Marc S. Itskowitz, MD, and Paul J. Lebovitz, MD A BSTRACT Almost all cases of pseudomembranous colitis reported during the past 3 decades have been associated with antimicrobial use. We report a case of nonantibiotic-associated pseudomembranous colitis and review similar cases in the literature that suggest the need for increased clinical awareness of this condition. A 77-year-old white female presented with a history of watery diarrhea, abdominal cramping, and a 30-lb weight loss during the past 6 weeks. She denied recent antibiotic use, which was confirmed by contacting her pharmacist. Colonoscopy revealed severe focal ulceration of the colonic mucosa and adherent yellow plaques in the rectum and sigmoid colon, pathologic features consistent with pseudomembranous colitis. The result of a stool cytotoxin assay was positive for Clostridium difficile. The patient was treated with oral vancomycin and exhibited rapid improvement. In a review of the literature, we found 9 well-documented cases of nonantibiotic-associated pseudomembranous colitis in patients without predisposing factors. Most of those patients were elderly women who presented with diarrhea and abdominal pain. The diagnosis of pseudomembranous colitis was confirmed by colonoscopy, by the identification of C difficile in stool culture, or by cytotoxicity assay. Treatment usually was initiated with oral vancomycin and dosages differed. In the 9 cases reviewed, the mortality rate was 11% and the rate of relapse, 33%. CLINICAL VIGNETTE Nonantibiotic-Associated Pseudomembranous Colitis: A Case Report and Review of the Literature (Adv Stud Med. 2003;3(10):571-574) seudomembranous colitis (PMC) was first described in 1893, when a patient who had severe diarrhea was found at autopsy to have “diphtheritic colitis.”1 PMC was attributed to mucosal ischemia or viral infection until 1977, when a toxin that produced cytopathic changes in tissue culture cells was identified in stool specimens from affected patients.2 Within a year of that report, Clostridium difficile, a spore-forming, gram-positive anaerobic P bacillus, had been identified as the source of the cytotoxin.3 Almost all cases of PMC reported during the past 3 decades have been associated with antimicrobial use. We report a case of nonantibiotic-associated PMC and review similar cases in the literature that suggest the need for increased clinical awareness of this condition. CASE REPORT A 77-year-old white female presented with a 6-week history of watery diarrhea, Dr Itskowitz is Assistant Professor of Medicine, Drexel University College of Medicine; Associate Program Director, Internal Medicine Residency Program, Allegheny General Hospital, Pittsburgh, Pennsylvania. Dr Lebovitz is Assistant Professor of Medicine, Drexel University College of Medicine; Director, Division of Gastroenterology, Allegheny General Hospital, Pittsburgh, Pennsylvania. Drs Itskowitz and Lebovitz have reported they have no financial or advisory relationships with corporate organizations related to this activity. Off-Label Product Discussion: The authors of this article do not include information on off-label use of products. Correspondence to: Marc Itskowitz, MD, Department of Internal Medicine, Allegheny General Hospital, 490 East North Avenue, Ste 103, Pittsburgh, PA 15212. Advanced Studies in Medicine 571 CLINICAL VIGNETTE abdominal cramping, and a 30-lb weight loss. Her medical history included a myocardial infarction 4 years prior to admission and a 10-year history of osteoarthritis, for which she had recently begun treatment with diclofenac 50 mg twice daily. The patient’s other medications included diltiazem 120 mg once daily and transdermal nitroglycerin 0.4 mg/hour for 12 hours daily. She denied recent antibiotic use, which was confirmed by contacting her pharmacist. Physical examination revealed an elderly white female with orthostatic hypotension, decreased skin turgor, and dry mucous membranes. Her abdomen was mildly distended with left lower quadrant tenderness. Rectal examination revealed no masses and the presence of loose dark stools that were negative for fecal occult blood. Colonoscopy revealed severe focal ulceration of the colonic mucosa with adherent yellow plaques in the rectum and sigmoid colon, pathologic features consistent with PMC (Figure). The stool cytotoxin assay was positive for C difficile. Treatment with oral vancomycin produced rapid improvement. LITERATURE In a review of the literature from 1966 to 1999, we found 9 well-documented cases of nonantibiotic-associated PMC in patients without predisposing factors (Table). Most patients were elderly (mean age, 69 years). There was a striking predominance of females (89%) among the cases reported. The most common clinical features Figure. Severe Focal Ulceration of Colonic Mucosa With Adherent Pseudomembranous Exudative Yellow Plaques 572 reported included diarrhea (in all patients), abdominal pain (3 patients), weight loss (2 patients), and anorexia (1 patient). The mean duration of symptoms prior to diagnosis was 26 days. The diagnosis of PMC was confirmed by colonoscopy in 7 of the patients and by the results of both stool culture and cytotoxicity assay for C difficile in 6 patients. Treatment was most commonly initiated with oral vancomycin at varying doses. In the 9 cases reviewed, 1 patient died and 3 patients relapsed. DISCUSSION Earlier teaching about the pathogenesis of PMC centered on the overgrowth of C difficile caused by antibiotic suppression of the normal bowel microflora, which appears to be the major risk factor for the development of PMC. However, the mechanism of disease is probably more complex, because many of the antibiotics that cause PMC are active against C difficile and other bowel microflora, and because diarrhea does not develop in many patients who become colonized with C difficile. Although C difficile can be detected in the stool of only 2% to 3% of healthy adults in the United States, retrieval of C difficile from stool occurs in 20% of asymptomatic adults who have recently been treated with antibiotics.4 PMC was reported before the antibiotic era; Finney’s original description of the disease preceded the advent of antimicrobial therapy by more than 40 years.1 Thus, factors other than antimicrobial therapy must account for the disturbance in bowel microflora and the enhanced toxin production, both of which predispose patients to PMC. The role of other medications in this disease is not known. PMC has been reported during gold therapy and during treatment with diclofenac, an anti-inflammatory agent that inhibits cyclooxygenase and reduces intracellular concentrations of free arachidonate in leukocytes. 5 Gentric and Pennec reported a case of diclofenac-induced PMC in 1992.6 That article presents the second reported case of PMC associated with diclofenac use. The complex interaction among the normal microflora of the intestine, antibiotics and other drugs that affect the microbial environment, and procedures that alter motility may contribute to the proliferation of pathogens.7 In the absence of antimicrobial treatment, PMC may occur after surgery and in patients with chronic, debilitating illnesses. Other risk factors for Vol. 3, No. 10 ■ November/December 2003 PSEUDOMEMBRANOUS COLITIS PMC include spinal fracture, intestinal obstruction, carcinoma, leukemia, chemotherapy for cancer, severe burns, uremia, intestinal obstruction, and heavy-metal poisoning.8 PMC is also a recognized complication of Hirschsprung’s disease unrelated to antibiotic use.9 It has been suggested that bowel ischemia may cause nonantibiotic-asso- ciated PMC.10 Antibiotic-associated susceptibility to C difficile appears to increase with age, and mesenteric ischemia occurs at a higher rate in elderly patients with diffuse vascular disease.11 Elderly patients with mesenteric ischemia may be at higher risk for the overgrowth of C difficile and for PMC. Additional studies are needed to address the quan- Table. Nonantibiotic-Associated Pseudomembranous Colitis: Features, Diagnosis,Treatment, and Outcome Patient Age (y), Gender Clinical Features Stool Culture Positive for C difficile Stool Culture Positive for C difficile Toxin Endoscopy Treatment Outcome 80, F10 Diarrhea for 8 d, weight loss of 6 lb No No Yes Vancomycin 500 mg po qd Improvement 92, F11 Diarrhea for 2 wk Yes Yes No Vancomycin 250 mg po tid for 3 d Improvement 78, F11 Diarrhea for 1 d Yes Yes No Vancomycin 250 mg po tid for 3 d Improvement 74, F11 Abdominal pain, diarrhea for 5 d Yes Yes Yes Vancomycin 250 mg po tid for 10 d Initial improvement; disease recurred, and patient underwent urgent colectomy 69, F12 Diarrhea for 3 mo No No Yes Metronidazole 1.5 g qd for 7 d Improvement 57, F13 Anorexia, abdominal pain, diarrhea for 2 mo; weight loss of 10 lb Yes Yes Yes Vancomycin 500 mg po q 6 h for 1 wk Initial improvement; patient required second course of vancomycin for recurrent disease, was readmitted with a colonic perforation, and died after surgery 22, M14 Abdominal pain, diarrhea for 4 wk Yes No Yes Vancomycin 250 mg po q 8 h Rapid improvement 67, F15 Diarrhea for 3 d No Yes Yes Vancomycin 1 g po bid for 10 d Partial improvement 82, F 16 Diarrhea, weakness, confusion Yes Yes Yes Vancomycin 500 mg po qid Initial improvement but disease recurred 2 wk later; no response to metronidazole 750 mg po tid for 8 d, after which patient improved with vancomycin 500 mg po qid and was discharged with treatment of vancomycin 125 mg po bid for prophylaxis F = female; qd = daily; po = by mouth; M = male; bid = twice daily; qid = 4 times daily; tid = 3 times daily. Advanced Studies in Medicine 573 CLINICAL VIGNETTE titative or qualitative changes that occur in the bowel microflora in patients with sustained hypoxemia and bowel ischemia. CONCLUSION PMC caused by C difficile may occur without prior antibiotic therapy, surgery, or overt systemic illness. The occurrence of nonantibiotic-associated PMC underscores the importance of obtaining a stool cytotoxicity assay for C difficile and of considering sigmoidoscopy in the evaluation of patients with acute and persistent diarrhea. Patients who have an acute diarrheal illness associated with fecal leukocytes often have been exposed to an infectious agent or have underlying inflammatory bowel disease. When more common causes of acute enteritis and colitis have been ruled out, PMC should be considered in patients who develop persistent diarrhea, even those without a history of antibiotic use. This case report and review of the literature demonstrate that PMC may occur in patients who have no underlying illness and have not received recent antibiotic therapy. REFERENCES 1. Finney JMT. Gastroenterostomy for cicatrizing ulcer of the pylorus. Johns Hopkins Hosp Bull. 1893;4 (May):53-55. 2. Larson HE, Parry JV, Price AB, Davies DR, Dolby J, Tyrrell DA. Undescribed toxin in pseudomembranous colitis. Br Med J. 1977;1:1246-1248. 3. George RH, Symonds JM, Dimock F, et al. Identification of Clostridium difficile as a cause of pseudomembranous colitis. Br Med J. 1978;1:695. 4. Viscidi R, Willey S, Bartlett JG. Isolation rates and toxigenic potential of Clostridium difficile isolates from various patient populations. Gastroenterology. 1981;81:5-9. 574 5. Reinhart WH, Kappeler M, Halter F. Severe pseudomembranous and ulcerative colitis during gold therapy. Endoscopy. 1983;15:70-71. 6. Gentric A, Pennec YL. Diclofenac-induced pseudomembranous colitis. Lancet. 1992; 340:126-127. 7. Grube BJ, Heimbach DM, Marvin JA. Clostridium difficile diarrhea in critically ill burned patients. Arch Surg. 1987;122:655-661. 8. Bartlett JG. Pseudomembranous enterocolitis and antibiotic-associated colitis. In: Feldman M, ed. Gastrointestinal and Liver Diseases. 6th ed. Philadelphia, Pa: WB Saunders; 1998:1633-1647. 9. Brearly S, Armstrong GR, Nairn R, et al. Pseudomembranous colitis: a lethal complication of Hirschsprung’s disease unrelated to antibiotic usage. J Pediatr Surg. 1987;22:257-259. 10. Laing RB, Dykhuizen RS, Smith CC, Gould IW, Reid TM. Community-acquired toxigenic Clostridium difficile diarrhoea in the normoxaemic elderly who have received no antimicrobials: soft evidence for ischaemic colitis? Scott Med J. 1996;41:15-16. 11. Aronsson B, Mollby R, Nord CE. Antimicrobial agents and Clostridium difficile in acute enteric disease: epidemiological data from Sweden, 198082. J Infect Dis. 1985;151:476-481. 12. Malcolm AJ. Pseudomembranous colitis in a colostomy. Br Med J. 1978;2:479. 13. Peikin SR, Galdibini J, Bartlett JG. Role of Clostridium difficile in a case of nonantibiotic-associated pseudomembranous colitis. Gastroenterology. 1980;79:948-951. 14. Howard JM, Sullivan SN, Troster M. Spontaneous pseudomembranous colitis. Br Med J. 1980; 281:356. 15. Wald A, Mendelow H, Bartlett JG. Non-antibioticassociated pseudomembranous colitis due to toxinproducing clostridia. Ann Intern Med. 1980; 92:798-799. 16. Moskovitz M, Bartlett JG. Recurrent pseudomembranous colitis unassociated with prior antibiotic therapy. Arch Intern Med. 1981;141:663-664. Vol. 3, No. 10 ■ November/December 2003