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1 Antimicrobial Stewardship: Why, When, Where and How? George G. Zhanel Professor: Department of Medical Microbiology/Infectious Diseases, Faculty of Medicine, University of Manitoba Director: Canadian Antimicrobial Resistance Alliance (CARA, Winnipeg, Canada Title of presentation umanitoba.ca

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

3 Research Funding/Conflicts NIH/CIHR/NSERC CFI MHRC MMSF MICH Manitoba Health Industry Abbott Affinium Apotex Arpida Astellas AstraZeneca Bayer Cangene Cerexa Chiron Cubist Daiichi Forest Industry GlaxoSmithKline Leo Janssen Ortho/Ortho McNeill Kane BioTech Merck Migenix Novartis Novopharm Optimer Pfizer Procter and Gamble Roche Sepracor Sunovion TaiGen Targanta The Medicines Co. Triton Trius Wyeth

4 Objectives 1.Understand the benefits of an antimicrobial stewardship program 2. Realize how easy it is to start or upgrade your antimicrobial stewardship program 3. Be aware of the various antimicrobial stewardship program interventions

5 Question #1 What is Antimicrobial Stewardship?

6 Antimicrobial Stewardship Bottom Line After confirming that the patient has an indication for antimicrobial therapy, antimicrobial stewardship is the: Right drug, at the Right time, using the Right dose, and Right duration Dryden M et al. J Antimicrob Chemother 2011; 66(11):

7 What is an Antimicrobial Stewardship Program (ASP)? - Specific program and interventions to monitor and direct antimicrobial use at a health care institution, thus providing a standard evidence-based approach to judicious antimicrobial use McGowan JE, ICHE 2012;334

8 Question #2 Why Care About Antimicrobial Stewardship?

9 Why Care About Antimicrobial Stewardship? - Up to 50% of antimicrobial use in hospitals is inappropriate - 77% (51/66) studies of interventions to improve antimicrobial use in hospitals had beneficial results Davey P. et al. Cochrane Database of Syst Rev Rosdahl VK et al. EU 2002; House of Lords Select Committee on Science and Technology 1998.

10 Potential Benefits of Antimicrobial Stewardship 1. Reduce antibiotic resistance (e.g. 3 rd Gen Cephalosporins and Enterobacter resistance) 2. Reduce drug-related adverse events (e.g. excessive antibiotic exposure and C.difficile) 3. Improve clinical outcomes (e.g. optimizing PK and PD) 4. Reduce health care costs SHEA, IDSA, PIDS. Infect Control Hosp Epidemiol. 2012;33(4): Drew-R. Antimicrobial Stewardship Programs: How to Start and Steer a Successful Program JMCP March Dellit TH et al. Clin Infect Dis. 2007;44(2):

11 Antimicrobial Stewardship in the 1980 s (Goal Reduce Costs) Prospective audit with intervention and feedback: - Issue: Obs/Gyn using cefoxitin for vag/abd hysterectomy and C-sections (published guidelines said cefazolin) - Effect of intervention on prescribing antimicrobials for prophylaxis in Obs/Gyn surgery (1100 tertiary bed hospital in Winnipeg) - Pre-intervention audit: Jan March 1987, 32% (39/123) used cefazolin Zhanel and Louie. AJHP 1989;46:

12 Antimicrobial Stewardship in the 1980 s (Goal Reduce Costs) - Intervention and feedback: May-July 1987, letter describing the findings of audit as well as Obs/Gyn surgery prophylaxis guidelines to Obs/Gyn. Sept 1987 Obs/Gyn section adopts guidelines and changes practice - Post-intervention: Sept - Nov 1988, 93% (98/105) used cefazolin - Outcome: Annual savings ~$25,000 Zhanel and Louie. AJHP 1989;46:

13 Resistance Perception Antimicrobial Stewardship Project If antimicrobial resistance is a problem, then where? (By hospital type) Academic HSC (n=27) Non-Academic HSC (n=86) 100% 80% 60% 40% 20% 0% 92% 96% 94% 92% 93% 96% 83% 65% A problem in your hospital A problem in Ontario A problem in Canada A problem in other parts of the world

14 Why are Antibiotic Resistant Infections Important to Infectious Diseases Greater morbidity and mortality Hospitalization and supportive care Increased use of: Laboratory and diagnostic tests Infection control procedures More expensive antimicrobials Length of hospital stay and lost work days Rubinstein and Zhanel. Lancet Infect Dis Lynch and Zhanel. Sem Resp Crit Care Med Cohen. Science 1992.

15 New systemic antibacterial agents approved by the US FDA Boucher et al. CID 2013;56(12):

16 Approach to Reducing Antimicrobial Resistance: Multi-pronged Approach 1. Infection prevention and control - Minimize spread of resistant organisms 2.Improve diagnostics (i.e. respiratory infections) - Minimize unnecessary antimicrobial use - Targeted (narrow spectrum) therapy 3.Continued discovery of new antimicrobials 4.Reduce resistance reservoirs (i.e. animal/environmental use) 5.Antimicrobial stewardship programs Fishman N. Am J Med 2006; 119 (Suppl 1): S53-S61 Dellit TH et al. Clin Infect Dis. 2007;44(2):

17 Question #3 What Are the Goals of Antimicrobial Stewardship In 2013?

18 Potential Benefits of Antimicrobial Stewardship 1. Reduce antibiotic resistance (e.g. 3 rd Gen Cephalosporins and Enterobacter resistance) 2. Reduce drug-related adverse events (e.g. excessive antibiotic exposure and C.difficile) 3. Improve clinical outcomes (e.g. optimizing PK and PD) 4. Reduce health care costs SHEA, IDSA, PIDS. Infect Control Hosp Epidemiol. 2012;33(4): Dellit TH et al. Clin Infect Dis. 2007;44(2):

19 Antimicrobial Stewardship Program (ASP) NUTS AND BOLTS - How - Who

20 Antimicrobial Stewardship Program (ASP) How do you start or upgrade??? - Create a business case that is not solely based on saving money - ID specialist and Director of Pharmacy - Be on the lookout for opportunities to levy support/resources - Nosocomial infection outbreaks - Institution priority on patient-safety - Accreditation Dellit TH et al. Clin Infect Dis. 2007;44(2):

21 Antimicrobial Stewardship Program (ASP) Team - ASP CORE members should include (not limited to): - ID Physician - Needs to be the stewardship champion - Pharmacist - Ideally has ID training (formal or informal) - Clinical microbiology - Infection prevention and control - Informational system specialist - Hospital epidemiologist SHEA, IDSA, PIDS. Infect Control Hosp Epidemiol. 2012;33(4):322-7 Dellit TH et al. Clin Infect Dis. 2007;44(2):

22 Antimicrobial Stewardship Program - Many different interventions have been successful: - No direct comparisons of interventions, therefore difficult to determine the most effective ones - Resources required to implement such interventions and programs are not well described Davey P. et al. Cochrane Database of Syst Rev Rosdahl VK et al. EU 2002; House of Lords Select Committee on Science and Technology 1998.

23 Antimicrobial Stewardship Program (ASP) - No one size fits all - ASPs should be tailored to each hospital and depends on: - Resources - Hospital size - Local antimicrobial use/resistance patterns - Patient population SHEA, IDSA, PIDS. Infect Control Hosp Epidemiol. 2012;33(4):322-7 Dellit TH et al. Clin Infect Dis. 2007;44(2):

24 Dellit TH et al. Clin Infect Dis. 2007;44(2): Examples of ASP strategies/interventions: - Education - Formulary - Formulary restriction and preauthorization - Selective reporting - Prospective audit with intervention and feedback - Guidelines and clinical pathways - Antimicrobial order forms - Streamlining and de-escalation of therapy - Dose optimization (optimize PK/PD) - Parenteral to oral conversion

25 Examples of ASP strategies/interventions: Education - Essential - Alone, not sufficient (B-II) - No sustained impact - Education + intervention (A-III) Dellit TH et al. Clin Infect Dis. 2007;44(2):

26 Examples of ASP strategies/interventions: Formulary (A-II) - proven and widely adopted - eg. 3 rd /4 th gen Cephs Dellit TH et al. Clin Infect Dis. 2007;44(2):

27 Examples of ASP strategies/interventions: Formulary restriction and preauthorization (A-II, B-II) - eg. Restrict to ID (eg. meropenem, daptomycin) -? Mandatory ID phone call/approval? -? Mandatory ID consult Dellit TH et al. Clin Infect Dis. 2007;44(2):

28 Examples of ASP strategies/interventions: Selective reporting (Clinical Microbiology) [A-III] - Blood/Urine E. coli - Susceptible to Ampicillin - Susceptible to Cefazolin Dellit TH et al. Clin Infect Dis. 2007;44(2):

29 Examples of ASP strategies/interventions: Prospective audit with intervention and feedback (A-I) - Very effective - Resource intensive Dellit TH et al. Clin Infect Dis. 2007;44(2):

30 Examples of ASP strategies/interventions: Guidelines and clinical pathways (A-I A-III) - eg. CAP pathway - National guidelines made local - Very effective - Guidelines (tough for section to adopt) Dellit TH et al. Clin Infect Dis. 2007;44(2):

31 Examples of ASP strategies/interventions: Antimicrobial order forms (B-II) - Many types - Can be effective (reinforce guidelines) - Need detail, no shortcuts Dellit TH et al. Clin Infect Dis. 2007;44(2):

32 Examples of ASP strategies/interventions: Streamlining and de-escalation of therapy A-II - eg. Severe infections in ICU - Very effective with ASP Dellit TH et al. Clin Infect Dis. 2007;44(2):

33 Treatment and De-escalation in Severe Infection Empiric broad spectrum treatment-asap Culture 3 days ASP re-evaluation: Cultures Clinical improvement De-escalation: 1 agent: change to narrow spectrum agent 2 agents: change to 1 agent Alvarez-Lerma and Grau. Drugs 2012;72: ; Boyd and Nailor. Pharmacother 2011;31: ; Waele et al. J Crit Care 2010;25: ; Eachempati et al. J Trauma 2009;66: Rotstein et al. CJIDMM 2008;19:19-53.; CCCTR. NEJM 2006;355: ; Craven et al. Inf Med 2005;1-12.; Rello et al. Crit Care Med 2004;32: ; Malacarne et al. JAC 2004;54: ; Paterson and Rice. CID 2003;36: ; Hoffken and Niederman. Chest 2002;122: ; Singh et al. Am J Resp Crit Care Med 2000;162:

34 Examples of ASP strategies/interventions: Dose optimization (A-II) Optimize PK/PD - T/MIC for ² -lactams - AUC/MIC and Cmax/MIC for FQ and aminoglycosides Dellit TH et al. Clin Infect Dis. 2007;44(2):

35 Pharmacodynamic Principles for Beta-Lactams The time drug concentration exceeds the MIC (T>MIC) is predictive of antibacterial effect Concentration Methods to Increase % Time > MIC - Higher doses - More frequent dosing T>MIC MIC 0 Time (h)

36 Limited improvement in target attainment by increasing to highest recommended doses cumulative TA >75% ƒt >MIC to 0.79 MER g q8h to 2 g q8h 1g q8h 2g q8h Zelenitsky and Zhanel. JAC to 0.65 PT g q6h to 4.5 g q6h 3.375g q6h Antibiotic 4.5g q6h to 0.81 CEF g q12h to 2 g q8h 2g q12h 2g q8h to 0.91 CBP mg q8h to 1 g q8h or 500 mg q6h 500mg q8h (2h) 1g q8 (4h)

37 Optimizing β-lactam Therapy: Maximizing Percent T>MIC Other dosing strategies to improve T> MIC Increased duration of infusion Continuous infusion» Administer loading dose, then use pump to give total daily dose IV over 24 hr period Prolonged infusion» Same dose and dosing interval, however, change duration of infusion (0.5 hr 3-4hr)

38 Significant benefit in target attainment for piperacillin-tazobactam by using prolonged infusions cumulative TA >75% ƒt >MIC to 0.80 to 0.79 MER g q8h 1g q8h (3h) Zelenitsky and Zhanel. JAC PT 0.60 to 0.77 CEF g q6h Antibiotic 2g q12h 3.375g q6h (3h) 2g q12h (3h) CBP mg q8h (2h) N/A

39 Extended-Infusion Dosing Strategy: Piperacillin / Tazobactam for P aeruginosa Infection Retrospective cohort study Extended (4 h) vs. intermittent (30 min) infusion Infusion schedule not associated with differences in mortality or length of stay for patients with APACHE II score <17 % of Patients % Patients With APACHE II Score e17 Extended infusion Intermittent infusion 31.6% Day Mortality P=0.04 APACHE II, Acute Physiological and Chronic Health Evaluation II. Lodise TP Jr et al. Clin Infect Dis. 2007;44: Length of Stay (d) P=0.02

40 Examples of ASP strategies/interventions: Parenteral to oral conversion (A-III) - High F% - Fluoroquinolones - TMP/SMX - Metronidazole - Clindamycin - Linezolid - Minocycline - Fluconazole - Voriconazole - Chloramphenicol

41 Measure What You Can Metrics and Evaluations: - Examples of ASP measurement options include: outcomes process - Defined daily dose (DDD) - Days of therapy (DOT) - Length of therapy (LOT) - Antimicrobial trends - Clostridium difficile rates - Antimicrobial expenditures - Grams of antimicrobials - If doing prospective audit and feedback: % of interventions accepted Dellit TH et al. Clin Infect Dis. 2007;44(2):

42 Displayed by Defined Daily Doses 8000 Number of defined daily doses per year Ciprofloxacin IV Piperacillin-Tazobactam Vancomycin IV Meropenem Ceftazidime Fiscal Years Comparative antibiotic utilization from 2005 to 2011

43 Our VAP Infection Rates

44 Antimicrobial Stewardship Program (ASP) Clinical examples that they work.

45 Antimicrobial Stewardship Program (ASP) Evidence - Location: Tertiary care hospital Quebec - ASP: Audit and feedback - 2 nd /3 rd Gen Cephs - Ciprofloxacin - Clindamycin - Macrolides - Outcomes - Total AB use/targeted AB use - C. difficile rates Valiquette L et al. Clin Infect Dis. 2007;45 Suppl 2:S112-21

46 Antimicrobial Stewardship Program (ASP) Evidence Valiquette L et al. Clin Infect Dis. 2007;45 Suppl 2:S112-21

47 Antimicrobial Stewardship Program (ASP) Evidence - Location: Univ teaching hospital Toronto - ASP: Audit and feedback in critical care units - 3 rd Gen Cephs - -lactam/ -lactamase inhibitors - Carbapenems - Fluoroquinolones - Vancomycin - Outcomes - Days of therapy - Length of stay - ICU mortality - Resistance rates - C. difficile Elligsen M et al. Infect Control Hosp Epidemiol. 2012; 33(4):

48 Antimicrobial Stewardship Program (ASP) Evidence Monthly use of broad-spectrum antibiotics in critical care patients and control medical and surgical ward patients Elligsen M et al. Infect Control Hosp Epidemiol. 2012; 33(4):

49 Antimicrobial Stewardship Program (ASP) Evidence GNB susceptibility in ICU Elligsen M et al. Infect Control Hosp Epidemiol. 2012; 33(4):

50 Antimicrobial Stewardship Program (ASP) Evidence - Location: Univ teaching hospital Philadelphia - ASP: Audit and feedback and prior authorization - Outcomes - Appropriate antibiotic selection - Clinical cure rates - Clinical failure rates - Resistance rates Gross. CID 2001:33(3):

51 Antimicrobial Stewardship Program (ASP) Evidence Outcomes in a randomized controlled trial comparing the University of Pennsylvania Hospital ASP to usual practice Gross. CID 2001:33(3): Elligsen M et al. Infect Control Hosp Epidemiol. 2012; 33(4):

52 Antimicrobial Stewardship and Carbapenems??? - Group 1 ertapenem - Group 2 - imipenem, meropenem, doripenem - Questions: - When to use Gp 1 vs Gp 2 - Does ertapenem use drive resistance to imip/merop

53 Broad-spectrum: Ertapenem (Gp 1) vs. Imipenem and Meropenem (Gp 2) Similar activity to imipenem/meropenem versus Gram-positive cocci Gram-negative bacilli Anaerobes Stable vs ² -lactamases (ESBL and AmpC) Less activity to imipenem/meropenem versus Enterococcus spp., P. aeruginosa and Acinetobacter spp. Zhanel and Hoban. Exp Rev Antiinf Ther 2005;3(1): Zhanel and Hoban. Drugs 2007;67(7):

54 Mean Carbapenem Use and Pseudomonas aeruginosa Susceptibility at 25 Hospitals during the 9 Years Surrounding Adoption of Ertapenem Use Density Ratio Percentage Susceptible Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Ertapenem Other Carbapenems Susceptibility 70 No relationship found between rate of ertapenem use and change in Pseudomonas aeruginosa carbapenem susceptibility over 9 years Eagye KJ & Nicolau DP Journal Antimicrobial Chemotherapy 2011;66:

55 Antimicrobial Stewardship Program (ASP) Where to start? Select the most obtainable targets for early successes - Select the low hanging fruit Examples of less effort-intensive resources include: - IV to PO conversion programs A-III - Formulary restrictions A-II, B-II - Prospective audit and feedback on a specific ` antimicrobial or a specific clinical syndrome A-I - Guidelines and clinical pathways (A-I A-III) Goff DA et al. Clin Infect Dis. 2012;55(4):

56 ASP Conclusions 1. Need a champion 2. Need new resources 3. Start small then spread 4. Engage those you want to change 5. Education is necessary but not sufficient 6. Don t use lack of technology or databases as a crutch not to improve 7. Measure what you can 8. Work within your existing culture/ workflow 9. Celebrate your successes and communicate these clearly

57 Ideal Antimicrobial Stewardship Program - ID physician champion - ID pharmacist - Committed CORE ASP team - Collaboration ASP/IC/PT - Medical administration support - Medical staff support - Multipronged ASP - various interventions - ongoing audit/intervention/feedback - Measured outcomes

58 Getting Started - Public Health Ontario website - CDC - IDSA - APUA Antimicrobial Stewardship