Fecal Transplantation, Through Colonoscopy, Is Effective Therapy for Recurrent Clostridium difficile Infection

Transcription

1 GASTROENTEROLOGY 2012;142: Fecal Transplantation, Through Colonoscopy, Is Effective Therapy for Recurrent Clostridium Infection EERO MATTILA,* RAIJA UUSITALO SEPPÄLÄ, MAARIT WUORELA, LAURA LEHTOLA, HEIMO NURMI, MATTI RISTIKANKARE, # VEIKKO MOILANEN,** KIMMO SALMINEN,, MAARIA SEPPÄLÄ, PETRI S. MATTILA, VELI JUKKA ANTTILA,* and PERTTU ARKKILA *Department of Infectious Diseases, Department of Otorhinolaryngology, and Department of Gastroenterology, Helsinki University Central Hospital, Helsinki; Department of Infectious Diseases and **Department of Gastroenterology, Satakunta Central Hospital, Pori; Turku City Hospital, Turku; Maria Hospital, Helsinki City Hospital, Helsinki; Department of Medicine, Turku University Central Hospital, Turku; # Laakso Hospital, Helsinki City Hospital, Helsinki, Finland BACKGROUND & AIMS: Treatment of recurrent Clostridium (CDI) with antibiotics leads to recurrences in up to 50% of patients. We investigated the efficacy of fecal transplantation in treatment of recurrent CDI. METHODS: We reviewed records from 70 patients with recurrent CDI who had undergone fecal transplantation. Fecal transplantation was performed at colonoscopy by infusing fresh donor feces into cecum. Before transplantation, the patients had whole-bowel lavage with polyethylene glycol solution. Clinical failure was defined as persistent or recurrent symptoms and signs, and a need for new therapy. RESULTS: During the first 12 weeks after fecal transplantation, symptoms resolved in all patients who did not have strain 027 C s. Of 36 patients with 027 C, 32 (89%) had a favorable response; all 4 nonresponders had a pre-existing serious condition, caused by a long-lasting diarrheal disease or comorbidity and subsequently died of colitis. During the first year after transplantation, 4 patients with an initial favorable response had a relapse after receiving antibiotics for unrelated causes; 2 were treated successfully with another fecal transplantation and 2 with antibiotics for CDI. Ten patients died of unrelated illnesses within 1 year after transplantation. No immediate complications of fecal transplantation were observed. CON- CLUSIONS: Fecal transplantation through colonoscopy seems to be an effective treatment for recurrent CDI and also for recurrent CDI caused by the virulent C 027 strain. Keywords: Bacteriotherapy; Gut Microbiota; Refractory C. Clostridium (CDI) is a common cause of both community- and hospital-acquired diarrhea, usually occurring after exposure to antibiotics. During the past few years, C has become more frequent, more severe, more refractory to standard treatment, and more likely to relapse. 1 4 Current treatment with metronidazole or vancomycin against CDI is suboptimal, especially in terms of high recurrence rates. Both of these antibiotics alter the normal gut flora that provides colonization resistance against C. 5 After successful initial therapy, up to 35% of patients experience a symptomatic recurrence after discontinuation of antibiotics for CDI. 6 A subset of patients will have multiple recurrences, and subsequent relapses occur in up to 50% 65% of patients. 7 Relapse is seen more frequently in individuals older than age 65 and requiring prolonged hospital stays. Also, recurrent CDI is associated with severe complications of megacolon, perforation, shock, or. 8 A number of new approaches have been used to treat multiple CDI recurrences. New drugs have been introduced including rifaximin, 9 nitazoxanide, 10 and fidaxomicin. 11 Immune therapy has been used such as intravenous immunoglobulin, 12 intravenous C toxin specific monoclonal antibodies, 13 and oral bovine antibody enriched whey, 14,15 as well as active vaccination. 16 Also, probiotic regimens with Saccharomyces boulardii 17 and Lactobacillus, 18 and with a nontoxigenic C strain, 19 have been used. However, all currently available treatment modalities have limited efficacy. Sometimes multiple relapses are extremely difficult to prevent without continuous vancomycin therapy. At present, there are few attractive choices or strategies for the treatment of a relapsing disease. 20 The re-establishment of the normal composition of the intestinal flora by fecal transplantation was first described in Despite this, there are still only a few published reports on fecal bacteriotherapy (fecal transplantation) in the treatment of recurrent CDI. In previous reports, various different transplantation methods have been used including stool infusion to the duodenum through a nasogastric tube or fecal enemas. Fecal transplantation in refractory cases of CDI have been used only occasionally in Finland since the 1990s. 27 C ribotype 027 was detected for the first time in Finland in After the appearance of ribotype 027, there were more patients with relapses of C and the relapses also were more difficult to treat with conventional antibiotic therapy for CDI. This encouraged the use of fecal transplantation for CDI, and it became a treatment option for selected patients. Abbreviation used in this paper: CDI, Clostridium by the AGA Institute /$36.00 doi: /j.gastro

2 March 2012 FECAL TRANSPLANTATION FOR RECURRENT CDI 491 We previously presented an abstract of the preliminary results of 37 patients from our series. 29 Here, we report the comprehensive results of our retrospective study of 70 patients with recurrent CDI treated with colonoscopyadministered stool in 5 different centers. The stool transplantations were performed using a standard method in all centers. Patients and Methods Patients This study was a retrospective review of all patients treated by fecal transplantation through colonoscopy in 5 hospitals: Helsinki University Central Hospital, Turku University Central Hospital, Satakunta Central Hospital, Turku Municipal Hospital, and Helsinki Municipal Hospital, from November 2007 though February The criterion for fecal transplantation in these hospitals was laboratory-confirmed recurrent CDI (positive culture and toxin) despite antimicrobial treatment for CDI. All patients were refractive to standard therapy, and fecal transplantation was used as a salvage therapy after attempts of conventional therapy had failed. Only patients who had received fecal transplantation through colonoscopy according to the predetermined protocol using colonoscopy were included in the study. Patient records were evaluated retrospectively. All the participating centers had electronic patient records including patient history, laboratory findings, and official information on the survival of the patient, which facilitated a reliable review of the information gathered in the study. Strain typing of isolated C colonies was performed using the DiversiLab system (biomérieux, Marcy l=etoile, France). This method is based on polymerase chain reaction amplification of repetitive extragenic palindromic sequences and it reliably can distinguish C ribotype 027 strain from other strains. 30 Stool Transplant Donor Screening Individuals who had not received antimicrobial therapy for the past 6 months and who did not have any intestinal symptoms were considered to be suitable for stool donation. Preferred stool donors were as follows: (1) relatives, (2) individuals who had intimate physical contact with the patients (spouse or significant partner), or (3) any other healthy donors. Our protocol for donor screening is summarized in Table 1. Blood samples of the donors included total blood count, C-reactive protein, creatinine, and liver enzyme levels. All stools were freshly passed. Sixty-one of the stool donors were close relatives Table 1. Screening of Donors Sample Infectious to be tested Laboratory tests Stool C Culture and toxin A/B test Enteric bacterial Selective media culture pathogens Ova and parasites Light microscopy Serum HBV HBV surface antigen HCV Anti-HCV antibodies by EIA HIV 1 and HIV 2 Anti-HIV antibodies by EIA Treponema pallidum Plasma reagin test EIA, enzyme immunoassay; HIV, human immunodeficiency virus. Table 2. Fecal Transplant Procedure Pretreatment for 4 or more days with vancomycin or metronidazole; discontinued 36 hours or more before transplant Donor stool obtained within 6 hours of transplant (20 30 ml) Donor stool manually homogenized in ml of water 100-mL suspension is infused into the cecum through the biopsy channel or other household members. In the remaining 9 cases, family members were not eligible or available as donors, and a healthy volunteer donated the stool. There were no food restrictions or recommendations for donors. Fecal Transplantation Preparation of donor stool and the patient for the procedure is presented in Table 2. The patients were pretreated with vancomycin or metronidazole until a reduction of symptoms occurred. This treatment was discontinued an average of 36 hours before the transplantation. Colonic lavage was performed by oral ingestion of4lofapolyethylene glycol solution (Colonsteril; Orion Oyj, Espoo, Finland) that contained 25 mmol/l NaCl, 40 mmol/l Na 2 SO 4, 10 mmol/l KCl, 20 mmol/l NaHCO 3, and 60 mg/ml polyethylene glycol. Ileocolonoscopy was performed by an experienced endoscopist. During endoscopy no evident contraindications for fecal transplantation could be observed in any of the patients prepared for the transplantation. Biopsy specimens were taken when considered appropriate by the endoscopist. The patients were given instructions for home cleaning and dis to reduce the possibility of C re- at home. The patients were advised to contact the hospital if they had any exacerbations of the symptoms or recurrence of diarrhea after transplantation. Most of the patients had a scheduled visit to the clinic or were contacted by telephone 12 weeks after the transplantation. Treatment failure was defined as persisting diarrhea with a positive C toxin stool test. Study Approval Fecal transplantations and the retrospective review of the patient records were approved by the institutional review boards of all the participating centers. All the patients were informed about the experimental nature of this treatment procedure and about the available results in other previously published reports and possible risks of the procedure. All of the patients provided informed consent. Results Patient Characteristics The mean age of the 70 patients was 73 years (range, y). Forty-two (60%) of the 70 patients were women. Sixty (86%) of the patients were outpatients. All the patients were positive for C stool cultures and had a positive C toxin test. The 027 ribotype strain was found in 36 (51%) patients. The mean time between the diagnosis of CDI and the initial stool transplantation was 133 days (range, days). There were a mean of 3.5 (range, 1 12) laboratoryproven previous episodes of CDI before transplantation (Table 3). The patients had an average of 4.5 courses of

3 Table 3. Characteristics of 70 Patients Who Underwent Stool Transplantation Patient no. Age, y Sex Index Index antibiotic RNA ribotype positive C tests antimicrobial courses for C Days from first C diagnosis Days from last relapse 1 77 Female Pneumonia Cefuroxime, 027 positive Outpatient Yes Resolution Resolution amoxicillin/clavulanic acid 2 67 Female Pneumonia Cefuroxime, roxithromycin, 027 negative Outpatient Yes Resolution Resolution ciprofloxacin 3 73 Female Pyelonephritis Ceftazidime 027 positive Outpatient Yes Relapse and 4 79 Male Pneumonia Cefuroxime 027 negative Outpatient Yes Resolution Resolution 5 88 Female Fever Cefuroxime 027 positive Outpatient Yes Resolution Death unrelated 6 83 Female Pneumonia, urinary tract Cefuroxime, ciprofloxacin 027 positive Outpatient Yes Resolution Resolution 7 80 Female Erysipelas Clindamycin 027 negative Inpatient Yes Resolution Death unrelated 8 77 Male Pneumonia Cefuroxime, 027 positive and Inpatient No Resolution Resolution amoxicillin/clavulanic acid 027 negative 9 82 Male Urinary tract Ciprofloxacin 027 positive Inpatient Yes Resolution Resolution Female Infected eczema Clindamycin 027 negative Outpatient Yes Resolution Resolution Female Pneumonia Cefuroxime 027 positive Outpatient Yes Resolution Death unrelated Female Pneumonia Cefuroxime, 027 negative Outpatient Yes Resolution Resolution amoxicillin/clavulanic acid Male Septicemia 3 different antimicrobial 027 negative Outpatient Yes Resolution Relapse Female Upper respiratory tract Amoxicillin/clavulanic acid 027 negative Outpatient Yes Resolution Death unrelated Female Pyelonephritis Ceftriaxone, amoxicillin 027 negative Outpatient Yes Resolution Resolution Female Sinusitis Azithromycin, 027 positive Outpatient Yes Resolution Resolution amoxicillin/clavulanic acid Female COPD, bronchitis No antimicrobial agent 027 positive Outpatient Yes Relapse and Female Septicemia Cefuroxime, vancomycin, 027 negative Outpatient Yes Resolution Relapse clindamycin Male Pneumonia Cefuroxime 027 positive Outpatient Yes Resolution Death unrelated Female No No antimicrobial agent No typing Outpatient Yes Resolution Relapse Female COPD, bronchitis Moxifloxacin, levofloxacin 027 positive Outpatient No Resolution Resolution Female Preoperative prophylaxis Cefuroxime 027 negative Outpatient Yes Resolution Resolution Female Perianal Clindamycin 027 negative Outpatient No Resolution Resolution Male Olecranon bursitis Cephalexin, metronidazole 027 negative Outpatient Yes Resolution Resolution Female Postoperative wound Cephalexin 027 negative Outpatient No Resolution Resolution Female Pneumonia Cefuroxime, levofloxacin 027 negative Outpatient Yes Resolution Resolution Female Uterine Cephalexin, metronidazole 027 negative Outpatient No Resolution Resolution Female Dental Amoxicillin/clavulanic acid 027 positive Outpatient Yes Resolution Resolution Female Uterine Cephalexin, metronidazole 027 negative Outpatient No Resolution Resolution Female Urosepticemia Ciprofloxacin 027 negative Outpatient Yes Resolution Resolution Male Olecranon bursitis Cephalexin 027 positive Outpatient Yes Resolution Resolution Female Puerperal endometritis Amoxicillin/clavulanic acid, 027 negative Outpatient Yes Resolution Relapse levofloxacin Male Postoperative wound Dicloxacillin 027 positive Outpatient Yes Resolution Resolution Male Pneumonia Cefuroxime, levofloxacin 027 positive Inpatient Yes Resolution Resolution Male Postoperative wound Clindamycin 027 negative Outpatient No Resolution Resolution Male Postoperative wound Piperacillin/tazobactam 027 positive Inpatient Yes Relapse and ST as outpatient or inpatient Donor family member, yes/no Outcome at3mo Outcome at 12 mo 492 MATTILA ET AL GASTROENTEROLOGY Vol. 142, No. 3

4 Table 3. Continued Patient no. Age, y Sex Index Index antibiotic RNA ribotype positive C tests antimicrobial courses for C Days from first C diagnosis Days from last relapse Male Erysipelas Clindamycin 027 negative Outpatient Yes Resolution Resolution Male Pneumonia after lung 3 different antimicrobial 027 negative Outpatient No Resolution Resolution transplantation Male Pneumonia Moxifloxacin 027 negative Outpatient Yes Resolution Resolution Female No No antimicrobial agent 027 negative Outpatient Yes Resolution Resolution Male Perianal abscess Cefuroxime, metronidazole 027 negative Outpatient Yes Resolution Resolution Female Urinary tract Trimethoprim/sulfamethoxazole 027 negative Outpatient Yes Resolution Resolution Male Pneumonia Ceftriaxone 027 negative Outpatient No Resolution Resolution Male Pneumonia, cellulitis 3 different antimicrobial 027 positive Outpatient Yes Resolution Death unrelated Female Appendicitis Cefuroxime, metronidazole 027 negative Outpatient Yes Resolution Resolution Female Meningitis, septicemia 3 different antimicrobial 027 positive Outpatient Yes Relapse and Male Pneumonia Ceftriaxone 027 positive Outpatient Yes Resolution Resolution Female Postoperative wound Cephalexin, clindamycin 027 negative Outpatient Yes Resolution Resolution Female Pneumonia Cefuroxime 027 positive Outpatient Yes Resolution Resolution Female Skin abscess Cephalexin, clindamycin 027 negative Outpatient Yes Resolution Resolution Male Erysipelas Cefuroxime 027 positive Outpatient Yes Resolution Resolution Female Erysipelas, leg ulcer More than 3 different 027 positive Inpatient Yes Resolution Death unrelated antimicrobial Male Preoperative prophylaxis Cefuroxime, metronidazole 027 positive Outpatient Yes Resolution Resolution Male Septicemia Ceftriaxone, levofloxacin 027 positive Outpatient Yes Resolution Resolution Male Abscess Clindamycin 027 positive Outpatient Yes Resolution Resolution Male Pyelonephritis Ceftriaxone, levofloxacin, 027 positive Outpatient Yes Resolution Resolution cefuroxime Male Pneumonia Ceftriaxone, moxifloxacin 027 positive Outpatient Yes Resolution Death unrelated Female Pyelonephritis Cephalexin, cefuroxime 027 positive Outpatient Yes Resolution Resolution Male No No antimicrobial agent 027 positive Outpatient Yes Resolution Death unrelated Female Pyelonephritis Cephalexin, cefuroxime 027 positive Inpatient Yes Resolution Resolution Female Pneumonia Cefuroxime 027 positive Inpatient Yes Resolution Resolution Female Diverticulitis 3 different antimicrobial 027 positive Outpatient Yes Resolution Resolution Male Aspiration pneumonia Ceftiraxone 027 negative Outpatient Yes Resolution Resolution Female Pneumonia, leg ulcer Cefuroxime, cephalexin, 027 positive Outpatient Yes Resolution Death unrelated levofloxacin Female Pyelonephritis Cefuroxime, cephalexin 027 positive Inpatient Yes Resolution Resolution Female Shunt 3 different antimicrobial 027 negative Outpatient Yes Resolution Resolution Male Sepsis 3 different antimicrobial 027 positive Outpatient Yes Resolution Resolution Female Erysipelas Ceftriaxone, cephalexin 027 positive Outpatient Yes Resolution Resolution Female Dental 3 different antimicrobial 027 negative Outpatient Yes Resolution Resolution Male Finger cellulitis Cephalexin 027 negative Inpatient Yes Resolution Resolution Second transplantation Female Tonsillitis Doxycycline 027 negative Outpatient Yes Resolution Resolution Female Travelers diarrhea Ciprofloxacin 027 negative Outpatient Yes Resolution Resolution Female Meningitis, septicemia 3 different antimicrobial COPD, chronic obstructive pulmonary disease; ST, stool transplantation. ST as outpatient or inpatient Donor family member, yes/no Outcome at3mo 027 positive Outpatient Yes Death unrelated Outcome at 12 mo Death unrelated March 2012 FECAL TRANSPLANTATION FOR RECURRENT CDI 493

5 494 MATTILA ET AL GASTROENTEROLOGY Vol. 142, No. 3 antibiotics for CDI before fecal transplantation (range, 2 12). These treatments included a variety of metronidazole, vancomycin, and rifaximin regimens, and 1 patient also received intravenous immunoglobulin therapy. The baseline characteristics varied slightly according to the hospital. In one tertiary care university hospital there were more young patients (5 of 11 were younger than age 40), and all were outpatients. In secondary care municipal hospitals the patients were, on average, older, and there also were inpatients. Most patients had received antibiotics commonly associated with the risk of developing CDI, remarkably often cephalosporins (47 of 70). One nurse developed an occupational C strain 027 after having taken care of a patient with a 027 strain. There were 2 peripartum CDIs. None of the 70 patients had definitive signs of inflammatory bowel disease at colonoscopy. In some patients microscopic evaluation showed mild epithelial damage, edema, and scattered neutrophilic infiltrate. One patient was found to have adenocarcinoma of the colon at colonoscopy. Her C non-027 resolved after fecal transplantation but she died of the carcinoma 3.5 months after the transplantation. Outcomes During the first 12 weeks of follow-up evaluation the transplantation resulted in the resolution of symptoms in all 34 (100%) patients with non-027 C s. Of the 36 patients with a 027 C, 32 (89%) had a favorable response. All 4 nonresponders with 027 C had serious conditions and died months after the transplantation. One patient had an especially severe CDI and was offered colectomy as a treatment option. He refused surgery and fecal transplantation was used as a salvage therapy. The second patient with a severe CDI had an incomplete pretransplantation lavage, did not have any response to transplantation, and died of CDI 2 months after the transplantation. The third patient had chronic obstructive pulmonary disease and developed severe diarrhea and died of CDI. The common feature of the earlierdescribed 3 patients was an especially aggressive pretransplantation CDI ribotype 027 with severe diarrhea. The fourth patient had end-stage myeloma. She had a recurrence of CDI after antibiotic treatments for pneumococcal septicemia and meningitis shortly after fecal transplantation. She got the second transplantation 24 days after the first transplantation but subsequently died of myelomarelated uremia. During the 1-year follow-up period, 4 patients with an initial favorable response had a relapse after receiving antibiotics for unrelated causes. Two of these patients were treated successfully with another fecal transplantation and 2 were treated successfully with antibiotics for recurrent CDI. Safety No immediately evident complications of fecal transplantation were observed. There were no reported transmitted s. Four patients infected with the ribotype 027 strain did not respond to transplantation and died within 3 months. No evidence could be shown that the of these patients could have been caused or facilitated by intestinal lavage, colonoscopy, or fecal transplantation. Except for these 4 patients, none of our patients had any severe adverse events that could be related to fecal transplantation. In addition to these 4 patients, 10 patients died of unrelated illnesses during the 1-year follow-up period. Discussion We present here an analysis of 70 patients with recurrent C who have been treated with fecal transplantation and followed up for 1 year. Sixty-six of 70 patients (94%) recovered, which is an outstanding result in a patient group refractory to other treatment methods. In our earlier study on recurrent C patients, who had, on average, a milder disease of recurrent CDI as compared with the present series, only 55% recovered with metronidazole and 56% with C immune whey during a 70-day follow-up period. 14 Our present series also included patients who were treated successfully with fecal transplantation after having failed rifaximin or intravenous immunoglobulin therapy. It should be noted that most of our patients were outpatients and that the results of our study are applicable mainly to outpatients, although inpatients seemed to have a favorable response as well. Nevertheless, this study confirms that the colonoscopy technique is feasible for fecal transplantation and shows that fecal transplantation is an effective treatment for recurrent C. A limitation of our study was that it was a retrospective review of patients who had undergone fecal transplantation. This raises the possibility that we could have missed patients with an unfavorable outcome from our series, which would have caused a bias in favor of fecal transplantation. Although this may have occurred, we consider this unlikely because to our knowledge we reviewed all the patients who had undergone fecal transplantation in the participating centers. Although our analysis was a retrospective review, the review of electronic databases of patient histories enabled a rather reliable analysis of the patients because patient survival as well as the electronic patient records were available for all the patients 1 year after the transplantation. C ribotype 027 is associated with a more severe diarrhea and with more recurrences. 31 In a recent study, a new macrocyclic antibiotic, fidaxomicin, was compared with vancomycin in the treatment of CDI. 32 CDI recurred significantly less often with fidaxomicin than with vancomycin (15% vs 25%) during 4 weeks of follow-up evaluation. However, among patients with C ribotype 027, fidaxomicin appeared to be no better than van-

6 March 2012 FECAL TRANSPLANTATION FOR RECURRENT CDI 495 comycin in preventing recurrences. The recurrence rates were 24% and 23%, respectively. In the present study, only 4 (11%) of our 36 patients with C ribotype 027 developed a recurrence during the 12 weeks of follow-up evaluation after fecal transplantation as compared with the recurrence rate of 24% after the fidaxomicin treatment after 4 weeks of follow-up evaluation in the previous study. Although the characteristics of the patients may be different in our study as compared with that of the fidoxamicin study and, therefore, the results are not directly comparable, our study shows that fecal transplantation is an effective treatment option for recurrent CDI and also for recurrent CDI caused by the virulent C ribotype 027. Four of our patients had CDI diarrhea despite fecal transplantation and died shortly after the transplantation. All 4 of these patients were seriously ill already before fecal transplantation and fecal transplantation was used as salvage therapy. Up to a 23% overall mortality rate has been reported with CDI at 30 days. 33 Thus, the mortality rate in our study does not appear to be greater than in some previously reported series, suggesting that fecal transplantation itself seems to be a rather safe procedure. Performing fecal transplant by colonoscopy has the advantage that it enables differential diagnostics of longlasting diarrhea, for example, to exclude inflammatory bowel disease, which is a risk factor for CDI, and to detect diverticulosis of the colon and colon carcinoma, which may be masked by CDI. The lavage before the colonoscopy conceivably results in a reduced colonic biomass, which may have facilitated the restoration of the colonic bacterial flora by the transplant. We recommend using fresh instead of frozen donor stool transplant because bacteria are presumably more viable in fresh stool, despite good results that also have been published using a frozen donor stool transplant. 37 There have been concerns regarding the risks, including perforation induced by colonoscopy in patients with active colitis. All of our patients were pretreated with antibiotics for CDI, which probably reduced inflammation, and possibly also the risk of perforation at the time of colonoscopy. The colonoscopy technique used seemed to be safe because none of our patients had any severe immediate adverse events that could be related directly to colonoscopy. Fecal transplantations also have been performed through a nasoduodenal catheter in the upper gastrointestinal tract or through a retention enema cathether into the colon. A possible disadvantage of the nasoduodenal delivery is that the viability of the transplanted bacteria may be compromised by the time the bacteria reach the colon as opposed to direct colonic delivery by colonoscopy. On the other hand, instillation of the fecal transplant through a nasoduodenal catheter or a retention enema may be easier to perform and may cause less discomfort and morbidity than colonic lavage, colonoscopy, and subsequent fecal transplantation. Comparative studies are needed to address which route of transplantation is the most appropriate for various presentations of CDI. In addition, future metagenomic studies of colonic microbiota may reveal clues of the specific microbes or microbe classes required to suppress CDI. The principal potential risk associated with fecal bacteriotherapy is transmission of contagious contained in the donor stool. There are risks of transmitting that do not cause a disease immediately after transplantation, but may complicate the treatment of the patient in the future. Such may include multidrugresistant gram-negative bacteria. Long-term studies after fecal transplantation need to be performed to address these issues. We suggest that tests be conducted to detect possible multidrug-resistant bacteria in donor stool to maximize the safety of the procedure. Despite evident risks associated with fecal bacteriotherapy, no reported transmitted s or significant immediate adverse effects have been reported to date. Although we did not systemically search for transmitted s in our patients, we have so far not found any clinical evidence of transmitted s related to the fecal transplant. Fecal transplantation seems to be safe also for patients with underlying serious conditions. Our study included one immunosuppressed lung transplantation patient who had a favorable response after fecal transplantation. Also, a patient with a fulminate life-threatening CDI has been treated successfully with fecal transplantation. 38 The results of fecal transplantation appear to be clearly better than any other treatment for recurrent CDI. Fortunately, refractory recurrent cases of CDI are quite rare compared with all of CDI cases. Even though fecal transplantation is not simple to perform and it has potential risks, fecal transplantation is an effective option for the treatment of recurrent CDI. References 1. Gravel D, Miller M, Simor A, et al. Health care-associated Clostridium in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009;48: Zilberberg MD, Shorr AF, Kollef MH. Increase in adult Clostridium -related hospitalizations and case-fatality rate, United States, Emerg Infect Dis 2008;14: Pepin J, Alary ME, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium colitis in Quebec, Canada. 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Ann Intern Med 2008;148: Received March 20, Accepted November 27, Reprint requests Address requests for reprints to: Eero Mattila, MD, Department of Infectious Diseases, Helsinki University Central Hospital, PO Box 348, FIN HUS, Finland. eero.mattila@hus.fi; fax: (35) Conflicts of interest The authors disclose no conflicts. Funding Supported by the Finnish Foundation for Gastroenterological Research (E.M.).