Version July 2025
INTRODUCTION —
Clostridioides difficile is a spore-forming, toxin-producing, and gram-positive anaerobic bacterium that causes antibiotic-associated colitis. It colonizes the human intestinal tract typically after the normal gut microbiota has been disrupted (frequently in association with antibiotic therapy). C. difficile infection (CDI) is one of the most common health care-associated infections and a significant cause of morbidity and mortality, especially among older adult hospitalized patients.
The clinical manifestations and diagnosis of CDI will be reviewed here. The treatment, epidemiology, and prevention of CDI are discussed separately. (See "Clostridioides difficile infection in adults: Treatment and prevention" and "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridioides difficile infection: Prevention and control".)
CDI in children is also discussed separately. (See "Clostridioides difficile infection in children: Microbiology, pathogenesis, and epidemiology" and "Clostridioides difficile infection in children: Clinical features and diagnosis" and "Clostridioides difficile infection in children: Treatment and outcome".)
CLINICAL MANIFESTATIONS —
CDI can cause a spectrum of manifestations ranging from asymptomatic carriage to fulminant disease with toxic megacolon [1-4]. The basis for this range of clinical manifestations is not fully understood but may be related to host, microbiota, and pathogen factors. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology".)
Timing of symptom onset — Symptoms of CDI typically, but not always, occur in the setting of antibiotic therapy (table 1). Symptoms of CDI may begin during or after antibiotic therapy, and most cases occur within two weeks of antibiotic therapy. Rarely, symptoms present as late as 10 weeks after cessation of antibiotic therapy [5]. However, a lack of antibiotic use does not rule out the possibility of CDI. In one study, approximately 30 percent of patients with community-acquired CDI had not been exposed to antibiotics [6]. Additional risk factors for CDI include age >65, recent hospitalization, and use of proton-pump inhibitors. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Risk factors'.)
Asymptomatic carriage — Individuals with asymptomatic carriage of C. difficile shed C. difficile in stool but do not have diarrhea or other clinical symptoms [7-9]. Asymptomatic C. difficile carriage occurs in up to 20 percent of hospitalized adults and 50 percent of long-term facility residents. These individuals serve as a reservoir for environmental contamination [8,9]. A sufficient host humoral immune response to C. difficile toxins may play a role in determining asymptomatic carriage.
Asymptomatic individuals do not warrant screening for C. difficile carriage, and individuals with asymptomatic carriage of C. difficile do not warrant treatment or contact precautions [1]. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridioides difficile infection: Prevention and control".)
Diarrhea with colitis — Watery diarrhea (≥3 loose stools in 24 hours) is the cardinal symptom of CDI. Other manifestations include lower abdominal pain and cramping, low-grade fever, nausea, and anorexia [2,10]. Diarrhea may be associated with mucus or occult blood, but melena or hematochezia are rare. Fever is associated with CDI in approximately 15 percent of cases; temperature >38.5°C may occur in the setting of nonsevere or severe CDI.
Physical examination may demonstrate lower abdominal tenderness. Lower gastrointestinal endoscopy (flexible proctoscopy, sigmoidoscopy, or colonoscopy) examination may be normal or demonstrate a spectrum of findings, from patchy, mild erythema and friability to severe pseudomembranous colitis (severe inflammation of the inner lining of the bowel) (picture 1 and picture 2). (See 'Radiographic and endoscopic findings' below.)
Additional features of severe or fulminant infection — Patients with acute CDI may develop signs of systemic toxicity with or without profuse diarrhea warranting admission to a hospital/intensive care unit or consideration for emergency surgery. Abdominal distention, fever, hypovolemia, and lactic acidosis can accompany diarrhea and abdominal pain in severe infection.
Fulminant colitis (previously referred to as severe, complicated CDI) may be characterized by hypotension or shock, ileus, or megacolon (image 1) [1,11]. Severe hypotension progressing to multisystem organ failure may occur in the setting of fulminant CDI and/or in the setting of bowel perforation with peritonitis. Megacolon should be suspected in patients with severe systemic toxicity together with radiographic evidence of large bowel dilatation (>7 cm diameter in the colon and/or >12 cm diameter in the cecum) (image 1). Megacolon may be complicated by bowel perforation; manifestations include abdominal rigidity, involuntary guarding, diminished bowel sounds, rebound tenderness, and severe localized tenderness in the left or right lower quadrants; abdominal radiographs may demonstrate free abdominal air. (See "Toxic megacolon".)
Patients with fulminant colitis warrant radiographic imaging (preferably computed tomography [CT] of the abdomen and pelvis) and prompt surgical evaluation. (See 'Postdiagnostic evaluation in severe/fulminant colitis' below and "Clostridioides difficile infection in adults: Treatment and prevention".)
Unusual presentations — Unusual manifestations of CDI include fulminant colitis with ileus, protein-losing enteropathy, and extracolonic involvement.
Ileus without diarrhea — Occasionally, CDI presents acutely as ileus, with little or no diarrhea. Diarrhea may be less prominent or absent due to pooling of secretions in a dilated, atonic colon. Such patients are usually severely ill, with colonic (and possibly small bowel) dilatation, often with colonic thickening, fever, and leukocytosis. In some cases, this presentation seems benign initially but progresses rapidly.
Other unusual presentations — Protein-losing enteropathy and extracolonic involvement in CDI are very rare.
●Protein-losing enteropathy – Protein-losing enteropathy with hypoalbuminemia has been described in association with acute CDI in the absence of fulminant colitis [12,13]. Inflammation of the bowel wall allows leakage of albumin into the lumen, causing colonic loss of albumin with inadequate compensatory hepatic synthesis. As a result, serum albumin levels may drop below 2 g/dL (20 g/L). Ascites and peripheral edema may be observed. The protein-losing enteropathy responds to appropriate medical therapy of the infection. (See "Protein-losing gastroenteropathy" and "Clostridioides difficile infection in adults: Treatment and prevention".)
●Extracolonic involvement – Rare cases of C. difficile appendicitis [14], small bowel enteritis, and extraintestinal involvement have been described [15]. Small bowel involvement with C. difficile enteritis is rare but may occur in older adults and/or patients with multiple comorbidities [16-18]. In some cases, patients have had prior colectomy with ileostomy; manifestations may include increased ileostomy output, and it may be possible to visualize pseudomembranes (raised white or tan plaques attached to epithelium) on the exposed ileal mucosa at the stoma. Such patients may be at increased risk for fulminant disease with a high mortality rate [17,18].
Rare cases of C. difficile cellulitis, soft tissue infection, bacteremia, and reactive arthritis have also been described [16,19,20].
Recurrent disease — Recurrent CDI is defined by resolution of CDI symptoms while on appropriate therapy, followed by reappearance of symptoms within two to eight weeks after treatment has been stopped [1].
Up to 25 percent of patients experience recurrent C. difficile within 30 days of completing treatment [21]. Less commonly, recurrent CDI can occur as late as two months after discontinuation of treatment. Once patients have experienced one recurrence, they are at significantly increased risk for further recurrences. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Recurrent infection'.)
Recurrent disease may be mild, severe, or fulminant [22]. One study including more than 1500 patients with CDI noted 34 percent of patients with recurrent infection needed hospital admission, 28 percent developed severe disease, and 4 percent developed fulminant colitis [23].
Recurrent symptoms may be due to relapse of the initial infecting strain or reinfection with a new strain [24-26]. Recurrent CDI often represents relapse rather than reinfection, regardless of the interval between episodes. Among 134 paired stool isolates from 102 patients with recurrent CDIs, isolates obtained two to eight weeks apart were identical in 88 percent of cases [27].
Persistent diarrhea without resolution during initial therapy should prompt an evaluation for other causes and should not be considered recurrent disease (see 'Differential diagnosis' below). In the absence of an alternative diagnosis, such patients should be considered to have refractory CDI. (See "Clostridioides difficile infection in adults: Treatment and prevention", section on 'Clinical approach to treatment'.)
LABORATORY FINDINGS —
CDI is commonly associated with an elevated white blood cell count of up to 15,000 cells/microL [28].
Criteria proposed for severe CDI (based on expert opinion) include white blood cell count >15,000 cells/microL or serum creatinine ≥1.5 mg/dL. Prospectively validated severity scores for CDI are needed [1].
Severe or fulminant infection may present with hypoalbuminemia, elevated creatinine concentration, and marked leukocytosis (white blood cell count ≥40,000 cells/microL) [28-30].
Unexplained leukocytosis in hospitalized patients (even in the absence of diarrhea) may reflect underlying CDI, although data are mixed. In a retrospective study of 248 hospitalized adults, white blood cell count ≥11,000 cells/microL was an independent risk factor for CDI (odds ratio [OR] 3.43, 95% CI 1.42-8.26) [31]. However, a retrospective, multicenter study of over 16,000 patients did not find any relationship between leukocytosis (white blood cell >15,000 cells/microL) and CDI in hospitalized patients [32]. Although there was an association between leukocytosis and CDI in outpatient and emergency department settings, accuracy was poor. In situations where unexplained leukocytosis is due to CDI, diarrhea typically develops one to two days later. (See "Approach to the patient with neutrophilia", section on 'Infection'.)
RADIOGRAPHIC AND ENDOSCOPIC FINDINGS —
Pseudomembranous colitis is the hallmark radiographic and endoscopic finding in CDI. Other radiographic and endoscopic findings may be seen but are nonspecific.
●Presence of pseudomembranous colitis – Pseudomembranous colitis (severe inflammation of the inner lining of the bowel) can be seen both on CT imaging and endoscopy. The finding of pseudomembranes on the inflamed mucosal surface is highly suggestive of CDI and should prompt diagnostic laboratory confirmation if not already performed (via stool assay or, in the setting of ileus, a rectal swab for toxin assay or anaerobic culture) [33]. (See 'Approach to diagnosis' below.)
On CT, the "accordion sign" is highly suggestive of pseudomembranous colitis. It consists of mucosal edema and inflammation involving the large bowel and is seen when orally administered contrast material becomes trapped between thickened haustral folds, giving the appearance of alternating bands of high attenuation (contrast material) and low attenuation (edematous haustra) [34-36].
On endoscopy, pseudomembranes manifest as raised yellow or off-white plaques up to 2 cm in diameter scattered over the colonic mucosa (picture 1 and picture 2). Some patients with pseudomembranous colitis have scattered lesions with relatively normal-appearing intervening mucosa, while others have a confluent pseudomembrane covering the entire mucosa. Pseudomembranes may be absent in the rectosigmoid area but present more proximally, although colonoscopy for proximal evaluation of the colon is not warranted for diagnosis of C. difficile given potential bowel tissue friability and risk of perforation [33,37].
Not all patients with CDI have pseudomembranes, particularly patients with mild or partially treated infection, and absence of pseudomembranes does not rule out CDI. Pseudomembranes are rarely observed in the setting of recurrent CDI or inflammatory bowel disease [38,39]. There are rare reports of other pathogens also capable of causing pseudomembranous colitis, and occasionally pseudomembranes are seen in patients with uremia or ischemic colitis. (See 'Differential diagnosis' below.)
Formation of pseudomembranes occurs following C. difficile toxin-induced ulcer formation on the mucosal surface of the intestine, which facilitates release of serum proteins, mucus, and inflammatory cells [40].
●Other radiographic findings – Common imaging modalities obtained in the workup for CDI include abdominal radiograph and CT of the abdomen and pelvis.
Abdominal radiographs are often unremarkable in patients with CDI, although they can detect colonic dilatation and the presence of toxic megacolon (image 1). Radiographic evidence of colonic dilatation (>7 cm in diameter) in the clinical setting of severe CDI is diagnostic of toxic megacolon. Other radiographic findings consistent with toxic megacolon include small bowel dilatation, air-fluid levels (mimicking an intestinal obstruction or ischemia), and "thumb printing" (scalloping of the bowel wall) due to submucosal edema (image 1 and image 2). In the setting of bowel perforation, free abdominal air may be observed. (See 'Postdiagnostic evaluation in severe/fulminant colitis' below and "Toxic megacolon".)
CT of the abdomen and pelvis often demonstrates colonic wall thickening (image 3) and low-attenuation mural thickening, corresponding with mucosal and submucosal edema (which may be visible as a "target sign" or "double halo sign" consisting of two or three concentric rings of different attenuation) [36]. Pericolonic stranding and ascites may be seen but are not specific for CDI.
●Other endoscopic findings – Findings, other than pseudomembranes, on lower gastrointestinal endoscopy in the setting of CDI include bowel wall edema, erythema, friability, and inflammation.
EVALUATION
When to suspect C. difficile infection — The diagnosis of CDI should be suspected in patients with acute diarrhea (≥3 loose stools in 24 hours) with no obvious alternative explanation, particularly in the setting of relevant risk factors (including current or recent antibiotic use, current or recent hospitalization, and advanced age) [1].
In addition, presence of pseudomembranous colitis on imaging or endoscopy is highly suggestive of CDI and should prompt laboratory testing if not already performed.
Patients with suspected CDI should be placed on contact precautions preemptively pending diagnostic evaluation. (See "Clostridioides difficile infection: Prevention and control", section on 'Contact precautions'.)
Approach to diagnosis — Approach to specimen collection and testing is discussed below.
Specimen collection
●For patients with diarrhea and suspected CDI, only liquid stool should be sent for C. difficile testing.
●For patients with ileus and suspected CDI, laboratory testing via rectal swab for glutamate dehydrogenase (GDH), enzyme immunoassay (EIA) toxin assays, nucleic acid amplification testing (NAAT), or anaerobic culture may be performed [41-44]. (See 'Ileus without diarrhea' above.)
●Formed stool from asymptomatic patients should not be submitted for laboratory testing, since presence of C. difficile toxin gene does not distinguish between CDI and asymptomatic carriage (which does not warrant treatment) [41,45-47].
Preferred approaches — Approach to testing is often determined by an institution's microbiology laboratory protocol and is not a decision needed to be made by the clinician. In general, we favor use of a two-tiered approach that combines a sensitive test (eg, GDH or NAAT) followed by a specific test (toxin A/B EIA) to help distinguish CDI from asymptomatic carriage (table 2) [1,48,49].
●NAAT followed by EIA for toxin A/B – A common two-tiered approach is to test with the highly sensitive NAAT and, if positive, to follow up with the EIA for toxin A/B. If both are positive, then CDI is established. However, if NAAT is positive but the EIA for toxin A/B is negative, this can either indicate asymptomatic carriage (detection of C. difficile deoxyribonucleic acid [DNA] without toxin production) or true infection with low production of toxin that was not detected on the EIA. In these cases, clinical correlation is required to assess whether there are any possible alternative diagnoses that can explain the patient's symptoms. (See 'Interpreting discordant results' below.)
●GDH and EIA for toxin A/B with NAAT – Another common two-tiered approach to CDI diagnosis involves using a highly sensitive test such as the GDH for initial testing followed by the highly specific EIA for toxin A/B. If both results are negative, CDI is not the cause of the diarrhea. If both results are positive, diagnosis of CDI is made. If the GDH is positive and the toxin EIA is negative, the NAAT is used to arbitrate. If the NAAT is negative, then CDI is unlikely. If the NAAT is positive, this can either indicate asymptomatic carriage (detection of C. difficile deoxyribonucleic acid [DNA] without toxin production) or true infection with low production of toxin that was not detected on the EIA. In these cases, clinical correlation is required to assess whether there are any possible alternative diagnoses that can explain the patient's symptoms. (See 'Interpreting discordant results' below.)
●GDH followed by EIA for toxin A/B – A less common, but least expensive, two-tiered approach is to test with the highly-sensitive GDH first and if positive, to send (or report) the toxin A/B EIA. This is the least expensive testing option and is the preferred option. If GDH is negative, then CDI is ruled out and EIA for toxin A/B does not need to be sent (or reported). If GDH is positive and toxin A/B EIA is positive, then CDI is confirmed. If GDH is positive but toxin A/B EIA is negative, this can either indicate asymptomatic carriage (detection of C. difficile deoxyribonucleic acid [DNA] without toxin production) or true infection with low production of toxin that was not detected on the EIA. In these cases, clinical correlation is required to assess whether there are any possible alternative diagnoses that can explain the patient's symptoms. (See 'Interpreting discordant results' below.)
Fecal leukocyte testing is not helpful for diagnosis of CDI [50].
Various other approaches are used across institutions. Details of the various available approaches to testing and their advantages and disadvantages are discussed below. (See 'Alternative approaches' below.)
Alternative approaches — Some institutions use different approaches for the diagnosis of CDI (table 2). These approaches are comprised of only highly sensitive tests and thus are prone to overdiagnosing CDI in patients with asymptomatic carriage.
●NAAT alone – The use of NAAT alone is the simplest diagnostic approach to CDI. This testing approach provides a highly sensitive, quick result. However, the NAAT cannot distinguish between active infection and asymptomatic carriage and thus is prone to overdiagnosing patients who otherwise would not need treatment. When this approach is used, it is imperative to limit testing to people with high suspicion of CDI to avoid detection of asymptomatic carriage.
●GDH antigen test followed by NAAT – Another less common approach is to test initially with the inexpensive GDH and, if positive, to then follow up with the NAAT. If NAAT is negative, then CDI is very unlikely. If both are positive, then the patient either has CDI or asymptomatic carriage of C. difficile. Because neither test is highly specific and cannot distinguish between active infection and asymptomatic carriage, this approach is prone to overdiagnosing patients who otherwise would not need treatment.
DIAGNOSIS
Establishing the diagnosis — The diagnosis of CDI is established via a combination of positive test results, depending on the approach used. Concordant positive tests on two or more tests (eg, toxin EIA, NAAT) is sufficient to diagnose CDI. Conversely, a negative NAAT is sufficient to rule out CDI. Discordant results in two-tiered algorithmic approaches require further clinical assessment and are discussed below. (See 'Interpreting discordant results' below.)
Growth of C. difficile on anaerobic culture is the gold standard for detecting C. difficile in stool but is rarely used due to low sensitivity and specificity, high use of resources, and long turnaround time for results.
Interpreting discordant results — As the use of two-tiered approaches for the diagnosis of CDI increases, discordant results have become more common (table 2). Discordant results occur when a positive NAAT results alongside a negative toxin EIA result (either with a NAAT followed by toxin EIA approach or the GDH and toxin EIA followed by NAAT approach). These discordant results indicate either active infection or asymptomatic carriage but cannot distinguish between them. Although many patients with discrepant results can forego treatment without adverse outcomes [51], we generally treat patients who are severely ill and those who do not have an alternative explanation for the diarrhea, because there is a lack of high-quality data establishing the safety of withholding treatment in these patient populations. (See "Clostridioides difficile infection in adults: Treatment and prevention".)
Data to guide treatment decisions in patients with discordant results are limited to mostly observational studies. In a meta-analysis of 26 observational studies comprising almost 13,000 patients with CDI (5566 of whom were NAAT+/Toxin-), all-cause 30-day mortality for patients with NAAT+/Toxin- results was higher for untreated patients compared with those who received treatment (13 versus 5 percent, RD -7.45 percent, 95% CI -12.29 to -2.6) [52].
In another quasi-experimental study where 632 patients with NAAT+/Toxin- results had only one of the results reported (thus prompting treatment if NAAT+ reported and foregoing treatment if only Toxin- reported), all-cause 30-day mortality was similar between the treated and untreated groups (9 versus 7 percent, adjusted odds ratio [aOR] 0.46, 90% CI 0.2 to 1.04) [51].
Diagnostic tests — Laboratory diagnosis of CDI requires demonstration of C. difficile toxin(s) or detection of toxigenic C. difficile organism(s) [53]. Due to limitations in the diagnostic methods, some microbiology laboratories use a two-tiered diagnostic approach to improve diagnostic accuracy (table 2). Individual testing methods will be discussed here. The various two-tiered approaches are discussed separately. (See 'Preferred approaches' above and 'Alternative approaches' above.)
It is important to note that C. difficile toxin degrades at room temperature and may be undetectable within two hours after collection. Therefore, specimens for testing based on toxin detection (EIA for C. difficile toxins and cell culture cytotoxicity assay) should be kept at 4ºC if delay in laboratory testing is anticipated. In addition, a suspected outbreak should prompt freezing of stool samples for later investigation.
●Individual diagnostic tests
•NAAT – NAATs (which include polymerase chain reaction) detect one or more genes specific to toxigenic strains; the critical gene is tcdB, which encodes for toxin B. NAATs are highly sensitive [54-57]; their sensitivity is greater than EIA and comparable with cytotoxicity assay [58-62]. NAATs are specific for toxigenic strains but do not test for active toxin protein production and can detect asymptomatic carriers of C. difficile. Therefore, only liquid stool samples from patients with ≥3 loose stools in 24 hours should be tested. Only a single stool sample should be tested. NAAT results can be available within as little as one hour. NAAT results may be falsely negative if stool specimen collection is delayed and the patient has been treated empirically for suspected CDI [63].
Given its high sensitivity and its inability to distinguish CDI from asymptomatic carriage, overdiagnosis of CDI has emerged as a risk of NAATs, resulting in antibiotic treatment of patients who may not require such therapy [64,65]. In a study of more than 1400 patients with suspected CDI, patients whose stool tested positive by NAAT but negative by immunoassay had a lower toxin load and less diarrhea than patients for whom both assays were positive [65]. For circumstances in which initial testing consisted of NAAT (with positive result), some favor subsequent testing with EIA for toxins A and B to bolster clinical specificity, although discordant results do not rule out active infection. (See 'Interpreting discordant results' above.)
•EIA for C. difficile GDH antigen – GDH antigen is an essential enzyme produced constitutively by all C. difficile isolates; however, its detection cannot distinguish between toxigenic and nontoxigenic strains [66-68]. Therefore, testing for GDH antigen is useful as an initial screening step in a multistep approach, which also consists of subsequent testing with more specific assays such as toxin A and B EIA or NAAT on specimens that are GDH antigen positive [69]. GDH antigen testing has good sensitivity, and results are available in less than one hour.
•EIA for C. difficile toxins A and B – Most C. difficile strains produce both toxins A and B, although some strains produce only one toxin [70-75]. Testing for both toxins by EIA gives a higher sensitivity than testing for just one toxin [1,64]. Many inexpensive assays are commercially available, and test results are available within hours. These assays can also be used on a rectal swab in a patient with ileus and suspected CDI. The sensitivity of EIA for toxins A and B is on average approximately 75 percent, but the sensitivity varies depending on the specific assay used; the specificity is high (up to 99 percent) [76,77]. There is a relatively high false-negative rate since 100 to 1000 pg of toxin must be present for the test to be positive [78]. Hence, GDH antigen testing is often used together with toxin EIA. If the GDH is positive but the toxin EIA is negative, adjudication with NAAT is beneficial. (See 'Preferred approaches' above and 'Interpreting discordant results' above.)
•Selective anaerobic culture – Selective anaerobic culture is seldom employed for clinical diagnosis as results take several days to finalize. Occasionally, culture of a rectal swab in a patient with ileus and suspected CDI can be useful for diagnosis, if clinically available. Culture on selective medium with toxin testing of isolated C. difficile is a highly sensitive diagnostic method, although culture alone cannot distinguish toxin-producing strains from non-toxin-producing strains [79]. Use of a second test (eg, EIA, cell culture cytotoxicity assay) is required to detect toxin production by cultured C. difficile strains. Treatment of stool with heat or alcohol to shock spores (to increase vegetative growth and remove contaminants) is sometimes used to improve yield. Culture is useful for epidemiologic studies but is generally too slow and labor intensive for routine clinical use [76].
•Cell culture cytotoxicity assay – The cell culture cytotoxicity assay is sensitive and specific but resource intensive and time consuming; it is not a routine clinical diagnostic test. The assay was developed contemporaneously with the discovery of C. difficile and has been used as a gold standard test for detection of C. difficile toxins. It is more sensitive than enzyme immunoassay, although it is limited by lack of standardization, the requirement for a cell culture facility, and slow turnaround time (approximately two days) [79,80]. The cell culture cytotoxicity assay is performed by adding a prepared stool sample (diluted, buffered, and filtered) to a monolayer of cultured cells [53,81,82]. If C. difficile toxin is present, it exerts a cytopathic effect characterized by cell rounding; specificity of the cytotoxicity is demonstrated by neutralization of the cytopathic effect with specific antiserum.
Limited role for repeat testing — There is no role for repeat laboratory testing (within seven days) during the same episode of diarrhea, and there is no indication to test for cure [1,83-89]. There is also no role for laboratory testing in asymptomatic patients or repeat testing of patients receiving treatment for acute CDI; stool assays may remain positive during or after clinical recovery, even up to six weeks post-treatment [90]. However, for patients with recurrent symptoms after initial resolution of diarrhea, repeat testing is warranted to evaluate for recurrent disease.
POSTDIAGNOSTIC EVALUATION IN SEVERE/FULMINANT COLITIS —
For patients with severe or fulminant colitis who have not yet undergone imaging, we obtain radiographic imaging of the abdomen and pelvis to evaluate for presence of toxic megacolon, bowel perforation, or other findings warranting surgical intervention. CT of the abdomen and pelvis with oral and intravenous contrast is the preferred imaging modality; plain films may be useful for circumstances in which CT is not readily available.
Endoscopy is rarely warranted in CDI. Often, it is performed when an alternative diagnosis is suspected that requires direct visualization and/or biopsy of the bowel mucosa. (See 'Differential diagnosis' below.) It may also be helpful for patients with ileus or fulminant colitis in the absence of diarrhea since it may allow visualization of pseudomembranes (severe inflammation of the inner lining of the bowel), a finding that is highly suggestive of CDI (picture 2). The decision to proceed with endoscopy should be made carefully; if pursued, limited flexible sigmoidoscopy is preferred with minimal or no air insufflation to avoid the risk of perforation of the inflamed colon.
Colon biopsy is not needed for diagnosis of CDI.
APPROACH TO RECURRENT OR PERSISTENT DIARRHEA —
Diagnosing disease recurrence is difficult, as the polymerase chain reaction (PCR) and the toxins in the EIA can be detected in stools even past six weeks following treatment and resolution of symptoms [91].
●Recurrence of diarrhea – Recurrent CDI should be suspected in patients in whom diarrhea resolved on CDI therapy and then recurred within two to eight weeks after treatment completion. The diagnostic approach for suspected recurrent C. difficile is the same as the approach for initial infection. (See 'Establishing the diagnosis' above.)
In patients with recurrence of symptoms and positive test results, it is difficult to distinguish whether a positive test result is due to a true active infection or is still positive from the recent infection. In these situations, clinical assessment of the symptoms and signs are necessary to determine whether repeat treatment is necessary. Ongoing diarrhea that never resolved (persistent diarrhea) is less likely due to a recurrence of infection and more likely either due to an alternative diagnosis such as postinfectious irritable bowel syndrome.
●Persistent diarrhea – Lack of response to appropriate therapy, such as oral vancomycin or fidaxomicin, is very rare. Loose stools may persist for weeks to months after treatment. It is therefore important to distinguish persistent, nonimproved diarrhea from improved but persistent loose stools. Patients with treated CDI typically have resolution of abdominal cramping/pain as well as some improvement in their diarrhea (eg, less frequency, less watery). Lack of any improvement in symptoms (including abdominal pain/cramping) with appropriate treatment should prompt evaluation for an alternative diagnosis. In patients in whom no alternative diagnosis was found, persistent diarrhea may be due to postinfectious irritable bowel syndrome.
In severe cases, colonoscopy with biopsy may be warranted to establish an alternative diagnosis in patients with persistent diarrhea. (See 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS —
C. difficile must be distinguished from other infectious and noninfectious causes of diarrhea. (See "Approach to the adult with acute diarrhea in resource-abundant settings", section on 'Evaluation' and "Approach to the adult with acute diarrhea in resource-limited settings".)
●Antibiotic-associated diarrhea – Antibiotic-associated osmotic diarrhea also presents with diarrhea but usually lacks the associated abdominal pain/cramping that comes along with CDI, as well as the other laboratory and imaging abnormalities that are often seen in CDI. Additionally, cessation of symptoms with discontinuation of oral intake is a distinguishing feature of osmotic diarrhea (figure 1). Differentiation of noninfectious antibiotic-associated diarrhea from CDI may be difficult, especially in patients who are asymptomatic C. difficile carriers. This is most relevant among patients in nursing homes or hospitals where the rate of asymptomatic carriage ranges from 10 to 50 percent (in community populations, the rate of asymptomatic carriage is ≤5 percent).
●Infectious diarrhea – Infectious diarrhea can be caused by a variety of pathogens, including viruses (eg, enterovirus), bacteria (eg, Shigella spp, Campylobacter spp), and parasites (eg, Giardia spp, Cryptosporidium spp) [92-96]. Bloody diarrhea can be a distinguishing feature between invasive enteric bacterial diarrhea and CDI, as CDI rarely causes grossly bloody diarrhea. Otherwise, clinical manifestations are similar to CDI. Diagnosis is established by clinical history, stool culture, ova and parasite smear, and gastrointestinal multiplex nucleic acid testing. (See "Approach to the adult with acute diarrhea in resource-abundant settings", section on 'Evaluation' and "Approach to the adult with acute diarrhea in resource-limited settings".)
●Noninfectious diarrhea – Causes of noninfectious diarrhea that may mimic CDI include postinfectious irritable bowel syndrome, inflammatory bowel disease (IBD), celiac disease, and microscopic colitis. The presence of fever and leukocytosis favors C. difficile or other infectious etiology, although certain inflammatory conditions, such as IBD, can also present with fever. (See "Approach to the adult with chronic diarrhea in resource-abundant settings".)
•Postinfectious irritable bowel syndrome – Postinfectious irritable bowel syndrome occurs in approximately 10 percent of patients who have been successfully treated for an initial episode of C. difficile. These patients may have up to 10 watery stools per day; this must be distinguished from a relapse of the original CDI based on established criteria (table 3). (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults".)
•Inflammatory bowel disease (IBD) relapse – Infection with C. difficile may complicate the course of inflammatory bowel disease (IBD) [97,98]. C. difficile may be difficult to distinguish from an IBD relapse given the similar symptoms of diarrhea, abdominal pain, and low-grade fever. Thus, a high index of suspicion is required when evaluating IBD patients with apparent flares, especially those who have recently received antibiotics and/or been hospitalized. Often, treatment for both is initiated as it is very difficult to distinguish the cause of symptoms and rule out CDI in patients with IBD who are colonized with C. difficile. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Approach to persistent gastrointestinal symptoms in adults with inflammatory bowel disease in remission".)
•Ischemic colitis – Ischemic colitis is a noninfectious cause of colonic inflammation due to inadequate blood flow. Symptoms typically include severe abdominal pain (usually acute but can occasionally be chronic) and bloody diarrhea. Leukocytosis is common, and fever can occasionally be present. It can also occasionally cause pseudomembranous colitis on imaging and/or endoscopy. In general, the presence of blood in stool can help differentiate ischemic colitis from CDI. (See "Colonic ischemia", section on 'Diagnosis'.)
•Microscopic colitis – Microscopic colitis is a chronic inflammatory disease of the colon characterized by chronic watery diarrhea. Although the chronicity of the diarrhea in microscopic colitis may suggest microscopic colitis rather than CDI (which tends to present more acutely), clinical manifestations are generally very similar. The diagnosis of microscopic colitis is established by histopathology following colonoscopy with biopsy. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management".)
•Celiac disease – Celiac disease is a small bowel disease associated with dietary gluten exposure intolerance; gastrointestinal symptoms, including chronic or recurrent diarrhea; malabsorption; weight loss; and abdominal distension or bloating. The diagnosis is established via serology and/or duodenal biopsy. (See "Diagnosis of celiac disease in adults".)
PATIENTS WITH INFLAMMATORY BOWEL DISEASE —
Enteric infections account for approximately 10 percent of symptomatic relapses in patients with inflammatory bowel disease (IBD); C. difficile accounts for approximately half of these infections [99]. Rates of CDI among patients with IBD appear to be increasing [100,101]. The association between IBD and C. difficile may be due to a variety of factors (including dysbiosis associated with colitis or with antibiotic use for treatment of other gastrointestinal pathogens) and frequent hospitalization for management of IBD flares. Rarely, C. difficile can trigger an initial bout of IBD [99].
CDI in patients with IBD requires prompt diagnosis and management since failure to diagnose the infection can lead to inappropriate treatment with glucocorticoids or immunosuppressive therapy.
The diagnosis requires laboratory testing. Endoscopy is usually not helpful because IBD patients generally do not develop pseudomembranes. Given preexisting colonic pathology, patients with IBD who develop C. difficile colitis require colectomy more frequently (20 percent in one series) [101].
There is a high prevalence of C. difficile carriage in patients with IBD. This was illustrated in a study of 122 patients with longstanding IBD in which the frequency of C. difficile carriage was higher in IBD patients than in healthy volunteers (8 versus 1 percent), in the absence of recent antibiotics or hospitalization [102]. Despite this observation, none developed symptomatic disease in the subsequent six months. The reason for this observation is not certain; possibilities include altered colonic microbial flora, mucosal inflammation, and impaired mucosal innate immunity.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Clostridioides difficile infection".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: C. difficile infection (The Basics)")
●Beyond the Basics topic (see "Patient education: Antibiotic-associated diarrhea caused by Clostridioides difficile (Beyond the Basics)")
SUMMARY
●General – Clostridioides difficile is a spore-forming, toxin-producing, and gram-positive anaerobic bacterium that causes antibiotic-associated colitis. It colonizes the human intestinal tract typically after the normal gut flora has been disrupted (frequently in association with antibiotic therapy). The antibiotics most frequently implicated in predisposition to C. difficile infection (CDI) are fluoroquinolones, clindamycin, cephalosporins, and broad spectrum penicillins (table 1).
●Clinical manifestations
•Timing of symptom onset – Symptoms of CDI may begin during or after antibiotic therapy, and most cases occur within two weeks of antibiotic therapy. However, a lack of antibiotic use does not rule out the possibility of CDI. (See 'Timing of symptom onset' above.)
•Asymptomatic carriage – Individuals with asymptomatic carriage of C. difficile shed C. difficile in stool but do not have diarrhea or other clinical symptoms. Asymptomatic individuals do not warrant screening for C. difficile carriage, and individuals with asymptomatic carriage of C. difficile do not warrant treatment or contact precautions. (See 'Asymptomatic carriage' above.)
•Clinical features of CDI – Watery diarrhea (≥3 loose stools in 24 hours) is the cardinal symptom of CDI. Other manifestations include lower abdominal pain and cramping, low-grade fever, nausea, and anorexia. In severe infection, abdominal distention, fever, hypovolemia, and lactic acidosis can accompany diarrhea and abdominal pain. (See 'Diarrhea with colitis' above and 'Additional features of severe or fulminant infection' above.)
Occasionally, CDI presents acutely as ileus, with little or no diarrhea. Such patients are usually severely ill, with colonic (and possibly small bowel) dilatation, often with colonic thickening, fever, and leukocytosis. In some cases, this presentation seems benign initially but progresses rapidly. (See 'Ileus without diarrhea' above.)
Protein-losing enteropathy and extracolonic involvement in CDI are very rare. (See 'Other unusual presentations' above.)
●Laboratory findings – CDI is commonly associated with an elevated white blood cell count of up to 15,000 cells/microL. Some experts consider a white blood cell count >15,000 cells/microL and/or serum creatinine ≥1.5 mg/dL in the setting of CDI as severe CDI. (See 'Laboratory findings' above.)
●Radiographic and endoscopic findings – Pseudomembranous colitis (the hallmark radiographic and endoscopic finding in CDI) can be seen both on CT imaging (image 3) and endoscopy (picture 2) and is highly suggestive of CDI. Other radiologic findings include colonic dilatation and toxic megacolon (image 1), colonic wall thickening (image 3), and submucosal edema. (See 'Radiographic and endoscopic findings' above.)
●Evaluation
•When to suspect CDI – The diagnosis of CDI should be suspected in patients with acute diarrhea (≥3 loose stools in 24 hours) with no obvious alternative explanation, particularly in the setting of relevant risk factors (including current or recent antibiotic use, current or recent hospitalization, and advanced age). (See 'When to suspect C. difficile infection' above.)
•Approach to diagnosis – For patients with suspected CDI, only liquid stool should be sent for C. difficile testing. In patients with ileus, a rectal swab can be sent instead. Other causes of diarrhea should be excluded prior to testing given the possibility of identifying asymptomatic C. difficile carriers. (See 'Approach to diagnosis' above.)
●Diagnosis
•Establishing a diagnosis – The diagnosis of CDI is established via a combination of positive test results, depending on the approach used (table 2). Concordant positive tests on two or more tests (eg, toxin EIA, NAAT) is sufficient to diagnose CDI. Conversely, a negative NAAT is sufficient to rule out CDI. Discordant results in two-tiered algorithmic approaches require further clinical assessment and are discussed below. (See 'Establishing the diagnosis' above.)
•Interpreting discordant results – Discordant results occur when a positive NAAT results alongside a negative toxin EIA result (either with a NAAT followed by toxin EIA approach or the GDH and toxin EIA followed by NAAT approach). These discordant results indicate either active infection or asymptomatic carriage but cannot distinguish between them (table 2). Although many patients with discrepant results can forego treatment without adverse outcomes, we generally treat patients who are severely ill and those who do not have an alternative explanation for the diarrhea, because there is a lack of high-quality data establishing the safety of withholding treatment in these patient populations. (See 'Interpreting discordant results' above.)
•Limited role for repeat testing – There is no role for repeat laboratory testing (within seven days) during the same episode of diarrhea, and there is no indication to test for cure. (See 'Limited role for repeat testing' above.)
