Clostridium difficile
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| Clostridium difficile Hall & O'Toole, 1935 |
Clostridium difficile (pronunciation ▶(?)) is a species of bacteria of the genus Clostridium which are gram-positive, anaerobic spore-forming rods. They cause pseudomembranous colitis, a severe infection of the colon, often after normal gut flora is eradicated by the use of antibiotics. Treatment is by stopping putative antibiotics and commencing specific anticlostridial antibiotics, e.g. metronidazole.
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Bacteriology
Characteristics
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, while its spores are gram negative. Clostridium shows optimimum 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.
C. difficile is an inhabitant of the human intestine, but normally behaves as a commensal without causing disease of any significance. Antibiotics, especially those with a broad spectrum of activity, cause disruption on normal intestinal flora. 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.
Toxins
Pathogenic strains elaborate one of two toxins, toxin A or B. These toxins are responsible for the diarrhea and inflammation seen in patients so infected.
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 (Larson et al), when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met.
Infection can range in severity from asymptomatic to severe and life threatening, and deaths have been reported. People are most often infected in hospitals, nursing homes or institutions, although C. difficile infection in the community, outpatient setting is increasing. Clostridium difficile overgrowth has been linked to use of broad-spectrum antibiotics such as cephalosporins and clindamycin, which are frequently used in hospital setting. 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.
Diagnosis and treatment
There has been debate about the emergence of a resistant strain: certain strains that express only the Toxin B are now present in many hositals and caution as to ordering both toxins should occur, in that many laboratories only test for the more prevalant Toxin A. This can contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes. Often clinicians begin treatment before results have come back based on clinical presentation to prevent such occurrences. Knowledge of the local epidemiology of intestinal flora of a particular institution can guide therapy. 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.
Patients should be treated as soon as possible when the diagnosis of CDC is made to avoid frank sepsis or bowel perforation. In a recent study, a patient who received a diagnosis of CDC on the basis of CT scan had an 88% probability of testing positive on stool assay. Wall thickening is the key CT finding in this disease. Once colon wall thickening is identified as being >4 mm, ancillary findings of pericolonic stranding, ascites, and colon wall nodularity increase the specificity of CDC with additive effects. 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. Patients who have antibiotic-associated diarrhea who have CT findings diagnostic of CDC merit consideration for treatment on that basis.
In those patients that develop systemic symptoms of Clostridium difficile colitis, colectomy may improve the outcome if performed before the need for vasopressors.
Pharmacology
Two antibiotics are effective against C. difficile. Metronidazole is first choice because of superior tolerability, lower price and comparable efficacy. Oral vancomycin can be used as well but is avoided due to theoretical concerns of converting intestinal flora into vancomycin resistant organisms. Such a selection out of organisms can create a larger problem with nosocomial infections, in addition to existing rates of methicillin resistance which is now being reported in almost all hospitals in North America and Europe. Furthermore, medicines traditionally used to stop diarhea paradoxically worsen the course of C. difficile. Loperamide and bismuth compounds are contraindicated in C. difficile colitis. 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. The dosage can be 4 grams daily, to up to four doses a day: caution should be excersised to prevent constipation, or drug interactions, most notably the binding of medicines by colestyramine, preventing their absorption.
Notable outbreaks
On June 4, 2004, 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 has spread into the Toronto, Ontario area, hospitalizing 10 people. One has died while the others have been released.
A similar outbreak has happened in Stoke Mandeville Hospital in the United Kingdom between 2003 and 2005. The local epidemiology of Clostridium difficile represents clues on how spead may be related to amount of time a patient may be institutionalized in hospital and or rehabilitation center. It also samples institutions' ability to notice increased rates, and respond by instituting more aggressive hand washing campaigns, quarenteen methods, and availability of yogurt to patients at risk for infection.
Both the Canadian and English outbreaks have been related to the seemingly more virulent 027 strain. This strain is now also implicated in an epidemic at 2 Dutch hospitals (Harderwijk and Amersfoort, both 2005). The theory of 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.
The emergence of Clostridium difficile that is resistant to either metronidazole or vancomycin has been reported as very rare. The emergence of strains of Clostridium difficile that are more contagious has been recorded. So as one analyzes the pool of patients with the spores, many who are asymtomatic will pass the organism to individuals who are immunocompromised and hence, susceptable to increasing rates of diahrea 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.
The evolution of protocols for patients with recurrent Clostridium difficile diarrhea has also presented a challenge: there is no universal regiment of length of time one should be treated who has recurrent disease, and what additional medicines should be added. Medicines such as rifampin and cholestyramine have been proposed, as well as, bio engineered lactobacillus that grows faster, have been made available. Saccharomyces boulardii (Brewers Yeast) mixed in with some apple juice and yogurt has also helped.
References
- Hall I, O'Toole E. Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child 1935;49:390.
- Larson HE, Price AB, Honour P, Borriello SP. Clostridium difficile and the aetiology of pseudomembranous colitis. Lancet 1978;1(8073):1063-6. PMID 77366.
- Fulminant Clostridium difficile: An Underappreciated and Increasing Cause of Death and Complications. Ann Surg 2002; 235 (March): 363-372
- Kirkpatrick IDC, Greenberg HM:AJR 2001; 176 (March): 635-639
- Yamada, Tadataka "Textbood of Gastroenterology" fourth edition: 1870-1875
- Lectures on the Markov method method in healthcare [1]
