By Austin Smith, PharmD Candidate and Lindsay Slowiczek, PharmD

April 2018

Long-Term Care Updates

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.

The updated guidelines also address therole of fecal transplantation in CDI.Candidates who could be consideredfor this therapy include patients withmultiple recurrences of whohave failed multiple antibiotic

treatments.4 In a systematic review byWang et al, adverse events of fecaltransplantation seemed to most oftenbe self-limited. Commonly reportedside effects included abdominaldiscomfort, diarrhea, transient fever,

nausea, vomiting, and constipation.8

Additional recommendations frominvestigators include an "inductioncourse" of 3 to 4 days of vancomycin

before the transplantation.4

Potential donor candidates for thisprocedure include those who have beencleared as non-infectious through bloodand fecal tests. Donor exclusion criteriainclude those who have receivedantibiotics in the last 3 months, pre-existing chronic conditions, malignantdiseases, chronic infections,autoimmune diseases, or patients taking

immunosuppressive agents.9

Fecal Transplantation

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).

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.

Clinical Definition Recommended Treatments

Initial episode, non-severe

● 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

Initial episode, severe● Vancomycin 125 mg orally, 4 times daily for 10 days OR● Fidaxomicin 200 mg orally, 2 times daily for 10 days

First recurrence

● Vancomycin 125 mg orally, 4 times daily for 10 days ifmetronidazole was used for 1st episode OR

● Use a prolonged tapered and pulsed vancomycin regimen ifstandard regimen was used OR

● Fidaxomicin 200 mg orally, twice daily for 10 days if vancomycinwas used for 1st episode

Second or subsequentrecurrence

● 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

Table 1. Therapy Recommendations in the 2018 Update4

An additional item not addressed in the updatedCDI guidelines, due to date of publication,includes the potential for improved efficacy offidaxomicin with extended-pulsed dosing. Arecent randomized, controlled, open-label trialby Guery et al administered fidaxomicin 200 mgtablets orally twice daily on days 1-5 (pulseddosing) and once daily on alternate days for days

7-25 (extended dosing).14 This regimen wascompared to standard vancomycin dosing. Thehypothetical justification behind this dosingregimen is the probable gut microbiota-sparingbenefits of maintaining lower concentrationscombined with longer therapy duration. Beforethis study, evidence of improved outcomes inextended-pulsed dosing had only beenaddressed in case series. The primary endpointof this study was sustained clinical cure 30 daysafter stopping treatment which was assessed in364 patients, all of whom were 60 years and

older. Fidaxomicin resulted in clinical cure in 70% ofpatients, compared to 59% of patients takingvancomycin (p=0.03). These data suggest that forevery 10 patients treated with fidaxomicin extended-pulsed dosing versus standard vancomycin dosing, 1additional patient will achieve clinical cure at 30 dayspost-treatment. Adverse events occurred at similarrates in the fidaxomicin and vancomycin groups (67%vs. 71%). Fidaxomicin was associated with slightlyhigher rates of constipation (6% vs. 3%), whereaspatients receiving vancomycin had higher rates ofother 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 beendirectly compared to standard fidaxomicin dosing or acomparable pulsed vancomycin regimen in humansubjects. This evidence may be discussed in futureCDI guidelines.

Indications ● C. difficile-associated diarrhea (CDAD)● Enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains)

Adult Dosingfor CDAD 125 mg orally 4 times daily for 10 days

AdverseReactions

Adverse events are similar, but not identical, to other oral vancomycin products.Most common (≥10%): nausea (17%), abdominal pain (15%), and hypokalemia (13%)

GeriatricConsiderations

● Renal function should be monitored during and after treatment due to possibility ofsystemic absorption.

● Geriatric patients may take longer to respond to therapy than younger adults.

Preparation Each kit contains 1 bottle of vancomycin hydrochloride USP powder and 1 bottle of pre-measured grape-flavored diluent.

Concentrations Vancomycin oral solution is available in a 25 mg/mL or 50 mg/mL concentrations

Contraindications Known hypersensitivity to vancomycin

Storage Refrigeration (36 to 46°F)

Table 2. Characterisitics of FirvanqTM (oral vancomycin hydrochloride solution)13

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-associatedinfection 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: 2010update 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 andchildren: 2017 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious DiseaseSociety 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 ofClostridium difficile-associated diarrhea, stratified by disease severity. 2007; 45:302–307. Accessed March2, 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.

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.

http://creighton.edu/pharmerica

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 infectionwith 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; 2018http://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 infectionin 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.

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