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IDSA GUIDELINES
This clinical practice guideline is a focused update on management of Clostridioides difficile infection (CDI) in adults specifically ad-
dressing the use of fidaxomicin and bezlotoxumab for the treatment of CDI. This guideline was developed by a multidisciplinary panel
representing the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA).
This guideline is intended for use by healthcare professionals who care for adults with CDI, including specialists in infectious diseases,
gastroenterologists, hospitalists, pharmacists, and any clinicians and healthcare providers caring for these patients. The panel’s recom-
mendations for the management CDI are based upon evidence derived from topic-specific systematic literature reviews. Summarized
below are the recommendations for the management of CDI in adults. The panel followed a systematic process which included a
standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach
(Grading of Recommendations Assessment, Development, and Evaluation). A detailed description of background, methods, evidence
summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text.
Keywords. Clostridioides difficile; guidelines; CDI.
I. IN PATIENTS WITH AN INITIAL CLOSTRIDIOIDES II. IN PATIENTS WITH RECURRENT CDI EPISODE(S),
DIFFICILE INFECTION EPISODE, SHOULD SHOULD FIDAXOMICIN BE USED RATHER THAN
FIDAXOMICIN BE USED RATHER THAN VANCOMYCIN?
VANCOMYCIN?
Recommendation:
Recommendation:
1. In patients with recurrent CDI episodes, we suggest
1. For patients with an initial Clostridioides difficile in- fidaxomicin (standard or extended-pulsed regimen) rather than
fection (CDI) episode, we suggest using fidaxomicin rather a standard course of vancomycin (conditional recommendation,
than a standard course of vancomycin (conditional recom- low certainty evidence). Comment: Vancomycin in a tapered
mendation, moderate certainty of evidence). Comment: This and pulsed regimen or vancomycin as a standard course are
recommendation places a high value in the beneficial effects acceptable alternatives for a first CDI recurrence. For patients
and safety of fidaxomicin, but its implementation depends with multiple recurrences, vancomycin in a tapered and pulsed
upon available resources. Vancomycin remains an acceptable regimen, vancomycin followed by rifaximin, and fecal micro-
alternative. biota transplantation are options in addition to fidaxomicin.
Clinical Practice Guidelines for C. difficile Infection • cid 2021:73 (1 September) • e1029
co-intervention along with standard-of-care (SOC) anti- recommendation for use of fecal microbiota transplantation
biotics rather than SOC antibiotics alone (conditional rec- (FMT) has not been changed, it should be noted that 3 sepa-
ommendation, very low certainty of evidence). Comment: rate safety alerts have been published by the U.S. Food and
This recommendation places a high value on potential clin- Drug Administration (FDA) since June of 2019, which out-
ical benefits, but implementation is often limited by fea- line adverse events or potential adverse events among recipi-
sibility considerations. In settings where logistics is not an ents of FMT. Two alerts document transmission of pathogenic
issue, patients with a primary CDI episode and other risk Escherichia coli from donor to FMT recipients, some of whom
factors for CDI recurrence (such as age ≥65 years, immuno- became ill and some of whom died [3–5]. The other alert con-
compromised host [per history or use of immunosuppressive cerns the potential for transmission of severe acute respiratory
therapy], and severe CDI on presentation) may particularly syndrome coronavirus 2 (SARS-CoV-2) [6]. As a reminder,
benefit from receiving bezlotoxumab. Data on the use of FMT is recommended only for patients with multiple recur-
bezlotoxumab when fidaxomicin is used as the SOC antibi- rences of CDI who have failed appropriate antibiotic treatments
otic are limited. The Food and Drug Administration warns and where appropriate screening of donor and donor fecal spe-
Clinical Pre-
sentation Recommended and Alternative Treatments Comments
Initial CDI Preferred: Fidaxomicin 200 mg given twice daily for 10 days Implementation depends upon available
episode resources
Alternative: Vancomycin 125 mg given 4 times daily by mouth for 10 days Vancomycin remains an acceptable alternative
Alternative for nonsevere CDI, if above agents are unavailable: Metronida- Definition of nonsevere CDI is supported by
zole, 500 mg 3 times daily by mouth for 10–14 days the following laboratory parameters: White
blood cell count of 15 000 cells/µL or lower
and a serum creatinine level <1.5 mg/dL
First CDI re- Preferred: Fidaxomicin 200 mg given twice daily for 10 days, OR twice …
currence daily for 5 days followed by once every other day for 20 days
Alternative: Vancomycin by mouth in a tapered and pulsed regimen Tapered/pulsed vancomycin regimen example:
125 mg 4 times daily for 10–14 days, 2
times daily for 7 days, once daily for 7 days,
and then every 2 to 3 days for 2 to 8 weeks
Disclosure and Management of Potential Conflicts of Interest disclosures is reviewed. See the Notes section at the end of this
All members of the expert panel complied with the IDSA policy guideline for the disclosures reported to IDSA.
on conflicts of interest (COIs), which requires disclosure of
any financial, intellectual, or other interest that might be con- Clinical Questions and Evidence Review
strued as constituting an actual, potential, or apparent conflict. The last iteration of the clinical practice guideline for
Evaluation of such relationships as potential COIs was deter- Clostridium difficile infection in adults and children was com-
mined by a review process, which included assessment by the pleted late 2017 and published in Clinical Infectious Diseases in
SPGC Chair, the SPGC liaison to the Guideline panel, and the early 2018 [1]. By the time of its publication and dissemination,
Board of Directors liaison to the SPGC, and if necessary, the new relevant evidence had emerged, which could either change
COI Ethics Committee. This assessment of disclosed relation- the current recommendations presented in the 2017 guideline
ships for possible COIs was based on the relative weight of the or require the development of new recommendations on topics
financial relationship (ie, monetary amount) and the relevance not previously addressed. Consequently, a list of relevant clin-
of the relationship (ie, the degree to which an independent ob- ical questions for this focused update was created, reviewed,
server might reasonably interpret an association as related to and approved by the panel.
the topic or recommendation of consideration). The reader As per the GRADE approach, all outcomes are not con-
of these guidelines should be mindful of this when the list of sidered equally important in the decision-making process.
Clinical Practice Guidelines for C. difficile Infection • cid 2021:73 (1 September) • e1031
These need to be ranked by importance to permit weighing the reference lists, regulatory agency websites for relevant informa-
balance of desirable and undesirable consequences and thus tion, as well as communicating with study sponsors for post
providing guidance on the optimal course of action as well as hoc analysis.
to determine the certainty of evidence for a specific recom- A subgroup of panelists (K. W. G., A. J. G.-L., S. J., A. M. S.)
mendation. Outcomes of interest were identified a priori by screened titles and abstracts of all identified citations. All po-
the panel and their relative importance for decision making tentially relevant citations were subjected to a full-text review,
(either “critical,” “important but not critical,” or “of limited im- using predefined inclusion and exclusion criteria that were tai-
portance”) was explicitly determined by voting for each PICO lored to meet the specific population, intervention, and com-
question. Critical and important outcomes (presented in their parator of each clinical question. Abstracts and conference
respective Summary of Findings Tables [Tables 2, 3 and 4]) were proceedings, letters to the editor, editorials, review articles, and
those that ultimately provided guidance on the optimal course unpublished data were excluded. The results of the literature
of action. Resource use (monetary costs and cost-effectiveness, search were supervised and thoroughly reviewed by the guide-
for example) was rated as “of limited importance” by the panel line methodologist for the final selection of the relevant articles.
Table 2. Summary of Findings Table, PICO 1: “In Patients With an Initial CDI Episode, Should Fidaxomicin Be Used Rather Than Vancomycin?”
No. of Partici- Certainty of the Relative Effect, RR Risk With Risk Difference With
Outcomes (Follow-up) pants (Studies) Evidence (GRADE) (95% CI) Vancomycin Fidaxomicin (95% CI)
Sustained response of CDI (fol- 1673 (4 RCTs) ⊕⊕⊕◯ 1.16 (1.09 to 1.24) 631 per 1000 101 more per 1000 (57
low-up: 4 weeks after EOT) [14–17] Moderatea,b more to 151 more)
CDI initial clinical curec (fol- 1673 (4 RCTs) ⊕⊕⊕◯ 1.00 (.96 to 1.04) 856 per 1000 0 fewer per 1000 (34
low-up: 2 days after EOT) [14–17] Moderatea,b,d fewer to 34 more)
Drug-related adverse events 1721 (4 RCTs) ⊕⊕◯◯ 1.02 (.76 to 1.36) 95 per 1000 2 more per 1000 (23
(follow-up: 4 to 12 weeks) [14–17] Low a,b,e fewer to 34 more)
All-cause mortality (follow-up: 1721 (4 RCTs) ⊕⊕⊕◯ .90 (.66 to 1.23) 87 per 1000 9 fewer per 1000 (30
4 to 12 weeks) [14–17] Moderatea,b,e fewer to 20 more)
Abbreviations: CI, confidence interval; EOT, end of therapy; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; PICO, Patient/Population, Intervention/
Indicator, Comparator/Control, Outcome; RCT, randomized controlled trial; RR, risk ratio; SOC, standard of care.
a
Despite many subgroup analyses without prior stratification of the randomization reported in the study, Cornely et al (2012) [15] and Louie et al (2011) [14] were not considered at high risk of
bias since the complete modified intention-to-treat population was used in our analysis. The Guery et al (2018) [16] study was at high risk of bias for self-reported outcomes due to potentially
inadequate blinding. Guery et al (2018) and Mikamo et al (2018) [17] were considered at unclear risk of bias for possible attrition bias (significant loss to follow-up for the primary endpoint
with imputation of missing data with failure for sustained clinical response).
b
Not rated down for indirectness since patients with an initial CDI episode represented most patients included in the 4 reported (between 80% and 85%).
c
Initial clinical cure was defined as no diarrhea for 2 consecutive days after completion of SOC antibiotic therapy administered for ≤16 days.
d
Outcome determined as the primary endpoint in Cornely et al (2012) [15] and Louie et al (2011) [14] (while Mikamo et al (2018) [17] used global cure rate). Not rated down for imprecision,
based on their prespecified margin of noninferiority of −10% (1-sided lower 97.5% CI).
e
The 95% CI includes the potential for both appreciable benefit as well as appreciable harm (ie, includes the null value) and few events reported do not meet the optimal information size.
No. of Partici- Certainty of the Relative Effect, Risk With Risk Difference With
Outcomes (Follow-up) pants (Studies) Evidence (GRADE) RR (95% CI) Vancomycin Fidaxomicin (95% CI)
Sustained response of CDI (fol- 253 (3 RCTs) ⊕⊕◯◯ 1.27 (1.05 to 558 per 151 more per 1000 (from
low-up: 30 days after EOT) [14–16] Lowa,b 1.54) 1000 34 more to 269 more)
Sustained response of CDI (fol- 75 (1 RCT) [16] ⊕◯◯◯ 1.56 (.99 to 410 per 229 more per 1000 (9
low-up: 90 days after EOT) Very lowa,c 2.44) 1000 more to 449 more)
CDI initial clinical cured (fol- 253 (3 RCTs) ⊕⊕◯◯ 1.03 (.94 853 per 26 more per 1000 (58
low-up: 2 days after EOT) [14–16] Lowa,e to1.14) 1000 fewer to 110 more)
Serious adverse events (fol- 75 (1 RCT) [16] ⊕◯◯◯ .68 (.35 to 410 per 132 fewer per 1000 (from
low-up: 90 days) Very lowa,f 1.29) 1000 345 fewer to 80 more
All-cause mortality (follow-up: 75 (1 RCT) [16] ⊕⊕◯◯ .81 (.20 to 103 per 19 fewer per 1000 (from
90 days) Lowf 3.38) 1000 150 fewer to 112 more)
Abbreviations: CI, confidence interval; EOT, end of therapy; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; PICO, Patient/Population, Intervention/
undesirable outcomes and the certainty in the evidence) and and edited as appropriate. The final evidence summaries were
the Evidence to Decision frameworks (summarizing the other presented to the whole panel for deliberation and drafting of
key factors considered when developing the recommenda- recommendations. Literature search strategies, Evidence Profile
tions such as values and preferences, resource use, equity, ac- tables, Evidence to Decision frameworks, and additional data,
ceptability, and feasibility) were developed in the GRADEpro such as forest plots and characteristics of included studies when
Guideline Development Tool [13] and reviewed by the Chair appropriate, can be found in the Supplementary Materials.
Table 4. Summary of Findings Table, PICO 3: “In Patients With a CDI Episode, Should Bezlotoxumab be Used as a Co-Intervention Along With Standard-
of-Care Antibiotics Rather Than Standard-of-Care Antibiotics Alone?”
No. of Partici- Certainty of the Relative Effect, Risk With SOC Risk Difference With Bezlotoxumab
Outcomes (Follow-up) pants (Studies) Evidence (GRADE) RR (95% CI) Antibiotics + SOC Antibiotics (95% CI)
CDI recurrence after ICC a 1246 (1 RCT) ⊕⊕⊕◯ .62 (.51 to .75) 326 per 1000 125 fewer per 1000 (174 fewer to
(follow-up: 12 weeks) [18] Moderateb,c 77 fewer)
CDI-associated hospital read- 1050 (1 RCT) ⊕◯◯◯ .46 (.29 to .71) 112 per 1000 61 fewer per 1000 (93 fewer to 28
mission (follow-up: 30 days) [19] Very lowc,d,e fewer)
Drug-related adverse events 1567 (1 RCT) ⊕⊕◯◯ 1.27 (.88 to 59 per 1000 16 more per 1000 (9 fewer to 41
(follow-up: 4 weeks) [18] Low b,c,f 1.85) more)
All-cause mortality (follow-up: 1567 (1 RCT) ⊕⊕◯◯ .94 (.66 to 76 per 1000 4 fewer per 1000 (30 fewer to 22
12 weeks) [19] Low b,c,f 1.34) more)
Abbreviations: CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; ICC, initial clinical cure; PICO, Patient/Population, Intervention/
Indicator, Comparator/Control, Outcome; RCT, randomized controlled trial; RR, risk ratio; SOC, standard of care.
a
Recurrent CDI after ICC was defined as a new episode of C. difficile infection after initial clinical cure of the baseline episode.
b
Despite many subgroup analyses without prior stratification of the randomization reported in the study, it was not considered at high risk of bias for this outcome since the complete mod-
ified intention-to-treat population was included in our analysis.
c
Rated down for indirectness due to concerns on the generalizability of the evidence to current practice: SOC antibiotics received in Wilcox et al (2017) [18] study were as follows: 46.7%
of patients received metronidazole, 47.7% received vancomycin, and only 3.6% received fidaxomicin; SOC antibiotics in current practice now include fidaxomicin and vancomycin, but not
metronidazole.
d
Rated down for risk of bias due to subgroup analysis addressing patients who were inpatients at the time of the randomization (post hoc analysis for prespecified risk factors without
stratified randomization).
e
Few events reported do not meet the optimal information size and suggest fragility of the estimate.
f
The 95% CI includes the potential for both appreciable benefit as well as appreciable harm (ie, includes the null value) and few events reported do not meet the optimal information size.
Clinical Practice Guidelines for C. difficile Infection • cid 2021:73 (1 September) • e1033
Development of Clinical Recommendations implicitly referred to as “not using the intervention.” “Research
All recommendations were labeled as either “strong” or “con- Needs” were noted for recommendations as deemed appro-
ditional” according to the GRADE approach [8]. The words priate by the panel.
“we recommend” indicate strong recommendations and “we Final presentation of evidence summaries and the develop-
suggest” indicate conditional recommendations. Figure 1 pro- ment of the recommendations was performed by 2 conference
vides the suggested interpretation of strong and conditional calls with the whole expert panel on 22 and 26 June 2020. All
recommendations for patients, clinicians, and healthcare members of the panel participated in the preparation of the
policymakers. In summary, a “strong” recommendation im- draft guideline and approved the recommendations.
plies that most individuals in this situation would want the
recommended course of action and only a small proportion Revision Process
would not, while a “conditional” recommendation means that Feedback was obtained from 3 external peer reviewers. The
the majority of individuals in this situation would want the IDSA Standards and Practice Guidelines Committee and Board
suggested course of action but many would not. The latter of Directors and the Society for Healthcare Epidemiology of
Figure 1. Approach and implications to rating the quality of evidence and strength of recommendations using the GRADE methodology. Unrestricted use of the figure
granted by the US GRADE Network. Abbreviation: GRADE, Grading of Recommendations Assessment, Development, and Evaluation.
Clinical Practice Guidelines for C. difficile Infection • cid 2021:73 (1 September) • e1035
Downloaded from https://academic.oup.com/cid/article/73/5/e1029/6298219 by guest on 31 January 2022
Figure 2. PRISMA flow diagram, PICOs 1 and 2 on the use of fidaxomicin vs vancomycin for initial or recurrent episode of CDI. Abbreviations: CDI, Clostridioides difficile
infection; PICO, Patient/Population, Intervention/Indicator, Comparator/Control, Outcome; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Rationale for Recommendation that the use of fidaxomicin is likely cost-effective, acceptable
The panel agrees that the overall balance of benefits and to patients and their providers, and feasible to implement
harms favors using fidaxomicin over vancomycin for an in- when considering the dosing and duration of fidaxomicin
itial episode of CDI and that the certainty of evidence was treatment.
moderate (see Supplementary Materials). Although the Achieving both initial and sustained clinical responses are
panel recognizes potential variability exists on how patients key goals of CDI therapy. The observed lower recurrence rates
value the avoidance of a subsequent CDI episode, the mod- following fidaxomicin therapy as compared with vancomycin
erate costs, and possible reduction in equity, the panel judges are an important advantage. Quality-of-life scores decrease
Clinical Practice Guidelines for C. difficile Infection • cid 2021:73 (1 September) • e1037
update identified a third RCT where information on patients and imprecise due to the very small number of patients ran-
experiencing recurrent CDI (≥1 recurrences) was available [16] domized (n = 20) [16] (see Supplementary Materials).
(see Figure 2). Randomization was stratified for the number of Evidence supporting an extended-pulsed regimen of
previous episode(s) of CDI in all 3 RCTs. Patients included in fidaxomicin comes from an in vitro human gut model study,
the Guery 2018 study (EXTEND trial) received an extended which showed persistence of fidaxomicin at the above in-
fidaxomicin regimen albeit amounting to the same total dose hibitory concentrations which might prolong suppression
of fidaxomicin as a standard course [16] (see Supplementary of C. difficile and facilitate recovery of a protective micro-
Materials). biota [33]. Indeed, this study provided the rationale for
The pooled analysis of the 3 included subgroups demon- the extended-pulsed fidaxomicin regimen that was used by
strates that fidaxomicin increased sustained response of CDI Guery et al [18]. Because fidaxomicin, like vancomycin, is
30 days after end of therapy compared with vancomycin (RR: minimally absorbed and achieves high fecal concentrations,
1.27; 95% CI: 1.05–1.54; low certainty evidence), while the ev- fidaxomicin in a tapered and pulsed regimen following sup-
idence failed to show a beneficial effect of fidaxomicin on sus- pressive treatment has been used successfully in patients
Clinical Practice Guidelines for C. difficile Infection • cid 2021:73 (1 September) • e1039
received one 60-minute intravenous infusion of bezlotoxumab vancomycin be given for more severe disease [39]. Following
(10 mg/kg body weight) in addition to SOC antibiotics (see these guideline recommendations, most patients received either
Supplementary Materials). metronidazole (47%) or oral vancomycin (48%) in the phase
The pooled analysis of these 2 RCTs demonstrates that the III bezlotoxumab clinical trials. However, based on decreasing
addition of bezlotoxumab reduced CDI recurrence after initial efficacy of metronidazole, SOC antibiotics now include vanco-
clinical cure at 12 weeks (RR: .62; 95% CI: .51–.75; moderate mycin and fidaxomicin in the updated 2017 IDSA-SHEA CDI
certainty evidence) and reduced CDI-associated hospital read- guidelines [1]. Despite planned subanalyses of the bezlotoxumab
mission at 30 days (RR: .46; 95% CI: .29–.71; very low certainty phase III trials demonstrating that the choice of SOC antibiotics
evidence), but failed to show a reduction in mortality (RR: .94; did not influence the effect on clinical outcomes, uncertainty
95% CI: .66–1.34; low certainty evidence). The certainty in the remains regarding the generalizability of this evidence when
evidence for benefits was initially rated as moderate, mainly fidaxomicin is used as the SOC antibiotic (fidaxomicin being
due to indirectness of the evidence when fidaxomicin is used as administered as the SOC antibiotic in <5% of the studied cohort
the SOC antibiotic (see Table 4). [n = 60 patients]) [19].
Figure 3. PRISMA flow diagram, PICO 3 on the use of bezlotoxumab as a cointervention along with standard of care. Abbreviations: PICO, Patient/Population, Intervention/
Indicator, Comparator/Control, Outcome; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Figure 4. Forest plot, PICO 3: Post hoc subgroup analysis of CDI recurrence after ICC (follow-up 12 weeks). Data published in Gerding et al, 2018 [19] (post hoc analysis
of Wilcox et al, 2017 [18]). Abbreviations: CDI, Clostridioides difficile infection; CI, confidence interval; ICC, initial clinical cure; M-H, Mantel-Haenszel test; PICO, Patient/
Population, Intervention/Indicator, Comparator/Control, Outcome; SOC, standard of care.
Clinical Practice Guidelines for C. difficile Infection • cid 2021:73 (1 September) • e1041
Figure 5. Forest plot, PICO 3: Post hoc subgroup analysis of CDI recurrence after ICC (follow-up 12 weeks). Data provided by company (Merck & Co., Inc.) through personal
communication with the guideline panel (post hoc analysis of Wilcox et al, 2017 [18]). Abbreviations: CDI, Clostridioides difficile infection; CI, confidence interval; ICC, initial
clinical cure; M-H, Mantel-Haenszel test; PICO, Patient/Population, Intervention/Indicator, Comparator/Control, Outcome; SOC, standard of care.
“implementation considerations” below), the moderate costs, recurrent CDI episode within the last 6 months but acknow-
and possible reduction in equity, the panel judges that patients’ ledges that implementing this recommendation also probably
values and preferences (especially for those experiencing re- reduces equity due to variation in medical insurance coverage.
Clinical Practice Guidelines for C. difficile Infection • cid 2021:73 (1 September) • e1043
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