin.

In those with recurrent CDI episodes, fidaxomicin (standard or extended-pulsed regimen), rather than a standard course of vancomycin, is recommended.

In patients who experience a recurrent CDI episode within the last 6 months, use bezlotoxumab as a co-intervention in combination with standard-of-care (SOC) antibiotics rather than SOC antibiotics only.

2018 Updated ISDA/SHEA guidelines

The following ISDA/SHEA guidelines were released in February 2018.[51, 52]

Diagnosis (adults)

Patients with unexplained and new-onset ≥3 unformed stools in 24 hours are the preferred target population for testing for CDI.

Use a stool toxin test as part of a multistep algorithm (ie, glutamate dehydrogenase [GDH] plus toxin; GDH plus toxin, arbitrated by nucleic acid amplification test [NAAT]; or NAAT plus toxin) rather than NAAT alone for all specimens when there are no preagreed institutional criteria for patient stool submission.

Use NAAT alone or a multistep algorithm for testing (ie, GDH plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) rather than a toxin test alone when there are preagreed institutional criteria for patient stool submission.

Do not perform repeat testing (within 7 days) during the same episode of diarrhea and do not test stool from asymptomatic patients, except for epidemiologic studies.

Diagnosis (pediatric)

Because of the high prevalence of asymptomatic carriage of toxigenic C difficile in infants, testing for CDI should never be routinely recommended for neonates or infants ≤12 months of age with diarrhea.

C difficile testing should not be routinely performed in children with diarrhea who are 1-2 years of age unless other infectious or noninfectious causes have been excluded.

In children ≥2 years of age, C difficile testing is recommended for patients with prolonged or worsening diarrhea and risk factors (eg, underlying inflammatory bowel disease or immunocompromising conditions) or relevant exposures (eg, contact with the healthcare system or recent antibiotics).

Treatment (adults)

Discontinue therapy with the inciting antibiotic agent(s) as soon as possible, as this may influence the risk of CDI recurrence.

Antibiotic therapy for CDI should be started empirically for situations where a substantial delay in laboratory confirmation is expected, or for fulminant CDI.

Either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of CDI. The dosage is vancomycin 125 mg orally 4 times per day or fidaxomicin 200 mg twice daily for 10 days.

In settings where access to vancomycin or fidaxomicin is limited, metronidazole is suggested for an initial episode of nonsevere CDI only. The suggested dosage is metronidazole 500 mg orally 3 times per day for 10 days. Avoid repeated or prolonged courses due to the risk of cumulative and potentially irreversible neurotoxicity.

For fulminant CDI, vancomycin administered orally is the regimen of choice. If ileus is present, vancomycin can also be administered per rectum. The vancomycin dosage is 500 mg orally 4 times per day and 500 mg in approximately 100 mL normal saline per rectum every 6 hours as a retention enema. Intravenously administered metronidazole should be administered together with oral or rectal vancomycin, particularly if ileus is present. The metronidazole dosage is 500 mg intravenously every 8 hours.

If surgical management is necessary for severely ill patients, perform subtotal colectomy with preservation of the rectum. Diverting loop ileostomy with colonic lavage followed by antegrade vancomycin flushes is an alternative approach that may lead to improved outcomes.

Treat a first recurrence of CDI with oral vancomycin as a tapered and pulsed regimen rather than a second standard 10-day course of vancomycin; OR treat a first recurrence of CDI with a 10-day course of fidaxomicin rather than a standard 10-day course of vancomycin; OR treat a first recurrence of CDI with a standard 10-day course of vancomycin rather than a second course of metronidazole if metronidazole was used for the primary episode.

Fecal microbiota transplantation is recommended for patients with multiple recurrences of CDI whose conditions have failed appropriate antibiotic treatments.

Treatment (pediatric)

Either metronidazole or vancomycin is recommended for the treatment of children with an initial episode or first recurrence of nonsevere CDI.

For children with an initial episode of severe CDI or with a second or greater episode of recurrent CDI, oral vancomycin is recommended over metronidazole.

Prevention

In 2018, The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) released strategies on the prevention of Clostridium difficile infection (CDI) in acute care settings (outbreak and endemic).[74]  Select strong recommendations are outlined below.

Diagnostic approach

Use a two-stage test (glutamate dehydrogenase [GDH] or nucleic acid amplification test [NAAT]) for toxin genes, followed by a highly sensitive toxin test or GDH in combination with a toxin test. If the toxin test is negative, clinicians can perform NAAT (if not already part of the first diagnostic step) or toxigenic culture on the basis of clinical assessment or local prevention requirements.

Surveillance

In an outbreak setting, perform CDI surveillance with timely feedback of infection rates on the hospital and the ward level.

In an endemic setting, surveilla CDI surveillance with timely feedback of infection rates.

Screening

In outbreak and endemic settings, ESCMID does not recommend healthcare workers be screened for C difficile gut colonization as a means of routine control measure for CDI.

Hand hygiene

ESCMID does not have specific recommendations about the most effective techique/product for removing C difficile spores.

Personal protective equipment (PPE)

In the outbreak setting, ESCMID strongly recommends use of PPE (gloves, gowns/disposable aprons) for reducing the transmission of C difficile or the incidence of CDI.

Contact precautions

In outbreak and endemic settings, ESCMID strongly recommends use of contact precautions for reducing both the transmission of C difficile and the incidence of CDI.

Environmental cleaning and disinfection

In the outbreak setting, institute daily environmental and terminal sporicidal disinfection of rooms of patients with CDI to reduce the transmission of CDI.

Antibiotic stewardship

In outbreak and endemic settings, restricting the use of antibiotic agents/classes is effective in lowering the rates of CDI. In addition, shortening the duration of antibiotic therapy is effective in lowering rates of CDI.

Treatment

In 2021, the ESCMID  updated their 2014 guidelines for the treatment of CDI, which included antibiotic treatment for all but very mild cases.[50] Suggested treatment recommendations are outlined below.

In nonsevere CDI, discontinue antibiotic therapy with the inciting antibiotic if possible. Closely monitor the patient for 48 hours.

Standard of care

First-line treatment: For the initial CDI, administer fidaxomicin 200 mg twice daily (BID) for 10 days. For a first recurrence, administer the standard of care plus bezlotoxumab. For two and more recurrences, administer fecal microbiota transplantation (FMT).

Second-line treatment: For the initial CDI, administer vancomycin 125 mg four times daily (QID) for 10 days. For a first recurrence, administer fidaxomicin 200 mg BID for 10 days. For two and more recurrences, administer either FMT or the standard of care plus bezlotoxumab.

High recurrence risk

First-line treatment: For the initial CDI, administer fidaxomicin 200 mg BID for 10 days.

Second-line treatment: For the initial CDI, administer the standard of care plus bezlotoxumab.

When the preferred option is not available

For the initial CDI, administer metronidazole 500 mg three times daily (TID) for 10 days. With the first and more recurrences, consider use of a vancomycin tapering and pulse strategy (125 mg QID for 2 weeks, followed by 125 mg BID for 1 week, then 125 mg daily for 1 week, then 125 mg every 48 hours for 1 week, and finally 125 mg every 72 hours for 1 week).

Severe CDI

For the initial CDI and first and more recurrences, administer vancomycin or fidaomicin. If oral administration is not possible, use local delivery (rectal or nasoduodenal delivery) with or without adjunctive intravenous (IV) metronidazole or IV tigecycline.

Severe-complicated CDI and refractory severe CDI

For the initial CDI and first and more recurrences, administer vancomycin or fidaomicin. Use a multidisciplinary approach and surgical consultation. In a setting of refractory severe CDI, consider administering IV tigecycline and FMT.

The 2014 ESCMID recommendations included the following[75, 76] :

• For patients with nonepidemic, nonsevere CDI clearly induced by antibiotic use, with no signs of severe colitis, it may be acceptable to stop antibiotic treatment and observe the clinical response for 48 hours.

• Antibiotic treatment is recommended for all except very mild cases actually triggered by antibiotic use; suitable treatments include metronidazole, vancomycin, and fidaxomicin.

• For mild/moderate disease, oral metronidazole (500 mg 3 times daily for 10 days) is recommended as the initial treatment.

• In patients for whom oral treatment is inappropriate, fidaxomicin may be used; specific indications include first-line treatment in patients with recurrence or at risk for recurrence.

• For patients with severe CDI, suitable antibiotic regimens include vancomycin (125 mg 4 times daily for 10 days; may be increased to 500 mg 4 times daily) or fidaxomicin (200 mg twice daily for 10 days).

• Use of fidaxomicin is not supported in life-threatening CDI.

• Use of oral metronidazole in severe or life-threatening CDI is discouraged.

• Fecal transplantation is recommended for multiple recurrent CDI.

• For patients with colonic perforation and/or systemic inflammation and deteriorating clinical condition despite antibiotic treatment, total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended.

• Additional management measures include discontinuing unnecessary antimicrobial therapy, adequate replacement of fluids and electrolytes, avoiding antimotility medications, and reviewing the use of proton pump inhibitors.

The World Society of Emergency Surgery (WSES) released guidelines on diagnosis and treatment of Clostridioides (Clostridium) difficile infection (CDI) in surgical patients in February 2019.[77]

Diagnosis

Diagnosis of CDI should be based on clinical signs and symptoms in combination with laboratory tests. Stool testing should only be performed on diarrheal stools from at-risk patients with clinically significant diarrhea (≥3 loose stools in 24 hours) with no obvious alternative explanation.

For patients with ileus who may be unable to produce stool specimens, polymerase chain reaction (PCR) testing of perirectal swabs is an acceptable alternative to stool specimen analysis.

Nucleic acid amplification testing (NAAT) for C difficile toxin genes appears to be sensitive and specific and may be used as a standard diagnostic test for CDI. NAAT may be performed as a single-step algorithm or included in a two-step algorithm starting with toxin enzyme immunoassay (EIA).

Glutamate dehydrogenase (GDH) testing is sensitive but does not differentiate between toxigenic and nontoxigenic strains. It may be used in association with toxin A/B EIA testing. Algorithms including screening with EIA for GDH followed by toxin assay may be suggested.

EIA for toxin A/B is fast, inexpensive, and highly specific but is relatively insensitive and is not recommended alone.

C difficile culture is relatively slow but sensitive and is rarely performed as a routine diagnostic test. It is recommended for subsequent epidemiologic typing and characterization of strains.

Repeat testing after a first negative sample during the same diarrheal episode may be useful only in selected cases with (a) ongoing clinical suspicion during an epidemic situation or (b) high clinical suspicion during endemic situations.

Computed tomography (CT) is suggested for patients with clinical manifestations of severe-to-complicated C difficile colitis; however, it is not sensitive enough for screening.

Ultrasonography (US) may be useful in critically ill patients suspected of having pseudomembranous colitis who cannot be transported to the CT suite.

Flexible sigmoidoscopy may be helpful in diagnosing C difficile colitis when there is a high level of clinical suspicion for CDI.

Antibiotic therapy

Unnecessary antibiotics should be discontinued if CDI is suspected. Unnecessary proton pump inhibitors (PPIs) should be discontinued in patients at high risk for CDI.

Empirical antibiotic therapy should be avoided unless CDI is strongly suspected. In such cases, empirical therapy for CDI should be considered while test results are awaited.

Oral metronidazole should be limited to treatment of an initial episode of mild-to-moderate CDI. Oral vancomycin is recommended for treatment of mild-to-moderate disease unresponsive to metronidazole. Repeated or prolonged courses of metronidazole should be avoided. Oral vancomycin and fidaxomicin are both recommended for treatment of severe CDI.

When oral antibiotics cannot reach the colon, vancomycin may be administered as a retention enema via a large rectal tube or catheter.

Fidaxomicin may be used to treat CDI, especially in patients at higher risk for recurrence (eg, elderly patients or those receiving concomitant antibiotics).

Surgical management

Patients with severe CDI who progress to systemic toxicity should undergo early surgical consultation and should be evaluated for potential surgical intervention.

For patients with fulminant colitis, total colectomy should be considered. However, diverting loop ileostomy with colonic lavage is a useful alternative.

Fulminant colitis should be treated with high-dose vancomycin (500 mg q6hr), orally or via enema or both, in combination with intravenous (IV) metronidazole (500 mg q8hr).

Supportive care

Early detection of shock and aggressive management of organ dysfunction are essential for improved outcomes in fulminant colitis. Supportive measures (eg, IV fluid resuscitation, albumin supplementation, and electrolyte replacement) should be provided to all patients with severe CDI.

Recurrent CDI

The first recurrence of CDI may be treated with vancomycin (particularly if metronidazole was used for the initial episode) or fidaxomicin. Antibiotic options for further recurrences include oral vancomycin in a tapered and pulsed regimen.

Probiotics

Limited direct evidence supports the use of probiotics in managing a first episode of CDI as an adjunct to antibiotics for immunocompetent patients.

Prophylactic probiotics may be considered for inpatients receiving antibiotics during a high-risk period before the disease develops. Probiotics should be not used in immunocompromised patients.

Probiotics for prevention of recurrent CDI may be an effective adjunct to standard antibiotic treatment (vancomycin) in patients with at least one prior episode of CDI.

Fecal microbiota transplantation

Fecal microbiota transplantation (FMT) may be an effective option for patients with multiple recurrences of CDI in whom appropriate antibiotic treatments have failed.

Monoclonal antibodies

Coadjuvant monoclonal antibody (bezlotoxumab) therapy may prevent CDI recurrences, particularly in patients who have CDI due to the 027 epidemic strain, are immunocompromised, or have severe CDI.

Intravenous immunoglobulin

IV immunoglobulin (IVIG) should be used only as adjunctive therapy in patients with multiple recurrences or fulminant CDI.

Enteral nutrition

Tube feeding patients should be clinically assessed due to their risk for developing CDI.

Antimotility agents

The use of antiperistaltic agents to treat CDI is discouraged. If such agents are used to control persistent symptoms, they must always be accompanied by medical therapy.

 [74]

In September 2018, the British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) released guidelines on best practices of fecal microbiota transplantation (FMT) for the treatment of Clostridium difficile infection (CDI) and for potential non-CDI indications in adults.[78]

FMT should be offered to patients with CDI who have had at least 2 recurrences and to patients who have had one recurrence and also have risk factors for additional recurrences.

Consider FMT in cases of refractory CDI.

Do not administer FMT as the initial treatment for CDI.

Recommend that FMT be considered for recurrent CDI only after recurrence following resolution of an episode of CDI treated with appropriate antimicrobials for at least 10 days.

Recommend considering extended/pulsed vancomycin and/or fidaxomicin before FMT is considered for recurrent CDI.

In cases of severe or complicated CDI, before offering FMT, recommend considering treatment with medications such as fidaxomicin and bezlotoxumab, which are associated with reduced risk of recurrence.

Recommend that FMT be offered after initial failure of FMT.

Clinicians should follow-up FMT recipients for at least 8 weeks in total.

Recommend that patients be warned about short-term adverse effects of FMT, particularly possible self-limiting GI symptoms, and be advised that serious adverse effects are rare.

Recommend that, after enteral tube administration, the tube be removed and oral water given following 30 minutes after tube administration.

Recommend that FMT be avoided in patients who have anaphylactic food allergy.

Suggest that FMT be offered with caution to patients who have CDI and decompensated chronic liver disease.

Recommend that FMT be offered with caution to immunosuppressed patients, in whom FMT appears to be efficacious without significant additional adverse effects.

Recommend that patients who are immunosuppressed and at risk of severe infection if exposed to Epstein–Barr virus (EBV) or cytomegalovirus (CMV) receive FMT only from donors who are negative for Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

Suggest that people be considered as potential FMT donors only if they are 18 to 60 years of age and have a body mass index of 18 to 30 kg/m2.

Pharmacologic therapy should be tailored according to the severity of C difficile infection (CDI). Treatment is not indicated for asymptomatic carriers. In very mild cases (ie, patients without fever, abdominal pain, or leukocytosis), in patients who do not have other comorbidities, cessation of causative antibiotics may be the only treatment necessary.

Approximately 15-25% of patients respond to conservative therapy, which allows for the reconstitution of normal colonic flora and reduces the risk of relapse. Specific therapy aimed at eradicating C difficile is indicated if symptoms are persistent or if antibiotics cannot be discontinued safely.

Oral metronidazole and oral vancomycin have similar efficacy rates in treating diarrhea caused by C difficile in mild to moderate infection but not in severe disease. Whereas metronidazole is the recommended first-line treatment for mild to moderate disease without complications, vancomycin is recommended first-line therapy for severe infection or for patients with risk factors for adverse outcomes, such as advanced age, critical illness, overall debility, or inflammatory bowel disease (IBD). Vancomycin, rifaximin, and fidaxomicin are useful in recurrent or persistent cases.

The oral administration of these medications is the preferred route, because C difficile remains within the colonic lumen without invading the colonic mucosa. Vancomycin is poorly absorbed in the intestinal tract, thereby promoting high concentrations within the intestines while significantly reducing the prevalence of adverse systemic effects.

The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommend a regimen of metronidazole (500 mg PO TID for 10-14 days) as first-line therapy for mild to moderate disease without complications (lower cost and similar efficacy to PO vancomycin in these patients).[5] For patients who are unable to tolerate oral medication, intravenous metronidazole is effective.

A study by Louie et al compared vancomycin (125 mg PO QID) with fidaxomicin (200 mg PO BID).[79] The study showed that fidaxomicin therapy had a similar efficacy and resulted in a significantly lower rate of recurrence of CDI not associated with the epidemic North American Pulsed Field type 1 strains. Fidaxomicin was approved by the FDA in May 2011.

In another study, a review of 11 trials (1463 adult patients total) comparing metronidazole with vancomycin or another agent, combined agents, or placebo, neither vancomycin nor fidaxomicin were clearly superior for the initial treatment of CDI. One study in the review, however, showed CDI recurrence in only 15% of patients treated with fidaxomicin, compared with 25% of patients treated with vancomycin.[80]

As noted above, for severe cases, vancomycin (125 mg PO QID for 10 days) is the recommended first-line therapy. Higher dosing (250 mg PO [or per nasogastric tube] QID) may be used in situations such as ileus. Excretion of the drug into bile and exudation from the inflamed colon results in bactericidal levels in feces. Intravenous vancomycin is ineffective and should not be used for C difficile. The SHEA and IDSA recommend metronidazole (500 mg IV q8h) with vancomycin (500 mg PO QID and/or 500 mg PR q6h in 100 mL normal saline as a retention enema) for severe or complicated cases of CDI.[5]

In several clinical trials, 200 mg of oral fidaxomicin administered every 12 hours for 10 days has been noninferior to 125 mg of oral vancomycin administered every 6 hours for 10 days for the treatment of C difficile.[60] No difference in cure rates based on C difficile disease severity was reported. Symptomatic improvement is generally expected within 2-3 days. In January 2020, the FDA approved fidaxomicin for children aged 6 months or older with C difficile-associated diarrhea (CDAD).[61]  

In a multicenter study including 1105 subjects with C difficile–associated diarrhea, 183 of whom had solid tumors or hematologic malignancies, fidaxomicin treatment was superior to vancomycin treatment in cancer patients, resulting in higher cure and sustained response rates for diarrhea, shorter time to resolution of diarrhea (TTROD), and fewer recurrences.[81, 82]

Cure rates for diarrhea in the study were lower overall in cancer patients (79.2%) than in others (88.6%).[82] Cure rates for noncancer patients were approximately the same with fidaxomicin (88.5%) as with vancomycin (88.7%); however, those for cancer patients were higher with fidaxomicin than with vancomycin (85.1% vs 74.0%), although the difference was not statistically significant. Median TTRODs in noncancer patients were 54 hours with fidaxomicin and 58 hours with vancomycin; those in cancer patients were 74 and 123 hours, respectively.

In the same study, the risk of recurrence was approximately twice as high with vancomycin as with fidaxomicin, regardless of whether the patients had cancer or not, but because cure and recurrence outcomes were better with fidaxomicin than with vancomycin in cancer patients, the relative odds of sustained response at 28 days in these patients were more than 2.5-fold higher for fidaxomicin than for vancomycin.[82]

Relapse

Relapse occurs in 20-27% of patients treated with metronidazole or vancomycin. Most recurrences occur 3 days to 3 weeks after discontinuing antibiotic treatment. Once a patient has one relapse, the risk for a second relapse is 45%.

Age greater than 65, severe underlying illnesses, and ongoing antibiotic treatments during C difficile therapy are all risk factors for recurrence. Recurrent infection tends to occur in patients who mount a poor host immune response to C difficile. Persistent disruption of the colonic microbial flora also confers an increased risk. Recurrent infection can result from reinfection with the same strain or a different strain of C difficile.

For the first relapse, the choice of antibiotic should be based on the severity of C difficile diarrhea/colitis. Mild symptoms of recurrence in patients who are otherwise well may be managed without further antibiotic therapy. Initial recurrence that is not severe can be treated with metronidazole. For subsequent recurrences, patients may benefit from vancomycin in a prolonged tapered and/or pulse regimen or fidaxomicin with or without probiotics. Rifaximin is also a potential option. 

Bezlotoxumab is a human monoclonal antibody that binds to C difficile toxin B and neutralizes its effects. The FDA approved this agent for use with the standard of care antibiotics to reduce recurrence of CDI in adults who are at a high risk of recurrence. Approval was based on the results from the global MODIFY I and MODIFY II studies that showed a single dose of bezlotoxumab is superior to placebo in the prevention of CDI recurrence through 12 weeks (P = 0.0003 for both trials).[64]  

The FDA approved rectal administration of microbiota for prevention of recurrent CDI.[70] The PUNCH CD3 phase 3 clinical trial reported successful treatment was 70.6% versus 57.5% with microbiota and placebo, respectively. More than 90% of the participants with successful treatment had sustained response through 6 months in both the microbiota and the placebo groups.[70]   

Probiotics

Probiotics are not recommended as a single agent for the treatment of active CDI owing to limited data supporting their benefit and a potential risk for septicemia.[5] Use of Saccharomyces boulardii and Lactobacillus species have shown mixed results in reducing the risk of CDI relapse. However, S boulardii has generated interest for the treatment of CDI, because it seems to inhibit the effects of toxins A and B on the human colonic mucosa.

Potential therapies

Rifaximin after treatment with vancomycin may reduce the risk of relapse, but rifaximin is not yet FDA approved for this indication.

Nitazoxanide, a medication used to treat parasites, has been shown to be as effective as vancomycin in a clinical trial for the treatment of C difficile.

A review of 10 clinical trials evaluating the treatment of an initial episode of CDI showed that nitazoxanide and teicoplanin did not demonstrate inferiority relative to vancomycin and metronidazole.[83] However, other antimicrobials, including rifampin, and the toxin-binding polymer tolevamer, did show inferiority compared with vancomycin and metronidazole.[83]

Intravenous immunoglobulin (IVIG), which contains C difficile antitoxin, has been reported as an effective adjunctive treatment for refractory and severe cases of C difficile colitis/diarrhea. In some individuals, a poor host immune response to C difficile may be a risk factor for the lack of clearance of C difficile and may be the reason for the benefit of IVIG.

A review of the literature and a retrospective review of 21 of 1230 patients with CDI who received IVIG showed that conventional treatments were used for an average of 8 days before IVIG was administered.[84] All of the patients reviewed had radiologic pancolitis or clinical ileus. Following treatment with IVIG, 9 (43%) of the patients survived with resolution of their colitis, whereas 12 (57%) of the patients died. Patients who survived showed resolution of their symptoms after an average of 10 days (range, 2-20 d).[84]

Cholestyramine binds toxins A and B of C difficile, but the clinical experience of different investigators has shown marked variation in results. Cholestyramine binds vancomycin and should not be used concurrently with vancomycin therapy. Although not as effective as primary therapy for C difficile, the advantage of anion-binding resins is that they do not alter the colonic flora.

Other investigational therapies include the following:

• Tolevamer: A toxin-binding polymer with no antimicrobial properties

• The antibiotics ramoplanin and OPT-80 (poor intestinal absorption)

• C difficile vaccination

Class Summary

The purpose of treatment is to eradicate C difficile infection (CDI) and/or promote restoration of the normal colonic flora.

Metronidazole (Flagyl)

Metronidazole is recommended as the treatment of choice for mild to moderate cases of CDI. This agent provides effective therapy, with reported response rates from 95-100%. Its in vitro activity is bactericidal and dose dependent. Standard dosing has been shown to promote fecal concentrations capable of a 99.99% reduction of C difficile.

Metronidazole is relatively inexpensive. Intravenous (IV) metronidazole may be administered to those patients who cannot tolerate oral (PO) medications because of its potential to accumulate in the inflamed colon. However, the IV route is not as effective as the PO route.

Bacitracin

Bacitracin inhibits the formation of major components of the bacterial cell wall and is bactericidal. This agent is used as an alternative therapy for CDI, but it is expensive and not as effective as metronidazole or vancomycin in clinical trials and is thus without sufficient data to warrant its use. Bacitracin is bitter and must be specially prepared in capsule form to prevent nausea. This agent is administered PO, and it is only negligibly absorbed from the gastrointestinal (GI) tract.

Class Summary

Oral vancomycin does not get absorbed and acts directly at the site of infection.

Vancomycin (Firvanq, Vancocin)

Vancomycin has excellent in vitro activity against C difficile. This agent kills the organism by inhibiting cell wall synthesis. Significant luminal levels after administration of PO vancomycin can be obtained because the drug is poorly absorbed from the GI tract. Its major disadvantage, however, is that it is relatively expensive.

Because of the cost and the concern over the emergence of vancomycin-resistant enterococci strains, this agent should be reserved for patients who cannot tolerate or do not respond to metronidazole, pregnant patients, and patients younger than 10 years.

Vancomycin is also preferred for severe cases and in patients who are high risk. Unlike IV metronidazole, IV vancomycin is not excreted into the GI lumen; therefore, it is difficult to deliver effective IV doses. Available orally as capsules or oral solution.

Class Summary

Fidaxomicin has a narrower antimicrobial spectrum and alters the gut microflora less compared with metronidazole and vancomycin.

Fidaxomicin (Dificid)

Fidaxomicin is a macrolide antibiotic indicated for C difficile–associated diarrhea in adults and children aged 6 months or older. This agent is bactericidal against C difficile in vitro and demonstrates a postantibiotic effect vs C difficile of 6-10 h. It inhibits RNA synthesis by binding to RNA polymerases.

Class Summary

Human monoclonal antibodies that bind to C difficile toxins may be considered with standard-of-care antibiotics to prevent recurrent infection.

Bezlotoxumab (Zinplava)

Bezlotoxumab is a human monoclonal antibody that binds to C difficile toxin B, thereby neutralizing its effects. It is administered as a single IV infusion in conjunction with standard-of-care antibiotics to reduce recurrence of C difficile infection (CDI) in adults who are at a high risk for recurrence.

Class Summary

Bile acid sequestrants bind C difficile toxin and other proteins. Although not as effective as primary therapy for C difficile, the advantage of bile acid sequestrant therapy is that it does not alter the gut microflora.

Cholestyramine (Questran)

Cholestyramine is used to treat diarrhea associated with pseudomembranous colitis. This agent forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits the enterohepatic reuptake of intestinal bile salts.

Note that cholestyramine binds vancomycin, which precludes combination therapy. This agent is available as a powder that must be mixed with water prior to ingestion. The efficacy of cholestyramine is inferior to that of metronidazole or vancomycin, but the drug may have a role under certain circumstances (eg, in patients who continue to relapse). This agent is not absorbed from the GI tract.

Class Summary

Microbiota-based live biotherapeutic provides a broad consortium of diverse microbes to the gut to reduce recurrent C difficile infection after antibiotic treatment.

Microbiota rectal (Rebyota)

Microbiota rectal product is indicated for prevention of recurrence of Clostridioides difficile infection (CDI) in adults, following antibiotic treatment for recurrent CD.