GASTROENTEROLOGY
1991;101:685-691
Acute Abdomen as the First Presentation of Pseudomembranous Colitis GEORGE TRIADAFILOPOULOS
and ANN E. HALLSTONE
Gastroenterology Section, Veterans Affairs Medical Center, Martinez, California; Gastroenterology Section, St. Mary’s Hospital, San Francisco, California; and Department Medicine, University of California, Davis, California
Acute abdomen was the presenting manifestation of pseudomembranous colitis in six men who had previously been treated with antibiotics and presented with abdominal distention, pain, fever, and leukocytosis with absent or mild diarrhea. Plain abdominal radiographs revealed megacolon in two, combined small and large bowel dilation in three, with one of them showing volvuluslike pattern, and isolated small bowel ileus in one. Emergency colonoscopy was performed successfully in all patients and revealed pseudomembranes in five and nonspecific colitis in one. All patients had positive latex test dificile, and two tested results for Clostridium positive for cytotoxicity. All patients were treated with IV metronidazole, resulting in resolution of symptoms and abdominal findings. In addition, two patients underwent colonoscopic decompression with improvement. Endoscopically, complete resolution of the pseudomembranes occurred at 4 weeks in all cases. No patient had a recurrence. It is concluded that (a) pseudomembranous colitis may present as abdominal distention mimicking small bowel ileus, Ogilvie’s syndrome, volvulus, or ischemia; (b) in such cases, emergency colonoscopy is safe and useful for diagnosis and therapeutic decompression and may obviate the need for surgery; and (c) treatment with IV metronidazole is effective. Colitis due to C. di#icile should be considered in the differential diagnosis of acute abdomen in patients previously treated with antibiotics.
C
lostridium
difficile infection may cause a spectrum of clinical manifestations ranging from an asymptomatic carrier state to fulminant colitis with toxic megacolon (1). Pseudomembranous colitis, the classic manifestation of C. difficile infection, is increasingly recognized as a cause of diarrhea in hospitalized patients receiving antibiotics and may occur sporadi-
of
tally or epidemically (2,3). Although fulminant and lethal C. difficile-induced colitis have been described (4), acute “surgical” abdomen as the first presentation of pseudomembranous colitis has not been reported. We report here six cases of acute, severe abdominal distention and tenderness simulating surgical abdomen as the presenting manifestation of pseudomembranous colitis. In such cases, emergency colonoscopy is safe and useful for diagnosis and therapy and may obviate the need for surgery. Patients and Methods All patients were men with a mean age of 64 years (range, 42-76 years) who were seen sporadically over a 14-month period at a 400-bed acute care Veterans Affairs Medical Center. During the same time period, 88 cases of C. dificile infection were diagnosed and treated at the same institution. Diarrhea was defined as a change in bowel habits leading to greater than five loose movements per day. The exact nature of the stool was not a criterion for the definition of diarrhea. Stool samples and colonic aspirates were collected from all patients and kept at 4°C during processing. Stool cultures for enteric pathogens including special cultures for Yersinia and Campylobacter were performed, and results were negative in all patients. C. dificile and its toxin were assayed using the cytotoxicity assay on monolayers of HeLa cells (5) and a commercially available latex particle agglutination assay (6). Urgent colonoscopy was performed in all patients without prior colonic lavage; follow-up colonoscopy was performed after irrigation of the colon with GoLYTELY (Braintree Laboratories, Inc., Braintree, MA]. Colonoscopic decompression was performed using a fenestrated tube positioned over a colonoscopically inserted guide wire (7).
Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; CT, computed tomography: KUB, kidneys, ureters, and bladder: NG, nasogastric; WBC, white blood cell. % 1991 by the American Gastroenterological Association 0016~5085/91/$3.00
686
C. DIFFICILE AND ACUTE ABDOMEN
Case Reports Case 1
A 63-year-old white man with non-Hodgkin’s lymphoma was admitted to the hospital 10 days after a g-week course of chemotherapy with MACOP-B because of fever, anorexia, neutropenia, oral and anal mucositis, and evidence of polymicrobial sepsis. Antibiotic therapy with IV vancomycin, ceftazadime, and piperacillin was instituted upon admission with ensuing improvement. Development of right hydronephrosis required placement of a nephrostomy tube. During his recovery, having been off chemotherapy for 6 weeks and antibiotics for 1 week, the patient developed fever to 38.3”C, acute abdominal pain, and obstipation after passing two loose, mucoid guaiac-positive stools. On examination, he had marked abdominal distention, diffuse abdominal tenderness, guarding, and hypoactive bowel sounds. A kidneys, ureters, and bladder (KUB) film showed dilation and edema of the right colon and small bowel and a sigmoid volvuluslike pattern. Ultrasonography of the abdomen revealed multiple stool-filled loops of markedly distended small and large bowel. Nasogastric suction was initiated. Emergency colonoscopy revealed extensive erythema and inflammation of the colon with pseudomembranes extending from the rectosigmoid colon to the splenic flexure with relative rectal sparing. Colonic biopsies showed normal glandular architecture, focal inflammatory cell infiltration of the lamina propria, and fibrinous exudation with mucus and entrapped neutrophils consistent with pseudomembranous colitis. Results of a C. difficile latex test were positive. The patient was treated with a 3-week course of vancomycin, 125 mg every 6 hours per nasogastric (NG) tube and metronidazole, 250 mg every 6 hours IV. His abdominal pain resolved within 2 days, and his abdominal distention completely resolved in 1 week. Colonoscopy 2 weeks later showed less erythema and 75% improvement of pseudomembranes. Results of a follow-up latex test for C. difficile were negative. The patient subsequently died 1 month later of sepsis and pneumonia unrelated to his pseudomembranous colitis.
Case 2 A 66-year-old white man was admitted to the hospital because of chronic obstructive pulmonary disease (COPD) exacerbation due to Haemophilus influenza and Serratia marcescens respiratory infection and was treated with oral trimethoprim/sulfamethoxazole. His medical history was significant for steroid-dependent COPD, lung cancer, and episodes of intermittent small-volume diarrhea related to multiple courses of antibiotics for bronchitis. During his hospitalization he developed marked abdominal distention without pain. On physical examination, he was afebrile, markedly distended, and tympanitic and had hypoactive, high-pitched bowel sounds and no guarding. His urinary bladder was distended and palpable up to the level of the umbilicus, and on rectal examination was found to have guaiac-positive formed stool. White blood cell (WBC) count was 25,800. Megacolon with a cecal diameter of 10 cm was revealed by KLJB. The urinary bladder was decompressed with insertion of a Foley catheter, NG suction was estab-
GASTROENTEROLOGY
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lished, and the patient was hydrated. Results of a latex test for C. dificile were positive. Urine cultures grew Escherichia coli, and treatment with cefopime was initiated. Emergency colonoscopy to the cecum showed moderate erythema and edema but no pseudomembranes and relative rectal sparing; colonic biopsies revealed acute and chronic inflammation. Colonoscopic decompression was also performed, resulting in partial relief of the abdominal distention. A lo-day course of IV metronidazole, 566 mg every 6 hours, led to complete resolution of the abdominal distention within 3 days. Results of a subsequent latex test were negative. The patient had no recurrence of his colitis during a year of follow-up. Case 3
A 65-year-old man with metastatic prostate cancer was admitted to the hospital because of upper gastrointestinal bleeding and urinary tract infection. On admission he was afebrile, and results of the abdominal examination were normal. Upper endoscopy revealed multiple gastric ulcers. He was treated with blood transfusions, IV trimethoprim/ sulfamethoxazole, and cimetidine. On the eighth hospital day the patient became febrile to 39°C and developed marked abdominal distention, generalized tenderness, tympany, and decreased bowel sounds. White blood cell count was 12,100, showing a leftward shift, and blood cultures were positive for Streptococcus faecalis and Clostridium pedringens. A KUB film showed isolated small bowel dilation with air-fluid levels on upright examination and thickening and irregularity of the sigmoid colon outline. Continuous NG suction was applied. Colonoscopy revealed extensive pseudomembranes diffusely covering an underlying friable and edematous mucosa. Colonic biopsies revealed focal, acute, and chronic inflammation. Latex test results for C. difficile were positive; results of stool cultures for other enteric pathogens including C. peqtiingens were negative. He was treated with a lo-day course of vancomytin, 125 mg every 6 hours per NG tube, and metronidazole, 500 mg every 6 hours IV, resulting in rapid resolution of his fever and leukocytosis. However, his abdominal distention and pain persisted, albeit it had improved. Repeat colonoscopy 10 days later showed 50% improvement of pseudomembranes and edema. Results of a follow-up latex test and cytotoxicity assay were both negative. Intravenous metronidazole, 500 mg every 6 hours, was continued for a total of 4 weeks until complete resolution of the abdominal distention and pain was achieved. Repeat colonoscopy upon completion of metronidazole therapy showed resolution of the pseudomembranes with only mild erythema present in the rectosigmoid. The patient has had no recurrence as of a 6-month follow-up. Case 4
A 42-year-old white man with a history of peptic ulcer disease and alcoholism was admitted for evaluation of acute renal failure, abdominal distention, and suprapubic pain and tenderness. He had no nausea, vomiting, or diarrhea. On admission he was febrile to 39.2”C with moderately distended abdomen, tympany, hypoactive bowel
September 1991
sounds, and hepatomegaly. Neurologically he had mild disorientation and tremor. Laboratory tests showed a WBC count of 17,100, blood urea nitrogen level of 26.8 mol/L (75 mg/dL), creatinine level of 370 pmol/L (4.2 mg/dL), and bacteriuria and pyuria. Urine cultures showed E. coli. A KUB film showed dilated loops of small and large bowel with multiple air-fluid levels and no free air. An NG catheter was placed for suction. Colonoscopy revealed erythema and edema diffusely with mucus hypersecretion and pseudomembranes extending from the rectosigmoid colon to the splenic flexure. Colonoscopic aspiration of intestinal fluid was positive for C. dijjkile by the latex test. The patient was treated with vancomycin, 250 mg every 8 hours per NG tube, and IV metronidazole, 500 mg every 6 hours, for 10 days. Six days after the initiation of therapy, colonoscopy revealed 75% improvement in pseudomembranes, and coionic aspirates were negative for C. difficile by both the latex and cytotoxicity assays. His hospital course was complicated by alcohol withdrawal with delirium tremens, aspiration pneumonia, and adult respiratory distress syndrome (ARDS). Additional antibiotic therapy was instituted with IV ceftazadime, 1 g every 8 hours, and gentamicin, 90 mg every 8 hours, and the patient was intubated and ventilated. On the eighth hospital day he developed thrombocytopenia to 20,000, and the disseminated intravascular coagulation panel was positive for fibrin split products and high monomers, consistent with thrombotic thrombocytopenic purpura. He underwent plasmapheresis and improved clinically. With resolution of thrombotic thrombocytopenic purpura, ARDS, and renal failure, his abdominal distention completely resolved. Results of colonoscopic examination and tests for C. dificile were again negative on follow-up 4 weeks later. Case 5 A 76-year-old black man was hospitalized for treatment of congestive heart failure, renal insufficiency, right hemiparesis, and a general debilitative state. While undergoing nutritional support and physical rehabilitation, he developed enterococcal urinary tract infection for which he received a course of imipenem-cilastatin. One month later, while still in the hospital, the patient developed acute pronounced abdominal distention, left-sided abdominal pain, mild diarrhea, and guaiac-positive stool. He was afebrile with a WBC count of 8900. A KUB film showed multiple loops of dilated small and large bowel with air-fluid levels. Nasogastric suction was applied. Emergency colonoscopy revealed diffuse erythema and edema and pseudomembranes. Results of both latex and cytotoxicity assays for C. difli’cile were positive. The patient received a IO-day course of IV metronidazole, 500 mg every 12 hours, resulting in resolution of his abdominal distention, pain, and diarrhea within 3 days. Results of follow-up colonoscopy and cytotoxicity and latex assays for C. difficile were negative I month later. Case 6 ment
A 68-year-old white man was hospitalized for treatof organic brain syndrome, COPD, and peripheral
TRIADAFILOPOULOS AND HALLSTONE 687
neuropathy. While hospitalized, he developed aspiration pneumonia and was treated with IV clindamycin. Five days later the patient developed acute infraumbilical abdominal pain, pronounced abdominal distention, obstipation, and fever to 38°C. On examination he had a markedly distended abdomen with hypoactive bowel sounds, pronounced tympanicity, and guaiac-positive stool. His WBC count was 18,600, showing a leftward shift. A KUB film showed megacolon with mild dilation of small bowel loops. Abdominal computed tomography (CT) scanning revealed prominent megacolon without evidence of mucosal edema and gallbladder sludge. Nasogastric suction was applied. Emergency colonoscopy showed diffuse pseudomembranes, erythema, and edema involving the entire colon. Colonic mucosal biopsies revealed focal acute inflammation with pseudomembrane formation. A decompression tube was placed. Results of both latex and cytotoxicity assays for C. diflcile were positive. Therapy was initiated with metronidazole, 250 mg every 6 hours IV, and was continued for 10 days. One day later, a follow-up KUB film revealed partial decompression of dilated colon. Fever and leukocytosis resolved over the next 48 hours, and his abdominal distention and pain improved significantly. Eight days later, a second colonoscopy revealed total resolution of the colonic pseudomembranes, and results of colonic mucosal biopsies were normal. Upon follow-up 1 month later, a mild degree of abdominal distention, pain, and radiographic evidence of colonic dilation persisted; results of both C. difficile assays were negative.
Results and Discussion
The major finding of our study is the demonstration of antibiotic-associated colitis without diarrhea as the underlying cause for acute abdominal distention and pain mimicking acute abdomen in six patients previously treated with antibiotics (Table 1). Furthermore, our study strongly supports the prompt use of colonoscopy with or without decompression for the early diagnosis of pseudomembranous colitis, distinction from other acute abdominal syndromes, and rapid institution of effective antimicrobial therapy against C. dificile. Toxic megacolon secondary to pseudomembranous colitis was first reported by Brown et al. in 1968 (8). Since that time, toxic megacolon secondary to C. dificile-induced colitis has only been infrequently reported, and in most cases the diagnosis of pseudomembranous colitis was made at surgery (9,lO). Our study expands further on these observations and documents that a combination of large and small bowel dilation may be the presenting features of pseudomembranous colitis. Furthermore, pseudomembranous colitis presented initially as acute abdomen in 6 patients over a l&month period, during which 88 cases of C. difficile infection were recognized and treated, suggesting that such occurrence (7%) is more common than is generally recognized.
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GASTROENTEROLOGY Vol. 101, No. 3
Table 1. Clinical Features of Patients With Acute Abdomen Due to Pseudomembranous
Age/Sex Symptoms/signs Pain Fever [“C) Distention Diarrhea WBC count C. dificile assays Cytotoxicity Latex Radiography
Colonoscopy Pseudomembranes Decompression Treatment
Colitis
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
63/M
66/M
65/M
42/M
76/M
68/M
+ 39.2 + _
+
-
+
38.3 + -
36.7
39.0
+ -
+ -
1200
25,800
12,100
17,100
-
ND
ND
+
+
+
+
36.8
38.0
+ +
+ -
8900
18,600
-
+
+
+
+
+
Combined small and large bowl ileus and volvulus pattern
Megacolon
Isolated small bowel ileus
Combined small and large bowel ileus
Combined small and large bowel ileus
Megacolon
Segmental
Absent + M 2glday x 10 days
Diffuse -
Segmental -
Diffuse
M 2 g/day x4wk, V 0.5 g/day x 10 days 4wk
M 2 g day, V 0.75 g/day
M 2 g/day x 10 days
Diffuse + M 1 g/day x 10 days
M 1 g/day, V 0.5 g/day x3wk
Response to therapy ND, not done; M, metronidazole;
2-7
days
V, vancomycin
1-3 days
10 days
-
1-3 days
l-3 days
through NG tube.
The clinical presentation of C. diffi’cile-induced colitis in our study simulated acute abdomen from other etiologies such as small bowel ileus, colonic pseudoobstruction (Ogilvie’s syndrome), volvulus, or ischemia. All six of our patients initially presented with a distended abdomen, tenderness, tympanicity, and hypoactive bowel sounds. Five of them had severe abdominal pain, and only one had mild diarrhea. Fever and leukocytosis were present in the majority of patients. These clinical features were accompanied by a variety of radiological findings on plain abdominal films, ranging from megacolon to isolated small bowel ileus and volvuluslike pattern. The prompt performance of colonoscopy was diagnostic in all six cases and therapeutic in two, with at least partial decompression of the colon. The procedure was uniformly well tolerated in all cases and led to timely institution of appropriate antibiotic therapy that was curative in all cases with no recurrence. Five of six patients had pseudomembranes, edema, and erythema of the colon, and four of them had relative rectal sparing. In the patient without pseudomembranes, the diagnosis was based on evidence of nonspecific colitis with positive latex test results for C. diffi’cile. Furthermore, colonoscopy was an important tool in excluding other disorders causing similar clinical manifestations such as ischemic or neutropenic colitis, sigmoid volvulus, diverticulitis,, or Ogilvie’s syndrome (11). In all six cases, the diagnosis of C. dijjficile infection was made by the commercially available, newly devel-
oped latex-agglutination test. Although the specificity of this test against C. difficile toxin A (enterotoxin) remains controversial ($2), it appears at least equivalent to that of the tissue culture cytotoxicity assay for the diagnosis of clinically important C. dificile infection with a specificity of 79%99% (13,14), and is currently used in the majority of hospitals across the country because of its rapidity and simplicity. Stool culture is the most sensitive test for the diagnosis of C. dificile infection, but it requires the use of a special inhibitory medium and anaerobic conditions of incubation that make it labor-intensive. With as many as 20% of hospitalized patients asymptomatically colonized with C. di’cile, false-positive results from culture alone make the results of this test less specific than those of stool-cytotoxicity assay (15).In two of our latex-positive patients with pseudomembranes, cytotoxicity assay results were negative, but such occurrence of falsely negative tests has previously been recognized by many investigators (1,6,12)and should not dissuade the clinician from the correct diagnosis. The alternative hypothesis, that of non-C. dificile-induced pseudomembranous colitis associated with a latex-assay-reacting species that responds to metronidazole therapy, should also be considered. However, such cases have not been reported in the literature. A C. di#icile toxin A gene probe would be usefu1 for the identification of toxigenic strains directly in clinical specimens, particularly with the use of the polymerase chain reaction, which enhances the sensitivity of the probe (16).Such a gene probe is
September
1991
currently being developed, and it is expected to facilitate the diagnosis of unusual cases of C. diffi’cile infection similar to the ones presented here. It is also important to note the evolution of this variant of C. di_ficile infection. In five patients with pseudomembranes who received follow-up colonoscopy 6-14 days after diagnosis while receiving antimicrobial therapy, there was generally more than 50%
TRIADAFILOPOULOS
AND HALLSTONE
689
clearance of the pseudomembranes (25%-loo%), and there was 100% clearance at 1 month. There was no particular trend in the direction of clearance; one patient showed marked improvement of the rectosigmoid at 1 week, whereas two others had more pronounced improvement proximally at 10-14 days. Therefore, there is a lag between clinical and endoscopic improvement that cannot be assessed by sigmoi-
690
C. DIFFICILE AND ACUTE
ABDOMEN
GASTROENTEROLOGY
Vol. 101, No. 3
Figure 2. A. Abdominal
CT scan showing isolated megacolon with colt mic dilation and colonic wall t .hickening.
B. Abdomim tl CT scan showing severe me !gacolon without evidence of c(clonic wall thickening. A mi nimal degree of small bowel dilation is also present.
doscopy. Furthermore, the mere presence of pseudomembranes does not dictate a need for continuation of antimicrobial therapy. The radiological findings in our patients were variable and nonspecific, making the diagnosis more challenging. Three of our patients had combined small and large bowel dilation with one showing a
volvulus-like pattern, two had megacolon, and 1 had isolated small bowel dilation (Figures 1 and 2). The small bowel dilation noted in four of our six patients was a surprising finding and, although in agreement with, a previous report (li’), has not been observed by others (18). The pathophysiology of this syndrome of C. dificile
September
TRIADAFILOPOULOS
1991
infection remains elusive. Experimentally, abnormal gut motility was recently shown using purified C. difficile toxins A and B. Toxin A, when given in vivo, induces inflammation, increases mucosal permeability, and stimulates motor activity in the rabbit ileum, but has no effect on isolated muscle strips studied in vitro (19). Toxin A-induced stimulation, therefore, appears to occur via intermediates derived from inflammatory cells of the lamina propria affecting the underlying muscularis. By contrast, toxin B has no effect in vivo but in vitro directly inhibits both spontaneous and carbachol-induced spiking activity (20). The two toxins may act in concert, because toxin A may increase membrane permeability to large molecules, thereby allowing toxin B to gain direct access to gut muscle where it exerts its effect. Therefore, it is possible that in some cases the predominant clinical manifestations of C. dificile infection are those of abnormal gut motility due to direct or indirect effects of the C. dijficile toxins on the intestinal smooth muscle. Vancomycin and metronidazole share’ equal efficacy in the treatment of C. dificile-induced colitis (21). Metronidazole has been used successfully in both the oral and IV forms, although no controlled trials comparing the two forms have been carried out. All our patients were treated with IV metronidazole because the presence of ileus could have compromised drug delivery to the colon, and three patients received additional vancomycin through the NG tube. The duration of therapy was also variable, ranging from 10 days to 4 weeks, the majority of patients receiving a lo-day course of treatment. Prompt resolution of symptoms occurred in all patients, fever and leukocytosis clearing first (within 1-2 days), followed by pain and abdominal distention (3 days to 1 week). With IV metronidazole therapy, all cases resolved completely and none had a recurrence. In conclusion, we suggest that antibiotic-associated pseudomembranous colitis should be added to the list of causes for acute abdomen, even in the abs.ence of diarrhea. This variant of C. dificile infection is more common than is generally appreciated and is not associated with diarrhea. Recognition of pseudomembranous colitis in these patients by emergency colonoscopy with or without decompression and early initiation of IV metronidazole therapy against C. diffcile may obviate the need for surgery and contribute to improved overall management. References 1. Trnka YM, LaMont JT. Clostridium dificile colitis. 1984;29:85-107. 2. Nolan NP, Kelly CP, Humphreys JF, Cooney C, Walsh TN, Weir DG, O’Briain DS. An epidemic of branous colitis: importance of person to person 1987;28:1467-1473.
3
4
5.
6.
7.
8.
9 10.
11. 12
13.
14.
15.
16.
17. 18.
AND HALLSTONE
691
Pierce PF Jr, Wilson R, Silva J Jr, Garagusi VF, Rifkin GD, Fekety R, Nunez-Montiel 0,Dowel1 VR, Hughes JM. Antibioticassociated pseudomembranous colitis: an epidemiologic investigation of a cluster of cases. J Infect Dis 1982;145:269-274. Mogg GM, Keighley M, Burdon DW, Alexander-Williams J, Youngs D, Johnson M, Bentley S, George RH. Antibioticassociated colitis: A review of 66 cases. Br J Surg 1979;66:738742. Larson HE, Parry JV, Price DR, Davies DR, Dolby J, Tyrell DA. Undescribed toxin in pseudomembranous colitis. Br Med J 1977;i:1246-1248, Peterson LR, Holter JJ, Shanholtzer CJ, Garrett CR, Gerding DN. Detection of Clostridium difficile toxins A (enterotoxin) and B (cytotoxin) in clinical specimens. Evaluation of a latex agglutination test. Am J Clin Path01 1986;86:208-211. Burke GW, Shellito PC. Treatment of recurrent colonic pseudoobstruction by endoscopic placement of a fenestrated overtube. Dis Colon Rectum 1987;30:615-619. Brown CH, Ferrante WA, Davis WD Jr. Toxic dilation of the colon complicating pseudomembranous enterocolitis. Am J DigDis 1968;13:813-821, Cone JB, Wetzel W. Toxic megacolon secondary to pseudomembranous colitis. Dis Colon Rectum 1982;25:478-482. Burke GW, Wilson ME, Mehrez IO. Absence of diarrhea in toxic megacolon complicating Clostridium dificile pseudomembranous colitis. Am J Gastroenterol 1983;83:304-397. Starling JR. Treatment of nontoxic megacolon by colonoscopy. Surgery 1983;94:677-682. Lyerly DM, Wilkins TD. Commercial latex test for Clostridium di’cile toxin A does not detect toxin. Am J Clin Microbial 1986;23:622-623. Biddle WL, Harms JL, Greenberger NJ, Miner PB. Evaluation of antibiotic-associated diarrhea with latex agglutination test and cell culture cytotoxicity assay for Clostridium dificile. Am J Gastroenterol 1989;84:379-382. Kelly MT, Champagne SG, Sherlock CH, Noble MA, Freeman HJ, Smith JA. Commercial latex agglutination test for detection of Clostridium dificile-associated diarrhea. J Clin Microbial 1987;25:1244-1247. McFarland LV, Mulligan ME, Kwok RYY, Stamm WE. Nosocomial aquisition of Clostridium dificile infection. N Engl J Med 1989;320:204-210. Tabaqchali S. Molecular studies on the epidemiology and pathogenicity of Clostridium difficile. Gut Festchrift 1989;4451. Feinberg SB. The roentgen findings in severe pseudomembranous enterocolitis. Radiology 1960;74:778-782. Stanley RJ, Melson GL, Tedesco FJ, Saylor JL. Plain-film findings in severe pseudomembranous colitis. Radiology 1976; 118:7-11.
19. Gilbert RJ, Triadafilopoulos G, Pothoulakis C, Giampaolo C, LaMont JT. Effect of purified Clostridium difficile toxin on intestinal smooth muscle. I. Toxin A. Am J Physiol 1989;256: G759-766. 20. Gilbert RJ, Pothoulakis C, LaMont JT. Effect of purified Clostridium difficile toxin on intestinal smooth muscle. II. Toxin B. Am J Physiol 1989;256:G767-772. 21. Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, Lee JT Jr. Prospective randomized trial of metronidazole versus vancomycin for Clostridium dificile-associated diarrhea and colitis. Lancet 1983;1:1043-1046.
Adv Int Med O’Connor R, pseudomemspread. Gut
Received June 21,199O. Accepted January 23, 1991. Address requests for reprints to: George Triadafilopoulos, M.D., Chief, Gastroenterology Section, Martinez Veterans Affairs Medical Center (lllG), 150 Muir Road, Martinez, California 94553.
1991;101:685-691
Acute Abdomen as the First Presentation of Pseudomembranous Colitis GEORGE TRIADAFILOPOULOS
and ANN E. HALLSTONE
Gastroenterology Section, Veterans Affairs Medical Center, Martinez, California; Gastroenterology Section, St. Mary’s Hospital, San Francisco, California; and Department Medicine, University of California, Davis, California
Acute abdomen was the presenting manifestation of pseudomembranous colitis in six men who had previously been treated with antibiotics and presented with abdominal distention, pain, fever, and leukocytosis with absent or mild diarrhea. Plain abdominal radiographs revealed megacolon in two, combined small and large bowel dilation in three, with one of them showing volvuluslike pattern, and isolated small bowel ileus in one. Emergency colonoscopy was performed successfully in all patients and revealed pseudomembranes in five and nonspecific colitis in one. All patients had positive latex test dificile, and two tested results for Clostridium positive for cytotoxicity. All patients were treated with IV metronidazole, resulting in resolution of symptoms and abdominal findings. In addition, two patients underwent colonoscopic decompression with improvement. Endoscopically, complete resolution of the pseudomembranes occurred at 4 weeks in all cases. No patient had a recurrence. It is concluded that (a) pseudomembranous colitis may present as abdominal distention mimicking small bowel ileus, Ogilvie’s syndrome, volvulus, or ischemia; (b) in such cases, emergency colonoscopy is safe and useful for diagnosis and therapeutic decompression and may obviate the need for surgery; and (c) treatment with IV metronidazole is effective. Colitis due to C. di#icile should be considered in the differential diagnosis of acute abdomen in patients previously treated with antibiotics.
C
lostridium
difficile infection may cause a spectrum of clinical manifestations ranging from an asymptomatic carrier state to fulminant colitis with toxic megacolon (1). Pseudomembranous colitis, the classic manifestation of C. difficile infection, is increasingly recognized as a cause of diarrhea in hospitalized patients receiving antibiotics and may occur sporadi-
of
tally or epidemically (2,3). Although fulminant and lethal C. difficile-induced colitis have been described (4), acute “surgical” abdomen as the first presentation of pseudomembranous colitis has not been reported. We report here six cases of acute, severe abdominal distention and tenderness simulating surgical abdomen as the presenting manifestation of pseudomembranous colitis. In such cases, emergency colonoscopy is safe and useful for diagnosis and therapy and may obviate the need for surgery. Patients and Methods All patients were men with a mean age of 64 years (range, 42-76 years) who were seen sporadically over a 14-month period at a 400-bed acute care Veterans Affairs Medical Center. During the same time period, 88 cases of C. dificile infection were diagnosed and treated at the same institution. Diarrhea was defined as a change in bowel habits leading to greater than five loose movements per day. The exact nature of the stool was not a criterion for the definition of diarrhea. Stool samples and colonic aspirates were collected from all patients and kept at 4°C during processing. Stool cultures for enteric pathogens including special cultures for Yersinia and Campylobacter were performed, and results were negative in all patients. C. dificile and its toxin were assayed using the cytotoxicity assay on monolayers of HeLa cells (5) and a commercially available latex particle agglutination assay (6). Urgent colonoscopy was performed in all patients without prior colonic lavage; follow-up colonoscopy was performed after irrigation of the colon with GoLYTELY (Braintree Laboratories, Inc., Braintree, MA]. Colonoscopic decompression was performed using a fenestrated tube positioned over a colonoscopically inserted guide wire (7).
Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; CT, computed tomography: KUB, kidneys, ureters, and bladder: NG, nasogastric; WBC, white blood cell. % 1991 by the American Gastroenterological Association 0016~5085/91/$3.00
686
C. DIFFICILE AND ACUTE ABDOMEN
Case Reports Case 1
A 63-year-old white man with non-Hodgkin’s lymphoma was admitted to the hospital 10 days after a g-week course of chemotherapy with MACOP-B because of fever, anorexia, neutropenia, oral and anal mucositis, and evidence of polymicrobial sepsis. Antibiotic therapy with IV vancomycin, ceftazadime, and piperacillin was instituted upon admission with ensuing improvement. Development of right hydronephrosis required placement of a nephrostomy tube. During his recovery, having been off chemotherapy for 6 weeks and antibiotics for 1 week, the patient developed fever to 38.3”C, acute abdominal pain, and obstipation after passing two loose, mucoid guaiac-positive stools. On examination, he had marked abdominal distention, diffuse abdominal tenderness, guarding, and hypoactive bowel sounds. A kidneys, ureters, and bladder (KUB) film showed dilation and edema of the right colon and small bowel and a sigmoid volvuluslike pattern. Ultrasonography of the abdomen revealed multiple stool-filled loops of markedly distended small and large bowel. Nasogastric suction was initiated. Emergency colonoscopy revealed extensive erythema and inflammation of the colon with pseudomembranes extending from the rectosigmoid colon to the splenic flexure with relative rectal sparing. Colonic biopsies showed normal glandular architecture, focal inflammatory cell infiltration of the lamina propria, and fibrinous exudation with mucus and entrapped neutrophils consistent with pseudomembranous colitis. Results of a C. difficile latex test were positive. The patient was treated with a 3-week course of vancomycin, 125 mg every 6 hours per nasogastric (NG) tube and metronidazole, 250 mg every 6 hours IV. His abdominal pain resolved within 2 days, and his abdominal distention completely resolved in 1 week. Colonoscopy 2 weeks later showed less erythema and 75% improvement of pseudomembranes. Results of a follow-up latex test for C. difficile were negative. The patient subsequently died 1 month later of sepsis and pneumonia unrelated to his pseudomembranous colitis.
Case 2 A 66-year-old white man was admitted to the hospital because of chronic obstructive pulmonary disease (COPD) exacerbation due to Haemophilus influenza and Serratia marcescens respiratory infection and was treated with oral trimethoprim/sulfamethoxazole. His medical history was significant for steroid-dependent COPD, lung cancer, and episodes of intermittent small-volume diarrhea related to multiple courses of antibiotics for bronchitis. During his hospitalization he developed marked abdominal distention without pain. On physical examination, he was afebrile, markedly distended, and tympanitic and had hypoactive, high-pitched bowel sounds and no guarding. His urinary bladder was distended and palpable up to the level of the umbilicus, and on rectal examination was found to have guaiac-positive formed stool. White blood cell (WBC) count was 25,800. Megacolon with a cecal diameter of 10 cm was revealed by KLJB. The urinary bladder was decompressed with insertion of a Foley catheter, NG suction was estab-
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lished, and the patient was hydrated. Results of a latex test for C. dificile were positive. Urine cultures grew Escherichia coli, and treatment with cefopime was initiated. Emergency colonoscopy to the cecum showed moderate erythema and edema but no pseudomembranes and relative rectal sparing; colonic biopsies revealed acute and chronic inflammation. Colonoscopic decompression was also performed, resulting in partial relief of the abdominal distention. A lo-day course of IV metronidazole, 566 mg every 6 hours, led to complete resolution of the abdominal distention within 3 days. Results of a subsequent latex test were negative. The patient had no recurrence of his colitis during a year of follow-up. Case 3
A 65-year-old man with metastatic prostate cancer was admitted to the hospital because of upper gastrointestinal bleeding and urinary tract infection. On admission he was afebrile, and results of the abdominal examination were normal. Upper endoscopy revealed multiple gastric ulcers. He was treated with blood transfusions, IV trimethoprim/ sulfamethoxazole, and cimetidine. On the eighth hospital day the patient became febrile to 39°C and developed marked abdominal distention, generalized tenderness, tympany, and decreased bowel sounds. White blood cell count was 12,100, showing a leftward shift, and blood cultures were positive for Streptococcus faecalis and Clostridium pedringens. A KUB film showed isolated small bowel dilation with air-fluid levels on upright examination and thickening and irregularity of the sigmoid colon outline. Continuous NG suction was applied. Colonoscopy revealed extensive pseudomembranes diffusely covering an underlying friable and edematous mucosa. Colonic biopsies revealed focal, acute, and chronic inflammation. Latex test results for C. difficile were positive; results of stool cultures for other enteric pathogens including C. peqtiingens were negative. He was treated with a lo-day course of vancomytin, 125 mg every 6 hours per NG tube, and metronidazole, 500 mg every 6 hours IV, resulting in rapid resolution of his fever and leukocytosis. However, his abdominal distention and pain persisted, albeit it had improved. Repeat colonoscopy 10 days later showed 50% improvement of pseudomembranes and edema. Results of a follow-up latex test and cytotoxicity assay were both negative. Intravenous metronidazole, 500 mg every 6 hours, was continued for a total of 4 weeks until complete resolution of the abdominal distention and pain was achieved. Repeat colonoscopy upon completion of metronidazole therapy showed resolution of the pseudomembranes with only mild erythema present in the rectosigmoid. The patient has had no recurrence as of a 6-month follow-up. Case 4
A 42-year-old white man with a history of peptic ulcer disease and alcoholism was admitted for evaluation of acute renal failure, abdominal distention, and suprapubic pain and tenderness. He had no nausea, vomiting, or diarrhea. On admission he was febrile to 39.2”C with moderately distended abdomen, tympany, hypoactive bowel
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sounds, and hepatomegaly. Neurologically he had mild disorientation and tremor. Laboratory tests showed a WBC count of 17,100, blood urea nitrogen level of 26.8 mol/L (75 mg/dL), creatinine level of 370 pmol/L (4.2 mg/dL), and bacteriuria and pyuria. Urine cultures showed E. coli. A KUB film showed dilated loops of small and large bowel with multiple air-fluid levels and no free air. An NG catheter was placed for suction. Colonoscopy revealed erythema and edema diffusely with mucus hypersecretion and pseudomembranes extending from the rectosigmoid colon to the splenic flexure. Colonoscopic aspiration of intestinal fluid was positive for C. dijjkile by the latex test. The patient was treated with vancomycin, 250 mg every 8 hours per NG tube, and IV metronidazole, 500 mg every 6 hours, for 10 days. Six days after the initiation of therapy, colonoscopy revealed 75% improvement in pseudomembranes, and coionic aspirates were negative for C. difficile by both the latex and cytotoxicity assays. His hospital course was complicated by alcohol withdrawal with delirium tremens, aspiration pneumonia, and adult respiratory distress syndrome (ARDS). Additional antibiotic therapy was instituted with IV ceftazadime, 1 g every 8 hours, and gentamicin, 90 mg every 8 hours, and the patient was intubated and ventilated. On the eighth hospital day he developed thrombocytopenia to 20,000, and the disseminated intravascular coagulation panel was positive for fibrin split products and high monomers, consistent with thrombotic thrombocytopenic purpura. He underwent plasmapheresis and improved clinically. With resolution of thrombotic thrombocytopenic purpura, ARDS, and renal failure, his abdominal distention completely resolved. Results of colonoscopic examination and tests for C. dificile were again negative on follow-up 4 weeks later. Case 5 A 76-year-old black man was hospitalized for treatment of congestive heart failure, renal insufficiency, right hemiparesis, and a general debilitative state. While undergoing nutritional support and physical rehabilitation, he developed enterococcal urinary tract infection for which he received a course of imipenem-cilastatin. One month later, while still in the hospital, the patient developed acute pronounced abdominal distention, left-sided abdominal pain, mild diarrhea, and guaiac-positive stool. He was afebrile with a WBC count of 8900. A KUB film showed multiple loops of dilated small and large bowel with air-fluid levels. Nasogastric suction was applied. Emergency colonoscopy revealed diffuse erythema and edema and pseudomembranes. Results of both latex and cytotoxicity assays for C. difli’cile were positive. The patient received a IO-day course of IV metronidazole, 500 mg every 12 hours, resulting in resolution of his abdominal distention, pain, and diarrhea within 3 days. Results of follow-up colonoscopy and cytotoxicity and latex assays for C. difficile were negative I month later. Case 6 ment
A 68-year-old white man was hospitalized for treatof organic brain syndrome, COPD, and peripheral
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neuropathy. While hospitalized, he developed aspiration pneumonia and was treated with IV clindamycin. Five days later the patient developed acute infraumbilical abdominal pain, pronounced abdominal distention, obstipation, and fever to 38°C. On examination he had a markedly distended abdomen with hypoactive bowel sounds, pronounced tympanicity, and guaiac-positive stool. His WBC count was 18,600, showing a leftward shift. A KUB film showed megacolon with mild dilation of small bowel loops. Abdominal computed tomography (CT) scanning revealed prominent megacolon without evidence of mucosal edema and gallbladder sludge. Nasogastric suction was applied. Emergency colonoscopy showed diffuse pseudomembranes, erythema, and edema involving the entire colon. Colonic mucosal biopsies revealed focal acute inflammation with pseudomembrane formation. A decompression tube was placed. Results of both latex and cytotoxicity assays for C. diflcile were positive. Therapy was initiated with metronidazole, 250 mg every 6 hours IV, and was continued for 10 days. One day later, a follow-up KUB film revealed partial decompression of dilated colon. Fever and leukocytosis resolved over the next 48 hours, and his abdominal distention and pain improved significantly. Eight days later, a second colonoscopy revealed total resolution of the colonic pseudomembranes, and results of colonic mucosal biopsies were normal. Upon follow-up 1 month later, a mild degree of abdominal distention, pain, and radiographic evidence of colonic dilation persisted; results of both C. difficile assays were negative.
Results and Discussion
The major finding of our study is the demonstration of antibiotic-associated colitis without diarrhea as the underlying cause for acute abdominal distention and pain mimicking acute abdomen in six patients previously treated with antibiotics (Table 1). Furthermore, our study strongly supports the prompt use of colonoscopy with or without decompression for the early diagnosis of pseudomembranous colitis, distinction from other acute abdominal syndromes, and rapid institution of effective antimicrobial therapy against C. dificile. Toxic megacolon secondary to pseudomembranous colitis was first reported by Brown et al. in 1968 (8). Since that time, toxic megacolon secondary to C. dificile-induced colitis has only been infrequently reported, and in most cases the diagnosis of pseudomembranous colitis was made at surgery (9,lO). Our study expands further on these observations and documents that a combination of large and small bowel dilation may be the presenting features of pseudomembranous colitis. Furthermore, pseudomembranous colitis presented initially as acute abdomen in 6 patients over a l&month period, during which 88 cases of C. difficile infection were recognized and treated, suggesting that such occurrence (7%) is more common than is generally recognized.
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Table 1. Clinical Features of Patients With Acute Abdomen Due to Pseudomembranous
Age/Sex Symptoms/signs Pain Fever [“C) Distention Diarrhea WBC count C. dificile assays Cytotoxicity Latex Radiography
Colonoscopy Pseudomembranes Decompression Treatment
Colitis
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
63/M
66/M
65/M
42/M
76/M
68/M
+ 39.2 + _
+
-
+
38.3 + -
36.7
39.0
+ -
+ -
1200
25,800
12,100
17,100
-
ND
ND
+
+
+
+
36.8
38.0
+ +
+ -
8900
18,600
-
+
+
+
+
+
Combined small and large bowl ileus and volvulus pattern
Megacolon
Isolated small bowel ileus
Combined small and large bowel ileus
Combined small and large bowel ileus
Megacolon
Segmental
Absent + M 2glday x 10 days
Diffuse -
Segmental -
Diffuse
M 2 g/day x4wk, V 0.5 g/day x 10 days 4wk
M 2 g day, V 0.75 g/day
M 2 g/day x 10 days
Diffuse + M 1 g/day x 10 days
M 1 g/day, V 0.5 g/day x3wk
Response to therapy ND, not done; M, metronidazole;
2-7
days
V, vancomycin
1-3 days
10 days
-
1-3 days
l-3 days
through NG tube.
The clinical presentation of C. diffi’cile-induced colitis in our study simulated acute abdomen from other etiologies such as small bowel ileus, colonic pseudoobstruction (Ogilvie’s syndrome), volvulus, or ischemia. All six of our patients initially presented with a distended abdomen, tenderness, tympanicity, and hypoactive bowel sounds. Five of them had severe abdominal pain, and only one had mild diarrhea. Fever and leukocytosis were present in the majority of patients. These clinical features were accompanied by a variety of radiological findings on plain abdominal films, ranging from megacolon to isolated small bowel ileus and volvuluslike pattern. The prompt performance of colonoscopy was diagnostic in all six cases and therapeutic in two, with at least partial decompression of the colon. The procedure was uniformly well tolerated in all cases and led to timely institution of appropriate antibiotic therapy that was curative in all cases with no recurrence. Five of six patients had pseudomembranes, edema, and erythema of the colon, and four of them had relative rectal sparing. In the patient without pseudomembranes, the diagnosis was based on evidence of nonspecific colitis with positive latex test results for C. diffi’cile. Furthermore, colonoscopy was an important tool in excluding other disorders causing similar clinical manifestations such as ischemic or neutropenic colitis, sigmoid volvulus, diverticulitis,, or Ogilvie’s syndrome (11). In all six cases, the diagnosis of C. dijjficile infection was made by the commercially available, newly devel-
oped latex-agglutination test. Although the specificity of this test against C. difficile toxin A (enterotoxin) remains controversial ($2), it appears at least equivalent to that of the tissue culture cytotoxicity assay for the diagnosis of clinically important C. dificile infection with a specificity of 79%99% (13,14), and is currently used in the majority of hospitals across the country because of its rapidity and simplicity. Stool culture is the most sensitive test for the diagnosis of C. dificile infection, but it requires the use of a special inhibitory medium and anaerobic conditions of incubation that make it labor-intensive. With as many as 20% of hospitalized patients asymptomatically colonized with C. di’cile, false-positive results from culture alone make the results of this test less specific than those of stool-cytotoxicity assay (15).In two of our latex-positive patients with pseudomembranes, cytotoxicity assay results were negative, but such occurrence of falsely negative tests has previously been recognized by many investigators (1,6,12)and should not dissuade the clinician from the correct diagnosis. The alternative hypothesis, that of non-C. dificile-induced pseudomembranous colitis associated with a latex-assay-reacting species that responds to metronidazole therapy, should also be considered. However, such cases have not been reported in the literature. A C. di#icile toxin A gene probe would be usefu1 for the identification of toxigenic strains directly in clinical specimens, particularly with the use of the polymerase chain reaction, which enhances the sensitivity of the probe (16).Such a gene probe is
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1991
currently being developed, and it is expected to facilitate the diagnosis of unusual cases of C. diffi’cile infection similar to the ones presented here. It is also important to note the evolution of this variant of C. di_ficile infection. In five patients with pseudomembranes who received follow-up colonoscopy 6-14 days after diagnosis while receiving antimicrobial therapy, there was generally more than 50%
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clearance of the pseudomembranes (25%-loo%), and there was 100% clearance at 1 month. There was no particular trend in the direction of clearance; one patient showed marked improvement of the rectosigmoid at 1 week, whereas two others had more pronounced improvement proximally at 10-14 days. Therefore, there is a lag between clinical and endoscopic improvement that cannot be assessed by sigmoi-
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Figure 2. A. Abdominal
CT scan showing isolated megacolon with colt mic dilation and colonic wall t .hickening.
B. Abdomim tl CT scan showing severe me !gacolon without evidence of c(clonic wall thickening. A mi nimal degree of small bowel dilation is also present.
doscopy. Furthermore, the mere presence of pseudomembranes does not dictate a need for continuation of antimicrobial therapy. The radiological findings in our patients were variable and nonspecific, making the diagnosis more challenging. Three of our patients had combined small and large bowel dilation with one showing a
volvulus-like pattern, two had megacolon, and 1 had isolated small bowel dilation (Figures 1 and 2). The small bowel dilation noted in four of our six patients was a surprising finding and, although in agreement with, a previous report (li’), has not been observed by others (18). The pathophysiology of this syndrome of C. dificile
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1991
infection remains elusive. Experimentally, abnormal gut motility was recently shown using purified C. difficile toxins A and B. Toxin A, when given in vivo, induces inflammation, increases mucosal permeability, and stimulates motor activity in the rabbit ileum, but has no effect on isolated muscle strips studied in vitro (19). Toxin A-induced stimulation, therefore, appears to occur via intermediates derived from inflammatory cells of the lamina propria affecting the underlying muscularis. By contrast, toxin B has no effect in vivo but in vitro directly inhibits both spontaneous and carbachol-induced spiking activity (20). The two toxins may act in concert, because toxin A may increase membrane permeability to large molecules, thereby allowing toxin B to gain direct access to gut muscle where it exerts its effect. Therefore, it is possible that in some cases the predominant clinical manifestations of C. dificile infection are those of abnormal gut motility due to direct or indirect effects of the C. dijficile toxins on the intestinal smooth muscle. Vancomycin and metronidazole share’ equal efficacy in the treatment of C. dificile-induced colitis (21). Metronidazole has been used successfully in both the oral and IV forms, although no controlled trials comparing the two forms have been carried out. All our patients were treated with IV metronidazole because the presence of ileus could have compromised drug delivery to the colon, and three patients received additional vancomycin through the NG tube. The duration of therapy was also variable, ranging from 10 days to 4 weeks, the majority of patients receiving a lo-day course of treatment. Prompt resolution of symptoms occurred in all patients, fever and leukocytosis clearing first (within 1-2 days), followed by pain and abdominal distention (3 days to 1 week). With IV metronidazole therapy, all cases resolved completely and none had a recurrence. In conclusion, we suggest that antibiotic-associated pseudomembranous colitis should be added to the list of causes for acute abdomen, even in the abs.ence of diarrhea. This variant of C. dificile infection is more common than is generally appreciated and is not associated with diarrhea. Recognition of pseudomembranous colitis in these patients by emergency colonoscopy with or without decompression and early initiation of IV metronidazole therapy against C. diffcile may obviate the need for surgery and contribute to improved overall management. References 1. Trnka YM, LaMont JT. Clostridium dificile colitis. 1984;29:85-107. 2. Nolan NP, Kelly CP, Humphreys JF, Cooney C, Walsh TN, Weir DG, O’Briain DS. An epidemic of branous colitis: importance of person to person 1987;28:1467-1473.
3
4
5.
6.
7.
8.
9 10.
11. 12
13.
14.
15.
16.
17. 18.
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Pierce PF Jr, Wilson R, Silva J Jr, Garagusi VF, Rifkin GD, Fekety R, Nunez-Montiel 0,Dowel1 VR, Hughes JM. Antibioticassociated pseudomembranous colitis: an epidemiologic investigation of a cluster of cases. J Infect Dis 1982;145:269-274. Mogg GM, Keighley M, Burdon DW, Alexander-Williams J, Youngs D, Johnson M, Bentley S, George RH. Antibioticassociated colitis: A review of 66 cases. Br J Surg 1979;66:738742. Larson HE, Parry JV, Price DR, Davies DR, Dolby J, Tyrell DA. Undescribed toxin in pseudomembranous colitis. Br Med J 1977;i:1246-1248, Peterson LR, Holter JJ, Shanholtzer CJ, Garrett CR, Gerding DN. Detection of Clostridium difficile toxins A (enterotoxin) and B (cytotoxin) in clinical specimens. Evaluation of a latex agglutination test. Am J Clin Path01 1986;86:208-211. Burke GW, Shellito PC. Treatment of recurrent colonic pseudoobstruction by endoscopic placement of a fenestrated overtube. Dis Colon Rectum 1987;30:615-619. Brown CH, Ferrante WA, Davis WD Jr. Toxic dilation of the colon complicating pseudomembranous enterocolitis. Am J DigDis 1968;13:813-821, Cone JB, Wetzel W. Toxic megacolon secondary to pseudomembranous colitis. Dis Colon Rectum 1982;25:478-482. Burke GW, Wilson ME, Mehrez IO. Absence of diarrhea in toxic megacolon complicating Clostridium dificile pseudomembranous colitis. Am J Gastroenterol 1983;83:304-397. Starling JR. Treatment of nontoxic megacolon by colonoscopy. Surgery 1983;94:677-682. Lyerly DM, Wilkins TD. Commercial latex test for Clostridium di’cile toxin A does not detect toxin. Am J Clin Microbial 1986;23:622-623. Biddle WL, Harms JL, Greenberger NJ, Miner PB. Evaluation of antibiotic-associated diarrhea with latex agglutination test and cell culture cytotoxicity assay for Clostridium dificile. Am J Gastroenterol 1989;84:379-382. Kelly MT, Champagne SG, Sherlock CH, Noble MA, Freeman HJ, Smith JA. Commercial latex agglutination test for detection of Clostridium dificile-associated diarrhea. J Clin Microbial 1987;25:1244-1247. McFarland LV, Mulligan ME, Kwok RYY, Stamm WE. Nosocomial aquisition of Clostridium dificile infection. N Engl J Med 1989;320:204-210. Tabaqchali S. Molecular studies on the epidemiology and pathogenicity of Clostridium difficile. Gut Festchrift 1989;4451. Feinberg SB. The roentgen findings in severe pseudomembranous enterocolitis. Radiology 1960;74:778-782. Stanley RJ, Melson GL, Tedesco FJ, Saylor JL. Plain-film findings in severe pseudomembranous colitis. Radiology 1976; 118:7-11.
19. Gilbert RJ, Triadafilopoulos G, Pothoulakis C, Giampaolo C, LaMont JT. Effect of purified Clostridium difficile toxin on intestinal smooth muscle. I. Toxin A. Am J Physiol 1989;256: G759-766. 20. Gilbert RJ, Pothoulakis C, LaMont JT. Effect of purified Clostridium difficile toxin on intestinal smooth muscle. II. Toxin B. Am J Physiol 1989;256:G767-772. 21. Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, Lee JT Jr. Prospective randomized trial of metronidazole versus vancomycin for Clostridium dificile-associated diarrhea and colitis. Lancet 1983;1:1043-1046.
Adv Int Med O’Connor R, pseudomemspread. Gut
Received June 21,199O. Accepted January 23, 1991. Address requests for reprints to: George Triadafilopoulos, M.D., Chief, Gastroenterology Section, Martinez Veterans Affairs Medical Center (lllG), 150 Muir Road, Martinez, California 94553.
