Participating FacultyAndrew Shorr, MD, MPH (Course Director)

Director of Pulmonary and Critical Care MedicineDirector, Medical Intensive Care UnitMedStar Washington Hospital Center

Professor of MedicineGeorgetown University School of Medicine

Washington, DCKeith A. Rodvold, PharmD, FCCP, FIDSA

Professor of Pharmacy Practice and MedicineColleges of Pharmacy and Medicine

University of Illinois at ChicagoChicago, Illinois

Brad Spellberg, MDChief Medical Officer

Los Angeles County, University of Southern California Medical CenterProfessor of Clinical Medicine

Associate Dean for Clinical AffairsKeck School of MedicineLos Angeles, California

DISCLOSURE OF CONFLICTS OF INTEREST – Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity:

Andrew Shorr, MD, MPH Reports receiving consulting fees from Achaogen Inc, Allergan(Course Director) Inc, Astellas Pharma US Inc, Bayer, Cidara Therapeutics Inc,

Medco, Paratek Pharmaceuticals Inc, TetraphasePharmaceuticals, and Theravance Biopharma; and receiving fees for non-CME/CE services from Astellas Pharma US Inc, Medco, Merck & Co Inc, and Pfizer Inc.

Disclosures

Keith A. Rodvold, PharmD, Reports receiving consulting fees from Achaogen Inc, Bayer, The FCCP, FIDSA Medicines Company, Motif, Nabriva Therapeutics, Paratek

Pharmaceuticals, Shionogi, Spero Therapeutics, TheravanceBiopharma, Wockhardt, and Zavante Therapeutics Inc; receiving fees for non-CME/CE services from Merck & Co Inc; served as a PI for Allergan Inc and Theravance Biopharma; and, served on the Safety Monitoring Board for Janssen.

Brad Spellberg, MD Reports receiving consulting fees from Adenium Biotech, Bayer, Cempra Pharmaceuticals, Entasis Therapeutics, F. Hoffmann-La Roche Ltd, Forge Therapeutics, Genentech Inc, MedImmune, Microbial Medical Inc, Tetraphase Pharmaceuticals, and Shionogi; and, has ownership interest in, BioAim Scientific Inc, Motif, MycoMed Technologies, and Synthetic Biologics Inc.

Disclosures cont’d

Disclosures cont’dPlanners and ManagersThe PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

The following ASiM CE, LLC planners and managers, Reshma Desai Carter, PharmD, and Daniel Guinee, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

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. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

11:00–11:30 AM Registration and Lunch

11:30–11:45 AM Introduction: Complicated and Multi-drug Resistant Gram-negative InfectionsAndrew Shorr, MD, MPH

11:45 AM – 12:15 PM Antibiotic StewardshipBrad Spellberg, MD

12:15–12:45 PM Emerging Options and Determining Optimal Treatment SelectionKeith A. Rodvold, PharmD, FCCP, FIDSA

12:45–1:00 PM Conclusions and Questions and Answer SessionFaculty Panel

Agenda

After completing this activity, the participant should be better able to:

• DISCUSS the prevalence of toxicities and administrative challenges with currently available IV formulations of treatments for serious infections.

• DESCRIBE challenges with the treatment of complicated and multi-drug resistant gram negative infections.

• EVALUATE emerging antibiotic treatment options for multi-drug resistant gram negative infections.

• UTILIZE appropriate antibiotic prescribing practice strategies to optimize treatment and prevent resistance.

Educational Objectives

Physician Continuing Medical Education This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and ASiM CE, LLC. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Postgraduate Institute for Medicine designates this live activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

DISCLAIMER - Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

This activity is supported by an educational grant from

Tetraphase Pharmaceuticals.

Educational Grant

Introduction: Complicated and Multidrug

Resistant Gram-negative Infections

Andrew Shorr, MD, MPH (Course Director)Director of Pulmonary and Critical Care Medicine

Director, Medical Intensive Care UnitMedStar Washington Hospital Center

Professor of MedicineGeorgetown University School of Medicine

Washington, DC

Overview Definitions Epidemiology Outcomes Drivers of resistance

The Vocabulary

Fraimow H, et al. Crit Care Clin. 2013;29:895-921. For educational purposes only.

Definitions of multidrug resistance and predominant mechanisms of resistance to traditional gram-negative antibiotics

ESBL = extended-spectrum β-lactamase; MDR = multidrug-resistant; PDR = pandrug resistant; XDR = extensive drug-resistant.

Defining ResistanceBreakpoints for susceptibility as approved by

EUCAST, SCLIS, and FDA (in μg/mL)

Fraimow H, et al. Crit Care Clin. 2013;29:895-921. For educational purposes only.

CLSI = Clinical and Laboratory Standards Institute; EUCAST = European Committee on Antimicrobial Susceptibility Testing; FDA = US Food and Drug Administration.

EPIC II Point prevalence study International ICUs (n = 1265) Population: 13796 patients; 51% infected

Cohort Mean SOFA: 6.3 28% medical, 72% surgery/trauma 56% on medical ventilation

Vincent JA, et al. JAMA. 2009;302:2323-2329.EPIC = Extended Prevalence of Infection in Intensive Care; ICU = intensive care unit; SOFA = Sequential Organ Failure Assessment.

Sites of Infection

Vincent JA, et al. JAMA. 2009;302:2323-2329.

No. (%)

Site of Infection All Western

EuropeEastern Europe

Central/South

America

North America Oceania Africa Asia

No. (%) 7087 (51.4) 3683 (49) 426 (56.4) 1290 (60.3) 607 (48.4) 285 (48.2) 89 (46.1) 707 (52.6)Respiratory

tract 4503 (63.5) 2332 (63.3) 305 (71.6) 851 (66) 345 (56.8) 165 (57.9) 41 (46.1) 464 (6 5.6)

Abdominal 1392 (19.6) 778 (21.1) 93 (21.8) 228 (17.7) 101 (16.6) 50 (17.5) 16 (18) 126 (17.8)

Bloodstream 1071 (15.1) 546 (14.8) 53 (12.4) 139 (10.8) 157 (25.9) 49 (17.2) 16 (18) 111 (15.7)Renal/urinarytract 1011 (14.3) 411 (11.2) 84 (19.7) 222 (17.2) 135 (22.2) 33 (11.6) 15 (16.9) 111 (15.7)

Skin 467 (6.6) 242 (6.6) 37 (8.7) 73 (5.7) 26 (4.3) 30 (10.5) 8 (9.0) 51 (7.2)

Catheter-related 332 (4.7) 171 (4.6) 21 (4.9) 73 (5.7) 16 (2.6) 15 (5.3) 4 (4.5) 32 (4.5)

CNS 208 (2.9) 100 (2.7) 20 (4.7) 40 (3.1) 14 (2.3) 11 (3.9) 4 (4.5) 19 (2.7)

Others 540 (7.6) 289 (7.8) 31 (7.3) 87 (6.7) 62 (10.2) 22 (7.7) 14 (15.7) 35 (5.0)

CNS = central nervous system.

What is the most accurate response to this statement?

Globally, the majority of ICU infections are due to Gram-Negative bacteria

A. True - 62% of positive cultures are Gram-NegativeB. True - as many as 31% of isolates are Acenitobacter spp.C. False - the majority of ICU infections are due to Gram-Positive

bacteriaD. False – Gram-Negative and Gram-Positive bacteria are cultured

almost equally

Globally, Majority of ICU Infections Are Due to Gram-Negative Bacteria

70% of infected patients have positive cultures; 62% are gram-negative. 31% of gram-negative cultures are Pseudomonas spp.

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Data from the EPIC II Study, a global, 1-day point prevalence study of 13796 patients from 1265 ICUs in 75 countries in 2007.

Pseudomonasspp.

Escherichia coli

Klebsiella spp.

OtherEnterobacterspp.

Acinetobacterspp.

Vincent JA, et al. JAMA. 2009;302:2323-2329.

CDC-Identified Threats: 2013

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10000

15000

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25000

30000

CRE ESBL AB MDR PA

CasesFatalities

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Case fatality rate is approximately 7% and does NOT vary by pathogen.URGENT THREAT

Data from: Centers for Disease Control and Prevention. Antibiotic/Antimicrobial Resistance: About Antimicrobial Resistance. CDC.gov Web site. Available at: http://www.cdc.gov/drugresistance/about.html. Updated April 6, 2017.

AB = Acinetobacter baumannii; CDC = Centers for Disease Control and Prevention; CRE = carbapenem-resistant Enterobacteriaceae; PA = Pseudomonas aeruginosa.

GNR Resistance in Europe: 2010–2013

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CRE ESBL E coli ESBL Kleb MDR AB

20102013

Perc

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Antimicrobial Resistance Surveillance in Europe, 2013

Data from European Centre for Disease Prevention and Control. Antimicrobial Resistance Surveillance in Europe: 2013. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2014.

GNR = gram-negative rods.

EU/EAA, 2014

ESBLsEvolving Pretest Probability

Klebsiella pneumoniae percentage of invasive isolates with combined resistance to third-generation cephalosporins, fluoroquinolones, and aminoglycosides

EU/EAA, 2010

European Centre for Disease Prevention and Control. Surveillance Atlas of Infectious Diseases. ECDC.eu Web site. Available at: http://atlas.ecdc.europa.eu/public/index.aspx. Accessed August 2017. For educational purposes only.

EU/EAA = European Union/European Economic Area.

P aeruginosa Resistance to Carbapenems, Europe 2015

European Centre for Disease Prevention and Control. Surveillance Atlas of Infectious Diseases. ECDC.eu Web site. Available at: http://atlas.ecdc.europa.eu/public/index.aspx. Accessed August 2017.

Evolving Pretest Probability

For educational purposes only.

EBSL: The Future Model to predict

epidemiologic projections for ESBLs

Focused on UTIs Inputs

National estimates of hospitalizations for UTI

Evolution in EBSL trajectory

Data sources: HCUP, literature reviews

Zilberberg MD, et al. Infect Control Hosp Epidemiol. 2013;34:940-946.

HCUP = Healthcare Cost and Utilization Project.

Predicted Trends in EBSL UTI Hospitalizations

Annual UTI hospitalization rates with the resistant pathogen of interest per 1000 hospitalizations, 2000–2009. MDR PA (A); ESBL–producing E coli (EC ESBL) (B); ESBL–producing K pneumoniae (KP ESBL) (C); CRE (D).

For educational purposes only.

Change in MDR AB: US Perspective

01020304050607080

1999 2012

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AB Resistance Based on Infection Site

0102030405060708090

CLABSI CAUTI VAP SSI

MDR3CRAB

Sievert DM, et al. Infect Control Hosp Epidemiol. 2013;34:1-14.

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CAUTI = catheter-associated urinary tract infections; CLABSI = central line-associated bloodstream infections; CRAB = carbapenems-resistant A baumannii; MDR3 = pathogen must test as I or R to at least 1 drug in 3 of the 6 following classes: ESC2, FQ2, aminoglycosides, carbapenems, piperacillin or piperacillin/tazobactam, and ampicillin/sulbactam; SSI = surgical site infections; VAP = ventilator-associated pneumonia.

Epidemic Can Become Endemic

Retrospective analysis Single-center

experience Longitudinal evaluation

of AB isolation n = 4484 first isolates

Munoz-Price LS, et al. Crit Care Med. 2013;41:2733-2742. For educational purposes only.

Outcomes: Predictors in GNR Septic Shock

Retrospective analysis Subjects: GNR

bacteremia resulting in septic shock

N = 1064 E coli: 27% K pneumoniae: 20% P aeruginosa: 17%

Endpoint: MortalityData from Zilberberg MD, et al. Crit Care Med. 2014;18:596.

Odds Ratio

95% CI P value

Non-IAAT 3.872 2.770 to 5.413 <.001Chronic liver disease 1.942 1.319 to 2.860 .001

Septic shock 1.846 1.335 to 2.553 <.001Pneumonia 1.766 1.237 to 2.522 .002Mechanical ventilation 1.669 1.172 to 2.376 .005APACHE II score (per 1 point)

1.076 1.047 to 1.105 <.001

Surgery 0.701 0.560 to 0.879 .002Admitted from home 0.677 0.489 to 0.936 .018Urosepsis 0.675 0.469 to 0.972 .034

Predictors of Hospital Mortality

APACHE II = Acute Physiology and Chronic Health Evaluation II; 95% CI = 95% confidence interval; IAAT = initially appropriate antibiotic therapy.

Predictors of receiving initially inappropriate antibiotic therapy may include all of the following, EXCEPT:

A. Multidrug resistant pathogensB. Transfer from another hospitalC. Previous antibiotic therapyD. All of the aboveE. None of the above

Inappropriate Therapy: A Modifiable Risk Factor

Odds Ratio 95% CI P value

Multidrug resistant 13.05 7.00–24.31 <.001HIV 3.64 1.02–12.95 .046Transferred from another hospital

2.86 2.00–4.08 <.001

Nursing home resident 2.28 1.35–3.84 .002Prior antibiotics 2.06 1.47–2.87 <.001Polymicrobial 1.90 1.30–2.77 .001Congestive heart failure 1.61 1.11–2.35 .013APACHE II score

(per 1 point)1.05 1.02–1.07 <.001

Predictors of Receiving Initially Inappropriate Antibiotic Therapy

Data from Zilberberg MD, et al. Crit Care Med. 2014;18:596.HIV = human immunodeficiency virus.

Appropriate Initial Therapy

Every hour’s delay until appropriate therapy resulted in a 12% increase in mortality. Compared with starting appropriate therapy within 1 hour of the onset of hypotension,

the OR for mortality increased from 1.67 in Hour 2 to 92.54 with delays >36 hours.

An earlier study of septic shock (n = 2731) explicitly demonstrated the importance of antimicrobial timing.

Kumar A, et al. Crit Care Med. 2006;34:1589-1596.

Odd

s R

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eath

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CI)

100

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1Time From Hypotension Onset (Hours)

OR = odds ratio.

Impact of Resistance on Outcomes:

Retrospective analysis of impact of appropriate therapy on mortality

1250 subjects with septic shock Inappropriate antibiotics: 3.4 times

independent increase in risk for death

NNT calculated per pathogen

For every 5 patients given appropriate therapy one added survivor!

Vazquez-Guillamet C, et al. Crit Care Med. 2014;42:2342-2349. For educational purposes only.

How Many Times Do We Have to Get It Right to Save One Life?

NNT = number needed to treat.

So How Did We Get Here?

Resistance Driving Resistance: The ESBL/Carbapenem Resistance Loop

Increased MDR enterics (ESBLs)

X transmission+

spread of R-genes

Select carbapenem-R strains

Increased carbapenem use

Increased carbapenem-R strains

Pseudomonas aeruginosa

Enterobacteriaceae

Acinetobacter

R = resistant.

Correlation Between Carbapenem Consumption and P aeruginosa

Resistance

Lepper PM, et al. Antimicrob Agents Chemother. 2002;46:2920-2925. For educational purposes only.

Car

bape

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)

Car

bape

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DD

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DDDs = defined daily doses.

Are We Even Dosing Antibiotics in the ICU Correctly?

Antimicrobial Pharmacodynamics

Time (Hours)

Con

cent

ratio

n

T >MIC

Cmax:MIC

MIC

AUC

Concentration-dependent:ie, aminoglycosides, colistin

FluoroquinolonesAUC:MIC

Time-dependent: ie, β-lactams

Abdul Aziz MH, et al. Semin Respir Crit Care. 2015;36:136-153.

AUC = area under the concentration–time curve; Cmax = maximum drug concentration over a dosing interval; MIC = minimal inhibitory concentration; T>MIC =duration of time that drug concentration remains above MIC.

Udy et al. Clin Pharmacokinet. 2010;49:1-16.

Explanation of Augmented Renal Clearance

ARC arises from interaction of: Systemic

inflammation Physiologic reserve

ARC noted in: Young patients Trauma patients

InflammationBurnsInfection

Pancreatitis Surgery

RBF IV fluids

Vasoactivemedications

GRF

SIRI

COVasodilation

Renalreserve

ARC

CO = cardiac output; GRF = glomerular filtration rate; RBF = renal blood flow.

B-lactam Underdosing in Patients with ARC?

ARC = supranormal glomerular filtration

CrCl >130 mL/min/1.73 m2

Cockcroft-Gault CrCl Most common in critically

ill patients with: SIRS/sepsis Trauma

Trou

gh

Con

cent

ratio

n:M

IC1

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100

50 100 150 200 250 300 350

CrCl (mL/min/1.73 m2)Baptista JP, et al. Crit Care. 2011;15:R139; Udy AA, et al. Chest. 2012;142:30-39.CrCl = creatinine clearance; SIRS = systemic inflammatory response syndrome.

Clinical Cure and All-Cause 28-Day MortalityDoripenem

7-Day CourseImipenem

10-Day Course

Clinical cure rateMITT 36 79 45.6 50 88 56.8 -11.2 -26.3; 3.8ME 28 57 49.1 36 59 66.1 -17.0 -34.7; 0.8

Creatinine clearance* (MITT)≥150 mL/min 8 18 44.4 20 28 71.4 -27.0 -55.4; 1.4≥80–150 31 15 48.4 37 19 51.4 -3.0 -26.8; 20.9>50–<80 23 12 52.2 18 9 50.0 2.2 -28.7; 33.0>30–≤50 5 0 0 2 1 50.0 -50.0≤30 2 1 50.0 3 1 33.3 16.7

All-cause 28-day mortalityMITT 17 79 21.5 13 88 14.8 6.7 -5.0; 18.5

*Calculated using Cockcroft-Gault formulas relating serum creatinine with age and body weight.

Kollef MH, et al. Crit Care. 2012;16:R218. MITT = microbiological intent to treat; ME = microbiologically evaluable.

B-lactam (BL) Infusion in Severe Sepsis (BLISS) Trial

Prospective, randomized, non-blinded Interventions

Intermittent bolus (IB) of BL vs Continuous infusion (CI)

Agents: cefepime, piperacillin/tazobactam, meropenem Subjects: (n = 140) Adults, severe sepsis, and organ dysfunction Endpoints

Clinical cure 14 days after discontinuation of antibiotics PK/PD targets (BL levels measured in central lab)

Abdul Aziz MH, et al. Intensive Care Med. Published online Jan. 2016.PK/PD = pharmacokinetics/pharmacodynamics.

BLISS

Abdul Aziz MH, et al. Intensive Care Med. 2016;42:1535-1545. For educational purposes only.

BLISS

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*P < .001, †P <.01.

Abdul Aziz MH, et al. Intensive Care Med. 2016;42:1535-1545.

*

Conclusions Resistance among GNR is increasing. Pattern is seen globally and in multiple

pathogen types. Resistance drives inappropriate therapy. We know very little about how to use

antibiotics in the patients who need them most urgently.

Antibiotic StewardshipBrad Spellberg, MD, FIDSA, FACP

Chief Medical OfficerLos Angeles County, University of Southern

California Medical CenterProfessor of Clinical Medicine

Associate Dean for Clinical Affairs Keck School of MedicineLos Angeles, California

Power of AntibioticsPower of AntibioticsDisease Pre-Antibiotic

Death RateDeath with Antibiotics

Change in Death

Community pneumonia1 35% 10% -25%

Hospital pneumonia2 60% 30% -30%

Heart infection3,4 100% 25% -75%

Brain infection5,6 >80% <20% -60%

Skin infection7,8 11% <0.5% -10%

By comparison…treatment of myocardial infarction with aspirin or fibrinolytic drugs9

-3%

1. IDSA. Position Paper. Clin Infect Dis. 2008;47:s249-s265; 2. IDSA/ACCP/ATS/SCCM. Position Paper. Clin Infect Dis. 2010;51:s150-s170; 3. Kerr AJ. Subacute Bacterial Endocarditis. Springfield, IL: Charles C. Thomas; 1955. 4. Lancet. 1935;226:383-384; 5. Lancet. 1938;231:733-7344. 6. Waring et al. Am J Med. 1948;5:402-418; 7. Spellberg et al. Clin Infect Dis. 2009;49:383-391; 8. Madsen. Infection. 1973;1:76-81; 9. Lancet. 1988;2:349-360.

Problem SummaryProblem Summary

We’re running out of antibiotics. Resistance continues to spread. Scientific challenges to discover new leads US regulations are unbearable. What companies do develop I don’t need.

Other than this, all is well…

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Year Drug Use Needed? Funded by?2009 Telavancin MRSA skin No Small company2010 Ceftaroline MRSA skin No Small company2012 Bedaquiline TB Yes TB alliance*2014 Tedizolid MRSA skin No Small company2014 Dalbavancin MRSA skin No Small company2014 Oritavancin MRSA skin No Small company2014 Ceftolozane-

tazobactamUTI/Intra-

abdominal Pseudomonas

Sort of Mid-sized company

2015 Ceftazidime-avibactam

UTI/Intra-abdominal CRE

Yes Large company

2017 Delafloxacin MRSA skin No Small company

2017 Meropenem-Vaborbactam

cUTI—CRE Yes Mid-Sized company

*Alliance for TB is a nonprofit organization founded by academics and public health advocates in partnership with funding from several governments, other nonprofits (eg, Gates), and major pharmaceutical companies—it is a Public-Private Partnership. www.tballiance.org

CRE = carbapenem-resistant Enterobacteriaceae; MRSA = methicillin-resistant Staphylococcus aureus; TB = tuberculosis; UTI = urinary tract infection.

The Future Unless…The Future Unless… Resistance will continue, guaranteed—

death, taxes, resistance.

Antibiotic Stewardship“…. the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out… In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.”

– Sir Alexander Fleming, The New York Times, June 1945

How Are We Doing 70 Years Later?How Are We Doing 70 Years Later?

From 2006–2012, overall days of therapy in hospital did not go down—broad-spectrum antibiotic use went up.

In a second study, modest initial outpatient declines plateaued, and broad-spectrum antibiotic use went up.

New Guidelines on StewardshipNew Guidelines on Stewardship

Entirely focused on the tactical What to do at the ground level Tools for stewardship in hospitals Composition of stewardship teams

Minimal focus on strategic (provider) How to alter human behavior? How to mitigate fear driving scripts? How to overcome patient forces?

New Guidelines on StewardshipNew Guidelines on Stewardship

No focus on grand strategy (societal) How to financially align societal interests with

provider and patient interests? How to incentivize healthcare organizations to

arm their programs with teeth? How to get payers, regulators, and specialty

societies aligned with basic principles?

New Guidelines on StewardshipNew Guidelines on Stewardship

Are We Serious About This or Not?Are We Serious About This or Not?

Tactics don’t work if not backed by strategy and grand strategy. We’ve been using the same lousy tactics for

decades. Things are not any better.“I’d love to implement antibiotic restrictions, but our docs won’t tolerate it.”

Common ScenariosCommon Scenarios#1: The Surgical Intern

Them: “Yeah I’ve got a patient with (perforated appendix, cholecystitis, cholangitis, etc). They’re spiking through ceftriaxone + metronidazole. I need piperacillin-tazobactam.”

Me: “It was community onset, right? Why would Pseudomonas be in there?”

Them: “Probably not Pseudomonas. But they’re spiking through ceftriaxone/metronidazole.”

Common ScenariosCommon Scenarios#1: The Surgical Intern

Me: “Piperacillin-tazobactam doesn’t kill susceptible Escherichia coli any deader than ceftriaxone, and this is not Pseudomonas.” (But note the fear is contagious—the more I insist it’s not Pseudomonas,the more likely it is the universe will make it be to spite me!)

#2: The ED or Medicine Resident

Them: “Yeah I’ve got a patient with GNB in the urine.”

Me: “Do they have symptoms?”

Them: “No. But they have GNB in urine.”

Me: “Right. That’s asymptomatic bacteriuria. We don’t treat that.”

Them: “I know. But there’s GNB in the urine, so I need the antibiotics.”

Common ScenariosCommon Scenarios

ED = emergency department; GNB = gram-negative bacillus.

#3: The ICU Fellow

Them: “I need meropenem and vancomycin.”

Me: “What are the indications?”

Them: “I have a crashing patient.”

Me: “Okay. I hear you. But looking at the computer, this is CAP, right?”

Them: “Yeah, it’s CAP. But the patient’s really sick. I need broad coverage.”

Common ScenariosCommon Scenarios

CAP = community-acquired pneumonia; ICU = intensive care unit.

Is This Really an Education Deficit?Is This Really an Education Deficit?

Do we really believe that physicians don’t know not to treat asymptomatic bacteriuria? If this was on a board exam, would they get the question wrong?

Do we think that the surgical team has logically thought through options and simply misunderstands how antibiotics work?

Do we think the ICU Fellow believes Pseudomonasand MRSA are common CAP pathogens?

Or Is This About Fear?Or Is This About Fear? Antibiotics are among the most potent of all anxiolytics—

they act on prescribers. When providers are afraid, they act instinctively.

Antibiotics sooth their fears. They act differently than how they would answer when

taking a board examination. This is about fear—and fear cannot be overcome by

rational education. It must be countered by psychology.

Antibiotic StewardshipAntibiotic Stewardship

Spellberg B, et al. JAMA. 2016;315:1229-1230. For educational purposes only.

We need to recognize that antibiotics are unique among drugs. Only they have transmissible resistance. Those that work today won’t work in the

future—they must be continually replaced. Every person’s use affects everyone else’s. Antibiotics are a shared societal trust—not true

of any other type of drug.

Antibiotic StewardshipAntibiotic Stewardship

Antibiotics and EntitlementAntibiotics and Entitlement

No one has a right to waste antibiotics—wasting them hurts everyone.

Traditional Approaches Focus on what the stewardship team

should look like—process Methods include: Education (yawn) Up-front restrictions Downstream de-escalation Care pathways, order sets, etc

Focus on the Diagnosis!Focus on the Diagnosis!

What is the DDx? What organisms cause those diseases? What antibiotics cover those organisms? Don’t talk to me about your fear—what are you

treating?DDx = differential diagnosis.

Basic ICU Principles Pseudomonal coverage is not required for

community-onset infections (except in unusual circumstances).

MRSA coverage is not required for most CAP, cellulitis, IAI, UTI.

FDA indication is irrelevant. The fact that drugs worked in clinical trials is

irrelevant. Be a responsible steward, please.

FDA = US Food and Drug Administration; IAI = intra-abdominal infections.

Short-Course TherapyShort-Course Therapy“The most viable strategy for reducing

antimicrobial selective pressure is to treat infections only for as long as is necessary.”

- Dr Lou RiceExecutive Chair of MedicineWarren Alpert School of MedicineBrown UniversityMaxwell Finland Lecture, 2008 Infectious Diseases Society of America Annual Meeting

Stewardship: The New MantraStewardship: The New Mantra

Standard antibiotic durations: 1–2 Constantine units—based on 1695-year-old decree

Stewardship: Shorter = BetterDiagnosis Short (d) Long (d) ResultCAP 3 or 5 7, 8, or 10 EqualHAP 7 10–15 EqualVAP 8 15 EqualPyelo 7 or 5 14 or 10 EqualIAI 4 10 EqualAECB ≤5 ≥7 EqualCellulitis 5–6 10 EqualOsteo 42 84 Equal

Numerous studies showing shorter therapy is as effective as longer

AECB = acute exacerbation of chronic bronchitis; d = days; HAP = hospital-acquired pneumonia; Osteo = osteomyelitis; Pyelo = pyelonephritis; VAP = ventilator-associated pneumonia.

CAP: Short Course

Singh et al. Am J Respir Crit Care Med. 2000;162:505-511; Dunbar et al. Clin Infect Dis. 2003;37:752-760; Zhao X ,et al. Diagn Microbiol Infect Dis. 2014;80:141-147; Pakistan Multicentre Amoxycillin Short Course Therapy (MASCOT) pneumonia study group. Lancet. 2002;360:835-841; Greenberg et al. Pediatr Infect Dis J. 2014;33:136-142; Dunbar LM, et al. Curr Med Res Opin. 2004;20:555-563; el Moussaoui et al. BMJ. 2006;332:1355; Uranga et al. JAMA Intern Med. 2016;176:1257-1265.

Multiple randomized trials showing 5 (or even 3) days not inferior to 7 to 10 days of antibiotic

Now includes a study of patients with PORT IV and V (Uranga et al. JAMA Intern Med. 2016;176:1257-1265.)

Reduced emergence of resistance with shorter-course therapy

PORT = Pneumonia Patient Outcomes Research Team.

HAP/VAP: Short Course Several randomized trials showing that 7–8

days as effective as 10–15 days Reduced emergence of resistance with

shorter-course therapy Original concerns regarding nonfermenting

GNB have not panned out; new guidelines recommend 7 days for all, irrespective of pathogen.

Capellier et al. PLoS One. 2012:7:e41290; Chastre et al. JAMA. 2003;290:2588-2598; Kalil et al. Clin Infect Dis. 2016;63:e61-e111.

Klompas et al. Clin Infect Dis. 2017;64:870-876.

VAP: “Ultra-Short Course” Retrospective study of VAP at Brigham from 2006–

2014 of patients started on antibiotic for “suspected VAP”

All had PEEP ≤5 and FiO2 ≤40% on the day antibiotic was started and for 2 days following.

Suspected VAP = endotracheal or BAL Cx ≥3 days after intubation + antibiotic given within 2 days of Cx

BAL = bronchoalveolar lavage; Cx = culture; FiO2 = fraction of inspired oxygen; PEEP = positive end-expiratory pressure.

VAP: “Ultra-Short Course”

Klompas et al. Clin Infect Dis. 2017;64:870-876. For educational purposes only.

Author’s conclusion: You can treat with ≤3 days of antibiotic for patients with VAP with low PEEP and FiO2.

My conclusion: You can treat with ≤3 days of antibiotic for patients who don’t have VAP.

If you’re going to treat uninfected patients with antibiotics, at least do the courtesy of treating for a short period of time.

VAP: “Ultra-Short Course”

Klompas et al. Clin Infect Dis. 2017;64:870-876.

Stewardship: The Power of Diagnostics

Fear drives inappropriate antibiotic use. Fear is based on diagnostic uncertainty. Rapid diagnostics provide psychological

reassurance to overcome the fear. Procalcitonin is a biomarker indicating it is

safe to withhold or shorten antibiotic therapy—it is not diagnostic.

80

Audit and feedback (peer comparison)

“Accountable justification” in EMR

“Suggested alternatives” in EMR

Stewardship: New Psychological Approaches

EMR = electronic medical record.

Stewardship: Benchmarking Antibiotic Use

Need to align physician and public interests Antibiotic use should be publicly reported and

payments to healthcare systems (and possibly providers) benchmarked to reward low use and penalize high use.

Analogous to infection prevention—always had IP programs, but infection rates didn’t go down until public reporting and pay for performance

IP = infection prevention.

Take-Home Messages1. Recognize and combat fear and entitlement; keep it

objective. What’s the DDx? What organisms are a concern?

2. Don’t use pseudomonal or MRSA coverage routinely—only when indicated.

3. Use short-course therapy4. Encourage diagnostics/biomarkers5. The future is audit/feedback and pay for

performance.

83

The Renegades: John Bartlett David Gilbert

Andy Shorr Lou Rice Neil Gaffin Paul Ambrose George Drusano John Rex David Shlaes Arjun Srinivasan

Acknowledgments

Emerging Options and Determining Optimal Treatment Selection:

Focus on New Agents for Complicated Urinary Tract Infections and Complicated

Intra-abdominal Infections

Keith A. Rodvold, PharmD, FCCP, FIDSAProfessor of Pharmacy Practice and Medicine

Colleges of Pharmacy and MedicineUniversity of Illinois at Chicago

Chicago, Illinois

Types of Severe Infections Recommended for General Antimicrobial Development

Infection Enrollment Criteria Endpoint

Complicated urinary tract infections(cUTI)

Risk factors plus symptoms plus pyuria

Resolution of symptoms and sterilization of urine

Complicated intra-abdominal infections (cIAI) Operative diagnosis Resolution of baseline symptoms

Acute bacterial skin and skin structure infection (ABSSSI) 75 cm2 of erythema 20% reduction in size of area of erythema at

48 hours of therapy

Community-acquired bacterial pneumonia (CABP)

Specific pulmonary symptoms plus high-level severity

Improvement in baseline symptoms at days 3–5 of therapy (specific scale)

Hospital-acquired bacterial pneumonia (HABP) Specific pulmonary symptoms 28-day all-cause mortality

Ventilator-associated bacterial pneumonia (VABP) Specific pulmonary symptoms 28-day all-cause mortality

Rex JH, et al. Clin Infect Dis. 2017 (Epub).

Recently Approved Antimicrobial Agents Ceftolozane-tazobactam

New cephalosporin plus an older β-lactamase inhibitor Two randomized phase III trials, per clinical indication, combined for approval

cUTIs, including pyelonephritis cIAIs, used in combination with metronidazole

Ceftazidime-avibactam Older cephalosporin plus a new β-lactamase inhibitor Initially approved on phase II data, followed by phase III trial results

cUTIs, including pyelonephritis cIAIs, used in combination with metronidazole

Delafloxacin Fluoroquinolone Two randomized, double-blind, double-dummy, non-inferiority trials

ABSSSIs Meropenem-vaborbactam

Older carbapenem plus a new β-lactamase inhibitor One randomized phase III trial

cUTIs, including pyelonephritis

Scott LJ. Drugs. 2016;76:231-242; Falcone M et al. J Antimicrob Chemother. 2016;71:2713-2722; Markham A. Delafloxacin: first global approval. Drugs.2017;10. (Epub); US FDA News release. August 29, 2017.

Delafloxacin: The Long and Winding Road to Approval

Markham A. Drugs. 2017;10.1007/s40265-017-0790-5 (Epub). For educational purposes only.FDA = US Food and Drug Administration; NDA = new drug application.

Meropenem-Vaborbactam A Phase III, Multi-Center, Randomized, Double-Blind, Double-Dummy Study to Evaluate the Efficacy, Safety, and Tolerability of

Carbavance (Meropenem/Vaborbactam) Compared to Piperacillin-Tazobactam in the of Treatment of cUTIs, including AP, in Adults (TANGO 1) (NCT02166476; ClinicalTrials.gov)

Similar percentage of subjects with AP (59.0%) and cUTI (40%); 19% removable and 21% non-removable source

EOVIT Microbial Eradication at TOC

m-MITT Population Meropenem-Vaborbactam

Piperacillin-Tazobactam

Meropenem-Vaborbactam

Piperacillin-Tazobactam

Overall (package insert) 98.4% 94.3% 76.5% 73.2%

AP 97.5% 94.1% 74.2% 63.3%

cUTI and removable source 100% 92.1% 60.0% 52.6%

cUTI and non-removable source 100% 95.3% 48.6% 48.8%

Meropenem/vaborbactam [package insert]. Parsippany, NJ: The Medicines Company; 2017; 27th ECCMID; Vienna, Austria; 2017; Abstracts OS0604 and P1289; Falagas ME et al. Expert Rev Anti Infect Ther. 2016;14:747-763.

AP = acute pyelonephritis; EOVIT = overall success at end of IV treatment; IV = intravenous; m-MITT = microbiological modified intent-to-treat; TOC = test of cure.

Similar percentage of subjects with AP (59.0%) and cUTI (40%); 19% removable and 21% non-removable source.

Developing Antimicrobial Drugs for Resistant Pathogens

Boucher HW, et al. J Infect Dis. 2017a;10.1093/infdis/jix211 (Epub); Rex JH, et al. Lancet Infect Dis. 2013;13:269-275. For educational purposes only.PK = pharmacokinetics.

Role of PK-PD for Optimizing Antimicrobial Dosing

Tangden T, et al. Intensive Care Med. 2017;43:1021-1032. For educational purposes only.

PD = pharmacodynamics.

New Antimicrobial Agents Being Developed to Treat Resistant

Gram-Negative BacteriaAgent Related Class Developer

Meropenem-vaborbactam BLBLI The Medicines Company

Imipenem-relebactam BLBLI Merck

Aztreonam-avibactam BLBLI Astra-Zeneca

Cefepime-zidebactam BLBLI Wockhardt

Cefiderocol Cephalosporin Shionogi

Plazomicin Aminoglycoside AchaogenEravacycline Tetracycline Tetraphase

Sulbactam-ETX2514 BLBLI Entasis Therapeutics

Murepavadin (POL7080) Macrocycle LptD inhibitor Polyphor

BLBLI = β-lactam-β-lactamase inhibitors combinations; LptD = lipopolysaccharide transport protein D.

Carbapenem Plus β-Lactamase Inhibitor Vaborbactam (RPX7009)

Cyclic boronic acid-based β-lactamase inhibitor Creates a covalent bond between boron moiety and serine hydroxyl β-lactamase

Good affinities for many class A and C serine β-lactamases High inhibitory potency against KPC-producing isolates

Currently combined with meropenem Relebactam (MK-7655)

Diazebicyclooctanone, non- β-lactam, β-lactamase inhibitor Similar chemical structure and spectrum of activity as avibactam

Class A and C activity with minor D activity Lacking activity against MBLs and most OXAs

Currently combined with imipenem-cilastatin

Falagas ME, et al. Expert Rev Anti Infect Ther. 2016;14:747-763; Papp-Wallace KM, et al. Infect Dis Clin North Am. 2016;30:441-464; Wong D, et al. Drugs. 2017;77:615-628.

KPC = Klebsiella pneumoniae carbapenemases; MBL = metallo-β-lactamase; OXA = oxacillinase.

Meropenem-Vaborbactam

Data Safety and Monitoring Board’s recommendation to discontinue randomization into the TANGO-2 trial was based on the results of an interim analysis of data.

Efficacy: Statistically significant differences favor meropenem-vaborbactam over best available therapy for clinical cure at the TOC visit in the protocol-specified primary population (all patients with microbiologically evaluable CRE).

Mortality rates: Lower among patients treated with meropenem-vaborbactam Renal toxicity: Lower rates of renal adverse events and serum creatinine increases among

patients treated with meropenem-vaborbactam than best available therapy – particularly among patients receiving colistin and aminoglycosides

The Medicines Company announces TANGO-2 trial of meropenem-vaborbactam (formerly, Carbavance) stopped early for superior benefit-risk compared to best available therapy for CRE [press release]. Parsippany, NJ: The Medicines Company; July 25, 2017.

Efficacy, Safety, Tolerability of Carbavance Compared to Best Available Therapy in Serious Infections Due to Carbapenem-Resistant Enterobacteriaceae, in Adults (TANGO 2); ongoing trial (NCT02168946; ClinicalTrials.gov)

CRE = carbapenem-resistant Enterobacteriaceae.

In Vitro Activity of Imipenem-Relebactam 4000 isolates collected from 11 hospitals in Brooklyn and Queens, NY, from November 2013 to

January 2014

Species (n)Imipenem Imipenem-Relebactam

MIC50 MIC90 MIC50MIC90

Escherichia coli (2778) 0.25 0.25 0.25/4 0.25/4

Klebsiella pneumoniae (891) 0.25 4 0.25/4 0.25/4

blaKPC-possessing K pneumoniae (111) 16 >16 0.25/4 1/4

Enterobacter spp. (211) 0.5 1 0.25 / 4 0.5 / 4

Pseudomonas aeruginosa (490) 2 16 0.5 / 4 2 / 4

Imipenem-resistant P aeruginosa (144) 8 >16 1 / 4 2 / 4

Acinetobacter baumannii (158) 4 >16 2 / 4 >16 / 4

blaOXA-23-possessing A baumannii (58) >16 >16 >16 / 4 >16 / 4

Lapuebla A, et al. Antimicrob Agents Chemother. 2015;59:5029-5031; Mavridou E, et al. Antimicrob Agents Chemother. 2015;59:790-795.

MIC values in mg/L. MIC = minimal inhibitory concentration.

Imipenem + Cilastatin –Relebactam (MK-7655A)

Phase II cIAIs trial (n = 351 randomized patients): 1:1:1 ratio in treatment groups of imipenem plus relebactam 250 mg, 125 mg, placebo Clinical response: 93.7%, 95.3%, 94.9% (microbiologically evaluable, n = 230)

Phase II cUTIs trial (n = 302 randomized patients): 1:1:1 ratio in treatment groups of imipenem plus relebactam 250 mg, 125 mg, placebo with switch therapy to

oral ciprofloxacin after 96 hours of IV study therapy Microbiological response: 95.5%, 98.6%, 98.7% (at end of IV therapy, n = 230) Composite response: 54.1%, 59.8%, 61.7% (at early follow-up [exploratory endpoint])

Efficacy and Safety of Imipenem + Cilastatin/Relebactam vs Imipenem + Cilastatin/Colistimethate Sodium in Imipenem-Resistant Bacterial Infection (RESTORE-IMI 1); ongoing trial (NCT02452047; ClinicalTrials.gov)

Imipenem/Relebactam/Cilastatin vs Piperacillin/Tazobactam for Treatment of Participants with Bacterial Pneumonia (RESTORE-IMI 2); ongoing trial (NCT02493764; ClinicalTrials.gov)

Lucasti C, et al. Antimicrob Agents Chemother. 2016;60:6234-6243; Sims M, et al. J Antimicrob Chemother. 2017;72:2616-2626; Falagas ME, et al. Expert Rev Anti Infect Ther. 2016;14:747-763.

Plazomicin (ACHN-490) Next-generation aminoglycoside (“neoglycoside”)

synthetically derived from sisomicin In vitro activity against both gram-positive and gram-

negative organisms, including isolates harboring any of the clinically relevant aminoglycoside-modifying enzymes (eg, acetyltransferases [AAC], nucleotidyltransferases [ANT], and phosphotransferases [APH])

Retains in vitro activity against aminoglycoside-resistant MDR, PDR, and XDR isolates of Enterobacteriaceae, except the New Delhi metallo-β-lactamase–positive isolate

Plazomicin is not active against isolates that produce acquired 16S-RMTase.

Krause KM, et al. Cold Spring Harb Perspect Med. 2016;6; Zhanel GG, et al. Expert Rev Anti Infect Ther. 2012;10:459-473; Falagas ME, et al. Expert Rev Anti Infect Ther. 2016;14:747-763; Doi Y, et al. Infect Dis Clin North Am. 2016;30:523-537. For educational purposes only.

MDR = multidrug-resistant; PDR = pandrug-resistant; XDR = extensive drug-resistant.

Plazomicin A Phase III, Randomized, Multicenter, Double-Blind Study to Evaluate the Efficacy

and Safety of Plazomicin Compared With Meropenem Followed by Optional Oral Therapy for the Treatment of Complicated Urinary Tract Infection, Including Acute Pyelonephritis, in Adults (NCT02486627, ClinicalTrials.gov)

Presented at: 27th ECCMID; April 22, 2017; Vienna, Austria. Abstract OS0250E.

Outcome Plazomicin Meropenem Difference (95% CI)Per Patient

m-MITT population 87.4% (167/191) 72.1% (142/197) 15.4% (7.5, 23.2)

ME population 90.5% (162/179) 76.6% (134/175) 13.9% (6.3, 21.7)

Per Pathogen (ME population)

Enterobacteriaceae 90.3% (167/185) 77.5% (141/182) 12.8% (5.4, 20.4)

AG-nonsusceptible 80.8% (42/52) 68.6% (35/51) 12.1% (-4.8, 28.7)ESBL 83.3% (40/48) 74.6% (41/55) 8.8% (-7.5, 24.4)

AG = aminoglycoside; CI = confidence interval; ESBL = extended-spectrum β-lactamase; ME = microbiologically evaluable.

Plazomicin A Phase III, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and

Safety of Plazomicin Compared with Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CARE) (NCT01970371; ClinicalTrials.gov)

Plazomicin in combination with meropenem or tigecycline Colistin in combination with meropenem or tigecycline Treatment of patients with bloodstream infection, HABP, VABP, or cUTI

Connolly L et al. Plazomicin (PLZ) Associated with Improved Survival and Safety Comapred to Colistin (CST) in Serious Carbapenem-Resistant Enterobacteriaceae (CRE) Infections: Results of the CARE Study. Presented at: 27th ECCMID; April 22, 2017; Vienna, Austria. Abstract OS0250F.

Plazomicin Colistin Difference(90% Exact CI)

RelativeReduction

Day 28 ACM or SDRC 23.5% (4/17) 50.0% (10/20) 26.5% (-0.7, 51.2) 53.0%

Day 28 ACM 11.8% (2/17) 40.0% (8/20) 17.25% (0.7, 52.5) 70.5%

ACM = all-cause mortality; SDRC = significant disease-related complications.

Cefiderocol (S-649266) Siderophore cephalosporin with a

catechol moiety and binds mainly to PBP-3 of gram-negative bacteria

Catechol moiety to form a chelating complex with ferric iron

Superior in vitro activity than β-lactam comparators against ESBL-, KPC-, or metallo- β-lactamase–positive Enterobacteriaceae isolates, and both MDR P aeruginosa and A baumannii strains

Ito-Horiyama T, et al. Antimicrob Agents Chemother. 2016;60:4384-4386; West KN, et al. Antimicrob Agents Chemother. 2016;60:729-734; Ito A, et al. J Antimicrob Chemother. 2016;71:670-6777; Falagas ME, et al. Expert Rev Anti Infect Ther. 2016;14:747-763; Tillotson GS. Infect Dis (Auckl). 2016;9:45-52. For educational purposes only.

Cefiderocol (S-649266) Completed trial (top-line results) (NCT02321800; ClinicalTrials.gov)

A Multicenter, Double-blind, Randomized, Clinical Study to Assess the Efficacy and Safety of Intravenous S-649266 in Complicated Urinary Tract Infections With or Without Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by Gram-Negative Pathogens in Hospitalized Adults in Comparison With Intravenous Imipenem/Cilastatin

Portsmouth D et al. Presented at: 27th ECCMID; April 22, 2017; Vienna, Austria. Abstract 7582; Falagas ME, et al. Expert Rev Anti Infect Ther. 2016;14:747-763.

Outcome Cefiderocol Imipenem-Cilastatin Difference (95% CI)Clinical/microbiological 72.6% (183/252) 54.6% (65/119) 18.58% (8.23, 28.92)Per-patient microbiological 73.0% (184/252) 56.3% (67/119) 17.25% (6.92, 27.58)

Ongoing trials: Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by

Carbapenem-Resistant Gram-Negative Pathogens (NCT02714595; ClinicalTrials.gov) Clinical Study of S-649266 for the Treatment of Nosocomial Pneumonia Caused by Gram-

Negative Pathogens (NCT03032380; ClinicalTrials.gov; not yet recruiting)

Intravenous Fosfomycin Completed trial (top-line results) (NCT02753946; ClinicalTrials.gov)

Randomized, Double-Blind, Comparative Study to Evaluate the Safety and Efficacy of Intravenous Fosfomycin (ZTI-01) vs Piperacillin/Tazobactam in the Treatment of cUTI/AP in Hospitalized Adults (ZEUS)

Zavante Therapeutics’ Zolyd Met Primary Endpoint in Pivotal ZEUS Study for Treatment of Complicated Urinary Tract Infections [press release]. San Diego, CA: Zavante Therapeutics Inc; April 5, 2017.

Outcome Fosfomycin Piperacillin-Tazobactam Difference (95% CI)

Clinical cure plus microbiological eradication 64.7% (119/184) 54.5% (97/178) 10.2% (-0.4, 20.8)

Clinical cure rates 90.8% 91.6%

465 patients were randomized to receive either 6 grams q8h of IV fosfomycin (18 grams total daily dose) or 4.5 grams q8h of IV piperacillin-tazobactam (13.5 grams total daily dose) for 7 days (14 days in patients with concurrent bacteremia).

Oral step-down therapy was prohibited.q8h = every 8 hours.

Tetracycline Antibiotics

Minocycline and tigecycline are tetracycline derivatives with antibacterial activity against A baumannii clinical isolates (including MDR and XDR strains).

Exhibit additive or synergistic bactericidal activity against isolates when combined with other antibacterials

Concerns with high mortality and increased recurrence of bacteremia when tigecycline MIC ≥2 mg/L

Greig SL, et al. Drugs. 2016;76:1467-1476; Lashinsky JN, et al. Infect Dis Ther. 2017;doi. 10.1007/s40121-017-0153-2; Chuang YC, et al. BMC Infect Dis. 2014;14:102; Cheng A, et al. Crit Care Med. 2015;43:1194-1204; Spellberg B, et al. Crit Care Med. 2015;43:1332-1334.

Tetracycline Doxycycline Minocycline Tigecycline

In Vitro Activity of Eravacycline Fully synthetic fluorocycline with broad-spectrum activity including MDR gram-

positive, gram-negative, aerobic and anaerobic organisms (reduced activity against P aeruginosa and Burkholderia cenocepacia)

Active against isolates containing tetracycline-specific efflux (Tet A and Tet B) and ribosomal protection proteins (Tet M and Tet O)

Active against Enterobacteriaceae harboring ESBLs and carbapenemases

Species (n) ESBL blaKPC blaOXAEravacyclineMIC50/MIC90

TigecyclineMIC50/MIC90

E coli (2866) 13% 0.17% - 0.12/0.5 4/>16

K pneumoniae (944) 33% 13% - 0.25/1.0 0.5/2.0

Enterobacter aerogenes (90) 22% 3.3% - 0.25/1.0 0.5/2.0

Enterobacter cloacae (124) 23% 3.2% - 0.5/1.0 0.5/2.0

A baumannii (158) 67% 0.63% 36% 0.5/1.0 2.0/4.0

Abdallah M, et al. Antimicrob Agents Chemother. 2015;59:1802-1805. MIC values in mg/L.

Intravenous Eravacycline Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated

Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE 1) Trial

Solomkin JS, et al. JAMA Surg. 2017;152:224-232.

Outcome Eravacycline Ertapenem Difference (95% CI)

m-MITT 86.8% (191/220) 87.6% (198/226) -0.8 (-7.1, 5.5)

Modified intent-to-treat (MITT) 87.0% (235/270) 88.8% (238/268) -1.8 (-7.4, 3.8)

Clinically evaluable (CE) 92.9% (222/239) 94.5% (225/238) -1.7 (-6.3, 2.8)

Eravacycline 1.0 mg/kg q12h vs ertapenem 1.0 gram q24h, minimum of 4 doses Treatment-emergent adverse events in each treatment group was similar for vomiting, anemia, pyrexia,

and diarrhea. Nausea: 22 eravacycline patients (8.1%); 2 ertapenem patients (0.7%) Phlebitis: 8 eravacycline patients (3.0%); 1 ertapenem patient (0.4%)

q12h = every 12 hours; q24h = every 24 hours.

Intravenous Eravacycline Completed trial (top-line results) (NCT02784704; ClinicalTrials.gov)

A Phase III, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared with Meropenem in Complicated Intra-abdominal Infections (IGNITE 4)

Press release. Parsippany, NJ: Tetraphase Pharmaceuticals; July 25, 2017.

Outcome Eravacycline Meropenem Difference (95% CI)m-MITT

12.5% non-inferiority margin (FDA) 90.8% (177/195) 91.2% (187/205) -0.4 (-6.3, 5.3)

MITT12.5% non-inferiority margin (EMA) 92.4% (231/250) 91.2% (228/249) 0.4 (-4.1, 5.8)

CE12.5% non-inferiority margin (EMA) 96.9% (218/225) 96.1% (222/231) 0.8 (-2.9, 4.5)

Treatment-emergent adverse event rates were similar in both treatment groups. Most commonly reported drug-related adverse events for eravacycline were infusion site reactions,

nausea, and vomiting (rate of <5%). Adverse event profile for IV eravacycline consistent with phase III IGNITE 1 and phase II clinical trials

in cIAIEMA = European Medicines Agency.

Intravenous Eravacycline A Phase III, Randomized, Double-Blind, Double-Dummy, Multicenter,

Prospective Study to Assess the Efficacy and Safety of IV Eravacycline Compared With Ertapenem in Complicated Urinary Tract Infections (IGNITE 3)

Ongoing trial (NCT03032510; ClinicalTrials.gov) Oral step-down therapy to levofloxacin

A Phase III, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared With Levofloxacin in Complicated Urinary Tract Infections (IGNITE 2)

IV-to-oral transition therapy did not achieve its primary endpoint of statistical non-inferiority compared to levofloxacin.

Eravacycline 1.5 mg/kg IV q24h followed by 200 mg orally q12h vs levofloxacin 750 mg IV q24h followed by 750 mg orally q24h

Press release. Watertown, MA: Tetraphase Pharmaceuticals, Inc. September 8, 2015.

Agents Targeting a Single MDR Pathogen

Sulbactam - ETX2514 ETX2514 is a broad-spectrum and potent inhibitor of class A, C, and D β-

lactamases. Sulbactam is a β-lactam agent that has intrinsic activity against A

baumannii (but widespread β-lactamase–mediated resistance to sulbactam).

Murepavadin (POL7080) Pseudomonas-specific antibiotic, with a novel mode of action Being developed for the treatment of the most severe P aeruginosa

infection – nosocomial pneumonia (including VABP and HABP)

27th ECCMID; Vienna, Austria; April 2017. Abstracts 4097, 5942, and 1308-1311; Srinivas N, et al. Science. 2010;327:1010-1013; Boucher HW, et al. J Infect Dis. 2017;10.1093/infdis/jix211.

Accelerating Global Innovation to Address Antimicrobial Resistance CARB-X (sprang from the US government’s Combating Antibiotic

Resistant Bacteria [CARB] initiative) A new global public-private partnership that in the next 5 years will

accelerate the progression of a diverse portfolio of innovative antibacterial products into clinical trials

At least 20 high-quality antibacterial products towards clinical development leveraging $455 million in BARDA funds with matching funds from Wellcome Trust

Boston University leads the project.

Outterson K, et al. Nat Rev Drug Discov. 2016;15:589-590; CARB-X Web site. Available at: http://www.carb-x.org. Accessed September 2017.BARDA = US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority.

CARB-X Funding – April 2017Company Agent/Device Target

Cidara Therapeutics Bifunctional immunotherapy (CD201) Acinetobacter, P aeruginosa, Enterobacteriaceae

ContraFect Recombinant lysin protein P aeruginosaEntasis Therapeutics Oral gram-negative combination (ETX0282) Gram-negative bacteriaForge Therapeutics LpxC inhibitor Gram-negative bacteriaMicrobiotix Virulence modifier (T3SS inhibitor) P aeruginosaOppilotech Targets synthesis of LPS Gram-negative bacteria

Redx Pharma Dual-acting topoisomerase inhibitor (NBTI) Acinetobacter, P aeruginosa, Enterobacteriaceae

Spero Therapeutics Potentiator (SPR741) Gram-negative bacteriaTetraphase Pharmaceuticals Next-generation tetracycline (TP-6076) Acinetobacter,

EnterobacteriaceaeVisterra Antibody-drug conjugate (VIS705) P aeruginosa

CARB-X Web site. Available at: http://www.carb-x.org. Accessed September 2017.

Discover New Antibiotics to Treat Superbugs

LPS = lipopolysaccharides; LpxC = UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetyl glucosamine deacetylase; NBBTI = novel bacterial type II topoisomerase inhibitor.

Company Agent/Device Target

Achaogen Inc. LpxC inhibitors P aeruginosa

Antabio SAS Pseudomonas elastase inhibitor P aeruginosa

Bugworks Research India Pvt Ltd.

Gyrase-topoisomerase inhibitor Gram-negative bacteria

DebiopharmInternational SA

Inhibitor of bacterial fatty acid biosynthesis Neisseria gonorrhoeae

EligoChem Ltd Helical antimicrobial peptide Gram-negative bacteria

Iterum Therapeutics Oral/IV sulopenem Gram-negative bacteria

VenatoRx Pharmaceuticals

B-lactamase–resistant PBP inhibitor Enterobacteriaceae

CARB-X Funding – July 2017Discover New Antibiotics to Treat Superbugs

PBP = penicillin-binding protein.CARB-X Web site. Available at: http://www.carb-x.org. Accessed September 2017.

Multidrug-Resistant Gram-Negative Pathogen

53-year-old female with a history of a deceased-donor renal transplant

MICU admission for idiopathic liver failure 3-week hospital course complicated by toxic

megacolon secondary to Clostridium difficile infection, polymicrobial empyema, and anuric renal failure

Developed septic shock and started on continuous renal replacement therapy

Ascites fluid, respiratory, and blood cultures positive for P aeruginosa

Antibiotic susceptibilities for the isolate cultured from ascites fluid

Antibiotic MIC (mg/L) InterpretationAmikacin 16 Susceptible

Aztreonam >16 Resistant

Cefepime >16 Resistant

Ceftazidime >16 Resistant

Ciprofloxacin >2 Resistant

Colistin 2 Susceptible

Gentamicin 8 Intermediate

Imipenem-cilastatin >8 Resistant

Levofloxacin >4 Resistant

Meropenem >8 Resistant

Piperacillin-tazobactam >64 Resistant

Ticarcillin-clavulanate >64 Resistant

Tobramycin 2 SusceptibleWenzler E, et al. Antimicrob Agents Chemother. 2017;61:e00484-17.MICU = medical intensive care unit.

Multidrug-ResistantGram-Negative Pathogen

What would your therapy of choice be for this patient at this point?A. Polymyxin BB. Piperacillin-tazobactam plus colistinC. Meropenem plus amikacinD. Ceftolozane-tazobactamE. Ceftazidime-avibactamF. Plazomicin (compassionate use)

Antibiotic MIC (mg/L) InterpretationCeftazidime-avibactam 6/4 Susceptible

Ceftolozane-tazobactam 24a Susceptible

Wenzler E, et al. Antimicrob Agents Chemother. 2017;61:e00484-17.

a Disk diffusion diameter of inhibition.