Dubreuil, PhD, PharmD -

LIRIC – UMR 995 – Inserm/Université Lille

France

BMR nouveaux antibiotiques

Lille

Octobre 2016

SFM Mars 2016LIRIC UMR 995 Dubreuil L

Bad bugs need new drug

MRSA

S. pneumoniae

SFM Mars 2016LIRIC UMR 995 Dubreuil L

Adverse effects –toxicity ���� Exit the floxacin’s :

gati tema, trova, tosuflo …

Needs for MRSA ?

Lack of activity against MDR gram-negative bacilli

+

Ertapenem + doripenem against KPC

MIC DISTRIBUTIONESBL/AmpC E. coli (n=1155)

E. coli MIC (µg/mL)Remarks Method

0.12 0.25 0.5 1 2 4 8 16 32 64 128 256 >512

0 0 0 0 5 18 165 76 27 1 0 0 0 CTX-M Agar MIC

0 0 0 0 3 10 53 16 5 0 0 0 0 non CTX-M-ESBL Agar MIC

0 0 0 0 1 3 20 13 2 1 0 0 0 AmpC Agar MIC

0 0 0 0 0 12 49 31 7 1 0 0 0 ESBL E-test

0 0 1 15 67 82 30 3 0 0 0 0 0 CTX-M group 1 E-test

0 0 1 6 26 71 25 3 0 0 0 0 0 CTX-M group 9 E-test

0 0 0 0 0 3 3 2 0 0 0 0 0 AmpC E-test

0 0 0 0 0 1 0 4 0 1 0 0 0 non CTX-M-ESBL E-test

0 0 0 0 0 0 5 1 0 0 0 0 0 CTX-M E-test

0 0 0 1 8 43 80 18 10 2 0 0 0 ESBL Agar MIC

0 0 0 0 2 8 40 18 6 0 0 0 0 CTX-M group 1 Vitek 2

0 0 0 0 2 7 13 5 0 0 0 0 0 CTX-M group 9 Vitek 2

0 0 0 0 0 0 3 1 0 0 0 0 0 ESBL Vitek 2

0 0 0 0 0 1 0 1 1 3 1 0 0 CTX-M group 1 E-test

0 0 0 0 0 0 0 0 0 1 0 0 0 CTX-M group 1 + AmpC E-test

0 0 0 0 0 0 0 0 1 0 0 0 0 CTX-M group 9 E-test

0 0 0 0 0 0 0 2 0 0 0 0 0 CTX-M group 9 + AmpC E-test

0 0 0 0 0 0 0 0 0 1 0 0 0 TEM-ESBL E-test

0 0 0 0 0 0 0 1 0 0 0 0 0 TEM-ESBL + AmpC E-test

0 0 0 0 0 0 1 1 2 2 0 0 0 AmpC E-test

Total 0 0 2 22 114 259 487 196 61 13 1 0 0

MIC90

= 16mg/L% 0.0 0.0 0.2 1.9 9.9 22.4 42.2 17.0 5.3 1.1 0.1 0.0 0.0

Cumul % 0.0 0.0 0.2 2.1 11.9 34.4 76.5 93.5 98.8 99.9 100.0 100.0 100.0

Monte Carlo simulation2000 g x 2 – PDT : 40 to 50%

• Healthy volunteers and non-ICU patients

• Data from Beecham

A. Muller & J. Mouton, internal data – analysis is still ongoing

In healthy volunteers => 8 to 16 mg/L

95% and 99% CI

• Healthy volunteers and non-ICU patients

• Data from Beecham

Monte Carlo simulation2000 g x 3 – PDT : 40 to 50%

A. Muller & J. Mouton, internal data – analysis is still ongoing

In healthy volunteers => 16 to 32 mg/L

95% and 99% CI

FORMULATIONS & REGIMEN

• Available formulations

– Negaban 1 g IV or IM

– Negaban 2 g IV (not licensed in the UK – variation ongoing)

• Standard and maximum dosing

– According to the SPCs:

• Standard : 1000 mg x 2

• Maximum dose : 2000 mg x 2

– In practice

• Standard : 2000 mg x 2

• Maximum dose : 2000 mg x 3

– Ongoing variation in FR, BE, LU (planned in the UK in 2016)

• Standard : 2000 mg x 2

• Maximum dose : 2000 mg x 3

• + continuous infusion 4000 and 6000 mg/day

*Amaddeo A. et al., poster presented during ECFC 2010

Strategies against MDR

The Shape of Cures to Come™

Cubist Pharmaceuticals

11

Ceftolozane/tazobactam = Zerbaxa1,5g X 8h

CEFTOLOZANE/TAZOBACTAM

Structure

� Ceftolozane/tazobactam is a novel 3′-aminopyrazolium cephalosporin and β-lactamase inhibitor combination being developed as a 2:1 ratio for treatment of serious Gram-negative bacterial infections

12Previous names: CXA-101, CXA-201, FR264205

Breakpoint: 1mg/l Enterobacteriaceae,

4 mg/l Pseudomonas

CEFTOLOZANE

Mechanism of Resistance

� Ceftolozane retains activity against AmpC-hyperproducing Pseudomonas due to its low affinity for the enzyme- MIC values were determined against AmpD-deficient P. aeruginosa

Takeda et al. Int J Antimicrob Agents. 2007 Nov;30(5):443-5.

� Kinetic parameters of the P. aeruginosa AmpC β-lactamase

13

CEFTOLOZANE

Mechanism of Resistance

� Similarities with other cephalosporins:

– Drug inactivation by β-lactamases

� Ceftolozane is little affected by other resistance mechanisms of Gram-negative bacteria, such as reduced uptake due to porin mutations or active efflux

Phenotype Strain

MIC (mg/L)

Ceftolozane Ceftazidime Imipenem Aztreonam

AmpC derepressed1 1405-con 4 128 2

AmpC deficient/OprD-1 1405-OprD- 1 128 16

AmpC derepressed/OprD1 1405-conD2- 4 2 2

Parent PAO1 0.5 2 1 4

MexAB-OprM2 PAO1-1455 0.5 8 1 >16

MexXY-OprN2 PAO1-Takai 1 0.25 1 4 2

Parent PS164 2 4 2 16

MexCD-OprJ2 PS164-921C 0.5 2 0.12 2

Livermore et al. Int J Antimicrob Agents. 2009 Nov;34(5):402-6Moulds et. al. ICAAC 2010. Poster C1-1415. 14

TAZOBACTAM

Mechanism of Action

� Tazobactam potentiates the in vitro activity of ceftolozane against the majority of ESBL+ Enterobacteriaceae1

– Tazobactam has dose dependent activity against a broad range of Gram-negative, plasmid mediated β-lactamases

– Tazobactam does not have meaningful activity against metallo-β-lactamases, KPCs or Class D enzymes

1. Livermore et. al. J Antimicrob Chemother. 2010 Sep;65(9):1972-42. Titelman et. al. Diagn Microbiol Infect Dis. 2011 May;70(1):137-41

Activity of Ceftolozane/tazobactam and Piperacillin/tazobactam against 169 ESBL-Producing E. coli and K. pneumoniae Strains2

16

CEFTOLOZANE/TAZOBACTAM

PACTS 2011: Comparative Activity Against Enterobacteriaceae

PACTS: Program to Assess Ceftolozane/Tazobactam Susceptibility; JMI laboratories 2011

EU data: France (n=687), Germany (N=334), Italy (N=437), Spain (N=483), and UK (N=171)17

Activity of NXL104 ( a new ß-lactamase

inhibitor) in Combination with ß-lactams

L. J. DUBREUIL1, S. MAHIEUX 1, C. NEUT 1, C.

MIOSSEC 2, J. PACE 2, A. BRYSKIER 3 Abstract E188 ICCAC San Francisco, September 2009

International Journal of Antimicrobial Agents 39 (2012) 500– 504

Avibactam

Simulated Target Attainment Data

� Thus a dose of 2000mg CAZ/500mg NXL104 given as a 2h infusion is intended for

Phase 3

*CT=1

CAZ MIC (µg/ml) 500mg CAZ/125mg NXL104

30-min infusion (Phase 2 cUTI

dose)

50% T>MIC & T>*CT

2000mg CAZ/500mg NXL104

30-min infusion (Phase 2 cIAI

dose)

50% T>MIC & T>*CT

2000mg CAZ/500mg

NXL104 2-h infusion

(Proposed Phase 3 dose)

50% T>MIC & T>*CT

0.125 55.6 86.3 96.1

0.25 55.6 86.3 96.1

0.5 55.6 86.3 96.1

1 55.4 86.3 96.1

2 51.9 86.3 96.1

4 31.8 86 96

8 5 78.8 92.1

16 0 41.9 57.1

32 0 5.9 8.6

Avibactam +

Cetfazidime ( P. aeruginosa and PK/PD ) Avicaz (USA) Zavicefta (France)

Activity against

TEM

Amp C (class C)

ESBL

KPC (class A)

Several Oxa (Class D)

Not against metallo enzymes ( Class B)

Ceftaroline + MRSA+ pneumococus PDSP

Aztréonam + VIM ( class B)

In vitro activity of ceftazidime, ceftaroline and aztreonam alone and in combination with

avibactam against European Gram-negative and Gram-positive clinical isolates

Raymond Testaa, Rafael Cantónb, Tommaso Gianic, María-Isabel Morosinib, Wright

W. Nicholsa, Harald Seifertd,e, Danuta Stefanike,

Gian Maria Rossolinic,f,g, Patrice Nordmannh,i,∗∗∗∗ IJAA 2015

Avibactam enhances the activities of ceftazidime, ceftaroline and aztreonam

against Enterobacteriaceae and P. aeruginosa but not against A. baumannii.

May The A+A Force Be With You!

Biedenbach et al.

Diazabicyclooctanes

DBO’s

Relebactam

Relebactam

Cefepime + tazobactam ESBL AmpC

SFM Mars 2016LIRIC UMR 995 Dubreuil L

Limits of new inhibitors

Aztreonam + avibactam

Activity on enterobateriaceae

MBL (VIM,IMP) + oxa 48 +BLSE+ ampC+

Resistance E. coli VIM1 +KPC3+TEM1

Resistance to avibactam

Mutations E. coli SHV1, KPC+ ESBL +porin mutation

(ompK 35, ompK37)

Relebactam KPC except mutation porin ompK36

BAS

Chemical structures.

Varbobactam = RPX 7009

+ imipenem = Carbavance KPC ampC

Inactif MBL et Oxacillinase de classe D

Until recently, ‘Carbavance’ was known as the combination

of biapenem and RPX7009. Then, there was a new moniker,

‘RPX2014/RPX7009’, also referred to as ‘Carbavance’

Gaps

Cefolozane –tazo

(KPC, metall- enzyme) certaines BLSE OXA 11,14,15,16

CEFTAZIDIME**- AVI

(Acineto, ANA , Gram +, metalloenzyme, NDM1 Pyo)

BLSE type OXA ou VEB

Carbapanémases OXA chez Acineto

Pyo si cefta –R par efflux

Siderophore sulfactam

Pyo si efflux

TEM 3 ou 5 (selon souches)

Klebsiella TEM1,SHV2, KPC2

Galani et al. J Chemother 2012

What do some think about new drugs?

SFM Mars 2016LIRIC UMR 995 Dubreuil L

Allaphase Pharma LLC

Aztreonam PLUS Avibactam – A New Bright Star in the Night

Sky

Eravacycline Conference Call: Unrevealing and Disappointing

Dalbavancin Approval Issues: A Case of Much Ado About

Nothing

What’s in a Name? Would ‘Carbavance’ Still Smell as Sweet?