Skip to main content

Steroid-refractory ulcerative colitis treated with corticosteroids, metronidazole and vancomycin: a case report



Increasing evidence elucidating the pathogenic mechanisms of ulcerative colitis (UC) has accumulated and the disease is widely assumed to be the consequence of genetic susceptibility and an abnormal immune response to commensal bacteria. However evidence regarding an infectious etiology in UC remains elusive.

Case presentation

We report a provocative case of UC with profound rheumatologic involvement directly preceded by Clostridium difficile infection and accompanying fever, vomiting, bloody diarrhea, and arthritis. Colonic biopsy revealed a histopathology suggestive of UC. Antibiotic treatment eliminated detectable levels of enteric pathogens but did not abate symptoms. Resolution of symptoms was procurable with oral prednisone, but tapering of corticosteroids was only achievable in combination therapy with vancomycin and metronidazole.


An infectious pathogen may have both precipitated and exacerbated autoimmune disease attributes in UC, symptoms of which could be resolved only with a combination of corticosteroids, vancomycin and metronidazole. This may warrant the need for more perceptive scrutiny of C. difficile and the like in patients with UC.

Peer Review reports


Clostridium difficile infection may be a compounding factor in ulcerative colitis (UC) with data suggestive of a role in disease exacerbation or initiation by the organism in a subset of patients [1]. Adjunctive antibiotic therapy, either broad-spectrum or gram positive-specific, has shown limited efficacy in UC [2, 3]. However, sporadic reports in which significant therapeutic potential was achieved [46] suggest that a distinct subclass of patients with an infectious-associated phenotype may exist. Although there have been an increasing number of case reports on ulcerative colitis complicated by cytomegalovirus infection [79], there are few with conclusive evidence of infection with Clostridium difficile. Herein, we report a case of steroid-resistant UC with profound rheumatologic involvement immediately preceded by C. difficile infection in which remission of UC symptoms was twice achieved in response to adjunct metronidazole and vancomycin therapy. The patient remained symptom-free without supportive therapy for a four-year period.

Case presentation

A 32-year-old white male presented with nausea, vomiting, crampy lower abdominal pain and diarrhea. His initial lab values were hemoglobin 15.6 g/dl (14–18 g/dl), hematocrit 45.8% (40–54%), sodium 131 mEq/l (135–146 mEq/l), potassium 3.9 mEq/l (3.5–5.5 mEq/l), bicarbonate 24 mEq/l (22–24 mEq/l), chloride 91 mEq/l (95–112 mEq/l), BUN 37 mg/dl (7–25 mg/dl), serum creatinine 1.6 mg/dl (0.7–1.4 mg/dl), and normal liver function tests. He was treated with intravenous fluids, Ciprofloxacin and anti-emetics, to which the diarrhea resolved in 2–3 days. After one month he had recurrent watery diarrhea accompanied with rectal pain, bleeding and vomiting. He also developed fever of 101.6 F.

The physical exam was remarkable for decreased bowel sounds and moderate lower abdominal tenderness. There were no masses or organomegalies palpable. The rectal exam was remarkable for tenderness and heme-positive mucus. The remainder of the physical exam was uneventful. Stool samples from the initial visit were positive for Clostridium difficile cytotoxin, and depicted many WBCs (neutrophils 99% and eosinophils 1%), suggesting an infectious etiology. Stool sample was negative for giardia lamblia, salmonella, shigella, campylobacter, aeromonas and plesiomonas. There was no predominance of staphylococcus, yeast, or pseudomonas.

The patient was initially started on Ciprofloxacin (500 mg bid.) for 3 days without symptom resolution. Metronidazole was added (250 mg tid.), but intolerance of the patient to metronidazole with exacerbations of nausea prompted the replacement to Vancomycin (250 mg qid) in conjunction with Ciprofloxacin for 7 days. During this initial treatment period, the patient characteristically developed migratory polyarticular joint pain and swelling involving the shoulders, elbows, fingers, hips and knees. Lack of response to antibiotics suggested an autoimmune disease as a contributing factor.

At this time a sigmoidoscopy and pinch biopsy revealed diffuse acute and chronic inflammation with cryptitis, mucin depletion, and glandular foreshortening and branching suggestive of UC (Fig. 1). The patient was treated with Asacol (400 mg bid.) in conjunction with metronidazole (250 mg qid). After 7 days of combined therapy with continued weight loss and no improvement, prednisone (60 mg qid.) was added, resulting in cessation of GI symptoms and moderate improvement in joint pain and swelling. After 7 days of continued improvement, the antibiotic and Asacol therapy were stopped. The patient was maintained on high dose steroids for 14 days. However, fever, gastrointestinal, and joint symptoms recurred upon tapering of prednisone to 20 mg a day. When symptoms recurred, a stool culture was negative for infectious agents including Clostridium difficile antigen, confirming an autoimmune component to disease pathology in this patient. Prednisone was increased to 30 mg per day at which point gastrointestinal symptoms resolved but joint swelling and pain continued. Over the course of 3 months prednisone tapering was attempted three additional times, with each resulting in symptom recurrence.

Figure 1
figure 1

Colonic mucosal inflammation in ulcerative colitis with loss of goblet cells and neutrophilic infiltrate (magnification ×100)

After 3 months of treatment, the patient experienced an acute dental abscess and was prescribed a combination vancomycin (250 mg tid) and metronidazole (250 mg tid). During this period, the patient was able to gradually reduce prednisone dosage without symptom recurrence. Antibiotics were continued for 30 days during which time prednisone was tapered completely. Symptoms did not recur and the patient remained symptom-free without further therapeutic intervention for 4.5 years.

After this prolonged period of remission of UC symptoms, a second episode similar to the first occurred. The patient once again presented with bloody diarrhea, nausea, vomiting, and joint pain. Stool cultures were Clostridium difficile positive by culture and cytotoxin. Once again the patient was treated with 60 mg daily of prednisone and metronidazole (250 mg tid). Symptoms did not resolve, and vancomycin (125 mg tid) was added, resulting in a significant improvement in symptoms. After 2 weeks of combined therapy metronidazole treatment was stopped and symptoms recurred within a week. Metronidazole was once again added, leading to resolution of symptoms. Combined antibiotic and steroid therapy continued for 2 months during which time prednisone was tapered completely and a second remission of UC symptoms was induced.


The patient was remarkable in several regards. The onset of UC and spondyloarthropathy coincided with C. difficile infection. While various therapeutic regimens of prednisone, vancomycin and metronidazole preceded a negative C. difficile toxin test, remission of UC symptoms could only be induced by the combination of these three medications. C. difficile toxin tests have shown varying efficacy in diagnosing pseudomembranous colitis. It has been demonstrated that toxin-negative patients with C. difficile positive stool culture may still have symptomatic pseudomembranous colitis [10]. Lynch et al showed that 46% of stool specimens from patients test negative by cytotoxin but positive by culture [11]. Likewise, others have shown that some cases of C. difficile infection cannot be detected by the cytotoxin assay and suggested that the organism has the ability to vary toxin production [1216]. The bacterium also tends to persist as an antibiotic-resistant vegetative spore, which explains the high frequency at which the symptoms recur following treatment.

Since toxin-negative patients have presented with C. difficile related diarrhea, it is reasonable to assume that the organism may exist undetectably in a symptomatic patient, but especially in a patient with inflammatory bowel disease (IBD). The elusiveness of the bacterium in diagnosis of C. difficile infected IBD patients was confirmed in 2001 by Markowitz et al. They demonstrated that single-toxin assays failed to identify C. difficile infection in approximately 40% of pediatric IBD patients and in a case report where a toxin A positive, toxin B negative variant was detected [14, 17]. It has also been shown that IBD patients have a higher incidence of C. difficile infection than in healthy controls [18]. When considered together with the case reported here, this information leads us to the hypothesis that a small subclass of UC pathology may actually have an infectious etiology resulting from chronic C. difficile infection.

IBD has been shown to be more prevalent in industrialized nations, where antibiotic treatment has its longest history [19]. The increase in IBD prevalence parallels rising antibiotic use over the last 50 years [20]. If an undetected antibiotic-resistant enteric pathogen is responsible for inducing or exacerbating IBD, then widespread antibiotic use may have contributed to the increased prevalence of IBD in these industrialized nations.

This case is especially interesting considering H. pylori and its recently discovered tendency to adhere to glycoconjugates expressed in inflamed gastric mucosa [21]. In light of this new information, it is tempting to speculate that C. difficile could similarly bind to inflamed colonic tissue in this subclass of UC patients. Further research in this area could yield valuable new data.

The potential utility of combined therapy is further suggested by the fact that antimicrobial resistance among C. difficile strains to metronidazole and with intermediate resistance to vancomycin is emerging in countries like Hong Kong (where one of 100 C. difficile isolates was resistant to metronidazole) and Spain (where 9% of 469 clinically significant C. difficile isolates were resistant to metronidazole, particularly in isolates recovered from HIV-positive patients and few patients also had intermediate resistance to vancomycin) [2224] It is interesting to note that no resistance was found to metronidazole or vancomycin among C. difficile strains from isolates in patients from UK, Germany, Brazil, Poland or Kuwait [2529]. The Public Health Laboratory Service (PHLS) Anaerobe Reference Unit (ARU) has also not been successful in detection of metronidazole resistance in any of their over 1000 C. difficile isolates tested [24]. The impact of drug resistance should be considered if long-term treatment is utilized in patients. However, a complicating factor in this context is that for metronidazole and vancomycin, minimum inhibitory concentration susceptibility breakpoints are usually set for isolates causing systemic infections that are based upon antimicrobial levels in blood (serum) and not on the levels in the intraluminal area, where higher drug concentrations can be achieved [30].


Recurrent relapses could only be suppressed in this patient by the combination therapy of corticosteroids, metronidazole and vancomycin. Our observations suggest that this combination therapy may be effective to confront and induce remissions of UC symptoms in patients with C. difficile toxin-positive refractory autoimmune symptomatologic UC as opposed to the use of a single agent.

An opportunistic C. difficile infection commonly results from the use of broad-spectrum antibiotics like quinolones. The frequent use of these antibiotics in treating IBD suggests that these patients could develop C. difficile infection during treatment, thereby exacerbating symptoms and preventing remission of UC symptoms. It may therefore be practical to probe for C. difficile infections more meticulously in patients with IBD.


  1. Bolton RP, Sherriff RJ, Read AE: Clostridium difficile associated diarrhoea: a role in inflammatory bowel disease?. Lancet. 1980, 1: 383-4. 10.1016/S0140-6736(80)90940-X.

    Article  CAS  PubMed  Google Scholar 

  2. Dickinson RJ, O'Connor HJ, Pinder I, Hamilton I, Johnston D, Axon AT: Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut. 1985, 26: 1380-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Trnka YM, LaMont JT: Association of Clostridium difficile toxin with symptomatic relapse of chronic inflammatory bowel disease. Gastroenterology. 1981, 80: 693-6.

    CAS  PubMed  Google Scholar 

  4. Peppercorn MA: Are antibiotics useful in the management of nontoxic severe ulcerative colitis?. J Clin Gastroenterol. 1993, 17: 14-7.

    Article  CAS  PubMed  Google Scholar 

  5. Turunen UM, Farkkila MA, Hakala K, Seppala K, Sivonen A, Ogren M, Vuoristo M, Valtonen VV, Miettinen TA: Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study. Gastroenterology. 1998, 115: 1072-8.

    Article  CAS  PubMed  Google Scholar 

  6. Chapman RW, Selby WS, Jewell DP: Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut. 1986, 27: 1210-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Papadakis KA, Tung JK, Binder SW, Kam LY, Abreu MT, Targan SR, Vasiliauskas EA: Outcome of cytomegalovirus infections in patients with inflammatory bowel disease. Am J Gastroenterol. 2001, 96: 2137-42. 10.1016/S0002-9270(01)02512-6.

    Article  CAS  PubMed  Google Scholar 

  8. Rachima C, Maoz E, Apter S, Thaler M, Grossman E, Rosenthal T: Cytomegalovirus infection associated with ulcerative colitis in immunocompetent individuals. Postgrad Med J. 1998, 74: 486-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Begos DG, Rappaport R, Jain D: Cytomegalovirus infection masquerading as an ulcerative colitis flare-up: case report and review of the literature. Yale J Biol Med. 1996, 69: 323-8.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sambol SP, Merrigan MM, Lyerly D, Gerding DN, Johnson S: Toxin gene analysis of a variant strain of Clostridium difficile that causes human clinical disease. Infect Immun. 2000, 68: 5480-7. 10.1128/IAI.68.10.5480-5487.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bond F, Payne G, Borriello SP, Humphreys H: Usefulness of culture in the diagnosis of Clostridium difficile infection. Eur J Clin Microbiol Infect Dis. 1995, 14: 223-6.

    Article  CAS  PubMed  Google Scholar 

  12. Siarakas S, Tambosis E, Robertson GJ, Funnell GR, Bradbury R, Gottlieb T: Comparison of two commercial enzyme immunoassays with cytotoxicity assay and culture for the diagnosis of Clostridium difficile related diarrhea. Pathology. 1996, 28: 178-81.

    Article  CAS  PubMed  Google Scholar 

  13. Poxton IR, McCoubrey J, Blair G: The pathogenicity of Clostridium difficile. Clin Microbiol Infect. 2001, 7: 421-7. 10.1046/j.1198-743x.2001.00287.x.

    Article  CAS  PubMed  Google Scholar 

  14. Cohen SH, Tang YJ, Hansen B, Silva J: Isolation of a toxin B-deficient mutant strain of Clostridium difficile in a case of recurrent C. difficile-associated diarrhea. Clin Infect Dis. 1998, 26 (2): 410-2.

    Article  CAS  PubMed  Google Scholar 

  15. Tang-Feldman Y, Mayo S, Silva J, Cohen SH: Molecular analysis of Clostridium difficile strains isolated from 18 cases of recurrent clostridium difficile-associated diarrhea. J Clin Microbiol. 2003, 41: 3413-3414. 10.1128/JCM.41.7.3413-3414.2003.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Alonso R, Gros S, Pelaez T, Garcia-de-Viedma D, Rodriguez-Creixems M, Bouza E: Molecular analysis of relapse vs. re-infection in HIV-positive patients suffering from recurrent Clostridium difficile associated diarrhoea. J Hosp Infect. 2001, 48: 86-92. 10.1053/jhin.2001.0943.

    Article  CAS  PubMed  Google Scholar 

  17. Markowitz JE, Brown KA, Mamula P, Drott HR, Piccoli DA, Baldassano RN: Failure of single-toxin assays to detect clostridium difficile infection in pediatric inflammatory bowel disease. Am J Gastroenterol. 2001, 96: 2688-90. 10.1016/S0002-9270(01)02687-9.

    Article  CAS  PubMed  Google Scholar 

  18. Greenfield C, Aguilar Ramirez JR, Pounder RE, Williams T, Danvers M, Marper SR, Noone P: Clostridium difficile and inflammatory bowel disease. Gut. 1983, 24: 713-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Farrokhyar F, Swarbrick ET, Irvine EJ: A critical review of epidemiological studies in inflammatory bowel disease. Scand J Gastroenterol. 2001, 36: 2-15. 10.1080/00365520150218002.

    Article  CAS  PubMed  Google Scholar 

  20. Demling L: Is Crohn's disease caused by antibiotics?. Hepatogastroenterology. 1994, 41: 549-51.

    CAS  PubMed  Google Scholar 

  21. Mahdavi J, Sonden B, Hurtig M, Olfat FO, Forsberg L, Roche N, Angstrom J, Larsson T, Teneberg S, Karlsson KA, Altraja S, Wadstrom T, Kersulyte D, Berg DE, Dubois A, Petersson C, Magnusson KE, Norberg T, Lindh F, Lundskog BB, Arnqvist A, Hammarstrom L, Boren T: Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science. 2002, 297: 573-8. 10.1126/science.1069076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wong SS, Woo PC, Luk WK, Yuen KY: Susceptibility testing of Clostridium difficile against metronidazole and vancomycin by disk diffusion and Etest. Diagn Microbiol Infect Dis. 1999, 34 (1): 1-6. 10.1016/S0732-8893(98)00139-4.

    Article  CAS  PubMed  Google Scholar 

  23. Pelaez T, Sanchez R, Blazquez R, Catalan P, Munoz P, Bouza E: Abstr. 34th. Intersci. Conf. Antimicrob Agents Chemother. 1994, 50-abstr. E-34

    Google Scholar 

  24. Brazier JS, Fawley W, Freeman J, Wilcox MH: Reduced susceptibility of Clostridium difficile to metronidazole. J Antimicrob Chemother. 2001, 48 (5): 741-2. 10.1093/jac/48.5.741.

    Article  CAS  PubMed  Google Scholar 

  25. Drummond LJ, McCoubrey J, Smith DG, Starr JM, Poxton IR: Changes in sensitivity patterns to selected antibiotics in Clostridium difficile in geriatric in-patients over an 18-month period. J Med Microbiol. 2003, 52 (Pt 3): 259-63. 10.1099/jmm.0.05037-0.

    Article  CAS  PubMed  Google Scholar 

  26. Pituch H, Obuch-Woszczatynski P, Glinka D, Lazinska B, Meisel-Mikolajczyk F, Luczak M: Assessment of susceptibility to metronidazole and vancomycin of Clostridium difficile strains isolated between 1998–2002. Med Dosw Mikrobiol. 2003, 55 (3): 253-8. Polish

    CAS  PubMed  Google Scholar 

  27. Ackermann G, Degner A, Cohen SH, Silva J, Rodloff AC: Prevalence and association of macrolide-lincosamide-streptogramin B (MLS(B)) resistance with resistance to moxifloxacin in Clostridium difficile. J Antimicrob Chemother. 2003, 51 (3): 599-603. 10.1093/jac/dkg112.

    Article  CAS  PubMed  Google Scholar 

  28. Pinto LJ, Alcides AP, Ferreira EO, Avelar KE, Sabra A, Domingues RM, Ferreira MC: Incidence and importance of Clostridium difficile in paediatric diarrhoea in Brazil. J Med Microbiol. 2003, 52 (Pt 12): 1095-9. 10.1099/jmm.0.05308-0.

    Article  CAS  PubMed  Google Scholar 

  29. Jamal WY, Mokaddas EM, Verghese TL, Rotimi VO: In vitro activity of 15 antimicrobial agents against clinical isolates of Clostridium difficile in Kuwait. Int J Antimicrob Agents. 2002, 20 (4): 270-4. 10.1016/S0924-8579(02)00180-2.

    Article  CAS  PubMed  Google Scholar 

  30. Alcantara CS, Guerrant RL: Update on Clostridium difficile infection. Curr Gastroenterol Rep. 2000, 2: 310-314.

    Article  CAS  PubMed  Google Scholar 

Pre-publication history

Download references


Written consent was obtained from the patient for the publication of patient's details. This work was supported by grants NIH 1 P20 RR15577, and NIH 1 P20 RR16478 from the National Institutes of Health, and a grant from FAIR, the Fund for Arthritis and Inflammatory Research Inc.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Michael Centola.

Additional information

Competing interests

The author(s) declare they have no competing interests.

Authors' contributions

All authors contributed equally to this work. All authors read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Miner, J., Gillan, M.M., Alex, P. et al. Steroid-refractory ulcerative colitis treated with corticosteroids, metronidazole and vancomycin: a case report. BMC Gastroenterol 5, 3 (2005).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Inflammatory Bowel Disease
  • Ulcerative Colitis
  • Vancomycin
  • Metronidazole
  • Inflammatory Bowel Disease Patient