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Narrative Review: The New Epidemic of Clostridium difficile–Associated Enteric Disease

John G. Bartlett, MD
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From John Hopkins University School of Medicine, Baltimore, Maryland.

Potential Financial Conflicts of Interest:Consultancies: Dr. Bartlett is on the HIV advisory boards of Abbott, Bristol-Myers Squibb, and GlaxoSmithKline Pharmaceuticals.

Requests for Single Reprints: John G. Bartlett, MD, Department of Medicine, Johns Hopkins University School of Medicine, 1830 Monument Street, 437, Baltimore, MD 21205; e-mail, jb@jhmi.edu.

Ann Intern Med. 2006;145(10):758-764. doi:10.7326/0003-4819-145-10-200611210-00008
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Antibiotic-associated diarrhea and colitis were well established soon after antibiotics became available. Early work implicated Staphylococcus aureus, but in 1978 Clostridium difficile became the established pathogen in the vast majority of cases. In the first 5 years (1978 through 1983), the most common cause was clindamycin, the standard diagnostic test was the cytotoxin assay, and standard management was to withdraw the implicated antibiotic and treat with oral vancomycin. Most patients responded well, but 25% relapsed when vancomycin was withdrawn. During the next 20 years (1983 through 2003), the most commonly implicated antibiotics were the cephalosporins, which reflected the rates of use; the enzyme immunoassay replaced the cytotoxin assay because of speed of results and technical ease of performance; and metronidazole replaced vancomycin as standard treatment, and principles of containment hospitals became infection control and antibiotic control. During the recent past (2003 to 2006), C. difficile has been more frequent, more severe, more refractory to standard therapy, and more likely to relapse. This pattern is widly distributed in the United States, Canada, and Europe and is now attributed to a new strain of C. difficile designated BI, NAP1, or ribotype 027 (which are synonymous terms). This strain appears more virulent, possibly because of production of large amounts of toxins, and fluoroquinolones are now major inducing agents along with cephalosporins, which presumably reflects newly acquired in vitro resistance and escalating rates of use. The recent experience does not change principles of management of the individual patient, but it does serve to emphasize the need for better diagnostics, early recognition, improved methods to manage severe disease and relapsing disease, and greater attention to infection control and antibiotic restraint.





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Hand Hygiene and C. difficile
Posted on November 30, 2006
Ted W. Gay
Tri City Medical Center
Conflict of Interest: None Declared

In the infection control section of his otherwise excellent review of the epidemic strain of C. difficile, Dr. Bartlett notes that standard recommendations of the Society for Healthcare Epidemiology of America (SHEA) include, ". . . soap and water for handwashing rather than alcohol- based hand hygiene." However, the reference (1) cited is a SHEA position paper from 1995 and does not even address alcohol-based hand hygiene. Indeed, the authors reviewed the available information on hand decontamination with nondisinfectant soap versus disinfectant soap and water and conclude, ". . . the emphasis should be on compliance with the use of handwashing (with either a disinfectant or soap) until more data are available in the clinical setting to support one handwashing agent over another."

Guideline for Hand Hygiene in Health-Care Settings (2) states, "None of the agents (including alcohols, chlorhexidine, hexachlorophene, iodophors, PCMX, and triclosan) used in antiseptic handwash or antiseptic hand-rub preparations are reliably sporocidal against Clostridium spp. or Bacillus spp." The authors note that soap and water may help to physically remove spores and that use of these products (cf alcohol-based products) is "prudent" during "outbreaks of C. difficile-related infections."

As the medical director of infection control in a community hospital that has seen only sporadic cases of C. difficile, I am more concerned about preventing transmission of multi-drug resistant organisms on the hands of healthcare workers, and alcohol based products are generally felt to be superior in this regard and they have led to increased compliance. I feel we are sending our healthcare workers mixed messages without scientific support when we tell them that alcohol-based products are inferior when caring for every patient with C. difficile, as Dr. Bartlett suggests.

1. Gerding DN, Johnson S, Peterson LR, Mulligan ME, Silva J Jr. Clostridium difficile-associated diarrhea and colitis. Infect Control hosp Epidemiol. 1995;16:459-77.

2. Centers for Disease Control and Prevention. Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Advisory Committee and the HIPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR 2002;51(No. RR-16:[17]

Conflict of Interest:

None declared

C. difficile - a new epidemic requiring new therapeutics?
Posted on December 20, 2006
Anne M Anglim
Keck School of Medicine-University of Southern California
Conflict of Interest: None Declared

Dear Editor:

We enjoyed Dr. Bartlett's overview of the current epidemic of C. difficile, in particular his implications regarding the need for different conceptualizations of therapeutics, as well as infection control (1). The presently circulating BI/NAP1 strain of C. difficile manifests a spectrum of disease which seems, not only more severe, but in some ways qualitatively distinct from "yesterday's Cdiff."

Over the previous 4 years, we have accumulated substantial experience treating severe C. difficile-associated disease (CDAD), previously in Florida, Ohio, and currently in Los Angeles, California. Based on this experience, We wish to echo some of Dr. Bartlett's points, and wish to join with other investigators in evaluation and discussion of the following issues:

1. Rapid and sensitive diagnostic tests: it is likely that delayed diagnosis may lead to more severe morbidity with this BI/NAP1 strain. A preliminary analysis of paired stool testing for C. difficile at Florida Hospital using EIA for toxin A/B and reflex testing of negative results with cell culture-based cytotoxin assay revealed about 20% of cases EIA(- ), CDTA(+). Thus, a substantial fraction of cases can escape detection using EIA as a sole modality.

2. Therapeutic failure of oral metronidazole(monotherapy); this appears to be quite common with severe CDAD accompanied by ileus. In patients with severe disease, especially associated with peritonitis, We have had excellent results using IV metronidazole, and continuous vancomycin administered via nasogastric tube 2 grams every 24 hours. This preparation uses parenteral vancomycin mixed in 250 ml of sterile irrigant, until patient improves. Due to the frequent presence of disease in the right colon, instillation of vancomycin by enema may be suboptimal. A randomized study of such a regimen, perhaps in conjunction with other therapies seems warranted. Moreover, the mechanism of metronidazole failure remains unclear. More data regarding metronidazole pharmacokinetcs in various segments of the gut,as well as resistance, are needed.

3. Relapsing/recurrent CDAD: We have successfully treated numerous patients with pulse dosing of oral vancomycin. The construction of this regimen has been quite empiric due to a paucity of specific data in the published literature; analysis of time to sporulation and germination in the presence and absence of antibiotic pressure would be very helpful in providing a scientific basis for the high efficacy of this regimen. Better understanding of elements influencing sporulation, ecologic determinants, pathogen virulence factors (2) and host immunity is needed.

4. Adjunct immunotherapies: like other investigators (3), intravenous immunoglobulin (IVIG),using 1-2 doses of 400 mg/kg appears to have been colon and life-saving in many cases we have treated. Whether this is based on disease affecting a significantly sicker population (with poor humoral immune response to toxin), or altered immunological properties of the circulating BI/NAP1 clone is unclear.

5. Finally, it is wholly unclear whether use of drotrecogin alfa in adjunct treatment of sepsis associated with C. difficile would be of incrimental benefit in patients otherwise meeting criteria for therapy.

Until eagerly anticipated therapies such as vaccines, CDT-specific monoclonal antibodies (CDA1, MDX1388: currently in phase II trials)(4), and polymeric IgA (5) are approved, we would suggest that formal evaluation of the above modalities may be of merit.


Anne M. Anglim, MD, MS Division of Infectious Diseases Keck School of Medicine-University of Southern California Los Angeles, California

(1). Bartlett JG. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med 2006; 145: 758-764.

(2). Haraldsen JD, Sonenshein AL. Efficient sporulation in Clostridium difficile requires disruption of the sigmaK gene. Mol Microbiol 2003; 48: 811-821.

(3). Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother 2004; 53: 882-884.

(4). Babcock GJ, Broering TJ, Hernandez HJ, et al. Human monoclonal antibodies directed against toxin A and B prevent Clostridium difficile- induced mortality in hamsters. Infect Immun 2006; 74: 6339-6347.

(5). Stubbe H, Berdoz J, Kraebenbuhl J-P, Corthesy B. Polymeric IgA is superior to monomeric IgA and IgG carrying the same variable domain in preventing Clostridium difficile toxin A damaging of T84 monolayers. J Immunol 2000; 164: 1952-1960.

Conflict of Interest:

None declared

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