Clostridium difficile is a spore-forming bacterium present in the soil, in human feces, and in environments such as hospitals, nursing homes, and child-care facilities. It is the most common cause of infectious diarrhea in the world. Symptoms include liquid diarrhea, dehydration, fever, appetite loss, and abdominal pain or tenderness. Populations most at risk include those who:

  • are elderly,
  • have a compromised immune system,
  • are taking, or have recently taken antibiotics,
  • are taking acid suppression medication (histamine2 receptor antagonists and proton pump inhibitors),
  • reside in a long-term care setting, and who
  • are, or have recently been, hospitalized.

Antibiotic use is a risk factor for developing a C. difficile infection since these medications affect the levels of good bacteria in our bodies, leaving room for the C. difficile bacteria to grow unchecked. Minimizing the use of non-essential antibiotic treatments is the first line of defense against this infection.

We can work together to avert the spread of these bacteria by exercising proper hygiene and hand-washing techniques in addition to using chlorine bleach based cleaning solutions on potentially infected surfaces or tools.

First published in the Inside Tract® newsletter issue 165 – January/February 2008
1. Dial S, et al. Use of gastric acid–suppressive agents and the risk of community-acquired Clostridium difficile–associated disease. Journal of the American Medical Association. 2005; 294:2989-2995.
2. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. American Journal of Gastroenterology. 1997;92:739-50.
3. Health Canada. C. Difficile (Clostridium Difficile). (Accessed August 4, 2011)

Clostridium Difficile Associated Diarrhea – Antibiotic Rick Factors

Diarrhea is a common side effect of antibiotic use. However, when Clostridium difficile (C. difficile) bacteria are the culprits in post-antibiotic use diarrhea, there is an increased risk of morbidity and mortality.


Clostridium difficile

Commonly found in hospitals and care facilities, C. difficile are anaerobic gram-positive bacillus1. Anaerobic means the bacteria do not need oxygen to survive so they live well in the colon. Part of the reason they persist in hospital environments is their ability to exist for months and even years in spore form, which can withstand heat and drying out.1 C. difficile produces specific toxins, which lead to these symptoms, commonly associated with infection:1

  • watery diarrhea for more than three days,
  • very strong smelling stools,
  • lower abdominal pain,
  • fever,
  • blood in the stool,
  • loss of appetite/weight loss,
  • nausea,
  • malaise, and
  • an atypical but significant consequence of C. difficile is that some who become infected do not get diarrhea, but rather the symptoms manifest as bloating and constipation.


Infectious diarrhea

Not all contact with C. difficile results in infectious diarrhea. Among those colonized by the bacteria, only 40-60% will develop symptoms.1 For C. difficile-associated diarrhea (CDAD) to develop, specific circumstances must transpire. Initially, there is some form of disruption – usually from antibiotic use – to the normal balance of bacteria native to the colon. Additionally, an individual must have exposure to C. difficile that thrive and multiply in the colon, which is now lacking its protective good bacteria. Finally, the growing population of C. difficile bacteria produces toxins, leading to the dangerous condition.

A stool sample test can assess for a C. difficile infection. Rather than test directly for the presence of the bacteria through common testing methods such as cultures or polymerase chain reaction (PCR), most institutions test for the presence of toxin B. If a C. difficile infection exists, medical treatment includes metronidazole or vancomycin therapy for 7-10 days.


Increasing frequency and severity

CDAD is becoming more frequent and more severe, as described in surveillance reports globally, nationally, and provincially.1,2,3

The Centre Hospitalier Universitaire de Sherbrooke reported an increase in new diagnoses, from 2.1 cases of CDAD per 1,000 admissions in 2002, to 10 cases per 1,000 admissions the following year, which was at the onset of a C. difficile outbreak in that facility.2 Infection Control surveillance involving British Columbian institutions found rates of C. difficile infection rose steadily between 2000 and 2004.3

The severity of CDAD is increasing. Recent outbreaks of C. difficile in Eastern Canada, the United States, the United Kingdom, and the Netherlands have also brought attention to a genetic subtype, the PCR ribotype 027 strain, associated with an increase in frequency and deaths.4 Levels of the bacterial toxins in this strain are found to be 16-23 times higher than other strains.4 Conservative estimates from two hospitals in Montreal indicate deaths of 24 patients attributed to CDAD, accounting for a quarter of all CDAD deaths nationwide during the year of the outbreak.2 During this timeframe, isolates of the PCR ribotype 027 strain accounted for 75.2% of all C. difficile isolates from one of these two Montreal hospitals, compared with 10.7% in Calgary, Alberta, and 5.9% in Surrey, BC.5 With growing rates of C. difficile infections, and the presence of a hypervirulent strain, community efforts should be directed toward effectively preventing this infection.


Risk factors

Mediating risk factors may provide a solution to the increasing CDAD threat. Risk factors can include the following:1

  • antibiotic use, particularly broad-spectrum antibiotics
  • increasing age
  • severe underlying illness
  • a weakened immune system
  • gastrointestinal surgery
  • frequent enema use
  • long-time hospital or home care stay

The current literature describes antibiotic risk factors that can contribute to CDAD in the hospital environment. However, since normal flora disruption can lead to CDAD up to 8 weeks later,6 elucidating community factors related to C. difficile infections will be important in slowing or halting increasing disease rates.


New research

Researchers with the Fraser Health Authority conducted a retrospective case-control study to address this lack of knowledge, using patient data from a 370-bed tertiary care hospital in the Metro Vancouver area. Subjects were acute care inpatients over the age of 18 who provided stool samples for a C. difficile toxin test. Control subjects included patients who did not test positive for C. difficile. There were 102 case subjects and 97 control subjects in total, matched by the following criteria:

  • age within 5 years
  • gender
  • comparable admission date
  • comparable exposure to the same ward, defined as admission date until index date (date of positive stool sample (case) or discharge date (control))

The study tracked these subjects and looked at rates of CDAD infection relative to the type of antibiotics prescribed. Furthermore, antibiotic use was analyzed separately in two phases: those used in the community (i.e. outside the hospital) and those used in the hospital. Different patterns of medication use and different risk factors for CDAD exist in these settings.

In the community setting, the researchers gathered information on medications dispensed from PharmaNet, a provincial registry administered by the College of Pharmacists of British Columbia, for the eight weeks prior to the C. difficile toxin test. In the hospital, data collection focused on the medications ordered and dispensed for the same period.

In the community, cotrimoxazole and antibiotics of the fluoroquinolone class were used more frequently in the group of patients who went on to develop CDAD. In the hospital setting, beta-lactam and beta-lactamase inhibitors, carbapenems, cephalosporins, clindamycin, macrolides, metronidazole, penicillins, quinolones, and vancomycin were used more often in the group that developed CDAD. Aminoglycosides and nitrofurantoin were not found to differ in rates of use between groups.

It is important to note that the study merely compares the rates of antibiotic use between the case group of patients who developed CDAD and the control group of patients who did not develop this disease. There is no determination of the magnitude of CDAD risk, but rather an extrapolation demonstrating the association between a statistically significant difference in antibiotic use between case and control subjects.


Moving forward

While the results from this study only make up part of the current body of evidence regarding antibiotics and CDAD risk, it is clear that antibiotics play a significant role in an individual’s risk for CDAD. It would be cavalier to label all antibiotics as dangerous, as they have an essential role to play in managing infection. However, as almost all antibiotics can increase a patient’s risk for Clostridium difficile diarrhea, an emphasis on antibiotic stewardship is important in the strategy for reducing Clostridium difficile-associated diarrhea rates.

Anthony Tung, B.Sc. (Pharm.) Clinical Pharmacist
Fraser Health Authority Surrey, British Columbia
First published in the Inside Tract® newsletter issue 168 – July/September 2008
1. Putanen SM, et al. Clostridium difficile-associated diarrhea in adults. Canadian Medical Association Journal. 2004;Jul;171(1):51-8.
2. Valiquette L, et al. Clostridium difficile infection in hospitals: a brewing storm. Canadian Medical Association Journal 2004;Jul;171(1):27–9.
3. Cheng L, et al., eds. Clostridium difficile associated diarrhea. Fraser Health Pharmacy News. Fall 2004.
4. Pepin J, et al. Mortality attributable to nosocomial Clostridium  difficile-associated disease during an epidemic caused by a  hypervirulent strain in Quebec. Canadian Medical Association Journal. 2005;Oct;173(9): doi:10.1503/cmaj.050978.
5. MacCannell DR, et al. Molecular analysis of Clostridium difficile PCR ribotype 027 isolates from Eastern and Western Canada. Journal of Clinical Microbiology. 2006;Jun;44(6):2147-52.
6. Simor AE, et al. Infection due to Clostridium difficile among elderly residents of a long-term-care facility. Clinical Infectious Diseases. 1993;Oct;17(4):672-8.

While Clostridium difficile (C. difficile) infections are still rare, they have risen rapidly worldwide in recent times. UK cases rose from less than one per 100,000 in 1994 to 4 per 100,000 ten years later. Infection rates increased four-fold in Quebec over the 13 years leading up to 2004, when C. difficile killed 117 people in that province. The rate of infection in Quebec hospitals is now as high as 12 per 1,000 patients. The Quebec strain is resistant to a group of antibiotics called fluoroquinolones, which may have contributed to its spread through that province.

It has been widely known that antibiotic use is a risk factor for C. difficile infection, and it usually occurs in hospitalized patients. According to recent research, Published in the Journal of the American Medical Association, in December, taking acid suppression medication (H2 receptor antagonists and proton pump inhibitors) is also a potential risk factor for C. difficile infection, and it seems to occur in community-based patients, not just in a hospital setting. The study suggests drugs that reduce gastric acidity provide a more hospitable environment for C. difficile bacteria to colonize.


About Clostridium difficile

C. difficile is a bacteria that can cause bowel infection. The usual symptoms are diarrhea, fever, and abdominal pain. Regular hand washing with soap and water is the prime method for prevention of C. difficile infection.

First published in the Inside Tract® newsletter issue 153 – January/February 2006
S Dial, J A C Delaney, A N Barkun, et al. Use of Gastric Acid–Suppressive Agents and the Risk of Community-Acquired Clostridium difficile–Associated Disease . Journal of the American Medical Association. 2005;294(23):2989-2995