Pharmacology Consult

Approaches to C. difficile prevention: Where are we now?

Clostridium difficile is a common hospital-acquired infection associated with increased morbidity and hospital cost. C. difficile is an especially difficult pathogen due to the transient contamination of hands and environmental surfaces with spores that can withstand common hygiene practices. Several risk factors are associated with hospital-acquired C. difficile infection, or CDI, including most antibiotics — especially third- and fourth-generation cephalosporins, fluoroquinolones, carbapenems and clindamycin. Other medications that increase the risk for developing CDI include chemotherapy, immunosuppression and proton pump inhibitors. Patient risk factors for developing CDI include older age, leukocytosis, comorbidities, renal failure, hypoalbuminemia and the need for tube feeding.

Interdisciplinary strategies for prevention

The core strategy to decrease hospital-acquired CDI is prevention. Despite the implementation of some other core strategies, our CDI rates remain higher than acceptable.

Kimberly Boeser

At our institution, we implemented an aggressive, three-pronged approach to C. difficile risk assessment. A C. difficile risk assessment tool using electronic medical records was developed and implemented in collaboration with pharmacy, infection prevention and environmental services staff. This tool assigns points for medications prescribed within the past 90 days and certain patient risk factors. For patients with a score meeting high-risk criteria, physician, nursing, patient and family education is provided by the infection preventionist, bedside nurse and the primary medical team. The patient room is marked for enhanced bleach cleaning on high-touch surfaces. A daily list of these high-risk patients is reviewed by an antimicrobial stewardship pharmacist, who conducts medication stewardship interventions on modifiable risk factors, like broad-spectrum antibiotic de-escalation or discontinuation or proton pump inhibitor discontinuation. This risk assessment tool has been useful for identifying high-risk patients, but its impact has not yet been fully realized.

Pharmacological treatment and prevention

Treatment guidelines for CDI were recently updated by the Infectious Diseases Society of America. The recommended treatment for an initial CDI episode includes oral vancomycin 125 mg four times daily, or fidaxomicin 200 mg twice daily for 10 days. This is a departure from the previous 2010 IDSA guidelines, which had recommended metronidazole as first-line therapy for nonsevere episodes. Bezlotoxumab, a monoclonal antibody, is the only product approved by the FDA to reduce the recurrence of CDI in adult patients. The guidelines do not provide recommendations for the use of bezlotoxumab because the cutoff date of the literature review that supported the guidelines fell before the publication of key bezlotoxumab clinical trial data.

Erin Weslander

Bezlotoxumab exerts its pharmacologic activity by binding to one of the structural domains on C. difficile toxin B (TcdB). This binding action is hypothesized to cause a blockade of the toxin’s carbohydrate binding pockets and ultimately prevent entry of TcdB into human colonic cells. In this manner, bezlotoxumab effectively neutralizes TcdB. Importantly, bezlotoxumab does not target the C. difficile bacterium itself, and thus cannot be used to treat active CDI. Patients with CDI who receive bezlotoxumab will also require treatment with a full course of standard-of-care antibiotics (ie, vancomycin, metronidazole or fidaxomicin) targeted at active CDI.

Bezlotoxumab is given in a single dose of 10 mg/kg, administered as an IV infusion over 60 minutes. The volume of distribution of bezlotoxumab is 7.33 L, with a clearance of 0.317 L per day and a half-life of 18.7 days; these pharmacokinetic parameters support the one-time dosing regimen. There are no data to support the safety and efficacy of repeat dosing of bezlotoxumab for the prevention of recurrent CDI. A recent analysis of data from phase 3 clinical trials showed that recurrence rates with bezlotoxumab were lower than those of placebo at 0 to 2, 3 to 4, or 5 or more days after the initiation of antibiotic therapy. Given that bezlotoxumab does not aid in achieving clinical cure of CDI and may be administered at any time before completion of antibiotic therapy without compromising efficacy, a more favorable reimbursement balance to health systems is likely when bezlotoxumab is administered in the outpatient setting following discharge rather than during hospitalization.

Clinical trial data supporting the approval for bezlotoxumab come from two phase 3 clinical trials, MODIFY I and MODIFY II. These randomized, multicenter, placebo-controlled trials included a total of 2,655 adult patients with primary or recurrent CDI who were receiving standard-of-care antibiotics for 10 to 14 days. Patients were randomly assigned in a 1:1:1 fashion to receive either a single dose of bezlotoxumab, a dose of bezlotoxumab plus actoxumab (a monoclonal antibody that targets C. difficile toxin A), or placebo. In MODIFY I, an additional study arm was treated with actoxumab alone, but it was not studied in MODIFY II because of a lack of efficacy. The primary endpoint of both trials was the proportion of participants with recurrent CDI during the 12-week follow-up period in the modified intent-to-treat (mITT) population. Secondary outcomes included CDI recurrence in patients who had achieved initial clinical cure, and in other patient subgroups with risk factors for recurrent CDI or adverse outcomes related to CDI. A further secondary outcome was sustained cure, also referred to as global cure, in which patients had initial clinical cure and no recurrence of infection through 12 weeks. Initial clinical cure was an exploratory outcome.

A total of 2,559 patients were included in the mITT population. In the pooled data analysis of the two trials, patients in the bezlotoxumab group experienced a recurrence rate of 16.5% vs. 26.6% in the placebo group (adjusted difference, –10; 95% CI, –14 to –6.) CDI recurrence in patients with initial clinical cure was 20.6% in the bezlotoxumab group vs. 33.2% in the placebo group (adjusted difference, –12.2; 95% CI, –17.1 to –7.4). Global cure was higher in the bezlotoxumab group at 63.5% vs. placebo at 53.7% (adjusted difference, 9.7; 95% CI, 4.8-14.5). According to the results, 80% of patients in each of the bezlotoxumab and placebo groups achieved clinical cure. Bezlotoxumab was favored over placebo for the decreased incidence of recurrent CDI in the prespecified subgroups of patients with risk factors for recurrence, except for the subgroup of patients with C. difficile 027, 078 or 244 strains. Of note, no significant differences were noted between the bezlotoxumab group and the bezlotoxumab plus actoxumab group in CDI recurrence, initial cure, recurrence in patients with initial clinical cure, or global cure.

Ashley Cubillos

Drug-related adverse events in the phase 3 trials were generally minor — usually related to the infusion of the drug, which occurred in 9% of study participants. The most frequent reactions were nausea, headache, dizziness, fatigue and pyrexia, and rates of these events were not significantly different among study groups. Notably, numerically more patients in the bezlotoxumab and actoxumab-bezlotoxumab groups experienced heart failure vs. placebo in the 12-week follow-up period (18 and 17 patients vs. nine patients, respectively). Primarily, heart failure occurred in patients with pre-existing congestive heart failure (CHF). Thus, a warning was added to the bezlotoxumab package insert to reserve use of bezlotoxumab in patients with CHF for circumstances in which the benefits outweigh the risks.

CDI is a complicated disease, and it continues to have a tremendous impact on patients’ quality of life and health care resources. The prevention and treatment of CDI are multifaceted, and both are extremely challenging, leading to slow progress to reduce hospital-acquired CDI rates. In our experience, and with our organizational focus on C. difficile, we have learned that all prevention strategies and treatment efforts need to be aggressive and run in parallel. Bezlotoxumab may be one additional strategy, but the selection of appropriate patients who can benefit from it remains a challenge given the significant cost of the drug. With minimal guidance for clinicians, the available data suggest that patients with even one risk factor for recurrence may benefit from bezlotoxumab. However, the most significant reduction in recurrent CDI is likely to be among patients with multiple risk factors.

Disclosures: Boeser, Cubillos and Weslander report no relevant financial disclosures.

Clostridium difficile is a common hospital-acquired infection associated with increased morbidity and hospital cost. C. difficile is an especially difficult pathogen due to the transient contamination of hands and environmental surfaces with spores that can withstand common hygiene practices. Several risk factors are associated with hospital-acquired C. difficile infection, or CDI, including most antibiotics — especially third- and fourth-generation cephalosporins, fluoroquinolones, carbapenems and clindamycin. Other medications that increase the risk for developing CDI include chemotherapy, immunosuppression and proton pump inhibitors. Patient risk factors for developing CDI include older age, leukocytosis, comorbidities, renal failure, hypoalbuminemia and the need for tube feeding.

Interdisciplinary strategies for prevention

The core strategy to decrease hospital-acquired CDI is prevention. Despite the implementation of some other core strategies, our CDI rates remain higher than acceptable.

Kimberly Boeser

At our institution, we implemented an aggressive, three-pronged approach to C. difficile risk assessment. A C. difficile risk assessment tool using electronic medical records was developed and implemented in collaboration with pharmacy, infection prevention and environmental services staff. This tool assigns points for medications prescribed within the past 90 days and certain patient risk factors. For patients with a score meeting high-risk criteria, physician, nursing, patient and family education is provided by the infection preventionist, bedside nurse and the primary medical team. The patient room is marked for enhanced bleach cleaning on high-touch surfaces. A daily list of these high-risk patients is reviewed by an antimicrobial stewardship pharmacist, who conducts medication stewardship interventions on modifiable risk factors, like broad-spectrum antibiotic de-escalation or discontinuation or proton pump inhibitor discontinuation. This risk assessment tool has been useful for identifying high-risk patients, but its impact has not yet been fully realized.

Pharmacological treatment and prevention

Treatment guidelines for CDI were recently updated by the Infectious Diseases Society of America. The recommended treatment for an initial CDI episode includes oral vancomycin 125 mg four times daily, or fidaxomicin 200 mg twice daily for 10 days. This is a departure from the previous 2010 IDSA guidelines, which had recommended metronidazole as first-line therapy for nonsevere episodes. Bezlotoxumab, a monoclonal antibody, is the only product approved by the FDA to reduce the recurrence of CDI in adult patients. The guidelines do not provide recommendations for the use of bezlotoxumab because the cutoff date of the literature review that supported the guidelines fell before the publication of key bezlotoxumab clinical trial data.

Erin Weslander
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Bezlotoxumab exerts its pharmacologic activity by binding to one of the structural domains on C. difficile toxin B (TcdB). This binding action is hypothesized to cause a blockade of the toxin’s carbohydrate binding pockets and ultimately prevent entry of TcdB into human colonic cells. In this manner, bezlotoxumab effectively neutralizes TcdB. Importantly, bezlotoxumab does not target the C. difficile bacterium itself, and thus cannot be used to treat active CDI. Patients with CDI who receive bezlotoxumab will also require treatment with a full course of standard-of-care antibiotics (ie, vancomycin, metronidazole or fidaxomicin) targeted at active CDI.

Bezlotoxumab is given in a single dose of 10 mg/kg, administered as an IV infusion over 60 minutes. The volume of distribution of bezlotoxumab is 7.33 L, with a clearance of 0.317 L per day and a half-life of 18.7 days; these pharmacokinetic parameters support the one-time dosing regimen. There are no data to support the safety and efficacy of repeat dosing of bezlotoxumab for the prevention of recurrent CDI. A recent analysis of data from phase 3 clinical trials showed that recurrence rates with bezlotoxumab were lower than those of placebo at 0 to 2, 3 to 4, or 5 or more days after the initiation of antibiotic therapy. Given that bezlotoxumab does not aid in achieving clinical cure of CDI and may be administered at any time before completion of antibiotic therapy without compromising efficacy, a more favorable reimbursement balance to health systems is likely when bezlotoxumab is administered in the outpatient setting following discharge rather than during hospitalization.

Clinical trial data supporting the approval for bezlotoxumab come from two phase 3 clinical trials, MODIFY I and MODIFY II. These randomized, multicenter, placebo-controlled trials included a total of 2,655 adult patients with primary or recurrent CDI who were receiving standard-of-care antibiotics for 10 to 14 days. Patients were randomly assigned in a 1:1:1 fashion to receive either a single dose of bezlotoxumab, a dose of bezlotoxumab plus actoxumab (a monoclonal antibody that targets C. difficile toxin A), or placebo. In MODIFY I, an additional study arm was treated with actoxumab alone, but it was not studied in MODIFY II because of a lack of efficacy. The primary endpoint of both trials was the proportion of participants with recurrent CDI during the 12-week follow-up period in the modified intent-to-treat (mITT) population. Secondary outcomes included CDI recurrence in patients who had achieved initial clinical cure, and in other patient subgroups with risk factors for recurrent CDI or adverse outcomes related to CDI. A further secondary outcome was sustained cure, also referred to as global cure, in which patients had initial clinical cure and no recurrence of infection through 12 weeks. Initial clinical cure was an exploratory outcome.

PAGE BREAK

A total of 2,559 patients were included in the mITT population. In the pooled data analysis of the two trials, patients in the bezlotoxumab group experienced a recurrence rate of 16.5% vs. 26.6% in the placebo group (adjusted difference, –10; 95% CI, –14 to –6.) CDI recurrence in patients with initial clinical cure was 20.6% in the bezlotoxumab group vs. 33.2% in the placebo group (adjusted difference, –12.2; 95% CI, –17.1 to –7.4). Global cure was higher in the bezlotoxumab group at 63.5% vs. placebo at 53.7% (adjusted difference, 9.7; 95% CI, 4.8-14.5). According to the results, 80% of patients in each of the bezlotoxumab and placebo groups achieved clinical cure. Bezlotoxumab was favored over placebo for the decreased incidence of recurrent CDI in the prespecified subgroups of patients with risk factors for recurrence, except for the subgroup of patients with C. difficile 027, 078 or 244 strains. Of note, no significant differences were noted between the bezlotoxumab group and the bezlotoxumab plus actoxumab group in CDI recurrence, initial cure, recurrence in patients with initial clinical cure, or global cure.

Ashley Cubillos

Drug-related adverse events in the phase 3 trials were generally minor — usually related to the infusion of the drug, which occurred in 9% of study participants. The most frequent reactions were nausea, headache, dizziness, fatigue and pyrexia, and rates of these events were not significantly different among study groups. Notably, numerically more patients in the bezlotoxumab and actoxumab-bezlotoxumab groups experienced heart failure vs. placebo in the 12-week follow-up period (18 and 17 patients vs. nine patients, respectively). Primarily, heart failure occurred in patients with pre-existing congestive heart failure (CHF). Thus, a warning was added to the bezlotoxumab package insert to reserve use of bezlotoxumab in patients with CHF for circumstances in which the benefits outweigh the risks.

CDI is a complicated disease, and it continues to have a tremendous impact on patients’ quality of life and health care resources. The prevention and treatment of CDI are multifaceted, and both are extremely challenging, leading to slow progress to reduce hospital-acquired CDI rates. In our experience, and with our organizational focus on C. difficile, we have learned that all prevention strategies and treatment efforts need to be aggressive and run in parallel. Bezlotoxumab may be one additional strategy, but the selection of appropriate patients who can benefit from it remains a challenge given the significant cost of the drug. With minimal guidance for clinicians, the available data suggest that patients with even one risk factor for recurrence may benefit from bezlotoxumab. However, the most significant reduction in recurrent CDI is likely to be among patients with multiple risk factors.

Disclosures: Boeser, Cubillos and Weslander report no relevant financial disclosures.