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Clinical Infectious Diseases
MAJOR ARTICLE
Safety and Durability of RBX2660 (Microbiota Suspension)
for Recurrent Clostridium difficile Infection: Results of the
PUNCH CD Study
Robert Orenstein,1 Erik Dubberke,2 Robert Hardi,3 Arnab Ray,4 Kathleen Mullane,5 Darrell S. Pardi,6 and Mayur S. Ramesh7; for the PUNCH CD Investigatorsa
1
Division of Infectious Diseases, Mayo Clinic–Arizona, Phoenix; 2Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; 3Chevy Chase Clinical Research, Capital
Digestive Care, Maryland; 4Ochsner Clinic, New Orleans, Louisiana; 5Section of Infectious Diseases and Global Health, University of Chicago Medicine, Illinois; 6Division of Gastroenterology and
Hepatology, Mayo Clinic, Rochester, Minnesota; and 7Henry Ford Hospital System, Detroit, Michigan
Background. Managing recurrent Clostridium difficile infection (CDI) presents a significant challenge for clinicians and patients. Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent CDI, yet availability of a standardized,
safe, and effective product has been lacking. Our aim in this study was to assess the safety and effectiveness of RBX2660 (microbiota
suspension), a commercially prepared FMT drug manufactured using standardized processes and available in a ready-to-use format.
Methods. Patients with at least 2 recurrent CDI episodes or at least 2 severe episodes resulting in hospitalization were enrolled in
a prospective, multicenter open-label study of RBX2660 administered via enema. Intensive surveillance for adverse events (AEs) was
conducted daily for 7 days following treatment and then at 30 days, 60 days, 3 months, and 6 months. The primary objective was
product-related AEs. A secondary objective was CDI-associated diarrhea resolution at 8 weeks.
Results. Of the 40 patients enrolled at 11 centers in the United States between 15 August 2013 and 16 December 2013, 34 received at least 1 dose of RBX2660 and 31 completed 6-month follow-up. Overall efficacy was 87.1% (16 with 1 dose and 11 with 2
doses). Of 188 reported AEs, diarrhea, flatulence, abdominal pain/cramping, and constipation were most common. The frequency
and severity of AEs decreased over time. Twenty serious AEs were reported in 7 patients; none were related to RBX2660 or its
administration.
Conclusions. Among patients with recurrent or severe CDI, administration of RBX2660 via enema appears to be safe and
effective.
Clinical Trials Registration. NCT01925417.
Keywords. fecal microbiota transplant; Clostridium difficile; microbiome; safety.
Clostridium difficile infection (CDI) has become one of the most
common healthcare-associated infections in the United States,
affecting more than 500 000 people annually [1]. Antimicrobial
therapy alone fails to achieve a long-lasting cure, with 20%–30%
of patients with an initial episode of CDI developing a recurrence and 40%–60% following a first recurrence [2–5]. A subset
of patients experience multiple recurrences, despite conventional antimicrobial management.
Fecal microbiota transplantation (FMT), which restores the
gastrointestinal microbiota, has emerged as a highly effective
therapy for recurrent CDI, with long-term success rates nearing
90% [2, 6, 7]. Increasingly, healthcare providers and affected patients have begun to seek out this procedure [8, 9]. An ambiguous
regulatory environment plus the lack of standardized product
and administration methods have created a situation where a regulated, safe, and effective product is critically needed. Most studies that have assessed the impact of FMT are retrospective case
series or systematic reviews of heterogeneously screened sources
of microbiota with limited safety data [6, 7, 10]. FMT products
have been administered through varied formulations, dosages,
and routes [6, 11–13]. Prospective studies are essential to ensure
availability of an FMT product that can be safely administered for
CDI and potentially other therapeutic applications.
Here, we report the results of the phase 2 PUNCH CD trial of
RBX2660 (microbiota suspension) (Rebiotix Inc., Roseville,
Minnesota). RBX2660 is a commercially prepared, standardized, next-generation FMT that was administered by enema
for recurrent CDI.
METHODS
Received 23 July 2015; accepted 4 November 2015; published online 12 November 2015.
a
The PUNCH CD investigators are listed in the Acknowledgement section.
Correspondence: R. Orenstein, Division of Infectious Diseases, Mayo Clinic in Arizona, 5777
E. Mayo Blvd, Phoenix, AZ 85054 ([email protected]).
Clinical Infectious Diseases® 2016;62(5):596–602
© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail [email protected].
DOI: 10.1093/cid/civ938
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The PUNCH CD study was a prospective open-label study conducted under a US Food and Drug Administration (FDA) investigational new drug application at 11 US medical centers
for the prevention of recurrent CDI following antimicrobial treatment. The primary aims were to assess the safety of
RBX2660 at 6 months and its effectiveness at resolving multiply
recurrent CDI at 8 weeks after the last administration. The institutional review board at each participating center approved
the study protocol; all patients provided written informed consent. An independent medical monitor provided oversight.
Study Population
Eligible participants were nonpregnant adults, aged ≥18 years
with recurrent CDI who had either at least 2 recurrences after
a primary episode and had completed a least 2 courses of standard-of-care oral antibiotic therapy for CDI or had at least 2 episodes of severe CDI resulting in hospitalization. In the study,
CDI was defined as the presence of diarrhea ( passage of 3 or
more unformed stools in 24 hours for at least 2 consecutive
days) and at least 1 positive stool test for the presence of C. difficile or its toxins, or colonoscopic or histopathologic findings
demonstrating pseudomembranous colitis, per Society for
Healthcare Epidemiology and Infectious Diseases Society of
America clinical practice guidelines [14]. All eligible participants in the PUNCH CD study completed required stool and
serum testing; agreed to abstain from nondietary probiotics,
vancomycin, metronidazole, fidaxomicin, rifaximin, nitazoxanide, and intravenous immunoglobulin for the duration of the
study unless prescribed for a recurrence; and were able to complete the required participant diary.
Exclusion criteria included uncontrolled diarrhea after completing a 10- to 14-day course of oral antibiotics; concurrent antibiotic therapy for a condition other than CDI; sensitivity or
intolerance to oral vancomycin; fecal transplant prior to study
enrollment; and history of inflammatory bowel disease, irritable
bowel syndrome, chronic diarrhea, celiac disease, cirrhosis of
the liver, or ascites. Other exclusion criteria were symptoms
caused by a confirmed intestinal pathogen other than C. difficile; colostomy; intraabdominal surgery within 60 days prior
to consent; evidence of active, severe colitis; history of short
gut syndrome or motility disorders; regular use of medications
that affected bowel motility; planned therapy in the next 3
months that was likely to cause diarrhea; planned surgery
requiring perioperative antibiotics within 6 months of study
enrollment; estimated life expectancy of <12 months; compromised immune system; taking steroids (≥20 mg a day) or
expected to be on steroids for more than 30 days after enrollment; neutropenia (neutrophil count <1000 cells/µL); known
or suspected history of illicit drug use; and breast-feeding or intending to become pregnant during the course of the study.
Donor Screening and Product Manufacture
RBX2660 is a microbiota suspension prepared from donated
human stool. Four donors were used to prepare the RBX2660
used in the study, and all completed a comprehensive initial
health and lifestyle questionnaire and then provided blood and
stool samples. Blood was tested for human immunodeficiency
virus; hepatitis A, B, and C; and syphilis. Stool samples were tested for C. difficile toxin, norovirus, rotavirus, adenovirus, ova and
parasites, vancomycin-resistant enterococci, methicillin-resistant
Staphylococcus aureus, Vibrios, Listeria, and enteric pathogens. A
questionnaire was completed at the time of every donation to
confirm continued health. A sample was retained from each donation and then pooled with other samples from the same donor
and subjected to repeat stool testing at 45-day intervals. Repeat
donor blood testing was performed at a minimum of 14 days
after the last donation in the cycle. If a donor passed the repeat
screening, the unit manufactured from the donations within that
donor cycle was released from quarantine. Each unit was identified by batch number and traceable to a specific donor and recipient. Good manufacturing processes and a standardized chain of
custody were used. Each dose of RBX2660 consisted of 50 g of
human stool/150 mL 0.9% saline/polyethylene glycol 3350 vehicle and contained ≥107 live organisms/mL of suspension in a
single-dose ready-to-use enema bag. Specific microbiome patterns of the donors were not available as part of the study. The
product was stored frozen at ≤−80°C in a secure location at the
manufacturer and then thawed prior to shipment to the clinical
site. The product could then be stored at room temperature for
up to 2 days prior to administration by enema. Process development testing demonstrated that product integrity was maintained
under these conditions.
Study Design and Intervention
The PUNCH CD study design is shown in Figure 1. Patients entered the study having been on a variety of previously unsuccessful antimicrobial regimens, principally standard-dose
vancomycin and a few on fidaxomicin, prior to screening. Following completion of a 10- to 14-day course of oral antibiotics
for CDI, the last 7 days of which were standardized to oral vancomycin 125 mg 4 times daily, followed by a 24- to 48-hour
washout period, a single dose of RBX2660 was administered
via enema. Bowel lavage was not required prior to administration of RBX2660. Patients were asked to have a bowel movement prior to treatment. After administration, participants
were observed for 1 hour for adverse events (AEs).
Patients maintained a diary to solicit symptoms and AEs
daily for the first 7 days following treatment. Study personnel
called patients weekly through the 60-day follow-up period to
assess for CDI recurrence and AEs. Participants were seen at
7, 30, and 60 days after RBX2660 administration. Similar telephone assessments took place at 3 and 6 months after administration of the final dose of RBX2660.
If patients developed diarrhea and recurrent CDI was suspected less than 8 weeks after receiving RBX2660, patients
were eligible to receive a second dose of RBX2660 within 10
days of the onset of diarrhea. A positive CDI test was not required prior to the second dose; no antimicrobials or bowel lavage were administered prior to administration of the second
dose of RBX2660. The follow-up schedule was reset after the
second dose and a new diary for solicited AEs was completed.
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Figure 1.
PUNCH CD study design. Abbreviation: CDI, Clostridium difficile infection.
Outcome Measures
RBX2660 Enema Administration
Safety
RBX2660 was administered by enema, most commonly in the
left lateral decubitus position. The mean time patients remained
in position after RBX2660 administration was 44 minutes
(range 15–75) for the first enema and 48 minutes (range 15–
60) for the second enema, if needed. It was well tolerated with
a mean retention time of 38 minutes for the first enema and 32
minutes for the second enema. Forceful expulsion was reported
by 4 participants after the first treatment and by 4 after the second treatment. The mean retention time prior to forced expulsion was 16 minutes for the first enema and 8 minutes for the
second enema. Six of the 8 who expelled the enema remained
treatment successes.
Safety was assessed by evaluating the incidence rate, severity, and
relatedness of AEs through 6 months after the last dose of
RBX2660. An AE was defined as any untoward medical event
that occurred during or after the administration of RBX2660,
whether or not the event was considered product-related. Adverse reactions were defined as any AE caused by RBX2660. A
serious AE (SAE) was defined according to FDA regulations [15].
Efficacy
The efficacy of RBX2660 was defined as the absence of CDIassociated diarrhea through 8 weeks after receipt of the last
dose of RBX2660.
Safety of RBX2660
Statistical Analyses
The study size was determined in conjunction with the FDA.
Descriptive statistics were used for analyses. Forty patients
were enrolled to ensure at least 30 patients were treated and followed through 6 months after receiving their final dose of
RBX2660.
RESULTS
Demographics
Forty patients were enrolled at 11 US centers between 15 August
2013 and 16 December 2013 (Figure 2). There were 6 screen
failures, and 34 patients received at least 1 dose of RBX2660.
Baseline characteristics of the 34 treated patients can be found
in Table 1. The 31 patients who completed 6-month follow-up
are included in the analysis.
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A total of 188 AEs were reported in 28 patients, and there were no
AEs in 3 patients. Overall, AEs declined over time; 72.9% of AEs
occurred from baseline through the 30-day visit. The most common AEs were gastrointestinal: the 4 most common being mild
to moderate diarrhea, flatulence, abdominal pain/cramping, and
constipation, all of which were self-limited. Of the AEs, 58.5%
(n = 110) were determined to be possibly, probably, or definitely
related to CDI. The second most commonly reported AEs were
infections (10%): 1 bacteremia at 6 months; 1 CD colitis at 60
days and 2 at 6 months; 1 CDI at day 7, 1 at day 30, and 2 at
day 60; 1 upper respiratory tract infection at baseline and 2 at
30 days; 1 pharyngitis at day 30 and 1 at day 60; 1 pneumonia
at day 30; 1 sinusitis and 1 tooth abscess at 6 months; and 2 urinary tract infections at day 30 and 1 at 6 months. See Table 2 for
additional details.
Table 1.
Baseline Patient Characteristics
Characteristic
N = 34
Mean age, y
66.8 (range, 26.7–89.6)
Sex
Female, no. (%)
23 (67.6)
Race
White, no. (%)
32 (94.2)
Mean body mass index, kg/m2
24.4 (range, 15.0–7.0).
Comorbidities, no. (%)
Gastrointestinal
21 (61.8)
Cardiovascular
19 (55.9)
Genitourinary
18 (52.9)
Psychiatric
9 (28.1)
Employment status, no. (%)
Not working
26 (76)
Full or part-time (no restrictions)
8 (24)
DISCUSSION
Figure 2.
Patient disposition.
Seven patients experienced a total of 20 SAEs (Table 3). None
of the SAEs were judged by the independent safety monitor to
be related to RBX2660 or its administration. These included 3
cases of recurrent CDI < 8 weeks post-treatment in 2 patients,
resulting in 3 hospitalizations. Several SAEs were related to preexisting conditions (1 patient died after she fell; fractured her
pelvis, which required hospitalization; and had respiratory
failure).
Efficacy of RBX2660
Results are reported on an as-treated basis. Of the 34 patients
who received at least 1 treatment with RBX2660, 31 were eligible
for efficacy assessment. Two patients dropped out after the first
dose and 1 patient died at 35 days of respiratory failure unrelated to RBX2660 administration. These 3 patients were not evaluable for efficacy at 8 weeks.
Of the 31 patients evaluated at 8-weeks follow-up, 16 (51.6%)
were considered a success after their first treatment. Fifteen patients received a second enema of RBX2660, and 14 were available for the efficacy assessment. Of these, 11/14 (78.6%) were
considered treatment successes. Therefore, of these 31 patients,
27 (87.1%) were considered treatment successes.
The results of this phase 2 study show that RBX2660 microbiota
suspension is safe and well tolerated in patients with CDI and
numerous comorbidities. When administered by enema,
RBX2660 has comparable clinical efficacy to that reported in
other studies of FMT [6, 16, 17]. Study patients were predominately elderly, which reflects the recurrent CDI population.
Enema delivery of RBX2660 was simple, well tolerated, and
safe, even in patients with complicated illnesses.
One challenge in assessing the therapeutic benefit of FMT
has been characterization of its safety and AE profile [6]. In
this study, of the 188 AEs reported by 28 patients, the majority
were gastrointestinal symptoms of mild-to-moderate severity.
Most of these resolved within 7 days following RBX2660 administration whether patients received 1 or 2 enemas. This prospective collection of safety data provides a clearer assessment of the
types of events experienced by patients undergoing FMT via
enema for recurrent CDI. No SAEs were considered related to
the product or administration procedure.
Data on the short- and long-term safety of FMT are limited,
despite its rapid uptake as a therapeutic intervention for CDI.
Few prospective studies have solicited AEs, and there are no
comparisons between means of administration of the FMT
products. Three systematic reviews and case series that included
more than 5 patients and use of nonstandardized FMT products
and procedures [3, 4, 7, 18] have concluded that AEs are infrequent. Minor and self-limited gastrointestinal symptoms similar to those seen in this study appear to be common [17].
Serious AEs have included both procedural and nonprocedural
complications. Colon microperforation, gastrointestinal bleeding, peritonitis, and pneumonia have been reported in case series after FMT via the colonoscopic or enteric feeding tube
routes [18, 19]. Case reports have cited hypotension [20], herpes
zoster [21], Escherichia coli bacteremia [22], flares of ulcerative
colitis [23], norovirus transmission [24], and significant weight
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Table 2.
Types of Adverse Events
Table 3.
Type
n (%)
Serious Adverse Events by Patient (20 in 7 Patients)
Patient
Serious Adverse Event
107 (56.9)
A
Severe abdominal pain, hospitalization
Diarrhea
26 (24.3)
B
Pelvic fracture, hospitalization
Flatulence
15 (14.0)
Abdominal pain
14 (13.1)
Constipation
14 (13.1)
Gastrointestinal disorders include
Abdominal distention
9 (8.4)
Anorectal discomfort
6 (5.6)
Nausea
5 (4.7)
Vomiting
5 (4.7)
Proctalgia
3 (2.8)
Bacteremia
1
Clostridium difficile colitis
3
C. difficile infection
4
Nasopharyngitis
2
Upper respiratory infection
3
Sinusitis
1
Tooth abscess
1
Pneumonia
1
Urinary tract infection
3
14 (7.4)
General disorders
Chills
5
Fever
4
Fatigue
3
Noncardiac chest pain
2
9 (4.8)
Respiratory disorders
Sore throat
3
Rhinorrhea
1
Respiratory failure
1
Hypoxia
1
Pulmonary edema
1
Pneumothorax
1
Chronic obstructive pulmonary disease exacerbation
1
Nervous system disorders
7 (3.7)
Musculoskeletal and connective tissue disorders
6 (3.2)
Injury, poisoning, procedural complications
5 (2.7)
Psychiatric disorders
4 (2.1)
Metabolism disorders
3 (1.6)
Skin and subcutaneous tissue disorders
3 (1.6)
Cardiac disorders
3 (1.6)
Surgical and medical procedures
3 (1.6)
Renal and urinary disorders
2 (1.1)
Investigations
1 (1.5)
Ear and labyrinth disorders
1 (1.5)
Neoplasms benign, malignant, and unspecified
1 (1.5)
Total
188 (100)
gain [25]. Kelly et al reported 12 (15%) serious AEs, including 2
deaths, within 12 weeks after FMT in a cohort of 80 immunocompromised hosts. One patient died during sedation for a colonoscopy [26]. A recent study of FMT capsules reported
abdominal pain and bloating in 20%; 4 serious AEs and 2 deaths
were felt to be unrelated to the product [12]. In a second study
that used an encapsulated product, 30% of patients experienced
cramps and bloating, which resolved within 3 days [13].
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Urinary tract infection
C
Acute chronic obstructive pulmonary disease
exacerbation, viral, hospitalization
D
Pulmonary edema due to noncompliance with
dialysis, hospitalization
Pneumonia
4 further episodes of CDI
Gram-negative bacteremia
19 (10.1)
Infections
600
Respiratory failure
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Hypoxemia
E
Recurrent CDI, hospitalization
Recurrent CDI, hospitalization
F
Adenocarcinoma lung
Pneumothorax after thoracoscopic biopsy
Chest pain after biopsy
Chemotherapy
G
Knife stab wound, hospital observation
All serious adverse events were unrelated to RBX2660 or its administration.
Abbreviation: CDI, Clostridium difficile infection.
Two randomized controlled trials of FMT predominantly recorded mild AEs similar to those found in our study [11, 27].
Van Nood et al reported the safety of FMT administered via a
nasoduodenal tube in 16 patients [11]. In this protocol, patients
received pretreatment with oral vancomycin and a bowel lavage.
Immediately post-infusion, 94% of the patients experienced diarrhea. Abdominal cramps (31%), belching (19%), nausea (6%)
without vomiting, and dizziness combined with diarrhea also
were reported. These AEs usually resolved within 3 hours of
the procedure. During follow-up, 3 of the patients (19%) had
constipation for which laxatives were required.
Administration of FMT by colonoscopic infusion may be
more challenging for the frail and elderly. Cammarota et al recently reported the results of a randomized controlled trial in
selected patients with a mean age of 75 years with moderate
CDI who could “tolerate colonoscopy” [27]. Patients received
a 3-day course of oral vancomycin followed by a 4-L bowel lavage and colonoscopic FMT. Several patients enrolled were
found to have unsuspected pseudomembranous colitis (35%)
at the time of colonoscopy and required 2-L bowel lavages followed by colonoscopic infusions every 3 days until their colitis
resolved. Immediately after colonoscopic delivery of the donor
feces infusion, 19 of the 20 patients (94%) had diarrhea and 12
of the 29 patients (60%) experienced bloating and abdominal
cramping, which resolved within 12 hours. No long-term safety
data were reported.
Though our study was designed primarily to evaluate safety,
the overall efficacy rate of 87% for RBX2660 is consistent with
results reported in the literature for fecal transplant products
(overall 85% resolution for recurrent CDI in a recent systematic
review) [6] and significantly exceeds the resolution rate of 20%–
30% obtained from standard-of-care antibiotics prescribed for
recurrent CDI [28–31].
Limitations of our study included lack of a control arm, small
sample size, and follow-up limited to 6 months. The sample size
was calculated to ensure an adequate sample to prospectively
solicit AEs but was not powered for statistical analysis. The
51.6% clinical response rate after the first treatment was lower
than that reported for colonoscopy or nasoenteric administration but is better than that reported in the largest series of
CDI patients treated by enema [16]. In that study, 94 patients
with recurrent CDI underwent FMT via retention enema without bowel prep. The success rate after 2 treatments was 54.7%.
Multiple (up to 4 enemas) FMTs led to an overall success rate of
86.2% with no corresponding rise in AEs. It may be that some
patients with recurrent CDI require multiple FMTs, as seen in
the Cammarota et al study, or alternatively that when no bowel
lavage is given after oral vancomycin, enough vancomycin remains within the colon, decreasing the effectiveness of the
first dose of RBX2660.
The long-term impact will remain unknown until registries are
established to record this data. In a systematic review of FMT, follow-up ranged from 3 weeks to 8 years, with no standardization
of data collection [7]. The majority of patients included in the
metaanalysis did not have long-term follow-up, and the case series with the longest follow-up included only 12 patients. [7].
Though a prolonged multiyear follow-up on a larger number
of patients compared with a control group would be needed to
assess the long-term impact of microbiota replacement, our prospective follow-up of the 31 recipients of RBX2660 to 6 months is
the longest controlled follow-up of a study population undergoing FMT and demonstrates a reassuring safety profile.
CONCLUSIONS
FMT continues to be widely used for the treatment of recurrent
CDI but remains poorly standardized. Both the short- and longterm health consequences remain to be determined. This is the
first study to prospectively and systematically solicit (not just record) and classify AEs in patients who received a standardized
intestinal fecal microbiota transplant product. RBX2660 demonstrated a satisfactory safety profile in this phase 2 study targeted at recurrent CDI that included rigorous documentation of
AEs. The overall 87.1% efficacy is in line with previously reported results of FMT for recurrent CDI. Administration of a standardized product by enema should decrease costs, complexity,
and risks compared with nasoduodenal tube or colonoscopic
administration. Long-term AE registries will be needed to address potential late complications.
Notes
Acknowledgments. E. D., as the senior co-author, provided substantial
assistance in data presentation and interpretation and in manuscript review.
Harriet Guthertz, Medical Writing and Communications Inc. (St. Paul,
Minnesota), provided assistance in preparing and editing the manuscript.
Rebiotix Inc. (Roseville, Minnesota) provided assistance with the study design, data acquisition, and statistical analyses.
The PUNCH CD investigators included the following: Erik R. Dubberke,
MD, MSPH, Washington University School of Medicine, St. Louis, Missouri; Robert Hardi, MD, Chevy Chase Clinical Research, Chevy Chase, Maryland; Ciaran Kelly, MD, Beth Israel Deaconess Medical Center, Boston,
Massachusetts; Paul Mariani, MD, Sanford Research, Fargo, North Dakota;
Bharat Misra, MD, Borland-Groover Clinic, Jacksonville, Florida; Kathleen
Mullane, DO, PharmD, University of Chicago Medicine, Chicago, Illinois;
Robert Orenstein, DO, Mayo Clinic, Phoenix, Arizona; Darrell S. Pardi, MD,
Mayo Clinic, Rochester, Minnesota; Connie S. Price, MD, Denver Health
Medical Center, Denver, Colorado; Mayur S. Ramesh, MD, Henry Ford
Hospital System, Detroit, Michigan; and Arnab Ray, MD, Ochsner Clinic
Foundation, New Orleans, Los Angeles. The independent medical monitor
was Dimitri Drekonja, MD, MS, Minneapolis Veteran’s Administration
Health Care System, Minneapolis, Minnesota.
Financial support. This work was supported by Rebiotix Inc., Roseville,
Minnesota.
Potential conflicts of interest. R. O. has received institutional grant support and consulting fees from Rebiotix. D. S. P. and E. D. have received institutional grant support from Rebiotix. K. M. reports grants from Astellas,
Cubist, Synexis, Chimerix, Merck, Summitt, GlaxoWelcome, Ansun, Actelion, Gilead, and Rebiotix during the conduct of the study, as well as personal fees from Astellas, Chimerix, Seres, outside the submitted work. All other
authors report no potential conflicts. All authors have submitted the ICMJE
Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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