Long-Term Care Updates April 2018 By Austin Smith, PharmD Candidate and Lindsay Slowiczek, PharmD is the most common healthcare-acquired infection (HAI) in the United States. 1,2 A 2014 prevalence survey reported that 12.8% of HAIs are caused by infections (CDI). 1 The previous clinical practice guidelines for CDI treatment were published in 2010. 3 Since this publication, many studies have examined therapeutic regimens used in the treatment of CDI. On February 15, 2018 the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) released updated guidelines addressing changes in diagnosis and treatment of CDI. The updates this newsletter will discuss include changes to first-line antibiotic therapy, fecal microbiota transplantation, a new monoclonal antibody therapy, and various additional recommendations related to CDI treatment. 4 Recent information related to CDI therapy not addressed in the guidelines, including a new vancomycin oral solution and a fidaxomicin extended-pulsed dosing regimen, will also be reviewed. One major update to the CDI guidelines is a change in the recommendations for first-line treatment. Metronidazole was previously preferred as first-line for mild-to-moderate infections. The previous recommendation was based on studies such as a 2007 randomized, controlled trial by Zar et al, which found no statistical difference between vancomycin and metronidazole for mild CDI. 5 In the years since this study was released, more evidence has been published justifying a shift away from metronidazole for patients with mild or moderate infection. In a retrospective cohort study by Siegfried et al and two randomized, controlled trials by Johnson et al, investigators assessed treatment response to initial therapy and rate of CDI recurrence in a total of 1,286 patients. 6,7 In the study by Siegfried et al, which included patients with mild-to-moderate CDI, treatment response was 97% for vancomycin compared to 82% for metronidazole (p=0.002). These data suggest for every 7 patients treated with vancomycin instead of metronidazole, one additional patient will experience clinical success, or a resolution of diarrhea and absence of severe abdominal discomfort due to CDI for more than 2 consecutive days. The recurrence rate following vancomycin treatment was 13% compared to 9% for metronidazole, though this difference was not significant (p=0.44). It is important to note that this study does not address the power required to detect a difference in recurrence rates. 6
A combined analysis of the studies by Johnson et al included patients with 3 or more bowel movements per day with loose consistency, a positive toxin assay result, or pseudomembrane on endoscopy, and no other likely cause of diarrhea. In these studies, metronidazole-treated patients had a response rate of 72.7%, which was inferior to the 81.1% response rate seen with vancomycin for patients of all disease severities (p=0.02). These studies showed that for every 12 patients treated with vancomycin instead of metronidazole, 1 additional treatment response will be seen. Patients also had greater clinical success taking vancomycin for their first occurrence of CDI, compared to metronidazole (82.7% vs. 75%; p= 0.04; NNT=13). When the combined study data was analyzed by disease severity, the investigators found no significant difference in rates of clinical success for mild, moderate, or severe CDI infection. The differences in recurrence rates were insignificant between the three subgroups, as well. Rates of CDI recurrence were similar between the two groups containing all severities of disease. 7 These two larger studies were each powered to detect a statistical difference in recurrence rates. The IDSA/SHEA guidelines do not provide clear recommendations on categorizing the severity of CDI, meaning studies such as these that discuss disease severity often use their own criteria for categorizing patients. The updated guidelines cite this evidence, among additional studies, as justification for the preference for vancomycin or fidaxomicin over metronidazole for all severities of CDI infections. The table below summarizes current therapy recommendations (see Table 1 on the next page). 4 The 2018 guideline updates recognize the approval of bezlotoxumab for adjunctive treatment in patients at high risk of CDI recurrence. This monoclonal antibody binds to toxin B and neutralizes it, preventing its toxic effects. 10 In two double-blind, randomized, placebo-controlled trials by Wilcox et al, bezlotoxumab showed significantly lower rates of CDI recurrence compared to placebo (16-17% recurrence vs 28%, p 0.001). Fecal Transplantation The updated guidelines also address the role of fecal transplantation in CDI. Candidates who could be considered for this therapy include patients with multiple recurrences of who have failed multiple antibiotic treatments. 4 In a systematic review by Wang et al, adverse events of fecal transplantation seemed to most often be self-limited. Commonly reported side effects included abdominal discomfort, diarrhea, transient fever, nausea, vomiting, and constipation. 8 Additional recommendations from investigators include an "induction course" of 3 to 4 days of vancomycin before the transplantation. 4 Potential donor candidates for this procedure include those who have been cleared as non-infectious through blood and fecal tests. Donor exclusion criteria include those who have received antibiotics in the last 3 months, preexisting chronic conditions, malignant diseases, chronic infections, autoimmune diseases, or patients taking immunosuppressive agents. 9
Table 1. Therapy Recommendations in the 2018 Update 4 Clinical Definition Initial episode, non-severe Initial episode, severe First recurrence Recommended Treatments Vancomycin 125 mg orally, 4 times daily for 10 days OR Fidaxomicin 200 mg orally, 2 times daily for 10 days OR Alternate regimen if other agents are not available: metronidazole 500mg orally, 3 times daily for 10 days Vancomycin 125 mg orally, 4 times daily for 10 days OR Fidaxomicin 200 mg orally, 2 times daily for 10 days Vancomycin 125 mg orally, 4 times daily for 10 days if metronidazole was used for 1st episode OR Use a prolonged tapered and pulsed vancomycin regimen if standard regimen was used OR Fidaxomicin 200 mg orally, twice daily for 10 days if vancomycin was used for 1st episode Second or subsequent recurrence Vancomycin tapered and pulsed regimen OR Vancomycin normal regimen followed by rifaximin 400 mg orally, 3 times daily for 20 days OR Fidaxomicin 200 mg orally, 2 times daily for 10 days OR Fecal microbiota transplantation Data from these studies suggest that for every 9 to 10 patients treated with bezlotoxumab, 1 CDI recurrence will be prevented compared to placebo. 11 As more studies are published comparing this agent to other therapies for recurrent CDI, future guideline updates will most likely address the role of bezlotoxumab in treatment. Though not mentioned in the guidelines, an important update to CDI therapy includes the approval of an oral vancomycin liquid, marketed as Firvanq. This reconstituted product will replace CutisPharma's currently available vancomycin compounding kit. The drug is expected to launch April 2nd, 2018. 12 Table 2 on the next page provides important information regarding Firvanq dosing and administration considerations.
Table 2. Characterisitics of Firvanq TM (oral vancomycin hydrochloride solution) 13 Indications Adult Dosing for CDAD Adverse Reactions Geriatric Considerations Preparation Concentrations C. difficile-associated diarrhea (CDAD) Enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) 125 mg orally 4 times daily for 10 days Adverse events are similar, but not identical, to other oral vancomycin products. Most common ( 10%): nausea (17%), abdominal pain (15%), and hypokalemia (13%) Renal function should be monitored during and after treatment due to possibility of systemic absorption. Geriatric patients may take longer to respond to therapy than younger adults. Each kit contains 1 bottle of vancomycin hydrochloride USP powder and 1 bottle of premeasured grape-flavored diluent. Vancomycin oral solution is available in a 25 mg/ml or 50 mg/ml concentrations Contraindications Storage Known hypersensitivity to vancomycin Refrigeration (36 to 46 F) An additional item not addressed in the updated CDI guidelines, due to date of publication, includes the potential for improved efficacy of fidaxomicin with extended-pulsed dosing. A recent randomized, controlled, open-label trial by Guery et al administered fidaxomicin 200 mg tablets orally twice daily on days 1-5 (pulsed dosing) and once daily on alternate days for days 7-25 (extended dosing). 14 This regimen was compared to standard vancomycin dosing. The hypothetical justification behind this dosing regimen is the probable gut microbiota-sparing benefits of maintaining lower concentrations combined with longer therapy duration. Before this study, evidence of improved outcomes in extended-pulsed dosing had only been addressed in case series. The primary endpoint of this study was sustained clinical cure 30 days after stopping treatment which was assessed in 364 patients, all of whom were 60 years and older. Fidaxomicin resulted in clinical cure in 70% of patients, compared to 59% of patients taking vancomycin (p=0.03). These data suggest that for every 10 patients treated with fidaxomicin extendedpulsed dosing versus standard vancomycin dosing, 1 additional patient will achieve clinical cure at 30 days post-treatment. Adverse events occurred at similar rates in the fidaxomicin and vancomycin groups (67% vs. 71%). Fidaxomicin was associated with slightly higher rates of constipation (6% vs. 3%), whereas patients receiving vancomycin had higher rates of other more common adverse events including anemia (3% vs. 6%), cardiac failure (2% vs. 6%), diarrhea (6% vs. 7%), fever (4% vs. 7%), pneumonia (3% vs. 6%), and urinary tract infection (3% vs. 7%). 14 Fidaxomicin extended-pulsed dosing has not yet been directly compared to standard fidaxomicin dosing or a comparable pulsed vancomycin regimen in human subjects. This evidence may be discussed in future CDI guidelines.
In addition to the previously mentioned guideline updates, there have also been changes to CDI testing preferences. The IDSA and SHEA recommend that facilities have their own algorithm for molecular tests, along with common antigen and stool toxin tests, instead of immunoassays alone. Pharmacists should continue to diligently monitor antimicrobial stewardship by minimizing the frequency and duration of high-risk antibiotics and the overall number of antibiotics a patient is receiving. While the previous guidelines advised against the use of probiotics in patients with CDI, the updated guidelines provide no recommendation for their use due to insufficient evidence and inconsistency between products. Specific probiotics may be addressed in later guideline updates. Finally, recommendations for pediatric dosing and infection management in this population have also been included in the new guidelines. 4 There have been many updates to the CDI practice guidelines based on evidence published in recent years. Most importantly, first-line therapy recommendations have been updated to recommend the use of vancomycin over metronidazole. In addition to updates addressed in the guidelines, new products such as oral vancomycin solution and bezlotoxumab have been approved which could impact the care of patients with CDI. Pharmacists should be aware of the guideline changes, how it may affect their practices, and be a resource for healthcare providers navigating these updates. 1. Magill SS, Edwards JR, Stat EM, et al. Multistate point-prevalence survey of health care-associated infections. 2014;370:1198-1208. Accessed March 2, 2018. http://www.nejm.org/doi/full/10.1056/nejmoa1306801. 2. Miller BA, Chen LF, Sexton DJ, Anderson DJ. Comparison of the burdens of hospital-onset, healthcare facility-associated infection and of healthcare-associated infection due to methicillin-resistant in community hospitals. 2011;32(4):387-390. Accessed March 2, 2018. https://www.ncbi.nlm.nih.gov/pubmed/21460491. 3. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). 2010;31(5):431-455. Accessed March 2, 2018. https://www.idsociety.org/uploadedfiles/idsa/guidelines-patient_care/pdf_library/cdiff2010a.pdf. 4. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for infections in adults and children: 2017 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). 2018;ISSN:1537-6591. Accessed March 2, 2018. DOI: 10.1093/cid/cix1085 5. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. 2007; 45:302 307. Accessed March 2, 2018. https://academic.oup.com/cid/article/45/3/302/358373. 6. Siegfried J, Dubrovskaya Y, Flagiello T, et al. Initial therapy for mild-to-moderate infection. 2016;24(4):210-216. Accessed March 2, 2018. DOI: 10.1097/IPC.0000000000000375.
7. Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for infection: Results from two multinational, randomized, clinical trials. 2014;59(3):345-354. Accessed March 2, 2018. https://academic.oup.com/cid/article/59/3/345/2895557. 8. Wang S, Xu M, Wang W, et al. Systematic review: Adverse events of fecal microbiota transplantation. 2016;11(8):e0161174. Accessed March 5, 2018. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161174. 9. Bakken JS, Borody T, Brandt LJ, et al. Fecal microbiota transplantation workgroup: Treating infection with fecal microbiota transplantation. 2011; 9:1044 1049. Accessed March 5, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3223289/ 10. Lexicomp. Hudson, OH. Wolters Kluwer Clinical Drug Information; 2018 http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6330293. Updated March 3, 2018. Accessed March 5, 2018. 11. Wilcox MH, Gerding DN, Poxton IA, et al. Bezlotoxumab for prevention of recurrent infection. 2017;376:305-317. Accessed March 5, 2018. http://www.nejm.org/doi/full/10.1056/nejmoa1602615. 12. CutisPharma announces FDA approval of FIRVANQ. Wilmington, MA. CutisPharma 2018. http://cutispharma.com/cutispharma-announces-fda-approval-firvanq/. Accessed March 5, 2018. 13. FIRVANQ [package insert]. Wilmington, MA. CutisPharma 2018. Accessed March 5, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208910s000lbl.pdf. 14. Guery B, Menichetti F, Anttila VJ, et al. Extended-pulsed fidaxomicin versus vancomycin for infection in patients 60 years and older (EXTEND): A randomized, controlled, open-label, phase 3b/4 trial. 2017;18(3):296-307. Accessed March 5, 2018. https://www.sciencedirect.com/science/article/pii/s147330991730751x?via%3dihub. http://creighton.edu/pharmerica