- Signs & Symptoms
What is Clostridium difficile (C. difficile)?
Clostridium difficile (C. difficile) is a bacterium that is related to the bacteria that cause tetanus and botulism. The C. difficile bacterium has two forms, an active, infectious form that cannot survive in the environment for prolonged periods, and an inactive, "noninfectious" form, called a spore, that can survive in the environment for prolonged periods. Although spores cannot cause infection directly, when they are ingested they transform into the active, infectious form.
C. difficile spores are found frequently in the following:
They can be found on the following:
- Toilet seats
- Rings (Jewelry)
- Infants' rooms
- Diaper pails
They even can be carried by pets. Thus, these environments are a ready source for infection with C. difficile.
What causes Clostridium difficile colitis?
Antibiotic-associated (C. difficile, C. diff) colitis is an infection of the colon caused by C. difficile that occurs primarily among individuals who have been using antibiotics. C. difficile infections are commonly acquired during hospital stays, infecting approximately 1% of patients admitted to hospitals in the United States. C. difficile may also be acquired in the community, however.
It is the most common infection acquired by patients while they are in the hospital. More than half a million C. difficile infections occur in hospitals in the US each year, with about 300,000 occurring while in the hospital or shortly after hospitalization. After a stay of only 2 days in a hospital, 10% of patients will develop an infection with C. difficile. C. difficile also may be acquired outside of hospitals in the community. It is estimated that about 200,000 infections with C. difficile occur in the community unrelated to hospitalization each year in the U.S.
Which antibiotics cause Clostridium difficile colitis?
Although the antibiotic clindamycin (Cleocin) has been widely recognized as causing C. difficile colitis, many commonly prescribed antibiotics also cause colitis. Examples of antibiotics that frequently cause C. difficile colitis include:
Antibiotics that occasionally cause C. difficile colitis include:
Antibiotics that rarely if ever cause C. difficile colitis include:
- metronidazole (Flagyl)
- vancomycin (Vancocin)
- aminoglycosides (such as gentamicin [Garamycin])
Metronidazole and vancomycin are two antibiotics that are used for treating C. difficile colitis; however, there are rare reports of C. difficile colitis occurring several days after stopping metronidazole.
While most C. difficile colitis in the US is caused by antibiotics, C. difficile colitis also can occur in patients without exposure to antibiotics. For example, patients with ulcerative colitis and Crohn's disease have been known to develop C. difficile colitis without exposure to antibiotics.
Since many antibiotics can cause C. difficile infection, all antibiotics should be used prudently. Self-administration or using antibiotics without an accurate diagnosis or a proper reason should be discouraged. On the other hand, the benefits of properly prescribed antibiotics for the right reasons usually far outweigh the risk of developing C. difficile colitis.
Antibiotics can sometimes cause diarrhea that is not due to C. difficile infection. The reason for the diarrhea is not clear. The practical implication is that not all diarrhea associated with antibiotics should be considered to be due to C. difficile and treated as such.
How does C. diff cause colitis?
C. difficile spores lie dormant inside the colon until a person takes an antibiotic. The antibiotic disrupts the other bacteria that normally are living in the colon and prevents C. difficile from transforming into its active, disease-causing bacterial form. As a result, C. difficile transforms into its infectious form and then produces toxins (chemicals) that inflame and damage the colon. The inflammation results in an influx of white blood cells to the colon. The severity of the colitis can vary. In the more severe cases, the toxins kill the tissue of the inner lining of the colon, and the tissue falls off. The tissue that falls off is mixed with white blood cells (pus) and gives the appearance of a white, membranous patch covering the inner lining of the colon. This severe form of C. difficile colitis is called pseudomembranous colitis because the patches appear like membranes, but they are not true membranes.
Not everybody infected with C. difficile develops colitis. Many infants and young children, and even some adults, are carriers (they are infected but have no symptoms) of C. difficile. C. difficile does not cause colitis in these people probably because of the following:
- The bacteria stay in the colon as non-active spores
- The individuals have developed antibodies that protect them against the C. difficile toxins
What are the signs and symptoms of Clostridium difficile colitis?
Patients with mild C. difficile colitis may have:
Patients with severe C. difficile colitis may have:
- A high fever of 102 F to 104 F (39 C to 40 C)
- Severe diarrhea (more than 10 watery stools a day) with blood
- Severe abdominal pain and tenderness
Severe diarrhea also can lead to dehydration and disturbances in the electrolytes (minerals) in the body. Rarely, severe colitis can lead to life-threatening complications such as toxic megacolon (markedly dilated colon), peritonitis (inflammation of the lining of the abdominal), and perforation of the colon.
How do medical professionals diagnose C. diff colitis?
A history of antibiotic use is important in the diagnosis of C. difficile colitis. Patients taking antibiotics (or recently having taken antibiotics) who develop abdominal pain, cramps, and diarrhea are usually tested for C. difficile infection. However, doctors do not always wait for the appearance of diarrhea to start testing for C. difficile since in rare instances C. difficile can cause abdominal pain and tenderness without diarrhea.
Patients with C. difficile colitis often have elevated white blood cell counts in the blood, and, in severe colitis, the white blood cell counts can be very high (20,000 to 40,000). Patients with C. difficile colitis also often have white blood cells in their stool when a sample of stool is examined under a microscope. Elevated white blood cell counts and white blood cells in the stool, however, only demonstrate that there is colitis and not that the cause of the colitis is C. difficile. More specific tests are necessary to determine whether C. difficile is the cause of the colitis.
The most widely used test for diagnosing C. difficile colitis is a test that detects toxins produced by C. difficile in a sample of stool. There are two different toxins, toxin A and toxin B, both capable of causing colitis. Accurate tests for both toxins are available commercially for use in all laboratories. Unfortunately, like most tests in medicine, these tests for toxins are not perfect; both false positive tests (finding toxins when there is no C. difficile) and false negative tests (not finding toxins when C. difficile is present) can occur. Therefore, other tests such as flexible sigmoidoscopy and colonoscopy often are necessary to look for pseudomembranes that are characteristic of C. difficile colitis.
Flexible sigmoidoscopy and colonoscopy
Flexible sigmoidoscopy is an examination in which a doctor inserts a flexible fiberoptic tube with a light and a camera on its end into the rectum and sigmoid colon. (The sigmoid colon is the segment of the colon that is closest to the rectum.) In most patients with C. difficile colitis, the doctor will find pseudomembranes in the rectum and the sigmoid colon. However, some patients with C. difficile colitis will have pseudomembranes only in the right colon (the segment of the colon farthest from the rectum). Patients with pseudomembranes confined to the right colon require a colonoscopy to see the pseudomembranes. (A colonoscope is a longer version of the flexible sigmoidoscope that is long enough to reach the right colon.)
X-ray examinations and computerized tomography (CT) examinations of the abdomen will occasionally demonstrate thickening of the wall of the colon due to inflammation, but these X-ray findings also are non-specific and only demonstrate that colitis is present. They do not demonstrate the cause of the colitis, for example, C. difficile.
What is the treatment for Clostridium difficile colitis?
Treatment of C. difficile colitis includes the following:
- Correction of dehydration and electrolyte (mineral) deficiencies
- Discontinuing the antibiotic that caused the colitis
- Using antibiotics to eradicate the C. difficile bacterium
In patients with mild colitis, stopping the antibiotic that caused the infection may be enough to cause the colitis and diarrhea to subside. In most cases, however, antibiotics are needed to eradicate the C. difficile bacteria.
Antibiotics that are effective against C. difficile include metronidazole (Flagyl) and vancomycin (Vancocin). People usually take these two antibiotics orally for 10 days. Both antibiotics are equally effective, but metronidazole is less expensive. Vancomycin is recommended in severe infections, primarily where it may be slightly more effective than metronidazole and, therefore, may be worth the additional expense. With either antibiotic, fever usually will resolve in 1-2 days, and diarrhea in 3-4 days. Several other antibiotics, some new and some older, have been used effectively against C. difficile recently, most notably fidaxomicin (Dificid). Fidaxomicin may be slightly more effective than vancomycin, but its cost is high. It has the advantage of being associated with fewer recurrences.
The choice of which antibiotic to use depends on the individual patient's situation and the preferences of the treating doctor. Some doctors will prescribe metronidazole first because it is much less expensive than vancomycin. Vancomycin may be reserved for patients who do not respond to metronidazole, are allergic to metronidazole, or develop side effects from metronidazole. Fidaxomicin, while most expensive, is associated with fewer relapses. Other doctors will prescribe vancomycin first for severe colitis because vancomycin can achieve much higher antibiotic levels in the colon than metronidazole (and higher antibiotic levels theoretically would be more effective in killing bacteria).
Why are there relapses of Clostridium difficile colitis?
Approximately 10% to 20% of successfully treated patients can experience a relapse of C. difficile colitis with a recurrence of diarrhea, abdominal cramps, and abdominal pain. Relapses typically occur days or even weeks after treatment is stopped. Some patients may experience several relapses.
The most likely explanation for relapse is that C. difficile has not been completely eradicated by the initial course of antibiotics. C. difficile in its active bacterial form is killed by either metronidazole or vancomycin, but the spores are resistant to killing. Several days after stopping antibiotics, the surviving spores transform into active bacterial forms which will multiply and produce toxins again.
Another reason for relapse is the body's inadequate production of antibodies against bacterial toxins. Antibodies are proteins that the body produces to fight bacterial, viral, and parasitic infections, as well as to protect the body from the harmful effects of toxins. Therefore, adults who are capable of producing adequate antibodies against C. difficile toxins usually do not develop C. difficile colitis. Some adults who cannot produce these antibodies are susceptible to relapses.
What are treatment options for relapses of Clostridium difficile colitis?
Treatment options for relapses of C. difficile colitis include:
- A second course of the same or a different antibiotic, primarily vancomycin or fidaxomicin
- Six weeks of treatment with decreasing doses of antibiotics
- An oral resin by mouth such as cholestyramine (Questran) binds toxins and inactivates them
- Non-pathogen (harmless) yeast by mouth such as Saccharomyces boulardii, for example, Florastor
Doctors usually treat patients who relapse with another 10-14-day course of metronidazole or vancomycin, and a majority of the patients so treated will recover. Nevertheless, some patients will have another relapse. Treatment options for multiple relapses include:
- Treatment with one of the options listed above that has not already been tried.
- Vancomycin for 6 weeks in decreasing doses (125 mg four times a day for 1 week, three times a day for another week, twice a day for another week, and so on), followed by 4 weeks of cholestyramine (Questran).
- Two weeks of vancomycin or metronidazole along with 4 weeks of S. boulardii (Florastor).
- Fecal microbiota (bacterial population) transplants are becoming more common for relapsing patients because of the great success rates. Feces from non-infected donors are made into a suspension. The source of the transplanted fecal microbiota can be healthy family members, acquaintances, or from stool banks. The fecal microbiota may be given by enema or by colonoscopy inserted into the rectum, by a feeding tube inserted through the mouth or nose into the upper small intestine, or by way of frozen capsules taken by mouth. The normal bacteria from the donor's stool displaces the C. difficile bacteria.
- Passive immunizations with human gammaglobulin have been tried, but have not been demonstrated to be consistently effective. The theory is that patients with multiple relapses typically have low levels of antibodies to C. difficile toxins. By giving patients who relapse gammaglobulin. containing large amounts of antibodies to C. difficile toxins, the patients' levels of antibodies to C. difficile toxins are increased. Pooled human gammaglobulin can be administered intravenously. However, this treatment is neither approved nor recommended.
- Active vaccination for C. difficile toxins. Vaccination can increase a patient's levels of antibodies to C. difficile toxins. This is a new treatment that has not become widely available.
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What is new in C. diff research?
The prevalence of C. difficile infection has been increasing steadily, particularly in the elderly. There have been reports from several hospitals of a newer, more virulent strain of C. difficile bacteria that produce large amounts of both toxins A and B as well as a third toxin. This strain produces more severe colitis than the usual strains. Patients infected by this strain are more seriously ill, require surgery more frequently, and die from the infection more frequently than patients infected with the usual strains. Currently, the commercially available diagnostic tests cannot distinguish this strain from the usual strains.
Traditionally, antibiotic use is often considered the most important factor for the development of C. difficile colitis. Increasingly though doctors are diagnosing C. difficile colitis in patients without previous antibiotic exposure. This is especially true in patients with Crohn's disease or ulcerative colitis. In one study of 92 patients with ulcerative colitis and Crohn's disease relapse, 10 patients tested positive for C. difficile. Another change that is occurring with C. difficile infection is that it is no longer restricted to patients in hospitals or nursing homes. A study of data from 2009 through 2011 found that community-associated C. difficile infections represent about one-third of all C. difficile colitis cases. Traditionally, antibiotic use is often considered the most important factor for the development of C. difficile colitis, but in this study, 36% of the patients had not been treated with antibiotics.
Doctors are witnessing increasing difficulty in treating C. difficile colitis. Firstly, resistance to metronidazole is on the rise. Secondly, colitis (along with symptoms of diarrhea and cramps) is taking longer to resolve and may require higher doses of vancomycin. Thirdly C. difficile colitis relapse (with recurrent diarrhea) is common. More troublesome still, many patients experience multiple relapses, often requiring prolonged (months) antibiotic (such as vancomycin) treatment.
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