Clostridium difficile

Clostridium difficile or CDF/cdf' (commonly mistaken pronunciation (help·info), alternatively and correctly pronounced /klɒsˈtrɪdiəm dɪˈfɪsɪli/) (also referred to as C. diff or C-diff) is a species of bacteria of the genus Clostridium which are Gram-positive, anaerobic, spore-forming rods (bacillus).^[1] C. difficile is the most significant cause of pseudomembranous colitis,^[2] a severe infection of the colon, often after normal gut flora is eradicated by the use of antibiotics. Treatment is by stopping any antibiotics and commencing specific anticlostridial antibiotics, e.g. metronidazole.

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Bacteriology

Clostridia are motile bacteria that are ubiquitous in nature and are especially prevalent in soil. Under the microscope after Gram staining, they appear as long drumsticks with a bulge located at their terminal ends. Clostridium difficile cells are Gram positive. Clostridium shows optimum growth when plated on blood agar at human body temperatures. When the environment becomes stressed, however, the bacteria produce spores that tolerate the extreme conditions that the active bacteria cannot. First described by Hall and O'Toole in 1935, "the difficult clostridium" was resistant to early attempts at isolation and grew very slowly in culture.^[3]

C. difficile is a commensal bacterium of the human intestine in a minority of the population. Patients who have been staying long-term in a hospital or a nursing home have a higher likelihood of being colonized by this bacterium. In small numbers it does not result in disease of any significance. Antibiotics, especially those with a broad spectrum of activity, cause disruption of normal intestinal flora, leading to an overgrowth of C. difficile. This leads to pseudomembranous colitis.

C. difficile is resistant to most antibiotics. It flourishes under these conditions. It is transmitted from person to person by the fecal-oral route. Because the organism forms heat-resistant spores, it can remain in the hospital or nursing home environment for long periods of time. It can be cultured from almost any surface in the hospital. Once spores are ingested, they pass through the stomach unscathed because of their acid-resistance. They change to their active form in the colon and multiply.

It has been observed that several disinfectants commonly used in hospitals may fail to kill the bacteria, and may actually promote spore formation. However, disinfectants containing bleach are effective in killing the organisms^[4].

Pseudomembranous colitis caused by C. difficile is treated with antibiotics, for example, vancomycin, metronidazole, bacitracin or fusidic acid.

Toxins

Pathogenic C. difficile strains produce various toxins. The most well-characterized are enterotoxin (toxin A) and cytotoxin (toxin B).^[1] These two toxins are both responsible for the diarrhea and inflammation seen in infected patients, although their relative contributions have been debated by researchers. Another toxin, binary toxin, has also been described, but its role in disease is not yet fully understood.^[5]

Role in disease

With the introduction of broad-spectrum antibiotics in the latter half of the twentieth century, antibiotic-associated diarrhea became more common. Pseudomembranous colitis was first described as a complication of C. difficile infection in 1978,^[6] when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met.

Clostridium difficile infection (CDI), can range in severity from asymptomatic to severe and life threatening, and many deaths have been reported, especially amongst the aged. People are most often infected in hospitals, nursing homes, or institutions, although C. difficile infection in the community, outpatient setting is increasing. Clostridium difficile associated diarrhea (aka CDAD) has been linked to use of broad-spectrum antibiotics such as cephalosporins and clindamycin, though the use of quinolones is now probably the most likely culprit, which are frequently used in hospital settings. 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.

The rate of Clostridium difficile acquisition is estimated to be 13 percent in patients with hospital stays of up to two weeks and 50 percent in those with hospital stays longer than four weeks.

Increasing rates of community-acquired Clostridium difficile-associated infection/disease (CDAD) has also been linked to the use of medication to suppress gastric acid production: H2-receptor antagonists increased the risk twofold, and proton pump inhibitors threefold, mainly in the elderly. It is presumed that increased gastric pH, (alkalinity), leads to decreased destruction of spores.^[7]

Diagnosis

Often clinicians begin treatment before results have come back based on clinical presentation to prevent complications. Knowledge of the local epidemiology of intestinal flora of a particular institution can guide therapy.

Symptoms and signs

In adults, a clinical prediction rule found the best signs are^[8] :

• significant diarrhea ("new onset of > 3 partially formed or watery stools per 24 hour period")
• exposure of antibiotics
• abdominal pain
• foul stool odour

The presence of any one of these findings has a sensitivity of 86% and a specificity of 45%.^[8] In this study of hospitalized patients with a prevalence of positive cytotoxin assays of 14%, the positive predictive value was 20% and the negative predictive value was 95%.

Cytotoxicity assay

C. difficile toxin detection as cytopathic effect in cell culture, and neutralized with specific anti-sera is the practical gold standard for studies investigating new CDAD diagnostic techniques. 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.^[9]

Enzyme-linked immunoabsorbant assay (ELISA) for toxin

Assessment of the A and B toxins by enzyme-linked immunoabsorbant assay (ELISA) for toxin A or B (or both) has:

• sensitivity 63-99%
• specificity 93-100%

At a prevalence of 15%, this leads to:

• positive predictive value 73%
• negative predictive value 96%

Experts recommend sending as many as three samples to rule-out disease if initial tests are negative. C. difficile toxin should clear from the stool of previously infected patients if treatment is effective.

Unfortunately, many hospitals only test for the prevalent toxin A. Strains that express only the B toxin are now present in many hospitals and ordering both toxins should occur. 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.^[10]

Computed tomography

In a recent study, a patient who received a diagnosis of CDC on the basis of computed tomography (CT scan) had an 88% probability of testing positive on stool assay.^[11] Wall thickening is the key CT finding in this disease. Once colon wall thickening is identified as being >4 mm, the best ancillary findings were:

• pericolonic stranding
• ascites
• colon wall nodularity

The presence of wall thickness plus any one of these ancillary findings yields:

• sensitivity of 70%
• specificity of 93%

Using criteria of >=10 mm or a wall thickness of >4 mm and any of the more-specific findings does not add significantly to the diagnosis but gives equally satisfactory results. In this study with a prevalence of positive C. difficile toxin of 54%, the positive predictive value was 88%. Patients who have antibiotic-associated diarrhea who have CT findings diagnostic of CDC merit consideration for treatment on that basis. A weakness of this study was not using a gold standard cytotoxicity assay.

Treatment

Many persons will also be asymptomatic and colonized with Clostridium difficile. Treatment in asymptomatic patients is controversial, also leading into the debate of clinical surveillance and how it intersects with public health policy.

It is possible that mild cases do not need treatment.^[12]

Patients should be treated as soon as possible when the diagnosis of Clostridium difficile colitis (CDC) is made to avoid frank sepsis or bowel perforation.

Pharmacotherapy

Three antibiotics are effective against C. difficile. Metronidazole 400mg orally three times daily is the drug of choice, because of superior tolerability, lower price and comparable efficacy^[13]. Oral vancomycin 125 mg four times daily is second-line therapy, but is avoided due to theoretical concerns of converting intestinal flora into vancomycin resistant organisms. However, it is used in the following cases: severe C. difficile diarrhea^[14] (the duration of diarrhea is reduced to 3 versus 4.6 days with metronidazole^{[citation needed]}); no response to oral metronidazole; the organism is resistant to metronidazole; the patient is allergic to metronidazole; the patient is either pregnant or younger than 10 years of age. Vancomycin must be administered orally because IV administration does not achieve gut lumen minimum therapeutic concentration. The use of linezolid may be considered too.

It has been known that drugs traditionally used to stop diarrhea worsen the course of C. difficile-related pseudomembranous colitis. Loperamide, diphenoxylate and bismuth compounds are indeed contraindicated, because slowing of fecal transit time is thought to result in extended toxin-associated damage. Cholestyramine, a powder drink occasionally used to lower cholesterol, is effective in binding both Toxin A and B, and slows bowel motility and helps prevent dehydration.^[15] The dosage can be 4 grams daily, to up to four doses a day: caution should be exercised to prevent constipation, or drug interactions, most notably the binding of drugs by cholestyramine, preventing their absorption. Powdered banana flakes given twice daily is an alternative to cholestyramine and allow for stool bulking. Treatment with probiotics ("good" intestinal flora) has also been shown effective. Provision of Saccharomyces boulardii (Florastor) or Lactobacillus acidophilus twice daily times 30 days along with antibiotics has been clinically shown to shorten the duration of diarrhoea. A last-resort treatment in immunosuppressed patients is intravenous immunoglobulin (IVIG).^[15]

Colectomy

In those patients that develop systemic symptoms of CDC, colectomy may improve the outcome if performed before the need for vasopressors.

Fecal bacteriotherapy

Fecal bacteriotherapy, a procedure related to probiotic research, has been suggested as a potential cure for the disease. It involves infusion of bacterial flora acquired from the feces of a healthy donor in an attempt to reverse bacterial imbalance responsible for the recurring nature of the infection. It has a success rate of nearly 95% according to some sources.^[16][17][18]

Recurrence

The evolution of protocols for patients with recurrent C. difficile diarrhea also present a challenge: there is no known proper length of time or universally accepted alternative drugs with which one should be treated. However, re-treatment with metronidazole or vancomycin at the previous dose for 10 to 14 days is generally successful. The addition of rifampin to vancomycin also has been effective. Prophylaxis with competing, nonpathogenic organisms such as Lactobacillus spp. or Saccharomyces boulardii has been found to be helpful in preventing relapse in small numbers of patients (see, for example, Florastor, or Lactinex). It is thought that these organisms, also known as probiotics, help to restore the natural flora in the gut and make patients more resistant to colonization by C. difficile.

Prevention

The most effective method for preventing CDAD is proper antimicrobial prescribing. In the hospital setting, where CDAD is most common, nearly all patients who develop CDAD are exposed to antimicrobials. Although this 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.

Infection control measures, such as wearing gloves when caring for patients with CDAD, have been proven to be effective at preventing CDAD. This works by limiting the spread of C. difficile in the hospital setting.

Treatment with various oral supplements containing live bacteria has been studied in efforts to prevent Clostridium difficile-associated infection/disease. A randomized controlled trial using a probiotic drink containing Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus was reported to have some efficacy. This study was sponsored by the company that produces the drink studied ^[19]. Although intriguing, several other studies have been unable to demonstrate any benefit of oral supplements of similar bacteria at preventing CDAD.^{[citation needed]} Of note, patients on the antibiotics most strongly associated with CDAD were excluded from this study.

Notable outbreaks

On June 4, 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 health care 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 yoghurt 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 toxin A and B, and that certain antibiotics may actually stimulate the bacteria to hyperproduce.

On December 2, 2005, The New England Journal of Medicine, in an article spearheaded by Drs. Vivian Loo, Louise Poirier, and Mark Miller, reported the emergence of a new, highly toxic strain of C. difficile, resistant to fluoroquinolone antibiotics, such as Cipro (ciprofloxacin) and Levaquin (levofloxacin), said to be causing geographically dispersed outbreaks in North America.^[20] The Centers for Disease Control in Atlanta has also warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.^[21]

As one analyzes the pool of patients with the spores, many who are asymptomatic will pass the organism to individuals who are immunocompromised and hence, susceptible to increasing rates of diarrhea and poor outcome. It seems notable that the clusters described above represent a challenge to epidemiologists trying to understand how the illness spreads via the convergence of information technology with clinical surveillance.

On October 1, 2006, the bacteria 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.^[22] 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"^[23]

On October 27, 2006, 9 deaths were attributed to the bacterium in Quebec, Canada.^[24]

On November 18th, 2006, the bacteria 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. 31 patients were diagnosed with Clostridium difficile and four (as of Sat. Nov 18th) were still under observation. Cleaning crews took measures in an attempt to clear the outbreak.^[25]

On February 27, 2007, a new outbreak was identified at Trillium Health Centre in Mississauga Ontario, where 14 people were diagnosed with the bacteria. The bacteria was the same strain as the one in Quebec. Officials have not been able to determine if C. difficile was responsible for deaths of four patients over the prior two months.^[26]

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.diff infection. In an inquest, the Coroner's Court found that the hospital had no designated infection control team or consultant microbiologist on staff. The bacteria was found to be the same strain, 027, as that in the Quebec outbreak. ^[27]

In October 2007, Maidstone and Tunbridge Wells NHS Trust was heavily criticized by the Healthcare Commission regarding its handling of a major outbreak of C. difficile in its hospitals in Kent from April 2004 to September 2006. In its report, the Commission estimated that about 90 patients "definitely or probably" died as a result of the infection. ^[28][29]

In November 2007, the 027 strain has spread into several hospitals in southern Finland, with ten deaths out of 115 infected patients reported on 2007-12-14. ^[30]

Cracking of the genetic code of the Quebec strain

On December 14, 2005, researchers at McGill University in Montreal, Quebec, led by Dr. Ken Dewar and Dr. Andre Dascal and in collaboration with province-organized NPO Genome Quebec's research facility, announced they had cracked the genetic code of the highly virulent Quebec strain of C. difficile. This was accomplished by using ultra high-throughput sequencing technology. The tests involved doing 400,000 DNA parallel sequencing reactions which took the bacterium's genome apart and reassembled it so it could be studied.^[20][31]

It is expected this will allow quicker detection of the disease and better treatment.

References

Further reading

• Dallal R, Harbrecht B, Boujoukas A, Sirio C, Farkas L, Lee K, Simmons R (2002). "Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications". Ann Surg 235 (3): 363-72. PMID 11882758.

• Martin S, Jung R (2005). Gastrointestinal infections and enterotoxigenic poisonings. In: Pharmacotherapy: A Pathophysiologic Approach (DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors)., 6th ed., McGraw-Hill, pp. 2042-2043. ISBN. 

• McDonald L, Killgore G, Thompson A, Owens R, Kazakova S, Sambol S, Johnson S, Gerding D (2005). "An epidemic, toxin gene-variant strain of Clostridium difficile". N Engl J Med 353 (23): 2433-41. PMID 16322603.

• Yamada T; Alpers DH (editors) (2003). Textbook of Gastroenterology, 4th ed., Lippincott Williams & Wilkins, pp. 1870-1875. ISBN 0-7817-2861-4. 

• van den Hof S, van der Kooi T, van den Berg R, Kuijper E, Notermans D (2006). "Clostridium difficile PCR ribotype 027 outbreaks in the Netherlands: recent surveillance data indicate that outbreaks are not easily controlled but interhospital transmission is limited". Euro Surveill 11 (1): E060126.2. PMID 16801713.

• Sunenshine R, McDonald L (2006). "Clostridium difficile-associated disease: New challenges from an established pathogen". Cleveland Clinic J. Med. 73: 187.

See also

• Nosocomial infection