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Clostridium Difficile

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Clostridium Difficile

Clostridium difficile
C. difficile colonies on a blood agar plate
Micrograph of Clostridium difficile
Scientific classification
Kingdom: Bacteria
Phylum: Firmicutes
Class: Clostridia
Order: Clostridiales
Family: Clostridiaceae
Genus: Clostridium
Species: C. difficile
Binomial name
Clostridium difficile
Hall & O'Toole, 1935

Clostridium difficile (pronunciation below) (from the Greek kloster (κλωστήρ), 'spindle', and Latin difficile, 'difficult, obstinate'),[1] also known as "CDF/cdf", or "C. diff", is a species of Gram-positive spore-forming bacterium that is best known for causing antibiotic-associated diarrhea (AAD). While it can be a minor normal component of colonic flora, the bacterium is thought to cause disease when competing bacteria in the gut have been wiped out by antibiotic treatment.[2] In severe cases, C. difficile can cause "pseudomembranous colitis," a severe inflammation of the colon.

C. difficile infection is a growing problem in inpatient healthcare facilities. Outbreaks occur when patients accidentally ingest spores of the bacteria while they are patients in a hospital (where 14,000 people a year in America alone die as a result),[3] nursing home, or similar facility. When the bacteria are in a colon in which the normal gut flora has been destroyed (usually after a broad-spectrum antibiotic such as clindamycin has been used), the gut becomes overrun with C. difficile. This overpopulation is harmful because the bacteria release toxins that can cause bloating and diarrhea, with abdominal pain, which may become severe. C. difficile infections are the most common cause of pseudomembranous colitis, and in rare cases this can progress to toxic megacolon, which can be life-threatening.

Latent symptoms of C. difficile infection often mimic some flu-like symptoms and can mimic disease flare in patients with inflammatory bowel disease-associated colitis.[4] Mild cases of C. difficile infection can often be cured by discontinuing the antibiotics responsible.[5] In more serious cases, oral administration of, first, oral metronidazole and—if that fails—then, second, vancomycin and if unsuccessful again, intravenous metronidazole can be used. Relapses of C. difficile AAD have been reported in up to 20% of cases.[5]

Signs and symptoms

Symptoms range from mild diarrhea to severe life-threatening colitis.[6] In adults, a clinical prediction rule found the best signs to be: significant diarrhea ("new onset of more than three partially formed or watery stools per 24-hour period"), recent antibiotic exposure, abdominal pain, fever (up to 40.5°C or 105°F), and a distinctive foul stool odour. In a population of hospitalized patients, prior antibiotic treatment plus diarrhea or abdominal pain had a sensitivity of 86% and a specificity of 45%.[7] In this study with a prevalence of positive cytotoxin assays of 14%, the positive predictive value was 20% and the negative predictive value was 95%.


With the introduction of broad-spectrum antibiotics and chemotherapeutic antineoplastic drugs in the second half of the 20th century, antibiotic- and chemotherapy-associated diarrhea became more common. Pseudomembranous colitis was first described as a complication of C. difficile infection in 1978,[8] when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met.

The many spores formed by C. difficile are resistant to most routine cleaning methods used on surfaces (except for diluted bleach). Spores of these bacteria can remain viable outside of the human body for very long periods of time, and this means the patients in a medical facility are often exposed to situations where they end up accidentally ingesting spores. Extremely rigorous infection protocols are required to decrease or eliminate this risk.[9]

C. difficile infection (CDI) can range in severity from asymptomatic to severe and life-threatening, especially among the elderly. People are most often nosocomially infected in hospitals, nursing homes, or other medical institutions, although CDI in the community, outpatient setting is increasing. The rate of C. difficile acquisition is estimated to be 13% in patients with hospital stays of up to two weeks, and 50% in those with hospital stays longer than four weeks.[10] C. difficile-associated diarrhea (CDAD) is most strongly associated with fluoroquinolones, cephalosporins, carbapenems, and clindamycin.[11][12][13] In addition to previous use of antimicrobials, use of proton-pump inhibitors (PPI) is associated with a two-fold increase in risk for CDI.[14]

The European Center for Disease Prevention and Control recommend the fluoroquinolones and the antibiotic clindamycin be avoided in clinical practice due to their high association with subsequent CDIs. Frequency and severity of C. difficile colitis remains high and seems to be associated with increased death rates. Immunocompromised status and delayed diagnosis appear to result in elevated risk of death. Early intervention and aggressive management are key factors to recovery.

Increasing rates of community-acquired CDI are associated with the use of medication to suppress gastric acid production: H2-receptor antagonists increased the risk 1.5-fold, and proton pump inhibitors by 1.7 with once-daily use and 2.4 with more than once-daily use.[15]

The emergence of a new, highly toxic strain of C. difficile, resistant to fluoroquinolone antibiotics, such as ciprofloxacin (Cipro) and levofloxacin (Levaquin), said to be causing geographically dispersed outbreaks in North America was reported in 2005.[16] The U.S. Centers for Disease Control (CDC) in Atlanta warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.[17]

In 2005, molecular analysis led to the identification of the C. difficile strain type characterized as group BI by restriction endonuclease analysis (REA), as North American pulse-field-type NAP1 by pulse-field gel electrophoresis (PFGE) and as ribotype 027; the differing terminology reflects the predominant techniques that were used for epidemiological typing, and this strain is referred to as C. difficile BI/NAP1/027.[18]

Some research suggests the overuse of antibiotics in the raising of livestock for meat consumption is contributing to outbreaks of bacterial infections such as C. difficile.[19]


Clostridia are motile bacteria, ubiquitous in nature, and especially prevalent in soil. Under the microscope, clostridia appear as long, irregularly (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 can tolerate extreme conditions that the active bacteria cannot tolerate.[5]

C. difficile is a commensal bacterium of the human intestine in 2–5% of the adult population.[5] Long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased colonization.[20] In small numbers, C. difficile does not result in significant disease. Antibiotics, especially those with a broad spectrum of activity (such as clindamycin) cause disruption of normal intestinal flora, leading to an overgrowth of C. difficile, which flourishes under these conditions. This can lead to pseudomembranous colitis, the generalized inflammation of the colon and the development of "pseudomembrane", a viscous collection of inflammatory cells, fibrin, and necrotic cells.[5]

Pathogenic C. difficile strains produce several known toxins. The most well-characterized are enterotoxin (Clostridium difficile toxin A) and cytotoxin (Clostridium difficile toxin B), both of which are responsible for the diarrhea and inflammation seen in infected patients, although their relative contributions have been debated.[5] 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.[21] Another toxin, binary toxin, has also been described, but its role in disease is not yet fully understood.[22]

Antibiotic treatment of CDIs can be difficult, due both to antibiotic resistance and physiological factors of the bacteria itself (spore formation, protective effects of the pseudomembrane).[5] Pseudomembranous colitis caused by C. difficile is treated with specific antibiotics, for example, vancomycin (Vancocin) or metronidazole (Flagyl).

C. difficile is transmitted from person to person by the fecal-oral route. However, the organism forms large numbers of heat-resistant spores, and these are not killed by alcohol-based hand cleansers or routine cleaning of surfaces. Thus, these spores remain viable in the hospital or nursing home environment for long periods of time, and, because of this, the bacteria can be cultured from almost any surface in the hospital. Once spores are ingested by a patient, they pass through the stomach unscathed because of their acid-resistance. They germinate into vegetative cells in the colon upon exposure to bile acids, and multiply.

Several disinfectants commonly used in hospitals are ineffective against C. difficile spores, and may actually promote spore formation. However, disinfectants containing bleach are effective in killing the organisms.[23]


Cytotoxicity assay

C. difficile toxins have a cytopathic effect in cell culture, and neutralized with specific anti-sera is the practical gold standard for studies investigating new CDAD diagnostic techniques.[5] Toxigenic culture, in which organisms are cultured on selective medium and tested for toxin production, remains the gold standard and is the most sensitive and specific test, although it is slow and labour-intensive.[24]


Assessment of the A and B toxins by enzyme-linked immunosorbent assay (ELISA) for toxin A or B (or both) has a sensitivity of 63–99% and a specificity of 93–100%: At a prevalence of 15%, this leads to a positive predictive value (PPV) of 73% and a negative predictive value (NPV) of 96%.

Previously, experts recommended sending as many as three stool samples to rule out disease if initial tests are negative. However, evidence suggests that repeat testing during the same episode of diarrhea is of limited value and should be discouraged.[25] C. difficile toxin should clear from the stool of previously infected patients if treatment is effective. However, many hospitals test only for the prevalent toxin A. Strains that express only the B toxin are now present in many hospitals, and ordering both toxins should occur.[26][27] Not testing for both may contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes.

Other stool tests

Stool leukocyte measurements and stool lactoferrin levels have also been proposed as diagnostic tests, but may have limited diagnostic accuracy.[28]


Testing of stool samples via real time polymerase chain reaction is able to pick up the disease about 90% of the time and when positive is wrongly positive about 4% of the time.[29]


One experimental technique for detecting Clostridium difficile is based on the observation that nurses were able to smell a faint but distinctive Clostridium difficile smell on affected patients' stools. It was then found that it was possible to train sniffer dogs to detect this smell on patients without taking a sample, with high specificity. An example is Cliff the Beagle, as the dog is known in the Netherlands, a succeeded experiment of the Vrije Universiteit in Amsterdam.[30]



The most effective method for preventing CDAD is proper antimicrobial prescribing. In the hospital setting, where CDAD is most common, nearly all patients that develop CDAD are exposed to antimicrobials. Although proper antimicrobial prescribing sounds easy to do, approximately 50% of antimicrobial use is considered inappropriate. This is consistent whether in the hospital, clinic, community, or academic setting. Several studies have demonstrated a decrease in CDAD by limiting antibiotics most strongly associated with CDAD or by limiting unnecessary antimicrobial prescribing in general, both in outbreak and non-outbreak settings.


There is some evidence that probiotics may be useful to prevent infection and recurrence.[31][32] Treatment with S. boulardii in those who are non-immunocompromised with C Diff may also be useful.[33][34] In 2010 the Infectious Diseases Society of America recommended against their use due to the risk of complications.[31][33] Subsequent reviews however did not find an increase in adverse effects with treatment[32] and overall treatment appears safe.[35]

Infection control

Infection control measures, such as wearing gloves when caring for patients with CDAD, have been proven to be effective at prevention. This works by limiting the spread of C. difficile in the hospital setting. In addition, washing with soap and water will eliminate the spores from contaminated hands, but alcohol-based hand rubs are ineffective.[36] Bleach wipes containing 0.55 percent sodium hypochlorite have been shown to kill the spores and prevent transmission between patients.[37] Installing lidded toilets and closing the lid prior to flushing also reduces the risk of contamination.[38]

Hydrogen peroxide vapor (HPV) systems used to sterilize a patient room post discharge has been shown to reduce infection rates and to reduce risk of infection to subsequent patients. One study (Boyce et al. 2008) showed that incidence of CDAD was reduced by 53% though use of HPV. A second study (Manian et al. 2010) showed a 42% reduction in CDAD rates through use of HPV.


In a limited clinical trial, a C. difficile anti-toxoid vaccine was reported to improve people's outcomes. Further testing will be required to validate this trial.[39]


Asymptomatic colonization with C. difficile is common. Treatment in those without symptoms is controversial. In general, mild cases do not require specific treatment.[5][40] Oral rehydration therapy is useful in treating dehydration associated with the diarrhea.


A number of different antibiotics are used for C. difficile with the available agents being more or less equally effective.[41]

  • Metronidazole is typically the initial drug of choice, because of lower price.[33]
  • Oral vancomycin is second line for mild to moderate cases and is recommended first line for severe disease.[33] Vancomycin and metronidazole; however, appear to be equally effective.[42]
  • Fidaxomicin has been found to be equally effective as vancomycin in those with mild to moderate disease.[43] It is tolerated as well as vancomycin[44] and may have a lower risk of recurrence.[41] It may be used in those who have recurrent infections and have not responded to the other antibiotics.[43]

Drugs used to slow or stop diarrhea such as loperamide may worsen C. difficile disease and are thus not recommended.[45] Cholestyramine, an ion exchange resin, is effective in binding both Toxin A and B, slowing bowel motility and helping prevent dehydration.[46] Cholestyramine is not recommended with vancomycin. A last-resort treatment in those who are immunosuppressed is intravenous immunoglobulin (IVIG).[46]


There is insufficient evidence to support the use of probiotics in the treatment of active disease.[33][47] and thus in this situation they are neither recommended as an add-on to standard therapy or for use alone.[48]

Stool transplant

Fecal bacteriotherapy, known in colloquial terms as stool transplant, is about 90% effective in those in whom antibiotics have not worked.[49] It involves infusion of bacterial flora acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection.[50] The procedure replaces normal, healthy colonic flora that had been wiped out by antibiotics, and reestablishes the persons resistance to colonization by Clostridium difficile.[51]


In those with severe C. dif colitis, colectomy may improve the outcomes.[52] Specific criteria may be used to determine who will benefit most from surgery.[53]


After a first treatment with metronidazole or vancomycin, Clostridium difficile recurs in about 20% of people. This increases to 40% and 60% with subsequent recurrences.[54]


Initially named Bacillus difficilis by Hall and O'Toole in 1935 because it was resistant to early attempts at isolation and grew very slowly in culture, it was renamed in 1970.[54][55]

Society and culture


Scientific names of organisms are Latin or Latinised Greek, in this case one of each. The anglicized pronunciation /klɒsˈtrɪdiəm dɨˈfɪsɨl/ is common, though a more classical /dɨˈfɪkɨl/ is also used. A common practice has developed of pronouncing difficile as /dfiˈsl/, as though it were French. The pronunciation varies because this is an example of international scientific vocabulary (ISV). The classical Latin sound is /dɨˈffɪkɨle/. One may also hear Spanish-influenced sound /diˈ and Italian- or church-Latin-influenced sound /dɪfˈfi.tʃi.le/.

Notable outbreaks

  • 4 June 2003, two outbreaks of a highly virulent strain of this bacterium were reported in Montreal, Quebec and Calgary, Alberta, in Canada. Sources put the death count as low as 36 and as high as 89, with approximately 1,400 cases in 2003 and within the first few months of 2004. C. difficile infections continued to be a problem in the Quebec healthcare system in late 2004. As of March 2005, it had spread into the Toronto, Ontario area, hospitalizing 10 people. One died while the others were being discharged.
  • A similar outbreak took place at Stoke Mandeville Hospital in the United Kingdom between 2003 and 2005. The local epidemiology of C. difficile may offer clues on how its spread may relate to the amount of time a patient spends in hospital and/or a rehabilitation center. It also samples institutions' ability to detect increased rates, and their capacity to respond with more aggressive hand-washing campaigns, quarantine methods, and availability of yogurt containing live cultures to patients at risk for infection.
  • It has been suggested that both the Canadian and English outbreaks were related to the seemingly more virulent Strain NAP1/027 of bacterium. This novel strain, also known as Quebec strain, has also been implicated in an epidemic at two Dutch hospitals (Harderwijk and Amersfoort, both 2005). A theory for explaining the increased virulence of 027 is that it is a hyperproducer of both toxins A and B, and that certain antibiotics may actually stimulate the bacteria to hyperproduce.
  • 1 October 2006, C. difficile was said to have killed at least 49 people at hospitals in Leicester, England over eight months, according to a National Health Service investigation. Another 29 similar cases were investigated by coroners.[56] A UK Department of Health memo leaked shortly afterwards revealed significant concern in government about the bacterium, described as being "endemic throughout the health service"[57]
  • 27 October 2006, nine deaths were attributed to the bacterium in Quebec, Canada.[58]
  • 18 November 2006, the bacterium was reported to have been responsible for 12 deaths in Quebec, Canada. This 12th reported death was only two days after the St. Hyacinthe's Honoré Mercier announced that the outbreak was under control. Thirty-one patients were diagnosed with Clostridium difficile. Cleaning crews took measures in an attempt to clear the outbreak.[59]
  • C. difficile was mentioned on 6,480 death certificates in 2006 in UK.[60]
  • 27 February 2007, a new outbreak was identified at Trillium Health Centre in Mississauga, Ontario, where 14 people were diagnosed with the bacteria. The bacteria were of the same strain as the one in Quebec. Officials have not been able to determine whether C. difficile was responsible for deaths of four patients over the prior two months.[61]
  • Between February and June 2007, three patients at Loughlinstown Hospital in Dublin, Ireland were found by the coroner to have died as a result of C. difficile infection. In an inquest, the Coroner's Court found that the hospital had no designated infection control team or consultant microbiologist on staff.[62]
  • Between June 2007 and August 2008, Northern Health & Social Care Trust Northern Ireland. Anrtim Area, Braid Valley, Mid Ulster Hospitals. During the enquiry expert reviewers concluded that Clostridium Difficile was implicated in 31 of these deaths, as the underlying cause in 15 and as a contributory cause in 16. During the time period the review also noted 375 instances of Clostridium Difficile infection in patients.[63]
  • November 2007, the 027 strain spread into several hospitals in southern Finland, with ten deaths out of 115 infected patients reported on 2007-12-14.[66]
  • November 2009, four deaths at Our Lady of Lourdes Hospital in Ireland, have possible links to Clostridium difficile infection. A further 12 patients tested positive for infection, and another 20 show signs of infection, 10 November 2009.[67]
  • March 2010, From February 2009 to February 2010 199 patients at Herlev hospital in Denmark was suspected of being infected with the 027 strain. In the first half of 2009, 29 died in hospitals in Copenhagen after they were infected with the bacterium[68]
  • May 2010, A total of 138 patients at four different hospitals in Denmark infected with the 027 strain ( Herlev, Amager, Gentofte and Hvidovre) plus some isolated occurrences at other hospitals.[69]
  • May 2010, Fourteen people killed in the Australian state of Victoria. Two years later the same strain of the bug was detected in New Zealand.[70]
  • 28 May 2011 an outbreak in Ontario, Canada has been reported, with 26 fatalities as of 24 July 2011.[71]


Genome sequencing

The first complete genome sequence of a Clostridium difficile strain was first published in 2005 by Sanger Institute in the UK. This was of the C. difficile strain 630, a virulent and multidrug-resistant strain isolated in Switzerland in 1982. Scientists at Sanger Institute have also recently sequenced genomes of about 30 Clostridium difficile isolates using next generation sequencing technologies from 454 Life Sciences and Illumina.[72]

Researchers at McGill University in Montreal, Quebec, Canada, 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.[16][73]

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.[74]


  • CDA-1 and CDB-1 (also known as MDX-066/MDX-1388 and MBL-CDA1/MBL-CDB1) is an investigational, monoclonal antibody combination co-developed by Medarex and Massachusetts Biologic Laboratories (MBL) to target and neutralize C. difficile toxins A and B, for the treatment of CDI. Merck & Co., Inc. gained worldwide rights to develop and commercialize CDA-1 and CDB-1 through an exclusive license agreement signed in April 2009. It is intended as an add-on therapy to one of the existing antibiotics to treat CDI.[75][76][77]
  • Nitazoxanide is a synthetic nitrothiazolyl-salicylamide derivative indicated as an antiprotozoal agent (FDA-approved for the treatment of infectious diarrhea caused by Cryptosporidium parvum and Giardia lamblia) and is also currently being studied in C. difficile infections vs. vancomycin.[78]
  • Rifaximin,[78] is a clinical-stage semi synthetic, rifamycin-based non-systemic antibiotic for CDI. It is FDA-approved for the treatment of infectious diarrhea and being developed by Salix Pharmaceuticals.
  • Rifalazil,[78]
  • Tigecycline[78] and
  • Ramoplanin.[78]

See also


External links


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