Table of Contents Author Guidelines Submit a Manuscript
Case Reports in Medicine
Volume 2012 (2012), Article ID 702910, 3 pages
Case Report

Refractory Clostridium difficile Infection Successfully Treated with Tigecycline, Rifaximin, and Vancomycin

1St. Matthew’s School of Medicine, USA
2Veterans Affairs New Jersey Healthcare System (VA NJHCS), East Orange, NJ 07018, USA
3Department of Infectious Disease, Appalachian Regional Hospital, Beckley, WV 25801, USA

Received 15 May 2012; Accepted 19 June 2012

Academic Editor: R. Coimbra

Copyright © 2012 Dominador Lao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The occurrence of Clostridium difficile colitis is on the rise and has become more difficult to manage with standard therapy. Thus, the need for alternative treatments is essential. Tigecycline is a glycylcycline antibiotic that has been shown to be effective against C. difficile through several published case reports and in in vitro studies. We present a case of C. difficile colitis that failed to respond to metronidazole and oral vancomycin therapy, but improved on a combination of rifaximin, tigecycline, and vancomycin.

1. Case Report

A 68-year-old Caucasian male with a history of multiple myeloma on lenalidomide/dexamethasone, diabetes, and end-stage renal disease on hemodialysis was admitted to the hospital for severe diarrhea and dehydration. On physical examination, he was found to be afebrile with benign abdominal exam. His white blood cell count (WBC) was normal. Fecal leukocytes were detected. Stool ova and parasites and bacterial stool cultures were negative. A computed tomography (CT) of the abdomen and pelvis showed diffuse thickening of the colon wall involving the entire colon and rectum consistent with infectious colitis. With the high suspicion of Clostridium difficile associated colitis, metronidazole 500 mg orally every 8 hours was empirically started. The cytomegalovirus serum polymerase chain reaction (PCR), enzyme immunoassay (EIA) for C. difficile toxin A/B and C. diffile PCR were all negative. Despite metronidazole treatment, his diarrhea persisted and on the 7th hospital day, he had a temperature of 101.8°F and rifaximin 550 mg orally twice daily was added. He responded rapidly to the combination treatment and the diarrhea and fever resolved by the 14th hospital day and he was discharged on metronidazole for 14 days. However, a week later the patient was readmitted to the hospital with diarrhea, nausea and abdominal pain. On physical examination, he was afebrile and appeared to be in mild distress with right-lower quadrant and suprapubic tenderness on palpation. His leukocyte count was 6,200 cells/μL and a repeat abdominal CT showed changes of pancolitis consistent with an infectious process. Metronidazole was continued and cefepime 1 gram intravenously every 24 hours was added. Stool culture showed only normal fecal flora and blood cultures were negative, however; the EIA C. difficile toxin stool assay was positive. His therapy was changed from metronidazole and cefepime to vancomycin 250 mg orally every 6 hours, as his symptoms restarted within 5 days of receiving rifaximin and while on metronidazole. Over the following nine days, the patient showed little response to therapy, averaging six loose bowel movements a day along with persistent abdominal tenderness and distention. He had a WBC count of 5,000 cells/μL with 32% bands, and a lactate level was elevated at 4 mmol/L. An abdominal X-ray showed no bowel distention. By the 10th hospital day, the patient developed leukocytosis with a WBC count of 17,200 cells/μL and was now considered to have failed vancomycin treatment. Tigecycline 100 mg intravenously once, followed by 50 mg every 12 hours and rifaximin 550 mg orally every 12 hours, was added to the vancomycin. Though the patient’s leukocyte count peaked at 19,900 cells/μL (during 2nd day of modified therapy), he responded well with a gradual decrease in leukocytosis, diarrhea, and abdominal pain. He was discharged on the 16th hospital day with resolution of symptoms after 4 days of tigecycline, rifaximin, and vancomycin treatment. He was continued on this antibiotic regimen for an additional ten days. One month after finishing antibiotics, the patient was free of symptoms.

2. Discussion

In the past decade, there has been an increase in the incidence of C. difficile infections (CDI) in North America in association with the spread of 027/NAP1/BI strain [1]. This epidemic strain has been associated with more severe disease and higher rate of recurrences. Oral vancomycin and metronidazole are considered the antimicrobial of the current standard of care; however recently there have been an increased number of reports of treatment failure with these drugs, especially metronidazole [2]. In a systematic review, Vardakas et al. reported a metronidazole and vancomycin treatment failure of 22.4% and 14.2% [3]. This high rate of clinical failure with these antimicrobials and the concerns C. difficile strains with decreased susceptibility to metronidazole and vancomycin [1] have prompted the use on nonconventional antimicrobial agents.

In this paper, we describe a case of vancomycin and metronidazole treatment failure that was successfully managed with the combination of rifaximin, tigecycline, and oral vancomycin. Rifaximin is an oral antibiotic which acts exclusively in the gastrointestinal tract. Though it does possess broad coverage against most Gram-positive organisms (including C. difficile) and nearly all enteric Gram-negative pathogens, it seems to have a little effect on normal gastrointestinal flora [4, 5] which is known to be protective for the development of CDI [6]. Rifaximin appears to be efficacious in treating CDI when used in conjunction with other antibiotics active against C. difficile. It has been used effectively with vancomycin via simultaneous administration, drug cycling, or sequential monotherapy [7, 8]. Also, El-Herte et al. reported a recent case of C. difficile in which the patient initially failed metronidazole and vancomycin therapy, but was successfully treated with a combination of rifaximin and tigecycline [9].

Tigecycline, a derivative of minocycline, is also a broad spectrum antibiotic active against Gram-positive and Gram-negative organisms. In addition to being indicated for the treatment of complicated skin and intra-abdominal infections, its effectiveness against C. difficile has been shown through several studies which reported consistently low-minimum inhibitory concentration (MIC)90 values ranging from 0.06 to 0.25 μg/mL [1013]. Although tigecycline was shown to decrease the number of microflora in a human gut model, there was no proliferation of C. difficile or increased production of its associated cytotoxin [12]. Similar results were reported in a study using a mouse model attributable to tigecycline’s relative sparing of native anaerobic bacteria and its inhibitory effect on C. difficile [14].

Several reports have been published describing the treatment of C. difficile colitis with tigecycline. There have been 8 cases in total, 7 of which were successful in treating refractory CDI using tigecycline as monotherapy [15, 16] or in combination with another antibiotics such as metronidazole [17] or rifaximin [9]. These 7 cases reported patient recovery within one week of therapy without recurrence of symptoms after a 3 month period. On the other hand, Kopterides et al. reported clinical failure in a patient with CDI treated with tigecycline for 14 days [18].

In conclusion, C. difficile colitis patients refractory to standard treatments are on the rise. It has become more crucial to find alternative approaches for treating such cases. Although data supporting the use of tigecycline for CDI is still lacking, this paper along with several others suggest that it may be an alternative for refractory or severe infections unresponsive to standard therapy. Not only have in vitro studies provided evidence to support this claim, but the literature reviewed here along with the case report demonstrated successful treatment in 8 out of 9 cases using tigecycline as monotherapy or in combination with other CDI antibiotics. Nevertheless, further investigations are needed to evaluate the safety and efficacy of newer antimicrobial agents such as tigecycline for routine treatment of refractory CDI.


  1. J. Freeman, M. P. Bauer, S. D. Baines et al., “The changing epidemiology of Clostridium difficile infections,” Clinical Microbiology Reviews, vol. 23, no. 3, pp. 529–549, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. D. N. Gerding and S. Johnson, “Management of Clostridium difficile infection: thinking inside and outside the box,” Clinical Infectious Diseases, vol. 51, no. 11, pp. 1306–1313, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. K. Z. Vardakas, K. A. Polyzos, K. Patouni, P. I. Rafailidis, G. Samonis, and M. E. Falagas, “Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence,” International Journal of Antimicrobial Agents, vol. 40, no. 1, pp. 1–8, 2012. View at Google Scholar
  4. A. Marchese, A. Salerno, A. Pesce, E. A. Debbia, and G. C. Schito, “In vitro activity of rifaximin, metronidazole and vancomycin against Clostridium difficile and the rate of selection of spontaneously resistant mutants against representative anaerobic and aerobic bacteria, including ammonia-producing species,” Chemotherapy, vol. 46, no. 4, pp. 253–266, 2000. View at Google Scholar · View at Scopus
  5. H. L. DuPont and Z. D. Jiang, “Influence of rifaximin treatment on the susceptibility of intestinal Gram-negative flora and enterococci,” Clinical Microbiology and Infection, vol. 10, no. 11, pp. 1009–1011, 2004. View at Publisher · View at Google Scholar · View at Scopus
  6. D. N. Gerding, “Clostridium difficile infection prevention: biotherapeutics, immunologics, and vaccines,” Discovery Medicine, vol. 13, no. 68, pp. 75–83, 2012. View at Google Scholar
  7. A. L. Berman, “Efficacy of rifaximin and vancomycin combination therapy in a patient with refractory Clostridium difficile-associated diarrhea,” Journal of Clinical Gastroenterology, vol. 41, no. 10, pp. 932–933, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. S. Johnson, C. Schriever, M. Galang, C. P. Kelly, and D. N. Gerding, “Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin,” Clinical Infectious Diseases, vol. 44, no. 6, pp. 846–848, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. R. I. El-Herte, T. A. Baban, and S. S. Kanj, “Recurrent refractory Clostridium difficile colitis treated successfully with rifaximin and tigecycline: a case report and review of the literature,” Scandinavian Journal of Infectious Diseases, vol. 44, no. 3, pp. 228–230, 2012. View at Google Scholar
  10. S. P. Hawser, “Activity of tigecycline against recent European clinical isolates of Clostridium difficile,” International Journal of Antimicrobial Agents, vol. 35, no. 1, pp. 97–98, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. T. Norén, I. Alriksson, T. Åkerlund, L. G. Burman, and M. Unemo, “In vitro susceptibility to 17 antimicrobials of clinical Clostridium difficile isolates collected in 1993-2007 in Sweden,” Clinical Microbiology and Infection, vol. 16, no. 8, pp. 1104–1110, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. S. D. Baines, K. Saxton, J. Freeman, and M. H. Wilcox, “Tigecycline does not induce proliferation or cytotoxin production by epidemic Clostridium difficile strains in a human gut model,” Journal of Antimicrobial Chemotherapy, vol. 58, no. 5, pp. 1062–1065, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. D. W. Hecht, M. A. Galang, S. P. Sambol, J. R. Osmolski, S. Johnson, and D. N. Gerding, “In vitro activities of 15 antimicrobial agents against 110 toxigenic Clostridium difficile clinical isolates collected from 1983 to 2004,” Antimicrobial Agents and Chemotherapy, vol. 51, no. 8, pp. 2716–2719, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. R. L. Jump, Y. Li, M. J. Pultz, G. Kypriotakis, and C. J. Donskey, “Tigecycline exhibits inhibitory activity against Clostridium difficile in the colon of mice and does not promote growth or toxin production,” Antimicrobial Agents and Chemotherapy, vol. 55, no. 2, pp. 546–549, 2011. View at Publisher · View at Google Scholar · View at Scopus
  15. B. L. Herpers, B. Vlaminckx, O. Burkhardt et al., “Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection,” Clinical Infectious Diseases, vol. 48, no. 12, pp. 1732–1735, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. E. Y. Cheong and T. Gottlieb, “Intravenous tigecycline in the treatment of severe recurrent Clostridium difficile colitis,” The Medical Journal of Australia, vol. 194, no. 7, pp. 374–375, 2011. View at Google Scholar · View at Scopus
  17. C. L. Lu, C. Y. Liu, C. H. Liao, Y. T. Huang, H. P. Wang, and P. R. Hsueh, “Severe and refractory Clostridium difficile infection successfully treated with tigecycline and metronidazole,” International Journal of Antimicrobial Agents, vol. 35, no. 3, pp. 311–312, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. P. Kopterides, C. Papageorgiou, A. Antoniadou et al., “Failure of tigecycline to treat severe Clostridium difficile infection,” Anaesthesia and Intensive Care, vol. 38, no. 4, pp. 755–758, 2010. View at Google Scholar · View at Scopus