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Recent developments in the management of recurrent Clostridioides difficile infection
Journal Pre-proof Recent developments in the management of recurrent Clostridioides difficile infection Rafael Mendo-Lopez, Javier Villafuerte-Gálvez, Nicole White, Monica V. Mahoney, Ciaran P. Kelly, Carolyn D. Alonso PII:
S1075-9964(19)30180-5
DOI:
https://doi.org/10.1016/j.anaerobe.2019.102108
Reference:
YANAE 102108
To appear in:
Anaerobe
Received Date: 27 March 2019 Revised Date:
23 September 2019
Accepted Date: 8 October 2019
Please cite this article as: Mendo-Lopez R, Villafuerte-Gálvez J, White N, Mahoney MV, Kelly CP, Alonso CD, Recent developments in the management of recurrent Clostridioides difficile infection, Anaerobe (2019), doi: https://doi.org/10.1016/j.anaerobe.2019.102108. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
1
Recent Developments in the Management of Recurrent Clostridioides difficile Infection
2 3
Mendo-Lopez, Rafael1; Villafuerte-Gálvez, Javier1; White, Nicole2; Mahoney, Monica
4
V.3; Kelly, Ciaran P.1,4; Alonso, Carolyn D.2,4.
5 6
1
7
Center, Boston, MA, USA
Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical
8 9 10
2
Department of Medicine, Division of Infectious Diseases, Beth Israel Deaconess Medical
Center, Boston, MA, USA.
11 12
3
Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA.
13 14
4
Harvard Medical School, Boston, MA, USA.
15 16 17 18 19
Corresponding author: Carolyn D. Alonso, MD.
20 21 22
Beth Israel Deaconess Medical Center Division of Infectious Diseases Director, Transplant and Immunocompromised Host ID Program
23 24 25 26
110 Francis Street LMOB GB Boston, MA 02215 Office phone: (617) 632-7706; Fax: (617) 632-7626 Email: [email protected]
27
1
Abstract:
2
Clostridioides (formerly Clostridium) difficile is responsible for a substantial burden of
3
nosocomial infection. Recurrent C. difficile infection (rCDI) remains a concern due to its
4
high morbidity, mortality, and cost. Despite the updated 2017 IDSA C. difficile treatment
5
guidelines, there remains a lack of well-studied preventive control measures and treatment
6
modalities for rCDI. There are ongoing efforts to develop novel therapies, such as new
7
antibiotics with a lesser impact on gut microbiota and more targeted therapies, such as
8
bacteriotherapy. This mini review highlights key rCDI management updates, preventive
9
measures and ongoing research on novel treatment strategies including bacteriotherapy.
10
Keywords:
11
bacteriotherapy.
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Clostridioides
difficile
infection,
recurrence,
prophylaxis,
antibiotics,
1
1- Introduction
2
Clostridioides (formerly Clostridium) difficile is a spore-forming and toxin-producing gram
3
positive bacterium responsible for a substantial burden of nosocomial infection. The
4
organism was recently reclassified based on phenotypic, chemotaxonomic and phylogenetic
5
characteristics (1). Recurrent C. difficile infection (rCDI) is defined as the reappearance of
6
symptoms of C. difficile infection (CDI) in conjunction with positive laboratory testing for C.
7
difficile (toxin enzyme immunoassay [EIA] or nucleic acid amplification test [NAAT]) in a
8
patient who has had an episode of CDI in the preceding two to eight weeks (2).
9
In the United States, the estimated burden of rCDI is 61,400 (95% CI: 40,200 to 82,600) and
10
21,600 (95% CI: 16,900 to 26,300) recurrences of healthcare-associated CDI (HA-CDI) and
11
community-associated CDI (CA-CDI), respectively (3). Moreover, one study found an
12
estimated attributable cost of rCDI of $10,580 (95% CI: $8,849-$12,446) per patient,
13
compared to the attributable cost of a primary episode of $24,205 (95% CI: $23,436-
14
$25,013) (4).
15 16
Identification of patients at increased risk of recurrence is key to better allocate interventions
17
to prevent recurrence. Older age, poor host immune function, severe underlying disease, and
18
receipt of additional antibiotics after discontinuation of CDI therapy have all been identified
19
previously as risk factors for rCDI (5,6).
20 21
CDI is the leading cause of healthcare-associated infections in U.S. hospitals with estimated
22
excess healthcare costs as high as $4.8 billion for acute care facilities alone (3). New
23
therapies and transmission prevention strategies are greatly needed. This mini review
1
highlights key rCDI management updates, rCDI preventive therapies, and summarizes
2
ongoing research on novel treatment strategies including bacteriotherapy.
3 4
2- Update on clinical management:
5 6
a. First recurrence (Figure 1)
7 8
Historically, the 2010 Infectious Diseases Society of America (IDSA) Clinical Practice
9
Guidelines for C. difficile Infection in Adults recommended that rCDI be treated according
10
to disease severity; metronidazole was recommended for treatment of mild to moderate
11
disease and oral vancomycin was suggested for severe cases (7). More recently, the
12
updated 2017 IDSA Clinical Practice Guidelines suggested several potential treatments for
13
first recurrence of CDI. These include a 10-day course of oral vancomycin (if
14
metronidazole was given for the initial episode), a tapered and pulsed vancomycin regimen
15
(if a standard regimen of PO vancomycin was given for the initial episode), or fidaxomicin
16
for a 10-day course (if a standard regimen of PO vancomycin was given for the initial
17
episode) (See details on Table 1) (2).
18 19
Alternative guidelines for the management of C. difficile include the 2013
20
recommendations for CDI management published by the American College of
21
Gastroenterology (ACG) which suggest repeating treatment with either metronidazole or
22
vancomycin pulse regimen (8). The 2014 European Society of Clinical Microbiology and
23
Infectious Diseases (ESCMID) guidelines suggest using fidaxomicin or vancomycin orally
24
for 10 days (9). A 10 day course of oral metronidazole is noted as an alternative, with a
25
lesser strength of quality of evidence to support its use. (9). The 2016 Australasian Society
1
of Infectious Diseases Updated Guidelines for the Management of C. difficile also endorse
2
using a 10-day course of oral vancomycin for first recurrence (10).
3 4
To date, a formal consensus has not been reached between the various guidelines’
5
committees with respect to a single approach for management of the first recurrence.
6
Differences between the recommendations issued by these guidelines may be driven by
7
multiple factors including the chronological publication of new evidence supporting a
8
specific intervention (i.e. inclusion of fidaxomicin starting in 2013), a gain in acceptance of
9
a specific intervention in clinical practice (inclusion of tapered and/or pulsed regimens
10
since 2017) or progressive accumulation of evidence of a treatment being inferior
11
(relegation of metronidazole to a second or third-line role).
12 13
b. Second or multiple recurrences (Figure 1)
14 15
Previously, for second or multiple CDI recurrences, the 2010 IDSA guidelines suggested
16
management with tapered and/or pulsed vancomycin (7). The updated 2017 IDSA/SHEA
17
guidelines recommend either tapered and/or pulsed vancomycin, a standard 10-day course
18
of vancomycin followed by a rifaximin “chaser” or fidaxomicin. FMT is suggested for
19
patients with multiple recurrences who have failed prior antibiotic treatment courses (2)
20
(Table 1, Figure 1).
21 22
The 2013 ACG guidelines differentiate between the second and beyond recurrence,
23
recommending a pulsed vancomycin regimen for the second recurrence, and fecal
24
microbiota transplantation (FMT) for subsequent recurrences (8). The 2014 ESCMID
1
Guidelines recommend three regimens for second or multiple recurrences: a standard 10-
2
day vancomycin course follow by pulsed vancomycin, a standard 10-day vancomycin
3
course follow by tapered vancomycin, or a 10-day course of fidaxomicin. Consideration for
4
FMT is suggested for patients experiencing multiple recurrences (9). The 2016
5
Australasian guidelines recommend a 14-day course of vancomycin with an optional taper,
6
fidaxomicin for 10 days, or FMT. For patients unable to proceed with FMT, a rifaximin
7
“chaser” is a potential alterative (10).
8 9
As with management of first recurrence, there is no consensus among the guidelines with
10
regards to treatment of multiply recurrent CDI, although consideration for FMT (after two
11
or more recurrences) is universally noted. With further clinical trials data expected in the
12
next few years, we anticipate that future guidelines are likely to move away from inclusion
13
of metronidazole and more strongly favor FMT and bacteriotherapy.
14 15 16
c. Preventing recurrence
17
Neither the 2010 IDSA/SHEA guidelines nor the 2014 ESCMID guidelines make
18
recommendations regarding prevention of CDI. The 2013 ACG guidelines, 2016
19
Australasian guidelines, and the 2017 IDSA/SHEA guidelines comment that there is
20
insufficient evidence to recommend the use of probiotics as a method of preventing CDI.
21
However, ongoing trials are studying their role in rCDI (NCT03647995 and
22
NCT02127814)(2).
23
1
Bezlotuxumab is the single pharmacological therapy with FDA approval for prevention of
2
CDI in adults who are receiving antibacterial drug treatment for CDI and who are at a high
3
risk for CDI recurrence (11) (further discussion below).
4 5 6
d. Prophylactic treatment (Table 2)
7
To date, none of the published guidelines have recommended specific pharmacologic
8
prophylaxis for rCDI beyond the treatment course for each discrete episode. However, in
9
clinical practice, the strategy of prophylactic CDI therapy has been used increasingly
10
despite robust clinical data supporting its efficacy. We sought to review the published data.
11 12
Five retrospective cohort studies evaluated the role of oral vancomycin prophylaxis (OVP)
13
in reducing the risk of rCDI among patients exposed to subsequent antibiotics (12–16).
14
These studies demonstrated a decrease in the risk of recurrence or CDI rate in patients with
15
at least one rCDI episode. However, other retrospective studies did not found any benefit of
16
OVP (17–19) (See details in Table 2).
17 18
While OVP appears to reduce risk of rCDI in high-risk patients receiving systemic
19
antibiotics, the optimal dosing regimen and the full extent of impact of prophylactic
20
therapy on the microbiome have not been established. Limitations of the previously cited
21
retrospective studies such as non-random allocation of treatment, dissimilar follow-up
22
times or treatment compliance may be overcome in three prospective studies currently
23
underway (NCT03200093/ NCT03462459: 125 mg PO vancomycin once daily or
24
NCT03466502: 125mg vancomycin twice daily in patients with undergoing antibiotic
25
treatment). Until then, OVP should be carefully considered on a case-by-case basis.
1 2
Fidaxomicin was studied against placebo for prophylaxis of CDI in an RCT involving
3
hematopoietic stem cell transplantation (HSCT) patients receiving fluoroquinolone
4
prophylaxis during neutropenia (20). Patients were randomized to fidaxomicin or placebo
5
daily, starting 2 days before the conditioning regimen or at the start of fluoroquinolone
6
prophylaxis and continued until 7 days after neutrophil engraftment, discontinuation of
7
fluoroquinolones, or receipt of any antibiotics for infection treatment. There was no
8
difference in primary outcome called “prophylaxis failure”, which was defined as
9
confirmed CDI, receipt of anti-CDI therapy, and missing CDI assessment for any reason
10
(28.6% fidaxomicin vs. 30.9% placebo, p=0.2778). There was a statistically significant
11
difference in the sensitivity analysis of laboratory-confirmed CDI cases (4.3% fidaxomicin
12
vs. 10.7% placebo, p<0.014). However, the study had a high withdrawal rate (35.7%),
13
which may affect its findings. Further investigation is needed to determine the role for
14
fidaxomicin as a prophylactic agent.
15 16
Metronidazole was observed in an open-label study in patients considered to be at high-risk
17
of developing hospital-acquired diarrhea. Patients received 7 days of metronidazole 500 mg
18
thrice daily or nothing. Metronidazole did not affect the incidence of antibiotic-associated
19
diarrhea (OR 0.26 [0.05-1.29], p=0.109), nor prevent CDI (OR 0.91 [0.84–0.99], p=0.069)
20
(21). Meanwhile, extended-CDI treatment of vancomycin or metronidazole as prophylaxis
21
has conflicting evidence (22). (See details in Table 2)
22
1
Prophylactic treatment may be beneficial for patients with certain high-risk characteristics
2
such as concomitant receipt of systemic antibiotics or historically more recurrence
3
episodes, but further clinical trials data are needed. Due to the dearth of large prospective
4
randomized data, the specific role for antimicrobials as prophylactic agents remains
5
unclear.
6 7 8 9 10 11
3- Novel agents a. Fidaxomicin Fidaxomicin is a bactericidal macrocyclic antibiotic which achieves high concentrations in
12
the gastrointestinal lumen yet has minimal systemic absorption. It is highly selective for
13
Clostridia, sparing much of the commensal gastrointestinal microbiota, and therefore lower
14
risk of microbiome dysbiosis (23).
15 16
Two phase III double-blinded RCTs demonstrated fidaxomicin non-inferiority compared to
17
standard vancomycin treatment (125 mg four times daily of oral vancomycin for 10 days)
18
(24,25). The first trial included 629 patients, and found a similar clinical cure rate (CCR)
19
between both treatments and a significantly lower recurrence rate (RecR) in the
20
fidaxomicin group (15.4% vs. 25.3, p=0.0005) (24). RecRs were similar between
21
fidaxomicin and vancomycin among patients with the NAP1/BI/027 strain, but among
22
patients with other strains, the RecR was lower with fidaxomicin (7.8%) compared to
23
vancomycin (25.5%). Similar results were found in the second trial which included 535
24
patients and found no difference in CCR and lower RecR in the fidaxomicin group (See
25
details Results in Supplemental Table 1) (25).
1 2
A recent open-label RCT found that extended-pulsed fidaxomicin achieved higher rates of
3
sustained clinical cure rate (SCR) at 30 days post-treatment compared with standard
4
vancomycin (70% vs. 59%, p=0.03) in patients over 60 years of age (26). The RecR was
5
also significantly lower for extended-pulsed fidaxomicin compared to vancomycin.
6
However, it is worth noting the potential for bias in this study as neither subjects nor
7
investigators were blinded.
8 9
A phase IV RCT (NCT02667418) is currently in progress with three arms comparing the
10
efficacy of fidaxomicin, standard vancomycin, or tapered and pulsed vancomycin as
11
treatment for rCDI with SCR at day 59 as the primary outcome.
12 13 14 15 16 17
b. New antibiotics: i. Cadazolid Cadazolid is a fluoroquinolone-oxazolidinone antibiotic that acts by inhibition of
18
bacterial protein synthesis. Given poor absorption in the gastrointestinal tract and a
19
narrow spectrum of activity, it is purported to target C. difficile without aggravating
20
gastrointestinal dysbiosis (27). In spite of its encouraging phase II RCT results, the
21
two published phase III trials showed opposite results (See details in Supplemental
22
Material Table 1) (28).
23
spectrum antibiotic with non-inferior efficacy to vancomycin.
24 25 26
ii. Surotomycin
Cadazolid failed to meet the expectation of a narrow
1
Surotomycin is a narrow spectrum cyclic lipopeptide that acts by disrupting the
2
bacterial membrane of C. difficile. A phase II trial demonstrated encouraging results
3
with lower RecR and higher sustained clinical cure when compared to oral
4
vancomycin (29). However, two phase III trials failed to demonstrate non-inferiority
5
of surotomycin compared to vancomycin (See Results in Supplemental Material
6
Table 1) (30,31). Thus, surotomycin has not been incorporated into guidelines based
7
strategies for management of CDI given lack of demonstrable benefit over treatment
8
with oral vancomycin.
9 10 11 12
iii. Ridinilazole Ridinilazole is a new narrow-spectrum antibiotic which impairs cell division.
13
Theoretically, its poor systemic absorption, good bactericidal activity against C.
14
difficile, and reduction of toxin A and B concentrations should render it effective
15
against CDI while minimizing the impact on gastrointestinal microbiota (32).
16 17
A phase II double-blinded clinical trial randomized 100 patients with primary or
18
recurrent CDI to ridinilazole or standard vancomycin for 10 days (33). Its primary
19
endpoint was SCR (defined as clinical cure at the end of treatment and no recurrence
20
within 30 days). Investigators found that ridinilazole had superior SCR compared to
21
vancomycin (SCR of 66.7% vs. 42.4%) with a treatment difference of 21.1% (90% CI
22
3.1 to 39.1; p=0.0004). RecR was evaluated as a secondary endpoint in patients who
23
were considered to have obtained clinical cure. Recurrence was noted in 14.3% of the
24
ridinilazole recipients versus 34.8% of the vancomycin recipients with an overall
1
treatment difference of -16.2% (90% CI -35.5 to 3.0) (See Results in Supplemental
2
Material Table 1).
3 4
In conclusion, ridinilazole may have potential as a novel agent for CDI management;
5
however, the small sample size of its phase II study limits generalization of its
6
efficacy and safety. Two ongoing phase III trials (NCT03595553 and NCT03595566)
7
will define its role in rCDI management.
8 9 10 11
Bezlotoxumab is a human monoclonal antibody which binds C. difficile toxin B with high
12
affinity, thereby preventing toxin from binding to host cells. In comparison to other agents
13
that are focused on treatment of established rCDI, bezlotoxumab is the only therapy
14
specifically FDA approved for rCDI prevention in patients being treated for primary CDI
15
with standard-of-care antibiotics.
c. Bezlotoxumab
16 17
The phase II trial found that combined actoxumab (a monoclonal antibody binding toxin A)
18
and bezlotoxumab had a significantly lower RecR compared to placebo (7% vs 25%,
19
p<0.001) (34). Two phase III RCTs (MODIFY I and II; results are described in
20
Supplemental Material Table 1) demonstrated that bezlotoxumab was associated with a
21
significantly lower rCDI rate for subjects over 18 years old who were treated with standard
22
of care antibiotics (35). The combination of actoxumab to bezlotoxumab did not confer any
23
further benefit in preventing recurrence.
24
1
A cost-effectiveness study found that bezlotoxumab, by preventing rCDI, led to a gain of
2
0.12 QALYs (equivalent to 43.8 more days of health) in a subject treated for primary CDI
3
compared to standard treatment. The cost of $19,824 per QALY gained is below the
4
standard willingness-to-pay threshold ($50,000/QALY), making the medication likely cost-
5
effective (36).
6 7 8 9 10 11
4- Bacteriotherapy a. Spores: SER-109 SER-109 is a spore therapy with a composition of approximately 50 species of
12
Firmicutes spores (Gram-positive microorganisms, including Clostridia and Bacilli)
13
derived from the stool of healthy donors. Its mechanism of action relies on metabolic
14
competition between spore-forming microorganisms and C. difficile.
15 16
In an open-label study, two doses of SER-109 were compared in two cohorts (15
17
patients each). The primary outcome was absence of CDI during an 8-week follow-up
18
period (37). The majority (86.7%) of the study population met the primary outcome.
19
There was no difference in prevention of rCDI noted between the cohorts
20
(Supplemental Material Table 2).
21 22
The results of an unpublished phase II clinical trial [(NCT02437487); results available
23
on clinicaltrials.gov)] which compared effects of SER-109 versus placebo on rCDI
24
prevention showed a non-significant difference in RecR within 8 weeks between the
25
SER-109 and placebo group (44.1% vs 53.3%, p=0.5018) (38). However, the small
1
sample size in both groups (59 subjects receiving SER-109 and 30 subjects receiving
2
placebo) may have underpowered the study.
3 4
Additionally, two phase III RCTs (NCT03183128 and NCT03183141) are currently
5
recruiting subjects to demonstrate the superiority of SER-109 compared to placebo for
6
rCDI prevention. In these trials, the SER-109 dose is four capsules four times a day for
7
three consecutive days and the primary outcome is the RecR within 8 weeks after
8
treatment. In conclusion, the role of SER-109 role in CDI management is still under
9
investigation.
10 11 12 13
b. Spores: Non-toxigenic Clostridium difficile (NTCD) NTCD strains are found in hospital settings colonizing inpatients, but they do not cause
14
clinical disease due to the lack of genes for toxin production. NTCD, specifically the
15
NTCD-M3 strain, has sparked attention for potential use as a preventive therapy for
16
CDI. It is hypothesized that NTCD competes with toxigenic C. difficile for the same
17
metabolic or adherence niche in the gastrointestinal tract, though the mechanism of
18
action has not been fully elucidated.
19 20
One phase II study which randomized 173 patients into three treatment groups of
21
different doses established the safety and tolerability of NTCD-M3 compared to
22
placebo for prevention of rCDI (39). CDI RecR within 6 weeks of the treatment period
23
showed NTCD-M3 had lower RecR compared to placebo (11% versus 30%, p=0.03).
24
However, when examined by dose, only the NTCD-M3 dose of 107 spores/day for 7
1
days demonstrated a significant decrease in the RecR compared to placebo (5% versus
2
30%; See Supplemental Material Table 2).
3 4
These findings suggest that NTCD-M3 at a dose of 107 spores/day for 7 days could be
5
an effective therapy to diminish CDI RecR. However, the small sample size of
6
investigations to date and the unknown duration of action of NTCD-M3 strain
7
colonization leave lingering questions and call for a phase III trial comparing NTCD-
8
M3 with placebo. A suggested primary endpoint of this phase III trial could be
9
recurrence of CDI within 12 weeks after infusion as this would allow for comparison
10
with bezlotuxumab, which was evaluated at that same interval during previous clinical
11
trials.
12 13 14 15 16 17
c. Fecal microbiota transplantation (FMT) i. First, second and multiple recurrences: FMT is the infusion of healthy fecal microbiota (donor) into a disrupted microbiome
18
(recipient) in order to restore its integrity and functionality to treat and prevent
19
recurrent CDI.
20 21
The 2017 IDSA Clinical Practice Guidelines recommend FMT for multiply rCDI, but
22
not for use in the first or second episode of rCDI due to lack of evidence to support its
23
use in these settings (2). A recent systematic review affirmed the efficacy of FMT in
24
non-responsive or recurrent CDI (Relative risk=0.41, 95% CI: 0.22-0.74, p<0.004)
25
(40), but further evaluation is needed regarding the role of FMT for first and second
1
recurrences of CDI. Ongoing trials (NCT03548051 and NCT03548051) are assessing
2
the safety and efficacy of FMT in patients with rCDI.
3 4 5 6 7 8
ii. Rebiotix (RBX2660) RBX2660 is a manufactured microbiota suspension prepared from stool of a healthy
9
donor. It is a commercially prepared product for FMT use; each dose contains a 150
10
mL suspension of ≥107 live microorganisms per mL and is packed in an enema bag. It
11
requires frozen storage at -80°C until thawing prior to administration.
12 13
Two phase II clinical trials were performed to determine the efficacy and safety of
14
this novel bacteriotherapy (41,42). In the first open-label clinical trial, an overall
15
efficacy in CDI-associated diarrhea resolution at 8-weeks of 87.1% for RBX2660 was
16
noted, with greater efficacy in the group that received two doses of RBX22660
17
(Supplemental Material Table 2). A second RCT found that one-dose of RBX22660
18
was superior to placebo for prevention of CDI at 8 weeks following treatment (RecR:
19
67% vs. 45%, p=0.048), but two doses were not (RecR: 61% vs. 45, p=0.152). It is
20
worth noting that the first study did not include a placebo control group and its
21
primary objective was product-related adverse events, which make the results
22
difficult to compare with other studies. Given differing results in the Phase II studies,
23
the role of RBX2660 in rCDI management remains uncertain, however an ongoing
24
phase III clinical trial (NCT03244644) may help clarify its efficacy.
25
1 2 3
iii. Oral FMT: OpenBiome Oral FMT is a per os treatment for rCDI; oral administration avoids the complications
4
of infusion via upper endoscopy or colonoscopy and also decreases the cost of
5
therapy. This bacteriotherapy is given as capsules of frozen fecal material, which
6
remain stored at -80°C prior to administration.
7 8
Two cohort studies have shown that oral FMT has an overall clinical resolution rate
9
of 90%, though resolution rate after a single dose is only 70-82% (43,44). Despite
10
favorable outcomes comparable with previous RCTs of FMT, it is worth noting the
11
lack of a control group or randomization in these cohort studies. Further randomized
12
control trials are needed to accurately determine the role of oral FMT in rCDI.
13 14
OpenBiome is a non-profit organization that operates a stool bank for FMT. It has
15
improved accessibility to fecal microbiota by maintaining a standardized preparation
16
of frozen stool from healthy donors for FMT (45).
17 18
In conclusion, oral FMT, currently accessible only via OpenBiome, is an effective
19
treatment for subjects with rCDI, but future RCTs are still required to incorporate
20
control groups such as placebo or standard treatment arms.
21 22
5- Future directions
23
Novel therapies for the management of recurrent C. difficile are currently under development.
24
The current pipeline includes a novel antibiotic ridinilazole (poised to enter phase III
25
development in 2019), several bacteriotherapy products, non-toxigenic C. difficile products and a
1
preventive therapy, DAV-132 (NCT03710694), which seeks to protect the gut microbiome
2
against intestinal dysbiosis related to antibiotic treatment. Furthermore, VE-303 (NCT03788434)
3
appears to be a promising preventive therapy for rCDI, which is a defined bacteriotherapy
4
seeking for restoring colonization resistance against gut pathogens, including C. difficile. With
5
multiple active studies underway, the new horizon of rCDI preventative therapies hinges on the
6
prevention and restoration of intestinal dysbiosis, seeking to disrupt this critical step in C.
7
difficile pathogenesis.
8 9 10
Funding:
11 12
This paper was not funded.
13 14
Disclosure of interest:
15
Monica V. Mahoney was on the advisory board of Tetraphase Pharmaceuticals Inc. and Spero
16
Therapeutics; received speaker fees from Tetraphase Pharmaceuticals Inc., and research funding
17
from Merck.
18
Ciaran P. Kelly was a scientific advisor for Artugen, Facile Therapeutics, First Light
19
Biosciences, Finch, Merck and Vedanta); received speaker fees from Biocodex, Matrivax, Merck
20
and Seres Health and research grants (to BIDMC) from the National Institutes of Health (NIAID
21
R01 AI116596, R01AI132711, U19 AI 109776), Institut Merieux and Merck.
1
Carolyn D. Alonso was a scientific advisor for Merck and Roche. Dr. Alonso has received
2
research funding from Merck and has NIH Loan Repayment Funding through the National
3
Institute of Allergy and Infectious Diseases (NIAID). Dr. Alonso has been involved in research
4
studies funded by Astellas and Vedanta Biosciences.
5
The other authors do not have any conflicts of interest associated with this publication.
6
6- References
7 8 9
1. Lawson PA, Citron DM, Tyrrell KL, Finegold SM. Reclassification of Clostridium difficile as Clostridioides difficile (Hall and O’Toole 1935) Prévot 1938. Anaerobe. 2016 Aug 1;40:95–9.
10 11 12 13
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11. Merck Sharp & Dohme Corp. ZINPLAVATM (bezlotoxumab)- Prescribing information [Internet]. 4002674. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761046Orig1s000Lbl.pdf
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12. Carignan A, Poulin S, Martin P, Labbé A-C, Valiquette L, Al-Bachari H, et al. Efficacy of Secondary Prophylaxis With Vancomycin for Preventing Recurrent Clostridium difficile Infections. Am J Gastroenterol. 2016 Dec;111(12):1834–40.
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13. Van Hise NW, Bryant AM, Hennessey EK, Crannage AJ, Khoury JA, Manian FA. Efficacy of Oral Vancomycin in Preventing Recurrent Clostridium difficile Infection in Patients Treated With Systemic Antimicrobial Agents. Clin Infect Dis. 2016 Sep 1;63(5):651–3.
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14. Ganetsky A, Han JH, Hughes ME, Babushok DV, Frey NV, Gill SI, et al. Oral Vancomycin Prophylaxis Is Highly Effective in Preventing Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients. Clin Infect Dis. 2019 May 30;68(12):2003-2009
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15. Knight EM, Schiller DS, Fulman MK, Rastogi R. Long-Term Efficacy of Oral Vancomycin Prophylaxis for the Prevention of Clostridium difficile Recurrence. J Pharm Pract. 2019 Feb 11;897190019825994.
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16. Morrisette T, Van Matre AG, Miller MA, Mueller SW, Bajrovic V, Abidi MZ, et al. Oral Vancomycin Prophylaxis as Secondary Prevention Against Clostridioides difficile Infection in the Hematopoietic Stem Cell Transplantation and Hematologic Malignancy Population. Biol Blood Marrow Transplant. 2019 Jun 27. pii: S1083-8791(19)30405-7
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17. Splinter LE, Kerstenetzky L, Jorgenson MR, Descourouez JL, Leverson GE, Saddler CM, et al. Vancomycin Prophylaxis for Prevention of Clostridium difficile Infection Recurrence in Renal Transplant Patients. Ann Pharmacother. 2018 Feb 1;52(2):113–9.
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18. Caroff DA, Menchaca JT, Zhang Z, Rhee C, Calderwood MS, Kubiak DW, et al. Oral vancomycin prophylaxis during systemic antibiotic exposure to prevent Clostridiodes difficile infection relapses. Infect Control Hosp Epidemiol. 2019 Jun;40(6):662–7.
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19. Bajrovic V, Budev M, McCurry KR, Brizendine KD. Vancomycin prophylaxis for Clostridium difficile infection among lung transplant recipients. J Heart Lung Transplant. 2019 Aug 1;38(8):874–6.
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20. Mullane KM, Drew J. Winston, Nooka A, Morris MI, Stiff P, Dugan MJ, et al. A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile– associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation. Clin Infect Dis. 2019;68(2):196–203.
5 6 7 8
21. Tobar-Marcillo M, Guerrero-Duran M, Avecillas-Segovia A, Pacchiano-Aleman L, Basante-Díaz R, Vela-Vizcaino H, et al. Metronidazole in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection in high-risk hospitalised patients. Gastroenterol Hepatol Engl Ed. 2018 Jun;41(6):362–8.
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22. Kaki R, Brooks A, Main C, Jayaratne P, Mertz D. Does Extending Clostridium difficile Treatment In Patients Who Are Receiving Concomitant Antibiotics Reduce The Rate Of Relapse? Internet J Infect Dis. 2016;15(1):1–5.
12 13
23. Venugopal AA, Johnson S. Fidaxomicin: A Novel Macrocyclic Antibiotic Approved for Treatment of Clostridium difficile Infection. Clin Infect Dis. 2012 Feb 15;54(4):568–74.
14 15 16
24. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, et al. Fidaxomicin versus Vancomycin for Clostridium difficile Infection. N Engl J Med. 2011 Feb 3;364(5):422– 31.
17 18 19 20
25. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012 Apr;12(4):281–9.
21 22 23 24
26. Guery B, Menichetti F, Anttila V-J, Adomakoh N, Aguado JM, Bisnauthsing K, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018 Mar 1;18(3):296–307.
25 26 27 28
27. Louie T, Nord CE, Talbot GH, Wilcox M, Gerding DN, Buitrago M, et al. Multicenter, Double-Blind, Randomized, Phase 2 Study Evaluating the Novel Antibiotic Cadazolid in Patients with Clostridium difficile Infection. Antimicrob Agents Chemother. 2015 Oct;59(10):6266–73.
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28. Gerding DN, Cornely OA, Grill S, Kracker H, Marrast AC, Nord CE, et al. Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. Lancet Infect Dis. 2019 Mar;19(3):265–74.
32 33 34
29. Lee CH, Patino H, Stevens C, Rege S, Chesnel L, Louie T, et al. Surotomycin versus vancomycin for Clostridium difficile infection: Phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial. J Antimicrob Chemother. 2016;71(10):2964–71.
35 36 37 38
30. Daley P, Louie T, Lutz JE, Khanna S, Stoutenburgh U, Jin M, et al. Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, Phase 3 trial. J Antimicrob Chemother. 2017 Dec 1;72(12):3462–70.
1 2 3 4
31. Boix V, Fedorak RN, Mullane KM, Pesant Y, Stoutenburgh U, Jin M, et al. Primary Outcomes From a Phase 3, Randomized, Double-Blind, Active-Controlled Trial of Surotomycin in Subjects With Clostridium difficile Infection. Open Forum Infect Dis. 2017 Jan 19;4(1):ofw275.
5 6 7
32. Vickers RJ, Tillotson G, Goldstein EJC, Citron DM, Garey KW, Wilcox MH. Ridinilazole: a novel therapy for Clostridium difficile infection. Int J Antimicrob Agents. 2016 Aug;48(2):137–43.
8 9 10 11
33. Vickers RJ, Tillotson GS, Nathan R, Hazan S, Pullman J, Lucasti C, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis. 2017 Jul;17(7):735–44.
12 13 14
34. Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, et al. Treatment with Monoclonal Antibodies against Clostridium difficile Toxins. N Engl J Med. 2010 Jan 21;362(3):197–205.
15 16 17
35. Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, et al. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017 26;376(4):305– 17.
18 19 20
36. Prabhu VS, Dubberke ER, Dorr MB, Elbasha E, Cossrow N, Jiang Y, et al. Costeffectiveness of Bezlotoxumab Compared With Placebo for the Prevention of Recurrent Clostridium difficile Infection. Clin Infect Dis. 2018 Jan 18;66(3):355–62.
21 22 23
37. Khanna S, Pardi DS, Kelly CR, Kraft CS, Dhere T, Henn MR, et al. A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection. J Infect Dis. 2016 Jul 15;214(2):173–81.
24 25 26
38. Seres Therapeutics, Inc. SER-109 Versus Placebo to Prevent Recurrent Clostridium difficile Infection (RCDI) - Study Results - ClinicalTrials.gov [Internet]. Available from: https://clinicaltrials.gov/ct2/show/results/NCT02437487
27 28 29
39. Gerding DN, Meyer T, Lee C, Cohen SH, Murthy UK, Poirier A, et al. Administration of Spores of Nontoxigenic Clostridium difficile Strain M3 for Prevention of Recurrent C difficile Infection: A Randomized Clinical Trial. JAMA. 2015 May 5;313(17):1719–27.
30 31 32
40. Moayyedi P, Yuan Y, Baharith H, Ford AC. Faecal microbiota transplantation for Clostridium difficile-associated diarrhoea: a systematic review of randomised controlled trials. Med J Aust. 2017 Aug 21;207(4):166–72.
33 34 35
41. Orenstein R, Dubberke E, Hardi R, Ray A, Mullane K, Pardi DS, et al. Safety and Durability of RBX2660 (Microbiota Suspension) for Recurrent Clostridium difficile Infection: Results of the PUNCH CD Study. Clin Infect Dis. 2016 Mar 1;62(5):596–602.
36 37
42. Dubberke ER, Lee CH, Orenstein R, Khanna S, Hecht G, Gerding DN. Results From a Randomized, Placebo-Controlled Clinical Trial of a RBX2660—A Microbiota-Based Drug for
1 2
the Prevention of Recurrent Clostridium difficile Infection. Clin Infect Dis. 2018 Sep 28;67(8):1198–204.
3 4 5
43. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile Infection. JAMA. 2014 Nov 5;312(17):1772–8.
6 7 8
44. Youngster I, Mahabamunuge J, Systrom HK, Sauk J, Khalili H, Levin J, et al. Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection. BMC Med. 2016 Sep 9;14(1):134
9 10 11 12
45. Smith MB, Kassam Z, Burgess J, Perrotta AR, Burns LJ, Mendolia GM, et al. Sa1064 The International Public Stool Bank: A Scalable Model for Standardized Screening and Processing of Donor Stool for Fecal Microbiota Transplantation. Gastroenterology. 2015 Apr 1;148(4):S-211.
13
Tables a) Table N 1: Comparison of guidelines for management for recurrent Clostridioides difficile infection (rCDI).
Recurrent C. difficile Infection
2013 ACG •
First recurrence
•
Same regimen as the • initial episode for 1014 days (Vancomycin PO • 125mg qid OR Metronidazole PO 500mg tid) • Severe cases: Vancomycin PO 125mg qid for 10-14 days
2014 ESCMID Fidaxomicin PO 200mg bid for 10 days Vancomycin PO 125 mg qid for 10 days OR Metronidazole PO 500mg tid for 10 days
2017 IDSA
2016 Australasian •
Vancomycin 125mg PO qid for 10 days
•
•
•
Vancomycin PO 125mg qid for 10 days (if received metronidazole for first episode) Tapered and/or pulsed vancomycin (if received standard vancomycin for first episode) OR Fidaxomicin 200mg bid for 10 days (if received standard vancomycin for first episode)
•
Fidaxomicin PO • Vancomycin PO 125 • Tapered and/or 200mg bid for 10 qid for 14 days +/pulsed vancomycin days OR vancomycin taper OR • • Vancomycin PO 125 • Fidaxomicin 200mg • Vancomycin PO mg qid for 10 days bid for 10 days 125mg qid for 10 followed by pulsed days followed by • Fecal microbiota a regimen (125rifaximin 400mg tid transplantation 500mg/day every 2-3 • Rifaximin chaser for 20 days OR days) for at least 3 • Fidaxomicin PO (following PO Second or multiple weeks OR 200mg bid for 10 vancomycin) recurrences • Vancomycin PO 125 days OR mg qid for 10 days • Fecal microbiota followed by taper transplantation b regimen (gradually decrease of the dose to 125 mg/day). • Fecal microbiota transplantationa following PO vancomycin. a Treatment recommendation for multiple rCDI (2 or more recurrence episodes). b Treatment is recommended for patients with multiple (at least 2 episodes) of rCDI, who have failed appropriate antibiotic therapy. 2nd recurrence: Tapered and/or pulsed vancomycin 3rd and beyond recurrences: Fecal microbiota transplantationa
•
b) Table N 2: Prophylaxis for C. difficile infection Agent (Reference) Vancomycina (12-19)
Population (N) Patients 18 years or older who experienced a primary or recurrent CDI and subsequently had a course of antibiotics (not for CDI) (n=551) Patients 18 years or older with CDI confirmed by stool PCR, with subsequent hospitalization receiving systemic antibiotics (n=203) Patients ≥18 years with a kidney transplant with h/o CDI and received broad spectrum antibiotics (n=36) Patients ≥18 years with lung transplantation (n=636)
Patients ≥18 years with a primary or recurrent CDI and subsequently received broad spectrum antibiotics (n=760)
Patients ≥18 years with allogeneic HSCT admitted as inpatients (n=145) Patients ≥18 years with a
Intervention (N) Vancomycin 125mg qid (n=227)
Comparison (N) No intervention (n=324)
Outcome AHR: -rCDI: 0.47 (95% CI: 0.32-0.69, p<0.0001). -Primary CDI: 0.91 (95% CI: 0.57-1.45, p=0.68)
Vancomycin 125mg PO bid (n=29) Vancomycin 250mg bid (n=42)
No intervention (n=132)
CDI incidence: 4.2% vs 26.6% (p<0.001)
Vancomycin 125 mg PO bid > 48 hr (n=12)
No intervention (n=24)
RecR: 0% vs. 8% (p=0.54)
Vancomycin PO 2-4 times daily (n=82)
No intervention (n=554)
CDI rate: 1% vs. 6% (p=0.059)
No intervention (n=567)
RecR: 9.8% vs. 9.4% at 90 days [Adjusted OR 0.63 (95% CI 0.35-1.14)]
Median dose: 125mg PO bid Vancomycin PO (dose not specified) (n=193)
Vancomycin 125 mg PO bid (n=90)
No intervention (n=55)
Vancomycin 125 mg PO
No intervention (n=59)
RecR: 11.4% vs. 9.5% at 180 days [Adjusted OR 0.72 (95% CI 0.41-1.29)] CDI rate: 0% vs. 20% (p<0.001) RecR: 6.3% vs. 28.8%
Fidaxomicinb (20)
Metronidazolec (21)
primary or recurrent CDI and received broad spectrum antibiotics (n=91) Patients ≥18 years with HSCT or hematologic malignancy with primary CDI receiving broad spectrum antibiotics (n=50) Patients18 years or older undergoing HSCT and planned fluoroquinolone prophylaxis (n=600)
qid (n=10)
Inpatients between 55 and 75 years of age receiving at least one broadspectrum antibiotic (n=96) Patients 18 years or older diagnosed with CDI who received concomitant antibiotics for other reasons (n=228)
Vancomycin 250 mg PO qid (n=22) Vancomycin 125 mg PO bid (n=21)
(OR 0.16, 95% CI 0.040.77, p=0.01)
No intervention (n=29)
RecR: 5% vs. 35% (p=0.016)
Fidaxomicin 200mg qd (n=301)
Placebo (n=299)
Metronidazole 500mg tid for 7 days (n=41)
Observation (n=55)
-CDI incidence: 4.3% vs. 10.7% (p=0.0014) -Composite outcome d: 28.6% vs. 30.8% (p=0.278) CDI rate: 0% vs. 9.1% (OR 0.91, 95% CI 0.840.99, p=0.069)
Extended-CDI treatment: Metronidazole or vancomycin for >14 days (n=127)
Regular CDI treatment: Metronidazole or vancomycin for 10-14 days (n=101)
- RecR: 23% vs. 17%, (OR:0.7, 95% CI 0.3-1.7, p=0.425) - Composite outcome e: 35% vs. 23% (OR:1.2, 95% CI 0.6-2.5, p=0.648) Abbreviations: PCR: polymerase chain reaction, CDI: C. difficile infection, rCDI: recurrent C. difficile infection, HSCT: Hematopoietic stem cell transplantation, AHR: adjusted hazard ratio, RecR: recurrence rate, OR: odd ratio. a Retrospective study, b Randomized controlled trial, c Randomized open-label study, d Composite outcome (Prophylaxis failure): confirmed CDI, receipt of CDI-effective medications (for any indication), and missing CDI assessment (for any reason, including death), e Composite outcome: Inhospital mortality and/or CDI relapse. Extended-CDI treatmenta (22)
1- Box Box 1: Commonly measured outcomes in C. difficile infection research •
•
• • • •
Clinical cure rate (CCR): Resolution of diarrhea (<3 unformed bowel movement/day for at least 2 days) on study treatment and maintained for 2 days after the end-oftreatment (18,19,22). Sustained clinical cure rate (SCR): percentage of subjects with sustained cure, which is defined as clinical cure with no recurrence (22-24). Recurrence rate (RecR): Reappearance of >3 unformed bowel movements/day within 4 weeks after end-of-treatment (18,19,22). Time to diarrhea resolution Absence of C. difficile positive diarrhea Number of daily bowel movements
2- Figure Figure 1: Management of recurrent C. difficile infection. Initial episode: received metronidazole First recurrencef Initial episode: received standard vancomycin
Standard vancomycina (2,9,10) Tapered and/or pulsed vancomycinb (2,8) Fidaxomicinc (2,9)
NEW ONSET OF SYMPTOMS OF CDI AFTER A PRIMARY EPISODE
Tapered and/or pulsed vancomycin (2,7-10)
Second or multiple recurrencesf
Standard vancomycin plus rifaximind (2,10) Fidaxomicin (2,9,10) Fecal microbiota transplantatione (2,810)
a
Standard vancomycin: 125mg PO qid for 10 days Tapered and pulsed vancomycin: 125mg PO qid for 10 days 125mg PO bid for 7 days 125mg PO daily for 7 days 125mg PO every 2-3 days for 2-8 weeks. c Fidaxomicin: 200mg PO bid for 10 days d Standard vancomycin plus rifaximin: Vancomycin 125mg PO qid for 10 days followed by rifaximin 400mg tid for 20 days. e Only for multiple recurrences of C. difficile infection f After treatment completion, clinician could consider adjunctive bezlotoxumab as a preventive therapy. b
Recent Developments in the Management of Recurrent Clostridioides difficile Infection Highlights: •
Recurrent C. difficile infection (rCDI) remains a significant concern due to its high morbidity and mortality.
•
We evaluate the current management proposed on the 2017 IDSA guideline and compare with the previous guidelines (2016 Australasian Society of Infectious Diseases Updated Guidelines, 2014 ESCMID Guidelines, 2013 ACG Guidelines, and 2010 IDSA Guidelines).
•
We review the outcomes of the ongoing trials related to novel antibiotics and bacteriotherapy.
•
Bezlotoxumab has proven effectiveness for the prevention of rCDI.
S1075-9964(19)30180-5
DOI:
https://doi.org/10.1016/j.anaerobe.2019.102108
Reference:
YANAE 102108
To appear in:
Anaerobe
Received Date: 27 March 2019 Revised Date:
23 September 2019
Accepted Date: 8 October 2019
Please cite this article as: Mendo-Lopez R, Villafuerte-Gálvez J, White N, Mahoney MV, Kelly CP, Alonso CD, Recent developments in the management of recurrent Clostridioides difficile infection, Anaerobe (2019), doi: https://doi.org/10.1016/j.anaerobe.2019.102108. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
1
Recent Developments in the Management of Recurrent Clostridioides difficile Infection
2 3
Mendo-Lopez, Rafael1; Villafuerte-Gálvez, Javier1; White, Nicole2; Mahoney, Monica
4
V.3; Kelly, Ciaran P.1,4; Alonso, Carolyn D.2,4.
5 6
1
7
Center, Boston, MA, USA
Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical
8 9 10
2
Department of Medicine, Division of Infectious Diseases, Beth Israel Deaconess Medical
Center, Boston, MA, USA.
11 12
3
Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA.
13 14
4
Harvard Medical School, Boston, MA, USA.
15 16 17 18 19
Corresponding author: Carolyn D. Alonso, MD.
20 21 22
Beth Israel Deaconess Medical Center Division of Infectious Diseases Director, Transplant and Immunocompromised Host ID Program
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110 Francis Street LMOB GB Boston, MA 02215 Office phone: (617) 632-7706; Fax: (617) 632-7626 Email: [email protected]
27
1
Abstract:
2
Clostridioides (formerly Clostridium) difficile is responsible for a substantial burden of
3
nosocomial infection. Recurrent C. difficile infection (rCDI) remains a concern due to its
4
high morbidity, mortality, and cost. Despite the updated 2017 IDSA C. difficile treatment
5
guidelines, there remains a lack of well-studied preventive control measures and treatment
6
modalities for rCDI. There are ongoing efforts to develop novel therapies, such as new
7
antibiotics with a lesser impact on gut microbiota and more targeted therapies, such as
8
bacteriotherapy. This mini review highlights key rCDI management updates, preventive
9
measures and ongoing research on novel treatment strategies including bacteriotherapy.
10
Keywords:
11
bacteriotherapy.
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Clostridioides
difficile
infection,
recurrence,
prophylaxis,
antibiotics,
1
1- Introduction
2
Clostridioides (formerly Clostridium) difficile is a spore-forming and toxin-producing gram
3
positive bacterium responsible for a substantial burden of nosocomial infection. The
4
organism was recently reclassified based on phenotypic, chemotaxonomic and phylogenetic
5
characteristics (1). Recurrent C. difficile infection (rCDI) is defined as the reappearance of
6
symptoms of C. difficile infection (CDI) in conjunction with positive laboratory testing for C.
7
difficile (toxin enzyme immunoassay [EIA] or nucleic acid amplification test [NAAT]) in a
8
patient who has had an episode of CDI in the preceding two to eight weeks (2).
9
In the United States, the estimated burden of rCDI is 61,400 (95% CI: 40,200 to 82,600) and
10
21,600 (95% CI: 16,900 to 26,300) recurrences of healthcare-associated CDI (HA-CDI) and
11
community-associated CDI (CA-CDI), respectively (3). Moreover, one study found an
12
estimated attributable cost of rCDI of $10,580 (95% CI: $8,849-$12,446) per patient,
13
compared to the attributable cost of a primary episode of $24,205 (95% CI: $23,436-
14
$25,013) (4).
15 16
Identification of patients at increased risk of recurrence is key to better allocate interventions
17
to prevent recurrence. Older age, poor host immune function, severe underlying disease, and
18
receipt of additional antibiotics after discontinuation of CDI therapy have all been identified
19
previously as risk factors for rCDI (5,6).
20 21
CDI is the leading cause of healthcare-associated infections in U.S. hospitals with estimated
22
excess healthcare costs as high as $4.8 billion for acute care facilities alone (3). New
23
therapies and transmission prevention strategies are greatly needed. This mini review
1
highlights key rCDI management updates, rCDI preventive therapies, and summarizes
2
ongoing research on novel treatment strategies including bacteriotherapy.
3 4
2- Update on clinical management:
5 6
a. First recurrence (Figure 1)
7 8
Historically, the 2010 Infectious Diseases Society of America (IDSA) Clinical Practice
9
Guidelines for C. difficile Infection in Adults recommended that rCDI be treated according
10
to disease severity; metronidazole was recommended for treatment of mild to moderate
11
disease and oral vancomycin was suggested for severe cases (7). More recently, the
12
updated 2017 IDSA Clinical Practice Guidelines suggested several potential treatments for
13
first recurrence of CDI. These include a 10-day course of oral vancomycin (if
14
metronidazole was given for the initial episode), a tapered and pulsed vancomycin regimen
15
(if a standard regimen of PO vancomycin was given for the initial episode), or fidaxomicin
16
for a 10-day course (if a standard regimen of PO vancomycin was given for the initial
17
episode) (See details on Table 1) (2).
18 19
Alternative guidelines for the management of C. difficile include the 2013
20
recommendations for CDI management published by the American College of
21
Gastroenterology (ACG) which suggest repeating treatment with either metronidazole or
22
vancomycin pulse regimen (8). The 2014 European Society of Clinical Microbiology and
23
Infectious Diseases (ESCMID) guidelines suggest using fidaxomicin or vancomycin orally
24
for 10 days (9). A 10 day course of oral metronidazole is noted as an alternative, with a
25
lesser strength of quality of evidence to support its use. (9). The 2016 Australasian Society
1
of Infectious Diseases Updated Guidelines for the Management of C. difficile also endorse
2
using a 10-day course of oral vancomycin for first recurrence (10).
3 4
To date, a formal consensus has not been reached between the various guidelines’
5
committees with respect to a single approach for management of the first recurrence.
6
Differences between the recommendations issued by these guidelines may be driven by
7
multiple factors including the chronological publication of new evidence supporting a
8
specific intervention (i.e. inclusion of fidaxomicin starting in 2013), a gain in acceptance of
9
a specific intervention in clinical practice (inclusion of tapered and/or pulsed regimens
10
since 2017) or progressive accumulation of evidence of a treatment being inferior
11
(relegation of metronidazole to a second or third-line role).
12 13
b. Second or multiple recurrences (Figure 1)
14 15
Previously, for second or multiple CDI recurrences, the 2010 IDSA guidelines suggested
16
management with tapered and/or pulsed vancomycin (7). The updated 2017 IDSA/SHEA
17
guidelines recommend either tapered and/or pulsed vancomycin, a standard 10-day course
18
of vancomycin followed by a rifaximin “chaser” or fidaxomicin. FMT is suggested for
19
patients with multiple recurrences who have failed prior antibiotic treatment courses (2)
20
(Table 1, Figure 1).
21 22
The 2013 ACG guidelines differentiate between the second and beyond recurrence,
23
recommending a pulsed vancomycin regimen for the second recurrence, and fecal
24
microbiota transplantation (FMT) for subsequent recurrences (8). The 2014 ESCMID
1
Guidelines recommend three regimens for second or multiple recurrences: a standard 10-
2
day vancomycin course follow by pulsed vancomycin, a standard 10-day vancomycin
3
course follow by tapered vancomycin, or a 10-day course of fidaxomicin. Consideration for
4
FMT is suggested for patients experiencing multiple recurrences (9). The 2016
5
Australasian guidelines recommend a 14-day course of vancomycin with an optional taper,
6
fidaxomicin for 10 days, or FMT. For patients unable to proceed with FMT, a rifaximin
7
“chaser” is a potential alterative (10).
8 9
As with management of first recurrence, there is no consensus among the guidelines with
10
regards to treatment of multiply recurrent CDI, although consideration for FMT (after two
11
or more recurrences) is universally noted. With further clinical trials data expected in the
12
next few years, we anticipate that future guidelines are likely to move away from inclusion
13
of metronidazole and more strongly favor FMT and bacteriotherapy.
14 15 16
c. Preventing recurrence
17
Neither the 2010 IDSA/SHEA guidelines nor the 2014 ESCMID guidelines make
18
recommendations regarding prevention of CDI. The 2013 ACG guidelines, 2016
19
Australasian guidelines, and the 2017 IDSA/SHEA guidelines comment that there is
20
insufficient evidence to recommend the use of probiotics as a method of preventing CDI.
21
However, ongoing trials are studying their role in rCDI (NCT03647995 and
22
NCT02127814)(2).
23
1
Bezlotuxumab is the single pharmacological therapy with FDA approval for prevention of
2
CDI in adults who are receiving antibacterial drug treatment for CDI and who are at a high
3
risk for CDI recurrence (11) (further discussion below).
4 5 6
d. Prophylactic treatment (Table 2)
7
To date, none of the published guidelines have recommended specific pharmacologic
8
prophylaxis for rCDI beyond the treatment course for each discrete episode. However, in
9
clinical practice, the strategy of prophylactic CDI therapy has been used increasingly
10
despite robust clinical data supporting its efficacy. We sought to review the published data.
11 12
Five retrospective cohort studies evaluated the role of oral vancomycin prophylaxis (OVP)
13
in reducing the risk of rCDI among patients exposed to subsequent antibiotics (12–16).
14
These studies demonstrated a decrease in the risk of recurrence or CDI rate in patients with
15
at least one rCDI episode. However, other retrospective studies did not found any benefit of
16
OVP (17–19) (See details in Table 2).
17 18
While OVP appears to reduce risk of rCDI in high-risk patients receiving systemic
19
antibiotics, the optimal dosing regimen and the full extent of impact of prophylactic
20
therapy on the microbiome have not been established. Limitations of the previously cited
21
retrospective studies such as non-random allocation of treatment, dissimilar follow-up
22
times or treatment compliance may be overcome in three prospective studies currently
23
underway (NCT03200093/ NCT03462459: 125 mg PO vancomycin once daily or
24
NCT03466502: 125mg vancomycin twice daily in patients with undergoing antibiotic
25
treatment). Until then, OVP should be carefully considered on a case-by-case basis.
1 2
Fidaxomicin was studied against placebo for prophylaxis of CDI in an RCT involving
3
hematopoietic stem cell transplantation (HSCT) patients receiving fluoroquinolone
4
prophylaxis during neutropenia (20). Patients were randomized to fidaxomicin or placebo
5
daily, starting 2 days before the conditioning regimen or at the start of fluoroquinolone
6
prophylaxis and continued until 7 days after neutrophil engraftment, discontinuation of
7
fluoroquinolones, or receipt of any antibiotics for infection treatment. There was no
8
difference in primary outcome called “prophylaxis failure”, which was defined as
9
confirmed CDI, receipt of anti-CDI therapy, and missing CDI assessment for any reason
10
(28.6% fidaxomicin vs. 30.9% placebo, p=0.2778). There was a statistically significant
11
difference in the sensitivity analysis of laboratory-confirmed CDI cases (4.3% fidaxomicin
12
vs. 10.7% placebo, p<0.014). However, the study had a high withdrawal rate (35.7%),
13
which may affect its findings. Further investigation is needed to determine the role for
14
fidaxomicin as a prophylactic agent.
15 16
Metronidazole was observed in an open-label study in patients considered to be at high-risk
17
of developing hospital-acquired diarrhea. Patients received 7 days of metronidazole 500 mg
18
thrice daily or nothing. Metronidazole did not affect the incidence of antibiotic-associated
19
diarrhea (OR 0.26 [0.05-1.29], p=0.109), nor prevent CDI (OR 0.91 [0.84–0.99], p=0.069)
20
(21). Meanwhile, extended-CDI treatment of vancomycin or metronidazole as prophylaxis
21
has conflicting evidence (22). (See details in Table 2)
22
1
Prophylactic treatment may be beneficial for patients with certain high-risk characteristics
2
such as concomitant receipt of systemic antibiotics or historically more recurrence
3
episodes, but further clinical trials data are needed. Due to the dearth of large prospective
4
randomized data, the specific role for antimicrobials as prophylactic agents remains
5
unclear.
6 7 8 9 10 11
3- Novel agents a. Fidaxomicin Fidaxomicin is a bactericidal macrocyclic antibiotic which achieves high concentrations in
12
the gastrointestinal lumen yet has minimal systemic absorption. It is highly selective for
13
Clostridia, sparing much of the commensal gastrointestinal microbiota, and therefore lower
14
risk of microbiome dysbiosis (23).
15 16
Two phase III double-blinded RCTs demonstrated fidaxomicin non-inferiority compared to
17
standard vancomycin treatment (125 mg four times daily of oral vancomycin for 10 days)
18
(24,25). The first trial included 629 patients, and found a similar clinical cure rate (CCR)
19
between both treatments and a significantly lower recurrence rate (RecR) in the
20
fidaxomicin group (15.4% vs. 25.3, p=0.0005) (24). RecRs were similar between
21
fidaxomicin and vancomycin among patients with the NAP1/BI/027 strain, but among
22
patients with other strains, the RecR was lower with fidaxomicin (7.8%) compared to
23
vancomycin (25.5%). Similar results were found in the second trial which included 535
24
patients and found no difference in CCR and lower RecR in the fidaxomicin group (See
25
details Results in Supplemental Table 1) (25).
1 2
A recent open-label RCT found that extended-pulsed fidaxomicin achieved higher rates of
3
sustained clinical cure rate (SCR) at 30 days post-treatment compared with standard
4
vancomycin (70% vs. 59%, p=0.03) in patients over 60 years of age (26). The RecR was
5
also significantly lower for extended-pulsed fidaxomicin compared to vancomycin.
6
However, it is worth noting the potential for bias in this study as neither subjects nor
7
investigators were blinded.
8 9
A phase IV RCT (NCT02667418) is currently in progress with three arms comparing the
10
efficacy of fidaxomicin, standard vancomycin, or tapered and pulsed vancomycin as
11
treatment for rCDI with SCR at day 59 as the primary outcome.
12 13 14 15 16 17
b. New antibiotics: i. Cadazolid Cadazolid is a fluoroquinolone-oxazolidinone antibiotic that acts by inhibition of
18
bacterial protein synthesis. Given poor absorption in the gastrointestinal tract and a
19
narrow spectrum of activity, it is purported to target C. difficile without aggravating
20
gastrointestinal dysbiosis (27). In spite of its encouraging phase II RCT results, the
21
two published phase III trials showed opposite results (See details in Supplemental
22
Material Table 1) (28).
23
spectrum antibiotic with non-inferior efficacy to vancomycin.
24 25 26
ii. Surotomycin
Cadazolid failed to meet the expectation of a narrow
1
Surotomycin is a narrow spectrum cyclic lipopeptide that acts by disrupting the
2
bacterial membrane of C. difficile. A phase II trial demonstrated encouraging results
3
with lower RecR and higher sustained clinical cure when compared to oral
4
vancomycin (29). However, two phase III trials failed to demonstrate non-inferiority
5
of surotomycin compared to vancomycin (See Results in Supplemental Material
6
Table 1) (30,31). Thus, surotomycin has not been incorporated into guidelines based
7
strategies for management of CDI given lack of demonstrable benefit over treatment
8
with oral vancomycin.
9 10 11 12
iii. Ridinilazole Ridinilazole is a new narrow-spectrum antibiotic which impairs cell division.
13
Theoretically, its poor systemic absorption, good bactericidal activity against C.
14
difficile, and reduction of toxin A and B concentrations should render it effective
15
against CDI while minimizing the impact on gastrointestinal microbiota (32).
16 17
A phase II double-blinded clinical trial randomized 100 patients with primary or
18
recurrent CDI to ridinilazole or standard vancomycin for 10 days (33). Its primary
19
endpoint was SCR (defined as clinical cure at the end of treatment and no recurrence
20
within 30 days). Investigators found that ridinilazole had superior SCR compared to
21
vancomycin (SCR of 66.7% vs. 42.4%) with a treatment difference of 21.1% (90% CI
22
3.1 to 39.1; p=0.0004). RecR was evaluated as a secondary endpoint in patients who
23
were considered to have obtained clinical cure. Recurrence was noted in 14.3% of the
24
ridinilazole recipients versus 34.8% of the vancomycin recipients with an overall
1
treatment difference of -16.2% (90% CI -35.5 to 3.0) (See Results in Supplemental
2
Material Table 1).
3 4
In conclusion, ridinilazole may have potential as a novel agent for CDI management;
5
however, the small sample size of its phase II study limits generalization of its
6
efficacy and safety. Two ongoing phase III trials (NCT03595553 and NCT03595566)
7
will define its role in rCDI management.
8 9 10 11
Bezlotoxumab is a human monoclonal antibody which binds C. difficile toxin B with high
12
affinity, thereby preventing toxin from binding to host cells. In comparison to other agents
13
that are focused on treatment of established rCDI, bezlotoxumab is the only therapy
14
specifically FDA approved for rCDI prevention in patients being treated for primary CDI
15
with standard-of-care antibiotics.
c. Bezlotoxumab
16 17
The phase II trial found that combined actoxumab (a monoclonal antibody binding toxin A)
18
and bezlotoxumab had a significantly lower RecR compared to placebo (7% vs 25%,
19
p<0.001) (34). Two phase III RCTs (MODIFY I and II; results are described in
20
Supplemental Material Table 1) demonstrated that bezlotoxumab was associated with a
21
significantly lower rCDI rate for subjects over 18 years old who were treated with standard
22
of care antibiotics (35). The combination of actoxumab to bezlotoxumab did not confer any
23
further benefit in preventing recurrence.
24
1
A cost-effectiveness study found that bezlotoxumab, by preventing rCDI, led to a gain of
2
0.12 QALYs (equivalent to 43.8 more days of health) in a subject treated for primary CDI
3
compared to standard treatment. The cost of $19,824 per QALY gained is below the
4
standard willingness-to-pay threshold ($50,000/QALY), making the medication likely cost-
5
effective (36).
6 7 8 9 10 11
4- Bacteriotherapy a. Spores: SER-109 SER-109 is a spore therapy with a composition of approximately 50 species of
12
Firmicutes spores (Gram-positive microorganisms, including Clostridia and Bacilli)
13
derived from the stool of healthy donors. Its mechanism of action relies on metabolic
14
competition between spore-forming microorganisms and C. difficile.
15 16
In an open-label study, two doses of SER-109 were compared in two cohorts (15
17
patients each). The primary outcome was absence of CDI during an 8-week follow-up
18
period (37). The majority (86.7%) of the study population met the primary outcome.
19
There was no difference in prevention of rCDI noted between the cohorts
20
(Supplemental Material Table 2).
21 22
The results of an unpublished phase II clinical trial [(NCT02437487); results available
23
on clinicaltrials.gov)] which compared effects of SER-109 versus placebo on rCDI
24
prevention showed a non-significant difference in RecR within 8 weeks between the
25
SER-109 and placebo group (44.1% vs 53.3%, p=0.5018) (38). However, the small
1
sample size in both groups (59 subjects receiving SER-109 and 30 subjects receiving
2
placebo) may have underpowered the study.
3 4
Additionally, two phase III RCTs (NCT03183128 and NCT03183141) are currently
5
recruiting subjects to demonstrate the superiority of SER-109 compared to placebo for
6
rCDI prevention. In these trials, the SER-109 dose is four capsules four times a day for
7
three consecutive days and the primary outcome is the RecR within 8 weeks after
8
treatment. In conclusion, the role of SER-109 role in CDI management is still under
9
investigation.
10 11 12 13
b. Spores: Non-toxigenic Clostridium difficile (NTCD) NTCD strains are found in hospital settings colonizing inpatients, but they do not cause
14
clinical disease due to the lack of genes for toxin production. NTCD, specifically the
15
NTCD-M3 strain, has sparked attention for potential use as a preventive therapy for
16
CDI. It is hypothesized that NTCD competes with toxigenic C. difficile for the same
17
metabolic or adherence niche in the gastrointestinal tract, though the mechanism of
18
action has not been fully elucidated.
19 20
One phase II study which randomized 173 patients into three treatment groups of
21
different doses established the safety and tolerability of NTCD-M3 compared to
22
placebo for prevention of rCDI (39). CDI RecR within 6 weeks of the treatment period
23
showed NTCD-M3 had lower RecR compared to placebo (11% versus 30%, p=0.03).
24
However, when examined by dose, only the NTCD-M3 dose of 107 spores/day for 7
1
days demonstrated a significant decrease in the RecR compared to placebo (5% versus
2
30%; See Supplemental Material Table 2).
3 4
These findings suggest that NTCD-M3 at a dose of 107 spores/day for 7 days could be
5
an effective therapy to diminish CDI RecR. However, the small sample size of
6
investigations to date and the unknown duration of action of NTCD-M3 strain
7
colonization leave lingering questions and call for a phase III trial comparing NTCD-
8
M3 with placebo. A suggested primary endpoint of this phase III trial could be
9
recurrence of CDI within 12 weeks after infusion as this would allow for comparison
10
with bezlotuxumab, which was evaluated at that same interval during previous clinical
11
trials.
12 13 14 15 16 17
c. Fecal microbiota transplantation (FMT) i. First, second and multiple recurrences: FMT is the infusion of healthy fecal microbiota (donor) into a disrupted microbiome
18
(recipient) in order to restore its integrity and functionality to treat and prevent
19
recurrent CDI.
20 21
The 2017 IDSA Clinical Practice Guidelines recommend FMT for multiply rCDI, but
22
not for use in the first or second episode of rCDI due to lack of evidence to support its
23
use in these settings (2). A recent systematic review affirmed the efficacy of FMT in
24
non-responsive or recurrent CDI (Relative risk=0.41, 95% CI: 0.22-0.74, p<0.004)
25
(40), but further evaluation is needed regarding the role of FMT for first and second
1
recurrences of CDI. Ongoing trials (NCT03548051 and NCT03548051) are assessing
2
the safety and efficacy of FMT in patients with rCDI.
3 4 5 6 7 8
ii. Rebiotix (RBX2660) RBX2660 is a manufactured microbiota suspension prepared from stool of a healthy
9
donor. It is a commercially prepared product for FMT use; each dose contains a 150
10
mL suspension of ≥107 live microorganisms per mL and is packed in an enema bag. It
11
requires frozen storage at -80°C until thawing prior to administration.
12 13
Two phase II clinical trials were performed to determine the efficacy and safety of
14
this novel bacteriotherapy (41,42). In the first open-label clinical trial, an overall
15
efficacy in CDI-associated diarrhea resolution at 8-weeks of 87.1% for RBX2660 was
16
noted, with greater efficacy in the group that received two doses of RBX22660
17
(Supplemental Material Table 2). A second RCT found that one-dose of RBX22660
18
was superior to placebo for prevention of CDI at 8 weeks following treatment (RecR:
19
67% vs. 45%, p=0.048), but two doses were not (RecR: 61% vs. 45, p=0.152). It is
20
worth noting that the first study did not include a placebo control group and its
21
primary objective was product-related adverse events, which make the results
22
difficult to compare with other studies. Given differing results in the Phase II studies,
23
the role of RBX2660 in rCDI management remains uncertain, however an ongoing
24
phase III clinical trial (NCT03244644) may help clarify its efficacy.
25
1 2 3
iii. Oral FMT: OpenBiome Oral FMT is a per os treatment for rCDI; oral administration avoids the complications
4
of infusion via upper endoscopy or colonoscopy and also decreases the cost of
5
therapy. This bacteriotherapy is given as capsules of frozen fecal material, which
6
remain stored at -80°C prior to administration.
7 8
Two cohort studies have shown that oral FMT has an overall clinical resolution rate
9
of 90%, though resolution rate after a single dose is only 70-82% (43,44). Despite
10
favorable outcomes comparable with previous RCTs of FMT, it is worth noting the
11
lack of a control group or randomization in these cohort studies. Further randomized
12
control trials are needed to accurately determine the role of oral FMT in rCDI.
13 14
OpenBiome is a non-profit organization that operates a stool bank for FMT. It has
15
improved accessibility to fecal microbiota by maintaining a standardized preparation
16
of frozen stool from healthy donors for FMT (45).
17 18
In conclusion, oral FMT, currently accessible only via OpenBiome, is an effective
19
treatment for subjects with rCDI, but future RCTs are still required to incorporate
20
control groups such as placebo or standard treatment arms.
21 22
5- Future directions
23
Novel therapies for the management of recurrent C. difficile are currently under development.
24
The current pipeline includes a novel antibiotic ridinilazole (poised to enter phase III
25
development in 2019), several bacteriotherapy products, non-toxigenic C. difficile products and a
1
preventive therapy, DAV-132 (NCT03710694), which seeks to protect the gut microbiome
2
against intestinal dysbiosis related to antibiotic treatment. Furthermore, VE-303 (NCT03788434)
3
appears to be a promising preventive therapy for rCDI, which is a defined bacteriotherapy
4
seeking for restoring colonization resistance against gut pathogens, including C. difficile. With
5
multiple active studies underway, the new horizon of rCDI preventative therapies hinges on the
6
prevention and restoration of intestinal dysbiosis, seeking to disrupt this critical step in C.
7
difficile pathogenesis.
8 9 10
Funding:
11 12
This paper was not funded.
13 14
Disclosure of interest:
15
Monica V. Mahoney was on the advisory board of Tetraphase Pharmaceuticals Inc. and Spero
16
Therapeutics; received speaker fees from Tetraphase Pharmaceuticals Inc., and research funding
17
from Merck.
18
Ciaran P. Kelly was a scientific advisor for Artugen, Facile Therapeutics, First Light
19
Biosciences, Finch, Merck and Vedanta); received speaker fees from Biocodex, Matrivax, Merck
20
and Seres Health and research grants (to BIDMC) from the National Institutes of Health (NIAID
21
R01 AI116596, R01AI132711, U19 AI 109776), Institut Merieux and Merck.
1
Carolyn D. Alonso was a scientific advisor for Merck and Roche. Dr. Alonso has received
2
research funding from Merck and has NIH Loan Repayment Funding through the National
3
Institute of Allergy and Infectious Diseases (NIAID). Dr. Alonso has been involved in research
4
studies funded by Astellas and Vedanta Biosciences.
5
The other authors do not have any conflicts of interest associated with this publication.
6
6- References
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Tables a) Table N 1: Comparison of guidelines for management for recurrent Clostridioides difficile infection (rCDI).
Recurrent C. difficile Infection
2013 ACG •
First recurrence
•
Same regimen as the • initial episode for 1014 days (Vancomycin PO • 125mg qid OR Metronidazole PO 500mg tid) • Severe cases: Vancomycin PO 125mg qid for 10-14 days
2014 ESCMID Fidaxomicin PO 200mg bid for 10 days Vancomycin PO 125 mg qid for 10 days OR Metronidazole PO 500mg tid for 10 days
2017 IDSA
2016 Australasian •
Vancomycin 125mg PO qid for 10 days
•
•
•
Vancomycin PO 125mg qid for 10 days (if received metronidazole for first episode) Tapered and/or pulsed vancomycin (if received standard vancomycin for first episode) OR Fidaxomicin 200mg bid for 10 days (if received standard vancomycin for first episode)
•
Fidaxomicin PO • Vancomycin PO 125 • Tapered and/or 200mg bid for 10 qid for 14 days +/pulsed vancomycin days OR vancomycin taper OR • • Vancomycin PO 125 • Fidaxomicin 200mg • Vancomycin PO mg qid for 10 days bid for 10 days 125mg qid for 10 followed by pulsed days followed by • Fecal microbiota a regimen (125rifaximin 400mg tid transplantation 500mg/day every 2-3 • Rifaximin chaser for 20 days OR days) for at least 3 • Fidaxomicin PO (following PO Second or multiple weeks OR 200mg bid for 10 vancomycin) recurrences • Vancomycin PO 125 days OR mg qid for 10 days • Fecal microbiota followed by taper transplantation b regimen (gradually decrease of the dose to 125 mg/day). • Fecal microbiota transplantationa following PO vancomycin. a Treatment recommendation for multiple rCDI (2 or more recurrence episodes). b Treatment is recommended for patients with multiple (at least 2 episodes) of rCDI, who have failed appropriate antibiotic therapy. 2nd recurrence: Tapered and/or pulsed vancomycin 3rd and beyond recurrences: Fecal microbiota transplantationa
•
b) Table N 2: Prophylaxis for C. difficile infection Agent (Reference) Vancomycina (12-19)
Population (N) Patients 18 years or older who experienced a primary or recurrent CDI and subsequently had a course of antibiotics (not for CDI) (n=551) Patients 18 years or older with CDI confirmed by stool PCR, with subsequent hospitalization receiving systemic antibiotics (n=203) Patients ≥18 years with a kidney transplant with h/o CDI and received broad spectrum antibiotics (n=36) Patients ≥18 years with lung transplantation (n=636)
Patients ≥18 years with a primary or recurrent CDI and subsequently received broad spectrum antibiotics (n=760)
Patients ≥18 years with allogeneic HSCT admitted as inpatients (n=145) Patients ≥18 years with a
Intervention (N) Vancomycin 125mg qid (n=227)
Comparison (N) No intervention (n=324)
Outcome AHR: -rCDI: 0.47 (95% CI: 0.32-0.69, p<0.0001). -Primary CDI: 0.91 (95% CI: 0.57-1.45, p=0.68)
Vancomycin 125mg PO bid (n=29) Vancomycin 250mg bid (n=42)
No intervention (n=132)
CDI incidence: 4.2% vs 26.6% (p<0.001)
Vancomycin 125 mg PO bid > 48 hr (n=12)
No intervention (n=24)
RecR: 0% vs. 8% (p=0.54)
Vancomycin PO 2-4 times daily (n=82)
No intervention (n=554)
CDI rate: 1% vs. 6% (p=0.059)
No intervention (n=567)
RecR: 9.8% vs. 9.4% at 90 days [Adjusted OR 0.63 (95% CI 0.35-1.14)]
Median dose: 125mg PO bid Vancomycin PO (dose not specified) (n=193)
Vancomycin 125 mg PO bid (n=90)
No intervention (n=55)
Vancomycin 125 mg PO
No intervention (n=59)
RecR: 11.4% vs. 9.5% at 180 days [Adjusted OR 0.72 (95% CI 0.41-1.29)] CDI rate: 0% vs. 20% (p<0.001) RecR: 6.3% vs. 28.8%
Fidaxomicinb (20)
Metronidazolec (21)
primary or recurrent CDI and received broad spectrum antibiotics (n=91) Patients ≥18 years with HSCT or hematologic malignancy with primary CDI receiving broad spectrum antibiotics (n=50) Patients18 years or older undergoing HSCT and planned fluoroquinolone prophylaxis (n=600)
qid (n=10)
Inpatients between 55 and 75 years of age receiving at least one broadspectrum antibiotic (n=96) Patients 18 years or older diagnosed with CDI who received concomitant antibiotics for other reasons (n=228)
Vancomycin 250 mg PO qid (n=22) Vancomycin 125 mg PO bid (n=21)
(OR 0.16, 95% CI 0.040.77, p=0.01)
No intervention (n=29)
RecR: 5% vs. 35% (p=0.016)
Fidaxomicin 200mg qd (n=301)
Placebo (n=299)
Metronidazole 500mg tid for 7 days (n=41)
Observation (n=55)
-CDI incidence: 4.3% vs. 10.7% (p=0.0014) -Composite outcome d: 28.6% vs. 30.8% (p=0.278) CDI rate: 0% vs. 9.1% (OR 0.91, 95% CI 0.840.99, p=0.069)
Extended-CDI treatment: Metronidazole or vancomycin for >14 days (n=127)
Regular CDI treatment: Metronidazole or vancomycin for 10-14 days (n=101)
- RecR: 23% vs. 17%, (OR:0.7, 95% CI 0.3-1.7, p=0.425) - Composite outcome e: 35% vs. 23% (OR:1.2, 95% CI 0.6-2.5, p=0.648) Abbreviations: PCR: polymerase chain reaction, CDI: C. difficile infection, rCDI: recurrent C. difficile infection, HSCT: Hematopoietic stem cell transplantation, AHR: adjusted hazard ratio, RecR: recurrence rate, OR: odd ratio. a Retrospective study, b Randomized controlled trial, c Randomized open-label study, d Composite outcome (Prophylaxis failure): confirmed CDI, receipt of CDI-effective medications (for any indication), and missing CDI assessment (for any reason, including death), e Composite outcome: Inhospital mortality and/or CDI relapse. Extended-CDI treatmenta (22)
1- Box Box 1: Commonly measured outcomes in C. difficile infection research •
•
• • • •
Clinical cure rate (CCR): Resolution of diarrhea (<3 unformed bowel movement/day for at least 2 days) on study treatment and maintained for 2 days after the end-oftreatment (18,19,22). Sustained clinical cure rate (SCR): percentage of subjects with sustained cure, which is defined as clinical cure with no recurrence (22-24). Recurrence rate (RecR): Reappearance of >3 unformed bowel movements/day within 4 weeks after end-of-treatment (18,19,22). Time to diarrhea resolution Absence of C. difficile positive diarrhea Number of daily bowel movements
2- Figure Figure 1: Management of recurrent C. difficile infection. Initial episode: received metronidazole First recurrencef Initial episode: received standard vancomycin
Standard vancomycina (2,9,10) Tapered and/or pulsed vancomycinb (2,8) Fidaxomicinc (2,9)
NEW ONSET OF SYMPTOMS OF CDI AFTER A PRIMARY EPISODE
Tapered and/or pulsed vancomycin (2,7-10)
Second or multiple recurrencesf
Standard vancomycin plus rifaximind (2,10) Fidaxomicin (2,9,10) Fecal microbiota transplantatione (2,810)
a
Standard vancomycin: 125mg PO qid for 10 days Tapered and pulsed vancomycin: 125mg PO qid for 10 days 125mg PO bid for 7 days 125mg PO daily for 7 days 125mg PO every 2-3 days for 2-8 weeks. c Fidaxomicin: 200mg PO bid for 10 days d Standard vancomycin plus rifaximin: Vancomycin 125mg PO qid for 10 days followed by rifaximin 400mg tid for 20 days. e Only for multiple recurrences of C. difficile infection f After treatment completion, clinician could consider adjunctive bezlotoxumab as a preventive therapy. b
Recent Developments in the Management of Recurrent Clostridioides difficile Infection Highlights: •
Recurrent C. difficile infection (rCDI) remains a significant concern due to its high morbidity and mortality.
•
We evaluate the current management proposed on the 2017 IDSA guideline and compare with the previous guidelines (2016 Australasian Society of Infectious Diseases Updated Guidelines, 2014 ESCMID Guidelines, 2013 ACG Guidelines, and 2010 IDSA Guidelines).
•
We review the outcomes of the ongoing trials related to novel antibiotics and bacteriotherapy.
•
Bezlotoxumab has proven effectiveness for the prevention of rCDI.