Clostridium difficile

Also known as: C.diff, C difficile, CDAD (Clostridium difficile-associated disease)

Industry of interest: Healthcare

Classification: Bacterium

Microbiology: Clostridium difficile is an anaerobic, Gram-positive, spore-forming rod, which can colonise the human gut and cause toxin-mediated, usually antibiotic-associated disease (Bartlett et al. 1978). C. difficile is closely related to C. botulinum, which causes Botulism and produces the so-called “Botox” toxin used for cosmetic purposes, C. tetani, which causes Tetanus and C. perfringens, which causes Gangrene (Gurtler et al. 1991).

C. difficile can produce toxin A or toxin B, both of which lead to inflammation and injury of the colon, which manifests as mild to severe diarrhoea. These toxins are encoded by separate genes (tcdA and tcdB) which are controlled by several regulatory genes including positive (tcdD) and negative (tcdC) regulators all of which are part of the Pathogenicity Locus (PaLoc) of the genome (Warny et al. 2005). Variations in the sequence of PaLoc can be detected by toxinotyping, which is used in combination with a variety of other techniques to differentiate distinct strains of C. difficile.
 

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Biology

There has been an alarming increase in the prevalence of C. difficile-associated disease  (CDAD) in both the USA and UK in recent years, although determining the exact prevalence is difficult, especially in the UK, due to recent changes in reporting methodology.

Under the old voluntary reporting scheme in the UK, the number of C. difficile isolates reported from faecal specimens in the UK increased by almost 200% from 22,008 in 2001 to 43,682 in 2004 (figure 1). An increase in the reporting of CDAD rather than an increase in the prevalence of CDAD could explain this alarming increase, but the true prevalence of C. difficile is likely to be very much higher than the number reported because these data are from a voluntary reporting scheme. A mandatory reporting scheme was introduced in January 2004 for C. difficile cases in patients 65 years or older.

CDAD has increased by a strikingly similar proportion over a similar time period in the USA, rising from 82,000 or 31/100,000 population in 1996 to 178,000 or 61/100,000 in 2003 (McDonald et al. 2006).

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Symptoms/Effects

C. difficile was first isolated in the 1930s, but its medical importance as a cause of antibiotic-associated diarrhoea and colitis (inflammation of the colon) was not recognised until the mid-1970s (Bartlett et al. 1978). For reasons that are not well understood, young children often carry C. difficile in their gut without developing C. difficile-associated disease (CDAD) (Merida et al. 1986). Asymptomatic carriage of C. difficile is much less common in adults – typically only 3% of healthy adults and 20-40% of hospitalised adults (Bartlett and Perl 2005). In order to cause disease, C. difficile must germinate from its spore-form in the anaerobic (oxygen-free) section of the colon. Exposure to antibiotics kills many of the normal gut flora giving C. difficile the opportunity to germinate, grow and produce the disease-causing toxin A or B (Bartlett et al. 1978;Yam and Smith 2005).

CDAD typically affects older or severely ill patients who are hospital inpatients or residents of long-term care facilities. Recently, however, both the frequency and severity of health-care-associated CDAD has increased due to the emergence of a new strain of C. difficile (Bartlett and Perl 2005). This strain lacks the tcdC negative regulator gene and has other changes, which cause it to produce excess amounts of exotoxin, thus increasing the severity of disease (Loo et al. 2005;Warny et al. 2005). This new strain probably originated in Canada but has since spread to the USA, UK and Europe (McDonald et al. 2005). The strain is termed type 027 (based on ribotyping) in the UK and BI/NAP1 (based on REA/PFGE typing) in the USA. There is recent evidence that severe CDAD is beginning to emerge outside of hospitals in the community in the USA (2005).  

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Technical

Treatment and control methods:

C. difficile is transmitted between patients either directly on the hands or healthcare workers or indirectly via contaminated environmental surfaces. Therefore, standard infection control measures, comprising hand-hygiene, prompt identification and isolation of infected patients and environmental decontamination are critical for the control of C. difficile (2004;Boyce and Pittet 2002). Although local procedures vary, stool samples will usually only be sent to hospital laboratories for a test to detect whether the C. difficile toxins are present during episodes of diarrhoea following antibiotic treatment. Samples are not routinely analysed to detect asymptomatic carriage.

Resilient C. difficile spores, designed for survival in unfavourable environments, will survive and persist in the hospital environment and can be transferred from environmental surfaces to healthcare worker’s hands (Bhalla et al. 2004). Several studies have underlined the importance of adequate environmental decontamination for the control of C. difficile in hospitals. Two studies have shown that a switch from detergent to hypochlorite (bleach) cleaning can reduce the incidence of CDAD on certain wards (Mayfield et al. 2000;Wilcox et al. 2004). However, this effect was not reproduced on all wards studied and the actual levels of C. difficile environmental contamination were not altered by the change of cleaning regime in one study (Wilcox et al. 2004) and were not measured in the other study (Mayfield et al. 2000). Other studies have indicated that the incidence of C. difficile infection correlates closely with environmental contamination (Fawley and Wilcox 2001) and that transmission of C. difficile correlates strongly with the intensity of environmental contamination (Samore et al. 1996), adding further evidence that environmental contamination is clinically significant in the cross-transmission of C. difficile.

Exposure to antibiotics increases the risk of developing CDAD (Yam and Smith 2005). Exposure to certain classes of antibiotics such as cephalosporins, clindamycin (Palmore et al. 2005) and fluoroquinolones (Muto et al. 2005;Pepin et al. 2005) carries a greater risk for the development of CDAD. Restriction of the use of these antibiotics, especially for at-risk groups, has proven effective for the reduction of CDAD (Settle et al. 1998).

Other methods for the control of C. difficile include probiotics (so-called “friendly bacteria”) to replace the gut flora lost through antibiotic exposure and there is a potential that C. difficile vaccination could be developed in the future (Aslam et al. 2005).

For those patients already infected with CDAD, antibiotics such as metronidazole or vancomycin are used to kill the C. difficile in the colon and halt the production of the toxin (Aslam et al. 2005). In severe cases, surgery may be required to remove the colon (colectomy).

Environmental survival:

Environmental contamination with C. difficile has been reported frequently from key items in the near-patient environment such as the bed-rail, sink, table, lights, curtain rails, commodes and other items of furniture (Verity et al. 2001;Wilcox et al. 2003). However, the actual level and frequency of contamination with C. difficile is probably higher than reported in many studies because of practical difficulties in culturing C. difficile.

Bacterial endospores are extremely resilient and will survive on environmental surfaces for years; one study reported that C. difficile survived on metal surfaces for more than one month with only a small log-reduction (French et al. 2004). Even vegetative bacteria, such as MRSA and Acinetobacter baumannii can survive on dry surfaces for almost a year (Wagenvoort and Joosten 2002). Several studies have shown that C. difficile spores persist despite standard terminal cleaning with hypochlorite (bleach) (2005;Verity et al. 2001;Wilcox et al. 2003).

Role of Bioquell:

Effective eradication of C. difficile spores from the hospital environment is one of the key measures for controlling the transmission of C. difficile. Bioquell uses 6-log Geobacillus stearothermophilus spores as Biological Indicators (BIs) to verify the efficacy of each HPV bio-decontamination cycle and Bioquell's Room Bio-Decontamination Service (RBDS) technology has been shown to kill C. difficile spores (French et al. 2004). RBDS has been successfully employed at a number of hospitals in the UK for the eradication of C. difficile including Stoke Mandeville Hospital in Buckinghamshire, where an outbreak of C. difficile type 027 was identified as being responsible for a number of deaths. RBDS has been used repeatedly as an integrated part of the outbreak response and has proven beneficial in reducing the number of CDAD cases at Stoke Mandeville. In June 2005, the Secretary of State for Health requested that the Healthcare Commission undertake an investigation into Buckinghamshire Hospitals NHS Trust to examine the arrangements that were in place to control infection and also to establish whether the trust has adequate arrangements to prevent and manage any further outbreak. The report on the results of the investigation at Stoke Mandeville Hospital will be published later this year (2006).

Bioquell initiated trials in the USA in 2005 with Dr John Boyce (Chief of Infectious Diseases Section, Hospital of St. Raphael, New Haven, CT and Clinical Professor of Medicine, Yale University School of Medicine) to investigate whether hospital-wide routine bio-decontamination would reduce the rate of CDAD. Encouraging preliminary results of the trials were presented at a scientific conference in December 2005 and further results will be released later in 2006.

References

(2005) Severe Clostridium difficile-associated disease in populations previously at low risk--four states, 2005. MMWR Morb. Mortal. Wkly. Rep. 54, 1201-1205.

(2004) National Clostridium difficile Standards Group: Report to the Department of Health. J Hosp. Infect 56 Suppl 1, 1-38.

Aslam,S., Hamill,R.J. and Musher,D.M. (2005) Treatment of Clostridium difficile-associated disease: old therapies and new strategies. Lancet Infect Dis 5, 549-557.

Bartlett,J.G., Moon,N., Chang,T.W., Taylor,N. and Onderdonk,A.B. (1978) Role of Clostridium difficile in antibiotic-associated pseudomembranous colitis. Gastroenterology 75, 778-782.

Bartlett,J.G. and Perl,T.M. (2005) The new Clostridium difficile--what does it mean? N Engl J Med 353, 2503-2505.

Bhalla,A., Pultz,N.J., Gries,D.M., Ray,A.J., Eckstein,E.C., Aron,D.C. and Donskey,C.J. (2004) Acquisition of nosocomial pathogens on hands after contact with environmental surfaces near hospitalized patients. Infect Control Hosp. Epidemiol. 25, 164-167.

Boyce,J.M. and Pittet,D. (2002) Guideline for Hand Hygiene in Health-Care Settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Infect Control Hosp. Epidemiol. 23, S3-40.

Fawley,W.N. and Wilcox,M.H. (2001) Molecular epidemiology of endemic Clostridium difficile infection. Epidemiol. Infect 126, 343-350.

French,G.L., Shannon,K.P. and Otter,J.A. (2004) Survival of nosocomial bacteria dried in air and killing by hydrogen peroxide vapour. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington DC.

Gurtler,V., Wilson,V.A. and Mayall,B.C. (1991) Classification of medically important clostridia using restriction endonuclease site differences of PCR-amplified 16S rDNA. J Gen. Microbiol. 137, 2673-2679.

Loo,V.G., Poirier,L., Miller,M.A., Oughton,M., Libman,M.D., Michaud,S., Bourgault,A.M., Nguyen,T., Frenette,C., Kelly,M., Vibien,A., Brassard,P., Fenn,S., Dewar,K., Hudson,T.J., Horn,R., Rene,P., Monczak,Y. and Dascal,A. (2005) A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 353, 2442-2449.

Mayfield,J.L., Leet,T., Miller,J. and Mundy,L.M. (2000) Environmental control to reduce transmission of Clostridium difficile. Clin Infect Dis 31, 995-1000.

McDonald,L.C., Killgore,G.E., Thompson,A., Owens,R.C., Jr., Kazakova,S.V., Sambol,S.P., Johnson,S. and Gerding,D.N. (2005) An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 353, 2433-2441.

McDonald,L.C., Owings,M. and Jernigan,D.B. (2006) Increasing rates of Clostridium difficile infection among patients discharged from US short-stay hospitals, 1996-2003. Emerg. Infect Dis.

Merida,V., Moerman,J., Colaert,J., Lemmens,P. and Vandepitte,J. (1986) Significance of Clostridium difficile and its cytotoxin in children. Eur. J Pediatr. 144, 494-496.

Muto,C.A., Pokrywka,M., Shutt,K., Mendelsohn,A.B., Nouri,K., Posey,K., Roberts,T., Croyle,K., Krystofiak,S., Patel-Brown,S., Pasculle,A.W., Paterson,D.L., Saul,M. and Harrison,L.H. (2005) A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp. Epidemiol. 26, 273-280.

Palmore,T.N., Sohn,S., Malak,S.F., Eagan,J. and Sepkowitz,K.A. (2005) Risk factors for acquisition of Clostridium difficile-associated diarrhea among outpatients at a cancer hospital. Infect Control Hosp. Epidemiol. 26, 680-684.

Pepin,J., Saheb,N., Coulombe,M.A., Alary,M.E., Corriveau,M.P., Authier,S., Leblanc,M., Rivard,G., Bettez,M., Primeau,V., Nguyen,M., Jacob,C.E. and Lanthier,L. (2005) Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 41, 1254-1260.

Samore,M.H., Venkataraman,L., DeGirolami,P.C., Arbeit,R.D. and Karchmer,A.W. (1996) Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. Am. J Med 100, 32-40.

Settle,C.D., Wilcox,M.H., Fawley,W.N., Corrado,O.J. and Hawkey,P.M. (1998) Prospective study of the risk of Clostridium difficile diarrhoea in elderly patients following treatment with cefotaxime or piperacillin-tazobactam. Aliment. Pharmacol. Ther. 12, 1217-1223.

Verity,P., Wilcox,M.H., Fawley,W. and Parnell,P. (2001) Prospective evaluation of environmental contamination by Clostridium difficile in isolation side rooms. J Hosp. Infect 49, 204-209.

Wagenvoort,J.H. and Joosten,E.J. (2002) An outbreak Acinetobacter baumannii that mimics MRSA in its environmental longevity. J Hosp. Infect 52, 226-227.

Warny,M., Pepin,J., Fang,A., Killgore,G., Thompson,A., Brazier,J., Frost,E. and McDonald,L.C. (2005) Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 366, 1079-1084.

Wilcox,M.H., Fawley,W.N., Wigglesworth,N., Parnell,P., Verity,P. and Freeman,J. (2003) Comparison of the effect of detergent versus hypochlorite cleaning on environmental contamination and incidence of Clostridium difficile infection. J Hosp. Infect 54, 109-114.

Wilcox,M.H., Fawley,W.N., Wigglesworth,N., Parnell,P., Verity,P. and Freeman,J. (2004) Detergent versus hypochlorite cleaning and Clostridium difficile infection. J Hosp. Infect 56, 331.

Yam,F.K. and Smith,K.M. (2005) "Collateral damage": antibiotics and the risk of Clostridium difficile infection. Orthopedics 28, 275-279.

 

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