1

New Antibiotics For GNB in the ICU

Setting: 2016 and Beyond

Marin H. Kollef, MD

Professor of Medicine

Virginia E. and Sam J. Golman Chair in

Respiratory Intensive Care Medicine

Washington University School of Medicine

St. Louis, Missouri

2

Conflicts of Interest Merck

Actavis

Arsanis

Cubist

Cardeas

Medimmune

Astrazeneca

Accelerate

Academy for Infection Management

Barnes-Jewish Hospital Foundation

3

Selected Resistance Mechanisms in

Gram-Negative Pathogens

1. Livermore DM. Clin Infect Dis. 2002;34:634-640. 2. Livermore DM, Woodford N. Trends in Microbiology. 2006;14:413-420. 3. Spratt BG. Science.

1994;264:388-393. 4. Chambers, HF. Penicillins. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia,

PA: Elsevier; 2005:281-293.

Decreased Permeability

Increased Efflux

b-Lactamases

Changes in Target Proteins Cytoplasm

Outer

Membrane

Inner

Membrane

Membrane

Alterations

4

Class A β-Lactamases Including ESBLs

Have Increased Significantly

Compilation of unique β-lactamase sequences from natural isolates

0

250

500

750

1965 1973 1981 1989 1997 2005 2013

Nu

mb

er

of

un

iqu

e β

-la

cta

mases

Class A (ESBLs incl.

CTX/TEM/SHV/KPC)

Class D (OXA)

Class C (AmpC)

Class B (IMP/VIM/NDM-1)

CTX-M-14 & CTX-M-15 are the primary drivers of

the increase in prevalence of ESBLs1

Figure : Based on Bush and Fisher. Annu Rev Microbiol. 2011;65:455.

Bush. Ann N Y Acad Sci. 2013;1277:84-90.

1. Bonnet ANTIMICRO AGENTS CHEMOTHERAPY, Jan. 2004, p. 1–14.

CTX-M-1, in reference to its hydrolytic activity against cefotaxime.

5

New antibacterial agents approved

by the US Food and Drug Administration

per 5-year period, through 2012.

Lack of New Antimicrobials

Molton JS, et al. Clin Infect Dis. 2013;56:1310-1318.

Boucher HW, e t al. Clin Infect Dis. 2013;56:1685-1694.

Approvals

New antibiotic approvals dropped dramatically, with only 3

new options for GNB in the past 15 years—leaving limited

options for these dangerous pathogens.

16

14

7

5

2

10

6

Resistance Influences Outcomes!

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In the Critically ill Patient – Hit Hard and Fast

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Pathogen Major resistance

mechanisms

Antibiotics affected Therapy

options*

E. coli ESBL All penicillins, narrow spectrum

cephalosporins, oxymino-beta-

lactams (cefotaxime, ceftazidime,

cefepime), aztreonam

Carbapenems

K. pneumoniae Carbapenemases (i.e.

KPC, NDM)

All penicillins, cephalosporins,

carbapenems

Polymyxins,

tigecycline

P. aeruginosa Active efflux, porin loss,

carbapenemases

Quinolones, aminoglycosides,

anti-pseudomonal penicillins,

cephalosporins, carbapenems

Polymyxins

A. baumanii Active efflux, porin loss,

amp-C,

cephalosporinases,

carbapenemases

Quinolones, penicillins,

cephalosporins, carbapenems

Polymyxins,

tigecycline

Current Treatment Options for

MDR GNB Infections

Pop-Vicas A, Opal SM. Virulence 2014;5:1–7.

*Based on limited clinical data

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The 10 × '20 Initiative: Pursuing a Global

Commitment to Develop 10 New Antibacterial

Drugs by 2020 - Stakeholders

IDSA, Clin Infect Dis. 2010;50:1081-1083.

• Governments

• Pharmaceutical and diagnostics industries

• Healthcare providers

• Policy and legal communities

• Medical/research universities

• Public health philanthropic organizations

• Patient advocacy groups

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New Drugs in the Pipeline for

Antibiotic-Resistant GNB Product Class

(Mechanism of

action)

Status Activity Targets

ESBL PA AB

Ceftolozane/tazobactam

(CXA-201; CXA-

101/tazobactam)

Cephalosporin/BLI

combination (cell

wall synthesis

inhibitor)

Antipseudomonal

Phase 3

cUTI, cIAI,

VAP

Yes Yes No

Ceftazidime-avibactam

(ceftazidime/NXL104)

Cephalosporin/BLI

combination (cell

wall synthesis

inhibitor)

Antipseudomonal

Phase 3 cIAI,

cUTI, HAP

Yes Yes No

Ceftaroline-avibactam

(CPT-avibactam;

ceftaroline/NXL104)

Anti-MRSA

cephalosporin/ BLI

combination (cell

wall synthesis

inhibitor)

Phase 2

cUTI

Yes No No

Boucher et al. Clin Infect Dis 2013;56:1685–1694.

ESBL = Enterobacteriacae; AB = Acinetobacter

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New Drugs in the Pipeline for

Antibiotic-resistant GNB Product Class

(Mechanism of action)

Status Activity Targets

ESBL P. aeruginosa AB

Imipenem/MK-7655

(Relebactam)

Carbapenem/BLI

combination (cell wall

synthesis inhibitor)

Phase

2/3 cUTI,

cIAI

Yes Yes No

Plazomicin (ACHN-

490)

Aminoglycoside (protein

synthesis inhibitor)

Phase 3

CRE

Yes No No

Eravacycline (TP-

434)

Fluorocycline (protein

synthesis inhibitor

targeting the ribosome)

Phase 3

cUTI

(?neg)

Yes No Yes

Brilacidin (PMX-

30063)

Peptide defense protein

mimetic (cell membrane

disruption)

Phase 2

ABSSSI

Yes ? No

Boucher et al. Clin Infect Dis 2013;56:1685–1694.

ESBL = Enterobacteriacae; AB = Acinetobacter

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New Drugs in the Pipeline for MDR GNB Product Class

(Mechanism of

action)

Status Activity Targets

ESBL PA AB

Carbavance

(Carbapenem+

novel boronic BLI)

Carbapenem/BLI

combination (cell wall

synthesis inhibitor)

Phase 3

cIAI,

HAP

Yes

Plus KPC

Yes Yes

BAL30072

(+/- carbapenem)

Siderophore

monosulfactam

(synergy with CAR)

Phase 1 No

(Yes with

carbapenem)

Yes Yes

S-649266

(Siderophore

cephalosporin)

“Trojan Horse”

Binds to iron taken to

peirplasmic space to

bind PBPs (cell wall

synthesis inhibitor)

Phase 2

cUTI,

cIAI

Yes

Plus KPC

Plus NDM

Yes Yes

Aztreonam +

avibactam

Monobactam/novel

BLI (cell wall

synthesis inhibitor)

Phase 2

cUTI,

cIAI

Yes

Plus KPC

Plus NDM

No No

Boucher et al. Clin Infect Dis 2013;56:1685–1694.

ESBL = Enterobacteriacae; AB = Acinetobacter

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Activity for Carbapenemase-Producing Bacteria and

Clinical Indications of New Antibiotics

Bassetti M, et al. Curr Opin Crit Care 2015;21:402-411.

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Pseudomonas aeruginosa (1019) MIC50 MIC90 Sensitive

Ceftolozane/tazobactam 0.5 4 94.1*

Ceftazidime 2 >32 73.6

Cefepime 4 >16 76.5

Doripenem 0.5 8 75.7

Meropenem 0.5 >8 73.7

Piperacillin/tazobactam 8 >64 69.5

Levofloxacin 0.5 >4 69.9

Gentamicin 2 >8 80.7

Amikacin 4 16 92.9

Colistin 1 2 98.5

*Percentage inhibited at C/T MICs of ≤8 mg/L; for comparison purposes only.

Activity of Ceftolozone/Tazobactam in NP

Pathogens From USA and Europe

Farrell DJ, et al. Int J Antimicrob Agents 2014;43:533-539.

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The CENIT study evaluated the in vitro activity of ceftolozane/tazobactam and

comparators against clinical isolates of P. aeruginosa ( n = 500) Spain

Tato M, et al. Int J Antimicrob Agents 2015 Nov;46(5):502-510.

16 Wagenlehner FM, et al. Lancet 2015;385:1949-1956.

ASPECT-cUTI –Phase 3 Study

17 The primary endpoint was a composite of micro eradication and clinical cure 5-9 days

after treatment in the mMITT group, with a non-inferiority margin of 10%.

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Wagenlehner FM, et al. Lancet 2015;385:1949-1956.

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ASPECT-cIAI –Phase 3 Study

Solomkin J, et al. Clin Infect Dis 2015;60:1462-1471.

20 Solomkin J, et al. Clin Infect Dis 2015;60:1462-1471.

21 Solomkin J, et al. Clin Infect Dis 2015;60:1462-1471.

22 Xiao AJ, et al. J Clin Pharmacol 2016 ;56:56-66.

PTA = Probability of Target Attainment

1.5 g 3.0 g

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Mean (SD) Ceftazidime Avibactam

Cmax 88.1 (14) 15.2 (14)

AUC (mg-h/L) 289 (15) 42.1 (16)

T1/2 (h) 3.27 (33) 2.22 (31)

CL (L/h) 6.93 (15) 11.9 (16)

Vss (L) 18.1 (20) 23.2 (23)

Clinical Pharmacology

PK parameters assessed following administration of 2.5 g in

healthy adult male subjects with normal renal function

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Organism Ceftazidime–avibactam Ceftazidime

MIC50/90 MIC range %S MIC50/90 MIC range %S

C. freundii 0.125/0.5 ≤0.06–2 100 0.5/>32 ≤0.25–>32 78.2

E. aerogenes 0.25/0.5 ≤0.06–16 98.5 0.5/>32 ≤0.25–>32 76.9

E. coli 0.12/0.25 ≤0.06–4 100 ≤0.25/1 ≤0.25–>32 94.9

ESBL-

producing

0.12/0.25 ≤0.06–1 100 16/>32 1–>32 34.8

AmpC-

hyperproducing

0.12/0.5 ≤0.06–2 100 16/>32 1–>32 41.4

K. oxytoca 0.12/2 ≤0.06–2 100 ≤0.25/0.5 ≤0.25–>32 99.3

K. pneumoniae 0.12/0.5 ≤0.06–8 99.9 ≤0.25/1 ≤0.25–.32 98.5

ESBL-

producing

0.5/1 ≤0.06–2 100 32/>32 4–64 66.7

OXA-48-

producing

0.25/0.5 <0.008–1 100 256/512 ≤0.12–512 N/A

KPC-

producing

0.25/1 ≤0.06–1 100 >256/>256 32–>256 0

Lagacé-Wiens P, et al. Core Evid 2014 Jan 24;9:13-25.

Pathogen Susceptibility

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Organism Ceftazidime–avibactam Ceftazidime

MIC50/90 MIC range MIC50/90 MIC range

Bacteroides fragilis 4/32 ≤0.06–>64 0.5/>32 0.5–>128

Other B.

fragilis complex

32/>128 4–>128 >128/>128 8–>128

Prevotella/Porphyro

monasspp.

2/4 ≤0.125–8 32/>128 0.5–>128

Fusobacterium spp. N/A ≤0.06–2 N/A 0.125–32

Lagacé-Wiens P, et al. Core Evid 2014 Jan 24;9:13-25.

Pathogen Susceptibility

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In vitro activity of ceftazidime-avibactam against 2014

isolates of P. aeruginosa from US medical centers

Huband MD, et al. AAC 2016 Jan 25. pii: AAC.03056-15. [Epub ahead of print]

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> 50 mL/min 30 – 50 mL/min

AvyCaz +

metronidazole

85% (322/379) 45% (14/31)

Meropenem 86% (321/373) 74% (26/35)

Within this subgroup, patients treated with AVYCAZ received a 33% lower daily

dose than is currently recommended for patients with CrCL 30 to 50 mL/min.

cIAI – Phase III

31 to 50 mL/min 1.25g (ceftaz 1g/Avi .5 g) q 8 hr

16 to 30 mL/min 0.94 g (ceftaz 0.75g/Avi 0.19g) q 12 hr

6 to 15 mL/min 0.94 g (ceftaz 0.75g/Avi 0.19g) q 24 hr

< 5* mL/min 0.94 g (ceftaz 0.75g/Avi 0.19g) q 48 hr

*Ceftazidime and Avibactam are both dialyzable, give post dialysis.

28 Avycaz Label

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Ceftazidime 2,000 mg +

avibactam 500 mg +

metronidazole 500 mg,

each IV q8h for 5 to 14

days

Randomized: n=101

CE: n=87

ME: n=68

mMITT: n=85

Favorable clinical

response at test-of-cure

visit:

CE: 92.0% (80/87)

ME: 91.2% (62/68)

mMITT: 82.4% (70/85)

Meropenem 1,000 mg IV

q8h for 5 to 14 days

Randomized: n=102

CE: n=90

ME: n=76

mMITT: n=89

Favorable clinical

response at test-of-cure

visit:

CE: 94.4% (85/90)

ME: 93.4% (71/76)

mMITT: 88.8% (79/89)

cIAI – Phase II

Most common sites of infection were appendix (47%) and stomach/duodenum

(26%), and the majority of patients (83%) had an APACHE II score of ≤10.

Lucasti C, et al. J Antimicrob Chemother 2013;68:1183–1192.

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Ceftazidime 500 mg +

avibactam 125 mg, each IV

q8h for a minimum of 4 days

(step-down to oral

ciprofloxacin was permitted)

Randomized: n=69

CE: n=28

ME: n=27

mMITT: n=46

Favorable microbiological

response at test-of-cure

visit:

ME: 70.4% (19/27)

mMITT: 67.4% (31/46)

Favorable clinical response

at test-of-cure visit:

CE: 85.7% (24/28)

Imipenem–cilastatin 500 mg

IV q6h for a minimum of 4

days (step-down to oral

ciprofloxacin was permitted)

Randomized: n=68

CE: n=36

ME: n=35

mMITT: n=49

Favorable microbiological

response at test-of-cure

visit:

ME: 71.4% (25/35)

mMITT: 63.3% (31/49)

Favorable clinical response

at test-of-cure visit:

CE: 80.6% (29/36)

cUTI – Phase II

Acute pyelonephritis was the primary diagnosis in 62% of trial participants.

Vazquez JA, et al. Curr Med Res Opin. 2012;28:1921–1931.

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For the FDA, mMITT and non-inferiority margin 10%

(1) Symptomatic resolution of UTI-specific symptoms except flank pain

(frequency/urgency/dysuria/suprapubic pain) and resolution of, or improvement in, flank

pain based on the patient-reported symptom assessment response at the Day 5 visit.

CAZ-AVI – doripenem: -2.39% and 10.42%

(2) Proportion of patients with both a symptomatic resolution of UTI-specific symptoms

at Test of Cure (TOC) visit and a favorable microbiological response at TOC.

CAZ-AVI – doripenem: 0.30% and 13.12%

For the EMA, the primary analysis of favorable microbiological response was

conducted at the TOC in the mMITT population and the non-inferiority margin was

12.5%.

CAZ-AVI – doripenem: 0.3% and 12.4%

RECAPTURE 1 and 2 (n = 1033) trials from 30 countries

32 Humphries RM, et al. AAC 2015;59:6605-6607.

66 yo woman with

pancreatic cancer,

splenic vein

thrombosis,

sepsis at UCLA.

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Geometric mean (SD) plasma and median ELF following administration of 2g

ceftazidime + 500 mg of avibactam (a) or 3g ceftazidime + 1000 mg of avibactam (b).

Nicolau DP, et al. JAC 2015;70:2862-2869.

Ceftazidime

Avibactam

34

Ceftazidime 16 >16 ≤0.25–>16 33

Meropenem >8 >8 ≤0.125–>8 31

Gentamicin 8 >8 ≤0.25–>8 45

Ciprofloxacin >4 >4 ≤0.125–>4 31

Trimetho-sulfa >4 >4 ≤0.5–>4 34

Tetracycline >16 >16 2–>16 10

Tigecycline 2 4 0.06–16 66

Eravacycline 0.5 1 ≤0.015–8

Acinetobacter

N = 158

MIC (μg/ml)

50% 90% Range %

Susceptible

Abdallah M, et al. Antimicrob Agents Chemother 2015;59:1802–1805.

Acinetobacter US Isolates

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A. baumannii

(n = 202)

MIC 50 MIC 90 MIC Range S/I/R

RX-P873 0.5 1 0.12–4

Ampicillin-

sulbactam

16 >32 0.5–>32 48.0/11.4/40.6

Ceftazidime >16 >16 0.5–>16 38.1/2.5/59.4

Cefepime 16 >16 0.25–>16 36.6/13.4/50.0

Ciprofloxacin >8 >8 0.06–>8 36.1/0.0/63.9

Tobramycin 4 >16 ≤0.25–>16 53.5/3.4/43.1

Amikacin 8 >32 ≤0.25–>32 58.4/6.0/35.6

Meropenem >8 >8 ≤0.06–>8 46.0/1.5/52.5

Colistin 1 2 0.25–>8 97.0/0.0/3.0

Tigecycline 1 4 0.12–>4

RX-P873 is a novel antibiotic (pyrrolocytosine) w/

high binding affinity for the bacterial ribosome and

in vitro activity against MDR-GNB

Flamm RK, et al. AAC 2015;59:2280-5.

36 Tsuji M, et al. Poster 256, ID Week 2014; October 9, 2014.

37 Tsuji M, et al. Poster 256, ID Week 2014; October 9, 2014.

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Actively Recruiting Clinical Trials of

Aerosolized Antibiotics Drug Sponsor Phase

Colistin NIAID I

Tobramycin/

Vancomycin

Wright State Univer IV

Amikacin/Fosfomycin Cardeas Pharma II

Amikacin Bayer/Nektar III

Vancomycin Seoul National Univer II

Arbekacin Meiji Seika Pharma I

Clinicaltrials.gov accessed Oct 2015

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[3H]tobramycin into bacterial cells after adding unlabeled fosfomycin. Values are

means ± SD from four independent experiments (*, P < 0.05; **, P < 0.005).

MacLeod DL, et al. AAC 2012;56:1529-1538.

Fosfomycin induces uptake of tobramycin in P.

aeruginosa in a dose-dependent fashion

40 Montgomery AB, et al. AAC 2014;58:3714–3719.

The amikacin-fosfomycin combination had a 5:2 ratio of amikacin to fosfomycin.

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PARI eFlow® Inline Nebulizer

Single patient use, multiple treatment nebulizer

Reusable controller

Continuous nebulization – Inspiratory arm acts as

reservoir chamber

Vibrating plate technology – Small particle size

– Humidity left on

Differences from other nebulizers – Multiple use

– Does not require multiple circuit breaks

– Small particle size provides less rain out and better peripheral delivery

Particle size 3.2 µ with

humidity

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Mean peak [amikacin] and [fosfomycin] in tracheal aspirates

after aerosolized fosfomycin 20 mg/mL (with amikacin 50

mg/mL) by PARI eFlow® Inline Nebulizer in 7 VAP patients

Montgomery AB, et al. Am J Respir Crit Care Med 2013; 187:A3236.

≥ 25x reference MIC of 256 μg/mL (i.e., ≥6,400 μg/mL)

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Antibiotic

Use

Antibiotic

Resistance

Counterintuitive

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Conclusions • Understand your local epidemiology

• Appropriate drug selection and Adequate

dosing/duration/infusion/timing

• Use microbiology results to de-escalate

• Employ new agents/technology as available

• Insure compliance w/ ASP

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Thank you!