This document discusses new antibiotic developments for ventilator-associated pneumonia (VAP). It outlines several new drugs in development or approval that show promise for treating multi-drug resistant Gram-negative and Gram-positive pathogens commonly seen in VAP. These include novel beta-lactamase inhibitor combinations like ceftolozane-tazobactam and ceftazidime-avibactam, as well as other classes such as aminoglycosides and tetracyclines. Ongoing and completed clinical trials evaluating some of these new agents for the treatment of VAP are also summarized.

1. New antibiotic developments
for VAP
Prof. Michael S. Niederman
Division of Pulmonary and Critical Care Medicine,
New York Presbyterian Hospital/Weill Cornell Medical Center

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• Michael S. Niederman , M.D., F.C.C.P
• Clinical Director
Associate Chief
Division of Pulmonary and Critical Care Medicine
• New York Presbyterian Hospital/Weill Cornell Medical Center
• Professor of Clinical Medicine
Weill Cornell Medical College
msn9004@med.cornell.edu
NEW ANTIBIOTICS DEVELOPMENTS FOR
VAP: CAN THIS HELP US IN THE ICU?

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Financial disclosure
• Dr Niederman is a speaker or consultant for:
– Bayer, Pfizer, Merck/Cubist , N8 Medical, Cempra, Paratek,
Thermo Fisher, Theravance
• He has received research grants from:
– Bayer, Cubist

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Bad bugs in the good old days: 1945
from Fleming’s research

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Increasingly common MDR pathogens
(not all causing pneumonia)
• ESKAPE pathogens needing better therapies than
those currently available
– Enterococcus faecium (VRE)
– Staphylococcus aureus (MRSA)
– Klebsiella spp. and Escherichia coli with ESBLs and
carbapenemases (KPCs)
– Acinetobacter spp.
– Pseudomonas aeruginosa with multi-drug resistance
– Enterobacter spp.
• Boucher HW, et al. Clin Infect Dis 2009;48:1-12
ESBL, extended-spectrum β-lactamase; KPC, Klebsiella pneumoniae carbapenemase; MDR, multi-drug resistant; MRSA, methicillin-resistant
S. aureus; VRE, vancomycin-resistant enterococci

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And it’s getting worse still!
• Class B MBLs are mostly of VIM- and IMP-types,
but the recently emerged NDM-type is becoming the
most threatening carbapenemase
– J Chemotherapy 2013;25:129-40
MBLs, metallo-β-lactamases

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Why is resistance so common?
We are using too many antibiotics!!

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IDSA initiative

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Practical issues in new antibiotic
development
• Need new, simplified, affordable regulatory path to
new drug approval. Need FDA and EMA assistance
• Financial: new antibiotic has net value of - $50 million
at discovery vs. $1 billion for musculoskeletal drug
– Antibiotics lose benefit with extensive use
– Guidelines promote short course use (vs. chronic use of
other drugs)
– Max cost of $1000-$3000 / case (vs. up to $80,000 for
chemotherapy)
– Bartlett JG, et al. Clin Infect Dis 2013;56:1445-50

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Why such slow antibiotic development?
Potential solutions
• Find new substances to screen
• New screening methods
• Treatments that do not kill the
microbe
• Private–public partnerships for
development of new agents
• Focus on resistant pathogens
and unmet needs to support
higher prices
• Use molecular diagnostics to
target antibiotic use and withhold
in viral infection
• Study short course therapy and
use of biomarkers, to minimize
overuse of antibiotics
• Enhance public commitment to
responsible antibiotic use
• Enhance infection prevention
Spellberg B, et al. Am J Respir Crit Care Med 2015;191:135-40

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New drugs: Early naïve enthusiasm BUT,
with caution
• Alexander Fleming in 1945
said (Nobel Prize Lecture):
• “There is the danger”, that
the ignorant man may
easily underdose himself
and by exposing his
microbes to non-lethal
quantities of the drug
make them resistant.”

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Unmet needs for new antibiotics
• Survey of EIN members, 562 responded
– Rate unmet needs on scale of 1–5 (low–high)
• Saw new antibiotic development as the best strategy
to meet unmet needs of resistance
EIN, Emerging Infections Network
Hersh AL, et al. Clin Infect Dis 2012;54:1677-8,
by permission of the Infectious Diseases Society of America

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New drugs for VAP due to Gram-positives
• Oxazolidinones that are active vs. linezolid-resistant MRSA
– Tedizolid: Lower MICs than linezolid vs. MRSA. Once daily dosing. No
serotonergic agent interactions. SSTI trials done. HCAP/VAP study
ongoing
– Radezolid: concentrates in macrophages and neutrophils
• Glycopeptide/cephalosporin heterodimer (TD-1607). For
serious Gram-positive infections, including VAP and bacteremia
(phase I)
• Tetracyclines
– Omadacycline: IV and oral for CAP (DRSP, S. aureus incl. MRSA,
atypicals, some GNB). Low protein binding. Less GI toxicity than
tigecycline. Comparable to linezolid in cSSTI. Few drug interactions,
little potential for Clostridium difficile?? If will be tested in VAP
CAP, community-acquired pneumonia; DRSP, drug-resistant Streptococcus pneumoniae; GI, gastrointestinal; GNB, Gram-negative bacteria;
HCAP, healthcare-associated pneumonia; SSTI, skin and skin structure infection; VAP, ventilator-associated pneumonia

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Tedizolid and linezolid vs. MSSA and
MRSA
ABSSSI, acute bacterial skin and skin structure infection; MSSA, methicillin-sensitive S. aureus
Chen KH, et al. Antimicrob Agents Chemother 2015;59:6262-5, doi: 10.1128/AAC.00390-15,
reproduced with permission from the American Society for Microbiology

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New drugs for VAP due to Gram-negatives
• Ceftolozane–tazobactam
• Ceftazidime–avibactam
• Aztreonam–avibactam: active vs. metallo-β lactamases
• Siderophore cephalosporin
• Carbavance (carbapenem/BLI)
• Meropenem/RPX7009 (Vaborbactam): enhanced KPC activity
• Imipenem–relebactam
• Plazomicin
• POL 7080 (macrolide Lpt D inhibitor)
– Vincent JL, et al. Crit Care 2016;20:133
• Cyclopeptide
– Murepavadin: bactericidal vs. P. aeruginosa, incl. MDR pathogens. Targets
bacterial outer membrane proteins, binds LPS. No clinical trials yet in VAP
BLI, β-lactamase inhibitor; LPS, lipopolysaccharide

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New β-lactamase inhibitors
Spectrum
β-lactamase inhibitor
Tazobactam Avibactam RPX7009 Relebactam
Class A narrow-spectrum X X X X
Class A ESBLs X X X X
Class A carbapenemases X X X
Some class C enzymes X X X X
Some class D enzymes X
Drawz SM, Bonomo RA. Clin Microbiol Rev 2010;14:160-201
Toussaint KA, Gallagher JC. Ann Pharmacother 2015;49:86-98

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Product Class (MOA) Status Activity targets
ESBL PA AB
Ceftolozane–tazobactam
(CXA-201; CXA-101–
tazobactam)
APPROVED
Cephalosporin–BLI
combination (cell wall
synthesis inhibitor)
Antipseudomonal
Phase 3 cUTI,
cIAI, VAP
Yes Yes No
Ceftazidime–avibactam
(ceftazidime/NXL104)
APPROVED
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
New drugs in the pipeline for antibiotic-
resistant Gram-negative bacteria
Boucher HW, et al. Clin Infect Dis 2013;56:1685-94
AB, Acinetobacter baumannii; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; MOA, mechanism of action;
PA, P. aeruginosa
Copyright permission
request under review by
OUP. Cost unknown

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New cephalosporin–BLIs (IV only)
• Ceftolozane–tazobactam (C–T) and ceftazidime–avibactam (CAZ–AVI)
active vs. MDR Gram-negatives, incl. P. aeruginosa. 2:1 cephalosporin–BLI
• CAZ–AVI active against KPC-producing organisms, AMP-C β-lactamases,
ESBLs, but not vs. metallo-β-lactamases, 4:1 cephalosporin–BLI
• Tazobactam has irreversible binding; avibactam binding is reversible and
can be recycled
van Duin D, Bonomo RA. Clin Infect Dis 2016;63:234-41,
by permission of the Infectious Diseases Society of America

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Activity of new cephalosporin–BLIs
Ceftolozane–tazobactam
Reprinted from: Liscio JL, et al. Int J Antimicrob Agents 2015;46:266-71, © 2015,
with permission from the International Society of Chemotherapy
cIn vivo activity refers to organisms isolated during clinical trials.
Medications may have greater in vitro activity beyond what is reported here
Ceftazidime–avibactam

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In vitro activity of ceftolozane–tazobactam
• 2968 isolates from pneumonia patients in US and Europe
Reprinted from: Farrell DJ, et al. Int J Antimicrob Agents 2014;43:533-9, © 2014,
with permission from the International Society of Chemotherapy

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In vitro activity of ceftazidime–avibactam
Reprinted from: Sharma R, et al. Clin Ther 2016;38:431-44, © 2016,
with permission from Elsevier

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Comparing the two new BL/BLI drugs
• Ceftazidime–avibactam
– Active vs. KPCs and
ESBLs
– 2000 mg CAZ + 500 mg
AVI for NP
– Predictable PK
– Rapid lung distribution
– Renal excretion
• Ceftolozane–tazobactam
– Stable against
pseudomonal resistance
mechanisms (Opr-D,
AmpC, efflux pumps)
– 2000 mg CToZ + 1000 mg
TAZ for VAP/NP
– Active vs. ESBLs
– Predictable PK
– Rapid lung distribution
– Renal excretion
– No KPC activity
NP, nosocomial pneumonia

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Dosing of the new cephalosporin BLIs
• For ceftolozane–tazobactam,
may need 3 g dose for VAP
over 60 min every 8 h1
• ELF is half of the plasma
concentration1
• 98.4% target attainment for MIC
of 8 mg/L in ELF with 3 g dose1
• 95.6% for >40% time above
MIC of 8 mg/L in ELF for 3 g
dose1
• Approved to give ceftazadime–avibactam
over 2 h as infusion
1. Xiao AJ, et al. J Clin Pharmacol 2016;56:56-66
ELF, (lung) epithelial lining fluid
van Duin D, Bonomo RA. Clin Infect Dis 2016;63:234-41,
by permission of the Infectious Diseases Society of America

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Target attainment in ELF following 1.5 g and
3 g doses of ceftolozane–tazobactam
1.5 g dose 3 g dose
Xiao AJ, et al. J Clin Pharmacol 2016;56:56-66.
Copyright © 2017, John Wiley & Sons, Inc.
Figures used according to Creative Commons License 4.0

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Product Class (MOA) Status Activity targets
ESBL PA AB
Imipenem/MK-7655
(Relebactam)
Carbapenem/BLI
combination (cell wall
synthesis inhibitor)
Active vs. KPCs
Phase 2/3
cUTI, CIAI,
HAP/VAP
Yes Yes No
Plazomicin (ACHN-490) Neoglycoside (protein
synthesis inhibitor)
Phase 3
CRE
Yes No No
Eravacycline (TP-434) Fluorocycline (protein
synthesis inhibitor
targeting the ribosome)
Phase 3
cUTI (failed
trial)
Yes No Yes
Brilacidin (PMX-30063) Peptide defense protein
mimetic (cell membrane
disruption)
Phase 2
ABSSSI
Yes ? No
Boucher HW, et al. Clin Infect Dis 2013;56:1685-94
New drugs in the pipeline for antibiotic-
resistant Gram-negative bacteria
CRE, carbapenem-resistant Enterobacteriaceae
Copyright permission
request under review by
OUP. Cost unknown

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Boucher HW, et al. Clin Infect Dis 2013;56:1685-94
New drugs in the pipeline for antibiotic-
resistant Gram-negative bacteria (cont’d)
Product Class (MOA) Status Activity targets
ESBL PA AB
Carbavance
(Carbapenem+novel
boronic β-lactamase
inhibitor)
Carbapenem
(biapenem)–BLI
combination (cell wall
synthesis inhibitor)
Phase 3
cIAI, HAP
Yes
Active vs. KPCs
and Class A
carbapenemases
Yes Yes
BAL30072
(+/- carbapenem)
Siderophore
monosulfactam (synergy
with carbapenem)
Phase 1 No
(Yes with
carbapenem)
Yes Yes
S-649266
(Siderophore
cephalosporin)
“Trojan Horse”
Binds to iron and
transported to
periplasmic space to
bind to PBPs (cell wall
synthesis inhibitor)
Phase 2
cUTI,
cIAI,
HAP/VAP
Yes Yes Yes
Copyright permission
request under review by
OUP. Cost unknown

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VAP trials
• Ceftolozane–tazobactam 3000 mg vs. meropenem for nosocomial VAP
– Cubist/Merck
– All-cause mortality endpoint, n=726
– ClinicalTrials.gov NCT; NCT02070757
• Imipenem–relebactam vs. piperacillin–tazobactam for HAP (including VAP).
Open label use of linezolid in both arms
– Merck
– 28-day survival, n=536
– ClinicalTrials.gov; NCT02493764, RESTORE-IMI 2
• Tedizolid 200 mg qd vs. linezolid 600 mg bid for nosocomial VAP
– Cubist/ Merck
– All-cause mortality endpoint at 28 days, n=726
– ClincialTrials.gov; NCT02019420

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Other trials: VAP
• Plazomicin for VAP due to CRE, APACHE II ≤30
– Test plazomicin with adjunctive antibiotic for all-cause mortality, 28 days
– Achaeogen
– ClinicalTrials.gov; NCT01970371
• Ceftazidime/avibactam vs. meropenem for nosocomial
pneumonia (can include VAP)
– Clinical cure as primary endpoint
– Astra-Zeneca, completed Jan 2016, 969 patients, data on line
– ClinicalTrials.gov; NCT01808092

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Ceftazidime–avibactam
• Ceftazidime–avibactam vs. meropenem for nosocomial
pneumonia (can include VAP)
• Clinical cure as primary endpoint
– 356 received ceftazidime–avibactam
• 245 clinical cure, 79 clinical failure, 32 indeterminate
– 370 received meropenem
• 270 clinical cure, 70 clinical failure, 30 indeterminate
– p=0.007 for NI margin of -12.5%
• Similar data for TOC and EOT visits and microbiologically
evaluable population
EOT, end of treatment; NI, non-inferiority; TOC, test of cure

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If we want to improve VAP management,
we need better trial design
• Trials designed for non-inferiority generally require
pathogens to be susceptible to the agents in both arms
• Often a new agent is tested with an accompanying
medication
• Design for superiority vs. best available therapy, using
new agent as adjunct to best available therapy?
• “Every system is perfectly designed to get the results it
gets”
– Paul Batalden, M.D., Professor Emeritus, Dartmouth,
member of IHI

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Conclusions
• Finally, there are some new agents in development and in
clinical trials
• May be new therapies for VAP, both IV and aerosol (adjunctive)
– BUT, trials designed for equivalence are a problem
• Most are modifications of older agents, or with the addition of
new β-lactamase inhibitors
• Some new classes: pleuromutilins, siderophore monosulfactam,
cyclopeptides, peptide defense protein mimetics
• How to use: monotherapy vs. MDR Gram negatives,
CARBAPENEM sparing??

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