tools for managing gram- negative resistancetools for managing gram-negative resistance jointly...

Tools for Managing Gram-Negative Resistance

Jointly provided by ProCE, LLC and the Society of Infectious Diseases Pharmacists, and supported by an educational grant from Merck.

A Virtual Midday Symposium to be Conducted at the 2020 ASHP Midyear Clinical Meeting & Exhibition

Samuel L. Aitken, PharmD, MPH, BCIDP@OncIDPharmD

Erin K. McCreary, PharmD, BCPS, BCIDP@ErinMcCreary

Faculty:

Moderator: Bruce M. Jones, PharmD, BCPS

About the Faculty

Samuel L. Aitken, PharmD, MPH, BCIDP Dr. Samuel L. Aitken is a Clinical Pharmacy Specialist in Infectious Diseases and director of the PGY2 Infectious Diseases Pharmacy Residency at The University of Texas MD Anderson Cancer Center in Houston, Texas. Additionally, Dr. Aitken serves as a faculty member in the Center for Antimicrobial Resistance and Microbial Genomics (CARMiG) at the UTHealth McGovern Medical School. Dr. Aitken’s research focuses primarily on the epidemiology, molecular mechanisms, and treatment of antimicrobial resistant bacteria in patients with hematologic malignancy. Dr. Aitken has an active role in patient care and in the training of pharmacy and medical trainees at the graduate and post-graduate levels. Dr. Aitken received his PharmD from the University at Buffalo School of Pharmacy and Pharmaceutical Sciences in 2011. He then completed a PGY1 Pharmacy Residency at

Yale-New Haven Hospital and an infectious diseases pharmacotherapy fellowship at the University of Houston and St. Luke’s Episcopal Hospital.

Bruce M. Jones, PharmD, BCPS Dr. Bruce M. Jones is an Infectious Diseases Clinical Pharmacy Specialist at St. Joseph’s/Candler Health System practicing in the Savannah City-Wide Antimicrobial Management Program. He also serves as an Adjunct Clinical Assistant Professor for the University of Georgia College of Pharmacy and a Clinical Preceptor for Mercer University, University of Georgia, and South University Schools of Pharmacy. He received his Doctor of Pharmacy degree from East Tennessee State University Gatton College of Pharmacy in Johnson City, Tennessee. He then completed a Postgraduate Year One (PGY1) Pharmacy Practice Residency at St. Joseph’s/Candler Health System. Dr. Jones is a member of IDSA, GSHP, ACCP, SIDP, and the Southeastern Research Group Endeavor (SERGE-45). Dr. Jones is board certified in Pharmacotherapy (BCPS).

Erin K. McCreary, PharmD, BCPS, BCIDP Dr. Erin McCreary is a Clinical Assistant Professor within the University of Pittsburgh Department of Medicine, Division of Infectious Diseases and an Infectious Diseases Clinical Pharmacist at UPMC. She received her PharmD from the Auburn University Harrison School of Pharmacy and completed her PGY1 Pharmacy and PGY2 Infectious Diseases residencies at the University of Wisconsin Health.

Dr. McCreary currently leads the UPMC System COVID-19 Therapeutics Committee and serves as a co-investigator for the REMAP trial, a global, adaptive, COVID-19 clinical trial. She also has taken on a role growing and developing UPMC’s telestewardship services via Infectious Disease Connect. She has published numerous peer-reviewed manuscripts in the areas of antimicrobial stewardship,

gram-negative resistance, and antifungal therapeutic drug monitoring. She has served the profession in numerous roles including most recently chair of the SIDP Publications and Podcast committee and incoming SIDP Executive Board member as Treasurer.

Her practice interests include infectious diseases and antimicrobial stewardship in immunocompromised hosts, gram-negative resistance, antimicrobial pharmacokinetic/pharmacodynamic optimization, and recommending cefazolin for patients with documented penicillin allergies. She is also passionate about professional leadership, mentorship, and preceptorship.


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Faculty:




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FacultyModerator:Bruce M. Jones, PharmD, BCPSInfectious Diseases Clinical Pharmacy SpecialistSt. Joseph's/Candler Health SystemSavannah, Georgia

Samuel L. Aitken, PharmD, MPH, BCIDPClinical Pharmacy Specialist, Infectious DiseasesDirector, PGY2 Infectious Diseases Pharmacy ResidencyDivision of PharmacyThe University of Texas MD Anderson Cancer CenterHouston, Texas

Erin K. McCreary, PharmD, BCPS, BCIDPClinical Assistant Professor, University of Pittsburgh School of MedicineInfectious Diseases Clinical Pharmacist, UPMCPittsburgh, Pennsylvania

Dr. Aitken has received honorarium as an advisory board member for Merck, and a research grant as investigator for Melinta. Dr. McCreary has received honorarium as an advisory board member for Summit, Entasis, Merck, AbbVie, and Shionogi. Dr. Jones has received honorarium as a speaker for Allergan, Tetraphaseand Paratek and grant funding as an investigator for Merck.

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Samuel L. Aitken, PharmD, MPH, BCIDP



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Learning Objectives

the most recent patterns of gram-negative resistance in the USExamine

the current and emerging treatments, dosing, coverage profiles, and recommended monitoring of treatment optionsDescribe

strategies to navigate formulary decision-making, including guidance on development of decision support tools and best practices for restricted useDiscuss

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Introduction and mechanisms of resistance



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We see these patients daily.

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• Highly toxic• Limited in vitro activity• Unclear “best” agent / agents

Historical treatment options are suboptimal

• Traditional diagnostics remain quite slow• No 1:1 relationship between resistance and gene

detection like in MRSA and VRE

Time to identification of MDRO organism delayed

• Creates significant bias in observational researchPatients who get MDROs tend to be sicker

Outcomes for Multidrug-resistant Organisms (MDROs) are bad (but getting better!)

Martin A, et al. Open Forum Infect Dis 2018;5(7):ofy150Tam VH, et al. Antimicrob Agents Chemother 2010;54(9):3717-22



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How did we get here?Mechanisms behind antibiotic resistance

Drug can’t get to target

Drug is modified

Drug can’t bind to target

Efflux, porins

Enzyme hydrolysis,

modificationModified,

protected, or bypass target

Munita JM, Arias CA. Microbiol Spectr. 2016.

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Enzymatic drug modification (β-lactams, aminoglycosides, quinolones)

Efflux (β-lactams, aminoglycosides, tetracyclines, quinolones)

Porin loss (β-lactams)

Target modification (quinolones, aminoglycosides, tetracyclines, polymyxins)

Target bypass (trimethoprim-sulfamethoxazole)

Created by Samuel Aitken using BioRender.com



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Audience Response

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A. OXA-48B. KPCC. NDMD. CTX-ME. CMY

Which of the following enzymes is not inhibited by avibactam?

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“Simplifying” the β-lactamasesMolecular class

(Ambler) Representative enzymes Active β-lactamase inhibitors Predicted β-lactam phenotype

A

TEM-1, SHV-1 Clavulanate, tazobactam, avibactam, vaborbactam, relebactamPenicillin resistant1GC/2GC variable

CTX-M, TEM+, SHV+“ESBLs”

Clavulanate, tazobactam, avibactam, vaborbactam, relebactam

3GC resistant TZP, ATM, FEP variableCarbapenem susceptible

KPC Avibactam, vaborbactam, relebactam Carbapenem resistantB IMP, VIM, NDM None ATM or FDC susceptible

C AmpCCMY Avibactam, vaborbactam, relebactam3GC resistantTZP, ATM variableFEP, carbapenem susceptible

D OXA-48 Avibactam Carbapenem resistantCephalosporin variable

Bush K. Antimicrob Agents Chemother. 2018;62(10)

1GC = first generation cephalosporin; 2GC = second generation cephalosporin; 3GC = third generation cephalosporin; ATM = aztreonam; FDC = cefiderocol; FEP = cefepime; TZP = piperacillin/tazobactam

• Nearly 3,000 unique β-lactamases described• No one drug to inhibit them all



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Key points on antimicrobial resistance

• Resistance in Enterobacterales is predominantly due to acquiredmechanisms• Resistance-harboring plasmids may transmit multiple resistance determinants• Specific mechanisms rarely lead to cross-class resistance

• Resistance in P. aeruginosa, A. baumannii, and other less common non-lactose fermenting Gram negatives is predominantly due to intrinsicresistance mechanisms• Resistance-harboring plasmids are relatively uncommon• Resistance mechanisms often lead to cross-class resistance

• Knowledge of resistance mechanisms informs better drug selection• Local epidemiology is important – the more detailed the better!

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The antibiotic pipeline has delivered

2014 Ceftolozane-tazobactam (Zerbaxa)2015 Ceftazidime-avibactam (Avycaz)2017 Delafloxacin (Baxdela) Meropenem-vaborbactam(Vabomere)2018 Plazomicin(Zemdri) Eravacycline(Xerava) Omadacycline(Nuzyra)2019 Imipenem-relebactam (Recarbrio) Lefamulin(Xenleta)2020 Cefiderocol (Fetroja)

Pew Charitable Trusts. Sept 2020.



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Our focus for today

2014 Ceftolozane-tazobactam (Zerbaxa)2015 Ceftazidime-avibactam (Avycaz)2017 Delafloxacin (Baxdela) Meropenem-vaborbactam(Vabomere)2018 Plazomicin(Zemdri) Eravacycline(Xerava) Omadacycline(Nuzyra)2019 Imipenem-relebactam (Recarbrio) Lefamulin(Xenleta)2020 Cefiderocol (Fetroja)

Pew Charitable Trusts. Sept 2020.

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Antibiotic-resistant Enterobacterales



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Audience Response

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A. 70%

According to U.S. CDC data, what proportion of carbapenem-resistant Enterobacterales produce carbapenemases?

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CRE = an organism resistant to ertapenem, meropenem, and/or imipenem OR possessing a carbapenemase

1. Carbapenemase producers• Acquisition of carbapenemase genes (e.g., KPC, OXA-48)• Associated with epidemic spread (e.g., ST-258)

2. Non-carbapenemase producers• Porin loss plus ESBL or AmpC (over)production• Generally selected for by prior carbapenem use

•Note! KPC ≠ CRE!

Carbapenem-resistant Enterobacterales (CRE)

Wilson BM, et al. Emerg Infect Dis 2017;23; Guh Y, et al. JAMA 2015;314(14):1479-87; Marimuthu K, et al. AAC ePub ahead of print 2019



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CRE does not equal KPC (or even carbapenemase)

Wilson BM, et al. Emerg Infect Dis 2017;23; Guh Y, et al. JAMA 2015;314(14):1479-87

• Non-carbapenemase producers account for ~50% of CRE nationwide• KPC-producing K. pneumoniae seem to be declining in frequency, but still most

common carbapenemase identified

E. cl

oaca

eK.

pne

umon

iae

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Mechanism of resistance K. pneumoniae (n = 545)

E. coli (n = 71)

Enterobacter spp.(n = 119)

Non-carbapenemase 52 (9.5%) 33 (46.5%) 73 (61.3%)Carbapenemase 493 (90.5%) 38 (53.5%) 46 (38.7%)

KPC 467 (95%) 29 (76%) 39 (85%)OXA-48-like 16 (3%) 5 (13%) --

NDM 16 (3%) 4 (11%) 2 (4%)Othera -- -- 5 (11%)

CRACKLE-2 – a national molecular survey of CRE

van Duin D, et al. Lancet Infect Dis. 2020 Jun;20(6):731-741.

aOther consists of NMC-A, VIM, and IMI

• KPC remains most commonly identified carbapenemase at a national level• Other mechanisms with relevance to treatment choice are commonly identified



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Local epidemiology matters – we must look to find

Senchyna F, et al. Diagn Microbiol Infect Dis. 2019;93(3):250-257; Aitken SL, et al. Clin Infect Dis 2016;63(7):954-8; Cerquiera GC, et al. Proc Natl Acad Sci USA 2017;114(5):1135-40

Stanford Hospital (Palo Alto, CA)

• > 50% non-carbapenemaseproducers

• KPC in only 5/24 isolates, more metallo-β-lactamases

MD Anderson Cancer Center

(Houston, TX)

• Non-carbapenemaseproducers and NDM-production predominate

Harvard-affiliated hospitals

(Boston, MA)

• 65% KPC-producers• Remainder generally

due to porin loss

321. Munoz-Price LS, et al. Lancet Infect Dis 2013;13:785–796; 2. Johnson & Woodford. J Med Microbiol 2013;62:499–513; 3. Glasner C, et al. Euro Surveill2013;18:pii=20525; 4. Poirel L, et al. J Antimicrob Chemother 2012;67:1597–1606; 5. Espedido BA, et al. Antimicrob Agents Chemother 2008;52:2984–7; 6. Grundmann H, et al. Lancet Infect Dis 2017;17:153–163.

KPCOXA-48IMPVIMNDMMixed

Global epidemiology of carbapenemases

Slide courtesy of Dr. Ryan K. Shields



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Parent drug (dose)

Parent drug characteristics

BLI (dose) BLI profile Dose ENT BP PSA BP

Ceftazidime (2g)

Third-gen cephalosporinHydrolyzed by AmpC, ESBL

Avibactam (0.5g)

DBO, non-β-lactam BLI

Class AClass CClass D (OXA-48)

2.5g q8h over 2h ≤ 8/4 ≤ 8/4

Ceftazidime-avibactam (Avycaz, CZA)

Carbapenemase productionESBL, AmpC expression with porin

loss

Metallo-β-lactamase (MBL) production

AVIBACTAM

β-lactamase inhibition =restored susceptibility

Avibactam does not inhibit MBLs, so these are resistant

BLI = β-lactamase inhibitor; DBO = diazabicyclooctane; ENT = Enterobacterales; PSA = P. aeruginosa; BP = breakpoint

Zhanel GC, et al. Drugs. 2013.

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Parent drug (dose) Parent drug characteristics

BLI (dose) BLI profile Dose ENT BP PSA BP

Meropenem (2g)

Stable against AmpC, ESBL hydrolysis

Vaborbactam (2g)

Boronic acid, non-β-lactam BLI

Class A- KPC!! Class C

4g q8h over 3h ≤ 4/4 NA

Meropenem-vaborbactam (Vabomere, MVB)

Carbapenemase-producing Enterobacterales

Porin mutationsEnhanced effluxMBL production

VABORBACTAM

Inhibits KPC and Class A/C enzymes

Meropenem-vaborbactamresistance seen with porin

mutants and MBL production

Note: you are giving 2g q8h (over 3 hours) of meropenemZhanel GC, et al. Drugs. 2018.



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Antibiotic MIC range MIC50 (mg/L) MIC90 (mg/L) % Susceptible % ResistantMeropenem 2 - >32 32 >32 0 96Meropenem-vaborbactam

< 0.03 - >32 0.06 1 99 1

Ceftazidime 1 - >64 >64 >64 3 95Ceftazidime-avibactam

64 1 4 98 2

Tigecycline 16 0.5 16 N/A N/A

Comparative activity of new β-lactams against KPC-producing Enterobacterales

Hackel MA. et al. Antimicrob Agents Chemother. 2017;62:e01904-17

• Both meropenem-vaborbactam and ceftazidime-avibactam restore activity against the majority of KPC-producing Enterobacterales

• Pre-existing resistance generally due to co-production of other carbapenemases (e.g., NDM)

36 Senchyna F, et al. Diagn Microbiol Infect Dis. 2019;93(3):250-257

%S Non-CP-CRE KPC OXA-48-like NDM SMECZA 100 100 100 0 100MVB 92.1 100 66.7 0 100

Comparative activity of MVB and CZA against CRE

• CZA and MVB are not interchangeable – local epidemiology must be considered• Meropenem (< 1) and MVB (< 4) have different breakpoints due to increased

meropenem dose (6g/day) and prolonged infusion (3h) with MVB

• Generally no significant advantage to MVB over dose-optimized meropenem alone for non-carbapenemase CRE



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Audience Response

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A. Meropenem-vaborbactamB. Ceftazidime-avibactamC. Ceftolozane-tazobactamD. None of the above

Colistin- or polymyxin-based combination therapy is superior to which of the antibiotics active against MDR Gram negatives?

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The new β-lactam/β-lactamase inhibitors save lives

Shields RK, et al. Antimicrob Agents Chemother 2017;61(8):e00883; van Duin D, et al. Clin Infect Dis 2018;66(2):163-171;Wunderink RG, et al. Infect Dis Ther. 2018;7(4):439-455Slide adapted from Ryan Shields

8% 8%

16%

45%

33% 33%

0%5%

10%15%20%25%30%35%40%45%50%

Shields et al van Duin et al Wunderink et al

CZA or MVB BAT

CZA

CZA: ceftazidime-avibactam; MVB: meropenem-vaborbactam; BAT: best-available therapy

CZA MVB

Mor

talit

y



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Meropenem-vaborbactam and ceftazidime-avibactam seem similarly effective for CRE

62%

19%29%

14%3%

69%

12%

27%

12%

0%0%

10%20%30%40%50%60%70%80%

Clinical success 30-day mortality 90-day mortality CRE recurrence Emergence ofresistanceCZA (n = 105) MVB (n = 2)

• Only single-center, retrospective data available

• Relative utility of CZA and MVB likely dependent on local mix of resistance mechanisms

Ackley R, et al. Antimicrob Agents Cheemother . 2020; 64(5):e02313-19

40Wunderink RG, et al. Infect Dis Ther. 2018;7(4):439-455

Wunderink et al. BAT Regimens All (N=15*), n (%)Monotherapy 4 (26.7)

Aminoglycoside 1 (6.7)Carbapenem 1 (6.7)Ceftazidime-Avibactam 1 (6.7)Polymyxin B/Colistin 1 (6.7)

Dual Therapy 7 (46.7)Carbapenem + Aminoglycoside 1 (6.7)Carbapenem + Polymyxin B/Colistin 1 (6.7)Carbapenem + Tigecycline 2 (13.3)Polymyxin B/Colistin + Aminoglycoside 3 (20.0)

Triple Therapy 1 (6.7)Carbapenem + Polymyxin/Colistin+Tigecycline 1 (6.7)

Four or More Drugs 2 (13.3)Carbapenem+Colistin+Tigecycline+Aminoglycoside 2 (13.3)

“Best” available therapy was an awful soup

Slide adapted from Dr. Ryan K. Shields



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• Safety and efficacy of ceftazidime-avibactam compared to polymyxin-based regimens (PBR) for CRE

• 43 patients with cancer, PBR = 19, CZA = 24

• All cause 30-day mortality25% (CZA) vs 42% (PBR)

• CZA associated with 58% improved patient-center outcome compared to PBR

Ceftazidime-avibactam maintains improved effectiveness in patients with cancer

Borjan J, et al. Poster #2246. IDWeek 2019.

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77%86%

77%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Clinical cure 14d survival 30d survival

Ceftazidime-avibactam is also effective against OXA-48 producers

Sousa A, et al. J Antimicrob Chemother 2018 Slide adapted from Dr. Ryan K. Shields



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Is all this life-saving “worth it”?Ceftazidime-avibactam

• Cost for 14-day course = ~$15,000 by AWP • Estimated absolute risk reduction in mortality = 23%

Cost-effectiveness versus colistin-based therapy modeled for CRE pneumonia and bacteremia in US

• Patients assigned probability of death, nephrotoxicity, discharge to home, long-term all cause mortality

• Included costs related to antibiotic therapy, nephrotoxicity, and healthcare utilization following hospital discharge

• Calculated quality-adjusted life-years (QALYs); evaluated willingness-to-pay thresholds per QALYColistin-based therapy

Cost: $108,800Average life expectancy: 1.82 years

1.26 QALYs per CRE case

Ceftazidime-avibactam-based therapyCost: $156,300

Average life expectancy: 2.53 years1.76 QALYs per CRE case

Incremental cost-effectiveness ratio

$95,000/QALY

Simon MS, et al. Antimicrob Agents Chemother. Sept 2019

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• MBLs do not hydrolyze aztreonam (but other β-lactamases do)

• Novel BLIs do not inhibit MBLs• Ceftazidime-avibactam (CZA) + aztreonam (ATM)

synergistic against VIM- and NDM-producing Enterobacterales

• In a collection of 15 MBL isolatesOnly 1 susceptible to ATMCZA + ATM synergistic for all isolates

• Combo generally inactive against MBL-producing Pseudomonas

Metallo-β-lactamases (MBLs)

Wenzler E, et al. Diagn Microbiol Infect Dis. 2017.; Jayol A, et al. J Antimicrob Chemother. 2018.; Davido B, et al. Antimicrob Agents Chemother. 2017.



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Ceftazidime-avibactam plus Aztreonam for MBLs

Falcone M, et al. Clin Infect Dis. 2020 May 19;ciaa586.

Factor HR (95% CI) P Value

Cardiovascular disease 6.62 (2.77–15.78)



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zwitterion

Structurally stable to enzyme

hydrolysis

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Parent drug (dose)


Stability profile Dose ENT BP

PSA BP

ACB BP

Cefiderocol(2g)

Siderophore / β-lactam

Class AClass BClass CClass D

2g q8h over 3h

q6h with ARC

≤ 4 ≤ 4 ≤ 4

Cefiderocol (Fetroja, FDC)

ACB = Acinetobacter baumannii; ARC = Augmented renal clearance; BLI = β-lactamase inhibitor


CREDIBLE-CR: MBLsFDC (N=16) vs BAT (N=7)

Clinical cure at end of treatment: 75% vs 14%Microbiological cure at end of treatment: 63% vs 14%



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Plazomicin• Novel semisynthetic aminoglycoside• Active against Enterobacterales harboring common aminoglycoside-modifying

enzymes• Often present in ESBL- and/or carbapenemase-producing organisms

• Not active in presence of ribosomal methyltransferase genes• Often present in metallo-β-lactamase producing organisms (but not always!)

Eljaaly K, et al. Drugs. 2019.

Antibiotic % susceptible MIC 50 / 90 (mcg/mL)Plazomicin 99 0.5 / 1Amikacin 57 16 / 32Tobramycin 13 > 8 / > 8Gentamicin 57 2 / > 8

Activity against CRE from U.S. surveillance (n = 97)

50 McKinnell, et al. N Engl J Med. 2019;380:8.

Does plazomcin have a clinical role?• Significantly reduced mortality for plazomicin-based

combination therapy relative to colistin-based combination therapy for serious CRE infections (12% vs 40%)• Requires therapeutic drug monitoring and adjustment as

do all aminoglycosides• No clear benefit of plazomicin when other

aminoglycosides are active• GREAT option for CRE UTI (including pyelo!!) when other

aminoglycosides are inactive



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So how do we treat CRE?• Depends on your local epidemiology and mechanisms of resistance• KPC: Ceftazidime-avibactam, meropenem-vaborbactam, and plazomicin are

superior to old drugs̶ Meropenem-vaborbactam may be active against ceftazidime-avibactam resistant

isolates̶ Imipenem-relebactam lacks clinical data, but is in vitro active̶ Role of combination therapy with new agents remains unclear; plazomicin was

only studied in combination• OXA-48: Ceftazidime-avibactam, cefiderocol, plazomicin• NDM: Ceftazidime-avibactam + aztreonam, cefiderocol, plazomicin• Non-CP-CRE: Ceftazidime-avibactam, dose-optimized meropenem• Do not use polymyxins!!

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This is what we like to see!

Strich JR, et al. Clin Infect Dis. 2020 Feb 28;ciaa061.



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Erin K. McCreary, PharmD, BCPS, BCIDP

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Pseudomonas aeruginosa



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Pseudomonas aeruginosa

https://www.cdc.gov/drugresistance/biggest-threats.html

Audience Response

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A. AmpC productionB. KPC acquisitionC. Efflux pump expressionD. Porin loss

What is the most common mechanism of resistance to imipenem in Pseudomonas aeruginosa?



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Multidrug-resistant Pseudomonas aeruginosa

Antibiotic AmpC Porin Efflux

Piperacillin-tazobactam X X

Cefepime X X

Ceftazidime X X

Meropenem X X

Imipenem X X

Main mechanisms of resistance for “old” antibiotics and Pseudomonas aeruginosa

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Resistance in Pseudomonas is…complicated

Resistance N (%) ATM C-T FEP CAZ IPM MEM TZPATM 410 (34) -- 88 44 49 46 45 35C-T 55 (5) 11 -- 9 7 25 22 15CAZ 267 (22) 21 81 20 -- 39 41 14FEP 287 (24) 20 83 -- 25 38 35 19IPM 392 (32) 44 90 54 59 -- 27 49MEM 316 (26) 28 86 41 50 10 -- 36TZP 322 (27) 17 85 28 29 39 38 --MDR 153 (13) 12 74 6 10 5 6 81 or more 648 (54) 37 92 56 59 40 51 50All 118 (10) -- 75 -- -- -- -- --

ATM = aztreonam; C/T = ceftolozane-tazobactam; CAZ = ceftazidime; FEP = cefepime; IPM = imipenem; MEM = meropenem; NS = nonsusceptible; TZP = piperacillin/tazobactam

Almarzoky Abuhussain SS, et al. J Thorac Dis. 2019;11(5):1896-1902.



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Ceftolozane-tazobactam (Zerbaxa, C/T)Parent drug

(dose)Parent drug

characteristicsBLI (dose) BLI stability

against hydrolysisDose ENT BP PSA BP

Ceftolozane(1-2g)

Novel cephalosporinSimilar to ceftazidime but ↑ potency for PSA due to modified side chain; higher affinity for all essential PBPs↓ efflux in PSA↑ stability against ESBLs compared to TZP, CAZ (TEM > SHV)↑ stability against AmpC in PSA (but not as much for ENT)

Tazobactam(0.5-1g)

Class A (ESBL and “lower”)Class C (AmpC, sort of)

1.5g q8h over 1h cIAI, cUTI

3g q8h over 1h HABP, VABP

≤ 2/4

NA

≤ 4/4

NA

BP = CLSI breakpoint; cIAI = complicated intraabdominal infection; cUTI = complicated urinary tract infection; ENT = Enterobacteriaceae; HABP, VABP = hospital-acquired and ventilator-associated bacterial pneumonia; PSA = Pseudomonas aeruginosa

Ceftazidime Ceftolozane


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• 20 hospitals, 205 patients•Median time to C/T: 9 days

Gallagher JC, et al. Open Forum Infect Dis. 2018.

• Clinical success: 73.8%• Micro cure: 70.9%

Factors - Mortality aOR (95% CI)C/T > 4 days after culture 5.55 (2.14-14.40)Factors – Clinical successC/T ≤ 4 days after culture 2.92 (1.40-6.10)Factors – Micro cureC/T ≤ 4 days after culture 2.59 (1.24-5.38)

Ceftolozane-tazobactam for serious multidrug-resistantPseudomonas aeruginosa infections



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• 6 centers, 200 patients• 69% HAP/VAP, 69% ICU• Mean time to C/T = 63.5h (~3 days)• Receipt of combination therapy: 15% C/T vs. 72% Polymyxin/AG

Pogue JM, et al. Clin Infect Dis. 2019.

Outcome C/T Polymyxin/AG

aOR(95% CI)

Clinical cure 81% 61% 2.72 (1.43-5.17)In-hospital mortality 20% 25% 0.62 (0.30-1.28)

AKINew RRT requirement

6%0%

34%7%

0.08 (0.03-0.22)

Audience Response

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A. VIM acquisitionB. Efflux pump expressionC. AmpC productionD. Porin loss

Avibactam restores ceftazidime activity in P. aeruginosa with which of the following ceftazidime-resistance mechanisms?



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Parent drug (dose)


BLI (dose) BLI stabilityagainst hydrolysis

Dose ENT BP PSA BP

Ceftazidime (2g)

Third-gen cephalosporinHydrolyzed by AmpC, ESBL

Avibactam (0.5g)


Class AClass CClass D (OXA-48)

2.5g q8h over 2h ≤ 8/4 ≤ 8/4

Ceftazidime-avibactam (Avycaz, CZA)

Ceftazidime-resistant P. aeruginosa =

AmpC mutationsAmpC overexpression

Enhanced efflux

AVIBACTAM

AmpC inhibition =restored susceptibility

Ceftazidime-avibactam resistance seen with mutated AmpC, efflux +

porin mutations

BLI = β-lactamase inhibitor; DBO = diazabicyclooctane


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C/T vs. CZA for Pseudomonas aeruginosa

Sader HS, et al. Diag Micro Infect Dis. 2019.

Clinical isolates from hospitalized patients with pneumonia collected from 70 US medical centers, 2017-2018

Organism (N) C/T (MIC50/MIC90) CZA (MIC50/MIC90)All Pseudomonas aeruginosa (2,215) 96% (1/2) 95.9% (2/8)MDR PSA (526) 83.7% (2/16) 83.5% (4/16)B-lactam-R PSA (274) 73.7% (4/>16) 73% (8/32)



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Local epidemiology matters when choosing between CZA and C/T!

• Know your local epidemiology!!!• Various mechanisms of resistance are at play!• Limited clinical data suggest CZA is just fine for susceptible P. aeruginosa

Grupper M, et al. Antimicrob Agents Chemother. 2017;61(10)Vena A, et al. Antibiotics (Basel). 2020;9(2)

% susceptibleCT (MIC50/MIC90)

% susceptibleCZA (MIC50/MIC90)

Meropenem-nonsusceptiblePseudomonas aeruginosa (290)

91 (1/4) 81 (4/16)

Pan-β-lactam resistant isolates (103) 79% 54%

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Parent drug (dose) Parent drug characteristics

BLI (dose) BLI stabilityagainst hydrolysis

Dose ENT BP PSA BP

Imipenem (0.5g)Cilastatin (0.5g)

Stable against ESBL hydrolysis

Relebactam (0.25g)


Class AClass C

1.25g q6h over 30m ≤ 1/4 ≤ 2/4

Imipenem-relebactam (Recarbrio, I-R)

Imipenem-resistant P. aeruginosa =

AmpC mutationsAmpC overexpression

Porin mutations

RELEBACTAM

AmpC inhibition =restored susceptibility

Imipenem-relebactam resistance seen with porin/efflux mutations,

AmpC mutations




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•HAP/VAP, cIAI, cUTI•Randomized 2:1 to 5-21 days of imipenem-relebactam

(N=21) or colistin + imipenem (N=10)• 77% P. aeruginosa• 16% Klebsiella spp.

Motsch J, et al. Clin Infect Dis. 2019. pii: ciz530

Serious ADEs10% (I-R) v. 31% (COL)

28-day mortality10% (I-R) v. 30% (COL)

Imipenem-relebactam versus colistin-based therapy for imipenem-resistant organisms

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Parent drug (dose)


Stability profile Dose ENT BP

PSA BP

ACB BP

Cefiderocol(2g)

Siderophore / β-lactam

Class AClass BClass CClass D

2g q8h over 3h

q6h with ARC

≤ 4 ≤ 4 ≤ 4

Cefiderocol (Fetroja, FDC)

ACB = Acinetobacter baumannii; ARC = Augmented renal clearance; BLI = β-lactamase inhibitor


CREDIBLE-CR: PseudomonasFDC (N=12) vs BAT (N=10)

Clinical cure at test of cure: 58% vs 50%Microbiological eradication at test of cure: 8% vs 20%



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So how do we treat β-Lactam resistant Pseudomonas aeruginosa?

• Depends on your local epidemiology and mechanisms of resistance• Ceftolozane-tazobactam is more effective and less toxic than

polymyxins or aminoglycosides• Outcomes are better if started earlier• Use the 3g dose

• Dose is 2.25g x 1, then 450mg q8h in HD (triple, not double)• Test all isolates to ceftolozane-tazobactam, ceftazidime-avibactam,

imipenem-relebactam• Remember: “carbapenem-resistant” may be other β-lactam

susceptible• Cefiderocol reserved for cases resistant to or failing BLBLIs

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Acinetobacter baumannii



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Carbapenem-resistant Acinetobacter baumannii

https://www.cdc.gov/drugresistance/biggest-threats.html

Audience Response

72

A. Ceftazidime-avibactamB. EravacyclineC. Ceftolozane-tazobactamD. Meropenem-vaborbactamE. Amoxicillin-clavulanate

Which of the following antimicrobials is expected to have in vitro activity against carbapenem-resistant Acinetobacter?



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73

Eravacycline

• Fluorocycline tetracycline• In vitro active against:

• Some KPC-, MBL- and OXA- producing Enterobacteriaceae • Acinetobacter baumannii and other non-lactose fermenters (NOT

Pseudomonas)• Similar spectrum of activity to tigecycline

• FDA breakpoint for Enterobacterales ≤0.5µg/mL• Not established for A. baumannii; minocycline is 4µg/mL

• Emerging real world data for CRE, Acinetobacter

Livermore DM, et al. Antimicrob Agents Chemother. 2016; 60:3840–3844

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Should we use colistin-carbapenem combination therapy against CRAB?

• No prospective trial has shown a benefit for combination therapy against Acinetobacter

• Optimal therapy remains unknown

• Synergistic combinations may depend on strain, sequence type

Paul M, et al. Lancet Infect Dis 2018;18:391-400; Durante-Maangoni E, et al. Clin Infect Dis 2013;57(3):349-58



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Cefiderocol: carbapenem-resistant Gram-negatives (CREDIBLE-CR)

18.8%24.8%

33.7%

12.2%18.4% 18.4%

0%5%

10%15%20%25%30%35%40%

14d 28d EOS

Mor

talit

y ra

teAll-cause Mortality

Cefiderocol (n = 101) BAT (n = 51)

• A. baumannii accounted for 46% of isolates

• Mortality imbalance appeared isolates to non-lactose fermenters (A. baumannii, P. aeruginosa, S. maltophilia)

Bassetti M, et al. Lancet Infect Dis. 2020(epub ahead of print)

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Cefiderocol: Hospital acquired / ventilator pneumonia (APEKS-NP)

65.0%

41.0%

67.0%

42.0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Clinical cure Microbiologic eradication

% re

achi

ng e

ndpo

nt

Cefiderocol (n = 145) Meropenem (n = 147)

• Cefiderocol and meropenem performed equivalently for meropenem-resistant organisms!

• Majority of meropenem-resistant organisms were A. baumannii

Wunderink RG, et al. Lancet Infect Dis. 2020(epub ahead of print)



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• Jury is still out on treatment of choice• New BLBLIs do not inhibit most common OXA enzymes• Cefiderocol has in vitro activity but questions remain regarding

efficacy• Don’t sleep on tetracyclines• Plazomicin has no additional benefit over other aminoglycosides• Combination therapy remains “go to” in practice (e.g., meropenem +

polymyxin + ampicillin/sulbactam or tetracycline)

So how do we treat carbapenem-resistant Acinetobacter baumannii?

78

And this is usually left out of this talk but…



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79

MDR infection rates are significantly higher in small community hospitals compared to tertiary care hospitals (Surveillance Network Database-USA)

CDC Threats Report 2019; Gandra S, et al. Clin Infect Dis. 2017;65:860-863.

80 CDC Threats Report 2019

Threat 2019 Report 2013 Report Comparison

ESBL 197,400 cases9,100 deaths

131,900 cases6,300 deaths

↑

CRE 13,100 cases1,100 deaths


≈

CRAB 8,500 cases700 deaths


↓

MDR PSA 32,600 cases2,700 deaths


↓



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MERINO Trial – We’re still debating

• TZP mortality by MIC: < 2 mcg/mL (14.8%) / > 2 (9.7%)• Official conclusion: piperacillin-tazobactam is not non-inferior to meropenem

• Unofficial conclusion: use carbapenems for ESBL-producing bloodstream infections!Harris PNA, et al. JAMA. 2018;320(10):984-994; Henderson A, et al. Clin Infect Dis. 2020.

82

MERINO Trial – Can we blame OXA-1?

Harris PNA, et al. JAMA. 2018;320(10):984-994; Henderson A, et al. Clin Infect Dis. 2020.



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Let’s talk tazobactam

MIC50/90 TZP C/TE. coli 4/64 0.5/2

K. pneumoniae 16/>64 1/16Shortridge D, et al. Microb Drug Resist. 2018;24:563-577Harris PNA, et al. JAMA. 2018;320(10):984-994Kollef M, et al. Lancet Infect Dis. 2019 Dec;19(12):1299-1311.

Trial / Population

Infection Treatment Groups Primary Endpoint Results for patients with ESBLs

C/TASPECT-NPN= 511 (mITT)

Ventilated nosocomial pneumonia

C/T 3g q8h vs. MEM 1g q8h Duration = 8-14 days Both drugs over 1h infusion

31.8% of C/T group = ESBL29.6% of MEM group = ESBL31.6% of ESBL-producing ENT were C/T resistant

28-day all-cause mortality in ITT population

Clinical cure at test of cure

C/T 24% vs. MEM 25.3% C/T noninferior C/T favored in vHAP

subgroup

C/T 62.3% vs MEM 62.5%

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Let’s talk tazobactamMIC50/90 TZP C/T

E. coli 4/64 0.5/2K. pneumoniae 16/>64 1/16

Harris PNA, et al. JAMA. 2018;320(10):984-994Kollef M, et al. Poster presentation: ECCMID 2019. Amsterdam, Netherlands.

Trial / Population

Infection Treatment Groups Primary Endpoint Results

TZPMERINON = 391 randomized

CRO-NS E. coli or K. pneumobacteremia

TZP 4.5g q6h vs. MEM 1g q8h Duration = 4-14 days (definitive treatment) Both drugs over 30m infusion

100% of isolates CRO-nonsusceptible

All-cause mortality at 30 days after randomization

TZP 12.3% vs. MEM 3.7% TZP not noninferior

Mortality for TZP: MIC ≤ 2 = 14.8% MIC ≥ 4 =9.7%

C/TASPECT-NPN= 511 (mITT)

Ventilated nosocomial pneumonia

C/T 3g q8h vs. MEM 1g q8h Duration = 8-14 days Both drugs over 1h infusion

31.8% of C/T group = ESBL29.6% of MEM group = ESBL31.6% of ESBL-producing ENT were C/T resistant

28-day all-cause mortality in ITT population

C/T 24% vs. MEM 25.3% C/T noninferior C/T favored in vHAP

subgroup

Mortality in mITT ESBL: 22.2% C/T, 27.8% MEM

Why does C/T seem to “work” for ESBLs and TZP “doesn’t”? • Ceftolozane is a more stable parent drug• We are giving 1g more/day tazobactam (over longer infusions) with 3g C/T



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So how do we treat ESBLs?Carbapenems are the gold-standard for ESBL infections

If susceptible, can consider:• Tigecycline, eravacycline intra-abdominal infection• Fosfomycin, nitrofurantoin cystitis• Fluoroquinolones, TMP/SMX most infection types

All of the new agents have in vitro activity against ESBLs• C/T and CZA are options in select scenarios

Polymicrobial infections, drug interactions (valproic acid/carbapenems)• No advantage for meropenem-vaborbactam or imipenem-relebactam over carbapenems alone• No advantage for plazomicin over other aminoglycosides in most scenarios

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Enzymatic drug modification (β-lactams, aminoglycosides, quinolones) Avibactam, vaborbactam, relebactam (PSA, CRE, ACB); plazomicin (CRE)

Efflux (β-lactams, aminoglycosides, tetracyclines, quinolones) Ceftolozane, cefiderocol (PSA); eravacycline (ACB)

Porin loss (β-lactams) Ceftolozane; cefiderocol (PSA)

Target modification (quinolones, aminoglycosides, tetracyclines, polymyxins) Eravacycline (CRE)

Target bypass (trimethoprim-sulfamethoxazole)

Created by Samuel Aitken using BioRender.com



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New IDSA guidance for AMR Gram-negatives!

•Provide organism- and site-specific guidance for ESBL, CRE, and P. aeruginosa• In general, recommend against colistin in nearly all

circumstances•Recommend against routine combination therapy•Guidance updated twice annually in response to new

evidence

Tamma PD, et al. Clin Infect Dis 2020(ePub ahead of print)https://www.idsociety.org/practice-guideline/amr-guidance/

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Antimicrobial Stewardship to Optimize Therapy



45

89

Stewardship program management of MDR GNR infectionsFormulary decisions, institution-specific guidelines, budget considerations, clinical education and training

Identification of patient at risk, initiation early appropriate therapy, local epidemiology

Diagnostic stewardship, tracking resistance patterns, susceptibility testing

Dose optimization, roles for adjunctive/combo therapy, monitor for adverse events and drug interactions

Track recurrence and/or emergence of resistance, report real-world experiences, contribute to national tracking efforts

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Traditional risk factors are not helpful

• Very sensitive, but incredibly non-specific

• See HCAP for why this is not a good approach

Use rapid diagnostics

• Pick the right one for your hospital –know your epidemiology!

• Cost-benefit of RDT + stewardship has been thoroughly described

Use new antibiotics when they should be

used (and test!)

• More patients with CRE die when receiving polymyxin-based therapies compared to novel agents

• Susceptibility testing is important

Principles of stewardship for MDR Gram negatives



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Streamlined susceptibility testing: ExampleDrug Requested Organisms Approved

Ceftazidime/avibactam Enterobacterales R to Erta AND Mero P. aeruginosa I or R to ≥3 β-lactams*

Ceftolozane/tazobactam Enterobacterales with ESBL and S to Erta and Mero P. aeruginosa I or R to ≥3 β-lactams*

Meropenem/vaborbactam Enterobacteriaceae R to Erta AND Mero Cefiderocol Acinetobacter spp. R to ampicillin/sulbactam AND meropenem

P. aeruginosa R to CZA, C/T, and I-RS. maltophilia, Achromobacter spp., Burkholderia spp.

Colistin Enterobacterales R to Erta, Mero AND ceftazidime/avibactam OR meropenem/vaborbactamP. aeruginosa R to ceftolozane/tazobactam ANDceftazidime/avibactamAcinetobacter spp. R to ampicillin/sulbactam AND meropenem

Minocycline Acinetobacter spp. R to ampicillin/sulbactam AND meropenemS. maltophilia

*β-lactam agents include aztreonam, cefepime, ceftazidime, meropenem, and piperacillin/tazobactam

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Conclusions

Greater cure with less toxicity should be a no-brainer; use these drugs in patients who warrant them

Local epidemiology is critical to knowing which agents to use and where Test all isolates for susceptibility if using for treatment, especially if previous exposure

The new antibiotics are nuanced – “broad spectrum” has lost meaning

Pharmacists must be the leaders in understanding how, why, when, and where to use these new agents



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CE Credit Instructions


December 7, 2020

1. To receive CE credit for this activity, you must complete the post-test and activity

evaluation online no later than Friday, January 8, 2021.

2. Visit www.ProCE.com/evaluation.

3. Click on the Evaluation button which is listed with the Tools for Managing Gram-

Negative Resistance - December 7, 2020 CE activity.

4. Login to the ProCE Center. Note: You will need to sign up for a new account if you

have not previously used the ProCE Center.

5. Enroll in the CE activity, then enter the Attendance Code: .

Note: the attendance code will be announced at the conclusion of the CE activity.

6. Take the post-test, complete the evaluation, and claim CE credit.

7. If you need assistance or have questions, please contact ProCE at 630.540.2848 or

via email at [email protected].

Note: It is ProCE policy that CE requirements (i.e. post-test, if applicable for the specific CE activity, and evaluation) be completed within 30 days of the live activity date to ensure an on-time submission to your CPE Monitor account.

PDF version of the handout is located at: www.ProCE.com/res/pdf/GNR2020Dec7.pdf

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