Bezlotoxumab (Zinplava)

Number: 0914

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses bezlotoxumab (zinplava).

1. Medical Necessity

   Aetna considers bezlotoxumab (Zinplava) medically necessary to reduce recurrence of Clostridium difficile infection (CDI) in members who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence when the following criteria are met:

   1. Member is 18 years of age or older; and
   2. Member has a confirmed diagnosis of CDI with documentation of the following: diarrhea (passage of 3 or more loose bowel movements in 24 or fewer hours) and a positive stool test for toxigenic C. difficile from a stool sample collected no more than 7 days prior; and
   3. Member is at high risk of CDI recurrence, defined as any of the following:
      1. Age greater than or equal to 65 years; or
      2. Long term use of systemic antibacterial drugs (excluding standard of care antibiotics); or
      3. History of 1 or more prior episodes of CDI within the previous 6 months; or
      4. Immunocompromised (defined as having an active hematologic malignancy, using an antineoplastic or immunomodulating agent, using corticosteroids, having received a prior solid organ transplant, being asplenic, being neutropenic/pancytopenic, or having AIDS/immunodeficient condition); or
      5. Clinically severe CDI (as defined by a Zar score of greater than or equal to 2); or
      6. Hypervirulent strain (ribotypes 027, 078 or 244); and
   4. Bezlotoxumab will be given in conjunction with standard of care antibiotics (Infusion will be given during the antibiotic treatment course). 

2. Experimental and Investigational

   The following are considered experimental and investigational:

   1. Bezlotoxumab for all other indications not listed in Section I; 
   2. Combination of bezolotoxumab and other human monoclonal antibodies to C. difficile toxin for treatment of CDI because the effectiveness of this approach has not been established.

3. Related Policies

   • CPB 0844 - Fecal Bacteriotherapy

Dosing Recommendations

The recommended dose of bezlotoxumab is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes. Bezlotoxumab should be administered during antibacterial treatment for CDI.

Aetna considers repeat administration of bezlotoxumab experimental and investigational. The safety and efficacy of repeat administration of bezlotoxumab in persons with CDI has not been studied.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365-96366	Intravenous infusion administration
HCPCS codes covered if selection criteria are met:
J0565	Injection, bezlotoxumab, 10 mg
Other HCPCS codes related to the CPB:
Actoxumab - no specific code:
ICD-10 codes covered if selection criteria are met (not all-inclusive):
A04.71 - A04.72	Enterocolitis due to Clostridium difficile

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Background

Clostridium difficile infection (CDI) is caused by bacteria that produce toxins, including toxin B. Symptoms of CDI include mild-to-severe diarrhea, abdominal pain and fever (Merck, 2016). The incidence of recurrent CDI is higher in certain patient populations, including people 65 years of age or older and those with compromised immune systems.

The U.S. Food and Drug Administration (FDA) has approved bezlotoxumab (Zinplava) injection 25 mg/mL to reduce recurrence of CDI in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence (Merck, 2016). The labeling states that bezlotoxumab is not indicated for the treatment of CDI. Bezlotoxumab is not an antibacterial drug and should only be used in conjunction with antibacterial drug treatment of CDI.

The safety and efficacy of bezlotoxumab was investigated in two randomized, double-blind, placebo-controlled, multicenter, Phase 3 trials (Trial 1 and Trial 2) in patients receiving Standard of Care (SoC) antibacterial drugs for treatment of CDI (Merck, 2016). Randomization was stratified by SoC (metronidazole, vancomycin, or fidaxomicin) and hospitalization status (inpatient vs. outpatient) at the time of study entry. Enrolled patients were 18 years of age or older and had a confirmed diagnosis of CDI, which was defined as diarrhea (passage of 3 or more loose bowel movements in 24 or fewer hours) and a positive stool test for toxigenic C. difficile from a stool sample collected no more than 7 days before study entry. Patients were excluded if surgery for CDI was planned, or if they had uncontrolled chronic diarrheal illness. Patients received a 10- to 14-day course of oral SoC and a single infusion of bezlotoxumab or placebo was administered during the course of SoC. Patients on oral vancomycin or oral fidaxomicin could have also received intravenous metronidazole. Choice of SoC was at the discretion of the health care provider. The day of the infusion of bezlotoxumab or placebo in relation to the start of SoC ranged from the day prior to the start of SoC to 14 days after the start of SoC with the median being day 3 of SoC.

The following risk factors associated with a high risk of CDI recurrence or CDI-related adverse outcomes were present in the study population: 51% were ≥ 65 years of age, 39% received one or more systemic antibacterial drugs (during the 12-week follow-up period), 28% had one or more episodes of CDI within the 6 months prior to the episode under treatment (15% had 2 or more episodes prior to the episode under treatment), 21% were immunocompromised and 16% presented at study entry with clinically severe CDI (as defined by a Zar score of ≥ 2) (Merck, 2016). A hypervirulent strain (ribotypes 027, 078 or 244) was isolated in 22% of patients who had a positive baseline culture, of which 87% (189 of 217 strains) were ribotype 027.

Patients were assessed for clinical cure of the presenting CDI episode, defined as no diarrhea for 2 consecutive days following the completion of a ≤14 day SoC regimen (Merck, 2016). Patients who achieved clinical cure were then assessed for recurrence of CDI through 12 weeks following administration of the infusion of bezlotoxumab or placebo. CDI recurrence was defined as the development of a new episode of diarrhea associated with a positive stool test for toxigenic C. difficile following clinical cure of the presenting CDI episode. Sustained clinical response was defined as clinical cure of the presenting CDI episode and no CDI recurrence through 12 weeks after infusion.

In trial 1, the sustained clinical response rate was 60.1% (232/386) in the bezlotoxumab arm compared to 55.2% (218/395) in the placebo arm, an adjusted diffference of 4.8 (-2.1 to 11.1) which failed to achieve statistical significance (Merck, 2016). The clinical failure rate was higher in the bezlotoxumab arm (22.5%) than in the placebo arm (17.2%). The rate of recurrence was 17.4 in the bezlotoxumab arm and 27.6 in the placebo arm. In trial 2, the sustained clinical response rate was 66.8% (264/395) in the bezlotoxumab arm versus 52.1% (197/378) in the placebo arm, an adjusted difference of 14.6 (7.7 to 21.4) which was a statistically signficant difference. The clincial failure rate was lower in the bezlotoxumab arm (17.5%) than in the placebo arm (22.2%). The rate of recurrence was 15.7% in the bezlotoxumab arm and 25.7% in the placebo arm.

In Trial 1, the clinical cure rate of the presenting CDI episode was lower in the bezlotoxumab arm as compared to the placebo arm and in Trial 2, the clinical cure rate was lower in the placebo arm compared to the bezlotoxumab arm (Merck, 2016). Patients in the bezlotoxumab and placebo arms who did not achieve clinical cure of the presenting CDI episode (no diarrhea for 2 consecutive days following the completion of a ≤14 day SoC regimen) received a mean of 18 to 19 days of SoC and had a mean of 4 additional days of diarrhea following completion of SoC. Additional analyses showed that by 3 weeks post study drug infusion the clinical cure rates of the presenting CDI episode were similar between treatment arms.

Efficacy results in patients at high risk for CDI recurrence (i.e., patients aged 65 years and older, with a history of CDI in the past 6 months, immunocompromised state, severe CDI at presentation, or C. difficile ribotype 027) were consistent with the efficacy results in the overall trial population in Trials 1 and 2 (Merck, 2016).

Zinplava is available as bezlotoxumab in single-dose vials of 1,000 mg/40 mL (25 mg/mL). The prescribing information recommends administering bezlotoxumab during antibacterial drug treatment for CDI (Merck, 2016). The recommended dose of bezlotoxumab in adults is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes. The labeling states that the safety and efficacy of repeat administration of bezlotoxumab in patients with CDI have not been studied.

Heart failure was reported more commonly in the two Phase 3 clinical trials in bezlotoxumab-treated patients compared to placebo-treated patients (Merck, 2016). These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of bezlotoxumab-treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period. Additionally, in patients with a history of CHF, there were more deaths in bezlotoxumab-treated patients [19.5% (23/118)] than in placebo-treated patients [12.5% (13/104)] during the 12-week study period. The causes of death varied, and included cardiac failure, infections, and respiratory failure. In patients with a history of CHF, bezlotoxumab should be reserved for use when the benefit outweighs the risk.

The most common adverse reactions occurring within 4 weeks of infusion with a frequency greater than placebo and reported in ≥4% of patients treated with bezlotoxumab and Standard of Care (SoC) antibacterial drug therapy versus placebo and SoC antibacterial drug therapy included nausea (7% vs 5%), pyrexia (5% vs 3%) and headache (4% vs 3%) (Merck, 2016).

Serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of bezlotoxumab-treated patients and 33% of placebo-treated patients (Merck, 2016). Heart failure was reported as a serious adverse reaction in 2.3% of bezlotoxumab-treated patients and 1.0% of placebo-treated patients.

In bezlotoxumab-treated patients, 10% experienced one or more infusion specific adverse reactions compared to 8% of placebo-treated patients, on the day of or the day after the infusion (Merck, 2016). Infusion specific adverse reactions reported in ≥0.5% of patients receiving bezlotoxumab and at a frequency greater than placebo were nausea (3%), fatigue (1%), pyrexia (1%), dizziness (1%), headache (2%), dyspnea (1%), and hypertension (1%). Of these patients, 78% experienced mild adverse reactions and 20% of patients experienced moderate adverse reactions. These reactions resolved within 24 hours following onset.

There is a potential for immunogenicity following administration of bezlotoxumab (Merck, 2016). The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bezlotoxumab in two Phase 3 studies with the incidence of antibodies in other studies or to other products may be misleading. Following treatment with bezlotoxumab in these two studies, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies.

Risk factors for CDI recurrence include:

• Age greater than or equal to 65 years;
• Long term use of systemic antibacterial drugs (excluding standard of care antibiotics);
• History of 1 or more prior episodes of CDI within the previous 6 months;
• Immunocompromised (defined as having an active hematologic malignancy, using an antineoplastic or immunomodulating agent, using corticosteroids, having received a prior solid organ transplant, being asplenic, being neutropenic/pancytopenic, or having AIDS/immunodeficient condition);
• Clinically severe CDI (as defined by a Zar score of greater than or equal to 2); or
• Hypervirulent strain (ribotypes 027, 078 or 244).

Johnson and Gerding (2019) stated that CDI is mediated by actions of toxin A and toxin B. Fully human monoclonal antibodies directed against the binding domains of these toxins were developed. Despite pre-clinical studies suggesting efficacy for the anti-toxin A monoclonal, actoxumab, the anti-toxin B monoclonoal, bezolotoxumab, alone was shown to be effective in clinical trials. Intravenous infusion of bezlotoxumab at a 10 mg/kg dosage as adjunctive treatment reduced the risk of recurrent CDI over placebo for adult patients at increased risk for CDI recurrence in 2 large randomized, double-blind, clinical trials. Significant benefit was noted for patients with 1 or more of the following pre-defined risks; age greater than 65 years, history of CDI, immuno-compromise, severe CDI. Overall, bezlotoxumab appeared to be safe, however, an unexplained increased risk of heart failure (HF) was noted for patients with underlying congestive heart failure (CHF). They authors concluded that further refinement of who would benefit most and when best to administer bezlotoxumab is needed.

van Prehn et al (2021) noted that in 2009, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published the 1st treatment guidance document for CDI.  This document was updated in 2014.  The growing literature on CDI anti-microbial treatment and novel treatment approaches, such as fecal microbiota transplantation (FMT) and toxin-binding monoclonal antibodies, prompted the ESCMID study group on C. difficile (ESGCD) to update the 2014 treatment guidance document for CDI in adults.  Key questions on CDI treatment were formulated by the guideline committee and included: What is the best treatment for initial, severe, severe-complicated, refractory, recurrent and multiple recurrent CDI? What is the best treatment when no oral therapy is possible?  Can prognostic factors identify patients at risk for severe and recurrent CDI and is there a place for CDI prophylaxis?  Outcome measures for treatment strategy included clinical cure, recurrence and sustained cure.  For studies on surgical interventions and severe-complicated CDI the outcome was mortality.  Appraisal of available literature and drafting of recommendations was carried out by the guideline drafting group.  The total body of evidence for the recommendations on CDI treatment consists of the literature described in the previous guidelines, supplemented with a systematic literature search on randomized clinical trials and observational studies from 2012 and onwards.  The Grades of Recommendation Assessment, Development and Evaluation (GRADE) system was used to grade the strength of the recommendations and the quality of the evidence.  The guideline committee was invited to comment on the recommendations.  The guideline draft was sent to external experts and a patients' representative for review.  Full ESCMID endorsement was obtained after a public consultation procedure.  Important changes compared with previous guideline included but are not limited to:

• Metronidazole is no longer recommended for treatment of CDI when fidaxomicin or vancomycin are available
• Fidaxomicin is the preferred agent for treatment of initial CDI and the 1st recurrence of CDI when available and feasible,
• FMT or bezlotoxumab (BEZ) in addition to SoC antibiotics are preferred for treatment of a 2nd or further recurrence of CDI,
• BEZ in addition to SoC is recommended for the 1st recurrence of CDI when fidaxomicin was used to manage the initial CDI episode, and
• BEZ is considered as an ancillary treatment to vancomycin for a CDI episode with high risk of recurrence when fidaxomicin is not available.

The authors stated that contrary to the previous guideline, in the current guideline emphasis is placed on risk for recurrence as a factor that determines treatment strategy for the individual patient, rather than the disease severity.

In a retrospective, matched, cohort study, these investigators examined the effectiveness of BEZ in recurrent CDI (rCDI) and patient-specific risk factors in a real-world setting.  This trial was carried out from 2015 to 2019 to compare BEZ to historical SoC therapy with vancomycin or fidaxomicin.  The primary outcome was incidence of 90-day rCDI; and secondary outcomes were incidence of all-cause hospital re-admission and all-cause mortality at 90 days, infusion-related reactions, and incidence of HF exacerbation.  Baseline confounding was addressed using inverse probability of treatment weighting (IPTW).  A total of 107 subject were included (54 BEZ and 53 SoC).  Mean number of prior CDI episodes was 2, median number of risk factors for rCDI was 4, and 28 % of subjects had severe CDI.  Incidence of 90-day rCDI was 11 % BEZ versus 43 % SoC (p = < 0.001) and 90-day all-cause re-admission was 40 % BEZ versus 64 % SoC (p = 0.011).  In IPTW-adjusted analyses, BEZ was associated with significantly reduced odds of rCDI (OR, 0.14; 95 % CI: 0.05 to 0.41) and all-cause re-admission (OR, 0.36; 95 % CI: 0.16 to 0.81).  No safety signals were detected with BEZ use.  The authors concluded that BEZ was effective for the prevention of rCDI and reduction in all-cause hospital re-admission for patients at high risk for recurrence, supporting current guideline recommendations.

Askar et al (2023) noted that about 25 % of patients with CDI will experience recurrence, which is greater in immunocompromised patients.  In a retrospective, cohort study, these investigators reported their experience with an institutional guideline targeting high-risk immunocompromised patients.  This study included consecutive patients with CDI who met institutional criteria for BEZ due to high risk for recurrent CDI between June 1, 2017, and November 30, 2018.  The primary endpoint of recurrent CDI within 12 weeks was compared between patients who received the SoC plus or minus BEZ.  A total of 23 patients received BEZ infusion plus SoC and were compared to 30 SoC patients; 84 % of patients were immunocompromised and 54.7 % were transplant recipients.  The primary endpoint occurred in 13 % of BEZ patients compared to 23.3 % of SoC patients.  No serious adverse effects were identified.  The authors concluded that BEZ was associated with a meaningful reduction in recurrent CDI in this cohort largely comprising immunocompromised and transplant patients.

Combination of Bezolotoxumab and Other Human Monoclonal Antibodies to C. Difficile Toxin for the Treatment of Clostridium Difficile Infection

Dzunkova and associates (2016) stated that antibiotics have significant and long-lasting impacts on the intestinal microbiota and consequently reduce colonization resistance against CDI. Standard therapy using antibiotics is associated with a high rate of disease recurrence, highlighting the need for novel treatment strategies that target toxins, the major virulence factors, rather than the organism itself. Human monoclonal antibodies (HuMabs) MK-3415A (actoxumab-bezlotoxumab) to C. difficile toxin A and toxin B, as an emerging non-antibiotic approach, significantly reduced the recurrence of CDI in animal models and human clinical trials. Although the main mechanism of protection is through direct neutralization of the toxins, the impact of MK-3415A on gut microbiota and its restoration has not been examined. Using a CDI murine model, these researchers compared the bacterial diversity of the gut microbiome of mice under different treatments including MK-3415A, vancomycin, or vancomycin combined with MK-3415A, sampled longitudinally. These investigators showed that CDI resulted in the prevalence of Enterobacter species; 60% of mice in the vehicle group died after 2 days and their microbiome was almost exclusively formed by Enterobacter. MK-3415A treatment resulted in lower Enterobacter levels and restoration of Blautia, Akkermansia, and Lactobacillus, which were the core components of the original microbiota. Vancomycin treatment led to significantly lower survival rate than the combo treatment of MK-3415A and vancomycin. Vancomycin treatment decreased bacterial diversity with predominant Enterobacter and Akkermansia, while Staphylococcus expanded after vancomycin treatment was terminated. In contrast, mice treated by vancomycin combined with MK-3415A also experienced decreased bacterial diversity during vancomycin treatment. However, these animals were able to recover their initial Blautia and Lactobacillus proportions, even though episodes of Staphylococcus overgrowth were detected by the end of the experiments. The authors concluded that MK-3415A (actoxumab-bezlotoxumab) treatment facilitated normalization of the gut microbiota in CDI mice. Moreover, they stated that it remained to be examined if the prevention of recurrent CDI by the antitoxin antibodies observed in clinical trials occurred through modulation of microbiota.

Posteraro and colleagues (2018) noted that CDI is the most common healthcare-associated infection worldwide. As standard CDI antibiotic therapies can result in unacceptably high recurrence rates, novel therapeutic strategies for CDI are necessary. A recently emerged immunological therapy is a monoclonal antibody against C. difficile toxin B. These investigators summarized the available pharmacological, pre-clinical, and clinical data for the CDI treatment based on anti-toxin A (actoxumab) and anti-toxin B (bezlotoxumab) HuMabs, and discussed the potentiality of a therapy that includes HuMab combined administration for CDI. The authors concluded that although only bezlotoxumab is indicated to reduce recurrence of CDI, experimental studies using a combination of HuMabs actoxumab and bezlotoxumab have shown that bolstering the host immune response against both the C. difficile toxins may be effective in primary and secondary CDI prevention. Besides neutralizing both the key virulence factors, combination of 2 HuMabs could potentially offer an advantage for a yet to emerge C. difficile strain, which is a steady threat for patients at high risk of CDI. However, as actoxumab development was halted, passive immunotherapy with actoxumab/bezlotoxumab is actually impracticable. They stated that future research will be needed to evaluate HuMab combination as a therapeutic strategy in clinical and microbiological cure of CDI.

Bezlotoxumab in Patients Receiving Metronidazole, Vancomycin, or Fidaxomicin for the Treatment of Clostridium Difficile Infection

Dubberke and colleagues (2020) noted that in the phase-III MODIFY I/II clinical trials, bezlotoxumab significantly reduced recurrence of CDI (RCDI) over 12 weeks.  Choice of CDI anti-bacterial treatment may affect CDI-related outcomes.  In a pre-specified analysis, these researchers examined if the magnitude of bezlotoxumab-induced RCDI reduction was influenced by the antibiotic used.  In the MODIFY I/II trials, subjects received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment.  Using pooled data from MODIFY I/II, initial clinical cure (ICC) and RCDI were evaluated in metronidazole-, vancomycin-, and fidaxomicin-treated subgroups.  Among 1,554 subjects in MODIFY I/II, 753 (48.5 %) received metronidazole, 745 (47.9 %) vancomycin, and 56 (3.6%) fidaxomicin.  Fewer subjects receiving metronidazole had a prior CDI episode in the previous 6 months (12.9 %) or greater than or equal to 1 risk factor for RCDI (66.0 %) versus subjects receiving vancomycin (41.2 % and 83.6 %, respectively) and fidaxomicin (55.4 % and 89.3 %, respectively).  ICC rates were similar in the bezlotoxumab (metronidazole, 81.0 %; vancomycin, 78.5 %; and fidaxomicin, 86.7 %) and placebo groups (metronidazole, 81.3 %; vancomycin, 79.6 %; and fidaxomicin, 76.9 %).  In placebo-treated subjects, the RCDI was lower in the metronidazole subgroup versus the vancomycin and fidaxomicin subgroups (metronidazole, 28.0 %; vancomycin, 38.4 %; and fidaxomicin, 35.0 %).  When analyzed by subsets based on history of CDI, RCDI rates were similar in the metronidazole and vancomycin groups; RCDI rates were lower in all antibiotic subgroups for bezlotoxumab versus placebo (metronidazole: rate difference [RD], -9.7 %; 95 % confidence interval [CI]: -16.4 % to -3.1 %; vancomycin: RD, -15.4 %; 95 % CI: -22.7 % to -8.0 %; fidaxomicin: RD, -11.9 %; 95 % CI: -38.1 % to 14.3 %).  The authors concluded that bezlotoxumab reduced RCDI versus placebo in patients receiving metronidazole and vancomycin, with a similar effect size in patients receiving fidaxomicin.

Comparison of Fecal Microbiota Transplantation with Bezlotoxumab in the Reduction of Risk of Recurrent Clostridium Difficile Infections

Alhifany and colleagues (2020) noted that the risk of recurrent CDIs (RCDIs) is high when treated with standard antibiotics therapy (SAT) alone.  It is suggested that the addition of fecal microbiota transplantation (FMT) or bezlotoxumab after SAT reduces the risk of RCDI.  In the absence of head-to-head randomized controlled trials (RCTs), these researchers compared the safety and efficacy of bezlotoxumab with FMT in reducing the risk of RCDI in hospitalized patients.  They carried out a systematic review and Bayesian network meta-analysis; a comprehensive search from inception to February 30, 2019 was conducted in 4 data-bases (Medline/PubMed, Embase, Scopus, ClinicalTrials.gov).  RCTs reporting the resolution of diarrhea associated with RCDI without relapse for at least 60 days after the end of treatments as the primary outcome were eligible for inclusion.  These investigators extracted author, year of publication, study design and binomial data that represented the resolution of diarrhea or adverse events (AEs) of monoclonal antibodies and FMT infusion.  Random-effects models were used for resolution rate of RCDI and AEs.  The Cochrane Risk of Bias tool was used to assess the quality of included RCTs.  Out of 1,003 articles identified, 7 RCTs involving 3,043 patients contributed to the review.  No difference was reported between single or multiple infusions of FMT and bezlotoxumab in resolving RCDI, (odds ratio [OR] 1.53, 95 % CI: 0.39 to 5.16) and (OR 2.86, 95 % CI: 1.29 to 6.57), respectively.  Patients treated with SAT alone or bezlotoxumab with SAT showed significantly lower rates of diarrhea than FMT (OR 0, 95 % CI: 0 to 0.09) and (OR 0, 95 % CI: 0 to 0.19), respectively.  There was no difference in terms of other AEs.  The authors concluded that this was the 1st network meta-analysis that has compared the recently FDA-approved bezlotoxumab with FMT for resolving RCDI.  The quality of the included RCTs was variable.  The findings of this study suggested no difference between single or multiple infusions of FMT and bezlotoxumab.  However, FMT was associated with a higher rate of non-serious diarrhea as opposed to SAT used alone or in combination with bezlotoxumab.

Bezlotoxumab for the Treatment of Clostridioides Difficile Infection in Cancer Patients

Cornely and colleagues (2020) stated that the incidence of CDI is reportedly higher and the cure rate lower in individuals with cancer versus those without cancer.  These researchers carried out an exploratory post-hoc analysis of the MODIFY I/II trials to examine how bezlotoxumab affected the rate of CDI-related outcomes in patients with cancer.  Subjects received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI anti-bacterial treatment.  A post-hoc analysis of CDI-related outcomes was performed in subgroups of MODIFY I/II patients with and without cancer.  Among 1,554 subjects in the modified intent-to-treat (mITT) population, 382 (24.6 %) were diagnosed with cancer (bezlotoxumab 190, placebo 192).  Of subjects without cancer, 591 and 581 received bezlotoxumab and placebo, respectively.  In the placebo group, ICC was achieved by fewer cancer patients versus participants without cancer (71.9 % versus 83.1 %; absolute difference, -11.3 %; 95 % CI: -18.6 % to -4.5 %); however, RCDI rates were similar in cancer (30.4 %) and non-cancer (34.0 %) subjects.  In subjects with cancer, bezlotoxumab treatment had no effect on ICC rate compared with placebo (76.8 % versus 71.9 %), but resulted in a statistically significant reduction in RCDI versus placebo (17.8 % versus 30.4 %; absolute difference, -12.6 %; 95 % CI: -22.5 % to -2.7 %).  The authors concluded that in this post-hoc analysis of patients with cancer enrolled in MODIFY I/II, the rate of RCDI in bezlotoxumab-treated subjects was lower than in placebo-treated subjects.  Moreover, these researchers stated that while these findings were encouraging, further research and real-world data are needed to confirm the efficacy of bezlotoxumab in preventing RCDI in individuals with cancer as a co-morbid condition.

The authors stated that this study had several drawbacks.  The analyses were retrospective and included a relatively small population of subjects with cancer.  The cancer subgroup was imbalanced compared with the non-cancer subgroup with regards to participant numbers, and baseline participant characteristics differed.  Moreover, this was a very heterogenous group of cancer patients and did not take into account the spectrum of illness of the patients included in the cancer subgroup (e.g., both patients with early-stage cancers as well as patients with late-stage metastatic disease were included in the cancer subgroup).  As this was a subgroup analysis of phase-III clinical trial data, the results may not be representative of a real-world population.

Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides Difficile Infection

Sferra et al (2023)noted that therapies to prevent recurrence of CDI in pediatric patients are needed.  Bezlotoxumab is approved for prevention of recurrent CDI in adults.  These investigators examined the pharmacokinetics, safety, tolerability, and effectiveness of bezlotoxumab in pediatric patients.  The MODIFY III Trial was a double-blind, placebo-controlled, multi-center study of bezlotoxumab in children (1 to less than 18 years) receiving anti-bacterial treatment for CDI.  Subjects were randomized 3:1 to receive a single infusion of bezlotoxumab (10 mg/kg) or placebo and were stratified by age at randomization (cohort 1: 12 to less than 18 years, cohort 2: 1 to less than 12 years).  The primary objective was to characterize bezlotoxumab pharmacokinetics to support dose selection for pediatric patients; the primary endpoint was the area under the bezlotoxumab serum concentration-time curve (AUC0-inf).  Safety, tolerability, and effectiveness were monitored for 12 weeks post-infusion.  A total of 148 subjects were randomized and 143 were treated: 107 with bezlotoxumab and 36 with placebo (cohort 1: n = 60; cohort 2: n = 83; median age of 9.0 years); 52.4 % of subjects were male and 80.4 % were white.  Geometric mean ratios (90 % CI) for bezlotoxumab AUC0-inf were 1.06 (0.95 to 1.18) and 0.82 (0.75 to 0.89) h * μg/ml for cohorts 1 and 2, respectively.  Bezlotoxumab 10 mg/kg was generally well-tolerated with an AE profile similar to placebo, including no treatment discontinuations due to AEs.  CDI recurrence was low and comparable for bezlotoxumab (11.2 %) and placebo (14.7 %).  The authors concluded that the findings of this study supported the bezlotoxumab dose of 10 mg/kg for pediatric patients; the same dose that has previously demonstrated safety and effectiveness for the prevention of CDI recurrence in adults.

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Appendix 

A Zar score calculator for CDI severity is available at the following website: Clostridium Difficile Diarrhea- Severity Assessment Score.

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References