Monoclonal Antibodies Use in Clostridium Difficile Infections
Authors: Karli Kurwicki, STLCOP Pharm.D. Candidate 2018 Kendall Shultes, Pharm.D.
Clostridium difficile infections (CDIs) affected approximately half a million patients in 2011 and its incidence continues to grow.1 CDIs are a major health concern as they can be associated with a mortality rate as high as 38%.2 CDIs add nearly $1 billion to the overall health-care related costs in the United States. A recurrence of CDI occurs in up to 35% of patients who have completed appropriate initial therapy.3 Patients who are associated with a higher risk of recurrent CDIs are age 65 years and older, severe initial CDI, use of proton-pump inhibitors or H2 receptor antagonists, prolonged hospitalization, and current use of antibiotics for other infections.4 With the high incidence of recurrence and growing costs, studies have sought additional therapies for treating and preventing CDIs. Studies have shown the benefit of monoclonal antibodies in both the initial treatment and prevention of CDI recurrence and may fill that niche.
The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) clinical practice guidelines recommend either vancomycin 125 mg by mouth four times daily or metronidazole 500 mg by mouth three times daily for 10-14 days for mild, moderate, and severe uncomplicated infections. Severe, complicated infections are treated more aggressively with a combination of vancomycin 500 mg by mouth and metronidazole 500 mg intravenously. SHEA and IDSA guidelines recommend this same treatment strategy for the first recurrence of CDI.5
In current practice, metronidazole is generally considered first line treatment for the initial CDI and recurrence of CDI. A recently published retrospective study comparing vancomycin and metronidazole treatment demonstrated that patients with severe CDI who received vancomycin had a statistically significant lower rate of mortality compared to patients who were given metronidazole (p = 0.01) however, there was no statistical or clinical difference between vancomycin and metronidazole in the prevention of CDI recurrence. As these medications are the mainstay of therapy but do not prevent the recurrence of CDIs, there is a need for a preventative agent to help lower the risk of recurrence.6
CDIs are caused by two exotoxins, TcdA and TcdB. Toxins TcdA and TcdB are found in healthy individuals’ gastrointestinal tract. When a patient is exposed to antibiotics, the activity against the natural bacteria in the gastrointestinal tract compromises the body’s natural defense against CDIs. This allows the toxins to bind to cell receptors in the gastrointestinal tract and upon entry into the cell, inactivate enzymes that lead to the release of interleukin 8 (IL-8) and an increase in cell permeability. The release of IL-8 and increased permeability of the cells leads to severe diarrhea that can occur several times per day.7
Monoclonal antibodies, such as actoxumab and bezlotoxumab, which bind to toxins A and B respectively, have shown great promise for preventing recurrence in patients who have had CDIs through neutralizing toxins and preventing binding to cells in the gastrointestinal tract.8 Two clinical trials, MODIFY I and MODIFY II, recently studied the use of monoclonal antibodies in the prevention of recurrent CDIs. Subjects in these trials were randomized to receive either bezlotoxumab 10 mg/kilogram (kg) alone, bezlotoxumab and actoxumab 10 mg/kg each, actoxumab 10 mg/kg alone in MODIFY I, or placebo in addition to their standard of care antibiotics which included vancomycin, metronidazole, or fidaxomicin. MODIFY I showed that actoxumab alone did not demonstrate efficacy and had more deaths and adverse effects associated with its therapy so it was not analyzed in MODIFY II. If randomized to the treatment group, patients received one 60-minute infusion along with their standard of care antibiotics as indicated above. Both studies demonstrated that bezlotoxumab statistically significantly decreased the recurrence of CDIs compared to placebo, MODIFY I 28% vs 17%, and MODIFY II 26% vs 16%, each p< 0.001. These trials also demonstrated that subjects receiving bezlotoxumab alone compared to placebo had improved sustained clinical cure rates (MODIFY I 60% vs. 55%; MODIFY II 67% vs. 52%). The results were statistically significant in MODIFY II (p< 0.001). Common adverse effects reported in the treatment groups from MODIFY I and II were headache, nausea, and diarrhea.3
Based on trials, bezlotoxumab is FDA approved for use in patients greater or equal to 18 years old who are receiving antibiotic treatment for a CDI and who have a high risk of recurrent CDI.9 Bezlotoxumab is given as a one-time infusion at 10 mg/kg given over 60 minutes. Bezlotoxumab needs to be given with a low protein binding filter (0.2-5 microns) and should be diluted prior to use with 0.9% sodium chloride or 5% dextrose. Once it has been diluted, bezlotoxumab can be stored at room temperature for 16 hours or in the refrigerator for 24 hours. Common adverse effects associated with bezlotoxumab are nausea, pyrexia, and headache. In clinical trials, patients with a history of heart failure who received bezlotoxumab experienced a worsening of their heart failure and it should be used cautiously in this patient population.9
Another agent with a similar mechanism of action as monoclonal antibodies is intravenous immune globulin (IVIG). It works by neutralizing toxins A and B to provide passive immunity against Clostridium difficile toxins. IVIG, although does not have FDA approval for use in recurrent CDI prevention, is currently used last line for CDIs as a salvage treatment and is reserved for use in severe, complicated CDIs when patients do not respond to other available therapies.5 Treatment of CDIs with IVIG in combination with metronidazole and vancomycin has been shown to decrease the rate of recurrence of CDIs by up to 14%.10 Unfortunately, a dose and duration for IVIG has not been standardized for the treatment of CDIs. A dose that has been studied for treatment of severe CDI is a single 400 mg/kg dose either three times weekly or as two single doses.11 Common adverse effects of IVIG are headache, pyrexia, edema, fatigue, nausea, and hypotension.12
CDI is a major healthcare problem affecting the United States and as the mortality rates for CDIs continue to grow, it is important to find a treatment that helps the initial cure rates and decreases the recurrence of CDIs. Monoclonal antibodies have shown great benefit in reducing the recurrence of CDIs when used with standard of care antibiotics. Although expensive, they offer promise in decreasing mortality associated with CDIs. As research continues, monoclonal antibodies, such as bezlotoxumab, should be added into clinical practice guidelines to increase initial clinical cure rates, decrease recurrence, and decrease mortality caused by Clostridium difficile infections.