Clostridioides (Clostridium) difficile

Clostridioides (Clostridium) difficile

Larry K. Kociolek

Erik R. Dubberke

Clostridioides difficile (formerly Clostridium difficile) was originally identified in the stool of a healthy, asymptomatic infant in 1935 (and was originally called Bacillus difficilis),1 but more than 40 years elapsed before C difficile was identified as the etiologic agent of antibiotic-associated pseudomembranous colitis (PMC) in 1978.2 Since that time, C difficile has emerged as the most important identifiable cause of healthcare-associated infectious diarrhea. C difficile is now the most common healthcare-associated pathogen in the United States,3 causing ˜500 000 infections and 29 000 deaths in the United States each year.4 In 2013, the U.S. Centers for Disease Control and Prevention (CDC) classified C difficile as an “urgent” public health threat that requires “urgent and aggressive action”.5 This call to action has led to new discoveries that have advanced C difficile infection (CDI) epidemiology, diagnosis, treatment, and prevention.


Increased understanding of the pathogenesis of CDI has guided the development of strategies for diagnosing, preventing, and treating C difficile. C difficile is an anaerobic Gram-positive rod. Strains that possess genes for production of toxins are considered toxigenic; nontoxigenic strains lack these genes and are considered nonpathogenic. The pathogenesis of CDI is multifactorial and complex. The series of events leading to CDI, and potential strategies for prevention, are shown in Figure 17-1.

CDI occurs in a susceptible host following exposure to spores from toxigenic strains of C difficile, but exposure alone is insufficient to cause CDI. C difficile spores are well suited to germinate in a dysbiotic intestinal environment, which often results from receipt of antibiotics shortly before or after C difficile exposure. Virtually any antibiotic is able to cause dysbiosis and increase the likelihood of developing CDI. Historically, C difficile strains were commonly resistant to clindamycin, which contributed to the well-known association of clindamycin and PMC. However, since that time, the emergence of fluoroquinolone resistance in epidemic strain ribotype (RT) 027 led to the recognition of fluoroquinolones as a major risk factor for CDI.6 Further, with the expanded use of broad-spectrum cephalosporins, and because of intrinsic cephalosporin resistance in C difficile, cephalosporins are also considered a major contributor to CDI.7

After C difficile spores germinate in the gut, vegetative cells express toxins that are cytocidal to colonocytes and initiate an inflammatory cascade that lead to CDI symptoms, most commonly a mild-to-moderate diarrheal illness (described in more detail below). While the importance of both toxins A (an enterotoxin) and B (a cytotoxin) have been described,6 it is currently believed that toxin B is the primary contributor to CDI based on animal models of infection8 and the observation of CDI caused by strains lacking toxin A.9 These findings are supported by recent data demonstrating lower risk of recurrent CDI in patients with high anti-toxin B antibody titers, while anti-toxin A antibody titers did not impact CDI recurrence risk.10 Some C difficile strains additionally express binary toxin, of which the specific role in CDI pathogenesis is not entirely clear.6 Interestingly, for reasons that are poorly understood, infants seem to be innately protected from clinical CDI despite frequent rates of colonization and toxin detection in the stool.11 Based on animal data, this phenomenon is thought to be potentially related to lack of toxin receptor expression in infants,12 but this is unproven in humans. The most common clinical manifestation of CDI is mild-to-moderate diarrhea, but the full spectrum of disease ranges from asymptomatic colonization or fecal excretion to mild-to-moderate diarrhea to fulminant colitis. Signs of fulminant colitis, which is associated with mortality, include CDI associated with hypotension or shock, toxic megacolon, or ileus.7 The association of ileus with fulminant CDI is important to note because diarrhea may be absent and CDI may not be considered in the differential diagnosis.

Sustained cure from CDI is more likely to occur with normalization of the intestinal microbiome and with a humoral immune response against C difficile toxins, particularly against toxin B.10,13 These important observations contributed to the rationale for development of biologic and immunologic strategies for CDI prevention, which are described in more detail below.


Epidemic Characteristics

Prior to the early 2000s, CDI surveillance was not routinely performed; however, outbreaks of particular strain types were reported to occur. For example, limited retrospective molecular epidemiology data suggested that restriction endonuclease analysis group B predominated in the 1980s.17 An outbreak of RT001 (also known as restriction endonuclease analysis group J) occurred in the United States between 1989 and 1992.18 In the early 2000s, CDI rates were observed to increase in the United States and Canada. While this epidemic mainly affected older adults, CDI rates also increased among younger populations who were previously considered low-risk populations.6 For example, in 2005, reports of severe CDI among patients in the community without exposure to healthcare facilities (sometimes without antibiotic exposure) and reports of CDI in peripartum women and children highlighted the concern that the epidemiology of CDI was expanding beyond traditional risk populations.19 Today, CA CDI is a well-described phenomenon. CA CDI accounts for approximately one-third of all CDIs among adults4 and more than two-thirds of all CDIs among children.20

This increased incidence was also associated with increased CDI severity and mortality. This epidemic was ultimately determined to be caused by the emergence of an epidemic strain, known as RT027, which had virulence factors distinct from prior epidemic strains, such as those previously described. These include binary toxin production, a loss-of-function mutation in the tcdC-negative repressor of toxins A and B (potentially leading to increased production of toxins A and B, although this is controversial), and fluoroquinolone resistance. It is thought that these features contributed to the widespread dissemination of this strain and its association with more severe disease phenotypes. With urgent and aggressive action to limit spread of this multidrug-resistant C difficile strain, RT027 incidence has declined in the United States. For example, RT027 accounted for 17% and 21% of CA- and healthcare-associated CDIs in 2012, respectively, but in 2017, RT027 only accounted for 6% and 15% of CA- and healthcare-associated CDIs in 2012, respectively. Nonetheless, RT027 remains the most common strain type of C difficile in healthcare facilities. However, RT106 has surpassed RT027 as the most common US strain type causing CA CDI and total CDI.21

Current US CDI Burden

The burden of CDI in the United States has been well characterized by the CDC Emerging Infections Program, which is a 10-state collaborative that performs active population laboratory-based CDI surveillance. According to the 2015 publication highlighting surveillance data collected in 2011, the US pooled mean crude incidence rates of CA CDI and healthcare-associated CDI were 48 and 93 cases per 100 000 persons, respectively, for an overall adjusted national CDI incidence of 147 cases per 100 000 persons.4 CDI rates varied from state to state with incidence rates of CA-CDI and healthcare-associated CDI ranging from 27 to 124 and 48 to 159 cases per 100 000 persons, respectively. CDI incidence rates are higher among women and white race, and incidence increases with age with adults older than 65 years having an incidence rate more than fourfold higher than those between 45 and 64 years old. The percentage of cases of healthcare-associated CDIs with symptom onset in acute care hospitals, nursing homes, and the community was ˜37%, 36%, and 28%, respectively. Overall, these data suggest that more than 450 000 incident CDI cases and 29 000 CDI-associated deaths (ie, crude mortality within 30 days of CDI diagnosis) occur in the United States annually.

Antimicrobial Use

Nearly every antibacterial agent given by either oral or parenteral routes has been associated with CDI. Historically, the most commonly implicated agent had been clindamycin,25 but the importance of other antibiotics, including broad-spectrum cephalosporins and carbapenems, is well described.26 As described above, since 2000, fluoroquinolones have been recognized as a class of antimicrobials with a particularly high risk of CDI.6 Fluoroquinolones were the most frequently implicated antimicrobial associated with CDI during multihospital outbreaks of RT027 in Canada27 and the United States.28 These data suggested that increasing fluoroquinolone use had facilitated dissemination of the once uncommon RT027 strain that developed high-level fluoroquinolone resistance.

Reservoirs and Modes of Transmission

With the emergence of exquisitely sensitive whole genome sequencing (WGS) to track C difficile, much has been learned about patient-to-patient transmission of C difficile. In a large hospital-based study in the United Kingdom, only 35% of new CDIs could be linked to another symptomatic patient with CDI.29 In children, other symptomatic patients are an even less common source of infection; only 10% of HO CDIs could be linked to another symptomatic patient, although use of polymerase chain reaction (PCR) for C difficile diagnosis may have biased these findings by including both colonized and infected children.30 These studies suggest the presence of other common reservoirs of infection, such as community reservoirs or asymptomatic C difficile carriers in healthcare settings. Rigorous molecular epidemiologic investigation using WGS suggests that while carriers do transmit C difficile, they transmit less frequently than symptomatic patients. In a multihospital Canadian study, 14% of CDIs could be linked to a patient with CDI, whereas only 6% of CDIs could be linked to asymptomatic carriers.31 Multiple studies in the United Kingdom similarly reported low frequency of transmission from asymptomatic carriers.32,33

Environmental surfaces contaminated with C difficile spores are a potential source of C difficile transmission, which could lead to healthcare-associated CDIs. The environment of patients with CDI and asymptomatic C difficile carriage34 is more frequently contaminated than the environment of other patients, and the degree of contamination has correlated with C difficile outbreaks.35,36,37 Floors and bathroom sites tend to be most heavily contaminated.38 In addition, commode chairs, sigmoidoscopes, bed pans, nursery baby baths, patient phones, and electronic thermometers have been found to be contaminated and can serve as reservoirs for healthcare-associated transmission of C difficile.39,40,41

If either the environment or asymptomatic carriers are important sources of infections, C difficile could be transmitted from those sources by direct contact or indirectly by the hands or gloves of patient care personnel. Hands35,36,42 are frequently contaminated with C difficile, and hand colonization rates as high as 59% after contact with a patient with CDI when gloves were not worn, which, in some instances, amounted to mere patient assessment and charting, have been documented.35 Vinyl glove use by hospital personnel when handling body substances was also associated with a significant reduction in the incidence of CDI on acute care wards.43 Thus, direct and indirect evidence supports transient hand carriage by patient care personnel as a mode of C difficile transmission.

Several studies performed in many different countries provide clinical and molecular epidemiologic evidence of potential community reservoirs for CDI, including food and animal sources. These reservoirs may be strain specific. In Europe, particular RTs, such as RT027, are associated with country- and hospital-based clustering, implicating the role of the healthcare environment in transmission. On the other hand, other RTs, including RT078, RT014, and RT020, do not demonstrate country- and hospital-based clustering, suggesting the existence of widely disseminated community reservoirs.44 Interestingly, these RTs have also been identified in animals45,46 and food products,47 and genetic linkages between community reservoirs and human clinical C difficile isolates have been established.46

Jun 8, 2021 | Posted by in INFECTIOUS DISEASE | Comments Off on Clostridioides (Clostridium) difficile
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