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JAC Advance Access originally published online on March 2, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):705-710; doi:10.1093/jac/dkl553
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide

Daniel M. Musher1,2,*, Nancy Logan1, Vaibhav Mehendiratta1, Nicolas A. Melgarejo1, Sagar Garud1 and Richard J. Hamill1,2

1 Medical Service (Infectious Disease Section), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA 2 Departments of Medicine and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA

* Correspondence address. Infectious Disease Section, Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-794-7386; Fax: +1-713-794-7045; E-mail: daniel.musher{at}med.va.gov

Received 3 November 2006; returned 6 December 2006; revised 20 December 2006; accepted 21 December 2006


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Objectives: Clostridium difficile-associated disease has increased in incidence and severity. Recommended treatments include metronidazole and vancomycin. Recent investigations, however, document the failure of metronidazole to cure a substantial proportion of patients with Clostridium difficile colitis, but oral administration of vancomycin raises concerns over selection of antibiotic-resistant organisms in the hospital environment. We have recently shown that nitazoxanide is as effective as metronidazole in initial therapy for C. difficile colitis. We hypothesized that this drug might be effective in treating patients who fail therapy with metronidazole.

Methods: In the present study, we identified 35 patients who failed treatment with metronidazole for C. difficile colitis; failure was defined as either no improvement in symptoms or signs of disease (28 patients) after ≥ 14 days of treatment with metronidazole or prompt recurrence on at least two occasions after initially responding to such treatment (seven patients). These patients were ill with numerous co-morbidities. Nitazoxanide, 500 mg twice daily, was given for 10 days; results from all patients are included.

Results: Twenty-six (74%) of 35 patients responded to nitazoxanide, of whom seven later had recurrent disease, yielding a cure rate of 19 of 35 (54%) from initial therapy. Three who initially failed and one who had recurrent disease were re-treated with, and responded to, nitazoxanide. Thus, the aggregate cure with nitazoxanide in this difficult-to-treat population was 23 of 35 (66%).

Conclusions: Nitazoxanide appears to provide effective therapy for patients with C. difficile colitis who fail treatment with metronidazole.

Keywords: antibiotic-associated diarrhoea , vancomycin , C. difficile


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Clostridium difficile-associated disease has emerged as a major nosocomial infection in North American and European hospitals, with a rising incidence, increasing severity and an increasing rate of failure to conventional therapy.1–4 Vancomycin was the first drug shown to provide effective treatment for this condition5 and, at least in the USA, remains the only one approved for this purpose by the Food and Drug Administration.6 Early studies, however, appeared to show metronidazole to be equally effective.6–8 Initially driven by the prohibitive cost of oral vancomycin, and subsequently by fear of selecting vancomycin-resistant bacteria in hospitals, health-care providers have tended to prescribe metronidazole, which is now recommended as first-line therapy for this condition,9,10 even though the response to vancomycin is somewhat more rapid.11 We4 and others3,12 have recently documented a substantial rate of failure with this therapy. When treatment with metronidazole fails, most infectious disease specialists13,14 recommend oral vancomycin, but continuing concerns over the high cost and the emergence of vancomycin-resistant bacteria, reinforced by federal guidelines discouraging excessive use of this medication,15 have motivated the search for alternative therapy.

Nitazoxanide, a nitrothiazolide, successfully treats infestation by intestinal parasites and is approved in the USA and UK to treat cryptosporidiosis and giardiasis.16,17 This drug acts by blocking anaerobic metabolism. In vitro, low concentrations of nitazoxanide or its breakdown product, tizoxanide, inhibit C. difficile.18 Two-thirds of an administered dose is excreted in the faeces.19 In a prospective, double-blind study, we20 recently found that nitazoxanide is at least as effective as metronidazole in treating patients with moderately severe or severe C. difficile colitis. Taken together, these factors motivated us to study nitazoxanide in patients with C. difficile colitis who had failed conventional therapy with metronidazole. Interestingly, Bartlett21 also suggested this possibility in a recent editorial on the subject.


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Study site

This study was carried out at the Michael E. DeBakey Veterans Affairs Medical Center, Houston. Patients in this system generally rely exclusively on this centre for their medical care. Medical and laboratory records are fully automated, and every encounter between a patient and the medical system is recorded electronically. Thus, follow-up data tend to be remarkably complete. During the time of this study, the therapy approved in our hospital for treating C. difficile colitis was metronidazole. For reasons summarized above, vancomycin was used infrequently, and an order to do so required approval by a member of the Infectious Disease Section.

Patients

Patients who had clearly failed conventional treatment for C. difficile colitis were asked to participate in an IRB-approved open-label study of nitazoxanide (Institutional Review Board, Baylor College of Medicine, Protocol H-15601). Therapeutic failure was defined as either: (i) the absence of a response to metronidazole and/or oral vancomycin therapy, defined as persistence of fever, diarrhoea (at least three loose or watery stools per day), abdominal pain and/or otherwise unexplained leucocytosis and a positive EIA for C. difficile toxin after ≥ 14 days of oral treatment with a total dosage ≥ 1.5 g of oral metronidazole or 500 mg of oral vancomycin daily; or (ii) on at least two occasions, an initial response to metronidazole or vancomycin, as defined by resolution of the above-named symptoms, followed within 30 days by recurrence. Because metronidazole may be effective in treating an initial recurrence of disease,22,23 in order to be included in this study, patients needed to have at least two bouts of recurrent symptoms and signs of colitis after a full course of treatment. Symptoms were present for ≥ 4 days before the diagnosis of recurrent disease was made. Nitazoxanide, 500 mg, was given twice daily, for 10 days. Initially, informed consent was sought in accordance with IRB guidelines. After the first 22 patients were treated, the results of the double-blind study comparing metronidazole to nitazoxanide were revealed,20 and nitazoxanide was placed on the hospital formulary, requiring approval for its use by one of the investigators (DMM or RJH). Thereafter, 13 additional patients who failed conventional therapy were treated with nitazoxanide but without informed consent being required. All patients were followed closely throughout their treatment and thereafter for 60 days in order to determine whether there was a recurrence. A separate IRB-approved protocol (Baylor IRB H-16175) authorized a review of all medical records after treatment had been completed. Data presented in this paper are from 35 consecutive patients who met the above criteria and were treated with nitazoxanide; results from all patients are included.

Response to treatment

Patients were seen regularly by an investigator after treatment with nitazoxanide was begun. Interviews with patients, family members and nurses were used to determine the number and quality of stools, and the persistence of fever, abdominal discomfort and/or leucocytosis was noted. Failure of therapy was defined by the persistence of at least three loose or watery stools per 24 h, along with fever, leucocytosis, abdominal pain and/or urgency. A response to treatment was defined as the absence of symptoms of disease as defined above. After the study was over, complete electronic medical records were reviewed for ≥ 60 days to verify all recorded information and to determine whether there had been a recurrence or possible recurrence of C. difficile colitis. Patients were said to have undergone an apparent cure when, after a response, there was no recurrence of symptoms or signs of colitis during the ensuing 60 days. An initial response to nitazoxanide followed by a return of these symptoms and signs together with a positive faecal C. difficile toxin assay was termed a recurrence.

Microbiology

C. difficile toxin was detected by EIA (PremierTM Toxins A&B, Meridian Bioscience, Cincinnati, OH, USA). Faecal samples from some patients were submitted in anaerobic transport containers to Microbiology Specialists Incorporated (Houston, TX, USA) for anaerobic culture. Definitive identification of C. difficile was by distinctive isoacid production on gas liquid chromatography. Susceptibilities to vancomycin, metronidazole, nitazoxanide and tizoxanide were studied by agar dilution. Isolates were sent to the Centers for Disease Control and Prevention (Atlanta, GA, USA) where Dr Charles E. Kilgore, Ms Angela Thompson and Dr L. Clifford McDonald graciously performed PFGE, toxinotyping and detection of binary toxin production.24


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Demographics

Thirty-five consecutive patients who were treated with nitazoxanide after failing conventional therapy for C. difficile colitis are included in this report. Thirty-three were male and two were female, consistent with gender distribution at our hospital. The mean age was 67.5 years (range 49–86). In 28 patients, symptoms and signs of C. difficile colitis had persisted without response despite treatment with metronidazole for ≥ 14 days; seven had at least two recurrences after appropriate treatment (Figure 1). Those with persistent disease had been treated with metronidazole for 17–45 days (mean = 2.4 days, median = 21 days); two also received > 14 days of vancomycin. Patients with recurrent disease had received at least two (mean = 2.6, median = 2) courses of treatment with metronidazole; two of these had also received at least one course of oral vancomycin.


Figure 1
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  		Figure 1.. Flow sheet showing an overview of the 35 patients studied and their outcome. Rx, treatment.

 
Patients in this series were very ill, each having numerous, serious co-morbid conditions; these are summarized in Table 1. Seven patients (20%) died during treatment or in the ensuing 30 days, giving further insight into the severity of illness.


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  		Table 1.. Risk factors in 35 patients who failed conventional therapy for Clostridium difficile colitis

 
Prior antibiotic use

Thirty-three (94%) patients had received antibiotics for a mean of 43.2 (range 8–131) antibiotic days, defined as sum of the number of days for each individual antibiotic, in the 8 weeks preceding the initial bout of C. difficile colitis.25 Two patients who had not taken antibiotics were undergoing radiation therapy for colon cancer (one case) or chemotherapy for lymphoma (one case). In all but two cases, there was at least one time period when the patient was receiving no antibiotics yet had persistent findings of C. difficile colitis.

Response to nitazoxanide

There appeared to be no differences in response to nitazoxanide among patients who had failed metronidazole and those who had recurrence of disease after initial responses. Thus, for ease of presentation, results are merged for the two groups, although Figure 2 shows actual outcomes for all 35 patients. Twenty-six of the 35 (74%) patients had a rapid resolution of symptoms and signs of colitis after nitazoxanide therapy was begun (Figure 2), including 20 of the 28 (71%) who had persisting disease despite metronidazole and 6 of the 7 (86%) who had recurrent disease (difference not significant, P = 0.65, Fisher's exact test). Diarrhoea stopped within a mean of 2.6 days (range 1–4). Febrile patients defervesced and leucocytosis, when attributable to the colitis, resolved within 4 days. Sixty days after treatment, 19 of these 26 (73%; 54% of the original 35 patients) remained free of symptoms or signs of colitis and were regarded as apparent cures.


Figure 2
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  		Figure 2.. Flow sheet showing all patients studied and the status of their C. difficile infection at each stage in the study. Nitazox, nitazoxanide; metronid, metronidazole; vanco, vancomycin.

 
Seven of the 26 patients who initially responded to nitazoxanide (27%; 20% of the original 35 patients) had recurrent C. difficile colitis within a mean of 12.1 (range 7–24) days after the completion of therapy (Figure 2). After the initial course of therapy with nitazoxanide, treatment of any subsequent failure or recurrence was selected by the primary care providers. Of these seven patients with recurrent disease, one was re-treated with nitazoxanide and responded. Four were treated with metronidazole, of whom two were cured and two failed to respond (one of these received vancomycin and metronidazole together without response). Two were treated with vancomycin of whom one initially responded but died before completion of therapy and one failed, eventually dying with persistent C. difficile colitis.

Nine of the 35 (26%) patients failed nitazoxanide (Figure 2). One died in the first week of therapy. Two were re-treated with metronidazole but failed to respond. One each of these was subsequently treated successfully with an additional course of nitazoxanide or vancomycin (responding only to a second course of this drug). Three were re-treated with nitazoxanide; one was cured, one was eventually cured after two additional courses of nitazoxanide, and one did not respond. Three were treated with long courses of vancomycin, but had persisting symptoms and signs of colitis until they died. Thus, in total, 23 of 35 (66%) patients with C. difficile colitis recalcitrant to standard therapies were eventually cured by nitazoxanide.

Microbiology

C. difficile was isolated from faecal samples of 15 patients. By agar dilution, all isolates were inhibited by metronidazole (median MIC = 1 mg/L, range 0.25–2 mg/L), vancomycin (median MIC 4 mg/L, range 1–8 mg/L), nitazoxanide (median MIC 1, range 0.25–2 mg/L) and tizoxanide (median MIC 0.5 mg/L, range 0.25–1 mg/L). In order to determine whether persistent or recurrent infection was due to a new, virulent strain of C. difficile we submitted 13 retrievable isolates to the Epidemiology and Laboratory Branch of the Centers for Disease Control and Prevention (Dr G. E. Kilgore, Ms A. Thompson and Dr L. C. McDonald). Two of the 13 (15%) were identical with the recently identified epidemic, toxin gene-variant strain, PFGE type NAP-1, toxinotype III, binary toxin positive24,26,27 (see Figure 3). Eight (62%) isolates were PFGE type NAP-2, toxinotype 0 and binary toxin negative. The remaining three (23%) isolates were of as-yet unnamed PFGE types.


Figure 3
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  		Figure 3.. PFGE of C. difficile isolated from 13 patients in this study. The figure shows that no single strain predominated. Eight of 13 isolates were NAP-2, toxinotype 0, and binary toxin negative, representing several different subtypes within PFGE NAP-2. Only two isolates were identified as the newly emerging NAP-1, toxinotype III, binary toxin positive epidemic strain.24

 

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Nosocomial C. difficile colitis has evolved into a major problem in developed countries.1–4,24,26 Recent studies3,4,12 indicate that as many as 20–25% of patients with this condition fail therapy with metronidazole, and another 20–25% have recurrent disease, substantially higher rates of failure than were previously reported.7 The usual therapy for patients who fail metronidazole has been oral vancomycin, but there is great reluctance to prescribe this drug because of concern for selection of vancomycin-resistant bacteria.15 Nitazoxanide has recently been shown to be at least as effective as metronidazole in the initial treatment of moderately severe to severe C. difficile colitis. Taken together, these factors motivated us to study nitazoxanide in treating patients who fail conventional therapy for this infection.

We identified 35 patients in whom C. difficile colitis had plainly failed treatment with metronidazole; 28 of these had persistent symptoms of colitis despite prolonged therapy with metronidazole, and seven had at least two relapses within a few weeks of an apparent response. A prompt response to nitazoxanide was seen in 26 (74%) cases, including 20 of the 28 (71%) who had persisting colitis despite metronidazole and six of the seven (86%) who had recurrent disease.

Of the 26 who responded to nitazoxanide, seven had recurrent C. difficile colitis, one of whom eventually responded to nitazoxanide. Of nine whose symptoms persisted during initial treatment with nitazoxanide, three were eventually cured by repeated course(s) of this drug. Thus, in aggregate, nitazoxanide produced a cure in 23 of 35 (66%) patients who had already failed other therapy, a response rate similar to that observed in initial treatment of unselected C. difficile colitis hospitalized patients with metronidazole.3,4 Achieving this rate of response in ill patients who had already failed prior therapy indicates a potentially important role for nitazoxanide in treating this disease.

PFGE showed that the majority of the strains studied were types other than the recently described NAP-1, toxinotype III, binary toxin positive isolate epidemic strain.24 This finding indicates that the new, epidemic strain is not solely responsible for the recent increase in incidence and severity of C. difficile colitis in hospitalized patients in the USA. In our patients, the high failure rate appears to be more closely related to host factors, reflecting a population that is older and sicker than in the past, and that has received more broad coverage antibiotic therapy. More widespread usage of proton pump inhibitors may also play a contributory role.28 Co-morbidities were prominent in our patients, and seven (20%) died within the 60 day study period. Further support for the central role of the host response in recurrent disease comes from our preliminary observation29 that most of our patients had low levels of antibody to toxins A and B both acutely and in follow-up, a finding that is consistent with susceptibility to recurrent disease.30 Antimicrobial resistance of C. difficile did not contribute to failure, because isolates from our patients were all susceptible to metronidazole, vancomycin, nitazoxanide and its metabolic product tizoxanide.

The chief limitation of this study is that, although prospective, it was open and non-comparative. At the time it was undertaken, there were precious few possible treatments, as emphasized by Louie23 in his recent editorial. It is always possible that these patients might readily have responded to an additional course of conventional therapy. D. Gerding has shown (unpublished, presented at Symposium on Clostridium difficile, Annual Meeting Infectious Disease Society of America, 12–15 October 2006) that some patients respond to metronidazole more slowly than was previously thought, and Pepin et al.22 have reported that metronidazole may bring about a response in one-third of patients who are re-treated for a recurrence following therapy with that drug. That is why our inclusion criteria were so stringent. Patients who failed metronidazole had been treated for at least 14 days (mean duration of treatment was 22.4 days), and those with recurrent disease all had at least two recurrences (mean number of recurrences, 2.6).

We have reviewed elsewhere6,31 the use of other therapeutic modalities for C. difficile colitis, including biological agents such as non-toxigenic C. difficile or other non-toxigenic bowel flora, antimicrobial agents such as bacitracin, teicoplanin and rifaximin,32 toxin-binding polymers,33 immune globulin34,35 or monoclonal antibody to C. difficile toxin,36 and non-steroidal anti-inflammatory drugs. As always, prevention is better than treatment, and continued emphasis on judicious use of antibiotics and appropriate infection control measures remain central to the art of good medical practice.


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This study was conceived and designed by the investigators who initiated the proposal and received funding to the Infectious Disease Section from Romark Pharmaceuticals. This company is privately owned, and none of the participants in this study has any share in the company or its profits. D. M. M. has received travel expenses and an honorarium for his appearance at a satellite symposium.


   Acknowledgements
 
This work was funded in part by the Department of Veterans Affairs through the Merit Review Program and by a grant from Romark Pharmaceuticals.


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1 Pepin J, Valiquette L, Alary ME, et al. (2004) Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 171:466–72.[Abstract/Free Full Text]

2 Archibald LK, Banerjee SN, Jarvis WR. (2004) Secular trends in hospital-acquired Clostridium difficile disease in the United States, 1987–2001. J Infect Dis 189:1585–9.[CrossRef][ISI][Medline]

3 Pepin J, Alary ME, Valiquette L, et al. (2005) Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 40:1591–7.[CrossRef][ISI][Medline]

4 Musher DM, Aslam S, Logan N, et al. (2005) Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 40:1586–90.[CrossRef][ISI][Medline]

5 Silva J Jr, Batts DH, Fekety R, et al. (1981) Treatment of Clostridium difficile colitis and diarrhea with vancomycin. Am J Med 71:815–22.[CrossRef][ISI][Medline]

6 Aslam S, Hamill RJ, Musher DM. (2005) Treatment of Clostridium difficile-associated disease: old therapies and new strategies. Lancet Infect Dis 5:549–57.[CrossRef][ISI][Medline]

7 Olson MM, Shanholtzer CJ, Lee JT Jr, et al. (1994) Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982–1991. Infect Control Hosp Epidemiol 15:371–81.[ISI][Medline]

8 Teasley DG, Gerding DN, Olson MM, et al. (1983) Prospective randomised trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhoea and colitis. Lancet 2:1043–6.[ISI][Medline]

9 Fekety R. (1997) Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 92:739–50.[ISI][Medline]

10 Annon. (1998) ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Am J Health Syst Pharm 55:1407–11.[Abstract/Free Full Text]

11 Wilcox MH and Howe R. (1995) Diarrhoea caused by Clostridium difficile: response time for treatment with metronidazole and vancomycin. J Antimicrob Chemother 36:673–9.[Abstract/Free Full Text]

12 Nair S, Yadav D, Corpuz M, et al. (1998) Clostridium difficile colitis: factors influencing treatment failure and relapse—a prospective evaluation. Am J Gastroenterol 93:1873–6.[ISI][Medline]

13 Layton BA, McDonald LC, Gerding DN, et al. Changing patterns of Clostridium difficile disease: a report from infectious disease physicians (Abstract 563). Annual Meeting, Infectious Disease Society of America3 October 2004Boston, MA, USA.

14 Lorber B. (2006) Update in infectious diseases. Ann Intern Med 145:354–60.[Free Full Text]

15 Anon. (1994) Preventing the spread of vancomycin resistance—a report from the Hospital Infection Control Practices Advisory Committee prepared by the Subcommittee on Prevention and Control of Antimicrobial-Resistant Microorganisms in Hospitals; comment period and public meeting—CDC. Notice. Fed Regist 59:25758–63.[Medline]

16 White CA Jr. (2004) Nitazoxanide: a new broad spectrum antiparasitic agent. Expert Rev Anti Infect Ther 2:43–9.[CrossRef][Medline]

17 Fox LM and Saravolatz LD. (2005) Nitazoxanide: a new thiazolide antiparasitic agent. Clin Infect Dis 40:1173–80.[CrossRef][ISI][Medline]

18 Dubreuil L, Houcke I, Mouton Y, et al. (1996) In vitro evaluation of activities of nitazoxanide and tizoxanide against anaerobes and aerobic organisms. Antimicrob Agents Chemother 40:2266–70.[Abstract]

19 Broekhuysen J, Stockis A, Lins RL, et al. (2000) Nitazoxanide: pharmacokinetics and metabolism in man. Int J Clin Pharmacol Ther 38:387–94.[ISI][Medline]

20 Musher DM, Logan N, Hamill RJ, et al. (2006) Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 43:421–7.[CrossRef][ISI][Medline]

21 Bartlett JG. (2006) New drugs for Clostridium difficile infection. Clin Infect Dis 43:428–31.[CrossRef][ISI][Medline]

22 Pepin J, Routhier S, Gagnon S, et al. (2006) Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis 42:758–64.[CrossRef][ISI][Medline]

23 Louie TJ. (2006) Treatment of first recurrences of Clostridium difficile-associated disease: waiting for new treatment options. Clin Infect Dis 42:765–7.[CrossRef][ISI][Medline]

24 McDonald LC, Killgore GE, Thompson A, et al. (2005) An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 353:2433–41.[Abstract/Free Full Text]

25 Wanahita A, Goldsmith EA, Marino BJ, et al. (2003) Clostridium difficile infection in patients with unexplained leukocytosis. Am J Med 115:543–6.[CrossRef][ISI][Medline]

26 Loo VG, Poirier L, Miller MA, et al. (2005) A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 353:2442–9.[Abstract/Free Full Text]

27 Warny M, Pepin J, Fang A, et al. (2005) Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 366:1079–84.[CrossRef][ISI][Medline]

28 Dial S, Delaney JA, Barkun AN, et al. (2005) Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 294:2989–95.[Abstract/Free Full Text]

29 Melgarejo NA, Musher DM, Logan N, et al. (2005) The emerging problem of metronidazole failure in Clostridium difficile colitis and the response to nitazoxanide. Infectious Disease Society 43rd Annual Meeting pp. 90 Abstract 319.

30 Kyne L, Warny M, Qamar A, et al. (2001) Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 357:189–93.[CrossRef][ISI][Medline]

31 Aslam S and Musher DM. (2006) An update on diagnosis, treatment, and prevention of Clostridium difficile-associated disease. Gastroenterol Clin North Am 35:315–35.[CrossRef][ISI][Medline]

32 Gerard L, Garey KW, DuPont HL. (2005) Rifaximin: a nonabsorbable rifamycin antibiotic for use in nonsystemic gastrointestinal infections. Expert Rev Anti Infect Ther 3:201–11.[CrossRef][Medline]

33 Louie TJ, Peppe J, Watt CK, et al. (2006) Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile-associated diarrhea. Clin Infect Dis 43:411–20.[CrossRef][ISI][Medline]

34 Wilcox MH. (2004) Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother 53:882–4.[Abstract/Free Full Text]

35 McPherson S, Rees CJ, Ellis R, et al. (2006) Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea. Dis Colon Rectum 49:640–5.[CrossRef][ISI][Medline]

36 Babcock GJ, Broering TJ, Hernandez HJ, et al. (2006) Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun 74:6339–47.[Abstract/Free Full Text]


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