Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults

Recommendation:

I. In patients with recurrent CDI episodes, we suggest fidaxomicin (standard or extended-pulsed regimen) rather than a standard course of vancomycin (conditional recommendation, low certainty evidence). Comment: Vancomycin in a tapered and pulsed regimen or vancomycin as a standard course are acceptable alternatives for a first CDI recurrence. For patients with multiple recurrences, vancomycin in a tapered and pulsed regimen, vancomycin followed by rifaximin, and fecal microbiota transplantation are options in addition to fidaxomicin.

III. 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?

I. For patients with a recurrent CDI episode within the last 6 months, we suggest using bezlotoxumab as a co-intervention along with SOC antibiotics rather than SOC antibiotics alone (conditional recommendation, very low certainty of evidence). Comment: This recommendation places a high value on potential clinical benefits, but implementation is often limited by feasibility considerations. In settings where logistics is not an issue, patients with a primary CDI episode and other risk factors for CDI recurrence (such as age ≥65 years, immunocompromised host [per history or use of immunosuppressive therapy], and severe CDI on presentation) may particularly benefit from receiving bezlotoxumab. Data on the use of bezlotoxumab when fidaxomicin is used as the SOC antibiotic are limited. The FDA warns that “in patients with a history of congestive heart failure (CHF), bezlotoxumab should be reserved for use when the benefit outweighs the risk.”

 

Background

Since publication of the 2017 Clinical Practice Guidelines for Clostridioides (formerly Clostridium) difficile infection (CDI) [1], new relevant evidence has emerged for treatment options in the management of CDI in adults. The previous guidelines included pediatric treatment recommendations, but the scope of this focused update is restricted to adults and includes new data for fidaxomicin and for bezlotoxumab, a monoclonal antibody targeting toxin B produced by C. difficile. Both of these agents have increased clinical efficacy and other advantages over older agents, but implementation may be challenging because of initial monetary cost and logistics. In addition, the shift towards more sensitive diagnostic strategies emphasizes the importance of selecting appropriate patient populations and establishing the correct diagnosis when considering the use of these agents. While additional data have been published for other treatment entities, the quality of the data was determined not sufficient to alter our current treatment recommendations. New estimates on the burden of CDI have also been reported by the Centers for Disease Control and Prevention [2]. While the adjusted estimate for total CDI burden nationally decreased by 24% from the previous report, they still estimated 462 100 cases annually and the burden of first CDI recurrences was unchanged. Recurrent CDI remains one of the most important treatment challenges for clinicians, with estimates of 31 300 and 38 500 recurrences for community-associated and healthcare-associated cases, respectively, in 2017 [2].

This focused update includes 3 new recommendations for the treatment of CDI in adults, 2 of which modify our previous recommendations on treatment of an initial CDI episode and treatment of a first recurrent CDI episode. The other recommendation is a new recommendation for use of an adjunctive treatment agent for CDI. These new recommendations are also included in an updated table from the previous guidelines (see Table 1, Recommendations for the Treatment of Clostridioides difficile Infection in Adults). While the previous recommendation for use of fecal microbiota transplantation (FMT) has not been changed, it should be noted that 3 separate safety alerts have been published by the U.S. Food and Drug Administration (FDA) since June of 2019, which outline adverse events or potential adverse events among recipients of FMT. Two alerts document transmission of pathogenic Escherichia coli from donor to FMT recipients, some of whom became ill and some of whom died [3–5]. The other alert concerns the potential for transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [6]. As a reminder, FMT is recommended only for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments and where appropriate screening of donor and donor fecal specimens has been performed, in accordance with these newer FDA recommendations [4, 5].

The purpose of this guideline is to provide evidence-based guidance on the most effective management of CDI and recurrent CDI in adult patients. The target audience for these guidelines includes general physicians, infectious diseases specialists, gastroenterologists, pharmacists, and other healthcare providers managing this condition.

Methodology

Clinical Practice Guidelines

Clinical Practice Guidelines are statements that include recommendations intended to optimize patient care by assisting practitioners and patients in making shared decisions about appropriate healthcare for specific clinical circumstances. These are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options [7]. The Infectious Diseases Society of America (IDSA) Handbook for Clinical Practice Guidelines Development provides more detailed information on the processes followed throughout the development of this guideline [8].

Guideline Panel Composition

The Chair of the Guidelines panel (S. J.) was selected by the IDSA Standards and Practice Guidelines Committee (SPGC). A total of 7 panelists comprised the full panel. The panel included physicians and pharmacists with expertise in infectious diseases, gastroenterology, pharmacy, medical microbiology, and epidemiology. Panelists also were diverse in gender, geographic distribution, and years of clinical experience. A guideline methodologist (V. L.) oversaw all methodological aspects of the guideline development and identified and summarized the scientific evidence using the “PICO” format (Patient/Population [P], Intervention/Indicator [I], Comparator/Control [C], Outcome [O]) questions. IDSA staff (Genet Demisashi, Rebecca Goldwater) oversaw all administrative and logistic issues related to the guideline panel.

Disclosure and Management of Potential Conflicts of Interest

All members of the expert panel complied with the IDSA policy on conflicts of interest (COIs), which requires disclosure of any financial, intellectual, or other interest that might be construed as constituting an actual, potential, or apparent conflict. Evaluation of such relationships as potential COIs was determined by a review process, which included assessment by the SPGC Chair, the SPGC liaison to the Guideline panel, and the Board of Directors liaison to the SPGC, and if necessary, the COI Ethics Committee. This assessment of disclosed relationships for possible COIs was based on the relative weight of the financial relationship (ie, monetary amount) and the relevance of the relationship (ie, the degree to which an independent observer might reasonably interpret an association as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. See the Notes section at the end of this guideline for the disclosures reported to IDSA.

Clinical Questions and Evidence Review

II. In Patients With Recurrent CDI Episode(s), Should Fidaxomicin Be Used Rather Than Vancomycin?

Background

As noted above, there is robust evidence supporting fidaxomicin treatment for patients with an initial episode of CDI. Recent additional studies have been identified that also support its use in recurrent CDI. Although optimal dosing regimens are still yet to be defined, fidaxomicin has pharmacologic characteristics that may favor use of this agent in the management of patients with recurrent CDI. With the understanding that risk of a subsequent recurrence increases with each episode of CDI, we continue to make a distinction between patients with a first CDI recurrence and those with multiple recurrences (≥2 recurrences) [30].

Summary of Evidence

The best available evidence identified to inform this recommendation consisted of subgroup analyses originating from 3 different RCTs [14, 15, 16]. The 2017 guideline discussed 1 study [31] reporting a pooled analysis of patient subgroups with a first CDI recurrence from 2 different RCTs comparing the efficacy of fidaxomicin with vancomycin [14, 15]. Our literature update identified a third RCT where information on patients experiencing recurrent CDI (≥1 recurrences) was available [16] (see Figure 2). Randomization was stratified for the number of previous episode(s) of CDI in all 3 RCTs. Patients included in the Guery 2018 study (EXTEND trial) received an extended fidaxomicin regimen albeit amounting to the same total dose of fidaxomicin as a standard course [16] (see Supplementary Materials).

The pooled analysis of the 3 included subgroups demonstrates that fidaxomicin increased sustained response of CDI 30 days after end of therapy compared with vancomycin (RR: 1.27; 95% CI: 1.05–1.54; low certainty evidence), while the evidence failed to show a beneficial effect of fidaxomicin on sustained response at 90 days (RR: 1.56; 95% CI: .99–2.44; very low certainty evidence). The use of fidaxomicin resulted in comparable CDI initial clinical cure (RR: 1.03; 95% CI: .94–1.14; low certainty evidence) but failed to show a reduction in all-cause mortality (RR: 0.81; 95% CI: .20–3.38; low certainty evidence). The evidence is very uncertain regarding the reduction in serious adverse events at 90 days with the use of fidaxomicin compared with vancomycin (RR: 0.68; 95% CI: 0.35–1.29; very low certainty evidence). The overall certainty in the evidence was rated as low due to serious concerns regarding imprecision (small number of events and small sample size of these subgroups) as well as risk of bias due to the unblinded design in the EXTEND trial (for self-reported outcomes) (see Table 3).

The previous iteration of the treatment guidelines included fidaxomicin as an option for treating recurrent CDI, although the preference for choosing fidaxomicin or vancomycin as treatment for patients with a first CDI recurrence was based solely on the treatment regimen given for the initial episode [1]. With the addition of a new RCT comparing fidaxomicin and vancomycin, which also included patients with recurrent CDI [16], evidence now suggests fidaxomicin should be preferred over vancomycin in this setting. It should be noted that vancomycin also predictably results in a successful initial clinical cure, even for patients with recurrent CDI, and vancomycin in an extended, tapered, and pulsed regimen has been used successfully in managing patients with multiple CDI recurrences [32]. We completed an additional ad hoc subgroup analysis of the RCT data for fidaxomicin and vancomycin, separating patients with 1 prior CDI recurrence and 2 or more recurrences; the RR for sustained response to fidaxomicin at 30 days following end of therapy in patients with 1 prior recurrence was 1.23 (95% CI: 1.01–1.49) and 2.0 (95% CI: .88–4.54) for patients with 2 or more prior recurrences. Both subgroups showed an increased in sustained response, despite the effect of fidaxomicin failing to achieve a statistical difference in patients with 2 or more prior recurrences. The certainty for the effect in the latter group was very low as data were only available from 1 study judged at high risk of bias (potential unblinding for a self-reported outcome) and imprecise due to the very small number of patients randomized (n = 20) [16] (see Supplementary Materials).

Evidence supporting an extended-pulsed regimen of fidaxomicin comes from an in vitro human gut model study, which showed persistence of fidaxomicin at the above inhibitory concentrations which might prolong suppression of C. difficile and facilitate recovery of a protective microbiota [33]. Indeed, this study provided the rationale for the extended-pulsed fidaxomicin regimen that was used by Guery et al [18]. Because fidaxomicin, like vancomycin, is minimally absorbed and achieves high fecal concentrations, fidaxomicin in a tapered and pulsed regimen following suppressive treatment has been used successfully in patients with multiple CDI recurrences [34]. Appropriate comparative data for these patients, however, are lacking. The RCT comparing extended-pulsed fidaxomicin with vancomycin (EXTEND trial) showed improved sustained responses and one of the lowest rates of recurrence ever reported (2% compared to 17% with vancomycin at day 40) [16]. The comparison in this study, however, was a standard course of vancomycin and the sustained response achieved was similar to that achieved in the phase III trials comparing a standard course of fidaxomicin with vancomycin [35]. In addition, the treatment phase of this regimen (200 mg fidaxomicin) was only given for 5 days, which was barely sufficient to resolve CDI in the in vitro model [33] and the time to diarrhea resolution in the EXTEND trial was 34.0 hours (95% CI: 25.0–49.0 hours) compared with 22.0 hours (95% CI: 10.0– 30.0 hours) for vancomycin [16].

Rationale for Recommendation

The panel agrees that the overall balance of benefits and harms favors using fidaxomicin rather than vancomycin for patients with CDI recurrence and that the certainty of evidence was low (see Supplementary Materials). Despite the moderate costs and possible reduction in equity, the panel judges that patients’ values and preferences, cost-effectiveness, acceptability, and feasibility further support the preferential use of fidaxomicin over vancomycin.

The panel recognizes potential variability on how patients value the avoidance of a subsequent CDI episode. Quality-of-life scores decrease in patients with recurrent CDI compared with patients with an initial episode of CDI, and further consistently decrease with increasing number of CDI episodes [23]. The panel’s expert experience also suggests that patients with multiple recurrent CDI episodes become increasingly desperate with each subsequent CDI episode and are willing to consider nonstandard or nonapproved therapies. Consequently, the panel judges that patients experiencing recurrent CDI will invariably put a high value on avoidance of a subsequent CDI episode. Furthermore, the use of fidaxomicin is considered likely acceptable to patients and their providers and feasible to implement when considering the dosage and duration of fidaxomicin.

Two industry-sponsored cost-effectiveness models using the EXTEND trial data reported that, despite higher acquisition costs than vancomycin, extended-pulsed fidaxomicin was cost-effective [26, 27]. The probability of cost-effectiveness for extended-pulsed fidaxomicin at a willingness-to-pay threshold of £30 000 (~USD 38 000) per QALY gained was 76% [26] and 99.9% at a threshold of €30 000 (~USD 35 000) per QALY gained [27]. Two non–industry-sponsored decision analyses for recurrent CDI found that fidaxomicin was more cost-effective than vancomycin for multiple CDI recurrences if FMT was not an option [36] and vancomycin was most cost-effective for first CDI recurrence in outpatients [37]. These results are highly influenced by the assumptions made and data input in the model. The panel agrees that the cost-effectiveness analysis probably favors the use of extended-pulsed fidaxomicin over vancomycin in patients with recurrent CDI but acknowledges that implementing this recommendation also probably reduces equity due to variation in medical insurance coverage.

Implementation Considerations

Although fidaxomicin is orally administered and is generally well tolerated, the cost is prohibitive without adequate insurance coverage. The average wholesale price of $4871 per 20-tablet package [29] has not dropped appreciably since launch of the drug in 2011, although patient-assistance mechanisms are available.

Conclusion and Research Needs

The panel suggests the use of fidaxomicin as the preferred therapy for patients with recurrent CDI episode(s) to improve sustained response after therapy. More well-designed RCTs for patients with recurrent CDI, particularly multiply recurrent CDIs, are needed to improve the strength of recommendations. In particular, studies with more appropriate controls for extended-pulsed fidaxomicin should help clarify the role of this dosing strategy for patients with recurrent CDI both in terms of efficacy and quality of life.

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III. 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?

Background

Bezlotoxumab was approved by the FDA in October 2016 and was the first humanized monoclonal antibody against C. difficile toxin B approved for the prevention of recurrent CDI in high-risk adults in conjunction with SOC antibiotics. Bezlotoxumab is given as a one-time infusion at a recommended dose of 10 mg/kg over 60 minutes. Bezlotoxumab has an elimination half-life of approximately 18 days, translating to measurable antibody concentrations up to 3 months after the one-time infusion [38]. These pharmacologic characteristics translated into 2 phase III clinical studies (MODIFY I/II) showing reduced rates of CDI recurrence in patients with CDI given bezlotoxumab compared with placebo.

Summary of Evidence

Our review of the literature identified 1 study reporting a pooled analysis of 2 phase III RCTs evaluating bezlotoxumab as an adjunctive therapy to SOC antibiotics in patients with primary or recurrent CDI [18]. The efficacy of adding bezlotoxumab to SOC antibiotics was measured on different patient-important outcomes such as CDI recurrence after initial clinical cure, CDI-associated hospital readmission, drug-related adverse events, and all-cause mortality. Patient-important outcomes were all reported in the study published by Wilcox et al [18], except for CDI-associated hospital readmission, which was only reported in a subgroup analysis of patients hospitalized at the time of randomization [18, 19] (see Figure 3). Efficacy was also measured in prespecified subgroups at risk for recurrent CDI, including age older than 65 years, history of CDI, compromised immunity, severe CDI, and infection with certain virulent strains (ribotypes 027/078/244). Of note, the determination of “immunocompromise” in the phase III trials was made by study investigators based on medical history or use of immunosuppressive therapy without further clarifications. CDI represented a primary episode for 73% of participants and severe CDI accounted for 16% of cases; however, the assessment of severity was performed at the point of randomization to the study drug rather than when SOC antibiotic treatment was initiated. Thus, it is likely that the true proportion of CDI cases with severe disease was greater than 16%. Approximately 68% of patients were hospitalized at the time of recruitment. Standard-of-care antibiotics consisted of vancomycin (48%), metronidazole (47%), and fidaxomicin (4%). Participants received one 60-minute intravenous infusion of bezlotoxumab (10 mg/kg body weight) in addition to SOC antibiotics (see Supplementary Materials).

The pooled analysis of these 2 RCTs demonstrates that the addition of bezlotoxumab reduced CDI recurrence after initial clinical cure at 12 weeks (RR: .62; 95% CI: .51–.75; moderate certainty evidence) and reduced CDI-associated hospital readmission at 30 days (RR: .46; 95% CI: .29–.71; very low certainty evidence), but failed to show a reduction in mortality (RR: .94; 95% CI: .66–1.34; low certainty evidence). The certainty in the evidence for benefits was initially rated as moderate, mainly due to indirectness of the evidence when fidaxomicin is used as the SOC antibiotic (see Table 4).

These 2 phase III trials enrolled patients between November 2011 and May 2015 [18]. During this time period, the IDSA-SHEA 2010 Clinical Practice Guidelines for CDI suggested that metronidazole be used for mild–moderate CDI and oral vancomycin be given for more severe disease [39]. Following these guideline recommendations, most patients received either metronidazole (47%) or oral vancomycin (48%) in the phase III bezlotoxumab clinical trials. However, based on decreasing efficacy of metronidazole, SOC antibiotics now include vancomycin and fidaxomicin in the updated 2017 IDSA-SHEA CDI guidelines [1]. Despite planned subanalyses of the bezlotoxumab phase III trials demonstrating that the choice of SOC antibiotics did not influence the effect on clinical outcomes, uncertainty remains regarding the generalizability of this evidence when fidaxomicin is used as the SOC antibiotic (fidaxomicin being administered as the SOC antibiotic in <5% of the studied cohort [n = 60 patients]) [19].

One study reanalyzed the modified intent-to-treat population of those who received bezlotoxumab or placebo in the phase III trial (n = 1554) by risk factors for recurrent CDI that were prespecified in the statistical analysis plan: age 65 years and older, history of CDI, compromised immunity, severe CDI, and certain virulent ribotypes (ribotypes 027/078/244) [19]. Placebo participants with any risk factor in the phase III trials experienced a recurrent CDI rate of 37.2% compared with 20.9% among those without a risk factor. Risk of CDI recurrence also increased with the number of risk factors; patients with 1 risk factor experienced a 31.3% likelihood of CDI recurrence compared with a 46.1% likelihood in patients with 3 or more risk factors. Absolute rate reduction for bezlotoxumab recipients was highest in patients with greater than or equal to 3 risk factors (−24.8%; 95% CI: −39.1% to −9.3%), 2 risk factors (−14.2%; 95% CI: −24.0% to −4.1%), or patients with 1 risk factor (−14.2%; 95% CI: −21.9% to −6.4%) compared with patients with no risk factors (−2.1%; 95% CI: −11.1% to 6.9%). Patients with primary CDI and no risk factors likewise did not benefit from bezlotoxumab. However, there was an effect seen in patients with primary CDI who also had risk factors for recurrence. The risk difference for patients with primary CDI and with at least 1 risk factor who received bezlotoxumab was −15.1% (95% CI: −22.0% to −8.1%) and −1.5% (95% CI: −10.7% to 7.7%) for primary CDI patients without any risk factor (see Figure 4).

To assess who might benefit the most from receiving bezlotoxumab in addition to SOC, we completed an additional post hoc subgroup analysis using data supplied by the sponsor of the MODIFY trials to estimate the effect of using bezlotoxumab on CDI recurrence after initial clinical cure at 12 weeks in patients with recurrent CDI. The risk difference for patients with 1 episode of CDI in the previous 6 months who received bezlotoxumab was −16.8% (95% CI: −29.2% to −4.5%) and −15.9% (95% CI: −33.1% to 1.4%) for patients with 2 or more episodes in the past 6 months. This effect was judged to be very uncertain due to the lack of stratification for these risk groups during randomization and the number of patients included in the subgroups. However, there was no heterogeneity (I²: 0%) between these subgroups and the pooled effect for patients with a recurrent CDI within the last 6 months was −17.4% (95% CI: −27.5% to −7.3%) (see Figure 5).

The evidence also suggests that drug-related adverse events did not differ among patients receiving bezlotoxumab from those not receiving bezlotoxumab (RR: 1.27; 95% CI: .88–1.85; low certainty evidence). Nevertheless, a post hoc analysis showed that patients with a history of congestive heart failure (CHF) who received bezlotoxumab may be at increased risk of heart failure and mortality in the 12 weeks following the infusion (RR: 2.64 [95% CI: 1.00–7.03] and 1.56 [95% CI: .83–2.92], respectively) [40].

The pivotal clinical trials have further been supported by 2 real-world studies that demonstrated similar reductions in CDI recurrence after initial clinical cure (ICC) among patients at high risk for recurrent CDI who received bezlotoxumab [41, 42]. One of these studies, a retrospective multicentered cohort study, evaluated 200 patients receiving bezlotoxumab in addition to SOC antibiotics (vancomycin in 130 patients [68.5%], fidaxomicin in 60 patients [30.0%], and metronidazole in 3 patients [1.5%]) from US outpatient infusion centers from 2017 to 2018 [41]. Most patients had prior CDI episodes (86.5%) and had at least 2 risk factors for recurrent CDI (79.0%). The rate of recurrent CDI at 90 days was 15.9% (31 of 195 patients), which did not differ when stratifying by SOC antibiotics received (vancomycin fixed dose in 10 out of 73 patients [13.7%], vancomycin tapered regimen in 11 out of 60 patients [18.3%], fidaxomicin in 9 out of 59 patients [15.2%]; P = .76). This finding further supports the subanalyses of the bezlotoxumab phase III trials demonstrating that the choice of SOC antibiotics did not influence the effect of bezlotoxumab on clinical outcomes, but the combined effect of bezlotoxumab to fidaxomicin will need to be studied further.

Rationale for Recommendation

The panel agrees that the overall balance of benefits and harms favors adding bezlotoxumab to SOC antibiotics for patients with a CDI episode and at least 1 risk factor for recurrence (recurrent CDI episode within the last 6 months, age ≥65 years, immunocompromised host, and severe CDI on presentation), but seems more favorable in patients with multiple risk factors of recurrent CDI and especially in patients with a prior CDI in the last 6 months (see Figure 4 and Supplementary Table 12). The certainty of evidence is moderate overall, but very low in subpopulations at high risk of CDI recurrence. Despite limited feasibility due to logistical considerations in certain settings (particularly for patients with primary CDI, see “implementation considerations” below), the moderate costs, and possible reduction in equity, the panel judges that patients’ values and preferences (especially for those experiencing recurrent CDI), cost-effectiveness, and acceptability for patients and providers further support the addition of bezlotoxumab to SOC antibiotics. Consequently, the panel suggests the addition of bezlotoxumab to SOC antibiotics in patients with a recurrent CDI within the last 6 months but also acknowledges that, in settings where logistics are not an issue, patients with a primary CDI episode and with at least 1 other risk factor for CDI recurrence may also benefit from receiving bezlotoxumab.

Two industry-sponsored cost-effectiveness studies using data from the MODIFY I and II clinical trials evaluated the addition of bezlotoxumab compared with SOC antibiotics alone using European and US cost estimates, respectively [43, 44]. Both models focused on cost-effectiveness of the addition of bezlotoxumab based on the same risk factors for recurrence studied in the MODIFY I/II studies and subanalyses. Using European cost estimates, the probability of cost-effectiveness for bezlotoxumab at a willingness to pay threshold of €21 000 (~USD 25 000) per QALY was highest for patients aged 65 years and older with at least 1 CDI recurrence in the previous 6 months (99.6%), followed by those with at least 1 CDI recurrence in the previous 6 months of any age (94.5%), or age 65 years and older (85.5%). All high-risk variables had at least a 50% probability of being cost-effective at that set threshold. Using US cost estimates demonstrated similar results. Bezlotoxumab was associated with 0.12 QALYs gained and was cost-effective in preventing CDI in the entire trial population, with an incremental cost-effectiveness ratio of $19 824/QALY gained. Subpopulations that were shown to be most cost-effective, especially if the subgroups had 1 or more episodes of CDI in the previous 6 months, were immunocompromised patients, patients aged 65 years or older, and patients with severe CDI on presentation. A non–industry-sponsored decision tree analysis found that bezlotoxumab plus vancomycin was less cost-effective than vancomycin for first recurrence in outpatients [37]. These results are highly influenced by the assumptions made and data input in the model.

The panel agrees that the cost-effectiveness analysis favors the addition of bezlotoxumab to SOC antibiotics in patients with a recurrent CDI episode within the last 6 months but acknowledges that implementing this recommendation also probably reduces equity due to variation in medical insurance coverage.

Implementation Considerations

The infusion of bezlotoxumab should be performed while a patient is receiving SOC antibiotics and has been shown to be effective in preventing CDI if administered at any time before ending antibacterial treatment [45]. Implementation, however, is often limited by logistical and feasibility considerations, particularly for patients with primary CDI. The population currently targeted for receipt of bezlotoxumab is quite different from the population included in the phase III RCTs. In the phase III RCT studies, the majority of participants had primary CDI episodes (73%) and were hospitalized at the time of recruitment (68%) [18]. In contrast, real-world experience indicates the majority of patients receiving bezlotoxumab have had prior CDI episodes (87%) and receive the infusion in outpatient infusion centers [41]. Identifying patients with primary CDI who might benefit from bezlotoxumab and establishing a referral to an infusion center is complicated by the fact that they are typically not seen by infectious diseases or gastroenterology specialists but are initially managed by primary care or other physicians often without experience managing CDI. The panel’s expert experience has shown that many patients have difficulty receiving bezlotoxumab even after referral, most commonly due to insurance denials. Despite these considerations, the use of bezlotoxumab is considered likely acceptable to patients and their providers and feasible to implement.

Conclusion and Research Needs

The panel suggests using bezlotoxumab as a co-intervention along with SOC antibiotics for patients with a recurrent CDI within the last 6 months to reduce the risk of a subsequent CDI recurrence after initial clinical cure. In patients with a history of CHF, the FDA warns that bezlotoxumab should be reserved for use when the benefit outweighs the risk. Head-to-head trials of differing anti-CDI recurrence strategies using narrow-spectrum antibiotics that target C. difficile, restoration of the microbiome using biotherapeutics or FMT, or augmentation of the host immune response with agents such as bezlotoxumab given alone or in combination (eg, in combination with fidaxomicin) are needed.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Disclaimer. It is important to realize that guidelines cannot always account for individual variation among patients. They are assessments of current scientific and clinical information provided as an educational service; are not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); should not be considered inclusive of all proper treatments, methods of care, or as a statement of the standard of care; do not mandate any particular course of medical care; and are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Whether and the extent to which to follow guidelines is voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances. While IDSA and SHEA make every effort to present accurate, complete, and reliable information, these guidelines are presented “as is” without any warranty, either express or implied. IDSA and SHEA (and its officers, directors, members, employees, and agents) assume no responsibility for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented. The guidelines represent the proprietary and copyrighted property of IDSA. Copyright 2021 Infectious Diseases Society of America. All rights reserved. No part of these guidelines may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of IDSA. Permission is granted to physicians and healthcare providers solely to copy and use the guidelines in their professional practices and clinical decision making. No license or permission is granted to any person or entity, and prior written authorization by IDSA is required to sell, distribute, or modify the guidelines, or to make derivative works of or incorporate the guidelines into any product, including but not limited to clinical decision-support software or any other software product. Except for the permission granted above, any person or entity desiring to use the guidelines in any way must contact IDSA for approval in accordance with the terms and conditions of third-party use—in particular, any use of the guidelines in any software product.

Acknowledgments. The expert panel expresses its gratitude for thoughtful reviews of an earlier version by Drs. Clifford McDonald, Timothy Planche, and Kelly Reveles. The panel thanks Genet Demisashi and Rebecca Goldwater for their continued support throughout the guideline process. The panel also expresses gratitude to librarian Shandra Knight for her continued literature support throughout the development of the guideline.

Financial support. Support for this guideline was provided by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.

Potential conflicts of interest. The following list is a reflection of what has been reported to IDSA. To provide thorough transparency, IDSA requires full disclosure of all relationships, regardless of relevancy to the guideline topic. Evaluation of such relationships as potential conflicts of interest is determined by a review process which includes assessment by the Standard and Practice Guidelines Committee (SPGC) Chair, the SPGC liaison to the development panel, and the Board of Directors liaison to the SPGC, and if necessary, the Conflict of Interest (COI) Ethics Committee. The assessment of disclosed relationships for possible COIs is based on the relative weight of the financial relationship (ie, monetary amount) and the relevance of the relationship (ie, the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. K. W. G. has served as a consultant/advisor to Merck and Synthetic Biologics; receives research grants from Summit Therapeutics, Paratek Pharmaceuticals, Acurx Pharmaceuticals, Tetraphase Pharmaceuticals, and the National Institutes of Health (NIH); and has received research grants from Tetraphase Pharmaceuticals. S. J. serves as an Advisory Board member for Bio-K+ and Acurx Pharmaceuticals; receives renumeration from Pfizer as a member of the Data Monitoring Committee and Ferring Pharmaceutical in developing an education monograph for transition of care for C. difficile; has served as an Advisory Board member for Cutis Pharma and Summit Therapeutics; and served on the Steering Committee for Synthetic Biologics. C. P. K. serves as an advisor for Matrivax, Vedanta, Merck, Cour, Acurx Pharmaceuticals, Finch, Microbiota, and Milky Way Life Science; has served as an advisor for Artugen, Glutenostix, Innovate, and Sanofi; receives honoraria from Merck for serving as a symposium speaker; has received honoraria from Biocodex for serving as a symposium speaker; has held stock in Glutenostix; receives research funding from the NIH and the National Institute of Allergy and Infectious Diseases; has received research funding from Instit Merieux, Merck, and Allergan; currently serves as the President of the Society for the Study of Celiac Disease and as the Secretary for the Foundation for Celiac Disease Outcome Measures; and his organization, Beth Israel Deaconess Medical Center, has received organizational benefits from the Sydney Frank Foundation and Milky Way Life Sciences. V. L. has received past research funding from the Fonds de Recherche du Québec Research (FRQ-S). A. M. S. has received honoraria from the American Society of Health-System Pharmacists. M. H. W. serves as an advisor for Summit and Seres; has served as an advisor for Merck and Astellas; receives research grants from Summit, Seres, the Centers for Disease Control and Prevention, the NIH, the UK Medical Research Council, and the European Union Innovative Medicines Initiative; and has received research grants from Merck and Astellas. A. J. G.-L. reports no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

1. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018; 66:e1–48.
2. Guh AY, Mu Y, Winston LG, et al; Emerging Infections Program Clostridioides difficile Infection Working Group. Trends in U.S. burden of Clostridioides
   difficile infection and outcomes. N Engl J Med 2020; 382:1320–30.
3. DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med 2019; 381:2043–50.
4. US Food and Drug Administration. Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms. 2019. Available at: https://www.fda. gov/vaccines-blood-biologics/safety-availability-biologics/important-safetyalert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse. Accessed 30 June 2021.
5. US Food and Drug Administration. Update to March 12, 2020 safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse events likely due to transmission of pathogenic organisms. 2020. Available at: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/update-march-12-2020-safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious. Accessed 30 June 2021.
6. US Food and Drug Administration. Safety alert regarding use of fecal microbiota for transplantation and additional safety protections pertaining to SARS-CoV-2 and COVID-19. 2020. Available at: https://www.fda.gov/vaccinesblood-biologics/safety-availability-biologics/safety-alert-regarding-use-fecalmicrobiota-transplantation-and-additional-safety-protections. Accessed 30 June 2021.
7. Institute of Medicine (US) Committee on Standards for Developing Trustworthy Clinical Practice Guidelines. Clinical practice guidelines we can trust. Washington, DC: National Academies Press, 2011.
   Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab549/6298219 by guest on 27 July 2021 16 • cid 2021:XX (XX XXXX) • Johnson et al
8. Infectious Diseases Society of America. IDSA handbook for clinical practice guidelines development. Available at: https://idsocietyorg.app.box.com/s/zumf9
   1rnftiv9xfzos5eot9sg2tgg2fr. Accessed 13 May 2020.
9. Review Manager (RevMan) [computer program]. Version 5.4. Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020.
   Available at: https://documentation.cochrane.org/revman-kb/studies-andreferences/cite-revman-web-in-a-reference-list.
10. Higgins JP, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343:d5928.
11. Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336:924–6.
12. Schünemann H, Brożek J, Guyatt G, Oxman A. Introduction to GRADE handbook. 2013. Available at: https://gdt.gradepro.org/app/handbook/handbook.html. Accessed 30 June 2021.
13. GRADEpro GDT. GRADEpro guideline development tool [software]. McMaster University, 2015 (developed by Evidence Prime, Inc.). Available at: gradepro.org.
    Accessed 13 May 2020.
14. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med
    2011; 364:422–31.
15. Cornely OA, Crook DW, Esposito R, et al; OPT-80-004 Clinical Study Group. 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; 12:281–9.
16. Guery B, Menichetti F, Anttila VJ, et al; EXTEND Clinical Study Group. Extendedpulsed 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; 18:296–307.
17. Mikamo H, Tateda K, Yanagihara K, et al. Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative phase III study in Japan. J Infect Chemother 2018; 24:744–52.
18. Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med 2017; 376:305–17.
19. Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence. Clin Infect Dis 2018; 67:649–56.
20. Goldstein EJ, Babakhani F, Citron DM. Antimicrobial activities of fidaxomicin. Clin Infect Dis 2012; 55(Suppl 2):S143–8.
21. Louie TJ, Cannon K, Byrne B, et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis 2012; 55(Suppl 2):S132–42.
22. Madoff SE, Urquiaga M, Alonso CD, Kelly CP. Prevention of recurrent Clostridioides difficile infection: a systematic review of randomized controlled trials. Anaerobe 2020; 61:102098.
23. Garey KW, Aitken SL, Gschwind L, et al. Development and validation of a Clostridium difficile health-related quality-of-life questionnaire. J Clin Gastroenterol 2016; 50:631–7.
24. Watt M, McCrea C, Johal S, Posnett J, Nazir J. A cost-effectiveness and budget impact analysis of first-line fidaxomicin for patients with Clostridium difficile infection (CDI) in Germany. Infection 2016; 44:599–606.
25. Reveles KR, Backo JL, Corvino FA, Zivkovic M, Broderick KC. Fidaxomicin versus vancomycin as a first-line treatment for clostridium difficile-associated diarrhea in specific patient populations: a pharmacoeconomic evaluation. Pharmacotherapy 2017; 37:1489–97.
26. Cornely OA, Watt M, McCrea C, Goldenberg SD, De Nigris E. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients aged ≥60 years (EXTEND): analysis of cost-effectiveness. J Antimicrob Chemother 2018; 73:2529–39.
27. Rubio-Terrés C, Aguado JM, Almirante B, et al. Extended-pulsed fidaxomicin versus vancomycin in patients 60 years and older with Clostridium difficile infection: cost-effectiveness analysis in Spain. Eur J Clin Microbiol Infect Dis 2019; 38:1105–11.
28. Bartsch SM, Umscheid CA, Fishman N, Lee BY. Is fidaxomicin worth the cost? An economic analysis. Clin Infect Dis 2013; 57:555–61.
29. Wolters Kluwer Clinical Drug Information, Inc; International Business Machines Corporation. IBM micromedex solutions. Available at: http://www.micromedex. com/. Accessed 22 September 2020.
30. Sheitoyan-Pesant C, Abou Chakra CN, Pépin J, Marcil-Héguy A, Nault V, Valiquette L. Clinical and healthcare burden of multiple recurrences of Clostridium difficile infection. Clin Infect Dis 2016; 62:574–80.
31. Cornely OA, Miller MA, Louie TJ, Crook DW, Gorbach SL. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis 2012; 55(Suppl 2):S154–61.
32. Sirbu BD, Soriano MM, Manzo C, Lum J, Gerding DN, Johnson S. Vancomycin taper and pulse regimen with careful follow-up for patients with recurrent Clostridium difficile infection. Clin Infect Dis 2017; 65:1396–9.
33. Chilton CH, Crowther GS, Todhunter SL, et al. Efficacy of alternative fidaxomicin dosing regimens for treatment of simulated Clostridium difficile infection in an in vitro human gut model. J Antimicrob Chemother 2015; 70:2598–607.
34. Soriano MM, Danziger LH, Gerding DN, Johnson S. Novel fidaxomicin treatment regimens for patients with multiple Clostridium difficile infection recurrences that are refractory to standard therapies. Open Forum Infect Dis 2014; 1:ofu069.
35. Gerding DN. Is pulsed dosing the answer to treatment of Clostridium difficile infection? Lancet Infect Dis 2018; 18:231–3.
36. Lapointe-Shaw L, Tran KL, Coyte PC, et al. Cost-effectiveness analysis of six strategies to treat recurrent Clostridium difficile infection. PLoS One 2016; 11:e0149521.
37. Lam SW, Neuner EA, Fraser TG, Delgado D, Chalfin DB. Cost-effectiveness of three different strategies for the treatment of first recurrent Clostridium difficile infection diagnosed in a community setting. Infect Control Hosp Epidemiol 2018; 39:924–30.
38. Yee KL, Kleijn HJ, Kerbusch T, et al. Population pharmacokinetics and pharmacodynamics of bezlotoxumab in adults with primary and recurrent Clostridium difficile infection. Antimicrob Agents Chemother 2019; 63:e01971–18.
39. Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431–55.
40. Merck & Co, Inc. ZINPLAVA™ (bezlotoxumab) injection, for intravenous use. Initial U.S. approval: 2016. Whitehouse Station, NJ: Merck & Co, Inc, 2016.
41. Hengel RL, Ritter TE, Nathan RV, et al. Real-world experience of bezlotoxumab for prevention of Clostridioides difficile infection: a retrospective multicenter cohort study. Open Forum Infect Dis 2020; 7:ofaa097.
42. Oksi J, Aalto A, Säilä P, Partanen T, Anttila VJ, Mattila E. Real-world efficacy of bezlotoxumab for prevention of recurrent Clostridium difficile infection: a retrospective study of 46 patients in five university hospitals in Finland. Eur J Clin Microbiol Infect Dis 2019; 38:1947–52.
43. Salavert M, Cobo J, Pascual Á, et al. Cost-effectiveness analysis of bezlotoxumab added to standard of care versus standard of care alone for the prevention of recurrent Clostridium difficile infection in high-risk patients in Spain. Adv Ther 2018; 35:1920–34.
44. Prabhu VS, Dubberke ER, Dorr MB, et al. Cost-effectiveness of bezlotoxumab compared with placebo for the prevention of recurrent Clostridium difficile infection. Clin Infect Dis 2018; 66:355–62.
45. Birch T, Golan Y, Rizzardini G, et al. Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection. J Antimicrob Chemother 2018; 73:2524–8.
    
    

Additional Resources

2018 IDSA/SHEA Clinical Practice Guidelines on Clostridium difficile Infection in Adults and Children

 

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