Clostridium Difficile
(C. difficile, C. diff)

• Clostridium difficile (or C. difficile, C. diff) colitis is a common infection of the colon that is typically associated with the use of antibiotics. It is, therefore, also called antibiotic-associated colitis. Another common name for this condition is pseudomembranous colitis.
• Clostridium is a family of bacteria containing several members. Some of the other well known bacteria in this group include Clostridium botulinum and Clostridium tetani, which are the causes of botulism and tetanus, respectively.
• There are typically two forms of Clostridium difficile; one is the inactive or non-infectious form, called the spore, and the other is the active and infectious form. The spore form can survive in the environment for a long time, whereas the active form cannot.
• Clostridium difficile colonize the intestinal tract by the oral route (mouth). This disease typically follows the disruption of the balance of normal colonic bacteria (normal flora), which is usually due to the use of antibiotics. Although C. diff spores may reside in the active form in the colon of some individuals (carrier state), they can also be ingested in this form (fecal-oral transmission).
• After being shed in the stool, C. diff may be found residing in many places, especially in hospitals, nursing homes, and other health care facilities.
• The common locations of the C. diff include:
  • furniture,
  • bathroom floors,
  • stethoscopes,
  • bedpans,
  • telephones,
  • fingernails,
  • floors,
  • diaper pails,
  • jewelry (rings),
  • infant's rooms,
  • toilet seats, and
  • other objects commonly used by patients and health care professionals.
• During the last 10 years, C. difficile infections have been observed to be more frequent, severe, and resistant to standard therapy. This is linked to the emergence of new strains of C. difficile and continued increase use of antibiotics. Large out breaks of C. difficile infections have been observed throughout North America and Europe. Not only are the incidence of these infections increasing in the hospital setting, but they are also occurring in the community setting (community acquired infections ).

In the colon, the C. diff spores are present in the inactive form. There are numerous different bacteria that typically reside in the colon and make up part of the normal flora of the colon. These bacteria prevent the activation of the C. diff spores into the active bacterial form.

However, when antibiotics are administered for the treatment of an infection, they may kill some of the normal colonic bacteria. This process disrupts the normal balance of gut bacteria and allows Clostridium difficile to become activated and infectious.

When C. diff becomes activated, it produces two different toxins (chemicals), toxin A and toxin B. These toxins may cause inflammation of the inner lining of the colon, resulting in pooling of white blood cells in the colon. If the inflammation is severe, it can result in destruction of the normal cells that line the inside of the colon. When these cells are shed, and a large number of white blood cells may appear as small whitish membranes when visualized by colonoscopy (camera placed inside the colon). These membranes are referred to as "pseudomembranes" because they are not real membranes, thus the name pseudomembranous colitis.

The inflammatory process may result in diarrhea, abdominal pain, fever, and other signs of infection.

It is important to note that not all antibiotics cause C. difficile colitis, and not everyone receiving antibiotics will develop this infection. It is also worth mentioning that diarrhea may occur due to antibiotics for other reasons and that not all antibiotic-associated diarrheas mean that the individual has C. difficile colitis. Many antibiotics can cause diarrhea as a side effect through unknown mechanisms.

Although any antibiotic is a potential risk factor for C. diff infection, the ones most commonly recognized are:

• clindamycin (for example, Cleocin),
• fluoroquinolones (for example, levofloxacin [Levaquin], ciprofloxacin [Cipro, Cirpo XR, Proquin XR]),
• penicillins, and
• cephalosporins.

Other risk factors for C. diff infection include:

• hospitalization,
• age greater than 65 years,
• the presence of chronic medical conditions, and
• severe illness.

Another possible additional risk factor is the suppression of gastric acid.

The symptoms of C. difficile colitis range from mild to severe. Watery diarrhea is the main symptom regardless of the severity of the infection, although it may not be present in every patient.

Some patients are carriers of the organism and do not develop an active infection. These individuals may shed the organism and cause environmental contamination.

Generally, mild C. diff infection (in addition to diarrhea) may result in:

• abdominal pain and cramping,
• bloating,
• nausea,
• vomiting,
• fatigue, and
• fever.

The diarrhea may occur up to 10 to 15 times daily. More severe infections may cause severe and profuse diarrhea, severe abdominal pain, and high fever. Toxic megacolon, which indicates a massively enlarged and distended colon, is a manifestation of severe disease. Severe cases may also be associated with generalized infection (sepsis) resulting in instability of blood pressure and heart rate, as well as disruption of the functions of other body organs (septic shock).

It is not clear why different individuals have different reactions to C. difficile infections.

If an individual has watery diarrhea, especially after administration of antibiotics or a recent hospitalization, C. difficile colitis should be suspected. Your physician should be notified in order to properly evaluate the diarrhea.

If the symptoms are severe, such as the presence of a high grade fever, severe diarrhea, moderate to severe abdominal pain, or signs of dehydration, hospitalization may be required for supportive care and treatment of the infection.

Similar to other illnesses, a thorough medical examination by the doctor is necessary in evaluating for C. difficile colitis. A careful review of all medications, especially antibiotics, and recent hospitalization or nursing home admissions should be carried out.

Laboratory tests include blood work including a basic chemistry panel and complete blood count (CBC). An elevated white blood cell count (WBC), or leukocytosis, is very common in C. diff infection. The WBC is typically elevated in any type of bacterial infection, but in C. diff infection it is markedly elevated, often much higher than with other infections.

There are two ways to detect the presence of C. difficile.

1. Testing for the toxin produced by the organism (toxin assays)
2. Detecting the actual organism. Although the detection of the organism in stool cultures is the most sensitive way of diagnosing C. difficile, it takes a few days to make this determination, which makes this a less useful method.

Stool samples should be collected and analyzed. The presence of C. diff toxins in the stool is diagnostic of the infection, and the results of stool analysis are generally available within a day or so. The actual detection of Clostridium difficile bacterium by stool cultures may also be done. This, however, may take a few days, which may delay the diagnosis and treatment. C. diff culture may be positive in a carrier; however, the strain of the organism may be one that does not cause infection.

Other tests used to diagnose C. difficile colitis are a CT scan of the abdomen, which may show thickening of the wall of the colon, signifying inflammation. This finding is not specific as it may be present in other inflammatory diseases of the colon; however, it may add further evidence for C. difficile colitis in the proper clinical setting.

Sigmoidoscopy and colonoscopy are other procedures which may be useful in the evaluation of C. difficile colitis. These procedures involve inserting an endoscope (a tube), which has a camera and a light source at the tip, into the colon from the rectum. Visualization of pseudomembranes suggests C. diff infection. These tests are not always necessary to diagnose the infection, but they may have a role in cases where the diagnosis is in doubt due to non-diagnostic stool tests, unresponsiveness to appropriate treatment, or unusual presentation of the disease with little or no diarrhea and fever.

Examination of the stool for white blood cells (fecal leukocytes) is also an easy and helpful way to indicate possible C. diff infection.

If C. diff infection is suspected, the doctor should be notified immediately. It is important to try to stay well hydrated by drinking adequate amounts of liquids in order to compensate for the fluid losses due to diarrhea. However, further management should be carried out under the supervision of a physician.

If the doctor suspects that C. difficile colitis is causing the diarrhea, the offending antibiotic will be stopped. Treatment of C. diff requires the use of antibiotics which are different from the ones that cause diarrhea. The antibiotics used to treat C. diff colitis include vancomycin (Vancocin) and metronidazole (Flagyl), with newer antibiotics being studied. It is ironic that the treatment of the C. diff infection caused by antibiotics is with different antibiotics.

In cases of severe illness and dehydration, the doctor may recommend admission to the hospital in order to start aggressive treatment with intravenous fluid and antibiotics, as well as for close monitoring for any metabolic disturbances and evidence of severe inflammation and distention of the colon. In severe cases, oral intake is stopped in order to give rest to the colon and prevent further stimulation of the bowel. Admission to the intensive care unit (ICU) may sometimes be necessary if there is evidence of unstable blood pressure and disturbance of other body functions.

It may take several days for the diarrhea to stop, despite prompt discontinuation of the offending antibiotics and aggressive medical care.

It is important to note that contrary to other causes of diarrhea, anti-diarrheal medications are discouraged in C. difficile colitis. This is because these drugs may slow down the removal of the bacteria and its toxins from the colon and, thus, prolong the infection.

In rare cases of severe infections with toxic megacolon, impending colon perforation, and severe generalized infection (sepsis) that may be life-threatening, surgery to remove the colon may be advised.

Many other antibiotics have been used for the treatment of C. diff infection; however, to date only metronidazole (Flagyl) and vancomycin (Vancocin) have been approved.

Rifaximin (Xifaxan), a newer antibiotic, has shown some benefit in reducing the recurrence rate if the drug is given immediately after completion of a course of vancomycin (Vancocin).

Intracolonic vancomycin (placing the antibiotic inside the colon through the rectum) has been studied in cases of refractory C. diff infection, but data showing the benefit of this approach are limited at this time.

Probiotics (such as Lactobacillus, Streptococcus salivarius, and Saccharomyces boulardii) are micro-organisms that are derived from food products, especially dairy products, and are non-infectious. Although these compounds are harmless, they have not been shown to be beneficial either in the treatment or prevention of C. difficile colitis. These drugs are, therefore, not recommended despite their widespread use.

Intravenous Immunoglobulin (IVIG) with C. diff antitoxin has been used in the treatment of recurrent infections, but the results are not better than the standard treatment.

Finally, fecal bacteriotherapy (or fecal enema) has been examined in patients with severe and recurrent disease. This treatment entails the introduction of feces, containing the usual gut bacteria (gut flora) obtained from healthy individuals, directly into the colon of the infected patient. This is believed to restore the normal gut flora that was altered by the use of antibiotics. While this approach has shown some promise, the data are very limited, and the procedure may be difficult from a practical standpoint.

Follow-up with a doctor after the completion of therapy for C. diff is strongly recommended. It is not necessary to repeat stool tests after the completion of therapy unless the symptoms persist (unresponsive to treatment) or recur after initial resolution (relapse).

Relapse and recurrent infections are not uncommon and are present in more than 20% of individuals who have C. diff infection. Therefore, if symptoms suggestive of C. difficile colitis recur at any time after the initial episode, prompt follow up with the physician is important.

Because individuals with C. difficile colitis are infectious, it is important to eliminate the spread of infection to others. This is best done by careful hand washing by both the infected person and others who come into contact with the individual. Washing hands with soap and water is the recommended approach. The use of alcohol-based disinfecting agents is not recommended since they are as not effective against C. diff spores.

Besides hand washing by everyone in contact with the patient, thorough cleaning of the environment is an important aspect of the prevention of the spread of C. difficile. Hypochlorite based solutions are more effective than other solutions in eliminating C. difficile.

In health care facilities, patients with C. diff infection are usually placed in isolation in order to prevent transmission to other patients. The isolation is discontinued after stool tests show no further evidence of infection (no toxins), or if the patient is doing well enough to return home. Isolation at home is usually neither necessary nor practical.

C. difficile colitis, or antibiotic-related colitis, generally has a favorable outcome as long as this condition is recognized early and prompt treatment is initiated.