Antimicrobial Stewardship Initiatives C Difficile Treatment Deanne Tabb PharmD, MT (ASCP) Infectious Disease Specialist

California Senate Bill No. 1311 (July 1st 2015) Existing law requires general acute care hospitals to develop a process for evaluating the judicious use of antibiotics, the result of which is required to be monitored by appropriate representatives and committees involved in quality improvement activities. Adopt and implement an antimicrobial stewardship policy in accordance with guidelines established by the federal government and professional organizations. This policy shall include a process to evaluate the judicious use of antibiotics in accordance with paragraph (3) of subdivision (a) of Section 1288.8. Develop a physician supervised multidisciplinary antimicrobial stewardship committee, subcommittee, or workgroup. Appoint to the physician supervised multidisciplinary antimicrobial stewardship committee, subcommittee, or workgroup, at least one physician or pharmacist who is knowledgeable about the subject of antimicrobial stewardship through prior training or attendance at continuing education programs, including programs offered by the federal Centers for Disease Control and Prevention, the Society for Healthcare Epidemiology of America, or similar recognized professional organizations. Report antimicrobial stewardship program activities to each appropriate hospital committee undertaking clinical quality improvement activities.

Team members • Antimicrobial Stewardship Team: Infectious Disease physician (Chair), ID pharmacist, Infection Control preventionist, Microbiology supervisor, Hospitalist, and Intensivist • LEAPT C. difficile Steering Committee: members from Clinical Transformation, Quality Management, Nursing, Pharmacy, Infection Control, Information Technology • Senior Nursing leaders • Unit nursing leadership • Frontline clinical staff • Risk Management

process • Antimicrobial Stewardship Team (AST) website created • Daily Activities include - Assessment of use of restricted antimicrobial agents - Pharmacokinetic management of antibiotics through TDM - Microbial follow up for inpatients and ED patients - Antibiogram development - Order set, empiric guideline, and pathway development - Assessments of intravenous (IV) to oral (PO) antibiotic - Antimicrobial dose optimization program

GOALs Increase appropriate use of antimicrobials Increase the rate of Infectious Disease indications accompanying physician orders for antimicrobials

Cdi GOALs To use antimicrobial stewardship initiatives to prevent Clostridium difficile colitis infections (CDI) Ensure appropriate treatment for C. difficile positive patients Improve timely initiation of C. difficile contact precautions Provide counseling and education to C. difficile patients

Background • Clostridium difficile is a gram-positive anaerobe • Considerable morbidity and mortality • Ensuring timely identification of patients with C. difficile infection followed by optimal treatment is important • Established risk factors for the development of C. difficile include: - Recent antibiotic use in the past 90 days - Extended period in a healthcare facility - Increased age (> 65) - Serious underlying illness (immunocompromised receiving chemotherapy) - Use of proton pump inhibitor or H2 antagonist

Scope of CDI Project • A dashboard was developed using a data extraction tool to evaluate the presence of any of the following in patients concurrently identified with C. difficile infection: Community acquired; healthcare facility related; nosocomial Recurrent Proton-pump inhibitor or H2 antagonist use Exposure to chemotherapy Severity of CDI illness Appropriateness of C. difficile therapy Discontinuation of concomitant offending antibiotics Use of antiperistaltic agent Previous exposure to clindamycin, cephalosporins, or fluoroquinolones Exposure to three or more antibiotics Durations of therapy beyond evidenced based recommendations Antimicrobial selection was assessed and prescribers were contacted with alternative recommendations outlined in the C. difficile clinical pathway Recommendations to discontinue anti-motility agents were also performed to prevent toxic mega colon

There are several classification systems taking into account a variety of severity markers Listed are several severity scoring systems and the various markers they use to recognize severity, ranging from age to leukocytosis to SCr ,albumin, radiologic findings, etc.

SEVERITY OF ILLNESS Clostridium difficile Infection Guidelines for Severity Classification IDSA Recommendation2 ACG Recommendation3 Mild/Moderate WBC ≤ 15,000 cells/mm3 AND SCr < 1.5 x baseline Diarrhea PLUS Anything not meeting severe/complicated criteria Severe WBC >15,000 cells/mm3 OR SCr ≥ 1.5 x baseline Albumin < 3 g/dL WBC ≥ 15,000 cells/mm3 Abdominal tenderness Severe Complicated Any one of the following… Hypotension/Shock Ileus Megacolon Any one of the following attributable symptoms… Admission to ICU Hypotension Fever ≥ 38ºC Ileus or Abdominal distension Altered mental status WBC ≥ 35,000 cells/mm3 Serum lactate > 2.2 mmol/L End organ failure IDSA (on the left) focuses on either leukocytosis or SCr elevation. The problem presented with this system is seen in patients with ESRD in whom SCr elevation isn’t relevant so the entire weight of severity classification is placed on leukocytosis. ACG doesn’t look at SCr at all, rather they require the presence of hypoalbuminemia in conjunction with either leukocytosis or abdominal tenderness.

CDI Classification and Initial Treatment per IDSA Definition Treatment Mild/Moderate WBC ≤ 15,000 cells/mm3 AND SCr < 1.5 x baseline Metronidazole 500mg PO TID Severe WBC > 15,000 cells/mm3 OR SCr ≥ 1.5 x baseline Vancomycine 125mg PO QID Severe Complicated Presence of Hypotension, Shock, Ileus, or Megacolon Vancomycin 500mg PO QID PLUS Metronidazole 500mg IV TID Duration of therapy10-14 days Cohen SH, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society of Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infection Control and Hospital Epidemiology. 2010; 31: 432-450

9 month retrospective chart review INTERNAL EVALUATION 9 month retrospective chart review February - October 2014 N = 63 patients

Internal Evaluation: Patient Demographics % Age3 Most Common Risk Factors Present in Past 90 days* 18-64 28 44% Fluroquinolones 21 33% >/= 64 35 56% Other Antibiotics Gender No Antibiotics Prior to CDI Diagnosis Male 30 48% PPIs 32 51% Female 31 52% H2-Antagonists 6 10% Reasons for Hospitalization Chemotherapy 7 11% Infection 20 32% Episode At Time of Study Enrollment Cardiac First Episode 56 89% Diabetes 3 5% Recurrence 5 GI Complaints 27 43% Comorbidities Affecting Guideline Parameters Other 19 30% End-Stage Renal Disease 10 16% Type of CDI Community Acquired Health-Facility Acquired 33 Nosocomial

RESULTS N = 63 Mild/moderate Severe/Severe Complicated IDSA (43%) ACG (38%) Severe/Severe Complicated Higher rate of Severe Complicated classification per ACG Positive Response on monotherapy: 63% (severe, severe/complicated IDSA 29%; 29% ACG: 19%; 43%

Combination Therapy (Vancomycin + Metronidazole 500 mg IV TID) Vancomycin 500mg N=1 (Resolved) Vancomycin 125-250mg Positive Response N = 8 (75%) Treatment Failure N = 3 (25%) ***All patients received 500mg Metronidazole (primarily IV, except 4 received po during backorder)

CONCLUSION ACG vs IDSA Compliance Equally predictive in distinguishing mild/moderate disease versus severe ACG overestimates the incidence of severe complicated Severe complicated patients per ACG had clinical resolution on monotherapy Compliance Utilization of the IDSA classification system is important to ensure optimal therapy selection in patients with CDI Lack of guideline compliance leads to treatment failure and extended length of stay for patients with CDI

The current algorithm is based off of the IDSA guidelines

Fecal Microbiota Transplant Protocol Fecal transplant should only be attempted in stable patients with a history of multiple recurrence and no other options Identify donor for transplant Provide dietary instructions for patient Obtain consent for transplant Confirm route of administration with ordering physician Coordinate consult with GI and endoscopy Calculate when patient’s CDI treatment will be completed Patient will need to be finished with antibiotics for 24-72 hours before transplant

Screening Stool Donors A preferred stool donor is an individual who has had intimate physical contact with the patient (spouse or significant partner) Stool donors are screened for evidence of previous exposure to contagious infectious agents which include: Toxin A or Toxin B of Clostridium difficile Disease causing bacteria and parasites Hepatitis A, B, and C viruses HIV-1, HIV-2 Syphilis Stool donor must be antibiotic naïve for past 90 days

Patient Stop all antibiotics 1-3 days prior to transplantation For NG tube/EGD administration: Administer pantoprazole 20 mg orally the evening before and the morning of procedure (if not already receiving a proton pump inhibitor) For enema or colonoscopy administration: May consider Golytely bowel preparation on the evening prior to transplant (discuss with GI consultant prior to scheduling procedure)

Stool Processing Obtain fresh stool sample (collection to administration should not exceed 6 hours) Weigh amount of stool needed for procedure (see dose below) then place measured amount in single use household blender i.e., neutrabullet or Bella blender. Add specified amount of normal saline based on site of administration listed below. Blend for 2-4 minutes under the microbiology biologic hood until sample is homogenized. Filter the suspension using sterile four-by-four (secure with thick rubber band) or screen filter. Allow adequate time for slow filtration. Discard blender, remaining filtrate, and any utensils used in preparation in a biohazard container

NG tube/EGD Cure rate: 76% (due to the impact of gastric acidity; ensure basic environment with PPI before administration) Dose: 5 - 30 g of stool. Compound approximately 200 grams of stool in 250 mL of sterile normal saline for a final concentration of 0.8 grams/mL, filter, then draw up 25 mL (final dose 20 grams) in 60 mL Slip Tip syringe (EGD scope compatible syringe), clean outside tip of syringe and cap. Label (same requirements as medication) sample and deliver immediately for administration. For NG tube administration: draw up 25 mL of filtrate into Luer lock syringe and cap Advantage: appropriate for pediatric population Disadvantage: potential degradation of the stool sample by gastric, pancreatic, or biliary enzymes.

Colonoscopy Cure rate: 96.3% Dose: 50 g of stool in 200 mL of normal saline for a final concentration of 0.25 grams/mL, filter, then transfer 120 mL of suspension into two 60 mL Slip Tip syringes (colonoscope compatible syringe). Label sample and deliver immediately for administration. Advantage: visualization of affected mucosa and ability to administer fecal transplant directly to site. Additionally the area can be inspected for any complications related to the infection. Disadvantage: perforation especially in patients with fulminant toxic megacolon.

Enema Cure rate: 88% to 95.4% Dose: 50 -150 g of stool in 200 mL of normal saline For enema: instill designated amount into rectal retention enema bulb, label sample and deliver for immediate nurse administration Advantage: appropriate for patients with fulminant toxic megacolon (when compared to colonoscopy) Disadvantage: retrograde leakage, and may require a series of enemas

Post-Procedure Avoid the excretion of donated stool for > 4 hours Post-transplant, bed rest as long as possible until next day Follow Pre/Post dietary instructions Patient should call provider if any signs of C. difficile infection return

What to eat before FMT Two weeks prior to the transplant eat a low fiber diet (fiber feeds microbiota, so a low fiber diet will starve the bad microbiota) Learn what foods work best for you. Avoid foods that will trigger diarrhea. This will be important before and after the fecal transplant. Eat unprocessed food and minimize gut stressors like processed food, gluten, sugar and alcohol.

What to eat after FMT Probiotics are not necessary. They may upset the new flora. The fecal transplant is the Ultimate Probiotic Don’t risk experimenting with a new diet Eat a high fiber diet for at least 3 months after fecal transplant fruits (raspberries, apples, bananas, raisins), grains (bran, barley, brown rice, oatmeal), legumes, nuts, seeds (lentils, baked beans, almonds) Fermented food, encourages growth of the good microbiota. yogurt with “active cultures,” cottage cheese, whey, kefir, pickled foods (pickles, beets, radish), Korean kimchi, sauerkraut, tempeh

Prescriber EDUCATION Stage severity of CDI and select appropriate therapy outlined in CDI algorithm (based on IDSA guidelines) Oasis  Antimicrobial Stewardship  Infectious Diseases  C. difficile folder  C. difficile Treatment Pathway Minimize Risk Factors associated with CDI Limit the use of Fluoroquinolones and proton pump inhibitors when possible Symptomatic improvement Expected within 96 hours of treatment initiation May consider consultation with Gastroenterology, Infectious Diseases or surgery as needed

Antimicrobial Stewardship Use antibiotics judiciously Select appropriate empiric therapy (Empiric guidelines available on AST website On Oasis under Medical) Please write ID indication in order when prescribing antibiotics or select indication in CPOE. Notify Dr. Tabb, ID pharmacist at #1420 to add additional indications in CPOE) Reevaluate the need for antibiotics at the 72-hour mark Streamline therapy once microbiology data available Set antibiotic duration of therapy

Questions