Arthritis in pseudomembranous colitis associated with an antibody to Clostridium difficile toxin.
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Biomedical subjects
Publications and source records attributed to D W Burdon.
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Since September 1977 we have seen 63 patients with Clostridium difficile and a faecal toxin, but only 33 had histological evidence of pseudomembranous colitis. We have conducted separate double blind trials of an antibiotic, vancomycin and an anion-exchange resin, colestipol, in patients with post-operative diarrhoea. Vancomycin was extremely effective at eradicating the organism and its faecal toxin. These changes were associated with a marked symptomatic improvement. Colestipol proved ineffective in absorbing the faecal toxin and caused no change in numbers of Clostridial difficile. There was no associated symptomatic response. Neither drug had any effect on diarrhoea not related to Clostridium difficile. A carrier state was created by those patients who continued to excrete the organism after Colestipol or placebo treatment. This was eradicated by subsequent treatment with vancomycin. Our brief experience with metronidazole is discussed and a rational basis for treatment advocated.
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In a prospective randomised trial in which 93 patients undergoing elective colorectal operations were given a short prophylactic course of metronidazole and kanamycin orally or systemically, postoperative sepsis occurred in only 3 (6.5%) of those given antimicrobials systemically, compared with 17 (36%) of those given oral prophylaxis (P less than 0.01). 15 of the 17 infections in patients who received antimicrobials orally were due to kanamycin-resistant bacteria present in the colon at operation. Bacterial overgrowth of Staphylococcus aureus was recorded in 6 of the patients who received oral therapy. Antibiotic-associated pseudomembranous colitis occurred in 7 patients, 6 of whom had received prophylaxis orally. These results indicate that oral administration of prophylactic antimicrobials in colon surgery should be avoided because of the risks of bacterial resistance, superinfection, and antibiotic-associated pseudomembranous colitis. Systemic per-operative antimicrobial prophylaxis is safer and more effective.
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We have reviewed 66 cases of antibiotic-associated colitis since March 1975, which have been associated with a 27 per cent mortality. We believe antibiotics may predispose patients to this condition which is caused by a toxin produced by Clostridium difficile. Although the disease is rare, it is more common than previously reported. The presentation, methods of diagnosis and treatment are discussed.
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The influence on colonic microflora of neomycin and metronidazole alone, or in combination, was studied in volunteers taking a normal diet. Bacterial counts on daily faecal samples revealed that metronidazole had no influence on anaerobic faecal bacteria. Neomycin on the other hand, was effective against sensitive aerobes. However, the combination of neomycin and metronidazole profoundly reduced both aerobic and bacteria. Assay of faecal antibiotic concentrations showed that neomycin achieved high intraluminal levels while metronidazole was undetectable or present at low concentrations.
The efficacy of vancomycin in pseudomembranous colitis was assessed in a prospective randomised controlled trial. Forty-four patients with postoperative diarrhoea were allocated to five days' treatment with either 125 mg vancomycin six-hourly or a placebo. Sixteen patients had high titres of the neutralised faecal toxin characteristic of pseudomembranous colitis; nine received vancomycin and seven placebo. At the end of treatment faecal toxins were present in one patient given vancomycin compared with five of the controls. Vancomycin caused the disappearance of Clostridum difficile from the stool in all except one patient, whereas toxicogenic strains of Cl difficile persisted in all but one of the controls. Histological evidence of psuedomembranous colitis had disappeared by the end of treatment in six out of seven patients given vancomycin compared with only one out of seven patients given vancomycin compared with only one out of five patients given placebo. In patients with faecal toxins bowel habit had returned to normal in seven of the vancomycin group compared with only one of the controls, but there was no significant difference in clinical response among patients without faecaal toxins. The results suggest that vancomycin eliminates toxin-producing Cl difficile from the colon and is associated with rapid clinical and histological improvement in patients with pseudomembranous colitis.
241 patients who had gastrointestinal operations were studied prospectively. Postoperative diarrhoea occurred in 58 patients (24%) and was significantly more common after exposure to antibiotics. 9 patients (4%) had high titres of a neutralisable faecal toxin characteristic of pseudomembranous colitis. Toxigenic Clostridium difficile strains were isolated from the stools of all patients with neutralisable faecal toxin. If pseudomembranous colitis is defined as the presence of neutralisable faecal toxin, then the diagnosis is often missed by sigmoidoscopy and rectal biopsy.
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Gastric aspirates were obtained from 12 healthy volunteers, 49 patients with duodenal ulcer, 14 with gastric ulcer and 35 with gastric carcinoma. The mean total viable bacterial counts in these groups were as follows: volunteers 0, duodenal ulcer 3.8 X 10(1), gastric ulcer 6.95 X 10(4), carcinoma 1.9 X 10(7) organisms/ml. The incidence of wound sepsis in patients without antibiotic cover was; duodenal ulcer 17 per cent, gastric ulcer 38 per cent, carcinoma 56 per cent. Regardless of the underlying pathology, patients with counts greater than 5 X 10(6) organisms/ml in the gastric aspirate had a 93 per cent incidence of wound sepsis, compared with 16 per cent in patients with counts of less than 5 X 10(6) organisms/ml (P less than 0.001). In the group with high counts all except one of the wound infections were caused by organisms present in the stomach at the time of operation. There was a good correlation in the bacteriology of apirates obtained during preoperative endoscopy compared with operative nasogastric samples (n = 31) both for viable counts (r = 0.93) and for the counts of individual organisms. Therefore, preoperative endoscopy can be used to identify patients who are at risk of developing wound sepsis after gastric surgery.
The influence of three types of preoperative mechanical bowel preparation on colonic microflora has been studied in 88 patients undergoing elective bowel resection and compared with 21 controls. Neither conventional bowel preparation (CBP) using oral magnesium sulphate, enemas and rectal washouts nor whole bowel irrigation (WBI) via a nasogastric tube influenced the type or number of organisms in the colon at the time of operation. The administration of an elemental diet (ED) was associated with only a small reduction the numbers of Escherichia coli (P less than 0.02). The addition of oral neomycin and metronidazole for 48 h before operation to all three methods of bowel preparation was associated with a highly significant reduction in the counts per ml of E. coli (P less than 0.001) and Bacteroides fragilis (P less than 0.001) in the colon. There was no correlation between the diameter of the lesion being resected with the numbers of bacteria in the colon even when oral neomycin and metronidazole were added to the bowel preparation.
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The microflora of the jejunum, ileum, and colon has been studied from operative samples in Crohn's disease (n = 30), ulcerative colitis (n = 15), and controls (n = 40). There was no significant difference in the flora of patients with ulcerative colitis compared with controls. In Crohn's disease there was a significant increase in E. coli (P less than 0.001) and B. fragilis (P less than 0.001) in the ileum and of E. coli (P less than 0.001) and lactobacilli (P less than 0.01) in the colon. The abnormal ileal flora in Crohn's disease was unrelated to serological evidence of disease activity (indices: ESR, serum albumin, serum seromucoids), diameter of the ileum, or excision of the ileocaecal valve. The abnormal colonic flora in Crohn's disease was not related to presence of macroscopic colitis.