Clostridium difficile

Clostridium difficile () (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. C. difficile is the most significant cause of pseudomembranous colitis ^*, 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.

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 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.

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 ^*.

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

Toxins

Pathogenic C. difficile strains produce various toxins. The most well-characterized are enterotoxin and cytotoxin, also known as toxins A and B, respectively. 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.

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.

Increasing rates of community-acquired Clostridium difficile-associated infection 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 leads to decreased destruction of spores (Dial et al 2005).

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 hospitals 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.

Pharmacotherapy

Three antibiotics are effective against C. difficile. Metronidazole 250 mg orally four times daily is the drug of choice, because of superior tolerability, lower price and comparable efficacy. 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: 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; the patient is critically ill because of C. difficile diarrhea (the duration of diarrhea is reduced to 3 versus 4.6 days with metronidazole). Vancomycin must be administrared 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 (Stroehlein 2004). 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. A last-resort treatment in immunosuppressed patients is intravenous immunoglobulin (IVIG, Stroehlein 2004).

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 one should be treated. However, retreatment 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 spp. has been found to be helpful in preventing relapse in small numbers of patients (see, for example, 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.

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 discharged.

A similar outbreak has happened in Stoke Mandeville Hospital in the United Kingdom between 2003 and 2005. The local epidemiology of C. difficile represents clues on how spread 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, quarantine 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 two 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.

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. Dr. L. Clifford McDonald of the Centers for Disease Control in Atlanta warns of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.

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, 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.

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 state-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 (Loo et al 2005).

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

References

PMID 11882758

PMID 77366.

PMID 16322602.

Martin S and Jung R. Gastrointestinal infections and enterotoxigenic poisonings. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach. 6th edition. New York: The McGraw-Hill Companies Inc; 2005;2042-2043.