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New antibiotics for XDR Gram-negatives o r
ID u t h
C M y a
Yehuda Carmeli, MD, MPH
Tel Aviv Medical Center, Israel

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Disclaimer
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fees, and other forms of financial support from:
o r
I have received grants, honoraria, travel support, consulting

ID t h
Achaogen Inc, Allecra Therapeutics, AstraZeneca, Biomerieux
SA, Durata Therapeutics, Merck & Co. Inc, Nabriva

u
Therapeutics, PPD, Rempex Pharmaceuticals, Roche

M a
Pharmaceuticals, Takeda Pharmaceutical Company Ltd.

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antibiotics (2017)
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WHO priority pathogens list for R&D of new

•
•
Priority 1: CRITICAL
e L o r
•
• ID t
Pseudomonas aeruginosa, carbapenem-resistant

u h
Acinetobacter baumannii, carbapenem-resistant

C M
Enterobacteriaceae, carbapenem-resistant, ESBL-producing

y a
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Activity of novel beta-lacam/inhibitors
ESBL AmpC Carbapenemases

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Pseudomonas Acinetob
spp. acter
Phase

L
Serine (KPC) Oxa48-like MBL
Ceftolozane-
tazobactam*
Ceftazidime-
+

++
-

++
-

++
-

+
e
-

-
++

++
o r
-

-
FDA
approved
FDA

h
avibactam* approved

I
Aztreonam-avibactam

Imipenem-relebactamD ++ ++ ++ + ++

u t + - 2

M a
++ ++ ++ - + - 3
(MK7655)
Meropenem-
vaborbactam
(RPX7009)

(WCK 5222)
SC
Cefepime-zidebactam

b y
++

++
++

++
++

++ ++
-

++
+

++
-

-
3

E ©
Cefiderocol (S49266) ++ ++ ++ ++ ++ ++ + 3
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Ceftolozane (CXA-101)
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L r
• Novel broad-spectrum cephalosporin with potent anti-pseudomonal activity

e o
ID u t h
C M y a
E S b v

© Zhanel GG et al. Drugs. 2014;74:31–51

Shlaes D. Ann N Y Acad Sci. 2013;1277:105–114
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Ceftolozane-tazobactam
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• Ceftolozane is hydrolysed by ESBLs and carbapenemases and by
some strains harboring stably derepressed AmpC β-lactamases
o r
• The addition of tazobactam provides protection from some of
these enzymes
ID u t h
C M y a
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aFixed
©
tazobactam concentration of 4 mg/L Zhanel GG et al. Drugs. 2014;74:31–51
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ID u t h
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© Zhanel GG et al. Drugs. 2014;74:31–51
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• In December 2014 ceftolozane-tazobactam was approved by the FDA to
treat cIAI & cUTI 1.5gr q8h
Ongoing clinical trial for VAP 3gr q8h
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e L o r
ID u t h
C M y a
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aComparators
©
include levofloxacin for cUTI and meropenem for cIAI
Popejoy M et al. ID week 2014; abstract 260
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206829lbl.pdf
 Ceftazidime-Avibactam
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Avibactam (NXL104) is a strong inhibitor of class A
i
e L
and class C enzymes

o r
ID u t h
C M y a
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© Stachyra T et al. Antimicrob Agents Chemother. 2010;54:5132–5138
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Ceftazidime-Avibactam
Avibactam– spectrum of β-lactamase inhibition
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Available
Serine enzymes
e L
b-lactamases

o
Metallo-enzymes r
h
“old” BLIs

ID Class A Class C Class D

u t Class B

C M a
Older TEM & SHV,
ESBLs: new TEM, SHV

y
& CTX-M
Amp C

CMY,
FOX,
DHA
OXA NDM-1
VIM-1

E S b KPC
carbapenemase

© Avibactam
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i
126 European isolates
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Cefatazidime-Avibactam in P. aeruginosa

e L o r
ID u t h
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© Levasseur P et al. Antimicrob Agents Chemother. 2012;56:1606–1608
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MICs of 42 KPC-producing
K. pneumoniae collected in the US
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25

Ceftazidime +
e L Ceftazidime
o r
h
20

D t
Number of isolates

avibactam 4 mg/L

15

M I u
10

C y a
E
0

S b
<0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 128 256 >512

© MIC (mg/L)

Endimiani A et al. Antimicrob Agents Chemother. 2009;53:3599–3601

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Clinical Development

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and HAP/VAP studies
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• Ceftazidime Avibactam completed successfully regulatory cUTI, IAI

o r
• Successful ceftazidime resistant pathogens study, however very few

ID
CRE patients.

u t h
• Based on these studies has received EU commission and FDA

M
approval

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REPRISE: resistant pathogen study

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• Open-label Phase 3 study of ceftazidime-avibactam and best-available-therapy (97%

L
carbapenems) in patients with cIAI or cUTI caused by CAZ-R Gram-negative pathogens

e o r
ID u t h
C M y a
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© Carmeli Y et al. Lancet ID 2016
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Post marketing CRE experience
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• Several large scale reported on the experience treating CRE
severe infections often in immunocompromised patients
o r
D t h
– Overall good success rate relative to severity of the infection (60-

I u
70%), double than the success in the comparison groups

M
emerged

C y a
– Several cases of emergence of ceftazidime-avibactam resistance

• de-novo mutations often accompanied by reduction in carbapenem MICs, yet,

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raising concerns of future resistance

©
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Imipenem-cilastin + relebactam (MK7655)
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vs imipenem-cilastin
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• Phase 2 studies of imipenem-cilastin + relebactam (MK7655)

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– cIAI completed2

ID
– cUTI completed3

u t h
C M a
• Phase 3 studies ongoing:
• HAP/VAP vs. piperacillin/tazobactam4

y
• Pathogen directed study5

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• ELF 53% of plasma1 1. Rhee EG. ICAAC 2013; abstract A-1028

©
2. https://clinicaltrials.gov/ct2/show/NCT01506271
3. https://www.clinicaltrials.gov/ct2/show/NCT01505634
4. www.ClinicalTrials.gov Identifier: NCT02493764
5. www.ClinicalTrials.gov Identifier: NCT02452047
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ID u t h
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© Livermore D et al. J Antimicrob Chemother. 2013;68:2286–2290
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• 365 non-susceptible
• 205 (56%) rendered susceptible by MK 7655

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Among 1101 P. aeruginosa isolates from the SMART surveillance program
• 67% susceptible to imipenem (MIC 2)

e L o r
ID u t h
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© Badal R et al. ICAAC 2013; abstract E-1163
Livermore D et al. J Antimicrob Chemother. 2013;68:2286–2290
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Carbavance : Meropenem-vaborbactam
(RPX7009)
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• RPX7009 is a cyclic boronate
β-lactamase inhibitor
e L o r
– combined with meropenem

ID u t h
C M y a
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© With permission from Hecker SJ. J Med Chem. 2015;Epub ahead of print. Copyright (2015) American Chemical Society
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ID u t h
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© Castanheira M. ASM 2016
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i
100 KPC-producing strains
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In vitro activity of meropenem-RPX7009 against

Antimicrobial
agent
≤0.25 0.5
e1
L
Cumulative % inhibited at MIC (µg/mL):

2 4
o r 8

Meropenem
ID 0.0 1.0 3.0 9.0

u t h 24.0 42.0

C M
MER/RPX 4 mg/L

MER/RPX 8 mg/L

y a74.0

79.0
78.0

85.0
83.0

91.0
88.0

97.0
92.0

98.0
96.0

98.0

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© Castanheira M et al. IDWeek 2014; abstract 257
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Efficacy & Clinical development
• Phase 3 studies meropenem 2 g - Vabrobactam 2 g IV, q8h:
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• Completed successfully cUTI study
– Showed superiority vs. peperacillin-tazobactam

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– Efficacy, safety and tolerability in patients with cUTI or pyelonephritis
o r
D
(vs. piperacillin-tazobactam)

I u t h
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©
– Pathogen-directed study in approximately 150 patients with suspected or known
serious infections due to CRE across multiple indications (vs. BAT) ClinicalTrials.gov Identifier: NCT02168946
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Cefiderocol (S 649266)
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• Siderophor cephalosporin - binds to iron and actively

o r
transported across the outer membrane into the periplasmatic
space

ID
• Highly stable to beta-lactamases
u t h
M a
• Active against MDR acinetobacter and Pseudomonas

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Cefiderocol (S 649266)
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ID u t h
C M y a
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©
Hackel S. Idweek 2016
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Cefiderocol (S 649266) clinical development
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• Completed successfully cUTI study

e L
– showed superiority at TOC vs. imipenem in a multicenter, double-blind,
o r
h
randomized, non-inferiority trial:

ID
eradication at test of cure (TOC)).
• Cefiderocol in 72.6 percent
u t
– 452 patients with cUTI (composite of clinical cure and microbiologic

M a
• Imipenem 54.6 percent
• weighted difference of 18.58 percent (95 percent CI: 8.23, 28.92).

C y
• Ongoing studies:

S b
– Pathogen directed
– HAP/VAP study

E ©
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Novel non-beta-lactam agents
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ESB
L
Amp
C
Carbapenemases

e L Pseudomonas
spp.
o r
Acinetobacter Phase

h
Serine Oxa48-like MBL

D t
(KPC)

Eravacycline ++

M I ++ ++ ++ ++

u
- ++ 3

Plazomicin

Murepavadin
(POL7080)

C
++ ++

y a ++ ++ ++/- ++

+++
+ 3

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©
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Murepavadin (pol7080-polyhor)
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•
•
First in class cyclopeptide
Targets outer membrane e L o r
•
• ID
Pathogen specific anti-pseudomonal agent

u
Excellent lung penetration ELF=Plasma levelst h
•
M a
Completed phase 2 – Bronchiectasis , VAP with encouraging

C
results
y
S b
– To be combined with standard of care

E ©
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• A Tetraphase compound
Eravacycline

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– synthetic tetracycline (fluorocycline)
– both IV and oral formulations
• Active against1:
e L o r
ID
– Gram +, including MRSA and Enterococci
• MIC50 ≤0.06 mg/L; MIC90 ≤0.25 mg/L
– Enterobacteriaceae including carbapenemase-producers (including MBLs)

u t h
M a
• MIC50 ≤0.25 mg/L; MIC90 ≤4 mg/L
– Acinetobacter, Stenotrophomonas maltophilia but not P. aeruginosa

C
• MIC50 ≤0.5 mg/L; MIC90 ≤2 mg/L

S b y
– Various anaerobes including Bacteroides fragilis
• In evaluation in Phase 3

E
– cIAI – enrolled 541 patients, met primary endpoint vs. ertapenem2

©
– cUTI – Failed in reaching the primary outcome non-infriority against Levofloxacin
– cUTI –with revised dosing is ongoing 1. Sutcliffe JA et al. Antimicrob Agents Chemother. 2013;57:5548–5558
2. ClinicalTrials.gov Identifier: NCT01844856
– Second cIAI study has completed recruiting 3. Globe news wire Sept. 8, 2015
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Plazomicin
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• Semi-synthetic aminoglycoside

ID u t h
• Stable against all transferable aminoglycosides modifying enzymes

C M y a
– however, ribosomal methyltransferases (carried in NDM strains)
lead to resistance

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©
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i b r
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ID u t h
C M y a
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© Galani I et al. J Chemother. 2012;24:191–194
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Plazomicin clinical development
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• Completed successfully Phase 2 cUTI study1

e L
• Completed successfully non-inferiority cUTI study (609 patients) vs. meropenem

o r
h
– At day 5: 88% vs 91%

ID
– At test of cure 82% vs. 70% (superiority)

• Completed Phase 3 CRE study bacteremia/pneumonia2

u t
• Results:

C M y a
– Cohort 1: 39 patients randomized comparing plazomicin and colistin+ tigecycline or meropenem
– Cohort 2: 30 patients open label including also cUTI.

– 28 days all cause mortality or severe complications 28% vs. 50%

–

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28 days all cause mortality 12% vs. 40%

© 1. Riddle V et al. ICAAC 2012; abstract L2-2118a

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Summary
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• New treatment modalities are emerging

e L o r
– New BL-BLI combinations expand treatment options against MDR Gram-
negative organisms

ID
– New Cephalosporins
– New non-beta-lactam agents
u t h
C M y a
• Improved activity against Pseudomonas, ESBLs, AmpC & carbapenemases
• Some ofer new treatment options against MDR Acinetobacter

S b
• Further clinical data, post marketing experience are needed

E
• Positioning and differentiation to incorporate into the armamentarium and

©
daily clinical use