Correspondence

Clostridium difficile Colitis

N Engl J Med 1994; 330:1754-1755June 16, 1994

Article

To the Editor:

The review of Clostridium difficile colitis (Jan. 27 issue)1 contains the misleading statement that “the laboratory diagnosis of C. difficile infection depends on the demonstration of C. difficile toxins in stool” by the stool-cytotoxin assay, which has a “high sensitivity (94 to 100 percent) and specificity (99 percent).” The studies cited to support this statement required a positive cytotoxin assay for their definition of a true positive case. Therefore, these studies cannot define the sensitivity of the cytotoxin test for the diagnosis of C. difficile-associated disease.

Mcfarland et al. found the cytotoxin assay to be neither completely sensitive nor specific for the diagnosis of C. difficile disease, since 57 percent of asymptomatic carriers were cytotoxin-positive and 26 percent of symptomatic patients were cytotoxin-negative2. Peterson et al. similarly found the sensitivity of a cytotoxin assay of a single stool specimen to be only 67 percent,3 and Gerding et al. found that as many as 11 percent of patients with positive C. difficile cultures and negative cytotoxin assays had pseudomembranous colitis detected by endoscopy4. The absence of detectable cytotoxin in some patients may result from the instability of the toxin in stool. Failure to recognize and treat C. difficile-associated disease in culture-positive, toxin-negative cases has been associated with increased morbidity and mortality5.

We recommend that stool specimens from patients with suspected C. difficile infection be submitted for both culture and cytotoxin assay, although we recognize that culture methods are not completely specific and toxin assays not completely sensitive. The culture of C. difficile also allows strain-typing studies if a nosocomial outbreak is suspected. C. difficile isolated from patients with negative stool-cytotoxin assays can be tested for the elaboration of cytotoxin in vitro. The therapeutic implications of these studies would depend on the clinical assessment of the patient; a trial of oral metronidazole or vancomycin would be appropriate in a patient with persistent symptoms who has had a negative cytotoxin assay and a positive culture for toxigenic C. difficile. These recommendations have been supported recently in an excellent review of the laboratory diagnosis of C. difficile infections6.

In summary, no single test can be used to establish or exclude the diagnosis of C. difficile-associated diarrhea. Despite recent advances in laboratory methods, clinical judgment still has a role.

Ferric C. Fang, M.D.
Nancy E. Madinger, M.D.
University of Colorado Health Sciences Center, Denver, CO 80262

6 References

1
Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330:257-262
Full Text | Web of Science | Medline

2
McFarland LV, Elmer GW, Stamm WE, Mulligan ME. Correlation of immunoblot type, enterotoxin production, and cytotoxin production with clinical manifestations of Clostridium difficile infection in a cohort of hospitalized patients. Infect Immun 1991;59:2456-2462
Web of Science | Medline

3
Peterson LR, Olson MM, Shanholtzer CJ, Gerding DN. Results of a prospective, 18-month clinical evaluation of culture, cytotoxin testing, and culturette brand (CDT) latex testing in the diagnosis of Clostridium difficile-associated diarrhea. Diagn Microbiol Infect Dis 1988;10:85-91
CrossRef | Web of Science | Medline

4
Gerding DN, Olson MM, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis in adults: a prospective case-controlled epidemiologic study. Arch Intern Med 1986;146:95-100
CrossRef | Web of Science | Medline

5
Lashner BA, Todorczuk J, Sahm DF, Hanauer SB. Clostridium difficile culture-positive toxin-negative diarrhea. Am J Gastroenterol 1986;81:940-943
Web of Science | Medline

6
Peterson LR, Kelly PJ. The role of the clinical microbiology laboratory in the management of Clostridium difficile-associated diarrhea. Infect Dis Clin North Am 1993;7:277-293
Web of Science | Medline

To the Editor:

The recent review of C. difficile colitis stated that vancomycin should be reserved for patients who cannot tolerate or who do not respond to metronidazole. We disagree with this recommendation when the colitis is severe. The study cited to demonstrate the equal efficacy of the two drugs1 included only 24 patients with fever, which we commonly see in patients with severe colitis. The cost comparison of the two regimens must include other factors. If vancomycin can hasten recovery from C. difficile colitis, it shortens expensive hospital stays.

In evaluating therapy, one must recognize the morbidity and mortality associated with C. difficile colitis, particularly in elderly patients. If one withholds what is possibly the best therapy, the opportunity to use that therapy may be lost. We have seen enough in our own experience (in the absence of data to the contrary) to believe that severe C. difficile colitis responds more quickly to vancomycin. However, given the emergence of vancomycin-resistant enterococci, the use of vancomycin may have to be limited even if it is more effective.

Daniel S. Berman, M.D.
Barry D. Wenglin, M.D.
White Plains Hospital Medical Center, White Plains, NY 10605

1 References

1
Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983;2:1043-1046
CrossRef | Web of Science | Medline

To the Editor:

Data at our institution show that previous administration of oral vancomycin is a risk factor for the acquisition of vancomycin-resistant enterococcus. In 1993, blood cultures from 47 patients grew vancomycin-resistant enterococcus, and 26 of these patients (55 percent) were positive for C. difficile toxin. A retrospective chart review showed that 16 of those 26 patients (62 percent) had received oral vancomycin. Our findings are in accord with those of Frieden et al.,1 who showed that the administration of vancomycin (oral or intravenous) is a risk factor for the acquisition of vancomycin-resistant enterococcus.

We now require that our division of infectious disease review and approve all requests for oral vancomycin. Vancomycin-resistant enterococcus is a problematic, potentially pathogenic entity for which treatment is nonexistent or unproved. Laboratory evidence shows that the gene for vancomycin resistance can be transferred from enterococci to Staphylococcus aureus2. Alternative agents to treat diarrhea caused by C. difficile infection are needed.

William M. Goldman, R.Ph., Pharm.D.
Annette Stahl Avicolli, R.Ph.
Suzanne Lutwick, R.N., C.I.C.
Maimonides Medical Center, Brooklyn, NY 11219

2 References

1
Frieden TR, Munsiff SS, Low DE, et al. Emergence of vancomycin-resistant enterococci in New York City. Lancet 1993;342:76-79
CrossRef | Web of Science | Medline

2
Nosocomial enterococci resistant to vancomycin -- United States, 1989-1993. MMWR Morb Mortal Wkly Rep 1993;42:597-599
Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Fang and Madinger recommend that all patients thought to have C. difficile infection should have stool samples submitted for both culture and toxin assay. We disagree with this advice and with the authors' interpretation of the studies quoted to support it. We recommend the toxin assay as the primary laboratory test to identify toxicogenic C. difficile in stool samples, for two reasons.

First, the cytotoxin assay is the most specific and sensitive test available1. Indeed, the difficulty mentioned by Drs. Fang and Madinger in defining its sensitivity stems from the fact that there is no better test with which to compare it. Some loss of sensitivity results from toxin degradation or improper handling of stool specimens, which may be overcome by submitting more than one stool sample and processing samples promptly.

Second, stool culture for C. difficile requires two to five days for an initial result and a further two to four days to test for toxin production in vitro -- a factor that limits the clinical usefulness of the assay. The results of the toxin assay can be available within 24 hours. We do not accept the contention that the cytotoxin assay lacks specificity on the basis of positive test results in asymptomatic persons. The test is highly specific for C. difficile toxin B, but many people who are colonized with toxicogenic C. difficile are asymptomatic carriers.

We agree that unrecognized cases of C. difficile colitis exist in our hospitals, but the routine application of C. difficile culture is not an effective means of improving this situation. Such culture is useful in epidemiologic studies and possibly in cases where C. difficile colitis is suspected but the diagnosis is not confirmed by toxin assay or by endoscopy. In such situations, a therapeutic trial of metronidazole or vancomycin is appropriate.

We agree with Drs. Berman and Wenglin that it is reasonable to use oral vancomycin as initial therapy in patients with fulminant C. difficile colitis2. However, we recommend metronidazole as the antimicrobial agent of first choice for the vast majority of patients with C. difficile diarrhea. Vancomycin is far more expensive than metronidazole, and a prospective randomized trial found both agents to be equally effective3. There is also evidence, as presented in our review, of a higher relapse rate among patients treated with vancomycin, which may ultimately increase both morbidity and cost. The recent reports highlighted by Goldman et al. that link vancomycin therapy to the emergence of vancomycin-resistant enterococcus add further support to our recommendation that vancomycin be reserved for fulminant or refractory cases.

We agree with Goldman et al. that alternative therapies for C. difficile colitis are needed. Oral administration of the yeast Saccharomyces boulardii4 and oral passive immunization against C. difficile toxins with bovine immunoglobulin concentrate5 are currently under investigation as non-antibiotic approaches to the treatment of this antibiotic-induced disease.

Ciaran P. Kelly, M.B.
Charalabos Pothoulakis, M.D.
J. Thomas Lamont, M.D.
Boston University Medical Center Hospital, Boston, MA 02118

5 References

1
Bartlett JG. Clostridium difficile-associated diarrhea and colitis. In: Gorbach SL, Barlett JG, Blacklow NR, eds. Infectious diseases. Philadelphia: W.B. Saunders, 1992:612-7.

2
Kelly CP, LaMont JT. Treatment of Clostridium difficile diarrhea and colitis. In: Wolfe MM, ed. Gastrointestinal pharmacotherapy. Philadelphia: W.B. Saunders, 1993:199-212.

3
Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983;2:1043-1046
CrossRef | Web of Science | Medline

4
McFarland LV, Bernasconi P. Saccharomyces boulardii: a review of an innovative biotherapeutic agent. Microb Ecol Health Dis 1993;6:157-171
CrossRef | Web of Science

5
Lyerly DM, Bostwick EF, Binion SB, Wilkins TD. Passive immunization of hamsters against disease caused by Clostridium difficile by use of bovine immunoglobulin G concentrate. Infect Immun 1991;59:2215-2218
Web of Science | Medline

Citing Articles (4)

Citing Articles

1
Eva Kaiser, Sascha Pust, Claudia Kroll, Holger Barth. (2009) Cyclophilin A facilitates translocation of the Clostridium botulinum C2 toxin across membranes of acidified endosomes into the cytosol of mammalian cells. Cellular Microbiology 11:5, 780-795
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2
Anna Wanahita, Elizabeth A. Goldsmith, Daniel M. Musher. (2002) Conditions Associated with Leukocytosis in a Tertiary Care Hospital, with Particular Attention to the Role of Infection Caused by Clostridium difficile. Clinical Infectious Diseases 34:12, 1585-1592
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3
PAUL D. M. PETTIT, BERND-UWE SEVIN. (2002) Intraoperative Injury to the Gastrointestinal Tract and Postoperative Gastrointestinal Emergencies. Clinical Obstetrics and Gynecology 45:2, 492-506
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4
L. R. Peterson, P. J. Kelly, H. A. Nordbrock. (1996) Role of culture and toxin detection in laboratory testing for diagnosis ofClostridium difficile-associated diarrhea. European Journal of Clinical Microbiology & Infectious Diseases 15:4, 330-336
CrossRef