Treatment options and new agents for serious Gram-negative ...

Treatment options and new agents for serious Gram-negative

infections

Yehuda Carmeli, MD, MPH

Tel Aviv Medical Center, Israel

I have received grants, honoraria, travel support, consulting fees, and other forms of financial support from:Achaogen Inc, Allecra Therapeutics, AstraZeneca, BasileaPharmaceutica LTD, Biomerieux SA, Cepheid, DaVolterra, Durata Therapeutics, Inc, Intercell AG, Merck & Co. Inc, PPD, Proteologics, Rempex Pharmaceuticals, Rib-X Pharmaceuticals, Syntezza Bioscience LTD, Takeda Pharmaceutical Company Ltd.

Disclaimer

CRE infections are associated with severe outcomes

Ben-David D. CMI 2011

CR A. baumannii BSI is associated with 14 days 50% CFR

Nutman A. CMI 2014

Colistin efficacy is doubtful

Yahav D et al. Clin Microbiol Infec 2012;18:18–29

All-cause mortality: Colistin vs. comparator antibiotics for sepsis

• 125 patients with KPC KP BSI

• The overall 30-day mortality – Monotherapy: 54.3% – Combination: 34.1%

Combination Therapy

Tumbarello M et al. Clin Infect Dis. 2012;55:943–950Akova M et al. Clin Microbiol Infect. 2012;18:439–448

Highest failure

Colistin/rifampin

Colistin/carbapenem

Colistin/tigecycline

Colistin/sulbactam

Colistin/aminoglycosides

Colistin/mixed comparator

Paul M et al. J Antimicrob Chemother. 2014;69:2305–2309

Activity of novel agentsAcinetobacterPseudomonas

spp.CarbapenemasesAmpCESBL

MBLOxa48-likeSerine (KPC)

-++----+Ceftolozane-tazobactam*

-++-+++++++Ceftazidime-avibactam*

-++++++++++Aztreonam-avibactam

-+-++++++Imipenem-relebactam(MK7655)

-+-++++++Meropenem-RPX7009

++-++++++++++Eravacycline

+++++++++++++Plazomicin

*FDA approved

• Novel broad-spectrum cephalosporin with potent anti-pseudomonal activity

Ceftolozane (CXA-101)

v

Zhanel GG et al. Drugs. 2014;74:31–51Shlaes D. Ann N Y Acad Sci. 2013;1277:105–114

Ceftolozane-tazobactam

• Ceftolozane is hydrolysed by ESBLs and carbapenemases and by some strains harboring stably derepressed AmpC β-lactamases

• The addition of tazobactam provides protection from some of these enzymes

Zhanel GG et al. Drugs. 2014;74:31–51aFixed tazobactam concentration of 4 mg/L

Zhanel GG et al. Drugs. 2014;74:31–51

• In December 2014 ceftolozane-tazobactam was approved by the FDA to treat cIAI & cUTI• Warning: Decreased efficacy in patients with baseline CrCl of 30 to ≤50 mL/min

Popejoy M et al. ID week 2014; abstract 260http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206829lbl.pdfaComparators include levofloxacin for cUTI and meropenem for cIAI

Stachyra T et al. Antimicrob Agents Chemother. 2010;54:5132–5138

Avibactam (NXL104) is a strong inhibitor of class A and class C enzymes

KPC carbapenemase

Avibactam – spectrum of β-lactamase inhibition

Older TEM & SHV, ESBLs: new TEM, SHV

& CTX-M

Class C Class D Class B

Amp C NDM-1VIM-1

OXA

b-lactamases

Metallo-enzymesSerine enzymes

Class A

CMY, FOX, DHA

Avibactam

Available BLIs

Lagacé-Wiens PRS et al. Antimicrob Agents Chemother. 2011;55:2434–2437

Avibactam in P. aeruginosa126 European isolates

Levasseur P et al. Antimicrob Agents Chemother. 2012;56:1606–1608

Effect of avibactam on CAZ MIC of carbapenem-resistant Enterobacteriaceae

Livermore D et al. Antimicrob Agents Chemother. 2011;55:390–394

0

5

10

15

20

25

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

MIC (mg/L)

Nu

mb

er

of

iso

late

s

CeftazidimeCeftazidime +avibactam 4 mg/L

MICs of 42 KPC-producingK. pneumoniae collected in the US

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

Current status

• FDA approved ceftazidime-avibactam* based on Phase 2 data– cIAI, in combination with metronidazole compared with meropenem

– cUTI including pyelonephritis compared with imipenem

– Warning: decreased clinical response in patients with baseline CrCl30-50 mL/min

• Phase 3 studies– cIAI (completed)1

– Resistant pathogen study (completed)2

– cUTI (ongoing)

– VAP (ongoing; ELF penetration 30-35%)

1. Mazuski JE et al. ECCMID 2015; 01912. Carmeli Y et al. ECCMID 2015; LBEV0366a

* In patients who have limited or no alternative treatment options

Clinical response rate (95% CI) at TOC visit(mMITT population)

Per-patient microbiological response rate (95% CI) at TOC visit (mMITT population)*

REPRISE: resistant pathogen study

*Per-patient microbiological outcomes for cIAI patients were presumed from clinical response

Carmeli Y et al. ECCMID 2015; LBEV0366a

• Open-label Phase 3 study of ceftazidime-avibactam and best-available-therapy (97% carbapenems) in patients with cIAI or cUTI caused by CAZ-R Gram-negative pathogens

Imipenem-cilastin + relebactam (MK7655)

• PK phase 1 study - completed1

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

– cIAI completed2

– cUTI ongoing3

• ELF 53% of plasma1

1. Rhee EG. ICAAC 2013; abstract A-10282. https://clinicaltrials.gov/ct2/show/NCT01506271

3. https://www.clinicaltrials.gov/ct2/show/NCT01505634

Livermore D et al. J Antimicrob Chemother. 2013;68:2286–2290

Among 1101 P. aeruginosa isolates from the SMART surveillance program• 67% susceptible to imipenem (MIC 2)• 365 non-susceptible

• 205 (56%) rendered susceptible by MK 7655

Badal R et al. ICAAC 2013; abstract E-1163Livermore D et al. J Antimicrob Chemother. 2013;68:2286–2290

Meropenem-RPX7009

• RPX7009 is a cyclic boronateβ-lactamase inhibitor

– Initially developed byRempex to be combinedwith biapenem, but later combined with meropenem

With permission from Hecker SJ. J Med Chem. 2015;Epub ahead of print. Copyright (2015) American Chemical Society

With permission from Hecker SJ. J Med Chem. 2015;Epub ahead of print. Copyright (2015) American Chemical Society

* *

*9f = meropenem-RPX7009

In vitro activity of meropenem-RPX7009 against100 KPC-producing strains

Antimicrobial

agent

Cumulative % inhibited at MIC (µg/mL):

0.25≤ 0.5 1 2 4 8

Meropenem 0.0 1.0 3.0 9.0 24.0 42.0

MER/RPX 4 mg/L 74.0 78.0 83.0 88.0 92.0 96.0

MER/RPX 8 mg/L 79.0 85.0 91.0 97.0 98.0 98.0

Castanheira M et al. IDWeek 2014; abstract 257

ClinicalTrials.gov Identifier: NCT02168946

Efficacy & Clinical development

• Phase 3 started late 2014meropenem 2 g - RPX7009 2 g IV, q8h:

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

– Pathogen-directed study in approximately 150 patients with suspected or known serious infections due to CRE across multiple indications (vs. BAT)

• A Tetraphase compound– synthetic tetracycline (fluorocycline)

– both IV and oral formulations

• Active against1: – Gram +, including MRSA and Enterococci

• MIC50 ≤0.06 mg/L; MIC90 ≤0.25 mg/L

– Enterobacteriaceae including carbapenemase-producers (including MBLs)• MIC50 ≤0.25 mg/L; MIC90 ≤4 mg/L

– Acinetobacter, Stenotrophomonas maltophilia but not P. aeruginosa• MIC50 ≤0.5 mg/L; MIC90 ≤2 mg/L

– Various anaerobes including Bacteroides fragilis

• In evaluation in Phase 3 – cIAI – enrolled 541 patients, met primary endpoint vs. ertapenem2

– cUTI – Failed in reaching the primary outcome non-infriority against Levofloxacin1. Sutcliffe JA et al. Antimicrob Agents Chemother. 2013;57:5548–5558

2. ClinicalTrials.gov Identifier: NCT018448563. Globe news wire Sept. 8, 2015

Eravacycline

Plazomicin

• Semi-synthetic aminoglycoside

• Stable against all transferable aminoglycosides modifying enzymes

– however, ribosomal methyltransferases (carried in NDM strains)lead to resistance

Galani I et al. J Chemother. 2012;24:191–194

Plazomicin clinical development

• Completed successfully Phase 2 cUTI study1

• Conducting superiority Phase 3 study in bacteraemia & VAP by CRE2

– comparing plazomicin and colistin

– in combination with either meropenem or tigecycline

• ELF penetration 13%

1. Riddle V et al. ICAAC 2012; abstract L2-2118a2. ClinicalTrials.gov Identifier: NCT01970371

Summary

• New treatment modalities are emerging

• New BL-BLI combinations expand treatment options against MDR Gram-negative organisms– Improved activity against Pseudomonas, ESBLs, AmpC & carbapenemases

• Treatments against MDR Acinetobacter are required

• Clinical efficacy still needs to be demonstrated in difficult to treat infections