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1 Using Influenza and Pneumococcal Vaccines to Lower Antibiotic Resistant Infections: An Antimicrobial Stewardship Strategy umanitoba.ca George G. Zhanel (Microbiologist/Pharmacologist) Professor: Department of Medical Microbiology/Infectious Diseases Max Rady College of Medicine, University of Manitoba and Director: Canadian Antimicrobial Resistance Alliance (CARA), Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada Title of presentation

2 Annual Deaths Attributable to Infections Caused by Antimicrobial Resistant Pathogens by 2050 Review on Antimicrobial Resistance. Available at:

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4 Canadian Antimicrobial Resistance Alliance (CARA) Antimicrobial Resistant Infections Surveillance/ epidemiology Rapid Diagnostics Mechanisms Treatment/ Prevention Patient outcomes

5 Research Funding/Conflicts NIH/CIHR/NSERC CFI MHRC/Research Mb MMSF Manitoba Health Thorlaksson Fdn Industry Abbott Achaogen Affinium Allergan Astellas AstraZeneca Avir Basilea Bayer Cangene Cipher Cubist Daiichi Forest Industry Galderma Iterum Janssen Ortho/Ortho McNeill Merck Novartis Paladin Paratek Pfizer Shionogi Sunovion TetraPhase The Medicines Co. Theravance Trius Triton Verity Zambon/Paladin Zoetis

6 Conflicts of Interest/Disclosure Slide - Presenter name: George Zhanel - Relationships with commercial entities: - Research funding: CIHR, NSERC, Achaogen, Astellas, Avir/Basilea, Cipher, Galderma, Iterum, Merck, Paladin, Paratek, Pfizer, Shionogi, Sunovion, TetraPhase, Verity - Speaker/consulting fees: Achaogen, Allergan, Avir/Basilea, Cipher, Merck, Paratek, Pfizer, TetraPhase, Verity, Zambon - Speaker fees for current program: Yes from Pharmacists Manitoba - This program has received an educational grant from Pfizer

7 2 Minute Vaccine Review

8 Life Expectancy at Birth (US) Age (Yrs) Year

9 The Success of Vaccines in the 20 th century Disease 20 th Century Annual Morbidity 2013 Reported Cases % Decreases Smallpox 29, % Diphtheria 21, % Pertussis 200,752 28,639 86% Tetanus % Polio (paralytic) 16,316 1 >99% Measles 530, >99% Mumps 162, >99% Rubella 47,745 9 >99% Congenital Rubella Syndrome (CRS) Haemophilus influenzae (B) % JAMA. 2007;298(18): ; CDC. MMWR August 15, 2014;63(32); ,000 (est.) 31 >99% Centers for Disease Control and Prevention. The Pink Book: Course Textbook 13 th Edition (2015). Appendix E: Impact of Vaccines in the 20 th and 21 st Centuries. Available at: 9

10 OBJECTIVES Influenza (Virus): - Understand that the majority of the morbidity and mortality occurs in high risk patients Review flu vaccination (who, when and how) Streptococcus pneumoniae (pneumococcus- Bacteria) infection: - Understand that the majority of the morbidity and mortality occurs in high risk patients Review PPSV23 and PCV13 vaccination (who, when and how)

11 Problem # 1 Influenza (Virus)

12 What Do I Want You to Know? 1. Influenza is Associated With a Lot of Morbidity and Mortality 2. The Majority of the Morbidity and Mortality Occurs in high risk patients

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16 Influenza remains a serious public health concern Annually in Canada, influenza is estimated to cause: 180,000 Emergency Room visits 3,500 Influenza-related deaths 12,200 Influenza-related hospital admissions 90% (age 65 +) 70% (age 65 +) 16 Schanzer et al. Vaccine. 2008;26: ; NACI ; Schanzer et al. Influenza Other Respir Viruses 2013;7(5): ; Dr. John Spika, PHAC 2015.

17 Potential Complications of Influenza DIRECT effects: Respiratory INDIRECT effects: Multi-Organ Systems TRIGGER for: Asthma & COPD exacerbations 1 acute myocardial infraction, ischemic heart disease, and cerebrovascular disease 4-6 Ear/Sinus Infection EXACERBATION of: Bronchitis and Pneumonia hypertension, renal disorder 7 and diabetes 1 17 Public Health Agency of Canada 2016.; Naghavi et al. Circulation 2003;107: Virmani et al. Arterioscler Thromb Vasc Biol 2000;20: ; MacIntyre et al. Heart 2013;99: Sheth et al. J Am Coll Cardiol 1999;33: ; Glezen et al. J Infect Dis 1982;146: ; CDC 2016.

18 Influenza Vaccination Lowered the Risk of Major Cause-Specific Mortality (n = 102,698 elderly) Reduction in Mortality Risk (%) Stroke a 65% Renal disease a Diabetes a Pneumonia a 60% 55% 53% COPD a All causes a 45% 44% Malignancy a 26% Heart disease b 22% 0 a P< b P<0.05. Cause of Mortality - 35,637 vaccinated - 67,061 unvaccinated - Followed for ~1 year - Mortality in high-risk (12.2% to 5.4%) - Mortality in low risk (3.0% to 1.8%) 18 Wang et al. Vaccine. 2007;25(7):

19 What Do I Want You to Do? Flu shot for anyone 6 mos +! - staff? - visitors?

20 Influenza Vaccine Effectiveness in Adults Younger adults 62-76% - Adults % Potential gap in vaccine effectiveness Monto AS, et al. (2009).Vaccine, 27,

21 High-Dose TIV is MORE Effective than Regular Dose Influenza Vaccine in Patients 65+ years Study performed jointly by the Center for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), and the Centers for Medicare and Medicaid Services (CMS) Izurieta et al studied CMS data influenza season among ~2.5 million Medicare beneficiaries (65+ years) comparing High-Dose TIV to standard-dose influenza vaccines High-Dose TIV reduced mortality by 36.4% High-Dose TIV resulted in: (Shay et al. J Infect Dis Mar 2) 22% 22% better protection against probable influenza illness better protection against influenza-related emergency department visits and hospitalizations 21 Izurieta et al. Lancet Infect Dis 2015;15:

22 What Do I Want You to Consider/Do? Consider and Offer? High Dose Flu shot in 65+ (NACI says it provides superior protection)

23 Problem # 2 Streptococcus pneumoniae (pneumococcus-bacteria) Infection - #1 Community acquired pneumonia (CAP) Leading Cause of Bacteremia/sepsis (IPD) - #1 Acute bacterial Sinusitis - #2 Acute exacerbations of COPD - #1 Otitis media Lynch and Zhanel. Curr Opin Pulm Med May;16(3):

24 What Do I Want You to Know? 1. Pneumococcal Infection is Associated With a Lot of Morbidity and Mortality 2. The Majority of the Morbidity and Mortality Occurs in Immunocompromised Patients and in Patients 65 + years of age

25 Lower respiratory tract infections, including pneumonia: 3 rd leading cause of death worldwide The 10 Leading Causes of Death in the World, Ischemic heart disease Stroke Lower respiratory infection* COPD Diarrheal diseases HIV/AIDS Trachea/bronchus/lung cancers Diabetes mellitus Road injury Prematurity 3,200, ,000,000 4,000,000 6,000,000 8,000,000 COPD = chronic obstructive pulmonary disease * Pneumococcal pneumonia is the leading known cause of lower respiratory tract infection mortality WHO. Media Centre Fact Sheets. Updated July Accessed December 18, Lozano R et al. Lancet. 2012;380(9859):

26 Percentage mean Frequency of causative organisms of CAP in Europe, S. pneumoniae is the most frequent pathogen in Community Acquired Pneumonia (CAP) 0 Welte T, et al. Thorax 2012;67: Causative organism

27 Hospitalization due to pneumococcal pneumonia increases with age CIHI DAD annual incidence of hospitalizations in Canada 2004/05 to 2009/10 due to pneumococcal pneumonia by age and year Incidence of pneumococcal pneumonia per 100,000 persons / / / / / /10 CIHI = Canadian Institute for Health Information DAD = Discharge Abstract Database Age Group McNeil S, Gray S, Zanotti G, et al. Clinical and economic burden of hospitalization due to Streptococcus pneumoniae pneumonia in Canada, 2004 to 2009 [Presented at the 8th Annual International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD), Iguaçu Falls, Brazil, March 2012]

28 Age (65 +) and Comorbidities increase pneumococcal pneumonia risk in adults Incidence (n per 100,000 population) Rates of Pneumococcal Pneumonia, by Age and Comorbidity (United States Health Care Claims Data, , N>26 Million) None Alcoholism Asthma Chronic heart disease Chronic liver disease 231 Chronic lung disease Chronic use of oral steroids Comorbidity risk group Diabetes years 65 years 276 Neuromuscular/ seizure disorders Rheumatoid Smokers arthritis/ Crohn s/ lupus Shea KM et al. Open Forum Infect Dis 2014;1(1):ofu024. doi: /ofid/ofu024.

29 Shea K, et al. Open Forum Infect Dis Risk of pneumococcal pneumonia increases with increasing at-risk conditions in adults (US adults) Estimated annual incidence of pneumococcal pneumonia in US adults, by number of comorbidities

30 What Do I Want You to Do? 1. Vaccinate with PPSV23 (Pneumovax) 2. Vaccinate with PCV 13 (Prevnar 13)

31 NACI RECOMMENDATIONS (UPDATED FEBRUARY 2014) PPSV23 FOR THOSE AT RISK FOR PNEUMOCOCCAL DISEASE 2 yrs of age with co-morbidities: Plus: 18 yrs 65 yrs Immuno-competent Immuno-compromised With these factors All persons Chronic heart disease Chronic lung disease Diabetes mellitus Chronic liver disease Cerebrospinal fluid leaks Cochlear implants Chronic neurologic condition that may impair clearance of oral secretions Asthma (requiring ongoing medical management) (NEW) Functional or anatomic asplenia, sickle cell, hemoglobinopathies HIV infection Immune deficiencies Immune suppression due to disease or treatment Hematopoietic stem cell transplant (recipient) Solid organ or islet transplant Malignant neoplasms, including leukemia and lymphoma Including chronic obstructive pulmonary disease, emphysema, and asthma. Chronic renal disease Residents of long term care facilities Homelessness, alcoholism, smokers, illicit drug use Asthma (if associated with COPD, emphysema or prolonged systemic corticosteroid) 1. Public Health Agency of Canada. Canadian Immunization Guide, Part 4: Active Vaccines. Pneumococcal Vaccine. Available at: pneu-eng.php#ru 2. Public Health Agency of Canada. Update on the Use of Pneumococcal Vaccines: Addition of Asthma as a High-Risk Condition. Available at:

32 Pneumovax 23 (23PPSV) Advantages Covers 23 serotypes Prevents Invasive Pneumococcal Disease (IPD) Safe Disadvantages (polysaccharide vaccine, B-cell only) Poor response in older pts., immunocompromised and in children < 2 yrs of age No immunologic memory No booster effect on revaccination Lower response after revaccination, hyporesponsiveness No, or very limited effect on carriage (no herd immunity) POOR, prevention of Community Acquired Pneumonia (CAP)

33 Effectiveness of PPSV23 in the General Population of 50 years of Age and Older: (Meta-analysis) Vaccine effectiveness for PPSV23 in preventing IPD was 50% - 54%...GOOD Vaccine effectiveness for PPSV23 in preventing CAP 4% -17%...POOR Kraicer-Melamed H, et al. Vaccine, 2016; 34 (13):

34 NACI RECOMMENDATIONS (UPDATED 2016) PCV13 for ADULTS: - Immunocompromised years of age

35 Prevnar 13 (PCV13) Advantages (conjugate vaccine, T-cell dependent) Prevents IPD AND CAP Safe Good response in the very old, immunocompromised and in children < 2 yrs of age Immunologic memory Booster effect on revaccination Eliminates nasopharyngeal carriage (herd immunity) Disadvantages Only covers 13 serotypes You don t use it very much in your patients, yet!

36 75% of pneumococcal pneumonia is nonbacteremic Meningitis Bacteremia 25% Bacteremic PPSV23 AND PCV13 Unmet Need Pneumococcal Pneumonia 75% Nonbacteremic PCV13 Huang SS, et al. Vaccine. 2011;29: Said MA, et al. PLoS One. 2013;8:e60273.

37 Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) The CAPiTA trial published in the New England Journal of Medicine A phase 4, randomized, placebo-controlled clinical trial of 13-valent pneumococcal conjugate vaccine efficacy in prevention of vaccine-serotype pneumococcal communityacquired pneumonia and invasive pneumococcal disease Bonten et al. N Engl J Med 2015;372:

38 A Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA) to describe the clinical efficacy of PCV13 Study Design (Netherlands) 84,496 Vaccine-Naïve Subjects Aged >65 Years RANDOMIZED 1:1 PCV13 Placebo Primary and Secondary Efficacy Objectives: Demonstrate the Efficacy of PCV13 in the Prevention of a First Episode of 1 Vaccine-type (VT) pneumococcal CAP Invasive or non-invasive 2 VT invasive pneumococcal disease 2 VT nonbacteremic (noninvasive) pneumococcal CAP Bonten et al. N Engl J Med 2015;372:

39 CAPiTA Efficacy Results: PCV13 Reduces IPD and CAP Vaccine efficacy (%) Reduction in Pneumococcal Disease With PCV13 46% P<0.001 Primary end point: Prevention of first episode of VT pneumococcal CAP 45% P=0.007 Secondary end point: Prevention of first episode of VT nonbacteremic/noninvasive pneumococcal CAP 75% P<0.001 Secondary end point: Prevention of first episode of VT IPD Statistically Significant Reductions in First Episode of Vaccine-Type (VT) Pneumococcal CAP With PCV13 Bonten et al. N Engl J Med 2015;372:

40 PCV13 Reduces Mortality Due to CAP in the Elderly Retrospective analysis on mortality rates after a 1 st hospitalization for CAP PCV13 was an independent protective factor for mortality-related pneumonia (adjusted OR: 0.599; 0.390±0.921) n=4,030 Mean age = 84.3 yrs Baldo V, et al. PLOS ONE DOI: /journal.pone November 15, 2016

41 Streptococcus pneumoniae Serotyping and Antimicrobial Susceptibility Assessment for Vaccine Efficacy (SAVE) Study in Canada: Present George Zhanel, Heather Adam, Mel Baxter, Alyssa Golden, Kim Nichol, Rachel Hink, Irene Martin, Walter Demczuk, Michael Mulvey, Matt Gilmour, Jack Johnson, Daryl Hoban the Canadian Antimicrobial Resistance Alliance (CARA) and James Karlowsky A Partnership Between the Canadian Antimicrobial Resistance Alliance (CARA) and the National Microbiology Laboratory (NML) Winnipeg, Canada Zhanel et al. JAC 2018.; Adam et al. JAC Karlowsky et al. JAC 2018.; Golden et al JAC 2018.

42 S. pneumoniae Serotypes in PCV13 (SAVE ) SAVE 2011 SAVE 2012 SAVE 2013 SAVE 2014 SAVE 2015 SAVE 2016 SAVE 2017 Percentage of Isolates A 6B 7F 9V 14 18C 19A 19F 23F Adam et al. JAC Adam et al. ASM Microbe PCV13 Serotypes

43 PCV13 is Reducing MDR S. pneumoniae Serotypes in Canada (SAVE ) % MDR Karlowsky et al. JAC 2018.; Adam et al ASM Microbe p =

44 Who and How To Immunize With PPSV23 and PCV 13

45 Carole 55 year old Immunocompromised 55 years of age, active and healthy Currently on anti-tnf therapy for severe plaque psoriasis No previous pneumococcal vaccination Does she need PPSV23 and/or PCV13?

46 NACI recommendation for pneumococcal vaccination for high-risk groups at-a-glance Risk Group Adults with hematopoietic stem cell transplants (HSCT) PCV13 Recommended PPSV23 Recommended PPSV23 Revaccination at 5 yrs Adults with HIV Adults with immunosuppressive conditions including: Asplenia (anatomical or functional) Sickle cell disease or other hemoglobinopathies Congenital immunodeficiencies* Immunosuppressive therapy Malignant neoplasms including leukemia and lymphoma Solid organ or islet cell transplant (candidate or recipient) * Involving any part of the immune system, including B-lymphocyte (humoral) immunity, T-lymphocyte (cell) mediated immunity, complement system (properdin, or factor D deficiencies), or phagocytic functions. Including use of longterm corticosteroids, chemotherapy, radiation therapy, post-organ-transplant therapy, and certain disease modifying antirheumatic drugs.

47 Florence Age 65 + (unknown vaccine status) 80 years of age Increasingly frail Used to walk several times a week, now quite sedentary Pneumococcal vaccination status unknown Does she need PPSV23 and/or PCV13?

48 NACI RECOMMENDATIONS (UPDATED FEBRUARY 2014) PPSV23 FOR THOSE AT RISK FOR PNEUMOCOCCAL DISEASE 2 yrs of age with co-morbidities: Plus: 18 yrs 65 yrs Immuno-competent Immuno-compromised With these factors All persons Chronic heart disease Chronic lung disease Diabetes mellitus Chronic liver disease Cerebrospinal fluid leaks Cochlear implants Chronic neurologic condition that may impair clearance of oral secretions Asthma (requiring ongoing medical management) (NEW) Functional or anatomic asplenia, sickle cell, hemoglobinopathies HIV infection Immune deficiencies Immune suppression due to disease or treatment Hematopoietic stem cell transplant (recipient) Solid organ or islet transplant Malignant neoplasms, including leukemia and lymphoma Including chronic obstructive pulmonary disease, emphysema, and asthma. Chronic renal disease Residents of long term care facilities Homelessness, alcoholism, smokers, illicit drug use Asthma (if associated with COPD, emphysema or prolonged systemic corticosteroid) 1. Public Health Agency of Canada. Canadian Immunization Guide, Part 4: Active Vaccines. Pneumococcal Vaccine. Available at: pneu-eng.php#ru 2. Public Health Agency of Canada. Update on the Use of Pneumococcal Vaccines: Addition of Asthma as a High-Risk Condition. Available at:

49 NACI Says Give BOTH PCV13 and PPSV23 at Age 65 + NACI

50 Bill 65+ and previous PPSV23 70 years of age, sedentary Heavy smoker COPD treated with ICS/LABA Acute flare-ups treated with prednisone Received PPSV23 vaccination 5 years ago (age 65) Does he need PPSV23 and/or PCV13? ICS = inhaled corticosteroid LABA = long-acting beta agonist

51 Conclusions - Risk factors for influenza and pneumococcal disease are similar - S. pneumoniae infections (CAP and IPD) common - Patients 65+ yrs, immunocompromised, cormorbid diseases greatest risk - Pneumococcal Vaccines - PCV13 (IPD and CAP) - PPSV23 (IPD)

52 Conclusions - Who to Vaccinate: - Influenza all 6 mos +, HD for PPSV23 (adults with comordid conditions, immunocompromised, 65yrs) - PCV13 (immunocompromised, 65yrs) - How to Vaccinate: - PCV13 first, then 8 weeks PPSV23 Guidelines changing

53 NACI Recommended for Manitoba Patient group Influenza PPSV23 PCV13 Children < 2 years yes no yes Adults 50+ years immunocompromised yes yes yes Adults 65+ years Yes HD YES yes yes Adults comorbid illness yes yes Not yet

54 Vaccine Coverage in Manitoba Patient group Influenza PPSV23 PCV13 Children < 2 years yes no yes Adults 50+ years immunocompromised yes yes yes Adults 65+ years Yes HD (LTC) - YES yes Not yet* Adults comorbid illness yes yes Not yet

55 PCV13 provincial/territorial funding for adults as per NACI recommendations for high-risk patients = Not Covered = Partial Coverage for all ages* = Complete Coverage for 50 yrs* = Complete Coverage for all ages* * Based on NACI recommendations that include the following immune-compromised conditions: HSCT, HIV, asplenia (anatomical or functional), sickle cell disease or other hemoglobinopathies, congenital immunodeficiencies, immunosuppressive therapy, malignant neoplasms including leukemia and lymphoma, solid-organ or islet-cell transplant (candidate or recipient)