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Recurrent Clostridium difficile infection: causality and therapeutic approaches
International Journal of Antimicrobial Agents 33, S1 (2009) S33 S36
Recurrent Clostridium difficile infection: causality and therapeutic approaches Stuart Johnsona,b, * a b
Medicine Service, Edward Hines Jr. Veterans Affairs Hospital, Hines, IL, USA Division of Infectious Diseases, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
ARTICLE
INFO
Keywords: Clostridium difficile Diarrhoea Recurrence
ABSTRACT Recurrent diarrhoea after successful treatment of the primary episode is a common complication of Clostridium difficile infection (CDI) and may be increasing in frequency. Evidence suggests that persistent alterations in the indigenous bowel flora and failure to mount an effective antibody response to C. difficile toxins are the main mechanisms whereby recurrent CDIs occur. Treatment of the first recurrence with the same agent used for the treatment of the primary episode is reasonable, but a different approach is needed for patients with multiple CDI recurrences. Prolonged, repeated courses of metronidazole are discouraged, but a practical first option in these patients is to use tapered-dose oral vancomycin followed by a pulsed-dose regimen. Other potential options include probiotic approaches, restoration of the normal flora, immunological approaches, toxin-binding approaches, and serial therapy with vancomycin followed by rifaximin. Randomised studies including a sufficient numbers of patients have not yet been conducted for the treatment of recurrent CDI and are needed to help guide the formulation of effective recommendations. © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Recurrent diarrhoea is a common and frustrating complication of Clostridium difficile infection (CDI); often frustrating for the treating physician as well as for the patient. Recurrent CDI occurs in ~20% of patients after the first episode 1 and these rates may be increasing. A 33% recurrence rate after the initial episode was recently reported in the setting of a multihospital outbreak in Quebec due to an epidemic hypervirulent strain 2 . These authors also reported complications of shock, colectomy, perforation, megacolon, or death in 11% of patients with first recurrence, highlighting the potential severity of recurrent CDI. In addition, the risk of a subsequent episode in a patient who has already had one recurrence is ~45% 3 . Finally, a subset of patients will have multiple recurrences. These patients typically respond to treatment for each episode, but symptoms recur within days to several weeks after discontinuation of the treating agent. * Stuart Johnson. Division of Infectious Diseases, Loyola University Chicago Stritch School of Medicine, 2160 South First Avenue, Fahey Center (Bldg. 54), Room 149, Maywood, IL 60153, USA. Tel.: +1 708 216 3232; fax: +1 708 216 8198. E-mail address: [email protected] (S. Johnson). 0924-8579/ $
Recurrent CDI should be distinguished from treatment failure as the mechanisms are likely to be different and the treatment should be different. Some authors, however, have included both outcomes in their definition of failure: no improvement in symptoms or signs of disease after a period of treatment or prompt recurrence on at least two occasions after initially responding to such treatment 4 . This group has also used the term ‘sustained response’ in reference to successful recovery without recurrence 5 . Regardless, the appropriate management of a patient who is not responding to treatment with metronidazole after a sufficient period of time is to switch treatment to oral vancomycin. On the other hand, a patient who initially responds to treatment with metronidazole can reliably be treated with the same agent for the first recurrence. Metronidazole was shown to be not inferior to vancomycin for the treatment of a first recurrence of CDI, and the treatment of a first recurrence with the same or a different agent made no difference in outcome 2 . 2. Causality Although the mechanisms whereby recurrent CDI occur have not been completely worked out, the intimate association
see front matter © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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S. Johnson / International Journal of Antimicrobial Agents 33 (2009) S33 S36
of CDI with prior or concurrent antibiotic use has suggested that disruption of the normal colonic flora and decrease in colonisation resistance is a critical factor for the development of recurrent CDI. The microflora of the human colon is diverse and not all species have been cultured and identified, but culture-independent methods have been developed to profile the microbiota of individuals and it has been shown that the microbiota of adults is dominated by species of the Bacteroidetes and Firmicutes divisions (phyla) 6 . Chang et al. performed a phylogenetic analysis of 16S rRNA-encoding gene sequences from faecal samples of patients with initial CDI episodes and recurrent CDI episodes 7 . Whereas the patients with initial CDI episodes and the control patients had a predominance of Bacteroidetes and Firmicutes species, the predominant species in the patients with recurrent CDI were quite different and these patients’ microbiotae exhibited significantly less diversity 7 . It is suspected that anaerobic bacteria provide the more important determinants of colonisation resistance to C. difficile 8,9 and antibiotics that disrupt these components of the microbiota might be particularly likely to precipitate CDI. In addition, the specific agents that are used to treat CDI, metronidazole and vancomycin, may be the precipitating antibiotics for the recurrent episode through their effect on the anaerobic flora of the gut. Louie et al. recently demonstrated that oral vancomycin had a profound effect on Bacteroides fragilis counts in patients with CDI: mean B. fragilis group counts decreased by a factor of >3 log after 10 days of treatment with vancomycin 10 . Factors other than indigenous microflora may also contribute to recurrent CDI. Immune responses to C. difficile and/or its toxins are also likely to play a role. Kyne et al. showed that patients with a single episode of CDI had higher serum levels of IgM against toxin A on day 3 of the first episode and IgG to toxin A on day 12 than did patients with recurrent CDI 11 . The proportion of patients with recurrent CDI was linearly associated with decreasing levels of anti-toxin A IgM and IgG measured at these time points. Recurrent CDI is not always due to relapse of the same C. difficile strain. Five different investigators using various typing methodologies consistently showed that a new strain was found in 33 56% of recurrent episodes 12 16 . Time to recurrence was moderately predictive of relapse with the same strain or reinfection with a new strain: the mean time to recurrence with the same strain was 14.5±10 days and for infection with a new strain was 42.5±39 days 12 . These studies suggest the importance of exogenous infection in patients rendered susceptible by decreased colonisation resistance and inadequate immune response. 3. Therapeutic approaches As previously mentioned, recurrent CDI is not a consequence of resistance to metronidazole or vancomycin, the two main agents used to treat CDI. Therefore, treatment of the first recurrent episode with the same agent used for the initial episode is a reasonable approach. Although metronidazole is an inexpensive and effective agent for most patients with CDI, patients with evidence of severe CDI should be treated with oral vancomycin regardless of whether it is the initial or recurrent episode. Using ad hoc severity criteria, Zar et al. showed vancomycin to be superior to metronidazole
Table 1. Strategies for managing patients with multiple Clostridium difficile infection recurrences Probiotic approaches Saccharomyces boulardii Lactobacillus Non-toxigenic Clostridium difficile Vancomycin approaches Tapering and/or pulsed vancomycin Vancomycin + rifampicin Normal flora restoration Faecal transplantation Bacteriotherapy Immunological approaches Intravenous immunoglobulin Active vaccination Toxin-binding approaches Cholestyramine/colestipol Tolevamer Rifaximin ‘chaser’ approach
in a recent, randomised, double-blinded, controlled study of CDI 17 . In addition, repeated courses of metronidazole beyond the first recurrence are discouraged because of the risk of neurotoxicity and hepatotoxicity with prolonged use of this agent 1 . Unfortunately, most of the data reported for managing patients with recurrent CDI and multiply recurrent CDI are anecdotal or reported in small case-series. The only randomised studies for the treatment of recurrent CDI have involved probiotics (Table 1). Surawicz et al. showed that 15 of 18 patients with recurrent CDI given high dose vancomycin 2 g/day for 10 days and Saccharomyces boulardii 1 g/day for 28 days had successful outcomes, compared with 7 of 14 patients treated with high-dose vancomycin and placebo (P = 0.05) 18 . This study, however, was a subset analysis of a larger study and needs to be repeated with larger numbers of patients to confirm its efficacy. In a similarly designed trial, Wullt et al. showed that Lactobacillus was not different from placebo: 7 of 11 patients responded to 10 days of metronidazole and 38 days of Lactobacillus plantarum 299v, compared with 3 of 9 patients treated with metronidazole and placebo (P = NS) 19 . A novel probiotic approach used successfully in two patients with recurrent CDI involved administration of a non-toxigenic strain of C. difficile 20 . This approach has high efficacy in the hamster model of CDI 21 , and formal clinical trials using a non-toxigenic C. difficile strain seen in high frequency among asymptomatic, hospitalised patients are planned. Although not studied in a randomised fashion, tapering and/or pulsed dosing of vancomycin is a frequently employed approach to interrupt multiple recurrences of CDI. McFarland et al. reviewed the placebo cohort from two clinical trials of S. boulardii as adjunctive CDI therapy 3 . In this retrospective review, tapering the dose or pulsed dosing of vancomycin was more likely to result in successful outcomes than low-, mid-, or high-dose vancomycin or any metronidazole regimen. A practical approach to patients with more than one recurrence is to use a tapering dose followed by pulsed dosing of vancomycin (e.g., vancomycin 125 mg four times daily (qid)
S. Johnson / International Journal of Antimicrobial Agents 33 (2009) S33 S36
×10 14 d, then twice daily (bid) for 7 d, then daily for 7 d, then 125 mg every 2 3 days for 2 8 weeks) 22 . A small, uncontrolled study showed that adding rifampicin to vancomycin may also be helpful in treating recurrent CDI patients 23 . One approach to restoring a more normal faecal flora has been to administer a faecal specimen from a normal donor (usually the spouse of the patient) to the patient with multiple recurrent CDI. Borody et al. reviewed eight reports in the literature from 1958 to 1998 using this faecal transplant approach and noted a 90% success rate among 67 patients where faecal slurries were delivered by nasoduodenal tube, gastrostomy or colonoscope 24 . A more recent study reported that only 1 of 16 treated patients with follow-up had a single recurrent episode following a faecal transplant given by nasogastric tube 25 . Tvede et al. used a bacteriotherapy approach in five patients with multiple recurrent CDI, whereby a mixture of 10 different facultative aerobic and anaerobic bacteria, diluted in normal saline, was administered by rectal instillation 26 . Their observation was that Bacteroides spp. colonisation correlated with loss of C. difficile and its toxin. These studies, while uncontrolled, support loss of colonisation resistance by certain indigenous flora as an important factor in the pathogenesis of recurrent CDI. With the understanding that immunity to C. difficile toxins is an additional factor in the pathogenesis of recurrent CDI, several investigators have exploited passive and active toxoid immunisation approaches. Since anti-toxin A IgG predicts the clinical outcome of infection with C. difficile 11,27 and serum antibodies to toxins A and B are prevalent in healthy populations 28 , intravenous immunoglobulin (IVIG) from pooled human donors has been used as adjunctive treatment for recurrent CDI 29 31 . Wilcox et al. recently reported their experience with IVIG in five patients with protracted or recurrent CDI using doses of 300 500 mg/kg given once or twice, or in one case, six times 32 . Three of the five patients had no further recurrence, one patient had a recurrence at 6 weeks and one patient died of intractable CDI. A potential refinement of this approach would be to develop hyperimmune serum with high titres of anti-C. difficile toxin antibodies, but this treatment is not yet available. Finally, a proofof-concept trial was conducted using a toxoid vaccination study on three patients with multiple CDI recurrences 33 . This vaccine, containing partially purified, inactivated toxins A and B, was given to these patients on days 0, 7, 28, and 56 while vancomycin treatment was continued. After vancomycin treatment was discontinued none of the patients had a recurrence and two of the three patients developed serum cytotoxin (toxin B) neutralising antibodies. More extensive testing of this vaccine approach will be conducted in the near future. Another approach has been to administer non-absorbed toxin-binding agents that have the potential advantage of avoiding further antibiotic-induced changes to the indigenous bowel flora. Cholestyramine and colestipol were the first agents to be used in this manner and, although there are anecdotal reports of efficacy in recurrent CDI, colestipol was shown to be no better than placebo for the treatment of CDI in an early comparative trial of CDI treatment 34 . These agents also have the potential to bind vancomycin, making them difficult to use as adjunctive treatment with vancomycin. Finally, there is little efficacy of cholestyramine in the hamster model of CDI, where hamsters are pre-treated
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with cholestyramine then given antibiotics and challenged with virulent C. difficile organisms 35 . This same animal model was used to demonstrate the superior efficacy of another polymer, tolevamer, which was specifically designed to bind C. difficile toxins 35 . Based on this promising work in hamsters and early clinical trials, tolevamer was compared with vancomycin and metronidazole in the largest clinical trial ever conducted in CDI 36 . Tolevamer was shown to be inferior to treatment with either vancomycin or metronidazole, but in those patients who responded to treatment with tolevamer, the recurrence rate was significantly lower than the rate seen in patients who responded to vancomycin and metronidazole 36 . It is possible that tolevamer may be effective as adjunctive therapy, but there are no current data to support this approach and the agent is not commercially available. Finally, out of frustration in our clinical experience with patients who failed multiple attempts to interrupt recurrent CDI episodes, we developed another approach using an agent that has been shown to be effective in the treatment of traveller’s diarrhoea, rifaximin 37 . This strategy involved discontinuation of vancomycin when the patients were asymptomatic and administering rifaximin 400 mg bid for the next 2 weeks. The term ‘chaser’ was invoked to convey the idea that rifaximin was not combined with vancomycin, or that rifaximin was used to treat symptomatic CDI, per se. The hope was that rifaximin, a non-absorbable agent with good activity against most C. difficile strains, might suppress vegetative growth of C. difficile and prevent the inevitable recurrence of symptomatic CDI in these patients, possibly through a different effect on the indigenous flora than that elicited by treatment with vancomycin. Our experience was very positive in the first eight patients with multiple CDI recurrences (mean±SD number of episodes, 5.8±1.5) treated using this strategy. Only one of these patients had a subsequent CDI episode and this patient responded to a second course of rifaximin without further episodes. A C. difficile isolate that was identical to a pre-rifaximin treatment isolate by REA typing was recovered from the stool of this patient after the second course of rifaximin. The post-treatment isolate had an MIC of >256 mg/mL for rifaximin compared with an MIC of 0.0078 mg/mL in the pre-treatment isolate. It is not clear how patients would respond to this approach if the pretreatment isolate had a high MIC to rifaximin, but these strains that appear resistant in vitro are present in clinical isolate collections with variable frequency 38 . Garey et al. have also reported success using rifaximin in five of six patients with recurrent CDI 39 . In this study, rifaximin was started while the patients were symptomatic and given at a dose of 400 mg three times daily (tid) for 2 weeks, followed by 200 mg tid for 2 weeks. Additional agents, such as nitazoxanide, may also be useful for patients who fail during, or have recurrences after, treatment with metronidazole 4 . In addition, treatment agents with a narrower spectrum of activity, such as the experimental drug OPT-80, might be particularly useful for treating patients with recurrent CDI 10 . Regardless of the management strategy used, patients with recurrent CDI need careful follow-up and reassurance. Our experience has been that most patients with recurrent CDI, even those with multiple recurrences, can be successfully treated with one or more of the above strategies.
S. Johnson / International Journal of Antimicrobial Agents 33 (2009) S33 S36
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Funding: United States Department of Veterans Affairs Research Service; Viropharma, Inc. Competing interests: Dr. Johnson has served on the advisory boards of Genzyme Corporation; Salix Pharmaceuticals Inc.; Acambis; and Optimer Pharmaceuticals Inc. Ethics approval: Not required for this review. References 1. Johnson S, Gerding DN. Clostridium difficile-associated diarrhoea. Clin Infect Dis 1998;26:1027 34. 2. Pepin J, Routhier S, Gagnon S, Brazeau I. Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis 2006;42:758 64. 3. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002;97:1769 75. 4. Musher DM, Logan N, Mehendiratta V, Melgarejo NA, Garud S, Hamill RJ. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother 2007;59:705 10. 5. Musher DM, Logan N, Hamill RJ, Dupont HL, Lentnek A, Gupta A, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 2006;43:421 7. 6. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006;124:837 48. 7. Chang JY, Antonopoulos DA, Kalra A, Tonelli A, Khalife WT, Schmidt TM, et al. Decreased diversity of the faecal microbiome in recurrent Clostridium difficile-associated diarrhoea. J Infect Dis 2008;197:435 8. 8. Vollaard EJ, Clasener HA. Colonization resistance. Antimicrob Agents Chemother 1994;38:409 14. 9. Borriello SP. 12th C.L. Oakley Lecture. Pathogenesis of Clostridium difficile infection of the gut. J Med Microbiol 1990;33:207 15. 10. Louie TJ, Emery J, Krulicki W, MacCannell D, Byrne B, Mah M. Quantitative C. difficile and anaerobic flora cultures during treatment of C. difficileassociated diarrhoea with PAR-101. In: Program and abstracts of the 16th European Congress of Clinical Microbiology and Infectious Diseases, 1 4 April 2006; Nice, France; Abstract p1649. 11. Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001;357:189 93. 12. Johnson S, Adelmann A, Clabots CR, Peterson LR, Gerding DN. Recurrences of Clostridium difficile diarrhoea not caused by the original infecting organism. J Infect Dis 1989;159:340 3. 13. O’Neill GL, Beaman MH, Riley TV. Relapse versus reinfection with Clostridium difficile. Epidemiol Infect 1991;107:627 35. 14. Wilcox MH, Fawley WN, Settle CD, Davidson A. Recurrence of symptoms in Clostridium difficile infection relapse or reinfection? J Hosp Infect 1998; 38:93 100. 15. Barbut F, Richard A, Hamadi K, Chomette V, Burghoffer B, Petit JC. Epidemiology of recurrences or reinfections of Clostridium difficileassociated diarrhoea. J Clin Microbiol 2000;38:2386 8. 16. Tang-Feldman Y, Mayo S, Silva Jr J, Cohen SH. Molecular analysis of Clostridium difficile strains isolated from 18 cases of recurrent Clostridium difficile-associated diarrhoea. J Clin Microbiol 2003;41:3413 4. 17. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhoea, stratified by disease severity. Clin Infect Dis 2007;45:302 7. 18. Surawicz CM, McFarland LV, Greenberg RN, Rubin M, Fekety R, Mulligan ME, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000;31:1012 7.
19. Wullt M, Hagslatt ML, Odenholt I. Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a doubleblind, placebo-controlled trial. Scand J Infect Dis 2003;35:365 7. 20. Seal D, Borriello SP, Barclay F, Welch A, Piper M, Bonnycastle M. Treatment of relapsing Clostridium difficile diarrhoea by administration of a non-toxigenic strain. Eur J Clin Microbiol 1987;6:51 3. 21. Sambol SP, Merrigan MM, Tang JK, Johnson S, Gerding DN. Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis 2002; 186:1781 9. 22. Kyne L, Kelly CP. Recurrent Clostridium difficile diarrhoea. Gut 2001;49: 152 3. 23. Buggy BP, Fekety R, Silva Jr J. Therapy of relapsing Clostridium difficileassociated diarrhoea and colitis with the combination of vancomycin and rifampin. J Clin Gastroenterol 1987;9:155 9. 24. Borody TJ. “Flora Power” faecal bacteria cure chronic C. difficile diarrhoea. Am J Gastroenterol 2000;95:3028 9. 25. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003;36:580 5. 26. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989;1:1156 60. 27. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000;342:390 7. 28. Viscidi R, Laughon BE, Yolken R, Bo-Linn P, Moench T, Ryder RW, et al. Serum antibody response to toxins A and B of Clostridium difficile. J Infect Dis 1983;148:93 100. 29. Leung DY, Kelly CP, Boguniewicz M, Pothoulakis C, LaMont JT, Flores A. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr 1991;118: 633 7. 30. Warny M, Denie C, Delmee M, Lefebvre C. Gamma globulin administration in relapsing Clostridium difficile-induced pseudomembranous colitis with a defective antibody response to toxin A. Acta Clin Belg 1995;50:36 9. 31. Beales IL. Intravenous immunoglobulin for recurrent Clostridium difficile diarrhoea. Gut 2002;51:456. 32. Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother 2004;53:882 4. 33. Sougioultzis S, Kyne L, Drudy D, Keates S, Maroo S, Pothoulakis C, et al. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhoea. Gastroenterology 2005;128:764 70. 34. Mogg GA, Arabi Y, Youngs D, Johnson M, Bentley S, Burdon DW, et al. Therapeutic trials of antibiotic associated colitis. Scand J Infect Dis Suppl 1980;22:41 5. 35. Kurtz CB, Cannon EP, Brezzani A, Pitruzzello M, Dinardo C, Rinard E, et al. GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis. Antimicrob Agents Chemother 2001;45:2340 7. 36. Louie T, Gerson M, Grimard D, Johnson S, Poirier A, Weiss K, et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhoea (CDAD). In: Program and abstracts of the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, 17 20 September 2007, Chicago, IL; Abstract K-425a. 37. Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN. Interruption of recurrent Clostridium difficile-associated diarrhoea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007;44:846 8. 38. O’Connor JR, Galang MA, Sambol SP, Hecht DW, Vedantam G, Gerding DN, et al. Rifampin and rifaximin resistance in clinical isolates of Clostridium difficile. Antimicrob Agents Chemother 2008;52:2813 7. 39. Garey KW, Jiang ZD, Bellard A, Dupont HL. Rifaximin in treatment of recurrent Clostridium difficile-associated diarrhea: an uncontrolled pilot study. J Clin Gastroenterol 2009;43:91 2.
Recurrent Clostridium difficile infection: causality and therapeutic approaches Stuart Johnsona,b, * a b
Medicine Service, Edward Hines Jr. Veterans Affairs Hospital, Hines, IL, USA Division of Infectious Diseases, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
ARTICLE
INFO
Keywords: Clostridium difficile Diarrhoea Recurrence
ABSTRACT Recurrent diarrhoea after successful treatment of the primary episode is a common complication of Clostridium difficile infection (CDI) and may be increasing in frequency. Evidence suggests that persistent alterations in the indigenous bowel flora and failure to mount an effective antibody response to C. difficile toxins are the main mechanisms whereby recurrent CDIs occur. Treatment of the first recurrence with the same agent used for the treatment of the primary episode is reasonable, but a different approach is needed for patients with multiple CDI recurrences. Prolonged, repeated courses of metronidazole are discouraged, but a practical first option in these patients is to use tapered-dose oral vancomycin followed by a pulsed-dose regimen. Other potential options include probiotic approaches, restoration of the normal flora, immunological approaches, toxin-binding approaches, and serial therapy with vancomycin followed by rifaximin. Randomised studies including a sufficient numbers of patients have not yet been conducted for the treatment of recurrent CDI and are needed to help guide the formulation of effective recommendations. © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Recurrent diarrhoea is a common and frustrating complication of Clostridium difficile infection (CDI); often frustrating for the treating physician as well as for the patient. Recurrent CDI occurs in ~20% of patients after the first episode 1 and these rates may be increasing. A 33% recurrence rate after the initial episode was recently reported in the setting of a multihospital outbreak in Quebec due to an epidemic hypervirulent strain 2 . These authors also reported complications of shock, colectomy, perforation, megacolon, or death in 11% of patients with first recurrence, highlighting the potential severity of recurrent CDI. In addition, the risk of a subsequent episode in a patient who has already had one recurrence is ~45% 3 . Finally, a subset of patients will have multiple recurrences. These patients typically respond to treatment for each episode, but symptoms recur within days to several weeks after discontinuation of the treating agent. * Stuart Johnson. Division of Infectious Diseases, Loyola University Chicago Stritch School of Medicine, 2160 South First Avenue, Fahey Center (Bldg. 54), Room 149, Maywood, IL 60153, USA. Tel.: +1 708 216 3232; fax: +1 708 216 8198. E-mail address: [email protected] (S. Johnson). 0924-8579/ $
Recurrent CDI should be distinguished from treatment failure as the mechanisms are likely to be different and the treatment should be different. Some authors, however, have included both outcomes in their definition of failure: no improvement in symptoms or signs of disease after a period of treatment or prompt recurrence on at least two occasions after initially responding to such treatment 4 . This group has also used the term ‘sustained response’ in reference to successful recovery without recurrence 5 . Regardless, the appropriate management of a patient who is not responding to treatment with metronidazole after a sufficient period of time is to switch treatment to oral vancomycin. On the other hand, a patient who initially responds to treatment with metronidazole can reliably be treated with the same agent for the first recurrence. Metronidazole was shown to be not inferior to vancomycin for the treatment of a first recurrence of CDI, and the treatment of a first recurrence with the same or a different agent made no difference in outcome 2 . 2. Causality Although the mechanisms whereby recurrent CDI occur have not been completely worked out, the intimate association
see front matter © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
S34
S. Johnson / International Journal of Antimicrobial Agents 33 (2009) S33 S36
of CDI with prior or concurrent antibiotic use has suggested that disruption of the normal colonic flora and decrease in colonisation resistance is a critical factor for the development of recurrent CDI. The microflora of the human colon is diverse and not all species have been cultured and identified, but culture-independent methods have been developed to profile the microbiota of individuals and it has been shown that the microbiota of adults is dominated by species of the Bacteroidetes and Firmicutes divisions (phyla) 6 . Chang et al. performed a phylogenetic analysis of 16S rRNA-encoding gene sequences from faecal samples of patients with initial CDI episodes and recurrent CDI episodes 7 . Whereas the patients with initial CDI episodes and the control patients had a predominance of Bacteroidetes and Firmicutes species, the predominant species in the patients with recurrent CDI were quite different and these patients’ microbiotae exhibited significantly less diversity 7 . It is suspected that anaerobic bacteria provide the more important determinants of colonisation resistance to C. difficile 8,9 and antibiotics that disrupt these components of the microbiota might be particularly likely to precipitate CDI. In addition, the specific agents that are used to treat CDI, metronidazole and vancomycin, may be the precipitating antibiotics for the recurrent episode through their effect on the anaerobic flora of the gut. Louie et al. recently demonstrated that oral vancomycin had a profound effect on Bacteroides fragilis counts in patients with CDI: mean B. fragilis group counts decreased by a factor of >3 log after 10 days of treatment with vancomycin 10 . Factors other than indigenous microflora may also contribute to recurrent CDI. Immune responses to C. difficile and/or its toxins are also likely to play a role. Kyne et al. showed that patients with a single episode of CDI had higher serum levels of IgM against toxin A on day 3 of the first episode and IgG to toxin A on day 12 than did patients with recurrent CDI 11 . The proportion of patients with recurrent CDI was linearly associated with decreasing levels of anti-toxin A IgM and IgG measured at these time points. Recurrent CDI is not always due to relapse of the same C. difficile strain. Five different investigators using various typing methodologies consistently showed that a new strain was found in 33 56% of recurrent episodes 12 16 . Time to recurrence was moderately predictive of relapse with the same strain or reinfection with a new strain: the mean time to recurrence with the same strain was 14.5±10 days and for infection with a new strain was 42.5±39 days 12 . These studies suggest the importance of exogenous infection in patients rendered susceptible by decreased colonisation resistance and inadequate immune response. 3. Therapeutic approaches As previously mentioned, recurrent CDI is not a consequence of resistance to metronidazole or vancomycin, the two main agents used to treat CDI. Therefore, treatment of the first recurrent episode with the same agent used for the initial episode is a reasonable approach. Although metronidazole is an inexpensive and effective agent for most patients with CDI, patients with evidence of severe CDI should be treated with oral vancomycin regardless of whether it is the initial or recurrent episode. Using ad hoc severity criteria, Zar et al. showed vancomycin to be superior to metronidazole
Table 1. Strategies for managing patients with multiple Clostridium difficile infection recurrences Probiotic approaches Saccharomyces boulardii Lactobacillus Non-toxigenic Clostridium difficile Vancomycin approaches Tapering and/or pulsed vancomycin Vancomycin + rifampicin Normal flora restoration Faecal transplantation Bacteriotherapy Immunological approaches Intravenous immunoglobulin Active vaccination Toxin-binding approaches Cholestyramine/colestipol Tolevamer Rifaximin ‘chaser’ approach
in a recent, randomised, double-blinded, controlled study of CDI 17 . In addition, repeated courses of metronidazole beyond the first recurrence are discouraged because of the risk of neurotoxicity and hepatotoxicity with prolonged use of this agent 1 . Unfortunately, most of the data reported for managing patients with recurrent CDI and multiply recurrent CDI are anecdotal or reported in small case-series. The only randomised studies for the treatment of recurrent CDI have involved probiotics (Table 1). Surawicz et al. showed that 15 of 18 patients with recurrent CDI given high dose vancomycin 2 g/day for 10 days and Saccharomyces boulardii 1 g/day for 28 days had successful outcomes, compared with 7 of 14 patients treated with high-dose vancomycin and placebo (P = 0.05) 18 . This study, however, was a subset analysis of a larger study and needs to be repeated with larger numbers of patients to confirm its efficacy. In a similarly designed trial, Wullt et al. showed that Lactobacillus was not different from placebo: 7 of 11 patients responded to 10 days of metronidazole and 38 days of Lactobacillus plantarum 299v, compared with 3 of 9 patients treated with metronidazole and placebo (P = NS) 19 . A novel probiotic approach used successfully in two patients with recurrent CDI involved administration of a non-toxigenic strain of C. difficile 20 . This approach has high efficacy in the hamster model of CDI 21 , and formal clinical trials using a non-toxigenic C. difficile strain seen in high frequency among asymptomatic, hospitalised patients are planned. Although not studied in a randomised fashion, tapering and/or pulsed dosing of vancomycin is a frequently employed approach to interrupt multiple recurrences of CDI. McFarland et al. reviewed the placebo cohort from two clinical trials of S. boulardii as adjunctive CDI therapy 3 . In this retrospective review, tapering the dose or pulsed dosing of vancomycin was more likely to result in successful outcomes than low-, mid-, or high-dose vancomycin or any metronidazole regimen. A practical approach to patients with more than one recurrence is to use a tapering dose followed by pulsed dosing of vancomycin (e.g., vancomycin 125 mg four times daily (qid)
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×10 14 d, then twice daily (bid) for 7 d, then daily for 7 d, then 125 mg every 2 3 days for 2 8 weeks) 22 . A small, uncontrolled study showed that adding rifampicin to vancomycin may also be helpful in treating recurrent CDI patients 23 . One approach to restoring a more normal faecal flora has been to administer a faecal specimen from a normal donor (usually the spouse of the patient) to the patient with multiple recurrent CDI. Borody et al. reviewed eight reports in the literature from 1958 to 1998 using this faecal transplant approach and noted a 90% success rate among 67 patients where faecal slurries were delivered by nasoduodenal tube, gastrostomy or colonoscope 24 . A more recent study reported that only 1 of 16 treated patients with follow-up had a single recurrent episode following a faecal transplant given by nasogastric tube 25 . Tvede et al. used a bacteriotherapy approach in five patients with multiple recurrent CDI, whereby a mixture of 10 different facultative aerobic and anaerobic bacteria, diluted in normal saline, was administered by rectal instillation 26 . Their observation was that Bacteroides spp. colonisation correlated with loss of C. difficile and its toxin. These studies, while uncontrolled, support loss of colonisation resistance by certain indigenous flora as an important factor in the pathogenesis of recurrent CDI. With the understanding that immunity to C. difficile toxins is an additional factor in the pathogenesis of recurrent CDI, several investigators have exploited passive and active toxoid immunisation approaches. Since anti-toxin A IgG predicts the clinical outcome of infection with C. difficile 11,27 and serum antibodies to toxins A and B are prevalent in healthy populations 28 , intravenous immunoglobulin (IVIG) from pooled human donors has been used as adjunctive treatment for recurrent CDI 29 31 . Wilcox et al. recently reported their experience with IVIG in five patients with protracted or recurrent CDI using doses of 300 500 mg/kg given once or twice, or in one case, six times 32 . Three of the five patients had no further recurrence, one patient had a recurrence at 6 weeks and one patient died of intractable CDI. A potential refinement of this approach would be to develop hyperimmune serum with high titres of anti-C. difficile toxin antibodies, but this treatment is not yet available. Finally, a proofof-concept trial was conducted using a toxoid vaccination study on three patients with multiple CDI recurrences 33 . This vaccine, containing partially purified, inactivated toxins A and B, was given to these patients on days 0, 7, 28, and 56 while vancomycin treatment was continued. After vancomycin treatment was discontinued none of the patients had a recurrence and two of the three patients developed serum cytotoxin (toxin B) neutralising antibodies. More extensive testing of this vaccine approach will be conducted in the near future. Another approach has been to administer non-absorbed toxin-binding agents that have the potential advantage of avoiding further antibiotic-induced changes to the indigenous bowel flora. Cholestyramine and colestipol were the first agents to be used in this manner and, although there are anecdotal reports of efficacy in recurrent CDI, colestipol was shown to be no better than placebo for the treatment of CDI in an early comparative trial of CDI treatment 34 . These agents also have the potential to bind vancomycin, making them difficult to use as adjunctive treatment with vancomycin. Finally, there is little efficacy of cholestyramine in the hamster model of CDI, where hamsters are pre-treated
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with cholestyramine then given antibiotics and challenged with virulent C. difficile organisms 35 . This same animal model was used to demonstrate the superior efficacy of another polymer, tolevamer, which was specifically designed to bind C. difficile toxins 35 . Based on this promising work in hamsters and early clinical trials, tolevamer was compared with vancomycin and metronidazole in the largest clinical trial ever conducted in CDI 36 . Tolevamer was shown to be inferior to treatment with either vancomycin or metronidazole, but in those patients who responded to treatment with tolevamer, the recurrence rate was significantly lower than the rate seen in patients who responded to vancomycin and metronidazole 36 . It is possible that tolevamer may be effective as adjunctive therapy, but there are no current data to support this approach and the agent is not commercially available. Finally, out of frustration in our clinical experience with patients who failed multiple attempts to interrupt recurrent CDI episodes, we developed another approach using an agent that has been shown to be effective in the treatment of traveller’s diarrhoea, rifaximin 37 . This strategy involved discontinuation of vancomycin when the patients were asymptomatic and administering rifaximin 400 mg bid for the next 2 weeks. The term ‘chaser’ was invoked to convey the idea that rifaximin was not combined with vancomycin, or that rifaximin was used to treat symptomatic CDI, per se. The hope was that rifaximin, a non-absorbable agent with good activity against most C. difficile strains, might suppress vegetative growth of C. difficile and prevent the inevitable recurrence of symptomatic CDI in these patients, possibly through a different effect on the indigenous flora than that elicited by treatment with vancomycin. Our experience was very positive in the first eight patients with multiple CDI recurrences (mean±SD number of episodes, 5.8±1.5) treated using this strategy. Only one of these patients had a subsequent CDI episode and this patient responded to a second course of rifaximin without further episodes. A C. difficile isolate that was identical to a pre-rifaximin treatment isolate by REA typing was recovered from the stool of this patient after the second course of rifaximin. The post-treatment isolate had an MIC of >256 mg/mL for rifaximin compared with an MIC of 0.0078 mg/mL in the pre-treatment isolate. It is not clear how patients would respond to this approach if the pretreatment isolate had a high MIC to rifaximin, but these strains that appear resistant in vitro are present in clinical isolate collections with variable frequency 38 . Garey et al. have also reported success using rifaximin in five of six patients with recurrent CDI 39 . In this study, rifaximin was started while the patients were symptomatic and given at a dose of 400 mg three times daily (tid) for 2 weeks, followed by 200 mg tid for 2 weeks. Additional agents, such as nitazoxanide, may also be useful for patients who fail during, or have recurrences after, treatment with metronidazole 4 . In addition, treatment agents with a narrower spectrum of activity, such as the experimental drug OPT-80, might be particularly useful for treating patients with recurrent CDI 10 . Regardless of the management strategy used, patients with recurrent CDI need careful follow-up and reassurance. Our experience has been that most patients with recurrent CDI, even those with multiple recurrences, can be successfully treated with one or more of the above strategies.
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Funding: United States Department of Veterans Affairs Research Service; Viropharma, Inc. Competing interests: Dr. Johnson has served on the advisory boards of Genzyme Corporation; Salix Pharmaceuticals Inc.; Acambis; and Optimer Pharmaceuticals Inc. Ethics approval: Not required for this review. References 1. Johnson S, Gerding DN. Clostridium difficile-associated diarrhoea. Clin Infect Dis 1998;26:1027 34. 2. Pepin J, Routhier S, Gagnon S, Brazeau I. Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis 2006;42:758 64. 3. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002;97:1769 75. 4. Musher DM, Logan N, Mehendiratta V, Melgarejo NA, Garud S, Hamill RJ. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother 2007;59:705 10. 5. Musher DM, Logan N, Hamill RJ, Dupont HL, Lentnek A, Gupta A, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 2006;43:421 7. 6. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006;124:837 48. 7. Chang JY, Antonopoulos DA, Kalra A, Tonelli A, Khalife WT, Schmidt TM, et al. Decreased diversity of the faecal microbiome in recurrent Clostridium difficile-associated diarrhoea. J Infect Dis 2008;197:435 8. 8. Vollaard EJ, Clasener HA. Colonization resistance. Antimicrob Agents Chemother 1994;38:409 14. 9. Borriello SP. 12th C.L. Oakley Lecture. Pathogenesis of Clostridium difficile infection of the gut. J Med Microbiol 1990;33:207 15. 10. Louie TJ, Emery J, Krulicki W, MacCannell D, Byrne B, Mah M. Quantitative C. difficile and anaerobic flora cultures during treatment of C. difficileassociated diarrhoea with PAR-101. In: Program and abstracts of the 16th European Congress of Clinical Microbiology and Infectious Diseases, 1 4 April 2006; Nice, France; Abstract p1649. 11. Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001;357:189 93. 12. Johnson S, Adelmann A, Clabots CR, Peterson LR, Gerding DN. Recurrences of Clostridium difficile diarrhoea not caused by the original infecting organism. J Infect Dis 1989;159:340 3. 13. O’Neill GL, Beaman MH, Riley TV. Relapse versus reinfection with Clostridium difficile. Epidemiol Infect 1991;107:627 35. 14. Wilcox MH, Fawley WN, Settle CD, Davidson A. Recurrence of symptoms in Clostridium difficile infection relapse or reinfection? J Hosp Infect 1998; 38:93 100. 15. Barbut F, Richard A, Hamadi K, Chomette V, Burghoffer B, Petit JC. Epidemiology of recurrences or reinfections of Clostridium difficileassociated diarrhoea. J Clin Microbiol 2000;38:2386 8. 16. Tang-Feldman Y, Mayo S, Silva Jr J, Cohen SH. Molecular analysis of Clostridium difficile strains isolated from 18 cases of recurrent Clostridium difficile-associated diarrhoea. J Clin Microbiol 2003;41:3413 4. 17. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhoea, stratified by disease severity. Clin Infect Dis 2007;45:302 7. 18. Surawicz CM, McFarland LV, Greenberg RN, Rubin M, Fekety R, Mulligan ME, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000;31:1012 7.
19. Wullt M, Hagslatt ML, Odenholt I. Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a doubleblind, placebo-controlled trial. Scand J Infect Dis 2003;35:365 7. 20. Seal D, Borriello SP, Barclay F, Welch A, Piper M, Bonnycastle M. Treatment of relapsing Clostridium difficile diarrhoea by administration of a non-toxigenic strain. Eur J Clin Microbiol 1987;6:51 3. 21. Sambol SP, Merrigan MM, Tang JK, Johnson S, Gerding DN. Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis 2002; 186:1781 9. 22. Kyne L, Kelly CP. Recurrent Clostridium difficile diarrhoea. Gut 2001;49: 152 3. 23. Buggy BP, Fekety R, Silva Jr J. Therapy of relapsing Clostridium difficileassociated diarrhoea and colitis with the combination of vancomycin and rifampin. J Clin Gastroenterol 1987;9:155 9. 24. Borody TJ. “Flora Power” faecal bacteria cure chronic C. difficile diarrhoea. Am J Gastroenterol 2000;95:3028 9. 25. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003;36:580 5. 26. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989;1:1156 60. 27. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000;342:390 7. 28. Viscidi R, Laughon BE, Yolken R, Bo-Linn P, Moench T, Ryder RW, et al. Serum antibody response to toxins A and B of Clostridium difficile. J Infect Dis 1983;148:93 100. 29. Leung DY, Kelly CP, Boguniewicz M, Pothoulakis C, LaMont JT, Flores A. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr 1991;118: 633 7. 30. Warny M, Denie C, Delmee M, Lefebvre C. Gamma globulin administration in relapsing Clostridium difficile-induced pseudomembranous colitis with a defective antibody response to toxin A. Acta Clin Belg 1995;50:36 9. 31. Beales IL. Intravenous immunoglobulin for recurrent Clostridium difficile diarrhoea. Gut 2002;51:456. 32. Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother 2004;53:882 4. 33. Sougioultzis S, Kyne L, Drudy D, Keates S, Maroo S, Pothoulakis C, et al. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhoea. Gastroenterology 2005;128:764 70. 34. Mogg GA, Arabi Y, Youngs D, Johnson M, Bentley S, Burdon DW, et al. Therapeutic trials of antibiotic associated colitis. Scand J Infect Dis Suppl 1980;22:41 5. 35. Kurtz CB, Cannon EP, Brezzani A, Pitruzzello M, Dinardo C, Rinard E, et al. GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis. Antimicrob Agents Chemother 2001;45:2340 7. 36. Louie T, Gerson M, Grimard D, Johnson S, Poirier A, Weiss K, et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhoea (CDAD). In: Program and abstracts of the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, 17 20 September 2007, Chicago, IL; Abstract K-425a. 37. Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN. Interruption of recurrent Clostridium difficile-associated diarrhoea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007;44:846 8. 38. O’Connor JR, Galang MA, Sambol SP, Hecht DW, Vedantam G, Gerding DN, et al. Rifampin and rifaximin resistance in clinical isolates of Clostridium difficile. Antimicrob Agents Chemother 2008;52:2813 7. 39. Garey KW, Jiang ZD, Bellard A, Dupont HL. Rifaximin in treatment of recurrent Clostridium difficile-associated diarrhea: an uncontrolled pilot study. J Clin Gastroenterol 2009;43:91 2.