OCTOBER 7-10 PHILADELPHIA, PENNSYLVANIA

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1 OMED 17 OCTOBER 7-10 PHILADELPHIA, PENNSYLVANIA 29.5 Category 1-A CME credits anticipated ACOFP / AOA s 122 nd Annual Osteopathic Medical Conference & Exposition Joint Session with ACOFP and Cleveland Clinic: Managing Chronic Disease Antibiotic Stewardship Constatine Tsigrelis, MD The American College of Osteopathic Family Physicians is accredited by the American Osteopathic Association Council to sponsor continuing medical education for osteopathic physicians. The American College of Osteopathic Family Physicians designates the lectures and workshops for Category 1-A credits on an hour-for-hour basis, pending approval by the AOA CCME, ACOFP is not responsible for the content.

2 Antibiotic Stewardship Constantine Tsigrelis, M.D. Staff Physician, Infectious Disease Cleveland Clinic October 7, 2017 None Disclosures 1

3 Outline What is antibiotic stewardship? Rationale and goals of antibiotic stewardship Core elements of antibiotic stewardship programs in hospitals - Nursing homes - Outpatient Question What is antibiotic stewardship? 1. Limiting all antibiotic use 2. Antibiotic cost reduction as primary objective 3. Discussion with ID for all antibiotic use beyond 24 hours 4. Optimization of antibiotic use & treatment of infections 2

4 What is Antibiotic Stewardship? Optimization of antibiotic use and treatment of infections Why do we need antibiotic stewardship? Estimated 20-50% of antibiotic use in US hospitals is either unnecessary or inappropriate Antibiotic use is the single most important factor associated with antibiotic resistance & C. difficile Antibiotics are unique compared to other medications - Misuse is associated with antibiotic resistance and C. difficile, which may spread to other patients causing harm to others not exposed to antibiotics 3

5 CDC How Antibiotic Resistance Happens CDC Public Domain. Available at: CDC Yearly Estimates CDC Public Domain. Available at: 4

6 Goals of Antibiotic Stewardship Improve quality & safety of care by decreasing morbidity & mortality from: - Antibiotic resistance - C. difficile infection - Infection treatment failures Decrease health care costs without impacting quality of care - Value (i.e. patient health outcomes achieved per dollar spent) Antibiotic stewardship programs have been shown to improve above outcomes and decrease health care costs IDSA, Antimicrobial Stewardship as a Medicare Condition of Participation. Available at: CoP-Letter%20MAR_2014.pdf Regulatory requirements 2014 CDC Recommended that all acute care hospitals implement Antibiotic Stewardship Programs 2015 White House: National Action Plan for Combating Antibiotic-resistant Bacteria Within 3 years, all acute care hospitals governed by the Centers for Medicare & Medicaid Services condition of participation will implement antibiotic stewardship programs Effective January 2017 The Joint Commission: Requirement that all hospitals have an antimicrobial stewardship program National Action Plan to Combat Antibiotic Resistance March Available at:

7 Centers for Medicare & Medicaid Services Proposed rule in JUNE 2016 that would update the requirements that hospitals must meet to participate in the Medicare and Medicaid programs Infection Control has been a condition of participation since 1986 Proposing changing to: Infection prevention and control and antibiotic stewardship programs We propose a new standard at (b) titled, Antibiotic stewardship program organization and policies, in order to require hospitals to have policies and procedures for, and to demonstrate evidence of, an active and hospital-wide antibiotic stewardship program. CMS Proposed Rule for Antibiotic Stewardship Programs: &disposition=attachment&contentType=pdf Case # 1 A 65 year-old-male nursing home resident is admitted with fever, chills, and severe back pain. He is placed on vancomycin and piperacillin-tazobactam. On hospital day # 2, blood cultures are growing methicillin susceptible Staphylococcus aureus. Vancomycin is stopped, and piperacillintazobactam is continued. You receive a call from an Infectious Disease pharmacist from the hospital Antibiotic Stewardship team discussing deescalating the patient to cefazolin. Which of the following antibiotic stewardship elements best describes this intervention? 1. Pre-authorization 2. Pre-approval 3. Prospective audit 4. Dose optimization 6

8 Implementing an Antibiotic Stewardship Program Implement policies & interventions that support optimal antibiotic use - Prioritize interventions based on needs of the hospital - May differ based on size / type of institution - There is no single template Antibiotic Stewardship Team Single program leader responsible for outcomes - Physicians (e.g. ID) have been highly effective in this role - Smaller community hospitals have used hospitalists as physician leaders Single pharmacist leader preferably with ID training Data analysis / IT support Microbiology & Infection prevention/control collaboration 7

9 Antibiotic Stewardship Core Elements Infectious Diseases Society of America (IDSA) & CDC guidelines suggest certain core elements 1. Prospective audit and feedback 2. Pre-authorization 3. Other supplemental strategies Prospective audit & feedback Prospectively audit (monitor) antibiotic use and microbiology data and provide feedback to practitioners Audit and feedback usually performed by pharmacist and/or physician Can use computer based surveillance programs to monitor antibiotic use and microbiology data Has been shown to improve antibiotic use, and reduce antibiotic resistance and C. difficile infection 8

10 Prospective audit & feedback De-escalation of empirical antibiotic therapy - Vancomycin + MSSA; Piperacillin-tazobactam + susceptible GNR Bug-drug mismatch - Multi-drug resistant GNR and not on appropriate antibiotic Duration of antibiotic therapy - Prolonged antibiotic therapy major risk factor for antibiotic resistance & C. difficile Inappropriate / redundant antibiotic combinations - Dual anaerobic coverage (e.g. piperacillin-tazobactam + metronidazole) & no C. diff IV to PO conversion - Antibiotics with excellent oral bioavailability, e.g. quinolones, azithromycin, doxycycline, fluconazole, linezolid, metronidazole, etc. - Associated with decrease length of stay and cost Other miscellaneous - Drug-drug interactions, etc. De-escalation Name MR# Patient location DE-ESCALATION ALERT Alert Date: 10/7/2017 MICROBIOLOGY 10/4/2017 Urine culture Escherichia coli >=100,000 cfu/ml Ampicillin Ampicillin-Sulbactam Cefazolin Ceftriaxone Levofloxacin Trimethoprim-Sulfamethoxazole S S S S S S CURRENT ANTIBIOTICS Vancomycin Piperacillin-Tazobactam Start date 0900 Start date

11 Case # 2 A 74 year-old-female is admitted with fever, chills, right flank pain, and vomiting. She has no history of multidrug-resistant organisms or healthcare exposure. You attempt to order a new antibiotic, ceftazidime-avibactam, but you receive an alert in the electronic medical record that does not allow you to place the order. Which of the following antibiotic stewardship elements best describes this intervention? 1. Clinical practice guidelines 2. Antibiotic time out 3. Prospective audit and feedback 4. Pre-authorization Pre-authorization Requires clinicians to get approval for certain restricted antibiotics before they are prescribed Most effective method of restricting antibiotic use Usually leads to immediate and significant reductions in antibiotic use Has been associated with decrease in antibiotic resistance and C. difficile infection Less clear impact on resistance in cases where restriction of 1 drug leads to greater use of alternative agent - e.g. Restriction of cephalosporins in 1 study (80% reduction in use), led to 44% reduction in ceftazidime-resistant Klebsiella. However, imipenem use increased 141%, accompanied by 69% increase in imipenem-resistant Pseudomonas. 10

12 Core Elements - Comparison Pre-authorization Clinicians are required to get approval for an antibiotic BEFORE it is prescribed + Reduces initiation of unnecessary / inappropriate antibiotics Optimizes empiric choices Addresses empiric use > downstream use of antibiotics Loss of prescriber autonomy Prospective audit & feedback Prospectively monitor antibiotic use and microbiology data and provide feedback to practitioners AFTER an antibiotic is prescribed + Can address de-escalation and duration of antibiotic therapy Provides educational benefit to clinicians Compliance is voluntary Prescribers may be reluctant to change therapy Supplemental Strategies 1. Evidence based clinical practice guidelines / order sets 2. Microbiology lab 3. Procalcitonin 4. Antibiotic Time Out 5. Documentation of antibiotic dose, duration, indication 6. Penicillin allergy evaluation / skin testing / desensitization protocols 7. Dosing optimization (e.g. vancomycin / aminoglycoside dosing, etc.) 8. Drug-drug interactions 9. Education 11

13 Clinical practice guidelines & order sets Evidence based practice guidelines (e.g. diagnosis, treatment) incorporating local antibiogram data Multidisciplinary development Can improve antibiotic use Common infections (e.g. pneumonia, urinary tract infection, etc...) Surgical prophylaxis Implementation can be facilitated via: - Incorporation of recommendations into Order sets - Provider education - Physician champion advocates - Feedback on adherence (e.g. quarterly, etc.) Microbiology Lab May assist in timely reporting of multi-drug resistant organisms Selective reporting of antibiotic susceptibilities - Only report select antibiotics Cascade reporting - Results of certain antibiotics only reported if there is resistance to primary antibiotic within that class - e.g. If organism is cefazolin susceptible, no reporting of ceftriaxone, cefepime, etc. Rapid diagnostic testing 12

14 Traditional Blood Culture System Blood Culture System Perform Gram stain GPC clusters GNR Rapid Diagnostic Testing (1 2 ½ hours for identification) Plate on blood agar Up to hours Aerobic bottle Anaerobic bottle Up to additional 24 hours Antimicrobial susceptibility testing Hill JT, et al. Evaluation of the nanosphere Verigene BC-GN assay for direct identification of gram-negative bacilli and antibiotic resistance markers from positive blood cultures and potential impact for more-rapid antibiotic interventions. J Clin Microbiol. 2014;52(10): Gram Stain GPC: Content Providers: CDC / Dr. Richard Facklam. Public Domain. Available at: Gram Stain GNR: Content Providers: CDC / Dr. W.A. Clark. Public Domain. Available at: Blood agar plate: Content Providers: CDC / Dr. Richard Facklam. Public Domain. Available at: Blood culture system and bottles images: Constantine Tsigrelis, MD Multiplex detection of pathogens with resistance determinants Biofire FilmArray (Multiplex PCR) (27 targets) Perform on positive blood culture Results in ~1 hour Blood culture identification panel (BCID) Nanosphere Verigene (Multiplex nucleic acid testing*) (29 targets) Perform on positive blood culture Results in ~2 to 2.5 hours *Proprietary Gold Nanoparticle Technology to detect protein targets +/- PCR for nucleic acid detection GRAM POSITIVE: Enterococcus Listeria monocytogenes Staphylococcus Staphylococcus aureus Streptococcus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes YEAST: Candida albicans Candida glabrata Candida krusei Candida parapsilosis Candida tropicalis GRAM NEGATIVE: Acinetobacter baumannii Haemophilus influenzae Neisseria meningitidis Pseudomonas aeruginosa Enterobacteriaceae Enterobacter cloacae complex Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Proteus Serratia marcescens ANTIBIOTIC RESISTANCE GENES: meca methicillin resistance vana/b vancomycin resistance KPC carbapenem resistance GRAM POSITIVE: Staphylococcus aureus Staphylococcus epidermidis Staphylococcus lugdunensis Streptococcus anginosus Group Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Enterococcus faecalis Enterococcus faecium Staphylococcus spp. Streptococcus spp. Listeria spp. YEAST: None GRAM NEGATIVE: Escherichia coli Klebsiella pneumoniae Klebsiella oxytoca Pseudomonas aeruginosa Acinetobacter spp. Citrobacter spp. Enterobacter spp. Proteus spp. ANTIBIOTIC RESISTANCE GENES: meca (methicillin) vana (vancomycin) vanb (vancomycin) CTX-M (ESBL) IMP (carbapenemase) KPC (carbapenemase) NDM (carbapenemase) OXA (carbapenemase) VIM (carbapenemase) Kothari A, et al. Emerging technologies for rapid identification of bloodstream pathogens. Clin Infect Dis. 2014;59(2):

15 Multiplex detection of pathogens with resistance determinants Important to involve antibiotic stewardship team with rapid diagnostic testing to maximize benefit Randomized trial, 617 patients with positive blood cultures - 3 arms: Standard blood culture Multiplex PCR (24/7) Multiplex PCR (24/7) + real-time audit / feedback by antibiotic stewardship team - Rapid Multiplex PCR led to quicker escalation of antibiotic therapy in both Multiplex PCR groups (by 14 hours) - Quicker de-escalation of antibiotic therapy for GPC (by 19 hours) but only if involve antibiotic stewardship team Less treatment of contaminants Less vancomycin and piperacillin-tazobactam Banerjee R, Teng CB, Cunningham SA, et al. Randomized Trial of Rapid Multiplex Polymerase Chain Reaction-Based Blood Culture Identification and Susceptibility Testing. Clin Infect Dis 2015;61(7): Precursor of calcitonin Procalcitonin Released primarily in response to bacterial toxins and bacteria-specific proinflammatory mediators (e.g. tumor necrosis factor, etc.) Attenuated by the cytokines typically released in response to viral infections (e.g. interferon-γ, etc.) Therefore, may be helpful in diagnosing bacterial infections, since serum procalcitonin levels rise and fall rapidly in bacterial infections Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011;171(15): Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy: A Systematic Review and Meta-analysis. J Hosp Med 2013;8(9):

16 Procalcitonin Meta-analysis (18 trials) ADULT ICU PATIENTS: - Procalcitonin-guided discontinuation of antibiotics in adult ICU patients reduced antibiotic duration, without increasing morbidity or mortality - In contrast, procalcitonin-guided intensification of antibiotics in adult ICU patients increased antibiotic usage and morbidity (increased ICU length of stay, increase in days on mechanical ventilation, increased renal dysfunction) ACUTE UPPER & LOWER RESPIRATORY TRACT INFECTIONS: - Procalcitonin-guided initiation or discontinuation of antibiotics in adult patients with acute upper and lower respiratory tract infections (primary care, ED, hospital wards) significantly reduced antibiotic duration without affecting morbidity or mortality Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy: A Systematic Review and Meta-analysis. J Hosp Med 2013;8(9): Procalcitonin Antibiotic Stewardship Guidelines (2016) - Suggest using serial procalcitonin measurements in adult ICU patients as an intervention to decrease antibiotic use (weak recommendation, moderate quality evidence) - If implemented, antibiotic stewardship programs should develop guidelines to assist clinicians in interpreting results 15

17 Antibiotic Time Out Prescriber-led review of antibiotic use Prompts a reassessment of the need for antibiotics or if able to de-escalate and the duration of treatment Documentation of antibiotic dose, duration, indication Want this information to be readily identifiable With changing physicians on teams, may not know why patient is on an antibiotic To ensure that antibiotics are de-escalated or discontinued as indicated 16

18 Other strategies Education - Education of providers involved in antibiotic prescribing - Patient education regarding appropriate use of antibiotics - Joint Commission requirement Antibiotic allergy - Penicillin allergy is associated with use of alternative agents, increased antibiotic resistance, longer hospital stays, increased healthcare costs - Penicillin and cephalosporin skin testing - Desensitization protocols Dosing optimization - e.g. Aminoglycoside and/or vancomycin monitoring and adjustment Drug-drug interactions - e.g. Alerts via computer based surveillance Ressner RA, et al. Antimicrobial Stewardship and the Allergist: Reclaiming our Antibiotic Armamentarium. Clin Infect Dis, Antibiotic Stewardship in Nursing Homes - CDC 2015 Antibiotics are among the most commonly prescribed medications in nursing homes Up to 70% of residents receive 1 or more courses of systemic antibiotics in a year Estimated 40-75% of antibiotics prescribed in nursing homes may be unnecessary or inappropriate Interventions are similar to hospital antibiotic stewardship programs CDC. The Core Elements of Antibiotic Stewardship for Nursing Homes. Atlanta, GA: US Department of Health and Human Services, CDC; Available at: 17

19 Outpatient Antibiotic Stewardship - CDC 2016 Around 60% of antibiotic use in humans in the United States is related to outpatient care In 2013 in the United States, around 269 million antibiotic prescriptions were dispensed from outpatient pharmacies Around 10% of adult visits and 20% of pediatric visits in the outpatient setting result in an antibiotic prescription Estimated that at least 30% of outpatient antibiotic prescriptions in the United States are unnecessary Sanchez GV, et al. Core Elements of Outpatient Antibiotic Stewardship. MMWR Recomm Rep 2016;65(6):1-12. CDC: Identify high-priority conditions for intervention 1. Conditions for which antibiotics are not indicated - e.g. Acute bronchitis, nonspecific upper respiratory infection, or viral pharyngitis 2. Conditions for which antibiotics may be indicated but are overdiagnosed - e.g. Strep pharyngitis without testing for Group A strep 3. Conditions for which watchful waiting or delayed prescribing may be appropriate, but underused - e.g. Acute otitis media or acute uncomplicated sinusitis Sanchez GV, et al. Core Elements of Outpatient Antibiotic Stewardship. MMWR Recomm Rep 2016;65(6):

20 CDC: Identify high-priority conditions for intervention 4. Conditions for which antibiotics may be indicated but a non-recommended agent is selected - e.g. Azithromycin rather than amoxicillin or amoxicillin/clavulanate for acute uncomplicated bacterial sinusitis 5. Conditions for which antibiotics are underused or the need for timely antibiotics is not recognized - e.g. Severe bacterial infections such as sepsis, etc. Sanchez GV, et al. Core Elements of Outpatient Antibiotic Stewardship. MMWR Recomm Rep 2016;65(6):1-12. CDC: Actions to improve outpatient antibiotic prescribing Evidence-based diagnostic criteria and treatment recommendations Use delayed prescribing practices or watchful waiting, when appropriate Require written justification in the medical record for non-recommended antibiotic prescribing Sanchez GV, et al. Core Elements of Outpatient Antibiotic Stewardship. MMWR Recomm Rep 2016;65(6):1-12. Meeker D, et al. Effect of Behavioral Interventions on Inappropriate Antibiotic Prescribing Among Primary Care Practices: A Randomized Clinical Trial. JAMA 2016;315(6):

21 Key Takeaways Antibiotic stewardship is optimization of antibiotic use & treatment of infections Estimated 20-50% of antibiotic use in US hospitals is either unnecessary or inappropriate % of antibiotics prescribed in nursing homes - 30% of outpatient antibiotic prescriptions Antibiotic use is the single most important factor associated with antibiotic resistance & C. difficile Core elements of an antibiotic stewardship program - Prospective audit and feedback - Pre-authorization - Supplemental strategies, such as clinical practice guidelines / order sets, rapid diagnostic testing, antibiotic time out, etc. 20