Combating Multidrug-Resistant Organisms: Strategic Considerations for Optimal Clinical Outcomes

Combating Multidrug-resistant Organisms: Strategic Considerations for Optimal Clinical Outcomes

COMBATING MULTIDRUG-RESISTANT ORGANISMS: STRATEGIC CONSIDERATIONS FOR OPTIMAL CLINICAL OUTCOMES

WELCOME AND INTRODUCTION

Thomas M. File Jr, MD, MSc, MACP, FIDSA, FCCP (Chair) Chair, Division of Infectious Disease Summa Health Akron, OH Professor, Internal Medicine Master Teacher and Chair, Infectious Disease Section Northeast Ohio Medical University Rootstown, OH

Faculty

Thomas M. File Jr, MD, MSc, MACP, James S. Lewis II, PharmD, FIDSA FIDSA, FCCP (Chair) ID Clinical Pharmacy Supervisor Chair, Division of Infectious Disease Oregon Health and Science University Summa Health Departments of Pharmacy & Infectious Diseases Akron, OH Portland, OR Professor, Internal Medicine Master Teacher and Chair, Infectious Disease Section Hans H. Liu, MD, FACP Northeast Ohio Medical University Director, Antimicrobial Stewardship Rootstown, OH Bryn Mawr Hospital George H. Karam, MD Mainline Health System Bryn Mawr, PA Paula Garvey Manship Chair of Medicine Department of Medicine Professor of Medicine Louisiana State University School of Medicine in Sidney Kimmel School of Medicine New Orleans Thomas Jefferson University Baton Rouge Branch Campus Philadelphia, PA Baton Rouge, LA 3

Disclosures

Thomas M. File, Jr, MD, MSc, MACP, FIDSA, FCCP (Chair) Grant/Research Support: Nabriva Therapeutics AG; Pfizer Inc Retained Consultant: Bayer HealthCare; Cempra Pharmaceuticals, Inc.; Melinta Therapeutics, Inc.; MotifBioSciences, Inc.; Nabriva Therapeutics AG; Paratek Pharmaceuticals Inc; Tetraphase Pharmaceuticals, Inc. George H. Karam, MD Retained Consultant: Philips Healthcare Non-Speakers Bureau Activities: Merck & Co, Inc James S. Lewis II, PharmD, FIDSA Retained Consultant: Accelerate Diagnostics, Inc; Achaogen, Inc; Astellas Pharma US, Inc; The Medicines Co.; Merck & Co, Inc; Paratek Pharmaceuticals, Inc Hans H. Liu, MD, FACP Retained Consultant: Cempra Pharmaceuticals, Inc. Speakers Bureau: Daiichi Sanyko Co., Ltd

Paradigm Medical Communications, LLC, staff members have no financial relationships to disclose.

Educational Review Systems, Inc., staff members have no financial relationships to disclose.

Independent peer reviewer has no financial relationships to disclose. 4

Accreditation

Physician Accreditation Statement Paradigm Medical Communications, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Physician Credit Designation Statement Paradigm Medical Communications, LLC designates this live activity for a maximum of 2.0 AMA PRA Category 1 Credits ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Pharmacist Accreditation and Designation Statement Educational Review Systems is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This program is approved for 2.0 hours (0.2 CEUs) of continuing pharmacy education credit. Proof of participation will be posted to your NABP CPE profile within 4 to 6 weeks for participants who have successfully completed the post-test. Participants must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. (Universal Activity Number 0761-9999-16-233-L01-P) This is a knowledge-based activity.

This activity is jointly provided by Educational Review Systems, Inc., and Paradigm Medical Communications, LLC.

Disclosure of Commercial Support

This activity is supported by educational grants from Allergan, Inc; Cempra Pharmaceuticals, Inc; Tetraphase Pharmaceuticals, Inc; and The Medicines Company

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• Attend the live activity. • At the conclusion of the activity, complete the post-survey and evaluation in the Evaluation section on your iPad. • Provide your name, email address, and select the credit hours you will be claiming. A certificate of participation/statement of completion will be issued 2 to 3 weeks following the meeting. Please note: to claim CPE credit , please make sure you include your date of birth and NABP number. All credit information will be uploaded into CPE Monitor within 30 days .

Continuing Education Information

Learning Objectives Upon proper completion of this activity, participants should be better able to: • Review pathogens responsible for most multidrug-resistant organism-related infections and their appropriate treatment. • Outline the appropriate integration of new and emerging antibiotics, alongside older, more established agents. • Summarize the tenets of effective antimicrobial stewardship, including the rationale, different interventions, and approaches to measuring process and outcomes.

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA.

Agenda

Topic Faculty Thomas M. File Jr, MD, MSc, Welcome and Introduction MACP, FIDSA, FCCP Multidrug-resistant Infections: Reviewing Common Hans H. Liu, MD, FACP Pathogens and General Treatment Strategies New and Emerging Antibiotics: Data and Practical George H. Karam, MD Recommendations Antimicrobial Stewardship: Effective James S. Lewis II, PharmD, FIDSA Implementation for Improved Clinical Outcomes Case Studies with Audience Participation All faculty

Impact of Drug-resistant Infection: High Morbidity and Mortality CDC Estimates on Limitations of CDC Estimates 2 US Antibiotic Resistance 1 • Based on small samplings from <10 states in 2011 • Reporting standards differ by state, not well enforced • <50% US states record deaths from prevalent superbugs

1. Centers for Disease Control and Prevention (CDC). www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf/. Accessed 10/20/16. 2. ‘Superbug’ scourge spreads as US fails to track rising human toll. www.reuters.com/investigates/special-report/usa-uncounted-surveillance/. Reuters. 9/7/16. 12

CDC Antibiotic Resistance Threats

• Clostridium difficile • Carbapenem-resistant Enterobacteriaceae (CRE) • Neisseria gonorrhoeae (cephalosporin resistance)

• MDR Acinetobacter • Drug-resistant nontyphoidal Salmonella • Drug-resistant Campylobacter • Drug-resistant Salmonella typhi • Fluconazole-resistant Candida • Drug-resistant Shigella • ESBLs • Methicillin-resistant S aureus (MRSA) • VRE • Drug-resistant Streptococcus pneumoniae • MDR Pseudomonas aeruginosa • Drug-resistant tuberculosis

• Vancomycin-resistant S aureus • Erythromycin-resistant Group A Streptococcus • Clindamycin-resistant Group B Streptococcus

ESBLs, extended-spectrum beta-lactamases; MDR, multidrug resistant; VRE, vancomycin-resistant enterococci CDC. Biggest Threats. 2013. www.cdc.gov/drugresistance/biggest_threats.html. Accessed 10/20/16. 13

Antimicrobial Resistance in the News • New strain of E coli resistant to “last resort” antibiotic, colistin • Mcr-1 gene

May 26, 2016

July 11, 2016 14

United Nations Responds to MDROs

• UN has met only 4 times in its “It is not that it may happen in the 70-y history re: health crisis 1 future. It is a very present reality— 2 • 2001: AIDS virus in all parts of the world...” • 2011: Noncommunicable diseases UN Secretary-General, Ban Ki-moon • 2014: Ebola virus • 2016: MDROs

AIDS, acquired immunodeficiency syndrome; MDRO, multidrug-resistant organism 1. United Nations. www.un.org/pga/71/2016/09/21/press-release-hl-meeting-on-antimicrobial-resistance/. Accessed 10/20/16. 2. UN News Centre. www.un.org/apps/news/story.asp?NewsID=55011#.WAUDwenfOM8. Accessed 10/20/16. 15

Antibiotic Misuse in Hospitals

• Increased Up to 50% of antibiotic use Antibiotic Pathogen Resistance 1 Exposure is inappropriate Risk • Consequences CRE Carbapenems 15-fold 2-4 • ESBL-producing C difficile Cephalosporins 6- to 29-fold 2-4 organisms • Increased MDR risk, prevalence increased mortality, healthcare costs, hospital LOS

LOS, length of stay 1. Centers for Disease Control and Prevention. Get Smart for Healthcare. www.cdc.gov/getsmart/healthcare/evidence.html. Accessed 10/20/16. 2. Patel G et al. Infect Control Hosp Epidemiol. 2008;29:1099-1106. 3. Zaoutis TE et al. Pediatrics. 2005;114:942-949. 4. Talon D et al. Clin Microbiol Infect . 2000;6:376-384. 16

Summary “We can either work to improve antibiotic use and prevent infections, or watch as the clock turns back to a world where simple infections kill people.” —Tom Frieden, MD, MPH Director of the CDC

MULTIDRUG-RESISTANT INFECTIONS: REVIEWING COMMON PATHOGENS AND GENERAL TREATMENT STRATEGIES

Hans H. Liu, MD, FACP Director, Antimicrobial Stewardship Bryn Mawr Hospital Mainline Health System Bryn Mawr, PA Professor of Medicine Sidney Kimmel School of Medicine Thomas Jefferson University Philadelphia, PA PQ

Polling Question 1 In your experience, which type of hospital-acquired infection is marked by the highest prevalence of MDROs? A. Central-line associated bloodstream infections B. Catheter-associated urinary tract infections C. Ventilator-associated pneumonia D. Surgical site infections E. ABSSSI

ABSSSI, acute bacterial skin and skin structure infection 19

The Decades-long Battle Between “Bugs” and Drugs

1940s 1950s 1960s 1970s 1980s 1990s 2000+ 2010+

E coli et al; Vanco-R Beta- Macrolide-R Mycobacterium Pen-R staph ; Pen-R enterococcus; lactamase Carbapenemase mycoplasma; S aureus TB P aeruginosa pneumococcus C difficile (+) GNRs (+) GNRs “Superbug”

Penicillin Ampicillin, Vancomycin Vancomycin Eventually 3rd gen. Aminoglycosides FQs?; 1st gen. semisyn. (again), linezolid, cephalosporins, (again), colistin ??? cephalosporin penicillins; extended gen. daptomycin; FQs, TB drugs aminoglycoside cephalosporins metronidazole, beta-lactam/ oral lactamase carboxypenicillin vancomycin combos

E coli , Escherichia coli ; FQs, fluoroquinolones; GNRs, gram-negative rods; Pen-R, penicillin-resistant; S aureus ; staphylococcus aureus ; TB, tuberculosis 21

Inappropriate Initial Empiric Antibiotic Selection

Mortality (% of patients) Definition Inappropriate antibiotic use Appropriate antibiotic use • Use of agent(s) to which isolated Bacteremia 1 62% 28% pathogens are later 2 69% 5 CA bacteremia 37% found nonsusceptible 3 35% Impact S aureus bacteremia 21% • VAP 4 51% Independent 29% determinant of 6 44% P aeruginosa bacteremia 22% mortality 1-4

CA, community-acquired; VAP, ventilator-associated pneumonia 1. Ibrahim EH et al. Chest . 2000;118:146-155. 2. Valles J et al. Chest . 2003;123:1615-1624. 3. Khatib R et al. Eur J Clin Microbiol Infect Dis . 2006;25:181-185. 4. Teixeira PJ et al. J Hosp Infect . 2007;65:361-367. 5. ATS and IDSA. Am J Respir Crit Care Med . 2005;171:388-416. 6. Bowers DR et al. Antimicrob Agents Chemother . 2013;57(3):1270-1274. 22

Polling Question 2 At your healthcare facility, which of the following is the greatest concern for surgical site infections? A. ESBL-producing Enterobacteriaceae B. CRE (carbapenem-resistant Enterobacteriaceae ) C. MDR P aeruginosa D. MDR Acinetobacter spp. E. S aureus

Focus on Gram-positive Pathogens

SENTRY Antimicrobial Surveillance Program: S pneumoniae Resistance to Beta-Lactams

PCV13 Introduction 20% Amoxicillin/clavulanate

15% Penicillin

Ceftriaxone PCV7 Introduction 10% %Nonsusceptible

1.5% 1.3% 0.9% Ceftaroline 0% 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Surveillance Year PCV, pneumococcal conjugate vaccine Reprinted from Diagnostic Microbiology and Infectious Disease, Volume 75, Number 1, Jones RN et al, Update on antimicrobial susceptibility trends among Streptococcus pneumoniae in the United States: report of ceftaroline activity from the SENTRY Antimicrobial Surveillance Program (1998–2011), page 108, Copyright 2013, with permission from Elsevier. 27

Susceptibility of S pneumoniae , 2010-2014, United States

Susceptibility Rates of S pneumoniae to Common Antibiotics 99.3 97.4 100 in North America (2010 vs 2014) 2010 2014 84.2 78.5 80 70.2 66.2 68.3 59.4 61.6 60 57

38.4 40 33.1 Susceptibility, % Susceptibility, 20

0 Penicillin Amoxicillin Erythromycin Tetracycline TMP/SMX Levofloxacin

TMP/SMX, trimethoprim/sulfamethoxazole Flamm RK et al. Presented at the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy and 28th International Congress of Chemotherapy Meeting (ICAAC/ICC); September 17-21, 2015; San Diego, CA. [Abstract C-554]. 28

Global Prevalence of Macrolide-Resistant Mycoplasma pneumoniae 1

Sporadic Reports in the US 2 US City, State Isolates, # Resistance Chicago, IL 23 17.4% Kansas City, MO 40 7.5% Hackensack, NJ 2 50% New York, NY 5 40% Seattle, WA 15 6.5% Birmingham, AL 6 16.7% TOTAL 91 13.2% 1. Cao B et al. Clin Respir J. 2015 Sept 14. [Epub ahead of print] 2. Zheng X et al. Emerg Infect Dis . 2015;21:470-472. 29

CDC. www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed 10/20/16. 30

Gram-positive MDROs Lead to Increased Mortality and Hospitalization

MRSA-Related All-cause Mortality and Hospitalization Within 1 y With MRSA Without MRSA 50 43.9 40 30 25.6 20 10.2 10 5.2 Event Rate y 100 per Rate Event 0 Death Death or Hospitalization

Reprinted from The Journal of Emergency Medicine, Volume 48 , Number 4, Pollack CV et al, Acute bacterial skin and skin structure infections (ABSSSI): practice guidelines for management and care transitions in the emergency department and hospital, page 512, Copyright 2015, with permission from Elsevier. 31

Outpatient Management of Serious Gram-positive Infections Strategies 1-6 Tips • Oral antibiotics • Presence/magnitude of fever • alone does not preclude QD parenteral antibiotic in ED outpatient management 1 • PICC insertion for next-day • Oritavancin, dalbavancin , follow-up, additional dosing tedizolid make outpatient • New extended half-life parenteral management possible 1,5,6 lipoglycopeptides for single-dose • Immunocompetent host status treatment 2-4 is key 1,5,6

ED, emergency department; PICC, peripherally inserted central catheter 1. Pollack CV Jr et al. J Emerg Med . 2015;48(4):508-519. 2. Boucher HW et al. N Engl J Med . 2014;370(23):2169-2179. 3. Nguyen HH et al. Clin Infect Dis . 2010;51(suppl 2):S220-S223. 4. Jauregui LE et al. Clin Infect Dis . 2005;41(10):1407-1415. 5. Belley A et al. Antimicrob Agents Chemother . 2013;57(1):205-211. 6. Corey GR et al. N Engl J Med. 2014;370(23):2180-2190. 32

Focus on Gram-negative Pathogens

Resistant Gram-negative Pathogens Are Common and Deadly

Pathogen Incidence/y Deaths/y

Carbapenem-resistant Enterobacteriaceae 9300 610

ESBL–producing Enterobacteriaceae 26,000 1700

MDR Acinetobacter species 7300 500

MDR Pseudomonas aeruginosa 6700 440

Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013 . Atlanta, GA. 34

Antibiotic-Resistant Threat Pathogens at Acute Care Hospitals, 2014

Surgical Site Infection CLABSI Pathogen No. tested (% resist) No. tested (% resist) MRSA 3212 (44) 2556 (47.3) VRE 3427 (18) 3079 (44.6) ESBL-producing 4184 (12.6) 2804 (21.1) Enterobacteriaceae CRE 4441 (1.3) 3199 (4.9) MDR Pseudomonas 1061 (6.5) 810 (15.7) MDR Acinetobacter 63 (47.6) 369 (36.6)

CLABSI, central line-associated bloodstream infection Weiner LM et al. MMWR . 2016;65(9):235-241. 35

Carbapenem Resistance in US Long-term Acute Care Hospitals

Susceptibility Trends for P aeruginosa Susceptibility Trends for K pneumoniae 100% 100% LTACH 1 LTACH 1 90% 90% LTACH 2 LTACH 2 80% LTACH 3 LTACH 3 80% 70% 70% 60% 60% 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% 0% Carbapenemase-producing Carbapenemase-producing % organisms, Carbapenemase-producing Carbapenemase-producing % organisms, 2008 2009 2010 2011 2012 2013 2014 2008 2009 2010 2011 2012 2013 2014

LTACH, long-term acute care hospital Sudan S et al. Session 42. Presented at IDWeek 2015. San Diego, CA; Oct 7-11, 2015. 36

Impact of MDR P aeruginosa

Multidrug susceptible MDR 1.0 P 0.8 =0.011

0.6

0.4

0.2

Proportion of Surviving of Proportion Patients 0.0 0 50 100 150 Time, d

Tam VH et al. Antimicrob Agents Chemother . 2010;54(9):3717-3722. Reproduced permission from American Society for Microbiology 37

MDRO Treatment Strategies • Pathogens/susceptibility • Optimize PK/PD • Extended or continuous infusion • Higher doses for beta-lactams (eg, cefepime, ampicillin/sulbactam) 1-4 • Old drugs (colistin IV)? • Aerosolized drugs (aminoglycosides, colistin)5 • New drugs (ceftolozane/tazobactam, ceftazidime/avibactam) • Variable combinations

IV, intravenous; PK/PD, pharmacokinetics/pharmacodynamics 1. Courter JD et al. Pediatr Blood Cancer . 2009;53(3):379-385. 2. Lodise TP Jr et al. Clin Infect Dis . 2007;44(3):357-363. 3. Chastre J et al. Crit Care Med . 2008;36(4):1089-1096. 4. Betrosian AP et al. Scand J Infect Dis . 2007;39(1):38-43. 5. Kwa AL et al. Clin Infect Dis. 2005;41(5):754-757. 38

MDRO Treatment Options: Variable Combinations

Variable combinations 1-3 100

• Polymyxin B + carbapenem, 75 tigecycline, aminoglycoside, quinolone, fosfomycin, and/or 50

beta-lactam Survival, % 25 Combination therapy • Cefepime, amikacin Monotherapy 0 • Cephalosporins, quinolones 0 10 20 30 Days 30-d mortality of patients with K pneumoniae carbapenemase–producing K pneumoniae isolate bloodstream infections ( P=0.002) 4

1. Gilad J et al. Drugs. 2008;68(2):165-189. 2. Rahal JJ. Clin Infect Dis. 2006;43(suppl 2):S95-S99. 3. Zusman O et al. J Antimicrob Chemother . 2016 Sep 13. [Epub ahead of print] 4. Tumbarello M et al. Clin Infect Dis . 2012;55(7):943-950. By permission of Oxford University Press. 39

What Are Your Chances of Encountering MDR Pathogens?

Previously healthy 31-y-old man with 3 young children develops boil on thigh. Despite oral 1 cephalexin, then oral TMP/SMX, he worsens (spreading local redness, induration, fever, chills). Common Older female smoker with self-described “bad Clinical Scenarios lungs” develops fever, chest discomfort, productive in 2016 2 cough. After 3 d oral FQ, says she is not better, and now has dizziness and diarrhea.

Elderly man has prostate biopsy in short procedure unit. Despite oral FQ and IV dose of aminoglycoside 3 periprocedure, he develops a higher fever and rigors later that day. 41

Considerations in Antibiotic Selection

Age

Known or Overall suspected health pathogens

Infection Site of site/duration residence

Prior Reason for antibiotics, hospitalization response

Predicting MDRO RISK SCORE PREDICTORS 2 (Score ≥4 = high risk) 1 • Hospitalized within previous • Hospitalized within previous 90 d • OR 4.87, 95% CI 1.90-12.4 90 d (4 pts ) • • Nursing home resident Nursing home resident • OR 3.55, 95% CI 1.12-11.24 (3 pts ) • ALERT 3 Chronic hemodialysis • (2 pts ) Prior use of broad-spectrum • antibiotics Critically ill (1 pt ) • Prior + culture for MDRO

CVD, cardiovascular disease; OR, odds ratio 1. Shorr AF et al. Clin Infect Dis . 2012;54(2):193-198. 2. Aliberti S et al. Clin Infect Dis . 2012;54(4):470-478. 3. Micek ST et al. Crit Care Med . 2014;42(8):1832-1838. 43

Appropriate Antimicrobial Usage: Considerations • Antimicrobial avoidance when not indicated • 4 “Ds” Right DRUG • Guidelines • Local resistance patterns • Patient risk stratification Right DOSE • PK/PD Right DE-ESCALATION Right DURATION

Summary • Gram-positive MDR is increasingly common • Macrolide and beta-lactam resistance in pneumococci • MRSA and VRE • Gram-negative MDR bacteria are a major threat • ESBL- and carbapenemase-producing enteric bacteria • Pseudomonas , Acinetobacter , etc • Colistin resistance emerging • Stay alert for MDR pathogens • Consider new agents and treatment regimens • De-escalate ASAP

NEW AND EMERGING ANTIBIOTICS: DATA AND PRACTICAL RECOMMENDATIONS

George H. Karam, MD Paula Garvey Manship Chair of Medicine Department of Medicine Louisiana State University School of Medicine in New Orleans Baton Rouge Branch Campus Baton Rouge, LA

FDA-approved IV Antibiotics, 2010–2015

In Vitro Activity Agent Approved Drug Class (Discovered, y) Indication(s) Against ESKAPE Pathogens? Ceftaroline 1 Oct 2010 Cephalosporin (1928) ABSSSI, CABP Dalbavancin 1 May 2014 Lipoglycopeptide (1953) ABSSSI Tedizolid 1 June 2014 Oxazolidinone(1955) ABSSSI Oritavancin 1 Aug 2014 Glycopeptide (1953) ABSSSI Ceftolozane/tazobactam 1 Dec 2014 Cephalosporin (1928) + BLI cIAI a, cUTI b Ceftazidime/avibactam 1 Feb 2015 Cephalosporin (1928) + BLI cIAI a, cUTI b Minocycline 2,3 April 2015 Tetracycline (1948) Various c aIn combination with metronidazole bIncluding acute pyelonephritis cGram-negative and Gram-positive cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; BLI, beta-lactamase inhibitor 1. Deak D et al. Ann Intern Med . 2016;165:363-372. 2. Nelson ML et al. Ann N Y Acad Sci . 2011;1241:17-32. 3. Business Wire. www.businesswire.com/news/home/20150420005501/en/FDA-Approves-Formulation-MINOCIN%C2%AE-minocycline-Injection. Accessed 10/20/16. 50

Classic Basis for Bacterial Resistance to Beta-lactam Antibiotics

βla, beta-lactamase; PBP, penicillin-binding protein Image courtesy of George H. Karam, MD 51

Mechanisms of Resistance in Antibiotic Classes Used to Treat Resistant Pathogens

Enzymatic Drug Class Permeability Altered Binding Sites Efflux Destruction Beta-lactams Beta-lactamases PBPs Altered DNA gyrase and FQs topoisomerase IV Adenolating and Aminoglycosides acetylating 30S ribosomal unit enzymes Modification Tetracyclines 70S ribosomal unit enzymes

Adapted from Karam G et al. Crit Care . 2016;20:136. 53

Focus on Gram-positive Infections: The MRSA Story

Polling Question 3 What do you perceive to be the biggest clinical challenge of the newest agents with activity against MRSA? A. A compromise in efficacy for convenience of dosing B. The increased price for improved safety C. Establishing the cost-effectiveness when compared to older agents

Ceftaroline

• 5th-generation cephalosporin based on CANVAS 1 and 2 (cSSSI)a2 activity against MRSA; high affinity for • N=1378 patients requiring IV therapy 1 S pneumoniae PBPs • Randomized to ceftaroline 600 mg IV q12h o S aureus (including MRSA, MSSA isolates); or vancomycin plus aztreonam (1 g each S pyogenes , S agalactiae , S pneumoniae; q12h), 5-14 d E coli , K pneumoniae , K oxytoca , H influenzae 1 FOCUS 1 and 2 (CABP) 3 • Efficacy similar to comparators 2,3 • N=613 patients hospitalized in non-ICU • Well tolerated, similar rates of AEs with CAP of PORT risk class 3 or 4 requiring IV therapy received two 500 mg o Most common: diarrhea, nausea, rash 1 doses of oral clarithromycin q12h, Day 1 • Randomized (1:1) to ceftaroline 600 mg IV aStudy term was cSSSI, but current indication is ABSSSI q12h or ceftriaxone 1 g IV q24h AE, adverse event; cSSSI, complicated skin and skin-structure infection; CAPB, community-acquired bacteria pneumonia; MSSA, methicillin-sensitive S aureus 1. Teflaro (ceftaroline fosamil) [prescribing information]. Forest Laboratories, Inc.; 5/31/16. 2. Corey GR et al. Clin Infect Dis. 2010;51(6):641-650. 3. File TM Jr et al. Clin Infect Dis. 2010;51(12):1395-1405. 56

Ceftaroline Integrated Analyses: Clinical Cure Rates CANVAS 1 and 2 (cSSSI)1 FOCUS 1 and 2 (CABP) 3 Vancomycin + aztreonam Ceftaroline Ceftaroline Ceftriaxone 84.3% 83.6% 2a 79.2% MITT 78.3% 2a 85.3% CE 86.6% 77.7% 76.6% 94.3% MRSA 93.4% 85.5% MITT 85.9% 92.7% CE 91.6% CE MITT aAdult patients with cSSSI and systemic inflammation or comorbidities randomized 2:1 to ceftaroline (600 mg IV q8h) or vancomycin (15 mg/kg q12h) plus aztreonam (1 g q8h) 5–14 d CE, clinically evaluable; MITT, modified intent-to-treat 1. Corey GR et al. Clin Infect Dis. 2010;51(6):641-650. 2. Dryden M et al. J Antimicrob Chemother . 2016 Sept 1. [Epub ahead of print] 3. File TM Jr et al. Clin Infect Dis. 2010;51(12):1395-1405. 57

Tedizolid

• Novel oxazolidinone 1 ESTABLISH 1 and 2 2,4 • Broad spectrum activity vs Gram- • N=1333 patients randomized to positives (MRSA, staphylococci, tedizolid 200 mg QD or linezolid 1 enterococci) 600 mg BID 2-4 • Noninferior to linezolid • S aureus (82%); rate of MRSA (35%) • Fewer drug interactions (SSRIs, Tedizolid Linezolid MAOIs) and AEs vs linezolid 1 81.6% 79.4% • IV and oral formulations allowing for easy step-down therapy 1 • Shorter duration of therapy vs linezolid (6 d vs 10 d) Early clinical success rate a aAbsence of fever at 48 to 72 h CN, coagulase-negative; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor 1. Durkin MJ et al. Ther Clin Risk Manage . 2015;11(5):857-862. 2. Prokocimer et al. JAMA . 2013;309:559-569. 3. Moran GJ et al. Lancet Infect Dis. 2014;14(8):696-705. 4. Shorr AF et al. Antimicrob Agents Chemother . 2015;59:864-871. 58

Dalbavancin

• Novel lipoglycopeptide, broad- DISCOVER 1 and 2 2 1 spectrum activity, incl. MRSA • N=1312 ABSSSI patients randomized to • 2 dalbavancin IV, Days 1 and 8 or vancomycin Noninferior to vancomycin IV ≥3 d a o Consistent across infection type/severity, underlying illness Dalbavancin Vancomycin

• Well tolerated 79.7% 79.8% o Fewer AEs vs vancomycin-linezolid 2 o Most common AEs: nausea, diarrhea, pruritus • New in 2016 : Single 1500 mg 3 b dose; 30-min IV infusion Early clinical success rate aOption to switch to oral linezolid for 10 to 14 days of therapy bCessation of spread of infection-related erythema and absence of fever at 48 to 72 h 1. Scott LJ. Drugs . 2015;75(11):1281-1291. 2. Boucher HW et al. N Engl J Med . 2014;370(23):2169-2179. 3. PR Newswire. 1/21/16. www.prnewswire.com/news- releases/allergan-announces-fda-approval-of-updated-label-for-new-dosing-regimen-for-dalvance-dalbavancin-300207674.html. Accessed 10/20/16. 59

Oritavancin

• Lipoglycopeptide derived from SOLO I and II 2-4 vancomycin analog 1 • N=1910 ABSSSI patients randomized to • Activity vs most Gram-positive and single-dose oritavancin vs 7-10 d anaerobic bacteria, including vancomycin IV vancomycin-resistant organisms, Oritavancin Vancomycin Enterococcus spp, MRSA 1 88.7% 84.7% 79% 82.7% 75.9% • Efficacy similar to vancomycin across 73% inpatient/outpatient settings 2,3 • Well tolerated 1-3 o Most common AEs: injection site Class I Class II Class III reaction, nausea, vomiting, pruritus Clinical response at early clinical evaluation

1. Kmeid J et al. Core Evid . 2015;10(2):39-47. 2. Corey GR et al. N Engl J Med . 2014;370(23):2180-2190. 3. Corey GR et al. Clin Infect Dis . 2015;60:254-262. 4. Deck DH et al. Infect Dis Ther . 2016;5(3):353-361. 60

Focus on Gram-negative Infections

Polling Question 4 Of the classic mechanisms of resistance, which is the most frequent target for new antibiotics directed against Gram-negative bacteria?

A. A porin channel closure B. β-Lactamases C. Efflux pumps D. Altered target binding sites

Clinical Approach to Gram-negative Resistance Due to β-Lactamases

ESBLs AmpC Carbapenemases β-Lactamases

Chromosomal Plasmid

E coli Serratia E coli Class A: KPC Klebsiella P aeruginosa Klebsiella Class B: NDM Acinetobacter Class D: Oxa-type a Indole + Proteus Citrobacter aMost characteristically found in Acinetobacter Enterobacter KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase (found in Enterobacteriaceae) Karam G et al. Crit Care . 2016;20:136. 63

Resistance in P aeruginosa • Regulated by genetic operons on chromosome of P aeruginosa o Outer membrane porins (carbapenems) o Efflux pumps (fluoroquinolones; meropenem) o AmpC beta-lactamases (noncarbapenem beta-lactams)

Lister PD et al. Clin Infect Dis. 2005;40:S105-S114. 64

Ceftolozane/Tazobactam

• Novel cephalosporin and beta-lactamase inhibitor with broad-spectrum activity o Ceftolozane stable in the presence of the 3 chromosomal mechanisms of resistance in P aeruginosa

Clinical Cure Rates per Pathogen (cIAI)1 Clinical Cure Rates per Pathogen (cUTI)2 Ceftolozane/tazobactam (1.5 g) Meropenem (1 g) Ceftolozane/tazobactam (1.5 g) 96% 100% Levofloxacin (750 mg) 100% 89% 80% 73% 100% 81% 75% 60% 80% 70% 67% 40% 60% 48% 47% 20% 40% 0% 20% ESBL-producing CTX-M-14/15 ESBLs 0% Enterobacteriaceae E coli K pneumoniae P aeruginosa 1. Solomkin J et al. Clin Infect Dis . 2015;60(10):1462-1471. 2. Zerbaxa (ceftolozane and tazobactam) [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2015. 65

Ceftolozane/Tazobactam: Phase 3 ASPECT Trials

Indication Design Regimen Outcome Randomized multinational, Ceftolozane/tazobactam • Ceftolozane/tazobactam noninferior to double-blind, (1.5 g) IV q8h x 7 d levofloxacin for composite cure (76.9% vs cUTI 1 noninferiority trial vs 68.4%, 95% CI 2.3-14.6) High-dose levofloxacin • Superiority indicated N=1068 hospitalized 750 mg IV QD x 7 d • AEs similar, not serious adults with cUTI a Ceftolozane/tazobactam Prospective, • Ceftolozane/tazobactam + metronidazole 1.5 g IV q8h + randomized, double- noninferior to meropenem for clinical cure metronidazole 500 mg cIAI 2 blind trial rate 24-32 d after initiation (83.0% vs IV q8h for 4 to 14 d 87.3%; weighted difference, -4.2%; 95% CI, vs N=993 hospitalized -8.91 to 0.54) Meropenem (1 g) IV q8h adults with cIAI • AEs similar (nausea, diarrhea) for 4 to 14 d aIncluding pyelonephritis 1. Wagenlehner FM et al. Lancet . 2015;385(9981):1949-1956. 2. Solomkin J et al. Clin Infect Dis . 2015;60(10):1462-1471. 66

Beta-Lactamase Inhibitors Beta-lactams Non-beta-lactams • Sulbactam • Avibactam C C • Clavulanate • Relebactam • • Tazobactam C N Vaborbactam O • ME1071

Ceftazidime/Avibactam

• 3rd-generation cephalosporin and MIC (mg/L) Pathogen 1 non-beta-lactam BLI Susceptible Resistant • 1 Broad-spectrum activity Enterobacteriaceae ≤8/4 ≥16/4 o Most ESBLs o KPCs P aeruginosa ≤8/4 ≥16/4 o P aeruginosa in presence of • MICs (vs ceftazidime or meropenem) some AmpC beta-lactamases ≤4 μg/mL for 16 PAO1 isogenic and certain strains lacking mutants, expressing multiple OprD combinations of beta-lactam resistance mechanisms 2

OprD, outer membrane porin 1. Avycaz (ceftazidime and avibactam) [prescribing information]. Verona, Italy: GlaxoSmithKline; 6/2016. 2. Torrens G et al. Antimicrob Agents Chemother . 2016;60(10):6407-6410. 68

Ceftazidime/Avibactam Susceptibility

P aeruginosa 1 KPC Producers 2 Ceftazidime Ceftazidime/avibactam MIC / 50 S/I/R Agent MIC , Range 90 by CLSI, % 76.1% 77.8% μg/mL Ceftazidime >32/>32 4 to >32 2.5/2.5/95.0 27.0% Ceftazidime/ ≤0.015 0.25/1 97.5 a 10.9% avibactam to >32 Ceftazidime Susceptibility, % Ceftazidime Susceptibility,

Isolates hyperproducing MDR isolates AmpC aSusceptible breakpoint of ≤8 μg/mL was applied CLSI, Clinical and Laboratory Standards Institute; I, intermediate; MIC, minimum inhibitory concentration; R, resistant; S, susceptible 1. Torrens G et al. Antimicrob Agents Chemother . 2016;60(10):6407-6410. 2. Castanheira M et al. Antimicrob Agents Chemother . 2015;59:3509-3517. 69

Ceftazidime/Avibactam Phase 3 RECLAIM1 and RECAPTURE 2 Trials

Indication Design Regimen Outcome Ceftazidime/avibactam 2 identical, randomized, • Noninferior clinical cure rate at TOC visit 2000 mg/500 mg + double-blind, trials • Effective in treating ceftazidime- metronidazole 500 mg, cIAI 1 nonsusceptible pathogens each IV q8h for 5 to 14 d N=1066 patients • Similar AEs: diarrhea, nausea, vomiting, vs meropenem 1000 mg hospitalized with cIAI fever IV q8h for 5 to 14 d Randomized, multicenter, Ceftazidime/avibactam • Noninferior to doripenem for patient- double-blind, double- 2000 mg/500 mg IV q8h reported symptom resolution at Day 5 and dummy, parallel-group, vs doripenem 500 mg IV combined symptom resolution/ comparative trials cUTI 2 q8h microbiological eradication at TOC • Highly effective empiric treatment, cUTI N=1033 patients Possible antibiotic switch • Similar AEs: headache, nausea, hospitalized with cUTI/ after ≥5 d constipation, diarrhea acute pyelonephritis

TOC, test of cure 1. Mazuski JE et al. Clin Infect Dis . 2016; 62(11):1380-1389. 2. Wagenlehner FM et al. Clin Infect Dis . 2016;63(6):754-762. 70

Phase 3 Antibiotics with Possible Activity Against ESKAPE or Urgent Threat Pathogens

Agent Drug Class Potential Indication(s) Solithromycin Macrolide (fluoroketolide) CABP, uncomplicated urogenital gonorrhea, urethritis (PDUFA date: 12/2016) Meropenem/vaborbactam Meropenem + novel boronic cIAI, HABP/VABP, febrile neutropenia, BSI, (NDA: Q1 2017?) β-lactamase inhibitor acute pyelonephritis Imipenem/ Carbapenem + novel cUTI, cIAI, HABP/VABP, acute pyelonephritis cilastatin + relebactam β-lactamase inhibitor Eravacycline Tetracycline cIAI, cUTI Plazomicin Aminoglycoside cUTI, catheter-related BSI, HABP/VABP, cIAI Delafloxacin (NDA: Q4 2016?) Fluoroquinolone ABSSSI Omadacycline Tetracycline CABP, ABSSSI, cUTI S-649266 Cephalosporin HAP, BSI, HABP, VABP, cUTI BSI, bloodstream infection; HABP, hospital-acquired bacterial pneumonia; HAP, healthcare-associated pnuemonia; NDA, new drug application; PDUFA, Prescription Drug User Fee Act; VABP, ventilator-associated bacterial pneumonia Pew Charitable Trusts. May 2016. www.pewtrusts.org/~/media/assets/2016/05/antibiotics-currently-in-clinical-development.pdf. Accessed 10/20/16. 71

Solithromycin a

• First fluoroketolide, activity against macrolide-resistant bacteria 1 o 4th-generation macrolide • Interacts with 3 ribosomal sites (vs 1 for older macrolides) 1

MIC 50 /MIC 90 , μg/mL Pathogen N1 Solithromycin Moxifloxacin M pneumoniae 1 26 ≤0.000032/≤0.000032 0.125/0.125 S pneumoniae 1 98 0.008/0.06 0.12/0.12 Legionella pneumophila 2 18 ≤0.015/0.031 ≤0.125/1 MRSA 3 357 0.06/>32 2/>4 S aureus 1 37 0.06/0.12 0.03/2 aInvestigational N1, number of baseline pathogens with MIC available 1. File TM Jr et al. Clin Infect Dis . 2016 Jul 22. [Epub ahead of print] 2. Mallegol J et al. Antimicrob Agents Chemother . 2014;58(2):909-915. 3. Farrell DJ et al. Antimicrob Agents Chemother. 2016;60:3662-3668. 72

Solithromycin: Noninferior to Moxifloxacin for CABP

SOLITAIRE-ORAL 1 SOLITAIRE-IV 2 • N=860 CABP patients (PORT class II to • N=863 CABP patients (PORT class II to IV) randomized to oral solithromycin IV) randomized 1:1 to 7 once-daily 5 d (800 mg Day 1, 400 mg Days 2-5, doses of IV-to-oral solithromycin or placebo Days 6-7) or oral moxifloxacin IV-to-oral moxifloxacin 7 d (400 mg, Days 1-7). • 400 mg IV Day 1; switched to oral when clinically indicated a

78.2% 77.9% 79.3% 79.7%

Solithromycin Solithromycin Moxifloxacin Moxifloxacin

Early clinical response Early clinical response aIV median of 3 d in each study group 1. Barrera CM et al. Lancet Infect Dis . 2016;16(4):421-430. 2. File TM Jr et al. Clin Infect Dis . 2016 Jul 22. [Epub ahead of print] 73

Activity of Beta-Lactamase Inhibitors Against Beta-Lactamases

Beta-lactamase Inhibitor Spectrum Tazobactam Avibactam Relebactam Vaborbactam Class A ESBLs + + + + Class A + + + carbapenemases (KPC) Class B MBLs Some class C enzymes +/- + + + Some class D enzymes +

Drawz SM et al. Rev Clin Microbiol Rev. 2010;14:160-201. Toussaint KA et al. Ann Pharmacother. 2015;49:86-98. 74

Meropenem/Vaborbactam (M/V) a

• Carbapenem + BLI TANGO-12 • Unique boronic acid BLI 1 • N=550 patients with cUTI or AP • Potent inhibitor of KPCs 1 randomized to M/V (2 g/2 g IV) q8h or • Activity against Gram (-) CREs, incl. pip/tazo (4 g/0.5 g) q8h; ≥15 doses KPCs with transition to oral if clinically • Positive topline phase 3 results indicated reported (TANGO-1) o Superior efficacy to 98.4% piperacillin/tazobactam for cUTI/AP 94.0% o Comparable safety, tolerability M/V • TANGO-2 ongoing Pip/tazo aInvestigational Overall success at EOIVT AP, acute pyelonephritis; EOIVT, end of IV therapy 1. Lapuebla A et al. Antimicrob Agents Chemother . 2015;59:4856-4860. 2. The Medicines Company. 6/27/16. www.themedicinescompany.com/ investors/news/medicines-company-announces-positive-top-line-results-phase-3-tango-1-clinical-trial. Accessed 10/20/16. 75

Imipenem/Relebactama

• Activity against E coli , K pneumoniae , Enterobacter spp (incl. KPC- producing isolates) o Loss of OmpK36 in KPC-producing K pneumoniae isolates affect susceptibility • No increased activity against A baumannii with addition of relebactam • Enhanced activity against P aeruginosa , incl. isolates with depressed oprD and increased AmpC expression • In imipenem-resistant isolates, increase in susceptibility to 92%

aInvestigational Lapuebla A et al. Antimicrob Agents Chemother. 2015;59:5029-5031. 76

Eravacycline a

• First fully synthetic tetracycline in • Potent in vitro activity against clinical development 1 carbapenem-resistant 3 • Broad-spectrum activity against A baumannii Gram (+), Gram (-), anaerobic 3 2 MIC 50 /MIC 90 , μg/mL bacteria (except P aeruginosa ) Pathogen o 2- to 4-fold more potent than Eravacycline Tigecycline tigecycline vs Gram (+) cocci A baumannii 0.5/2 2/8 o 2- to 8-fold more potent than tigecycline vs Gram (-) bacilli

aInvestigational 1. Liu F et al. Curr Opin Chem Biol . 2016;32:48-57. 2. Zhanel GG et al. Drugs . 2016;76:567-588. 3. Pogue JM et al. Clin Infect Dis. 2015;60:1304-1307. 77

Activity Against Carbapenemase-Producing Pathogens • In vitro activity against New Delhi metallo-β- lactamases (NDM carbapenemases)1 o Aztreonam/avibactam o Colistin o Eravacycline o Fosfomycin (as part of combination therapy) 2

1. Zmarlicka MT et al. Infect Drug Resist. 2015;8:297-309. 2. Seija V et al. Int J Infect Dis. 2015;30:20-26. 78

Summary

• New antibiotics directed at resistant Gram-positive organisms must overcome problem of altered PBPs as major mechanism of resistance • Major focus of many new antibiotics for infections caused by resistant Gram-negative pathogens is focused on overcoming beta-lactamase production • Efflux is the mechanism of resistance common to many classes of antibiotics and often explains basis for MDR • Understanding of mechanisms of resistance allows for informed decision making for incorporating new antibiotics in a program of antimicrobial stewardship

ANTIMICROBIAL STEWARDSHIP: EFFECTIVE IMPLEMENTATION FOR IMPROVED CLINICAL OUTCOMES James S. Lewis II, PharmD, FIDSA ID Clinical Pharmacy Supervisor Oregon Health and Science University Departments of Pharmacy and Infectious Diseases Portland, OR

Why Develop an ASP? BECAUSE IT WORKS

Reduces antibiotic resistance 1,2 • >Half a million antibiotic-resistant HAIs could be prevented in 5 y • Increased likelihood of adequate initial therapy Improves patient outcomes 2 • Reduced mortality • Fewer AEs, recurrences, readmissions Saves money 2 • Earlier switch from IV to oral therapy • LOS reductions

ASP, antimicrobial stewardship program; HAI, healthcare-acquired infection 1. Slayton RB et al . MMWR Morb Mortal Wkly Rep . 2015;64(30):826-831. 2. Barlam TF et al. Clin Infect Dis. 2016;62:e51-e77. 81

National Action Plan for Combating Antibiotic-Resistant Bacteria

Goals • Slow emergence of resistant bacteria • Strengthen national surveillance efforts • Advance development/use of rapid and innovative diagnostic tests to identify resistant bacteria • Accelerate research and development for new therapies • Improve international collaboration and capacities for antibiotic resistance prevention, surveillance, control, and antibiotic research and development

PQ National Action Plan. Mar 2015. www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_ antibotic-resistant_bacteria.pdf. Accessed 10/20/16. 82

Polling Question 5 Joint Commission standards for AS will be enacted soon—how prepared is your healthcare institution?

A. Totally ready B. Pretty close C. Long way to go D. Yikes!!!

Why Develop an ASP? BECAUSE YOU HAVE TO

• Effective January 1, 2017 • For hospitals, critical access hospitals, nursing homes • Must establish protocols • Educate staff involved in antimicrobial ordering/monitoring when hired, then annually PQ

The Joint Commission. Issued 6/22/16. www.jointcommission.org/assets/1/6/HAP-CAH_Antimicrobial_Prepub.pdf. Accessed 10/20/16. 84

Polling Question 6 How familiar are you with the new 2016 IDSA/SHEA guidelines on Implementing an Antibiotic Stewardship Program ?

A. They’re committed to memory B. I skimmed the highlights C. I know they were released, but I haven’t read them D. What guidelines?

Joint Commission and IDSA/SHEA: 2016 Antimicrobial Stewardship Guidelines

Recommendations JC 1 IDSA/SHEA 2 • Preauthorization • IV to oral conversion • Care of patients with C difficile • Formulary restrictions • Assess appropriateness of antibiotic use in specific indications (CABP, ABSSSI, UTI) • PK monitoring services – aminoglycosides, vancomycin • Minimize treatment duration

1. The Joint Commission. Issued 6/22/16. www.jointcommission.org/assets/1/6/HAP-CAH_Antimicrobial_Prepub.pdf. Accessed 10/20/16. 2. Barlam TF et al. Clin Infect Dis 2016;62:e51-e77. 86

Joint Commission: Multidisciplinary ASP Team

Required a per Joint Commission 1 Key People Are Missing

ID Physician Infection Microbiologists Hospitalists Preventionist Pharmacist Intensivists Surgeons

Nurses 2

aPart-time staff or consultants acceptable

1. The Joint Commission. Issued 6/22/16. www.jointcommission.org/assets/1/6/HAP-CAH_Antimicrobial_Prepub.pdf. Accessed 10/20/16. 2. Olans RN et al. Clin Infect Dis . 2016;62(1):84-89. 87

CDC’s Core Elements of the ASP Team

Accountability Tracking

Drug expertise Reporting

Action Education

Centers for Disease Control and Prevention (CDC). www.cdc.gov/getsmart/healthcare/pdfs/core-elements.pdf. Accessed 10/20/16. 88

Other Select 2016 IDSA/SHEA Recommendations (Any Level of Evidence)

• Provider-led antibiotic review • Computerized decision support • Alternative dosing strategies for beta-lactams • Rapid viral tests for respiratory pathogens • Penicillin skin testing • Stratified antibiograms • Rapid diagnostics for blood cultures • Procalcitonin in ICU

ICU, intensive care unit Barlam TF et al. Clin Infect Dis 2016;62:e51-e77. 89

Data-Driven AS

• Electronic health records 1,2 • Surveillance (eg, EPIC, TheraDoc) • Tracking: Monitoring antibiotic prescribing and resistance patterns 3 • Clinical pharmacy programs 1 • Rapid diagnostic tests speed selection of optimal antibiotic(s) 1 • PCR (eg, Cepheid Xpert-MRSA/SA, C difficile )2 • Nucleic acid (eg, Nanosphere Verigene) • Fluorescence in situ hybridization using PNA FISH (eg, AdvanDx Quick FISH, Candida species) • MALDI-TOF

MALDI-TOF, matrix-assisted laser desorption/ionization time of flight; PCR, polymerase chain reaction; PNA FISH, peptide nucleic acid probes 1. Goff DA et al. Pharmacotherapy . 2012;32(8):677-687. 2. Centers for Disease Control and Prevention. www.cdc.gov/getsmart/healthcare/implementation/ core-elements.html. Accessed 10/20/16. 2. Cepheid. 061914. http://ir.cepheid.com/releasedetail.cfm?ReleaseID=855545. Accessed 10/20/16. 90

The Impact of Rapid Diagnostics

AS Oversight in rmPCR + AS Group

Timeline, h 0 12 24 36 48 60 72 Control E IDD AST (n=169) rmPCR * ID E D AST (n=147) rmPCR * * † + AS ID E D AST (n=165)

*P<0.05 vs control †P<0.05 vs control and rmPCR groups AST, antimicrobial susceptibility testing; D, de-escalation; E, escalation; ID, organism identification; rm, rapid multiplex Banerjee R et al. Clin Infect Dis . 2015;61(7):1071-1080. By permission of Oxford University press. 91

Comparison of Clinical, Microbiologic, and Cost Outcomes

Control rmPCR rmPCR + AS Outcome P value n=207 n=198 n=212 LOS after enrollment, d, 7 (4-12) 6 (4-12) 7 (4-12) 0.61 median (IQR) ICU stay after enrollment, d, 3 (2-4) 2 (1-5) 3 (2-4) 0.90 median (IQR) 30-d mortality 22 (10.6) 20 (10.1) 18 (8.5) 0.74

Mean overall hospitalization $65,450 $66,887 $68,729 0.78 (median costs) ($27,192) ($23,935) ($29,064) $5377 $5680 $5743 Mean test (median costs) <0.001 ($2082) ($2585) ($2774)

IQR, interquartile range Banerjee R et al. Clin Infect Dis . 2015;61(7):1071-1080. 92

Comparison of Antibiotic Duration of Therapy

Duration of Therapy a, h Antibiotic Control rmPCR rmPCR + AS P value Vancomycin b 8.2 0 0 0.032 (n=169) Nafcillin, oxacillin, or cefazolin 42 71 85 0.035 (n=50) Piperacillin/tazobactam 56 44 45 0.012 (n=214)

aCalculated as difference between date and time of antibiotic start and stop orders bIn organisms not requiring vancomycin Banerjee R et al. Clin Infect Dis . 2015;61(7):1071-1080. 93

Duration of Antibiotic Use: The Shorter, The Better Similar outcomes in clinical trials: • ABSSSI: tedizolid, 6 d = 10 d 1 • cIAI: short-course (≈4 d) = longer course (≈8 d) 2 • AP: ciprofloxacin, 7 d = 14 d 3 • CAP: 5 d = 10 d 4

1. Moran GJ et al. Lancet Infect Dis . 2014;14(8):696-705. 2. Sawyer RG et al. N Engl J Med . 2015;372(21):1996-2005. 3. Sandberg T et al. Lancet . 2012;380(9840):484-490. 4. Uranga A et al. JAMA Intern Med. 2016;176(9):1257-1265. 94

Measuring ASP: Process and Outcomes?

Process Measures Outcome Measures

• Excess DOT • Hospital LOS • Duration of therapy • 30-d mortality • Proportion of patients adherent with • Unplanned hospital readmission within facility-based guideline or treatment 30 d algorithm • Proportion of patients diagnosed with • Proportion of patients with revision of hospital-acquired C difficile infection or antibiotics based on microbiology data other AEs related to antibiotic treatment • Proportion of patients converted from • Proportion of patients with clinical failure IV oral (eg, need to broaden therapy, infection recurrence)

DOT, days of therapy Barlam TF et al. Clin Infect Dis 2016;62:e51-e77. 95

Antimicrobial Stewardship Toolkit

Antimicrobial Stewardship Toolkit. www.ahaphysicianforum.org/resources/appropriate-use/antimicrobial/ASP-Toolkit-v4.pdf. Accessed 10/20/16. 96

Summary • AS is everywhere in 2016 • Strong leadership needed • Administration, ID physicians, ID pharmacists • Rapid diagnostics • Expensive, but will change field markedly • Low-hanging fruit: de-escalation, duration of therapy • Ample tools available

ID, infectious disease 97

CASE STUDIES WITH AUDIENCE PARTICIPATION

Moderated by Thomas M. File Jr, MD, MSc, MACP, FIDSA, FCCP (Chair)

Case Study 1 52-y-old male in ICU on ventilator, 5 d post-operation, ruptured diverticular abscess • On ertapenem • Prior admission 2 mo ago for AECOPD (piperacillin/tazobactam) • Develops fever, pulmonary infiltrates • Temp: 39.1 °C; pulse: 110 bpm; BP: 130/90 mm Hg; lungs: bilateral rhonchi • WBC: 18,000/mm 3 • ET aspirate: new purulent secretions; Gram stain-GNR AECOPD, acute exacerbations of chronic obstructive pulmonary disease; BP, blood pressure; bpm, beats per minute; ET, endotracheal tube; WBC, white blood cell count PQ Image courtesy of Thomas M. File, Jr, MD 99

Polling Question 7

What is your choice of therapy for GNR? A. Antipseudomonal beta-lactam a (standard infusion) +/- aminoglycoside B. Antipseudomonal beta-lactam (prolonged infusion) +/- aminoglycoside C. Colistin D. New BLI combination b (ceftolozane/tazobactam or ceftazidime/avibactam) +/- aminoglycoside E. Any of the above + aerosolized colistin or aminoglycoside

aPiperacillin/tazobactam; cefepime/ceftazadime; meropenem, imipenem,doripenem PQ bUnapproved use 100

Polling Question 8

Case study 1 (continued) : Patient’s blood culture + next day for K pneumoniae (+ KPC based on rmPCR test method) What is your choice of therapy for GNR?

A. Antipseudomonal beta-lactam a (prolonged infusion) +/- aminoglycoside B. Colistin C. Ceftolozane/tazobactam b +/- aminoglycoside D. Ceftazidime/avibactam b +/- aminoglycoside E. Any of the above + aerosolized colistin aPiperacillin/tazobactam; cefepime/ceftazadime; meropenem, imipenem,doripenem bUnapproved use 101

Case Study 2 46-y-old male smoker with diabetes treated with a macrolide for bronchitis 1 wk ago • Fever • Cough for 3 d • New confusion • Temp: 38.8°C • Pulse: 110 bpm • RR: 30 breaths/min • Auscultation, rhonchi RLL • O2 saturation: 92% room air PQ RLL, right lower lobe; RR, respiration rate Image courtesy of Thomas M. File, Jr, MD 102

Polling Question 9 Which antibiotic would you choose to treat this patient?

A. Levofloxacin B. Ceftriaxone C. Ceftaroline D. Piperacillin/tazobactam E. Ertapenem

Image courtesy of Thomas M. File, Jr, MD 103

CMS Hospital Readmissions Reduction Program • 3% fines for “higher than average” 30-d readmissions 1,2 US Hospitals Fined for 30-d Readmissions, No. 1 • Pneumonia 2800 2610 • Myocardial infarction 2600 • Heart failure 2400 2217 2225 • COPD 2200 • Total hip/knee replacement 2000 2013 2014 2015 CMS, Centers for Medicare and Medicaid Services PQ 1. Modern Healthcare. 10/2/14. www.modernhealthcare.com/article/20141002/news/310029947. Accessed 10/20/16. 2. CMS. 2016. www.cms.gov/medicare/medicare-fee-for-service-payment/acuteinpatientpps/readmissions-reduction-program.html. Accessed 10/20/16. 104

Polling Question 10

Case study 2 (continued) : Blood culture + for S pneumoniae MIC: ceftriaxone 4 μg/mL; ceftaroline 0.25 μg/mL; penicillin 4 μg/mL; levofloxacin 1 μg/mL What is your choice of therapy?

A. Levofloxacin B. Ceftriaxone C. Ceftaroline D. Azithromycin E. Vancomycin

105

Case Study 3

56 y-old male with acute onset of pain and redness of leg, recurrent cellulitis of the leg

• He has had several similar episodes previously • Temp: 38.6 °C • Pulse: 90 bpm

PQ Image courtesy of Thomas M. File, Jr, MD 106

Polling Question 11 Which antibiotic would you choose to treat this patient?

A. Vancomycin B. Cefazolin C. Penicillin D. Linezolid

Image courtesy of Thomas M. File, Jr, MD 107

Management of SSTIs: IDSA 2014 Nonpurulent Purulent Mild (cellulitis) Mild (localized furuncle)

Oral antibiotics (eg, PCN, cephalosporin) Incision and drainage (I & D) Moderate (systemic signs a) Moderate (systemic signs a)

IV antibiotics (eg, PCN G, cefazolin) I & D; culture and sensitivity Severe (failed oral therapy; Antibiotics (eg, TMP/SMX, doxycycline) systemic signs a) Severe (failed I & D + oral a Broad-spectrum IV antibiotics antibiotics or systemic signs ) (eg, vancomycin + piperacillin/tazobactam) IV antibiotics with MRSA coverage (vancomycin, daptomycin, linezolid, televancin, ceftaroline) aTemp >38°C, heart rate >90 bpm, RR 24 breaths/min, abnormal WBC count, immunocompromised PCN, penicillin; SSTI, skin and soft tissue infections Stevens DL et al. Clin Infect Dis . 2014;59(2):e10-52. 108

Case Study 4

36-y-old female noted onset of tender nodule of the leg 4 d earlier • Increasing pain • Fever • Surrounding erythema • Temp: 38.6 °C; BP: 120/70 mm Hg • Pulse: 100 bpm • 10 x 7 cm erythema with central fluctuance and purulence • WBC: 13,000/mm 3 • Creatine: 0.6 mg/dL PQ Image courtesy of Thomas M. File, Jr, MD 109

Polling Question 12 Which antibiotic would you choose to treat this patient?

A. IV/Oral linezolid or tedizolid B. IV vancomycin C. IV penicillin D. IV oritavancin or dalbavancin E. IV nafcillin

PQ Image courtesy of Thomas M. File, Jr, MD 110

Polling Question 13

Case study 4 (continued) : Incision and drainage in ED; IV vancomycin; observed in CDU. Next morning: afebrile, erythema reduced >25%. Culture = MRSA. She does not wish to be admitted.

Which course of management would you choose?

A. Oral trimethoprim/sulfamethoxazole B. Oral linezolid C. Home IV vancomycin with PICC line D. IV oritavancin or dalbavancin

CDU, clinical decision unit Image courtesy of Thomas M. File, Jr, MD 111

ABSSSI Treatment: Cost Considerations

• ABSSSI hospitalization in US: • Mean LOS: 4.9 d 1 • Mean costs of inpatient vancomycin treatment: $5973 to $9885 2 • Switch inpatient vancomycin outpatient oritavancin 2 • Savings of $1752.46 to $6475.87 per patient • Single-dose outpatient ABSSSI treatment 3 • Estimated cost reduction to US payors of $1.05 per member/mo

1. Pollack CV Jr et al. J Emerg Med . 2015;48(4):508-519. 2. Lodise TP et al. Clin Ther . 2016;38(1):136-148. 3. Jensen IS et al. J Manag Care Spec Pharm . 2016;22(6):752-764. 112

Case Study 5

82-y-old female transferred from LTC facility with fever, decreased mental status, on ciprofloxacin for UTI Pertinent findings: • Long-term Foley catheter • BP: 90/60 mm Hg • WBC: 15,000/mm 3 • + pyuria • Blood and urine cultures positive for P aeruginosa resistant to “routine” drugs tested: • Ciprofloxacin, piperacillin/tazobactam, cefepime, meropenem, gentamicin PQ LTC, long-term care 113

Polling Question 14

Which antibiotic regimen would you choose to treat this patient?

A. Colistin B. Prolonged infusion with meropenem +/- aminoglycoside C. Amikacin D. Ceftolozane/tazobactam E. Ceftazidime/avibactam

114

Summary • Novel antibiotics are effective and should be considered for coverage of MDROs when appropriate • Empiric use of novel antibiotics will depend on clinical presentation/likelihood of MDROs • De-escalate ASAP

115

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©2016 Paradigm Medical Communications, LLC, except where noted 54 Combating Multidrug-Resistant Organisms: Strategic Considerations for Optimal Clinical Outcomes The Ernest N. Morial Convention Center ● New Orleans, LA ● Wednesday, October 26, 2016

1. According to US surveillance data from 2011, which of the following beta-lactams is associated with the lowest Streptococcus pneumoniae resistance rate? A. Amoxicillin/clavulanate B. Ceftaroline C. Ceftriaxone D. Penicillin

Rationale: A 14-year longitudinal survey of S pneumoniae (18,911) strains conducted by the SENTRY Antimicrobial Surveillance Program between 1998 and 2011 showed significant increases in resistance to amoxicillin/clavulanate (18.9%), penicillin at a MIC of ≥4 μg/mL (14.8%), and ceftriaxone (11.7%) among 2011 isolates. In contrast, ceftaroline (99.1%-100.0% susceptible depending on breakpoint criteria) exhibited high levels of potency .

2. A 67-year-old male has been in an intensive care unit (ICU) on a ventilator for 13 days after major trauma. He is on day 6 of antimicrobial therapy for ventilator-acquired pneumonia. Two days ago, he required additional surgery to resect ischemic bowel. Postoperatively, he develops a severe wound infection associated with drainage from which a Gram stain shows Gram-negative bacilli. According to a 2016 report from the Centers for Disease Control and Prevention, which of the following pathogens is most likely to be multidrug-resistant in this case? A. Enterococci B. Enterobacteriaceae C. Pseudomonas D. Acinetobacter

Rationale: According to data on surgical site infections reported to the National Healthcare Safety Network in 2014 by approximately 4000 short-term acute care hospitals across the United States, of 63 infections that tested positive for Acinetobacter, 47.6% were multidrug-resistant.

3. An 82-year-old female is transferred from a nursing home with fever and decreased mental status. She is on day 3 of a fluoroquinolone for complicated urinary tract infection. She has a long-term Foley catheter; blood pressure, 90/60 mm Hg; 15,000 white blood cells/μL; pyuria; urinalysis loaded with bacteria. Blood and urine cultures are positive for antibiotic-resistant K pneumoniae . Which of the following antibiotics is most likely to be effective for this infection? A. Ceftazidime/avibactam B. Piperacillin/tazobactam C. Levofloxacin D. Meropenem

Rationale: The infection is likely caused by a carbapenem-resistant K pneumoniae (KPC). Of the agents listed, only ceftazidime/avibactam is likely to be active against KPC. The addition of avibactam extends the spectrum of ceftazidime/avibactam to include most Enterobacteriaceae, including AmpC, extended-spectrum beta- lactamases, and KPC carbapenemases.

4. Which of the following investigational antibiotics is a novel fluoroketolide with activity against macrolide- resistant bacteria, including key typical and atypical pathogens of community-acquired bacterial pneumonia? A. Solithromycin B. Plazomicin C. Meropenem/vaborbactam D. Omadacycline

Rationale: Solithromycin, an investigational antibiotic (with an FDA decision expected December 2016), is the only antibiotic fitting the description above. The classes of the other investigational antibiotics listed are as follows: plazomicin (an aminoglycoside); meropenem/vaborbactam (meropenem + novel boronic beta-lactamase inhibitor); omadacycline (tetracycline).

5. A 36-year-old woman presents to the emergency department with a painful, purulent leg nodule (erythema, 10 x 7 cm) and fever (38.6°C). She receives incision and drainage and intravenous (IV) vancomycin and is kept in the observation unit overnight. The next day, the patient is hemodynamically stable and erythema is reduced >25%; culture shows methicillin-resistant Staphylococcus aureus (MRSA). Blood cultures are negative. The patient is an IV drug user with a history of noncompliance. Which of the following treatments would provide the most appropriate MRSA coverage while allowing for outpatient treatment of this patient? A. Oral trimethoprim/sulfamethoxazole (TMP/SMX) B. Oral linezolid C. Home IV vancomycin with peripherally inserted central catheter (PICC) line D. IV oritavancin or dalbavancin

Rationale: Oritavancin and dalbavancin are both available as single-dose IV infusions, making them appropriate for the outpatient treatment of ABSSSI, particularly in a patient with a history of drug use and noncompliance. Neither oral TMP/SMX nor oral linezolid provide adequate coverage for MRSA. Home IV programs rarely accept IV drug users with PICC line, since the PICC line could be used for other drugs.

6. A 75-year-old woman is transferred from a long-term care facility for urosepsis. She is placed on piperacillin/tazobactam. On day 3, she is clinically improved and blood and urine cultures reveal pan- susceptible K pneumoniae . According to evidence-based antimicrobial stewardship, which of the following is most appropriate? A. Continue piperacillin/tazobactam and treat for 7 days total B. Continue piperacillin/tazobactam and treat for 14 days total C. De-escalate to cefazolin and treat for 7 days total D. De-escalate to cefazolin and treat for 14 days total

Rationale: Both de-escalation and limiting duration of therapy are principles of antimicrobial stewardship that are recommended by current guidelines. These guidelines are based on studies demonstrating equivalent outcomes in patients who are switched from empiric therapy to pathogen-direct therapy, and in patients who receive shorter course versus longer course antibiotic therapy.