Christine Lee

Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial

BACKGROUND & AIMSnUlcerative colitis (UC) is difficult to treat, and standard therapy does not always induce remission. Fecal microbiota transplantation (FMT) is an alternative approach that induced remission in small series of patients with active UC. We investigated its safety and efficacy in a placebo-controlled randomized trial.nnnMETHODSnWe performed a parallel study of patients with active UC without infectious diarrhea. Participants were examined by flexible sigmoidoscopy when the study began and then were randomly assigned to groups that received FMT (50 mL, via enema, from healthy anonymous donors; n = 38) or placebo (50 mL water enema; n = 37) once weekly for 6 weeks. Patients, clinicians, and investigators were blinded to the groups. The primary outcome was remission of UC, defined as a Mayo score ≤2 with an endoscopic Mayo score of 0, at week 7. Patients provided stool samples when the study began and during each week of FMT for microbiome analysis. The trial was stopped early for futility by the Data Monitoring and Safety Committee, but all patients already enrolled in the trial were allowed to complete the study.nnnRESULTSnSeventy patients completed the trial (3 dropped out from the placebo group and 2 from the FMT group). Nine patients who received FMT (24%) and 2 who received placebo (5%) were in remission at 7 weeks (a statistically significant difference in risk of 17%; 95% confidence interval, 2%-33%). There was no significant difference in adverse events between groups. Seven of the 9 patients in remission after FMT received fecal material from a single donor. Three of the 4 patients with UC ≤1 year entered remission, compared with 6 of 34 of those with UC >1 year (P = .04, Fishers exact test). Stool from patients receiving FMT had greater microbial diversity, compared with baseline, than that of patients given the placebo (P = .02, Mann-Whitney U test).nnnCONCLUSIONSnFMT induces remission in a significantly greater percentage of patients with active UC than placebo, with no difference in adverse events. Fecal donor and time of UC appear to affect outcomes. ClinicalTrials.gov Number: NCT01545908.

Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial.

IMPORTANCEnClostridium difficile infection (CDI) is a major burden in health care and community settings. CDI recurrence is of particular concern because of limited treatment options and associated clinical and infection control issues. Fecal microbiota transplantation (FMT) is a promising, but not readily available, intervention.nnnOBJECTIVEnTo determine whether frozen-and-thawed (frozen, experimental) FMT is noninferior to fresh (standard) FMT in terms of clinical efficacy among patients with recurrent or refractory CDI and to assess the safety of both types of FMT.nnnDESIGN, SETTING, AND PARTICIPANTSnRandomized, double-blind, noninferiority trial enrolling 232 adults with recurrent or refractory CDI, conducted between July 2012 and September 2014 at 6 academic medical centers in Canada.nnnINTERVENTIONSnPatients were randomly allocated to receive frozen (nu2009=u2009114) or fresh (nu2009=u2009118) FMT via enema.nnnMAIN OUTCOMES AND MEASURESnThe primary outcome measures were clinical resolution of diarrhea without relapse at 13 weeks and adverse events. Noninferiority margin was set at 15%.nnnRESULTSnA total of 219 patients (nu2009=u2009108 in the frozen FMT group and nu2009=u2009111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT: nu2009=u200991, fresh FMT: nu2009=u200987) in the per-protocol population. In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group (difference, -1.6% [95% CI, -10.5% to ∞]; Pu2009=u2009.01 for noninferiority). In the mITT population the clinical resolution was 75.0% for the frozen FMT group and 70.3% for the fresh FMT group (difference, 4.7% [95% CI, -5.2% to ∞]; Pu2009<u2009.001 for noninferiority). There were no differences in the proportion of adverse or serious adverse events between the treatment groups.nnnCONCLUSIONS AND RELEVANCEnAmong adults with recurrent or refractory CDI, the use of frozen compared with fresh FMT did not result in worse proportion of clinical resolution of diarrhea. Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier:NCT01398969.

Prospective, Randomized Inpatient Study of Oral Metronidazole versus Oral Metronidazole and Rifampin for Treatment of Primary Episode of Clostridium difficile–Associated Diarrhea

BACKGROUNDnTo date, no randomized trial to address the use of adjunctive rifampin in addition to metronidazole for the treatment of Clostridium difficile-associated diarrhea has been reported. Rifampin has excellent in vitro activity against C. difficile and penetrates into cellular materials where the organisms may persist.nnnMETHODSnThis was a prospective, randomized, single-blinded study of 39 patients that compared therapy with metronidazole alone versus therapy with metronidazole and rifampin for 10 days to treat laboratory-confirmed primary episode C. difficile-associated diarrhea. Twenty patients were randomly assigned to the metronidazole group, and 19 were randomly assigned to the metronidazole and rifampin group. Data were analyzed by intention-to-treat analysis using the 2-tailed Kaplan-Meier method and the log-rank test.nnnRESULTSnAdjunctive rifampin treatment for 10 days, compared with treatment with metronidazole alone for 10 days, was associated with a similar median time to symptom improvement (9.0 days vs. 6.5 days; P=.74), a similar median time to first relapse (26 days vs. 16 days; P=.23), a similar proportion of patients with relapse by study day 40 (42% vs. 38%; P=1.0), and a similar proportion of patients experiencing nonfatal adverse events (37% vs. 40%; P=.55). There were a significantly higher number of deaths in the metronidazole and rifampin group, compared with the metronidazole group (6 of 19 patients vs. 1 of 20 patients; P=.04), but there were fewer laboratory-confirmed relapses by study day 40 (2 vs. 4; P=.66).nnnCONCLUSIONSnWe conclude that there is no role for routine rifampin as an adjunct to treatment with metronidazole for hospitalized patients with C. difficile-associated diarrhea. The cure rates for both treatment groups remain unacceptably low, and better treatments are urgently needed.

The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema.

Clostridium difficile infection (CDI) is one of the most frequent causes of healthcare-associated infections, and its rates are also increasing in the community. The management of CDI has become a major challenge, given growing rates of recurrences and failures with standard antibiotic therapy. Mounting evidence suggests that fecal microbiota transplantation (FMT) may be effective; however, as there is a paucity of data with regard to repeat FMT for primary non-response to this treatment, this study examined the outcome of multiple FMTs for recurrent CDI. Case records were reviewed for 94 patients who underwent FMT via retention enema for recurrent or refractory CDI during the period 2008–2012. Demographic information, treatment data, and clinical resolution rates were examined for single FMT and cumulative resolution was assessed for multiple FMTs in the context of ongoing symptoms. The cumulative clinical resolution following four or more FMTs was 86xa0%. When antibiotic therapy was used between FMTs, the clinical resolution rate increased to 92xa0%. There were no reported adverse events and no patients who were cured with FMT had further episodes of CDI at 6–24 months follow-up. Multiple FMTs administered through enemas is an effective, safe, and simple therapy for the management of recurrent or refractory CDI.

A Canadian Working Group report on fecal microbial therapy: Microbial ecosystems therapeutics

A working group from across Canada comprised of clinician and basic scientists, epidemiologists, ethicists, Health Canada regulatory authorities and representatives of major funding agencies (Canadian Institutes of Health Research and the Crohns and Colitis Foundation of Canada) met to review the current experience with fecal microbial therapy and to identify the key areas of study required to move this field forward. The report highlights the promise of fecal microbial therapy and related synthetic stool therapy (together called microbial ecosystems therapeutics) for the treatment of Clostridium difficile colitis and, possibly, other disorders. It identifies pressing clinical issues that need to be addressed as well as social, ethical and regulatory barriers to the use of these important therapies.

Zanamivir use during transmission of amantadine-resistant influenza A in a nursing home.

OBJECTIVEnTo describe the use of zanamivir during an influenza A outbreak.nnnPOPULATIONnResidents of a 176-bed long-term-care facility for the elderly in Newmarket, Ontario, Canada, 90% of whom received influenza vaccine in the fall of 1998.nnnOUTBREAKnWhen respiratory illness due to influenza A was confirmed, infection control measures and amantadine prophylaxis were initiated. Despite these measures, transmission of influenza A continued.nnnINTERVENTIONnZanamivir inhalations, 10 mg daily for prophylaxis and 10 mg twice daily for treatment of influenza.nnnRESULTSnThere were 13 definite and 66 probable outbreak-associated cases of influenza A. Twelve (15%) cases developed pneumonia, 7 (9%) were hospitalized, and 2 (2.6%) died. All 12 culture-positive cases yielded influenza A/Sydney/H3N2/05/97-like virus, a 1998/99 vaccine component. The three isolates obtained prior to the initiation of amantadine were amantadine-susceptible; all nine obtained after prophylaxis was instituted were amantadine-resistant. One hundred twenty-nine (92%) of 140 residents who were offered zanamivir accepted it and were able to attempt inhalations. Of these 129, 78% (100) had no difficulty in complying with inhalations. Difficulty with inhalations was associated with decreased functional and mental status. Fifteen (58%) of 26 residents fully dependent in activities of daily living had difficulty compared to 14 (14%) of 100 others (P<.001). Twenty-two (45%) of 49 residents not oriented to person, place, or time had difficulty compared to 7 (10%) of 77 others (P<.001). In the 2 weeks after zanamivir prophylaxis, only 2 new cases of respiratory illness occurred, neither confirmed as influenza. No side effects were identified in 128 zanamivir-treated residents.nnnCONCLUSIONnA minority of nursing home residents have difficulty following instructions for zanamivir inhalations. Zanamivir was well tolerated, and its use was temporally associated with termination of an outbreak that amantadine had failed to control.

Prevention of Clostridium difficile infection with Saccharomyces boulardii: a systematic review.

BACKGROUNDnClostridium difficile is a major cause of antibiotic-associated diarrhea within the hospital setting. The yeast Saccharomyces boulardii has been found to have some effect in reducing the risk of C difficile infection (CDI); however, its role in preventive therapy has yet to be firmly established.nnnOBJECTIVEnTo review the effectiveness of S boulardii in the prevention of primary and recurrent CDI. Benefit was defined as a reduction of diarrhea associated with C difficile. Risk was defined as any adverse effects of S boulardii.nnnMETHODSnA literature search in MEDLINE, EMBASE, CINAHL and the Cochrane Library was performed. Included studies were English language, randomized, double-blind placebo controlled trials evaluating S boulardii in CDI prevention.nnnRESULTSnFour studies were reviewed. Two studies investigated the prevention of recurrence in populations that were experiencing CDI at baseline. One trial showed a reduction of relapses in patients experiencing recurrent CDI (RR=0.53; P<0.05). The other demonstrated a trend toward reduction of CDI relapse in the recurrent treatment group of patients receiving high-dose vancomycin (RR=0.33; P=0.05). Two other studies examined primary prevention of CDI in populations that had been recently prescribed antibiotics. These studies lacked the power to detect statistically significant differences. Patients on treatment experienced increased risk for thirst and constipation.nnnCONCLUSIONnS boulardii seems to be well tolerated and may be effective for secondary prevention in some specific patient populations with particular concurrent antibiotic treatment. Its role in primary prevention is poorly defined and more research is required before changes in practice are recommended.

Capturing the diversity of the human gut microbiota through culture-enriched molecular profiling

BackgroundThe human gut microbiota has been implicated in most aspects of health and disease; however, most of the bacteria in this community are considered unculturable, so studies have relied on molecular-based methods. These methods generally do not permit the isolation of organisms, which is required to fully explore the functional roles of bacteria for definitive association with host phenotypes. Using a combination of culture and 16S rRNA gene sequencing, referred to as culture-enriched molecular profiling, we show that the majority of the bacteria identified by 16S sequencing of the human gut microbiota can be cultured.MethodsFive fresh, anaerobic fecal samples were cultured using 33 media and incubation of plates anaerobically and aerobically resulted in 66 culture conditions for culture-enriched molecular profiling. The cultivable portion of the fecal microbiota was determined by comparing the operational taxonomic units (OTUs) recovered by 16S sequencing of the culture plates to OTUs from culture-independent sequencing of the fecal sample. Targeted isolation of Lachnospiraceae strains using conditions defined by culture-enriched molecular profiling was carried out on two fresh stool samples.ResultsWe show that culture-enriched molecular profiling, utilizing 66 culture conditions combined with 16S rRNA gene sequencing, allowed for the culturing of an average of 95xa0% of the OTUs present at greater than 0.1xa0% abundance in fecal samples. Uncultured OTUs were low abundance in stool. Importantly, comparing culture-enrichment to culture-independent sequencing revealed that the majority of OTUs were detected only by culture, highlighting the advantage of culture for studying the diversity of the gut microbiota. Applying culture-enriched molecular profiling to target Lachnospiraceae strains resulted in the recovery of 79 isolates, 12 of which are on the Human Microbiome Project’s “Most Wanted” list.ConclusionsWe show that, through culture-enriched molecular profiling, the majority of the bacteria in the human gut microbiota can be cultured and this method revealed greater bacterial diversity compared to culture-independent sequencing. Additionally, this method could be applied for the targeted recovery of a specific bacterial group. This approach allows for the isolation of bacteria of interest from the gut microbiota, providing new opportunities to explore mechanisms of microbiota–host interactions and the diversity of the human microbiota.

Multicenter, Randomized Clinical Trial To Compare the Safety and Efficacy of LFF571 and Vancomycin for Clostridium difficile Infections

ABSTRACT Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is a semisynthetic thiopeptide with potency against C. difficile in vitro. In this phase 2 exploratory study, we compared the safety and efficacy (based on a noninferiority analysis) of LFF571 to those of vancomycin used in adults with primary episodes or first recurrences of moderate C. difficile infection. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy in the per-protocol population. Secondary endpoints included clinical cures at the end of therapy in the modified intent-to-treat (mITT) population, the time to diarrhea resolution, and the recurrence rate. Seventy-two patients were randomized, with 46 assigned to receive LFF571. Based on the protocol-specified definition, the rate of clinical cure for LFF571 (90.6%) was noninferior to that of vancomycin (78.3%). The 30-day sustained cure rates for LFF571 and vancomycin were 56.7% and 65.0%, respectively, in the per-protocol population and 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Using toxin-confirmed cases only, the recurrence rates were lower for LFF571 (19% versus 25% for vancomycin in the per-protocol population). LFF571 was generally safe and well tolerated. The incidence of adverse events (AEs) was higher for LFF571 (76.1% versus 69.2% for vancomycin), although more AEs in the vancomycin group were suspected to be related to the study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued the study due to an AE. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.)

Epidemiology and Outcome of Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus (MRSA) in Canadian Hospitals

Background MRSA remains a leading cause of hospital-acquired (HAP) and healthcare-associated pneumonia (HCAP). We describe the epidemiology and outcome of MRSA pneumonia in Canadian hospitals, and identify factors contributing to mortality. Methods Prospective surveillance for MRSA pneumonia in adults was done for one year (2011) in 11 Canadian hospitals. Standard criteria for MRSA HAP, HCAP, ventilator-associated pneumonia (VAP), and community-acquired pneumonia (CAP) were used to identify cases. MRSA isolates underwent antimicrobial susceptibility testing, and were characterized by pulsed-field gel electrophoresis (PFGE) and Panton-Valentine leukocidin (PVL) gene detection. The primary outcome was all-cause mortality at 30 days. A multivariable analysis was done to examine the association between various host and microbial factors and mortality. Results A total of 161 patients with MRSA pneumonia were identified: 90 (56%) with HAP, 26 (16%) HCAP, and 45 (28%) CAP; 23 (14%) patients had VAP. The mean (± SD) incidence of MRSA HAP was 0.32 (± 0.26) per 10,000 patient-days, and of MRSA VAP was 0.30 (± 0.5) per 1,000 ventilator-days. The 30-day all-cause mortality was 28.0%. In multivariable analysis, variables associated with mortality were the presence of multiorgan failure (OR 8.1; 95% CI 2.5-26.0), and infection with an isolate with reduced susceptibility to vancomycin (OR 2.5, 95% CI 1.0-6.3). Conclusions MRSA pneumonia is associated with significant mortality. Severity of disease at presentation, and infection caused by an isolate with elevated MIC to vancomcyin are associated with increased mortality. Additional studies are required to better understand the impact of host and microbial variables on outcome.