Clostridium difficile infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Clostridium difficile infection is caused by the bacterium C. difficile, a a spore-forming, toxin-producing, obligate anaerobic, gram-positive bacillus. The incidence of C. difficile infection is estimated to be 140 per 100,000 individuals. In USA, the majority (65%) of cases are associated with healthcare settings, and 25% of cases are associated with previous hospitalizations. The most important risk factor for the development of C. difficile infection is history of antibiotic use within the past 12 weeks. Other important risk factors include recent hospitalization (< 12 weeks), advanced age (> 65 years), immunodeficiency (primary or secondary causes), inflammatory bowel disease, and exposure to colonized/infected individuals. C. difficile spores are transmitted via the fecal-oral route. Following ingestion, spores germinate to the vegetative form in the small intestine and eventually colonize in the large intestine in susceptible patients. C. difficile does not result in clinical manifestations in the majority of cases, whereby normal GI flora resists the growth of C. difficile, and the host immune responses adequately clear the infection before the development of clinical manifestations. However, in susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), which act synergically and mediate adhesion to the colonic mucosa, luminal fluid accumulation, and development of clinical manifestations. The onset of clinical manifestations may occur within 2 hours up to several months following antibiotic administration. Patients typically develop mild/moderate watery diarrhea (possibly bloody) associated with colicky diffuse abdominal pain, nausea, malaise, and low-grade fever. If left untreated, patients may develop colitis (with or without pseudomembrane formation). Approximately 3% of patients develop complications, which might be colonic (fulminant colitis) or extracolonic. The majority of patients with C. difficile infection recover without sequelae and are responsive to antimicrobial therapy. Nonetheless, C. difficile infection is associated with a high lifetime recurrence rate that ranges between 20% to 60%, and most recurrences occur a few weeks following the successful completion of antimicrobial therapy. The gold standard for the diagnosis of C. difficile infection is cell culture cytotoxic assay, but it is rarely used clinically (difficult technique and time consuming). Among symptomatic patients, C. difficile infection is diagnosed either by enzyme immunoassay (ELISA) for toxins A and/or B in stools or by DNA-based tests (PCR). C. difficile infection may be classified based on the clinical severity of the disease. and the severity of the infection dictates the choice of antimicrobial therapy and the need for surgical consultation/management. Administration of oral metronidazole is recommended for patients with mild symptoms, whereas oral vancomycin is recommended for severe disease.

Clostridium difficile was first isolated in 1935 during an experiment from fecal extracts of healthy neonates. The association between C. difficile and antibiotic-associated pseudomembranous colitis was first made in 1978. In 2003, a resistant, hypervirulent strain of C. difficile (NAP/BI/027 strain) with increased synthesis of toxins A and B was first identified.

Spores of C. difficile are transmitted via the fecal-oral route to the human host. Spore ingestion may be community-acquired (soil and food) or healthcare-associated (hospitals and clinics). Following ingestion, the acid-resistant spores of C. difficile are able to survive the human gastric acidity. C. difficile does not result in clinical manifestations in the majority of cases, whereby normal GI flora resists the growth of C. difficile, and the host immune responses adequately clear the infection before the development of clinical manifestations. However, in susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), which act synergically and mediate adhesion to the colonic mucosa, luminal fluid accumulation, and development of pseudomembranous colitis. These toxins are able to glycosylate Rho GTPase (involved in actin cytoskeleton) and cause the formation of abnormal G-actin (leading to characteristic rounding of cells). Additionally, they stimulate macrophage-induced cytokine production and subsequent neutrophilic infiltration to the site of inflammation, which in part contributes to the disruption of the intestinal barrier and the development of clinical manifestations associated with the infection. On gross examination, colonic pseudomembranes with yellow colored plaque formation are typical. On microscopic examination, erosions within colonic crypts or formation of mushroom-like exudates with hemorrhage and necrosis are characteristic features.

C. difficile infection is caused by Clostridium difficile, a spore-forming, toxin-producing, oligate anaerobic, gram-positive bacillus.

C. difficile infection may be classified based on the clinical severity of the disease. The severity of the infection dictates the choice of antimicrobial therapy and the need for surgical consultation/management. Mild disease is defined as isolated diarrhea, whereas severe/complicated disease is defined as either delirium, shock, organ failure, high-grade fever, or marked leukocytosis.

Clostridium difficile infection must be differentiated from other diseases that cause acute inflammatory diarrhea, abdominal pain, fever, and ileus, including other causes of colitis (ischemic, collagenous, ulcerative), malabsorptive syndromes, diverticulitis, appendicitis, malignancies, drug-induced causes, and infections, such as salmonellosis, shigellosis, or gastrointestinal infections with Escherichia coli or Campylobacter jejuni.

The incidence of C. difficile infection is estimated to be 20 per 100,000 person-years. In USA, the majority (65%) of cases are associated with healthcare settings, and 25% of cases are associated with previous hospitalizations. Although patients of all age groups may develop C. difficile infection, elderly patients > 65 years may have up to eight-fold increased risk of developing C. difficile infection compared with younger patients. Whites and female patients are more predisposed to develop C. difficile infections. Although C. difficile is abundantly reported in Europe and the United States, the infection is a global burden.

The most important risk factor for the development of C. difficile infection is antibiotic use. Although C. difficile infection has been described with almost all antibiotics, ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones are most classically and most commonly associated with development of C. difficile infection. Other important risk factors include recent hospitalization (< 12 weeks), advanced age (>65 years), immunodeficiency (primary or secondary causes), inflammatory bowel disease, and exposure to colonized/infected individuals. The association between gastric acid suppression and C. difficile infection has not been well established.

Following ingestion of C. difficile spores, patients are colonized with the organism. Typically, young healthy individuals with adequate immune responses are able to clear the organism without development of any clinical manifestations. But patients with risk factors, such as recent antibiotic use, recent hospitalization, advanced age, or immunodeficiency, are at an increased risk of developing persistent colonization and/or developing signs and symptoms of the infection. The onset of clinical manifestations may occur within 2 hours up to several months of antibiotic use. Patients typically develop mild/moderate watery diarrhea (possibly bloody) associated with colicky diffuse abdominal pain, nausea, malaise, and fever. If left untreated, patients may develop colitis (with or without pseudomembrane formation). Approximately 3% of patients develop complications, which might be colonic (fulminant colitis) or extracolonic (small intestine involvement, bacteremia, skin infections, reactive arthritis, abscess formation, empyema, or death). The majority of patients with C. difficile infection recover without sequelae and are responsive to antimicrobial therapy. Nonetheless, C. difficile is associated with a high lifetime recurrence rate that ranges between 20% to 70%, most of which occur a few weeks following the successful completion of antimicrobial therapy.

Clinical manifestations may range from an asymptomatic course to a severe/fatal presentation. Common symptoms include acute-onset, foul-smelling watery diarrhea, crampy diffuse or lower abdominal pain, low-grade fever, malaise, anorexia, nausea, and weight loss. Alarming symptoms that may be suggestive of colonic complications of C. difficile infection include worsening abdominal pain and diarrhea, high-grade fever, dry mucus membranes, and peripheral edema.

Patients with C. difficile infection typically have low-grade fever and abdominal tenderness on physical examination. Additional signs on physical examination may be suggestive of worsening infection, complicated disease, or failure of antimicrobial therapy. Significant findings on physical examination include significant derangements in vital signs, including high-grade fever, tachycardia, or hypotension, signs of dehydration, peripheral edema which might be suggestive of hypoalbuminemia, or worsening abdominal tenderness, distention, palpable masses, or inactive bowel sounds, which may suggest toxic megacolon, abscess development, or ileus.

Testing is generally not necessarily for patients with formed stools (no diarrhea). The gold standard for diagnosis of C. difficile infection is cell culture cytotoxic assay, but it is rarely used clinically (difficult technique and time consuming). Among patients with diarrhea,C. difficile infection is diagnosed either by enzyme immunoassay (ELISA) for toxins A and/or B in stools or by DNA-based tests (PCR) that detect bacterial toxin genes in stools. Although both ELISA and DNA-based tests may be performed sequentially, only one positive test is sufficient to diagnose C. difficile infection. Both ELISA and DNA-based tests also have a high negative predictive value > 95% among average-risk patients, and generally negative results warrants the search for alternative diagnoses. The advantage of DNA-based tests over ELISA is that it may detect the presence of BI/NAP1/027 strain, which alters the management plan. However, DNA-based tests may also detect clinically irrelevant findings that may delay the diagnosis. Stool culture requires anaerobic culture and may not be available. Although not diagnostic, additional blood testing may be necessary to monitor for possible development of complications or the success/failure of antimicrobial therapy.

Abdominal X-ray may be required for patients suspected to have toxic megacolon. Signs on abdominal x-ray that may be suggestive of toxic megacolon include enlarged, dilated colon > 6-7 cm, loss of colonic haustrations, small intestinal dilation, presence of air-fluid levels, or submucosal edema with thumbprinting.

Abdominal CT scan is the imaging of choice for patients with C. difficile pseudomembranous colitis or patients with suspected complications. Abdominal CT scan findings may include marked colonic wall thickening or nodularity, irregular bowel walls, pericolonic stranding, or ascites formation.

In patients with suspected C. difficile infection and inconclusive laboratory diagnostic findings, atypical presentation, or unsuccessful antimicrobial therapy, either a sigmoidoscopy or colonoscopy is indicated. During endoscopy, multiple biopsies should be obtained for microscopic histopathological analysis. On gross examination, colonic pseudomembranes with yellow colored plaque formation are typical findings.

On microscopic examination, erosions within colonic crypts or formation of mushroom-like exudates with hemorrhage and necrosis are characteristic features of C. difficile infection.

Treatment is generally recommended for average-risk patients who are symptomatic with positive lab findings for C. difficile infection. For patients with C. difficile risk factors, empiric therapy is recommended for symptomatic patients regardless of lab findings. Antimicrobial therapy is tailored acccording to the clinical severity of the infection. Administration of oral metronidazole is recommended for patients with mild symptoms, whereas oral vancomycin is recommended for severe disease.

Indications for surgery include peritoneal signs, persistent bacteremia, progressive clinical disease with organ damage (e.g. renal or pulmonary disease), or evidence on CT scan demonstrating worsening infection.

There are no vaccines available for the prevention of C. difficile infection. Individuals in healthcare settings may reduce the risk of C. difficile infection by washing hands using soap and water (alcohol-based products are not effective), minimizing unnecessary use of antibiotic administration, and properly isolating infected patients with adequate post-discharge room disinfection.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Clostridium difficile was first isolated in 1935 during an experiment from fecal extracts of healthy neonates. The association between C. difficile and antibiotic-associated pseudomembranous colitis was first made in 1978. In 2003, a resistant, hypervirulent strain of C. difficile (NAP/BI/027 strain) with increased synthesis of toxins A and B was first identified.

• In 1935, Hall and O’Toole were the first to isolate Clostridium difficile from fecal extracts of healthy neonates. Following isolation, the bacterium was originally named Bacillus difficilis because the isolation process during the original experiment was difficult.^[1]
• The association between C. difficile and antibiotic-associated pseudomembranous colitis was first made in 1978.^[1][2]

• Cell-cytotoxicity assay was first developed by Te-Wen Chang, who demonstrated that Clostridium sordellii antitoxin is produced among patients with pseudomembranous colitis and is able to neutralize the cytotoxic effects of an unidentified toxin (later to be identified as C. difficile toxin B).^[3][4]

• In 2003, a resistant, hypervirulent strain of C. difficile (NAP/BI/027 strain) with increased synthesis of toxins A and B was first identified. The emergence of the new strain was attributed to fluoroquinolone administration.^[5][6][7]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Spores of C. difficile are transmitted via the fecal-oral route to the human host. Spore ingestion may be community-acquired (soil and food) or healthcare-associated (hospitals and clinics). Following ingestion, the acid-resistant spores of C. difficile are able to survive the human gastric acidity. C. difficile does not result in clinical manifestations in the majority of cases, whereby normal GI flora resists the growth of C. difficile, and the host immune responses adequately clear the infection before the development of clinical manifestations. However, in susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), which act synergically and mediate adhesion to the colonic mucosa, luminal fluid accumulation, and development of pseudomembranous colitis. These toxins are able to glycosylate Rho GTPase (involved in actin cytoskeleton) and cause the formation of abnormal G-actin (leading to characteristic rounding of cells). Additionally, they stimulate macrophage-induced cytokine production and subsequent neutrophilic infiltration to the site of inflammation, which in part contributes to the disruption of the intestinal barrier and the development of clinical manifestations associated with the infection. On gross examination, colonic pseudomembranes with yellow colored plaque formation are typical. On microscopic examination, erosions within colonic crypts or formation of mushroom-like exudates with hemorrhage and necrosis are characteristic features.

• Spores of C. difficile are transmitted via the fecal-oral route to the human host.
• Spore ingestion may be community-acquired (soil and food) or healthcare-associated (hospitals and clinics).
• C. difficile spores are heat-, acid-, and antibiotic-resistant.

• Both C. difficile virulence strain and host susceptibility factors are needed for the development of clinical manifestations.
• Following ingestion, the acid-resistant spores of C. difficile are able to survive the human gastric acidity.

• The spores germinate to the vegetative form in the small intestine and eventually colonize in the large intestine among susceptible patients (e.g. recent history of antibiotic administration with antibiotic-induced disruption of the normal GI flora). In contrast, the normal GI flora in a healthy patient prevents the growth of C. difficile (colonization resistance phenomenon), and adequate immune responses clear the infection even before clinical manifestations develop.

• In susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), both of which mediate the development of pseudomembranous colitis.

Exotoxins A and B are cytotoxic virulence factors that are able to glycosylate and inactivate Rho GTPases and cause colonocyte death and loss of intestinal barrier.

In the majority of individuals, the toxin production is countered by adequate host antitoxin responses.

Among susceptible patients, however, the infectious injury is extensive, resulting in diarrhea and colitis.

Following the development of clinical manifestations, host immune responses may be either adequate (leading to complete resolution of the infection) or inadequate (leading to recurrence of clinical manifestations).

• In susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), both of which mediate the development of pseudomembranous colitis.
• Not all strains of C. difficile are equally virulent.^[1][2]
• The virulence of an individual strain is directly associated with the amount of toxin A and B produced.^[1]

Toxin A mass is 308 kDa, whereas toxin B mass is 269 kDa.

Although both toxins may be expressed from a single promoter, each toxin has its individual set of promoters and ribosomal binding sites along the toxic genes within the toxicon.

Both toxins act synergically and both induce vascular permeability and hemorrhage by binding to specific host receptors.^[3]

Both toxins have monoglucosyltransferase activity at the N-terminus. Toxins are able to glycosylate Rho GTPase (involved in actin cytoskeleton) and cause the formation of abnormal G-actin (normally F-actin). In turn, G-actin induces the development of cell rounding, which is characteristic of toxin-induced cytopathy.^[4][5][6]

Toxin A, but not toxin B, is associated with luminal fluid accumulation and may be responsible for the diarrhea associated with C. difficile infection.^[3]

Toxin A is thought to stimulate cytokine production by macrophages (Il-1, IL-8, leukotrienes), which may be responsible for the subsequent neutrophilic migration and inflammation.

Although toxin A has been studied more extensively than toxin B, virulence by strains with toxin B only virulence factor has been reported.^[7] The mechanism by which toxin B acts is yet to be understood.

• Other less clinically important virulence factors that have been isolated include the following:

Enterotoxic protein

High-molecular weight protein

Actin-specific ADP-ribosyl-transferase

DCT binary toxin

Fimbiae

SlpA S-layer

Cwp84 cysteine protease

Fibronectin binding protein

Cwp66

• Although some C. difficle strains contain fimbriae or flagellae, the main adhesin component of the organism is thought to be exotoxin A.^[1]

• Since, C. difficile toxin A mediates the adhesion of the organism to the host intestinal wall, more virulent strains with more exotoxin A are able to adhere better than strains of reduced virulence.^[8]

• Typically, C. difficile adheres to the wall of the terminal ileum and the cecum, which justifies the development of ileocecitis in the majority of patients.^[8]

• The role of other adhesive properties of C. difficile, including hydrophobic surfaces and charge interactions with the human host, have been studied to a lesser extent.^[9]

• Host intestinal mucus serves as a chemoattractant for C. difficile.^[10][11]

• Chemotaxis is further facilitated by the organism’s motility, which is mediated by flagellae.^[1]

C. difficile expresses several enzymes that help in the breakdown of host mucosal integrity and organism growth^[12][13]:

• Hyaluronidase: Major enzyme that converts hyaluronic acid from mucus glycoproteins into N-acetylglucosamine needed for nutritional growth
• Chondroitin-4-sulphatase
• Heparinase (weak activity)
• Collagenase (weak activity)

On gross pathology, the following characteristic features may be present in C. difficile colitis:

• Colonic pseudomembranes with yellow colored plaque formation
• Areas of hemorrhage, which may be either multifocal, segmental, or diffuse
• Hyperemic congestion
• Marked edema formation of the intestinal wall
• Superficial erosions and ulcer formation

On microscopic pathology, the following characteristic features may be present in C. difficile colitis:

• Erosions within colonic crypts with pseudomembrane formation, which contains neutrophils, fibrin, and necrotic debris
• Linear neutrophilic infiltration at the level of the lamina propria and within areas of necrosis
• Necrotizing enteritis with or without hemorrhage
• Submucosal edema
• Inflammatory exudates (mushroom-like)

Template:WH Template:WS

For more details about the conditions that are associated with the development of C. difficile infection (e.g. list of antibiotics), click here.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

C. difficile infection is caused by Clostridium difficile, a spore-forming, toxin-producing, obligate anaerobic, gram-positive bacillus.

• Clostridium difficile (etymology and pronunciation), also known as C. difficile, C. diff, or sometimes CDF/cdf, is a species of Gram-positive spore-forming bacteria.^[1]
• Clostridia (members of the genus Clostridium) are anaerobic, motile bacteria, ubiquitous in nature, and especially prevalent in soil. Under the microscope, they appear as long, irregular (often drumstick- or spindle-shaped) cells with a bulge at their terminal ends. Under Gram staining, C. difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. When stressed, the bacteria produce spores that are able to tolerate extreme conditions that the active bacteria cannot tolerate.^[2]
• C. difficile may become established in the human colon; it is present in 2–5% of the adult population.^[2]

• Pathogenic C. difficile strains produce multiple toxins. The most well-characterized are enterotoxin (Clostridium difficile toxin A) and cytotoxin (Clostridium difficile toxin B), both of which may produce diarrhea and inflammation in infected patients (Clostridium difficile colitis), although their relative contributions have been debated.^[2] Toxins A and B are glucosyltransferases that target and inactivate the Rho family of GTPases. Toxin B (cytotoxin) induces actin depolymerization by a mechanism correlated with a decrease in the ADP-ribosylation of the low molecular mass GTP-binding Rho proteins.^[3]
• Another toxin, binary toxin, also has been described, but its role in disease is not fully understood.^[4]
• Antibiotic treatment of C. diff infections may be difficult, due both to antibiotic resistance and physiological factors of the bacteria (spore formation, protective effects of the pseudomembrane).^[2] The emergence of a new, highly toxic strain of C. difficile, resistant to fluoroquinolone antibiotics, such as ciprofloxacin and levofloxacin, said to be causing geographically dispersed outbreaks in North America, was reported in 2005.^[5]
• C. difficile is transmitted from person to person by the fecal-oral route. However, the organism forms heat-resistant spores that are not killed by alcohol-based hand cleansers or routine surface cleaning. Thus, these spores survive in clinical environments for long periods. Because of this, the bacteria may be cultured from almost any surface. Once spores are ingested, their acid-resistance allows them to pass through the stomach unscathed. They germinate and multiply into vegetative cells in the colon upon exposure to bile acids.

• In 2005, molecular analysis led to the identification of the C. difficile strain type characterized as group BI by restriction endonuclease analysis, as North American pulse-field-type NAP1 by pulsed-field gel electrophoresis and as ribotype 027; the differing terminology reflects the predominant techniques used for epidemiological typing. This strain is referred to as C. difficile BI/NAP1/027.^[6]

• The first complete genome sequence of a C. difficile strain was first published in 2005 by Sanger Institute in the UK. This was of the strain 630, a virulent and multiple drug-resistant strain isolated in Switzerland in 1982. Scientists at Sanger Institute have sequenced genomes of about 30 C. difficile isolates using next-generation sequencing technologies from 454 Life Sciences and Illumina.^[7]
• Researchers at McGill University in Montreal sequenced the genome of the highly virulent Quebec strain of C. difficile in 2005 using ultra-high-throughput sequencing technology. The tests involved doing 400,000 DNA parallel-sequencing reactions of the bacterium’s genome, which had been fragmented for sequencing. These sequences were assembled computationally to form a complete genome sequence.^[5][8]
• In 2012, scientists at University of Oxford sequenced C. difficile genomes from 486 cases arising over four years in Oxfordshire using next-generation sequencing technologies from Illumina.^[9]

• At least eight mainly temperate bacteriophages have been isolated from C. difficile, ranging in genome size from about 30 to about 60 kb.^[10] Both environmentally and clinically derived C. difficile strains carry a diverse and prevalent set of prophages.^[10]

• The species name is New Latin, from the Greek and Latin difficile, “difficult, obstinate”.^[11].

• C. difficile infection is caused by Clostridium difficile. C. difficile has the following characteristic features:
• Bacillus
• Gram-positive
• Obligate anaerobe
• Spore-forming (spores are acid-, heat-, and antibiotic-resistant)
• Toxin-producing (exotoxins A and B)
• Motile
  
• C. difficile is difficult to isolate and grow in cultures. Because the organism is very sensitive to oxygen (obligate anaerobe), spore formation is essential for the organism to be transmitted from one host to another.

• 
  Clostridium difficile enterotoxin, CPE, is the principal toxin involved in C. difficile foodborne illness. From Public Health Image Library (PHIL). ^[12]
• 
  Gram-positive C. difficile bacteria from a stool sample culture obtained using a .1µm filter. From Public Health Image Library (PHIL). ^[12]
• 
  Gram-positive C. difficile bacteria from a stool sample culture obtained using a .1µm filter. From Public Health Image Library (PHIL). ^[12]
• 
  Gram-positive C. difficile bacteria from a stool sample culture obtained using a .1µm filter. From Public Health Image Library (PHIL). ^[12]
• 
  Gram-positive C. difficile bacteria from a stool sample culture obtained using a .1µm filter. From Public Health Image Library (PHIL). ^[12]
• 
  Gram-positive C. difficile bacteria from a stool sample culture obtained using a .1µm filter. From Public Health Image Library (PHIL). ^[12]
• 
  Illustration depicts the ultrastructural morphology exhibited by a single Gram-positive Clostridium difficile bacillus. From Public Health Image Library (PHIL). ^[12]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

C. difficile infection may be classified based on the clinical severity of the disease. The severity of the infection dictates the choice of antimicrobial therapy and the need for surgical consultation/management. Mild disease is defined as isolated diarrhea, whereas severe/complicated disease is defined as either delirium, shock, organ failure, high-grade fever, or marked leukocytosis.

Shown below is a table that classifies C. difficile infection based on clinical features and lab findings. The severity of the infection dictates the choice of antimicrobial therapy.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Clostridium difficile infection must be differentiated from other diseases that cause acute inflammatory diarrhea, abdominal pain, fever, and ileus, including other causes of colitis (ischemic, collagenous, ulcerative), malabsorptive syndromes, diverticulitis, appendicitis, malignancies, drug-induced causes, and infections, such as salmonellosis, shigellosis, or gastrointestinal infections with Escherichia coli or Campylobacter jejuni.

Clostridium difficile infection must be differentiated from other diseases that cause acute inflammatory diarrhea, abdominal pain, fever, and ileus:

• Other causes of colitis

Ischemic colitis

Ulcerative colitis

Collagenous colitis

Eosinophilic colitis

Lymphocytic colitis

Indeterminate colitis

• Crohn’s disease
• Diverticulitis
• Appendicitis
• Malabsorptive syndromes
• Malignancy, such as colon cancer
• Infections

Bacterial infections

Viral infections, including HIV

Parasitis infections, such as amebiasis or giardiasis

Fungal infections

• Mesenteric ischemia
• Thrombosis
• Drug-induced (e.g. cocaine, oral contraceptive, gold, isotretinoin, laxative abuse, allopurinol, antibiotics adverse effect, chemotherapy, NSAIDs)
• Allergic proctitis
• Graft vs. host disease (GVHD)
• Immunodeficiency syndromes
• Vasculitis
• Behcet disease
• Sarcoidosis

The table below lists common infectious pathogens that are known to cause acute inflammatory diarrhea:^[1][2]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

The incidence of C. difficile infection is estimated to be 140 per 100,000 individuals. In USA, the majority (65%) of cases are associated with healthcare settings, and 25% of cases are associated with previous hospitalizations. Although patients of all age groups may develop C. difficile infection, elderly patients > 65 years may have up to eight-fold increased risk of developing C. difficile infection compared with younger patients. Whites and female patients are more predisposed to develop C. difficile infections. Although C. difficile is abundantly reported in Europe and the United States, the infection is a global burden.

• The incidence of C. difficile infection is estimated to be 140 per 100,000 individuals and approximately 1,500 per 100,000 hospital discharges.^[1]

In the U.S. Veterans Affairs system, approximately 0.5% of admissions have c diff^[2][3].

• Patients of all age groups may develop C. difficile infection.
• Elderly patients > 65 years may have up to eight-fold increased risk of developing C. difficile infection compared with younger patients.^[1]

• There is a slight female predisposition to the development of C. difficile infection with a female to male ratio of 1.26.^[1]

• Caucasian individuals are more likely to develop C. difficile infection.^[1]

• The estimated number of incident C. difficile infection in USA is estimated to be approximately range between approximately 397,000 and 508,500.^[1]

• In USA, the majority (65%) of cases are associated with healthcare settings, and 25% of cases are associated with previous hospitalizations.^[1]

• In USA, the NAP1 C. difficile strain is more common in healthcare settings than in community settings.
• In 2011, approximately 29,000 deaths have been attributed to C. difficile infection in USA.^[1]
• Several C. difficile outbreaks have been reported in Canada, USA, and Europe.

• Although C. difficile is abundantly reported in Europe and the United States, the infection is a global burden.
• The burden of C. difficile in developing countries is difficult to estimate due to scarcity of available data.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The most important risk factor for the development of C. difficile infection is antibiotic use within the past 12 weeks. Although C. difficile infection has been described with almost all antibiotics, ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones are most classically and most commonly associated with development of C. difficile infection. Other important risk factors include recent hospitalization (< 12 weeks), advanced age (>65 years), immunodeficiency (primary or secondary causes), inflammatory bowel disease, and exposure to colonized/infected individuals. The association between gastric acid suppression and C. difficile infection has not been well established.

The most important risk factor is antibiotic use within the past 12 weeks.^[1][2][3] Although C. difficile infection has been described with almost all antibiotics, the following antibiotics are most classically and most commonly associated with development of C. difficile infection^[1][2][3]:

• Ampicillin
• Amoxicillin
• Cephalosporins
• Clindamycin
• Fluoroquinolones

• The majority of C. difficile infections are hospital-acquired.
• The risk associated with hospitalization may persist up to 12 weeks following index hospitalization.^[1][2][3]

• Elderly patients > 65 years have an approximately 8-fold increased risk of developing C. difficile infection compared with younger adults.^[1][2][3]

• Exposure to infected or colonized host increases the risk of C. difficile infection.^[1][2][3]

• Immunodeficiency results in inadequate host immune responses that normally prevent the vegetation and growth of C. difficile.^[1][2][3]

• Immunodeficiency may be primary or secondary. Secondary causes of immunodeficiency include chemotherapy, organ transplant and use of immunosuppressive therapy, or HIV.

• Inflammatory bowel disease (either Crohn’s disease or ulcerative colitis) is significantly associated with increased risk of C. difficile infection.
• Hospitalized patients with IBD flare-up should always undergo diagnostic testing for C. difficile infection.

• There are multiple reports of increased risk of C. difficile infection with gastric acid suppression.^[4]
• Nonetheless, the true association between gastric acid suppression and C. difficile infection is yet to be discovered, since ‘”C. difficile spores are acid-resistant, and any reduction in gastric acidity may not necessarily be associated with increased risk of infection.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Following ingestion of C. difficile spores, patients are colonized with the organism. Typically, young healthy individuals with adequate immune responses are able to clear the organism without development of any clinical manifestations. But patients with risk factors, such as recent antibiotic use, recent hospitalization, advanced age, or immunodeficiency, are at an increased risk of developing persistent colonization and/or developing signs and symptoms of the infection. The onset of clinical manifestations may occur within 2 hours up to several months following antibiotic administration. Patients typically develop mild/moderate watery diarrhea (possibly bloody) associated with colicky diffuse abdominal pain, nausea, malaise, and fever. If left untreated, patients may develop colitis (with or without pseudomembrane formation). Approximately 3% of patients develop complications, which might be colonic (fulminant colitis) or extracolonic (small intestine involvement, bacteremia, skin infections, reactive arthritis, abscess formation, empyema, or death). The majority of patients with C. difficile infection recover without sequelae and are responsive to antimicrobial therapy. Nonetheless, C. difficile is associated with a high lifetime recurrence rate that ranges between 20% to 60%, most of which occur a few weeks following the successful completion of antimicrobial therapy.

• Following ingestion of C. difficile spores, patients are colonized with the organism.
• Typically, young healthy individuals with adequate immune responses are able to clear the organism without development of any clinical manifestations.
• In contrast, patients with risk factors, such as recent antibiotic use, recent hospitalization, advanced age, or immunodeficiency, are more predisposed to persistent colonization and/or develop signs and symptoms of the infection.
• The carrier stage may be as short as 2 hours following antibiotic administration to several months.^[1][2]

• The onset of clinical manifestations may occur within 2 hours up to several months following antibiotic administration.^[2]
• Patients typically develop mild/moderate watery diarrhea (possibly bloody) associated with colicky diffuse abdominal pain, nausea, malaise, and low-grade fever.^[2]
• Diarrhea typically persists for more than 2 days, and patients commonly develop colitis with or without pseudomembrane formation.
• A minority of patients do not develop diarrhea. Instead, stool analysis demonstrating increased stool leukocytes may be the only clinical manifestation.^[3]

• If left untreated, patients may develop pseudomembranous colitis, which is characterized by the development of yellowish plaques in the colorectal mucosa.
• Clinical manifestations include abdominal pain, watery diarrhea, and fever with worsening symptoms, dehydration, and further elevation in the concentration of inflammatory markers.^[3]

• In the minority of patients (approximately 3%), clinical manifestations may persist, and C. difficile infection may have a complicated course.
• Fulminant colitis, extracolonic manifestations, and death have been more frequently reported since the emergence of the hypervirulent C. difficile strain.^[3]

• Approximately one-fourth of patients adequately treated with antimicrobial therapy develop recurrence within 4 weeks of therapy completion.^[4]
• Approximately 20-60% of patients experience a lifetime recurrence of C. difficile infection with a new strain following successul completion of antimicrobial therapy.^[4][5]

• Fulminant colitis: A relatively rare, but fatal, complication of C. difficile infection. Manifestations typically include worsening abdominal pain, prolonged ileus, megacolon, and high-grade fever.

If left untreated, C. difficile infection may progress, and patients may develop extracolonic complications^[6][3][7]:

• Pseudomembrane formation in small intestine
• Ulcer formation in the small intestine
• Ileal-pouch anal anastomosis
• Dehydration
• Acute kidney injury

• Bacteremia
• Reactive arthritis
• Tenosynuvitis
• Visceral (e.g. splenic abscess) or intraabdominal abscess
• Appendicitis
• Cellulitis
• Necrotizing fasciitis
• Prosthetic device infection
• Osteomyelitis
• Empyema
• Death

• The majority of patients with C. difficile infection recover without sequelae and are responsive to antimicrobial therapy.
• Patients with comorbidities and risk factors, such as immunodeficiency or inflammatory bowel disease, are at an increased risk of developing complications.
• C. difficile is associated with a high lifetime recurrence rate that ranges between 20% to 60%. Patients are not necessarily reinfected with the same strain.
• The majority of recurrent cases occur within a few weeks of successful completion of antimicrobial therapy.

Template:WH Template:WS