adult infectiouS diSeaSeS noteS
Something old, something new,
something borrowed...
Louis Valiquette MD MSc FRCPC1, Kevin B Laupland MD MSc FRCPC2,3
A
lthough knowledge of the complex interactions within our intestinal microbiota is relatively new, fecal microbiota transplantation (FMT) has been practiced for a long time. For more than a
millennium, human fecal suspensions have been used to treat various
ailments. The first literary evidence of oral fecal administration for the
treatment of food poisoning and diarrhea dates back to the fourth
century in China as detailed in the first Chinese handbook of emergency medicine written by Ge Hong (1). Later, in the 16th century, Li
Shizhen described the use of several different human stool preparations for the treatment of various gastrointestinal diseases (1). The
first report of FMT for the treatment of pseudomembranous colitis
dates back to 1958 (2). In this case series involving four patients, all
responded spectacularly. In 1983, Schwan et al (3) published the first
report of FMT in a patient with a confirmed Clostridium difficile infection (CDI). Since then, the experiences of more than 250 CDI
patients treated with FMT has been published in the medical literature, with an overall success rate of approximately 90% (4,5).
A hypervirulent strain of C difficile (NAP1/BI/027) has plagued
several hospitals across Canada since 2003. This strain is associated
with disease of increased severity, and higher rates of mortality and
recurrence compared with other strains (6,7). In general, most patients
with CDI will respond to antimicrobial therapy with oral metronidazole or vancomycin. However, recurrence is common and represents
one of the most challenging situations in treating CDI patients.
Furthermore, some patients will present with a succession of recurrences, which has a major impact on both their quality of life and
utilization of health care resources. For example, from 1998 to 2008 in
Sherbrooke, Quebec, more than 1300 CDI episodes occurred and, of
these, one-third experienced one recurrence, one-third of these
experienced a second recurrence, and one-third a third episode and so
on (unpublished data).
To treat patients with recurrent disease, several different therapeutic approaches have been suggested; however, none are supported
by empirical data. Many experts recommend the use of a tapering or
pulsed regimen of oral vancomycin (8). Recently, a new antibiotic,
fidaxomicin, has been shown by two multicentric randomized clinical
trials to significantly decrease the risk of a first recurrence (9,10).
When compared with patients receiving a standard regimen of oral
vancomycin, patients treated with fidaxomicin experienced an absolute recurrence risk reduction of 9.8% in the first trial and 14.2% in
the second trial (both in modified intention to treat analysis). In a
subgroup analysis, patients who experienced a single episode of recurrence within three months of enrollment demonstrated similar results
(11). Apart from some anecdotal cases, data are lacking to support
fidaxomicin use in patients who experience multiple recurrences (12).
The unproven efficacy in patients infected with the NAP1 strain is
also a limitation in some of these individuals.
Until recently, FMT was only supported by case series and by systematic reviews of case series, with all of the limitations inherent in
these types of studies. However, in February 2013, stimulating data
were published by van Nood et al (13). The investigators completed
an open-label randomized clinical trial in which they initially planned
to enroll 120 patients. The main outcome was the absence of relapse
at 10 weeks. The three arms of the study compared 13 patients with
high-dose vancomycin (500 mg orally for 14 days), 13 patients with
high-dose vancomycin (for 14 days) and bowel lavage, and 16 patients
with an abbreviated high-dose vancomycin regimen (four to five days)
and bowel lavage with FMT administered via a nasogastric tube. The
trial was stopped by the data and safety monitoring board on the basis
of superior FMT outcome after 43 patients (one was excluded) had
been enrolled over a 28-month period. In fact, 13 FMT patients (81%)
were cured on their first infusion compared with seven (27%) in the
combined control arms. Three patients, who did not respond initially
to their first infusion, received a second administration and two of
them were cured, yielding a combined efficacy of 94% in favour of
FMT.
There are a number of other important findings and considerations
arising from this trial. First, the investigators compared the fecal flora
between donors and enrollees (before and after FMT). The flora diversity scores were highly similar between donors and enrollees after FMT,
indicating the FMT had recreated a healthy, diverse flora. Second, they
offered off-protocol FMT to patients who were initially enrolled in the
non-FMT arms and who relapsed. Fifteen of 18 patients were cured
using the off-protocol FMT (83% success rate). In spite of these landmark results, some limitations must be addressed. Even if the authors
referred to the vancomycin regimen as ‘standard’, it is clearly not the
general approach suggested in published guidelines (8). High-dose
vancomycin has never been shown to be superior in the treatment of
relapsing CDI and could have had a negative impact on the fecal flora
compared with a lower dose. Furthermore, some authors have suggested that high colonic concentrations of vancomycin could be
inhibitory to Bacteroides and Bifidobacteria species (14). It is also
important to recognize that the proportion of patients infected with
ribotype 027 strains was very low in this clinical trial. Consequently,
these results might have been different in Canada or other jurisdictions where the prevalence rate of ribotype 027 infection remains
high. A group of investigators from Toronto (Ontario) is currently
conducting a trial to compare vancomycin tapering with standard
vancomycin plus FMT via enema (clinicaltrials.gov).
Although FMT was occasionally practiced before publication of
the trial by van Nood et al (13), since this paper was released, several
centres across Canada have started or are in the process of developing
FMT clinics. However, several questions and challenges remain.
Depending of the technique used, FMT can be relatively invasive (eg,
total colonoscopy or insertion of a nasogastric tube) and may necessitate specific expertise and/or setting. Moreover, a donor needs to be
identified and screened for transmissible diseases. To facilitate the
process, donors are usually family members. Recent data from FMT
using frozen stools of an unrelated screened donor has shown to be as
effective as FMT using fresh stools from a family member (15).
Screening varies according to published protocols, but usually involves
stool testing (ova and parasites, bacterial cultures, and C difficile toxin
A and B testing) and serum testing (HIV-1, HIV-2, hepatitis A, B and
C, and rapid plasma reagin). Donors with risk factors for these
1Department
of Microbiology-Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec; 2Departments of Medicine, Critical Care
Medicine, Pathology and Laboratory Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta; 3Department of
Medicine, Royal Inland Hospital, Kamloops, British Columbia
Correspondence: Dr Louis Valiquette, Université de Sherbrooke, 3001 12ème Avenue Nord, Sherbrooke, Quebec J1H 5N4.
Telephone 819-346-1110 ext 12568, fax 819-829-3289, e-mail louis.valiquette@usherbrooke.ca
Can J Infect Dis Med Microbiol Vol 24 No 2 Summer 2013
©2013 Pulsus Group Inc. All rights reserved
63
Valiquette and Laupland
infections should be excluded a priori (intravenous drug user, returned
traveller from endemic regions, etc). There are almost as many techniques of stool preparation as practitioners performing FMT (16). We
believe that the technique does not need to be overly complicated. It
should involve fresh stools mixed with saline or water and be instilled
via a fecal enema. For this approach, the key element is volume. A
minimum volume of 300 mL has been suggested by some authors while
others have used as much as 1.5 L of infusion (16). Anecdotally, the
results are generally highly favourable regardless of the technique used,
even when self-administered at home (17)! The largest challenge lies
mostly in convincing patients, potential donors and health professionals to overcome the ‘ick’ factor associated with FMT.
A group of Ontario investigators recently published information
about a stool substitute to be used in FMT known as ‘RePOOPulate’
(18). This preparation includes 33 different intestinal bacteria isolated
in pure culture from a single healthy donor. It has been sucessfully
administered to two patients with recurrent CDI. If this approach is
found to be efficacious, it could serve as an alternative to fresh stool
with no risk of disease transmission, a standardized inoculum and with
limited repulsive factor. However, normal stool is comprised of more
than 4000 different bacterial species, many of which are exceedingly
difficult to culture in a laboratory (19). Furthermore, interactions
between the normal flora and colonic mucosal cells are complex.
Therefore, at this point, it is very difficult predict whether this
approach will be successful clinically. It is motivating to know that the
same research team is conducting a clinical trial (clinicaltrials.gov).
After more than 1700 years of experience, FMT has only recently
been supported by experimental clinical trial evidence in CDI. While
proponents of FMT have argued that there may be role for FMT in the
treatment of other diseases, such as inflammatory bowel disease, obesity and diabetes mellitus, evidence supporting its use beyond recurrent
CDI is lacking. We now have the clinical trial data to support what we
expected from previous anecdotal experience. The challenge is now to
refine and optimize FMT protocols and search for comparable standardized culture-based biotherapies for CDI.
REFERENCES
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Can J Infect Dis Med Microbiol Vol 24 No 2 Summer 2013
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