Historically, the mortality associated with CDI has been low. Death as a direct or indirect result of CDI occurred in between 2% and 9% of cases [10,13]. However, the mortality rate associated with CDI varies according to the patient variables and disease. While many patients with C. difficile-associated diarrhea recover without specific therapy, symptoms may be prolonged and debilitating. Progression to C. difficile colitis is a serious matter and carries a mortality rate as high as 25% in elderly patients who are frail [10]. Reports focusing on patients who are more seriously ill indicate mortality rates of between 10% and 30%. As incidence rates have risen over the past decade, so too have mortality rates, and both reflect, in part, an increase in the virulence of C. difficile strains. Several hypervirulent outbreaks have been caused by the North American Pulsed Field type 1 and polymerase chain reaction (PCR) ribotype 027 (BI/NAP1/027) strain [5,16]. This virulent strain has been associated with increased production of toxins A and B, fluoroquinolone resistance, and the production of binary toxin. The role of binary toxin is not clear, but it may synergistically increase the virulence of toxins A and B. The virulent strain BI/NAP1/027 has been reported in most states throughout the United States and in several countries in Europe [16]. Preventive strategies for BI/NAP1/027 are similar to those taken for other strains, including barrier methods, use of disposable equipment, handwashing (with soap and water), environmental disinfection techniques, and antimicrobial stewardship. Vaccines are under development to target the toxins, and a novel drug (SYN-004 [ribaxamase]) for preventing C. difficile is under investigation [17].

C. difficile is an anaerobic, gram-positive, spore-forming bacillus within the genus Clostridioides. Also in this genus is C. mangenotii. C. mangenotii has been found in human feces, marine sediment, and soil [18].

C. difficile-associated diarrhea may be accompanied by the passage of mucus or occult blood in the stool, but melena or hematochezia is rare. Fever, cramping, abdominal discomfort, and a peripheral leukocytosis are relatively common, but are found in fewer than half the patients [10]. Extraintestinal manifestations, such as arthritis and bacteremia, occur but are very rare. C. difficile ileitis or pouchitis may be seen, rarely, in patients who have had a total colectomy for complicated CDI or some other indication [10]. Patients with severe disease have the potential for developing colonic ileus or dilatation (toxic megacolon). On occasion, the atypical case presents with abdominal pain and distention accompanied by leukocytosis but having minimal or no diarrhea. Other features of CDI include volume depletion and dehydration, electrolyte disturbances, azotemia, and hypoalbuminemia—all markers of severity. Serious complications include toxic megacolon, bowel perforation, hypotension, renal failure, systemic inflammatory response syndrome, sepsis, and/or death within 30 days of diagnosis [10,22].

Three populations at highest risk of acquiring C. difficile are the elderly, patients receiving antibiotics, and those with long hospital stays. However, other groups, including surgery patients and the immunocompromised, are also at risk for CDI. It is important that steps be taken to prevent infection in these patients, when possible.

Advanced age is considered a risk factor for CDI, as evidence by the higher age adjusted incidence of CDI [23]. Age older than 65 years is considered a risk factor both for acquisition of C. difficile and for the development of C. difficile-associated diarrhea [23,24]. This difference in prevalence is not attributable to a greater exposure to antibiotics among older adults. The Society for Healthcare Epidemiology of America (SHEA) suggests that the greater morbidity and mortality of CDI in elderly populations may be due to age-related changes in fecal flora, immunosenescence, or the presence of other underlying diseases [23]. Frequent interactions with healthcare systems also may place the older adults at greater risk for CDI. Data from the EIP show that in 2010, exposure to health care preceded 94% of CDI. Of those, 75% were inpatient exposures, with the remaining 25% associated with long-term care facilities and outpatient care settings [25,26].

The cycle of transmission for C. difficile consists of the following steps:

The primary mode of C. difficile transmission is person-to-person spread through the fecal-oral route, principally within healthcare facilities [10]. Asymptomatic patients (carriers) colonized with C. difficile may be shedding spores, a source of environmental contamination that facilitates transmission of infection to more vulnerable patients within the facility. Person-to-person contact permits C. difficile spores to pass readily from carriers and their bedding to the hands and clothing of healthcare workers. The hands of healthcare workers, transiently contaminated with C. difficile spores, are probably the main means by which the organism is spread during non-outbreak periods [10]. Studies have found a prevalence of asymptomatic colonization with C. difficile of 7% to 26% in acute care facilities and 5% to 7% in long-term care facilities, although other studies indicate the prevalence of asymptomatic colonization may be closer to 20% to 50% in facilities where CDI is endemic [37]. In a prospective, blinded cohort study in two university hospitals, the rate of hospital-acquired CDI among patients admitted to the same ward as an asymptomatic carrier was 4.6%, compared with 2.6% among patients residing in a ward having no asymptomatic carrier [38]. The risk of acquiring CDI correlated with the amount of exposure and length of stay.

Environmental contamination also has an important role in transmission of C. difficile in healthcare settings. Aside from transmission on healthcare professionals' hands and clothing, there have also been outbreaks traced back to electronic rectal thermometers, inadequately cleaned commodes, and bedpans shared between patients [10]. Environmental samples of C. difficile also have been obtained from homes, parks, chain stores, fast food restaurants, and other commercial sites [39,40,41,42].

A case definition of CDI should include symptoms (usually diarrhea) and either a stool test result positive for C. difficile toxins, or detection of toxigenic C. difficile, or colonoscopic findings demonstrating pseudomembranous colitis. Clinical manifestations of infection with toxin-producing strains of C. difficile can be as varied as nonsymptomatic carriage, mild-to-moderate diarrhea, or a fulminant pseudomembranous colitis. A history of antimicrobial use within three months of the onset of diarrhea is characteristic. The most common symptoms of mild-to-moderate C. difficile disease are [10]:

Hospitalized patients and persons residing in long-term care facilities should be tested for CDI whenever they develop unexplained and new-onset diarrhea, defined as three or more unformed stools in 24 hours [10]. The diagnosis of CDI is made in one of two ways: a stool positive for C. difficile toxins or toxigenic strain of the organism, or endoscopic/histologic findings of pseudomembranous colitis. Testing of stool from asymptomatic patients is not clinically useful, even when used as a test of cure, and is not recommended except in epidemiologic studies [10]. Diagnostic stool evaluation should be considered in the patient with clinically significant diarrhea (i.e., three or more loose stools for at least two days), or performed immediately in the patient with severe diarrhea (10 to 15 stools in a 24-hour period), especially if combined with fever or recent antibiotic usage.

A number of tests are used for the detection of toxins or toxigenic strains in stool, and the results can be available in hours [10]. The two most commonly employed by clinical laboratories are the enzyme immunoassay (EIA) and the PCR. Two additional tests—a selective anaerobic culture and the cell culture cytotoxicity assay—are highly sensitive and specific but are labor-intensive and too slow (two days or more) for clinical use.

EIA testing for C. difficile toxin A and B is rapid and specific, but less sensitive than PCR or the cell cytotoxin assay. The relatively low sensitivity (about 75%) is because detection requires that a threshold level of toxin be present in the sample.

EIA for glucose dehydrogenase (GDH) antigen is a rapid and highly sensitive way to detect the presence of C. difficile in stool but cannot distinguish between toxigenic and non-toxigenic strains. This assay is useful as an initial screening test but requires an additional step (e.g. PCR or specific culture) for confirmation.

PCR testing for the detection of toxin A and toxin B genes is highly sensitive and specific, and results can be available within one to two hours [10]. The disadvantage is that the test is so sensitive that false positives may occur if the patient is simply a carrier of C. difficile. About half of the hospital laboratories in the country now employ PCR, either alone or as part of a multi-step protocol that begins with EA screening for GDH or toxin.

Pseudomembranous colitis can only be diagnosed with certainty by direct visualization via colonoscopy and/or by histopathology via mucosal biopsy. Unfortunately, visualization only detects pseudomembranes in 51% to 55% of cases that are diagnosed by combined clinical and laboratory criteria [45]. The American College of Radiology recommends abdominal computed tomography scanning as the imaging modality of choice for C. difficile when pseudomembranous colitis, other complications of CDI, or other intra-abdominal pathology is suspected [46]. Marked colonic wall thickening is the most common finding. Other features may include ascites, irregularity of the bowel wall, and pericolonic stranding.

Mild-to-moderate illness is defined in the IDSA guidelines as CDI in the presence of a white blood cell count ≤15,000/mcL and serum creatinine <1.5 mg/dL [10]. In order to reduce selective pressure for vancomycin resistance in enterococci, previous recommendations were to initiate treatment with metronidazole for cases of mild-to-moderate illness. The 2021 focused guideline update recommends fidaxomicin over metronidazole for treatment of an initial or first recurrent episode of CDI [24]. The dosage is 200 mg twice daily for 10 days. Fidaxomicin is a first-in-class oral macrocyclic antibiotic with potent bactericidal activity against C. difficile [47,48]. Unlike vancomycin and metronidazole, fidaxomicin has a narrow spectrum of activity against normal gut flora. In settings in which access to fidaxomicin is limited, it is suggested to use vancomycin or metronidazole if the episode of CDI is not severe [24]. The suggested regimen is metronidazole 500 mg orally three times daily for 10 days, while the vancomycin dose is 125 mg orally four times per day for 10 days. The response to treatment is usually prompt, with a significant reduction in the rate of stooling within 24 to 48 hours. There are reports indicating that some patients infected with the BI/NAP1/027 strain respond more slowly, even unsatisfactorily, to metronidazole [16,49].

A colectomy can be life-saving for patients with megacolon, colonic perforation, acute abdomen, and potentially with septic shock. However, such patients are often elderly and, in the presence of elevated serum lactate levels and other markers of sepsis, are at risk for high operative mortality and postoperative complications. Surgery consultation should be requested early for severely ill patients, especially when there is marked leukocytosis or signs of megacolon. If surgery is necessary, subtotal colectomy with preservation of the rectum is the preferred approach [10].

The recurrence of symptoms following a successful course of therapy, and necessitating further treatment, remains a challenging problem. Up to 25% of patients treated for CDI have already experienced at least one previous episode [10]. In most cases, the recurrence of diarrhea represents relapse of the initial infection and is thought to be caused by residual vegetative spores that once again proliferate after therapy is lifted. The SHEA/IDSA guidelines list three options for re-treatment of a first recurrence of CDI [24]:

Hand hygiene is considered to be one of the cornerstones of the prevention of nosocomial transmission of C. difficile, as it is for many healthcare-acquired infections. Studies have confirmed that hand washing will reduce infections, but studies have also revealed that healthcare compliance with hand hygiene is poor [58]. Alcohol hand hygiene products have been viewed as a breakthrough for compliance and ease of hand hygiene [59,60]. Unfortunately, the C. difficile spore is highly resistant to killing by alcohol. Mechanically washing with soap and water is much more effective, but even then only removes 90% of the pathogen load [61].

The use of additional isolation techniques, such as Contact Precautions in addition to Standard Precautions, with patients with active CDI has been employed during breakouts with varied success. This addresses the transmission of C. difficile via patients with active CDI, but healthcare professionals' hands and the environment are equally efficient modes of disease transmission. Therefore, adhering to hand hygiene standards and stringent surface decontamination are equally important. The following descriptions of Contact Precautions are summarized from the 2007 Standard Precautions guideline and the 2017 SHEA/IDSA C. difficile guidelines [10,56]. The CDC website also provides updated guidance for clinicians and healthcare facilities on prevention of CDI, including isolation precautions, disinfection and sterilization, and hand hygiene [71].

Every healthcare facility should have a written housekeeping schedule for the routine cleaning of the environment. Routine cleaning removes so-called visible dirt, which can harbor micro-organisms. Soap and water can be used to remove visible dirt from most surfaces, such as walls, doors, ceilings, and floors. A disinfectant should be used when there are signs of contamination. The level of asepsis in cleaning depends on the likelihood of contamination. The World Health Organization suggests classifying areas within a healthcare facility into four zones [72]:

Improving hospital layout can have a markedly positive effect on the transmission of C. difficile from patient to patient [81]. In a cohort study of nosocomial acquisition of CDI, it was noted that double rooms had a higher rate of acquisition than single rooms, as did the exposure of a patient to a roommate with a positive C. difficile culture [10]. Another study example compared an older hospital with fewer single beds, higher bed occupancy, a low use of broad-spectrum antibiotics, and no antibiotic stewardship program to a newer facility with these programs. The more modern hospital with more private rooms had a lower rate of CDI; however, it was impossible to elucidate causation [10]. The difficulty comes in finding studies that provide enough quality, evidence-based information that bears out the theory of hospital layout affecting the CDI rate [10].

C. difficile accounts for 20% to 30% of all antibiotic-associated diarrhea and is the most commonly identified reason for infectious diarrhea in hospital settings [10]. Because CDI is not a reportable disease in the United States, data are sparse. Only 20 states mandate hospital reporting either under state law or by incorporating the federal reporting requirements of the CMS. While state laws are more common, incorporation of federal reporting requirements is increasing. State surveillance activities have been heavily influenced by the CMS reporting requirements, which became mandatory in 2013. States that have not mandated reporting have taken other actions to reduce CDIs by implementing prevention collaboratives offered by the CDC [12].