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FSHP 2017 ANNUAL MEETING Disclosure #FSHP2017

I do not have (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an Infectious Diseases Bootcamp organization whose philosophy could potentially bias my What you really need to know presentation. Joe Pardo, PharmD, BCPS-AQ ID, AAHIVP The views expressed in this presentation reflect those of the North FL/South GA Veterans Health System author, and not necessarily those of the Department of Veterans Affairs.

2017 ANNUAL MEETING

Objectives #FSHP2017 You May Have Seen for…#FSHP2017 • Review common pitfalls in selection • Asymptomatic bacteriuria • The flu • Describe the process and impact of de-escalation of • Other viral infections (i.e. upper respiratory tract) • Contaminated blood cultures • Colonization (presence of bacteria without infection) • Discuss antimicrobial dosing strategies to optimize • Chronic [uninfected] wounds/stasis ulcers utilization of antimicrobials • Endotracheal tube aspirates • Enterococcus in respiratory cultures • Poor source control (“More cowbell”) • Identify common multi-drug resistant organisms (MDRO) and appropriate treatment options • Non-infectious fever/leukocytosis • “Just in case”

2017 ANNUAL MEETING 2017 ANNUAL MEETING

A New Context for Misuse #FSHP2017 A New Context for Antibiotic Misuse #FSHP2017 • Aug 5, 2017 (today) @ 3:30 PM: Humans

4.5 billion years old • July 31, 2017 (this past Monday): Dinosaurs

• Early July 2017: Mammals and flowers What if you collapsed the entire history of earth into one calendar year… • May – June 2017: Multicellular plants and animals

Aug 5, 2016 @ 4PM Aug 5, 2017 @ 4PM • Oct 2016 – Apr 2017: Single-celled organisms Earth Created Present Day • Aug – Sep 2016: Life yet to evolve

Yong E. I Contain Multitiudes. New York, NY: HarperCollins Publishers, 2016. Print. 2017 ANNUAL MEETING Yong E. I Contain Multitiudes. New York, NY: HarperCollins Publishers, 2016. Print. 2017 ANNUAL MEETING

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A New Context for Antibiotic Misuse #FSHP2017 A New Context for Antibiotic Misuse #FSHP2017

2017 ANNUAL MEETING 2017 ANNUAL MEETING

A New Context for Antibiotic Misuse #FSHP2017 A New Context for Antibiotic Misuse #FSHP2017

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A New Context for Antibiotic Misuse #FSHP2017 A New Context for Antibiotic Misuse #FSHP2017

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The Human Microbiome #FSHP2017 Microbiome By The Numbers #FSHP2017 • You are about 10% human • There are ~100 Trillion microbes in/on your body • ~150x more genes than the human genome

Functions of the Microbiome The Human Microbiome: “The sum of all microbial life living in Immune Regulation Metabolism (Diet) or on the human body” Energy Biogenesis Metabolism (Medications) Synthesis of Psychoactive Vitamin Biosynthesis compounds

Lynch SV et al. N Engl J Med. 2016;375:2369-79. 2017 ANNUAL MEETING Li D et al. Biotechnol Adv. 2016;34:1210-24. 2017 ANNUAL MEETING

Microbiota Transplant Studies #FSHP2017 Ongoing Probiotic Studies #FSHP2017 • Type II Diabetes • Hematopoietic stem cell transplant • Obesity/Metabolic syndrome • Colon cancer • Migraines • Immune function in astronauts • • Metabolic syndrome • Graft versus host disease • Liver disease Prevention of • Type II diabetes • Severe depression • Allergic rhinitis • Obesity • Recurrent urinary tract infection • Parkinson’s disease • Portal hypertension • Constipation • Autism spectrum disorder • Idiopathic arthritis • Body composition • Chronic constipation/Chronic diarrhea • Lactose intolerance • Bipolar disease • Smoking cessation • Crohn’s disease/Ulcerative colitis • Acute pancreatitis • Cirrhosis • Hepatic encephalopathy • Obsessive compulsive disorder • Pouchitis • Epilepsy • Non-alcoholic fatty liver disease • Type I diabetes • Schizophrenia • Chronic kidney disease • Chronic lower back pain • Peanut allergy • MRSA enterocolitis • Anxiety • Running/cycling performance • Exercise induced muscle damage • Hepatic encephalopathy • Immune thrombocytopenia • Mania • Cognition • Primary sclerosing cholangitis • Asthma • Stress in university students • Acute malnutrition • Psoriatic arthritis • Atopic dermatitis • Rheumatoid arthritis • Prevention of cholangitis • Reversal of MDRO colonization • Chronic (sinonasal microbiota • Influenzae • • Bacterial vaginosis • Chronic inflammation in HIV infection transplant) • Neonatal hyperbilirubinemia • Gluten sensitivity • Pollen allergies • Severe depression • Endothelial function • Human papillomavirus • Nonalcoholic & alcohol-related cirrhosis • Low birth weight • Nosocomial pneumonia • Skin health • Acute decompensated cirrhosis • Inflammation in HIV infection • Spina bifida • Gingivitis • Body composition in shift workers • Bone mineral density • Primary sclerosing cholangitis • Chronic diarrhea/constipation • Women’s health • Chronic lung disease • Hepatitis B reactivation • Eczema • Prevention of infections • Fibromyalgia • Attention deficit disorder Clinicaltrials.gov • Crohns disease/ulcerative colitis 2017 ANNUAL MEETING 2017 ANNUAL MEETING Clinicaltrials.gov

Antibiotic Therapy: Risk vs. Benefits #FSHP2017 Curtailing Treatment of ASB #FSHP2017 • Look for red flags • Ask questions • What brought the patient to the hospital? • Why did the patient come to clinic today? “UTI found The interplay between the human body, the • Why & when was the UA/UC collected? environment, and the microbiome is complex. • Evidence of inflammation? Contamination? on UA.” • What has been done since? How is the patient? • Bridge the fear gap Our knowledge of how antibiotics affect • System-wide approaches health is incomplete. • Remove UA/UC orders from certain order sets • Do not reflex UA orders to UC orders • Release UC results by request only1 • Stewardship bundles2-3

1. Leis JA et al. Clin Infect Dis. 2014;58:980-83. 2017 ANNUAL MEETING 2. Zhang X et al. Am J Emerg Med. 2017;35:594-98. 2017 ANNUAL MEETING 3. Kelley D et al. Infect Control Hosp Epidemiol. 2014;35:193-5.

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#FSHP2017 Saves Lives, but #FSHP2017 • De-escalate therapy when possible • Reduction in the anti-infective spectrum via discontinuation or switching to a more narrow agent

EMPIRIC THERAPY 2017 ANNUAL MEETING 2017 ANNUAL MEETING

How to De-escalate #FSHP2017 How to De-escalate #FSHP2017 • Look for de-escalation opportunities at 48 – 72 hours • Look for de-escalation opportunities at 48 hr, or sooner!

Clinical Pearl If blood cultures are negative at 48 hours, there is a >99% chance they will remain negative (or turn positive for a contaminant).

Goff DA et al. Pharmacotherapy. 2012;32:677–87. 2017 ANNUAL MEETING Pardo J et al. Ann Pharmacother. 2014;48:33-40. 2017 ANNUAL MEETING

How to De-escalate #FSHP2017 How to De-escalate #FSHP2017 • Look for de-escalation opportunities at 48 hr, or sooner!

• Antibiotic Time Out • Does the patient have a bacterial infection? • Are they on the correct antibiotic, with the correct route and dose? • Can we use a more narrow antibiotic? Diagnosis is the rate limiting step. • Duration of therapy?

• Prospective Audit With Feedback • Review from an expert (not on the primary team)

Barlam TF et al. Clin Infect Dis. 2016; DOI: 10.1093/cid/ciw118 Centers for Disease Control and Prevention. Core Elements of Hospital Antibiotic Stewardship Programs. 2014 2017 ANNUAL MEETING 2017 ANNUAL MEETING

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Rapid Diagnostic Tests (RDTs) #FSHP2017 RDTs: A Case Study #FSHP2017 • PNA-FISH: Peptide nucleic acid in-situ hybridization • FilmArray BCID with stewardship intervention at an academic medical center • Targeted polymerase chain reaction (PCR) assays • Case-Control study to determine impact on patients with • FilmArray Blood Culture Identification Panel (BCID)(BioFire) gram positive bacteremia and candidemia • Verigene Gram Positive Blood Culture Test (Luminix) • Verigene Gram Negative Blood Culture Test (Luminix) • Xpert MRSA/SA BC (Cepheid) • LightCycler SeptiFast (Roche) – Not available in U.S.

• MALDI-TOF: Matrix assisted laser desorption/ionization time-of-flight mass spectrometry

• Magnetic Resonance: T2Candida System

2017 ANNUAL MEETING Pardo J et al. Diagn Microbiol Infect Dis. 2016;84:159-64. 2017 ANNUAL MEETING

RDTs: A Case Study #FSHP2017 RDTs: Meta-Analysis #FSHP2017 • FilmArray BCID with stewardship intervention at an  Faster organism identification and active therapy academic medical center  Earlier de-escalation  Earlier discharge Summary of Outcomes Historical Control  • Faster organism identification Cost savings BCID Group  • Less vancomycin for MSSA and Increased utilization of infectious diseases consultation contaminated blood cultures  Improved mortality in some studies • Faster time to active VRE therapy Current tests are an improvement, but… • Fewer delayed discharges 1. Less data for gram negative infections • Lower overall costs 2. Must be coupled with stewardship team involvement 3. Still largely dependent on traditional culture growth

Pardo J et al. Diagn Microbiol Infect Dis. 2016;84:159-64. MSSA: methicillin-sensitive Staphylococcus aureus,VRE: Vancomycin-resistant enterococci 2017 ANNUAL MEETING Timbrook TT et al. Clin Infect Dis; 2017;64:15-23. 2017 ANNUAL MEETING

#FSHP2017 Shifting Gears #FSHP2017

Sometimes we can’t de-escalate.

“When I was your age, we had this thing called Empiric Therapy.” 2017 ANNUAL MEETING 2017 ANNUAL MEETING

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Management of 2 Common MDROs#FSHP2017 Vancomycin-Resistant Enterococci #FSHP2017 1. Vancomycin-resistant Enterococci (VRE) • Usually Enterococcus faecium (could be other species) • Altered peptidoglycan precursors 2. Extended-spectrum beta-lactamase producing • vanA, vanB, vanC, vanD, vanE, vanG, vanL, vanM, vanN Enterobacteriaceae (ESBL-E) VSE VRE

VSE: Vancomycin-sensitive enterococci Hughes D. Nat Rev Genet. 2003;4:432-41. 2017 ANNUAL MEETING Miller WR et al. Expert Rev Anti Infect Ther. 2014;12:1221-36 2017 ANNUAL MEETING

Management of VRE Infections #FSHP2017 Linezolid vs Daptomycin for VRE BSI #FSHP2017 • Remember: Some VRE will be sensitive to ampicillin! • The best antibiotic for VRE bacteremia is still debated. • (…Most VRE will be resistant to ampicillin) • (What we can agree on: avoid tigecycline)

…Does ampicillin sensitivity always matter? “Linezolid might be a little better, or they are about the same.” • Treatment of ampicillin-resistant VRE UTI - Most individual studies, and 3 meta-analyses.1, 2, 3 • UF Health Shands: 91% clinical cure with aminopenicillins • Henry Ford Hospital: 86% clinical cure with aminopenicillins “Daptomycin is superior.” • (Don’t forget about other oral options: nitrofurantoin, fosfomycin) - The largest study to date, a nationwide propensity matched cohort study.4 BSI: bloodstream infection 1. Chuang Y et al. BMC Infect Dis. 2014;14:687 2. Balli EP et al. Antimicrob Agents Chemother. 2014;58:734-39 Shultz J et al. ICAAC 2012. K-274. 3. Zhao M et al. Int J Antimicrob Agents. 2016;48:231-8. Cole KA et al. Antimicrob Agents Chemother. 2015;59:7362-66. 2017 ANNUAL MEETING 4. Britt N et al. Clin Infect Dis. 2015;61:871-8. 2017 ANNUAL MEETING

Linezolid vs Daptomycin for VRE BSI #FSHP2017 Daptomycin Dosing for VRE BSI #FSHP2017 • Prefer daptomycin for endovascular infections Britt1 Survival with standard, medium Chuang2 Mortality by MIC and and high dose daptomycin daptomycin dose quartile • Consider the anticipated duration of therapy • Consider baseline lab values • Consider drug-drug interactions • • Consider ease of administration • Consider drug costs • If daptomycin is used, a high dose is warranted

1. Britt NS et al. Clin Infect Dis. 2017;64:605-13 2017 ANNUAL MEETING 2. Chuang YC et al. Clin Infect Dis. 2017;64:1026-34 2017 ANNUAL MEETING

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Management of 2 Common MDROs#FSHP2017 What is an ESBL? #FSHP2017 1. Vancomycin-resistant Enterococci (VRE) • ESBLs: Complicating infections since 1985. 1. Hydrolyze penicillins, oxyimino-cephalosporins, aztreonam 2. Do not hydrolyze cephamycins and carbapenems 2. Extended-spectrum beta-lactamase producing 3. Are generally inhibited by beta-lactamase inhibitors Enterobacteriaceae (ESBL-E) • E.coli, Klebsiella spp., Enterobacter spp., Serratia spp., Proteus spp., others • 1999: “Report all ESBL producers as resistant to all penicillins, cephalosporins, and aztreonam regardless of MIC.” - CLSI

• 2010: “Do not specifically test for ESBL production. Choose antibiotics based on MIC and current breakpoints.” - CLSI

CLSI: Clinical and Laboratory Standards Institute 1. Bradford PA. Clin Microbiol Rev. 2001;14(4):933-951. 2017 ANNUAL MEETING 2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. M100-S27 2017 ANNUAL MEETING

ESBL-Producing Enterobacteriaceae#FSHP2017 ESBL-Producing Enterobacteriaceae#FSHP2017 • [I think] Most would agree: • [I think] Most would agree: • Do not treat with 3rd generation cephalosporins • Do not treat with 3rd generation cephalosporins • You can certainly treat with carbapenems • You can certainly treat with carbapenems • You can certainly treat with appropriate non-β-lactams • You can certainly treat with appropriate non-β-lactams

• Consider fosfomycin for cystitis1, 2 • Cephamycins: Cefoxitin & Cefotetan • ≥ 90% of ESBL-producing E. coli are sensitive • Good in vitro activity 1 • 60-90% of ESBL-producing K. pneumoniae are sensitive • Concerns with in vivo resistance selection 2 • Acute uncomplicated cystitis: 3g PO once • One study showing inferior outcome versus carbapenems • Complicated cystitis: 3g PO q48h x 3 doses • Cefepime and Piperacillin/Tazobactam • These drugs are not ceftriaxone or cefotaxime • Some data show similar outcomes versus carbapenems3 • Some data show outcomes are worse3

1. Infectious Diseases Society of America: Guidelines for the treatment of acute 1. Lee CH et al. J Antimicrob Chemother. 2007;60:410-13. uncomplicated cystitis and pyelonephritis in women. Clin Infec Dis. 2011;52:e103-120. 2. Yang CC et al. BMC Infect Dis. 2012;12:206. 2. Falagas ME et al. Clin Microbiol Rev. 2016;29:321-47 2017 ANNUAL MEETING 3. Tamma PD et al. Clin Infect Dis. 2017;64:972-80. 2017 ANNUAL MEETING

Carbapenem-Sparing Considerations #FSHP2017 Carbapenem-Sparing Considerations #FSHP2017 • What has happened in the last 2-3 days? • Site of infection • Dosing 100.0 • Cefepime 2g IV q8h, and/or prolonged infusion Traditional Infusion (30min) • Piperacillin-tazobactam 4.5g IV q6h, and/or prolonged infusion Extended Infusion (3-4 hrs) 10.0 Continuous Infusion Concentration (mcg/mL) MIC 1.0

T>MIC Gained

0.1 02 4 68 Time (h) 2017 ANNUAL MEETING 2017 ANNUAL MEETING

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Carbapenem-Sparing Considerations #FSHP2017 Bootcamp: Take Home Points #FSHP2017 • What has happened in the last 2-3 days? • We have a lot to learn about antibiotics and our bodies • Site of infection • Dosing • Rapid diagnostics will continue to change infectious • Cefepime 2g IV q8h, and/or prolonged infusion diseases practice • Piperacillin-tazobactam 4.5g IV q6h, and/or prolonged infusion

• Minimum inhibitory concentration • Linezolid and high dose daptomycin are both options for VRE bacteremia • Severity of illness • Newer anti-infectives? • Carbapenems are NOT the only choice for ESBL-E

2017 ANNUAL MEETING 2017 ANNUAL MEETING

Sue #FSHP2017 FSHP 2017 ANNUAL MEETING

Infectious Diseases Bootcamp What you really need to know Joe Pardo, PharmD, BCPS-AQ ID, AAHIVP North FL/South GA Veterans Health System

2017 ANNUAL MEETING

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