Antibiotic Risk Factors for C. Difficile Associated Diarrhea
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.