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Clostridium Difficile Colitis Update

by Kirsten Weiblen, October 2006

Clostridium difficile is a slow-growing, gram positive, anaerobic bacillus.  Clostridia species form spores which are resistant to ultra-violet radiation, temperature extremes and common hospital disinfectants. These spores are highly persistent and ubiquitous in the environment. C. difficile produces two types of toxins; toxin A, an enterotoxin, and toxin B, a cytotoxin. Both toxins bind to specialized receptors on intestinal mucosal cells and play a role in the organism's pathogenicity. These toxins can act synergistically. In addition, a third binary CDT toxin exists in some strains. The pathenogenicity of this toxin is currently less clear.

Since its identification as the causative organism in pseudomembranous colitis in 1978, infectious outbreaks have sporadically occurred in several hospitals throughout the US. This has brought about various institutional responses, including restricting certain antibiotics, changing housekeeping procedures, and establishing active multidisciplinary antibiotic management programs. These measures in combination have met with some level of success.[i] Restricting the use of clindamycin has reduced Clostridium difficile-related diarrhea (CDAD) in some hospitals in the short term[ii], but increasingly other broad-spectrum antibiotics such as cephalosporins and quinolones cause the disease, so restricting clindamycin as a sole containment policy is of very limited use.

New insight into the pathenogenesis of C. difficile infections has recently been gained. A highly toxinogenic strain was identified in six US states, and in Alberta and Quebec, Canada between 2001 and 2004.[iii] The Society for Healthcare Epidemiology of America said at its 15^th annual meeting in April 2005 that this strain, designated as ribotype 027, toxinotype III, has caused outbreaks in 7 hospitals in 6 US states. The toxinotype III strain produces 16 times more toxin A and 20 times more toxin B in vitro than the more commonly isolated toxinotype 0 strain. This may be due to the deletion of the tcdC gene, a negative regulator of toxin production. This gene limits toxin production in the log (exponential) phase of bacterial growth, delaying its production until the stationary phase of growth.[iv] This strain of C. difficile is responsible for the recent epidemic at Stoke Mandeville Hospital in the UK, announced on June 5^th, 2005. This epidemic affected 300 persons at the small specialty hospital and killed 12 patients, precipitating possible government action regarding hospital hygiene and the interaction between infected patients, staff, and visitors. Subsequent to the reports at Stoke-Mandeville, fourteen other UK hospitals were found to have patients infected with the 027 strain.[v] Clostridium difficile has recently become a reportable disease in the UK. It’s occurrence is not yet a mandatory reporting issue in the US or Canada.

On July 6^th,, 2005 the 027 strain was identified at two hospitals in the Netherlands.[vi] Of particular concern was a lack of apparent clinical response to metronidazole. This phenomenon had been empirically observed previously in Canada. Curiously, the strain was susceptible to metronidazole in vitro by E-test.

A disturbance in the usual contingent of human gut flora brings about C. difficile super infection and resultant diarrhea and colitis. This disruption of microbial flora is most commonly associated with orally administered antibiotics and/or broad- spectrum antibiotics. Canadian interventionists have reported a possible relationship between the use of proton pump inhibitors and the disease, but in view of the very rapid formation of large amounts of toxin, it is unclear how large a role the use of these medications play in the pathenogenesis of the toxinotype III strain. The odds ratio of the instance of proton inhibitor use in a smaller (n=94) case-control study portion of their research was nearly equivalent to that of other risk factors, such as hospital admission in the last 3 months (2.7 and 2.6, respectively). In addition, patients placed on proton pump inhibitors are often more ill than other patients.[vii]

Since the year 2000, mortality per case of C. difficile has been rising. Data presented at the 2004 Infectious Diseases Society of America meeting has indicated that the C. difficile is resistant to fluoroquinolones, especially levofloxacin.[viii] [ix]  Previously, quinolones were thought to pose a low risk of C. difficile infection.[x] Other evidence suggests that resistance to metronidazole may be occurring, as well as documented resistance to macrolides and clindamycin. The risk of infection is now highest with cephalosporins and ampicillin/amoxicillin, presumably because they are the most widely used antibiotics. Indeed, almost all classes of antibiotics have been implicated, and even brief exposure to any single antibiotic can cause C. difficile colitis.

The C. difficile species involved in major hospital outbreaks appear to have both a dominant clonal strain and resistance to a commonly used antibiotic. C. difficile selects for specific antibiotic resistance and then can proliferate largely because it is resistant to that antibiotic. The antibiotic itself is responsible for obliterating much of the host's protection by suppressing the bowel flora. C. difficile then produces copious amount of toxins. Hence, reduction of overall antibiotic use is necessary to reduce endemic CDAD rates in hospitals.

A recently reported randomized control study demonstrates the value of changing overall antibiotic usage patterns. It involved 807 uncomplicated acute bronchitis patients treated in primary care facilities that were assigned to one of three treatment arms, including: no antibiotics offered (n = 273), delayed antibiotics via a written prescription  (n = 272), and immediate antibiotics ( n = 262). According to responses from 78% of the patients, there was little difference in resolution of symptoms. Prescribing practices that involved the delayed use or the non-use of antibiotics were effective in 70% to 90% of patients, resulted in adequate symptom control, and were acceptable to patients.[xi] This study is important because evidence suggests that community-acquired C. difficile may be a problem.  Since January 2005, this hospital has seen many cases of community-acquired C. difficile-associated diarrhea. Nearly all the patients were previously treated with amoxicillin, Augmentin or a cephalosporin. This trend indicates that outpatient prescribing practices will play a role in the future of the disease.

Clostridium difficile colitis is no longer confined to elderly and very infirm nursing home or hospitalized patients. As with MRSA and VRE, utilizing strict enteric contact isolation is an essential means of controlling CDAD spread. Mandating hand-washing with chlorhexidine (not alcohol) before and after patient contact for all staff and visitors, full personnel protective gowning and gloving, exclusive use of diagnostic equipment such as stethoscopes and blood-pressure cuffs on one and only one patient, and cleaning rooms and equipment with a chlorine-based disinfectant must be initiated. Other approaches to combating the disease include improved surveillance and disease data collection, rapid same-day toxin testing and reporting, and developing new molecular typing systems using whole genome sequences of C. difficile. Further understanding of the mode of action of the pathogen, development and application of new treatment strategies, stressing the need for using non-antibiotic treatment modalities such as the use of antitoxin, probiotic treatment and fecal donation, will also be necessary.

C. difficile is present in the gut of 50% of all neonates and in 7% of adults. It has only recently been considered a pathogen instead of a commensurate organism. Its emergence is related to the widespread use of broad-spectrum antibiotics. Policies must be put in place that include the strict practice of enteric contact isolation and an active antibiotic management program,  in order to reduce CDAD incidence and protect patients and staff.

UPDATE: October 2006

–    A study from 6 North Carolina hospitals has indicated that community-acquired C. difficile-associated diarrhea (CA-CDAD) is indeed an increasing problem. Moreover, the spread of the disease may not involve the prior use of antibiotics. C. difficile has been known to spread from patient to patient in hospitals. Now there is some basis to believe that it can spread among healthy individuals in the community as well. “Of a total of 1137 cases of CDAD reviewed at 6 North Carolina hospitals between Jan and Dec 2005, nearly one in 5 (209, 18 percent) were acquired in the community, with 50 percent of those cases not originating from prescription of an antimicrobial, stressed Dr. McDonald.” Cit. ProMed archive number 20061018.2990, Costridium difficle, community acquired – USA (NC).

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