BMR nouveaux antibiotiques Dubreuil, PhD, PharmD - LIRIC UMR 995 Inserm/Université Lille France

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1 BMR nouveaux antibiotiques Dubreuil, PhD, PharmD - LIRIC UMR 995 Inserm/Université Lille France Lille Octobre 2016

2 Bad bugs need new drug MRSA LIRIC UMR 995 Dubreuil L S. pneumoniae SFM Mars 2016

3 Adverse effects toxicity Exit the floxacin s : gati tema, trova, tosuflo Needs for MRSA? Lack of activity against MDR gram-negative bacilli LIRIC UMR 995 Dubreuil L SFM Mars 2016

4 + Ertapenem + doripenem against KPC

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6 MIC DISTRIBUTION ESBL/AmpC E. coli (n=1155) E. coli MIC (µg/ml) Remarks Method > CTX-M Agar MIC non CTX-M-ESBL Agar MIC AmpC Agar MIC ESBL E-test CTX-M group 1 E-test CTX-M group 9 E-test AmpC E-test non CTX-M-ESBL E-test CTX-M E-test ESBL Agar MIC CTX-M group 1 Vitek CTX-M group 9 Vitek ESBL Vitek CTX-M group 1 E-test CTX-M group 1 + AmpC E-test CTX-M group 9 E-test CTX-M group 9 + AmpC E-test TEM-ESBL E-test TEM-ESBL + AmpC E-test AmpC E-test Total % MIC 90 = 16mg/L Cumul %

7 Monte Carlo simulation 2000 g x 2 PDT : 40 to 50% Healthy volunteers and non-icu patients Data from Beecham 95% and 99% CI In healthy volunteers => 8 to 16 mg/l A. Muller & J. Mouton, internal data analysis is still ongoing

8 Monte Carlo simulation 2000 g x 3 PDT : 40 to 50% Healthy volunteers and non-icu patients Data from Beecham 95% and 99% CI In healthy volunteers => 16 to 32 mg/l A. Muller & J. Mouton, internal data analysis is still ongoing

9 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

10 Strategies against MDR

11 Cubist Pharmaceuticals The Shape of Cures to Come Ceftolozane/tazobactam = Zerbaxa 1,5g X 8h 11

12 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 Breakpoint: Previous names: CXA-101, CXA-201, FR mg/l Enterobacteriaceae, 4 mg/l Pseudomonas 12

13 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 Kinetic parameters of the P. aeruginosa AmpC β-lactamase Takeda et al. Int J Antimicrob Agents Nov;30(5):

14 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 MIC (mg/l) Phenotype Strain Ceftolozane Ceftazidime Imipenem Aztreonam AmpC derepressed con AmpC deficient/oprd OprD AmpC derepressed/oprd conD Parent PAO MexAB-OprM 2 PAO >16 MexXY-OprN 2 PAO1-Takai Parent PS MexCD-OprJ 2 PS C Livermore et al. Int J Antimicrob Agents Nov;34(5):402-6 Moulds et. al. ICAAC Poster C

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16 TAZOBACTAM Mechanism of Action Tazobactam potentiates the in vitro activity of ceftolozane against the majority of ESBL+ Enterobacteriaceae 1 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 Activity of Ceftolozane/tazobactam and Piperacillin/tazobactam against 169 ESBL-Producing E. coli and K. pneumoniae Strains 2 1. Livermore et. al. J Antimicrob Chemother Sep;65(9): Titelman et. al. Diagn Microbiol Infect Dis May;70(1):

17 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

18 Activity of NXL104 ( a new ß-lactamase inhibitor) in Combination with ß-lactams Avibactam L. J. DUBREUIL 1, 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)

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25 Simulated Target Attainment Data CAZ MIC (µg/ml) 500mg CAZ/125mg NXL min infusion (Phase 2 cuti dose) 50% T>MIC & T>*C T 2000mg CAZ/500mg NXL min infusion (Phase 2 ciai dose) 50% T>MIC & T>*C T 2000mg CAZ/500mg NXL104 2-h infusion (Proposed Phase 3 dose) 50% T>MIC & T>*C T *C T = Thus a dose of 2000mg CAZ/500mg NXL104 given as a 2h infusion is intended for Phase 3

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27 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)

28 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.

29 May The A+A Force Be With You!

30 Biedenbachet al.

31 Diazabicyclooctanes DBO s Relebactam

32 Relebactam

33 Cefepime + tazobactam ESBL AmpC

34 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 LIRIC UMR 995 Dubreuil L SFM Mars 2016

35 BAS

36 Chemical structures. Varbobactam = RPX 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

37 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

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43 Galani et al. J Chemother 2012

44 Allaphase Pharma LLC What do some think about new drugs? 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? LIRIC UMR 995 Dubreuil L SFM Mars 2016