1. Impact of oral vancomycin prophylaxis on the occurrence of Clostridium difficile infection in allogeneic hematopoietic stem cell transplant recipients Eric J. Urnoski, PharmD PGY-1 Pharmacy Resident Hackensack University Medical Center Hackensack, New Jersey NJSHP Residency Forum June 9, 2016

2. Risk Factors for CDI 2 Allo-HSCT Patient Risks for CDI Antibiotic use  Fluoroquinolones, clindamycin, cephalosporins, others Prophylaxis for HSCT; neutropenic fever; infections Immunosuppression  Neutropenia, ↓IgG antibody production, malignancy, chemotherapy, total body irradiation Myeloablative chemotherapy; baseline malignancy Advanced age  Risk ↑ 10x if > 65 years of age Regularly transplant patients > 65 years of age Prolonged hospitalization  ↑ duration of exposure to spores in healthcare setting Prolonged length-of-stay (LOS) Acid suppressive therapy (AST)  Conflicting data; alteration of GI flora AST initiated on HSCT admission Chemotherapy  Alteration of GI flora and integrity Myeloablative chemotherapy; impaired immune response Leffler DA, et al. N Engl J Med 2015;372:1539-1548. Surawicz CM, et al. Am J Gastroenterol 2013;108:478-498. Cohen SH, et al. Infect Cont Hosp Epidemiol 2010;31(5):431-455. Garzotto AR, et al. Support Care Cancer 2015;23:1569-1577.

3. Allo-HSCT Patient Concerns CDI incidence is 15/1000 hospitalized patients – 10-15% all-cause mortality in general population CDI reported in up to 20% of HSCT patients – Incidence is 2.3-7% in all oncology patients CDI incidence has – ↑ 13.4% yearly from 2000-09 in HSCT – ↑ 1.1% per year in non-transplant patients Up to 25% of CDI patients have ≥ 1 occurrence – 45-65% future risk after second occurrence HSCT is independently associated with CDI CDI is independently associated with mortality with patients with GvHD CDI & severe GvHD significantly associated with mortality Pharmacological prophylaxis? – Vancomycin – Fidaxomicin 3 Cohen SH, et al. Infect Cont Hosp Epidemiol 2010;31(5):431-455. Kumar Guddati A, et al. Int J Hematol 2014;99:758-765. Garzotto AR, et al. Support Care Cancer 2015;23:1569-1577. Dubberke ER, et al. Clin Transplant 2010;24(2):192-198. Surawicz CM, et al. Am J Gastroenterol 2013;108:478-498. Esmaily-Fard A, et al. Pharmacother 2014;34(11):1220-1225. Van Hise NW, et al. Presented at the 54 th Annual Meeting of the Interscience Conference on Antimicrobial Agents and chemotherapy (ICAAC). September 5-9, 2014; Washington, DC.

4. Study Rationale There are no guideline recommendations for utilizing antimicrobials for prophylaxis of CDI in allo-HSCT patients with a past history of CDI The role of antimicrobial prophylaxis for CDI and the possible impact on occurrence of acute GvHD and VRE bacteremia are unknown 4 Surawicz CM, et al. Am J Gastroenterol 2013;108:478-498. Cohen SH, et al. Infect Cont Hosp Epidemiol 2010;31(5):431-455. Leffler DA, et al. N Engl J Med 2015;372:1539-1548. Garzotto AR, et al. Support Care Cancer 2015;23:1569-1577

5. Study Objectives 5 Primary Objective To assess occurrence of CDI in two cohorts of HSCT patients Cohort A = CDI history receiving oral vancomycin prophylaxis Cohort B = No CDI history and no vancomycin prophylaxis Secondary Objectives To examine the development of Acute GvHD VRE bacteremia All-cause mortality at one year

6. Hackensack University Medical Center 775 bed academic medical center – 4 adult oncology inpatient units (75 beds) > 6,000 HSCT performed since 1990 > 400 HSCT performed annually – Top 10 program in volume of HSCT – Largest HSCT center in tri-state area 6

7. Study Design Institutional review board approved, retrospective, single-center study Electronic medical record (EMR) used to identify patients hospitalized for allo-HSCT between January 1, 2013, and December 31, 2014 7

8. Study Design 8 CDI History No CDI Prophylaxis Allo-HSCT No CDI History CDI Prophylaxis No CDI Occurrence CDI Occurrence No CDI Occurrence CDI Occurrence VRE & GvHD 1 year post-HSCT Cohort A Cohort B

9. Inclusion Criteria Patients ≥ 18 years of age Hospitalized at Hackensack University Medical Center for allo-HSCT between January 1, 2013, and December 31, 2014 At least one readmission within one year of allo-HSCT date 9

10. Exclusion Criteria Patients not readmitted at Hackensack University Medical Center within one year of allo-HSCT Patients with a documented history of CDI who were not started on oral vancomycin prophylaxis during initial allo-HSCT admission 10

11. Study Definitions CDI history – Documented in EMR CDI occurrence – Diarrhea PLUS – Positive C. difficile enzyme immunoassay GvHD – Documented in EMR VRE bacteremia – Positive blood culture 11

12. Enrollment 12 80 Patients excluded 128 Patients included Cohort A 10 Patients with CDI history receiving prophylaxis Cohort B 118 Patients with no CDI history not receiving prophylaxis 208 Allo-HSCT patients screened 74 Patients not admitted within 365 days of HSCT 6 Patients with CDI history with no vancomycin prophylaxis

13. Baseline Characteristics Cohort A n = 10 Cohort B n = 118 Total Population n = 128 Mean Age, years 52.2 (35 – 66)52.4 (20 – 73) Mean Admission Height, inches 66.7 (58 – 74)66.5 (56 – 76) Mean Admission Weight, kilograms 87.9 (57 – 131.4)82.2 (43.2 – 135)82.7 (43.2 – 135) Mean Admission Ideal Body Weight, kilograms 65.4 (45.5 – 77.7)63.3 (45.5 – 86.8)63.5 (45.5 – 86.8) Mean BMI kilograms/m 2 30.6 (21.7 – 47.1)28.6 (18.4 – 47.9)28.8 (18.4 – 47.9) Male n, (%) 7 (70%)71 (60.2%)78 (60.9%) Female n, (%) 3 (30%)47 (39.8%)50 (39.1%) 13 BMI = Body Mass Index

14. Primary Cancer Diagnoses 14

15. Baseline HSCT Characteristics HSCT Characteristics n, (%) Cohort A n = 10 Cohort B n = 118 Total Population n = 128 HSCT Donor Source Related4 (40%)47 (39.8%)51 (39.8%) Unrelated6 (60%)71 (60.2%)77 (60.2%) Cell Source PBSC9 (90%)102 (86.4%)111 (86.7%) Bone Marrow1 (10%)16 (13.6%)17 (13.3%) Donor CMV Status Positive4 (40%)66 (55.9%)70 (54.7%) Negative6 (60%)52 (44.1%)58 (45.3%) Recipient CMV Status Positive4 (40%)67 (56.8%)71 (55.5%) Negative6 (60%)51 (43.2%)57 (44.5%) 15 PBSC = Peripheral blood stem cell CMV = Cytomegalovirus

16. CDI Risk Factors Cohort A n = 10 Cohort B n = 118 Total Population n = 128 Mean number of admissions 4.6 (2 – 11)3.57 (2 – 10)3.7 (2 – 11) Mean cumulative LOS, days 77.8 (22 – 203)54.9 (20 – 175)56.7 (20 – 203) Mean cumulative number of antimicrobials 20.1 (4 – 41)13.2 (3 – 51)13.7 (3 – 51) 16

17. Outcomes Secondary Outcome Cohort A n = 10 Cohort B n = 118 Total n = 128 VRE bacteremia n, (%) 2 (20%)10 (8.5%)12 (9.4%) GvHD n, (%) 10 (100%)90 (76%)100 (78%) One year all-cause mortality n, (%) 5 (50%)39 (33%)44 (34%) 17 Primary Outcome Cohort A n = 10 Cohort B n = 118 Total n = 128 CDI occurrence n, (%) 2 (20%)*12 (10%)14 (11%) * One patient initially received prophylactic vancomycin, and developed CDI on a subsequent admission when prophylaxis was not administered

18. CDI Occurrences in Cohort A 18 Patient 85*Patient 92 Age, Gender66 year-old Female56 year-old Male Primary Cancer Diagnosis B Cell Acute Lymphoblastic LeukemiaMultiple Myeloma HSCT InformationRelated PBSCUnrelated PBSC Cumulative LOS79 days111 days Number of Admissions66 VRE bacteremiaNoYes Cumulative antimicrobials 2431 Death within one yearNoYes Days to CDI onset291154 *Prophylaxis only during first 3 admissions

19. CDI Occurrences in Cohort A: A Closer Look 19 Prophylaxis Timeline of Patient 85 Admission 1: 23 days Admission 2: 7 days Admission 3: 5 days CDI prophylaxis x 23 days 3 Antibiotics 6 Antibiotics CDI prophylaxis x 7 days 3 Antibiotics CDI prophylaxis x 5 days Admission 4: 18 days 6 Antibiotics No CDI prophylaxis Admission 5: 7 days 3 Antibiotics No CDI prophylaxis Admission 6: 12 days 4 Antibiotics CDI onset with no prophylaxis

20. CDI Occurrences in Cohort B 20 CDI Occurrences n = 12 out of 118 patients Mean Age, years53.4 (35 – 73) Male gender8 (66.7%) Primary Cancer Diagnosis Leukemia Lymphoma Multiple Myeloma MPN 4 (33.3%) 3 (25%) 1 (8.3%) Related HSCT Donor8 (66.7%) PBSC Cell Source11 (91.7%) Mean Cumulative LOS, days81.8 (20 – 149) Mean number of admissions5 (2 – 10) VRE bacteremia1 (8.3%) Mean cumulative antimicrobials19.8 (6 – 43) Acute GvHD10 (83.3%) Death within one year7 (58.3%) Mean days to CDI onset92.9 (10 – 222)

21. Limitations Retrospective analysis of allo-HSCT recipients admitted at a single center Initial occurrences of CDI post-HSCT and GvHD were recorded Prophylaxis was limited to initiation at HSCT admission Antimicrobial therapy reported as exposure Patients with CDI history not initiated on prophylaxis upon HSCT admission were excluded 21

22. Conclusions & Future Directions Data collection and analysis is ongoing Oral vancomycin prophylaxis to prevent occurrences of CDI in allo- HSCT patients with a history of CDI remains unclear Larger, prospective trials are needed to determine impact of oral vancomycin prophylaxis on the occurrence of CDI, GvHD, VRE, and all-cause mortality in this patient population 22

23. Acknowledgements Dorothy McCoy, PharmD, BCPS AQ-ID Maribel A. Pereiras, PharmD, BCOP, BCPS Michael A. Wynd, PharmD, BCPS Rani Sebti, MD Cristina E. Cicogna, MD 23

24. Question Which of the following is not a risk factor for CDI in the allo- HSCT patient population? A. Chemotherapy B. Female gender C. Prolonged hospital stay D. Antimicrobial use 24

25. Question Which of the following is not a risk factor for CDI in the allo- HSCT patient population? A. Chemotherapy B. Female gender C. Prolonged hospital stay D. Antimicrobial use 25

26. Impact of oral vancomycin prophylaxis on the occurrence of Clostridium difficile infection in allogeneic hematopoietic stem cell transplant recipients Eric J. Urnoski, PharmD PGY-1 Pharmacy Resident Hackensack University Medical Center Hackensack, New Jersey NJSHP Residency Forum June 9, 2016 26

27. References 1.Leffler DA, Lamont JT. Clostridium difficile Infection. N Engl J Med 2015;372:1539-1548. 2.Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108:478-498. 3.Cohen SH, Gerdin DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Cont Hosp Epidemiol 2010;31(5):431-455. 4.Garzotto AR, Merida Garcia A, Munoz Unceta N, et al. Support Care Cancer 2015;23:1569-1577. 5.Kumar Guddati A, Kumar G, Ahmed S, et al. Incidence and outcomes of Clostridium difficile-associated disease in hematopoietic stem cell transplant recipients. Int J Hematol 2014;99:758-765. 6.Dubberke ER, Reske KA, Srivastava A, et al. Clostridium difficile-associated disease in allogenic hematopoietic stem cell transplant recipients: risk associations, protective associations, and outcomes. Clin Transplant 2010;24(2):192-198. 7.Esmaily-Fard A, Tverdek FP, Crowther DM, et al. The use of fidaxomicin for treatment of relapsed Clostridium difficile infections in patients with cancer. Pharmacother 2014;34(11):1220-1225. 8.Van Hise NW, Bryant AM, Crannage AJ, et al. Evaluation of secondary prophylaxis with oral vancomycin on the incidence of recurrent Clostridium difficile infections in high risk patients. Presented at the 54 th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 5-9, 2014; Washington, DC. 27

28. Resident’s Role 28 Literature review Background presentation to infectious diseases and pharmacy teams Developed data tool and IRB protocol submission Presented abstract at ASHP Midyear in New Orleans, LA Received approval from IRB Began data collection Began data analysis Eastern States Conference Sept 2015 Oct 2015 Nov 2015Dec 2015Jan 2016Feb 2016Mar 2016Apr 2016 May 2016 Continued data collection, analysis, and drafted abstract for ID Week

29. Vancomycin for Secondary Prophylaxis Background/Patient Population 1 – To determine if secondary prophylaxis with oral vancomycin impacts incidence of recurrent CDI – “High risk” patients = history of CDI – Recorded baseline age, gender, race, proton-pump inhibitor (PPI) use, and probiotic use – 71 patients receiving vancomycin 125-250 mg PO BID vs. 132 patients in control arm 2-3 Results – 1 patient (1%) receiving vancomycin had a recurrence compared to 35 patients (37%) in the control arm (p = 0.0001) 1. Van Hise NW, et al. Presented at the 54 th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 5-9, 2014; Washington, DC. 2. http://formularyjournal.modernmedicine.com/formulary-journal/content/tags/c-difficile/oral- vancomycin-can-help-prevent-recurrent-c-difficile-in?page=full. Accessed September 14, 2015. 3. http://www.medpagetoday.com/MeetingCoverage/ICAAC/47539. Accessed September 13, 2015. 29

30. Vancomycin for Secondary Prophylaxis Results (Continued) – Benefits of prophylaxis were seen in: Patients ≥ 65 yrs of age (p = 0.003) PPI at home (p = 0.0002) PPI inpatient (p = 0.0001) – Authors reported benefits seen for: Aminopenicillins, cephalosporins, FQ, aztreonam, vancomycin, and combination of vancomycin/piperacillin-tazobactam/levofloxacin Major conclusion – Oral vancomycin prophylaxis was associated with a significant decrease in the incidence of recurrent CDI Van Hise NW, et al. Presented at the 54 th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 5-9, 2015; Washington, DC. 30

31. Ongoing Research Vancomycin prophylaxis in recurrent CDI 1 – Vancomycin 125 mg PO daily within 48 hrs of 1 st dose of broad-spectrum antibiotic x 10 days vs. placebo – Inclusion: CDI with 16 weeks prior to study – No mention of oncology population Safety and efficacy of FDX versus placebo for prophylaxis against CDI in adults undergoing HSCT (DEFLECT-1) 2 – Phase 3b, multicenter, randomized placebo controlled study – FDX 200 mg once daily at start of conditioning or when FQ are initiated – Therapy continued until 7 days post FQ therapy OR neutrophil engraftment (whichever is latest) – Excluded: Current CDI and/or use of drugs such as oral vancomycin or metronidazole – No mention on whether focus is for primary or secondary CDI prophylaxis 1.https://clinicaltrials.gov/ct2/show/NCT02237859?term=recurrent+clostridium+difficile&rank=3. Accessed 09/12/2015. 2.https://clinicaltrials.gov/ct2/show/NCT01691248?term=deflect-1&rank=1. Accessed 09/11/2015. 31

32. Subsequent Occurrences 32 Cohen SH, et al. Infect Cont Hosp Epidemiol 2010;31(5):431-455. Surawicz CM, et al. Am J Gastroenterol 2013;108:478-498. SHEA/IDSA GuidelinesGastroenterology Guidelines First Recurrence -Repeat initial regimen -Stratify to disease severity -Repeat initial regimen -If severe, use pulsed dose oral vancomycin Repeated Recurrences -Pulse/tapered oral vancomycin preferred -Prolonged metronidazole may  neurotoxicity -Oral vancomycin preferred -Metronidazole may ↑ risk of neuropathy Antibiotic Prophylaxis -No recommendation -Metronidazole does not reach therapeutic levels in feces of patients without active colitis -No recommendation

33. Fidaxomicin in Oncology Patients Background – CDI is a serious concern in oncology patients due to multiple persistent risk factors which make them prone to recurrences – Prior trials demonstrated fewer recurrences with fidaxomicin (FDX) than vancomycin – Limited data exists for treating oncology patients with recurrent CDI Patient population 22 patients between 2011-13 at MD Anderson Cancer Center treated with FDX 200 mg BID x 10-28 days for primary CDI unresponsive to vancomycin or metronidazole or recurrent CDI 9 lymphoma; 7 leukemia; 6 solid tumor – 9 had prior HSCT; 5 receiving active chemotherapy 16 patients had recurrent CDI; 10/16 were at least a 2 nd recurrence Esmaily-Fard A, et al. Pharmacother 2014;34(11):1220-1225. 33

34. FDX in Oncology Patients Results – Clinical response to FDX was 91% for all CDI cases – Overall sustained clinical response was 82% Sustained clinical response 90% for recurrent CDI cohort 2 patients failed FDX, 1 of which had fatal colitis/GVHD – 2 patients (9%) had recurrent CDI within 30 days of FDX Major Conclusions FDX was safe and effective for treatment of CDI unresponsive to standard therapies and recurrent CDI in the oncology population Esmaily-Fard A, et al. Pharmacother 2014;34(11):1220-1225. 34

35. CDI Prevention: Probiotics 2010 SHEA/IDSA – Not recommended for primary prevention – Conflicting data on role in recurrent CDI prevention – Potential risk for bacteremia or fungemia 2013 Gastroenterology – Insufficient date for primary CDI prevention – Limited data to support use for recurrence prevention2 35 Cohen SH, et al. Infect Cont Hosp Epidemiol 2010;31(5):431-455. Surawicz CM, et al. Am J Gastroenterol 2013;108:478-498. Association of Professionals in Infection Control. Guide to preventing Clostridium difficile infections. 2013. https://cdifffoundation.files.wordpress.com/2013/07/probiotic.jpg 2013 Association of Professionals in Infection Control – FDA does not support probiotics for prevention – GI microflora is diverse and probiotics are nutritional supplements – Immunocompromised patients at increased risk of fungemia

36. CDI Treatment Recommendations Cohen SH, et al. Infect Cont Hosp Epidemiol 2010;31(5):431-455. Surawicz CM, et al. Am J Gastroenterol 2013;108:478-498. Mild- Moderate CDI Diarrhea with WBC ≤ 15 and SCr ≤ 1.5 x baseline Metronidazole 500 mg PO q 8 hrs x 10- 14 days Alternate: Fidaxomicin 200 mg PO q 12 x 10 days Severe CDI Diarrhea with WBC ≥15 or SCr ≥ 1.5 x baseline Albumin 15 Vancomycin 125 mg PO q 6 hrs x 10- 14 days Severe Complicated Signs of shock, hypotension, severe colitis, perforation, toxic megacolon, ileus, WBC ≥ 35, etc. Vancomycin 125- 500 mg PO q 6 hrs PLUS metronidazole 500 mg IV q 8 hours* 36 * Can use vancomycin enema if complete ileus or toxic colitis

37. Data Collection Tool 37

38. Data Collection Tool 38

39. Data Collection Tool 39

40. CDI Prevention Contact precautions Patient isolation Hand hygiene Disinfection of surfaces with chlorine-containing agents Antimicrobial stewardship Vaccines? – Toxoid vaccine in phase 3 clinical trials for primary prevention of CDI Exclusion: immunosuppressive medication within 6 months or “severe illness” Cohen SH, et al. Infect Cont Hosp Epidemiol 2010;31(5):431-455. https://clinicaltrials.gov/ct2/show/NCT01887912?term=clostridium+difficile+toxoid&rank=5. Accessed 09/09/15. 40

41. Primary Cancer Diagnosis Cohort A: Primary Cancer Diagnoses 41

42. Primary Cancer Diagnoses Cohort A: Primary Cancer Diagnoses 42