overcoming the challenges of multidrug-resistant bacterial...

This activity is jointly provided by ProCE, Inc. and the Society of Infectious Diseases Pharmacists, and supported by an educational grant from Achaogen, Inc., Merck & Co., Paratek Pharmaceuticals, Inc., and The Medicines Company.

A Midday Symposium Conducted at the 52nd ASHP Midyear Clinical Meeting & Exhibition

Orlando, Florida

Overcoming the Challenges of Multidrug-Resistant Bacterial Infections: New Solutions to an Urgent Crisis Wednesday, December 6, 2017

Orange County Convention Center West Room W102, Level 1

Overcoming the Challenges of Multidrug-Resistant Bacterial Infections: New Solutions to an Urgent Crisis

A symposium conducted at the 52nd ASHP Midyear Clinical Meeting & Exhibition

Activity Description

The inappropriate selection and mismanagement of antimicrobials have led to critical problems in infectious disease (ID) management, particularly drug resistance. The emergence of multidrug‐resistant (MDR) bacteria and other organisms, or “super bugs,” is occurring at an alarming rate worldwide, endangering the efficacy of ID therapies and posing an ominous threat to public health. Yet few therapeutic agents are available to treat MDR infections, prolonging the crisis that subjects patients to persistent illness, associated healthcare costs, and greater mortality risk.

Because infections that were once curable are becoming significant causes of death, cooperative efforts are needed to reduce the emergence and spread of MDR bacterial infections. Although pharmacists specially trained in ID often take the lead in antimicrobial stewardship, all pharmacists can make a difference in optimizing antimicrobial therapy, thereby improving clinical outcomes and patient safety.

Pharmacists who attend this symposium will improve their knowledge of the epidemiology of MDR infections and key resistance patterns in gram‐negative and gram‐positive bacteria. Discussion will also cover new treatment strategies and controversies to consider with the use of older antibiotics in the face of growing resistance. The use of new and emerging antimicrobial agents will also be reviewed, including optimal drug selection for certain patient populations or those with complicated infections.

Location / Agenda

Orange County Convention Center West Room W102 Orlando, Florida

December 6, 2017 10:45 AM ‐ 11:30 AM Registration 11:30 AM ‐ 1:00 PM Educational Activity

Learning Objectives

The target audience for this activity includes pharmacists in health‐system settings. At the completion of this activity, the participant will be able to:

Describe the changing epidemiology and clinical implications of multidrug‐resistant infections Discuss evidence‐based treatment approaches in the setting of significant antibiotic resistance Review new and emerging antimicrobial agents for gram‐positive and gram‐negative bacterial infections, alongside existing antibiotics, to help direct

optimal selection of therapy in clinical practice Identify antimicrobial stewardship interventions for the use of new antimicrobial agents

Faculty / Funding

Jason C. Gallagher, PharmD, FCCP, FIDSA, BCPS Clinical Professor Clinical Specialist, Infectious Diseases Director, PGY2 Residency in Infectious Diseases Pharmacy Temple University Philadelphia, Pennsylvania

Jamie Kisgen, PharmD, BCPS‐AQ ID Pharmacotherapy Specialist ‐ Infectious Diseases Antimicrobial Stewardship Program PGY1 Pharmacy Practice Residency Coordinator Sarasota Memorial Health Care System Sarasota, Florida

This activity is supported by an educational grant from Achaogen, Inc., Merck & Co., Paratek Pharmaceuticals, Inc., and The Medicines Company.

Accreditation

This CE activity is jointly provided by ProCE, Inc. and the Society of Infectious Diseases Pharmacists. ProCE, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE Universal Activity Number 0221‐9999‐17‐428‐L01‐P has been assigned to this live knowledge‐based activity (initial release date 12‐06‐17). This activity is approved for 1.5 contact hours (0.15 CEU) in states that recognize ACPE providers. The activity is provided at no cost to participants. Participants must complete the online post‐test and activity evaluation no later than January 5, 2018 to receive pharmacy CE credit. No partial credit will be given. Statements of completion will be issued online at www.ProCE.com, and proof of completion will be posted in NABP CPE Monitor profiles.

Faculty Disclosure

It is It is the policy of ProCE to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Gallagher is a Consultant and/or Speaker for Achaogen, Allergan, Astellas, CutisPharma, Merck, Paratek, Shionogi, and The Medicines Company, and is a P&T Committee Member for PerformRx. Dr. Kisgen has no relevant commercial or financial relationships to disclose. A portion of grant funds received by ProCE from Achaogen, Inc., Merck & Co., Paratek Pharmaceuticals, Inc., and The Medicines Company will be used to compensate the faculty for this presentation. The opinions expressed in this activity should not be construed as those of the CE provider or Achaogen, Inc., Merck & Co., Paratek Pharmaceuticals, Inc., or The Medicines Company. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this activity may include the discussion of drugs for unlabeled indications. Use of drugs outside of labeling should be considered experimental, and participants are advised to consult prescribing information and professional literature.

ProCE, Inc. 848 W. Bartlett Road Suite 3E Bartlett, IL 60103 www.ProCE.com

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About the Faculty

Jason C. Gallagher, PharmD, FCCP, FIDSA, BCPS

Dr. Jason Gallagher is Clinical Professor at Temple University School of Pharmacy and Clinical Pharmacy Specialist in Infectious Diseases at Temple University Hospital, where he maintains a clinical practice. Dr. Gallagher is also the Director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple, which has been providing pharmacists with advanced training in infectious diseases pharmacy since 2008.

Dr. Gallagher graduated with a Doctor of Pharmacy from Rutgers University in 2001. He then completed residency programs in Pharmacy Practice at Virginia Commonwealth University – Medical College of Virginia Hospital and in Infectious Diseases in the Immunocompromised Host at Duke University Medical Center. He is a past President of the Society of Infectious Diseases Pharmacists, a past President of the Mid‐Atlantic College of Clinical Pharmacy, and former Chair of the ACCP Infectious Diseases

Practice and Research Network. Dr. Gallagher serves on numerous committees for professional associations in infectious diseases and in pharmacy and is currently serving on the Board of Pharmacy Specialties Infectious Diseases Specialty Council. He is a co‐author of four editions of Antibiotics Simplified, co‐editor of two editions of Frequently Prescribed Medications, and the author of over 150 publications, abstracts, and book chapters. His research interests focus on the treatment of patients with antibiotic‐resistant infections. Dr. Gallagher is a Fellow of the American College of Clinical Pharmacy and the Infectious Diseases Society of America.

Jamie Kisgen, PharmD, BCPS-AQ ID

Dr. Kisgen currently serves as the Pharmacotherapy Specialist in Infectious Diseases and PGY1 Residency Program Coordinator at Sarasota Memorial Hospital in Sarasota, Florida. His responsibilities include co‐directing the Antibiotic Stewardship Program, providing staff education, research, and precepting pharmacy students and residents. Dr. Kisgen has been a clinical assistant professor with the University of Florida College of Pharmacy since 2009, serving as an APPE preceptor, classroom facilitator, and a frequent lecturer in the Pharmacotherapy course sequence. He serves on numerous committees for professional organizations and is currently Chair of the Society of Infectious Diseases Pharmacist Education Center (SIDPEC) Committee. He is also a Board Certified Pharmacotherapy Specialist with Added Qualifications in Infectious Diseases. Dr. Kisgen graduated with his Pharm.D. from the University of Florida College Of

Pharmacy. He completed a PGY1 Pharmacy Practice Residency at Tampa General Hospital and a PGY2 Infectious Diseases Specialty residency at Boston Medical Center.

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3ProCE, Inc.www.ProCE.com

52nd ASHP Midyear Clinical Meeting & ExhibitionOvercoming the Challenges of Multidrug‐Resistant Bacterial Infections: New Solutions to an Urgent Crisis December 6, 2017

Jason C. Gallagher, PharmD, FCCP, FIDSA, BCPS Clinical ProfessorTemple University

Jamie Kisgen, PharmD, BCPS (AQ-ID)Pharmacotherapy Specialist - Infectious DiseasesSarasota Memorial Health Care System

JointlyprovidedbyProCE,Inc.andtheSocietyofInfectiousDiseasesPharmacistsandsupportedbyaneducationalgrantfromAchaogen,Inc.,Merck&Co.,Paratek Pharmaceuticals,Inc.,andTheMedicinesCompany.

Overcoming the Challenges of Multi-Drug Resistant Bacterial Infections: New Solutions to an Urgent Crisis

Describe the changing epidemiology and clinical implications of multidrug-resistant infections

Discuss evidence-based treatment approaches in the setting of significant antibiotic resistance

Review new and emerging antimicrobial agents for gram-positive and gram-negative bacterial infections, alongside existing antibiotics, to help direct optimal selection of therapy in clinical practice

Identify antimicrobial stewardship interventions for the use of new antimicrobial agents

Learning Objectives





At least 2 million people acquire resistant bacterial infections every year in the U.S.

• At least 23,000 die as a result of the infection

• Many more die from other conditions that were complicated by the infection

Resistant pathogens lead to higher healthcare costs because they often require more expensive drugs and extended hospital stays

Total cost to U.S. society: ~ $20 billion annually

A Few Numbers…

CDC Antibiotic resistance threats in the United States, 2013



CDC Threat Report


MRSA Epidemiology




Audience Response

In which of the following infections are we seeing a decline in hospitalizations related to S. aureus?

A. Pneumonia

B. Bacteremia

C. Endocarditis

D. Skin and skin structure infections

U.S. Rates of S. aureus Hospitalization

Adapted from Klein EY, et al. Clin Infect Dis 2017 Jul 26. [Epub ahead of print]



Agent Challenges

Vancomycin• Cidal-ish• Narrow therapeutic index (AUC/MIC, nephrotoxicity)• Concern for emergence of resistance (hVISA, VISA)

Linezolid• Bacteriostatic• Drug-drug interactions (eg, serotonergic agents)• Adverse effects with prolonged use (eg, cytopenias)

Daptomycin• Not indicated for pneumonia• Concern for decreased efficacy in renal impaired patients• Possible emergence of resistance with prolonged use

Challenges With Current Agents

Agent Challenges

Tigecycline• BBW: higher all-cause mortality in meta-analysis• Low serum drug concentration • GI toxicity

Telavancin• Nephrotoxicity, QTc prolongation• Concern for decreased efficacy in renally impaired patients• What is the right dose? (weight-based vs flat dose)

Ceftaroline• Limited data for MRSA outside of ABSSSI• Neutropenia associated with long-term use• Possible emergence of resistance with prolonged use

Challenges With Current Agents



Pneumonia Bacteremia/Endocarditis Bone/Joint Meningitis

Vancomycin ✔ ✔ ✔ 1st line

Linezolid ✔ Salvage Only B‐II 2nd line

Daptomycin ✖ ✔ B‐II 2nd line

Telavancin ✔ Phase 3 Data PendingMay 2018

Ceftaroline CABPPhase 1/2 in

Pediatrics 2020

Gaps in Therapy for MRSA

✔ FDA Approved Indication ✖ Not Recommended Some Clinical Data Available

Tunkel AR, et al. Clinical Infectious Diseases 2017;64:34-65

New Treatment Strategies for Current Drugs



Despite low prevalence of MRSA, a large number of hospitalized patients are started empirically on anti-MRSA therapy1

Recent studies have highlighted the potential use of MRSA nasal screen to guide therapy in patients with suspected pneumonia2

• Negative nasal swab result has shown NPV of 94% to >99%

• Vancomycin has little to no effect on S. aureus nasal colonization

Role for stewardship:

• Shorter duration of vancomycin therapy (decrease of 2 to 2.1 days)3,4

• Lower number of vancomycin levels and monitoring costs3,5

Role of Rapid PCR of Nares in Pneumonia

1. Self WH., et al. Clin Infect Dis 2016 63:300-3092. Smith EA, et al. Am J Infect Control 2017. 1;45(11):1295-12963. Baby N, et al. Antimicrob Agents Chemother 2017;61:e02432-16.4. Willis C, et al. Am J Health-Syst Pharm. 2017; 74:1765-735. Smith MN, et al. J Crit Care 2017;38:168-71.

Spread the Word Through Education



MRSA bacteremia continues to be challenging with high mortality rates and median time to clearance of >7 days

Ceftaroline is the first FDA-approved anti-MRSA cephalosporin

Recent studies have shown that ceftaroline is effective for SAB as monotherapy or in combination (most commonly with daptomycin)

May need to consider higher doses (600 mg q8h) to reach target attainment and decrease risk of resistance

Concern for neutropenia with prolonged use (>10 days)

Ceftaroline for S. aureus Bacteremia

Casapao AM, et al. Antimicrob Agents Chemother 2014; 58: 2541–6.Zasowski EA, et al. Antimicrob Agents Chemother. 2017;61(2):e02015-16.

Ceftaroline for S. aureus Bacteremia Retrospective, multicenter, observational study

126 patients with MRSA BSI treated with ≥72 hours of ceftaroline

0%

20%

40%

60%

80%

Overall(n=126)

Monotherapy(n=89)

Combo(n=37)

Clinical Success Mortality Key Observations:• Used as 2nd or 3rd line in nearly 90% of patients

• Clearance following the initiation of ceftaroline:

- 50% of patients within 3 days

- >80% of patients within 7 days

• Higher APACHE II scores and comorbid malignancy independently associated w/ failure

• No relationship between ceftaroline MIC or ceftaroline dosing frequency and failure

• Neutropenia seen in 3 patients after 13-20 days

Zasowski EA, et al. Antimicrob Agents Chemother. 2017;61(2):e02015-16.



What Is the Role for New Agents?

Updated R&D Chart

0

2

4

6

8

10

12

14

16

1983-1987 1988-1992 1993-1997 1998-2002 2003-2007 2008-2013 2014-2017

Number of New Antimicrobial Agents

Adapted from Boucher HW, et al. Clin Infect Dis. (2009) 48(1): 1-12



Drug Indications Approval Date

Dalbavancin (Dalvance) ABSSSI May 2014

Tedizolid (Sivextro) ABSSSI June 2014

Oritavancin (Orbactiv) ABSSSI August 2014

Ceftolozane/tazobactam (Zerbaxa) cUTI, cIAI December 2014

Ceftazidime/Avibactam (Avycaz) cUTI, cIAI February 2015

Bezlotoxumab (Zinplava) C. difficile Infection October 2016

Delafloxacin (Baxdela) ABSSSI June 2017

Meropenem/Vaborbactam (Vabomere) cUTI September 2017

Bad Bugs/New Drugs: 2014 – 2017

Audience Response

Which of the following has reliable activity against MRSA and vancomycin-resistant enterococci?

A. Dalbavancin

B. Oritavancin

C. Tedizolid

D. All of the above

E. B & C



New Gram-Positive Agents

Dalbavancin

Oritavancin

Tedizolid

Delafloxacin

Lipoglycopeptide (analog of teicoplanin) Mechanism of action:

• Binds D-alanyl-D-alanine residue of Lipid II, inhibiting cross-linking of peptidoglycans, destabilizing the cell wall, causing cell death

• Lipophilic side chain anchors it to cellular membrane, strengthening adherence to the target site

Concentration dependent, bactericidal AUC/MIC correlates best with activity FDA approved indications: acute bacterial skin and skin

structure infections (ABSSSI)

Dalbavancin (Dalvance®)

Roberts KD, et al. Pharmacotherapy 2015;35(10):935–948



ABSSSI recommended dose:

• 1000 mg IV day 1, followed by 500 mg IV day 8

• 1500 mg IV x 1 dose

Effective half-life = 8.5 hours

Dose adjusted for reduced renal function (CrCl <30 mL/min)

• No dose adjustment necessary with hemodialysis

No adjustment for mild liver dysfunction

Infused over 30 minutes

Cost ~ $4500/course

Dalbavancin: Dosing and Costs


Catheter-related bloodstream infections• Phase 2, open-label, multicenter, RCT of adult patients with CRBSI

compared weekly dalbavancin (n=33) vs vancomycin (n=34)• Overall success (micro-ITT): dalbavancin 87% vs vancomycin 50%

Osteomyelitis• Phase 2, single-center, open-label, RCT • 1500 mg day 1 and day 8, compared to standard of care 4-6 weeks• Goal enrollment of 80 patients; ongoing but not recruiting (in Ukraine)

Pediatrics • Phase 3 RCT in pediatric patients with ABSSSI (ongoing: due 2019)

Dalbavancin: Ongoing Studies and Potential Off-Label Uses

https://clinicaltrials.gov/ct2/results?cond=&term=dalbavancin&cntry1=&state1=&recrs=

Raad I, et al. Clin Infect Dis 2005; 40:374-380



Lipoglycopeptide (analog of vancomycin) Multiple mechanisms of action:

• Binds D-alanyl-D-alanine residue of Lipid II, inhibiting cross-linking of peptidoglycans, destabilizing the cell wall, causing cell death

• Disruption of bacterial membrane integrity, leading to depolarization, permeabilization, and cell death

Concentration dependent, bactericidal AUC/MIC correlates best with activity FDA approved indications:

• Acute bacterial skin & skin structure infections (ABSSSI)

Oritavancin (Orbactiv®)


ABSSSI recommended dose: 1200 mg IV ONCE

Terminal half-life: 8-10 days

No adjustment for renal or hepatic impairment

Contraindicated with heparin (within 5 days)

Inhibits CYP1A2, 2B6, 2C9, 2C19; weak inducer of CYP3A4, 2D6

Infused over 3 hours

Only compatible with D5W (1000 mL of volume)

Cost ~ $2900 per dose

Oritavancin: Dosing and Cost




Single-center case series involving 10 patients

• 8 patients with bacteremia, 1 case of bursitis, 1 deep tissue

• Most common: history of IVDU or refused OPAT

• 70% cure rate (2 failed therapy, 1 not clinically evaluable)

Multicenter, retrospective, observational, registry study

• Skin structure or other systemic infection (ie, bacteremia, prosthetic joint infection, osteomyelitis)

• Ongoing, but not recruiting – completion October 2017

Potential role as OPAT therapy for endocarditis, diabetic foot infections, bone/joint infections, and VRE infections

Oritavancin: Ongoing Studies and Off-Label Uses

Stewart CL, et al. Infect Dis Ther. 2017 Jun;6(2):277-289

https://clinicaltrials.gov/ct2/results?cond=&term=oritavancin&cntry1=&state1=&Search=Search

Long-Acting Lipoglycopeptide Summary

Pros

• Single-dose regimen• Concentration dependent,

bactericidal• Active against MDR gram-

positive pathogens• Oritavancin can cover VRE

• No need for TDM• No need for extended IV

access (eg, PICC)

Cons

• Higher cost compared with others

• No opportunity to de-escalate• Limited data for other

indications • Long half-life

• Hypersensitivity reaction?• Concerns for resistance



Choose only one if possible• Limit confusion for MDs, nurses, RPhs, and case managers

Possible uses• Not an ideal candidate for oral antibiotics or once-daily OPAT• Key patient groups: homeless, lack of transportation, live too far

from infusion center, indigent, IV drug users• May be an option in emergency department or observation unit

as part of a skin and skin structure infection clinical pathway Drug assistance programs available for indigent patients Overall opinion: They have the potential to be game changers if

positive results are seen for invasive MRSA infections

Stewardship Recommendation

Member of oxazolidinone class (similar to linezolid)

Given as prodrug (tedizolid phosphate), which is converted quickly by phosphatases in vivo to active form

Free AUC/MIC correlates best with activity

FDA approved indications:

• Acute bacterial skin and skin structure infections (ABSSSI)

• 200 mg IV/PO daily for 6 days

No adjustment for renal or liver dysfunction

Tedizolid (Sivextro®)

Kisgen JJ, et al. Am J Health Syst Pharm. 2014 Apr 15;71(8):621-33



Mechanism of action

• Similar to linezolid

• Inhibits protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit, preventing the formation of 70S complex

• Cross resistance with other drug classes is unlikely

More potent activity against MDR gram-positive pathogens allows for lower amounts of drug to be given

May have less risk for adverse effects (limited data)

• MAO inhibition, bone marrow effects

• Phase 3 trial compared 6 days of tedizolid vs 10 days of linezolid

Tedizolid: What’s Unique About It?

Kisgen JJ, et al. Am J Health Syst Pharm. 2014 Apr 15;71(8):621-33

Tedizolid Summary

Pros

• Once-daily dosing • Available in IV and oral

formulations• Active against MDR gram-

positive pathogens (including VRE)

• No CI with serotonergic agent

Cons

• Higher cost (~$280/day)• Limited data for other

indications• Limited safety data beyond 6

days• Poorer response in setting of

neutropenia



Bone and joint infections: • Phase 2 single-center, single-arm study looking at tedizolid

– completion January 2019 Nosocomial pneumonia:

• Phase 3 study comparing tedizolid to linezolid – completion October 2018

Pediatrics: • Phase 3 study in adolescents with complicated skin and soft

tissue infections – completion February 2019• Phase 3 study in pediatric patients with complicated skin

and soft tissue infections – completion February 2021

Tedizolid: Ongoing Studies and Off-Label Uses

https://clinicaltrials.gov/ct2/results?cond=&term=tedizolid&cntry1=&state1=&Search=Search

Second-/third-line treatment of ABSSSI when other options are not feasible

May be beneficial in patients who would otherwise be given PO linezolid but are restricted due to drug interactions

• Eg, receiving concomitant serotonergic agents

Drug assistance program is available for outpatient therapy (copay assistance and indigent care program)

Overall opinion: minimal role at this point in treatment paradigm

Tedizolid: Stewardship Recommendation



Anionic fluoroquinolone

Concentration-dependent bactericidal activity

Free AUC/MIC correlates best with activity

Indications: acute bacterial skin and skin structure infections (ABSSSI)

• 300 mg IV over 1 hour q12h or 450 mg PO q12h

IV dose must be adjusted for renal function

• Dose is 200 mg IV q12h if eGFR is 15-29 mL/min/1.73 m2

• Not recommended in ESRD or dialysis

Delafloxacin (BaxdelaTM)

Cho JC, et al. Pharmacotherapy 2017 Oct 23 [Epub ahead of print]

Mechanism of action:

• Equally potent activity against topoisomerase IV and DNA gyrase

• More potent activity in acidic environments due to molecule having a weak acid property

Broad spectrum of activity against gram-negative, atypical, and anaerobic, gram-positive bacteria (including MRSA)

No QTc prolongation found in initial studies

Renal adjustments based on MDRD, not Cockcroft/Gault

Delafloxacin: What’s Unique About It?

Cho JC, et al. Pharmacotherapy 2017 Oct 23 [Epub ahead of print]



Community-acquired bacterial pneumonia (CABP):

• Phase 3 RCT comparing delafloxacin vs moxifloxacin

• Estimated completion: November 2018

Acute bacterial exacerbation of chronic bronchitis (ABECB)

• Phase 2 RCT dose-ranging study found similar clinical response and safety compared to levofloxacin

• No urgent need; not clear if company will pursue further studies

Uncomplicated gonorrhea:

• Phase 3 RCT comparing single-dose delafloxacin vs ceftriaxone terminated early due to “insufficient efficacy” with delafloxacin

Delafloxacin: Ongoing Studies and Off-Label Uses

https://clinicaltrials.gov/ct2/results?cond=&term=delafloxacin&cntry1=&state1=&recrs=Cho JC, et al. Pharmacotherapy 2017 Oct 23 [Epub ahead of print]

Delafloxacin Summary

Pros

• Broad coverage against MDR pathogens, including MRSA and Pseudomonas

• May have role in polymicrobial infections

• No risk of QTc prolongation or phototoxicity in Phase I

Cons

• It’s a fluoroquinolone• Limited safety data – any

surprises to come?• Too broad for most patients• Concern for resistance and

Clostridium difficile• Renal adjustments based on

MDRD may cause confusion



Treatment of polymicrobial ABSSSI when all other IV or PO options are not feasible

Drug assistance program is available for outpatient therapy (copay assistance and indigent care program)

Would like to see data for diabetic foot infections and osteomyelitis

Overall opinion: minimal role at this point in treatment paradigm

Delafloxacin: Stewardship Recommendation

Improving Discharge Management



Drug (Class) Company Indications Phase Comments/Opinion

OmadacyclineAminomethylcyclines

Paratek ABSSSI, CABP 3• Broad spectrum, carbapenem & FQ

sparing, IV/PO formulation, No MP3*• Save for MDR gram-negatives

EravacyclineTetracycline

Tetraphase cIAI, cUTI 3• Broad spectrum, carbapenem-sparing• No Pseudomonas coverage• Save for MDR gram-negatives

LefamulinPleuromutilin

NabrivaTherapeutics

ABSSSI, CABP 3• Broad spectrum (MRSA, VRE, atypicals),

IV/PO formulation, no risk of cross resistance with other classes

ZabofloxacinFluoroquinolone

Dong WhaPharmaceutical

CABP 3• More potent than moxifloxacin against GP• Minimal role at this time

Pipeline for Gram-Positive Agents

Abbas M, et al. Clin Microbiol Infect 2017 Oct;23(10):697-703.

http://pewtrusts.org/antibiotic-pipeline

* MP3: Morganella, Proteus, Providencia, Pseudomonas

Drug (Class) Company Indications Phase Comments/Opinion

Fusidic acidFusidane

MelintaABSSSI

Bone/Joint Infections

2 & 3

• Available in Europe, Canada for decades• PO formulation, no risk of cross resistance with

other classes• May have a role on bone/joint infections

IclapramDiaminopyrimidine

Motif BioSciences

ABSSSI 3

• Similar mechanism as TMP/SMX• Less risk of nephrotoxicity but concern for QTc• Originally rejected by FDA in 2008, but new

studies were done to address concerns

SolithromycinFluoroketolide

MelintaCABP,

Gonorrhea

Complete Response

Letter

• Quinolone-sparing option• Rejected by FDA due to safety concerns• Not clear if Melinta will continue to pursue

additional studies and regulatory approval

Pipeline for Gram-Positive Agents

Abbas M, et al. Clin Microbiol Infect 2017 Oct;23(10):697-703.

http://pewtrusts.org/antibiotic-pipeline





What Are Our Greatest Threats?

http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf

CRE

Gonorrhea

Pseudomonas

Acinetobacter

ESBL+ GNRs



Audience Response

Proportionally, which organism had the greatest increase in carbapenem resistance in the US in the last 10 years?

A. Acinetobacter baumanni

B. Escherichia coli

C. Klebsiella pneumoniae

D. Pseudomonas aeruginosa

It’s Bad Out There




It Can Get Worse

63%

57%

26%

58%36%

8%

14%

30%



Timeline of Antibiotic Class Discoveries

Adapted from Fischbach et al. Science 2009; 325:1089-1093.

DHFR = dihydrofolate reductase

Polymyxins: There Are Differences

Photography by Dr. Kimberly Toussaint

CMS Colistin

Renal Excretion

Non-Renal Elimination

Infusion

Poly B

Non-RenalElimination

Infusion

Renally

good reason

Renallydosed for no good reason

Good kidneys eliminate too wellGood kidneys

eliminate too well

Polymyxin B Colistimethate



Audience Response

Which of these drugs is typically active against CRE in the US?

A. Ceftolozane-tazobactam

B. Ceftazidime-avibactam

C. Meropenem-vaborbactam

D. A and B

E. B and C

Audience Response

Which of these drugs is unlikely to be useful for a urinary tract infection caused by CRE?

A. Ceftazidime-avibactam

B. Colistin

C. Meropenem-vaborbactam

D. Polymyxin B



Colistin Is Given as a Prodrug With Interpatient Variability

0

0.5

1

1.5

2

2.5

3

3.5

4

0 2 4 6 8

Based on: Plachouras D et al. Antimicrob Agents Chemother 2009;53:3430-6.

Colistin plasm

a concentration (mg/L)

Time (hours)

Colistin Plasma Concentrations After 1st Dose

Colistin Is Given as a Prodrug With Interpatient Variability

0

0.5

1

1.5

2

2.5

3

3.5

4

0 2 4 6 8

Based on: Plachouras D et al. Antimicrob Agents Chemother 2009;53:3430-6.

Colistin plasm

a concentration (mg/L)

Time (hours)

Colistin Plasma Concentrations After 4th Dose



Polymyxin B Has More Predictable PK

Sandri AM et al. Clin Infect Dis 2013;57:524-31.

Study (Year) Cohort N Nephrotoxicity

Garnacho‐Montero (2003) VAP (ICU) 21 23.8%

Michalopoulos et al (2005) ICU 43 18.6%

Hachem et al (2007) Cancer 31 23%

Hartzell et al (2009) All 66 41%

Garonzik et al (2009) ICU 89 48%

Cheng et al (2010) Pseudomonas; 65% ICU 84 14%

Doshi et al (2011) ICU 49 31%

Pogue et al (2011) All; 75% ICU 126 43%

Collins et al (2013) All; 79% ICU 174 48%

Durante‐Mangoni et al (2013) Acinetobacter; 61% ICU101 (COL)

101 (COL+RIF)28.7% (COL)

23.7% (COL+RIF)

Colistin Nephrotoxicity: How Toxic Is It?



Should We Be Using Polymyxin B?

Phe K et al. Antimicrob Agents Chemother 2014;58:2740-6.Akajagbor D et al. Clin Infect Dis 2013;57:1300-3.

23.1 21.1

33.9

55.3

0

10

20

30

40

50

60

ITT (n=225) Matched Cohort (n=76)

Prevalence of Nephrotoxicity

(%)

Polymyxin B

Colistin p=0.004

Higher Prevalence of Nephrotoxicity with Colistin

60.4

41.8

0

10

20

30

40

50

60

70

Colistin Polymyxin B

Prevalence of ARF (%

)

Higher Incidence of Acute Kidney Injury with Colistin

p=0.02

Prospective, multicenter, pharmacokinetic point-prevalence study

Midpoint and trough concentrations drawn and interpreted in relation to the known or presumed MIC of the infecting organism

“Snapshot picture of beta-lactam antibiotic concentrations in critically ill patients on a single day”

DALI: Defining Antibiotic Levels in Intensive Care Patients

Roberts JA et al. Clin Infect Dis 2014;58:1072-83.



Up to 500-fold differences in unbound concentrations of antibiotics at both sampling points

DALI Study

Antibiotic (No. of Patients)

Dosing and PK/PD Data

Cefazolin (n = 14)

Cefepime(n = 14)

Ceftriaxone(n = 33)

Doripenem(n = 13)

Piperacillin (n = 109)

Meropenem(n = 89)

Dosage per 24h, g 3.0 (3-4) 6.0 (5-6) 2.0 (2-4) 1.75 (1.5-3)12.0

(12-16)3.0 (3-4)

50% fT>MIC achieved

100% 78.6% 97% 100% 80.6% 95%

100% fT>MIC achieved

78.6% 78.6% 93.9% 76.9% 67% 69.7%


Achieved 50% fT>MIC Did not achieve

Overall population 84% 16%*

Prolonged infusion (33%) 93% 7%

Intermittent infusion (67%) 80% 20%

DALI Study: Not Attaining Targets Was Associated With Failure

*Associated with clinical

failureOR 0.68 (95% CI 0.52‐0.91)

*Associated with clinical

failureOR 0.68 (95% CI 0.52‐0.91)

ParameterOR (95% CI)50% fT>MIC

OR (95% CI)100% fT>MIC

APACHE II 0.94 (0.92‐0.96)* 0.94 (0.92‐0.96)

SOFA score 0.97 (0.94‐1.00) 0.97 (0.94‐1.01)

50% fT>MIC 1.03 (1.01‐1.04)*

100% fT>MIC 1.02 (1.01‐1.05)




DrugBrandname

Type of beta‐lactamase inhibitor

Approval Indications

Ceftolozane‐tazobactam

Zerbaxa® Beta‐lactam based 2014 cUTIs, cIAIs

Ceftazidime‐avibactam

Avycaz®Diazabicyclooctane(non‐beta‐lactam)

2015 cUTIs, cIAIs

Meropenem‐vaborbactam

Vabomere® Boronic acid based 2017 cUTIs

What’s New?

Audience Response

You are evaluating ceftolozane-tazobactam for formulary inclusion. For which organism would it likely be most useful?

A. MDR Acinetobacter baumanni

B. Colistin-resistant E. coli

C. Carbapenem-resistant Klebsiella pneumoniae

D. MDR Pseudomonas aeruginosa



Ceftolozane• Cephalosporin with potent anti-

pseudomonal activity• Similar to ceftazidime with different

side chain• Destroyed by ESBLs and

carbapenemases• Relatively stable vs AmpC

Tazobactam• Protects ceftolozane from many

ESBLs and cephalosporinases• Not active vs AmpC beta-

lactamases, carbapenemases

Ceftolozane-Tazobactam: An Old BLI Makes a New Friend

Zhanel GG et al. Drugs 2014;74:31‐51.

Ceftolozane

Tazobactam

Spectrum – strong against

• Many gram-negative bacilli

• Pseudomonas aeruginosa, including ceftazidime- and carbapenem-resistant strains

• Enterobacteriaceae, including many ESBL-producing strains

Spectrum – weak against

• Ceftazidime-resistant Enterobacter spp

• Carbapenemase-producing Enterobacteriaceae

• Gram-positive anything and gram-negative anaerobes

Ceftolozane-Tazobactam: Spectrum Pros and Cons

Zhanel GG et al. Drugs 2014;74:31‐51.



CharacteristicCeftolozane‐Tazobactam

Piperacillin‐Tazobactam

Brand name Zerbaxa® Zosyn®

Drug‐to‐inhibitor ratio 2:1 8:1

Parent drug susceptibility to AmpC beta‐lactamases

Little High

Activity against anaerobes Limited High

Contribution of inhibitor to Pseudomonas activity

Little Little

Ceftolozane-Tazobactam Compared With Piperacillin-Tazobactam

Ceftolozane-Tazobactam: Phase 3 Clinical Trials

PopulationCeftolozane/tazobactam

Levofloxacin %∆ (95% CI)

mMITT 306/398 (76.9%) 275/68.4 (68.4%) 8.5 (2.3‐14.6)

PP 284/341 (83.3%) 266/353 (75.4%) 8.0 (2.0‐14.0)

PopulationCeftolozane‐

tazobactam + MTZMeropenem %∆ (95% CI)

MITT 323/389 (83.0%) 364/417 (87.3%) ‐4.2 (‐8.9‐0.5)

ME 259/275 (94.2%) 304/321 (94.7%) ‐1.0 (‐4.5‐2.6)

Intra‐abdominal Infections

Solomkin J et al. Clin Infect Dis 2015;60:1462‐71. Wagenlehner FM et al. Lancet 2015;385:1949‐56.

Urinary Tract Infections



Ceftolozane-Tazobactam Is Active Against Resistant Pseudomonas

96.1

76.882.9 82.4 80.3 74.979

11

22 22 19.415.2

70.9

2.39.1 10.9 7.4

2.90

10

20

30

40

50

60

70

80

90

100

TOL/TAZ TZP CAZ FEP MER LVX

All

MDR

XDR

Adapted from: Farrell DJ et al. Antimicrob Agents Chemother 2013;57:6305‐10.

(1971)

(310)

(175)

Suscep

tible (%)

Pseudomonas isolates susceptible to study drug

TOL‐TAZ = ceftolozane‐tazobactamTZP = piperacillin‐tazobactamCAZ = ceftaidimeFEP = cefepimeMER = meropenemLVX = levofloxacin

Ceftolozane-Tazobactam: Limited Experience in MDR Pseudomonas infections

Characteristic (n=34) Results

Age (median, IQR) 57 (42‐66)

Charlson Comorbidity Index (median, IQR) 4 (2.25‐5)

APACHE II score (median, IQR) 20 (13‐27)

ICU, n(%) 23 (67.7)

Solid organ transplant, n(%) 15 (44.1)

Number of TOL‐TAZ days, median (range) 14 (3‐42)

Clinical success, n(%) 24 (70.6)

Microbiological cure, n(%) 21 (61.8)

Retrospective study of 34 patients in 3 hospitals with multi‐drug resistant Pseudomonas infections treated with TOL‐TAZ for at least 48 hours

Molnar EM et al. IDWeek 2017.



Ceftolozane-Tazobactam: What’s HAPpening Now

Phase 1 ELF study showed ceftolozaneELF/plasma AUC ratio was 0.48

Phase 3 ASPECT‐NP study is underwayNote: Dose is 3 g IV q8h

Chandorkar G et al. J Antimicrob Chemother 2012;67:2463-9.https://clinicaltrials.gov/ct2/show/NCT02070757?term=ceftolozane&recrs=ab&rank=3

Ceftazidime• Third-generation antipseudomonal

cephalosporin• Susceptible to ESBL and KPC enzymes,

but not porin channel changes that affect carbapenems

Avibactam• Novel beta-lactamase inhibitor not based

on beta-lactam structure• Active against ESBLs, KPC-type and

OXA-48 carbapenemases• Not active against metallo-beta-

lactamases

Ceftazidime-Avibactam

Avibactam

Ceftazidime



Spectrum, strong against:


• Pseudomonas aeruginosa

• Enterobacteriaceae producing KPC and ESBL enzymes

Spectrum, weak against:

• Gram-positive organisms

• GNRs producing metallo-beta-lactamases

• Gram-positive anything and gram-negative anaerobes

Ceftazidime-Avibactam: Spectrum Pros and Cons

Shaeles DM. Ann NY Acad Sci 2013;1277:105–114.

Ceftazidime-Avibactam: Phase 3 Clinical Trials

Group CAZ/AVI 2.5 g q8h + MTZ Meropenem 1 g q8h %∆ (95% CI)

mMITT 337/413 (81.6%) 349/410 (86.1%) ‐3.5 (‐8.64‐1.58)

MITT 429/520 (82.5%) 444/523 (84.9%) ‐2.4 (‐6.90‐2.10)

Group CAZ/AVI 2.5 g q8h Doripenem 500 mg q8h %∆ (95% CI)

Pt Sx d5 276/393 (70.2%) 276/417 (66.2%) 4.0 (‐2.39‐10.42)

Clin Cure 280/393 (71.2%) 269/417 (64.5%) 6.7 (0.3‐13.12)

Micro 304/393 (77.4%) 296/414 (71.0%) 6.4 (0.33‐12.36)

Intra‐abdominal Infections

Mazuski JE et al. Clin Infect Dis 2016;62:1380‐9. Wagenlehner FM et al. Clin Infect Dis 2016;63:754‐62.

Urinary Tract Infections



Ceftazidime-Avibactam: Phase 3 Clinical Trials

Group CAZ/AVI 2.5g q8h Meropenem 1gm q8h %∆ (95% CI)

cMITT 245/356 (68.8%) 270/370 (73.0%) ‐4.2 (‐10.76‐2.46)

CE 199/257 (77.4%) 211/270 (78.1%) ‐0.7 (‐7.86‐6.39)

Hospital‐acquired and Ventilator‐associated Pneumonia

Torres A. IDWeek 2017.

No differences in response rates in CAZ-resistant pathogens

No differences in response rates in CAZ-resistant pathogens

Ceftazidime-Avibactam Is Active Against Many Resistant GNRs

Adapted from: Sader HS et al. Int J Antimicrob Agents 2015;46:53‐9.Sader HS et al. Antimicrob Agents Chemother 2015;59:3656‐9.

Organisms from ICU Patients

CAZ‐AVI = ceftazidime‐avibactam TZP = piperacillin‐tazobactamCAZ = ceftazidime MER = meropenemFEP = cefepime COL = colistin

Suscep

tible (%)

Ceftazidime‐avibactam

activity against Pseudomonas

All (3902) ‐ 96.9%MDR (580) ‐ 81%XDR (338) ‐ 73.7%



Ceftazidime-Avibactam Is Active Against KPC-producing GNRs

Castanheira M et al. Antimicrob Agents Chemother 2015;59:3509‐17.

Percent of KPC‐producing K. pneumoniae susceptible

CAZ‐AVI = ceftazidime‐avibactam CAZ = ceftazidime ATM ‐ aztreonamTZP = piperacillin‐tazobactam MER = meropenem GEN = gentamicinTGY = tigecycline

Ceftazidime-Avibactam: ESBL-Producing Infections

REPRISE studied CAZ-AVI or “best available” therapy vs CAZ-resistant GNRs for cUTIs or cIAIs

Carmeli Y et al. Lancet Infect Dis 2016;16:661‐3.

Clinical cure

Micro cure



Ceftazidime-Avibactam: Emerging Data for CRE Infections

Agent NIPTW‐

Mortalityp‐value

CAZ‐AVI 38 9%0.0012

Colistin 99 32%

van Duin D et al. Clin Infect Dis 2017 (epub ahead of print)Shields RK et al. Antimicrob Agents Chemother 2017;61:e00883‐17.

Agent N Clinical Success 90‐d mortality

CAZ‐AVI 13 85% 8%

Carbapenem + Aminoglycoside 25 48% 44%*

Carbapenem + Colistin 30 40% 37%^

Others 41 37% 51%*

p<0.05 between CAZ‐AVI and all groupsCompared with CAV‐AVI*p<0.05 ^p=0.07

Multicenter Retrospective Study of Patients with Infections with CRE

Single‐Center Retrospective Study of Patients with CRE Bacteremia

Meropenem• Potent antipseudomonal carbapenem

with broad spectrum• Resistant to destruction from ESBLs,

cephalosporinases

Vaborbactam• Boronic acid beta-lactamase inhibitor• Active vs ESBLs and KPCs but not

metallo-beta-lactamases• Does not add activity against

Pseudomonas

Meropenem-Vaborbactam

Vaborbactam

Meropenem

Toussaint K, Gallagher JC. Ann Pharmacother 2015;49:86‐98.



Spectrum, strong against:


• Carbapenem-susceptible Pseudomonas aeruginosa

• Enterobacteriaceae producing KPC and ESBL enzymes

Spectrum, weak against:

• Carbapenem-resistant Pseudomonas aeruginosa

• GNRs producing metallo-beta-lactamases or OXA-enzymes

Meropenem-Vaborbactam: Spectrum Pros and Cons

Shaeles DM. Ann NY Acad Sci 2013;1277:105–114.

Meropenem-VaborbactamPhase 3 Clinical Trials

Endpoint Meropene‐Vaborbactam 4 g q8h Piperacillin‐tazobactam 4.5 g q8h %∆ (95% CI)

EOT(IV) 183/186 (98.4%) 165/175 (94.3%) 4.1 (0.3‐8.8)

TOC 124/162 (76.5%) 112/153 (73.2%) 3.3 (‐6.2‐13)

Complicated Urinary Tract Infections

Vabomere package insert, 2017.



Meropenem-Vaborbactam:Active Against Resistant Enterobacteriaceae

Castanheira M et al. Antimicrob Agents Chemother 2017;61:e00567-17.

Activity Against Enterobacteriaceae Collected Worldwide in 2014

Meropenem-VaborbactamPhase 3 Clinical Trials

Group Meropenem‐Vaborbactam 4 g q8h Best Available Therapy %∆ (95% CI)

Clinical Cure EOT 18/28 (64.3%) 5/15 (33.3%) 31.0 (1.2‐60.7)

Clinical Cure TOC 16/28 (57.1%) 4/15 (26.7%) 30.5 (1.5‐59.4)

28‐d Mortality 5/28 (17.9%) 5/15 (33.3%) ‐15.5 (‐43.2‐12.3)

Kaye K et al. IDWeek 2017.

Patients with CRE Infections, including cUTI, cIAI, HAP/VAP, BSI

Data Safety Monitoring Board recommended stopping study early due to difference in outcomes

Data Safety Monitoring Board recommended stopping study early due to difference in outcomes



Utility of New Agents

Agent ESBLsCRE

(KPCs)Carbapenem-RPseudomonas CRE (NDM)

MDRAcinetobacter

Ceftolozane-tazobactam

Ceftazidime-avibactam

Meropenem-vaborbactam

Looking Forward in the GNR Pipeline

Agent Class Company Notes

Plazomicin Aminoglycoside AchaogenSuperior to meropenem for cUTIs

Lower mortality for CRE BSIs compared to colistin

Imipenem‐relebactamCarbapenem‐beta‐lactamase

inhibitorMerck Diazabicyclooctane inhibitor

CefiderocolSiderophorecephalosporin

Shionogi

Novel mechanism that relies on active iron transport

Superior to imipenem‐cilastatin in cUTI study



Likely Utility of Pipeline Agents

Agent ESBLs CRE (KPCs)Carbapenem-RPseudomonas CRE (NDM)

MDRAcinetobacter

Plazomicin

Imipenem-relebactam

Cefiderocol

Barriers



Drug

Predicted Impact

CommentsJ. Gallagher J. Kisgen

Ceftolozane/tazobactam Moderate MajorReplacing aminoglycosides for beta-lactam-R Pseudo

Ceftazidime/avibactam Major Major Replacing polymyxins for CRE

Meropenem/vaborbactam Moderate ModerateBetter inhibitor than avibactam for KPCs, worse for Pseudomonas

Dalbavancin, Oritavancin Major Major Why give daily OPAT?

Tedizolid Incremental Incremental+ No MAOI effects- Linezolid is generic

Delafloxacin Incremental Incremental If only… N. gonorrhea

So… What Do We Think?

Slide courtesy of Dr. Conan MacDougall

The Enthusiasm Problem



New drugs are here and more are coming!

• (We’re not used to this)

New drugs are here, more are coming, and they’re not cheap!

• (We’re getting used to this)

Barriers exist to optimizing the use of new agents

Antimicrobial stewardship is key in balancing clinical good with economical reality

Conclusions

Klein EY, Mojica N, Jiang W, et al. Trends in Methicillin-Resistant Staphylococcus aureus Hospitalizations in the United States, 2010-2014. Clin Infect Dis 2017 Jul 26. doi: 10.1093/cid/cix640. [Epub ahead of print]

Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009;48:1-12.

Self WH, Wunderink RG, Williams D, et al. Staphylococcus-aureus Community –acquired Pneumonia: Prevalence, Clinical Characteristics, and Outcomes. Clin Infect Dis 2016 63:300-309

Smith EA, Gold HS, Mahoney MV, et al. Nasal methicillin-resistant Staphylococcus aureus screening in patients with pneumonia: A powerful antimicrobial stewardship tool. Am J Infect Control 2017. 1;45(11):1295-1296

Baby N, Faust AC, Smith T, et al. Nasal methicillin resistant Staphylococcus aureus (MRSA) PCR testing reduces the duration of MRSA-targeted therapy in patients with suspected MRSA pneumonia. AntimicrobAgents Chemother 2017;61:e02432-16.

Smith MN, Erdman MJ, Ferreira JA, et al. Clinical utility of methicillin-resistant Staphylococcus aureus nasal polymerase chain reaction assay in critically ill patients with nosocomial pneumonia. J Crit Care 2017;38:168-71.

Zasowski EJ, Trinh TD, Claeys KC, Casapao AM, Sabagha N, Lagnf AM, et al. Multicenter observational study of ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother. 2017;61(2):e02015-16.

References



Zhanel GG, Calic D, Schweizer F, et al. New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin. Drugs 2010;70:859-886

Raad I, Darouche R, Vazquez J, et al. Efficacy and Safety of Weekly Dalbavancin Therapy for Catheter-Related Bloodstream Infection Caused by Gram-Positive Pathogens. Clin Infect Dis 2005; 40:374-380

Stewart CL, Turner MS, Frens JJ, et al. Real-World Experience with Oritavancin Therapy in Invasive Gram-Positive Infections. Infect Dis Ther. 2017 Jun;6(2):277-289

Flanagan S, Bartizal K, Minassian SL, et al. In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrob Agents Chemother. 2013;57(7):3060–3066

Roberts KD, Sulaiman RM, Rybak MJ. Dalbavancin and Oritavancin: An Innovative Approach to the Treatment of Gram-Positive Infections. Pharmacotherapy 2015;35(10):935–948

Kisgen JJ, Mansour H, Unger NR, et al. Tedizolid: a new oxazolidinone antimicrobial. Am J Health Syst Pharm. 2014 Apr 15;71(8):621-33

Cho JC, Crotty MP, White BP, et al. What is Old is New Again: Delafloxacin, a Modern Fluoroquinolone. Pharmacotherapy 2017 Oct 23 [Epub ahead of print]

Abbas M, Paul M, Huttner A. New and improved? A review of novel antibiotics for Gram-positive bacteria. Clin Microbiol Infect. 2017 Oct;23(10):697-703.

References




Panel Discussion

CE Credit Instructions

Overcoming the Challenges of Multidrug‐Resistant Bacterial Infections: New Solutions to an Urgent Crisis

December 6, 2017 ‐ Orlando, Florida

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