Comment l EUCAST fixe les concentrations critiques (Breakpoints), Associations inhibiteurs de ß-lactamases et ß-lactamines. Nouvelles molécules

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1 Comment l EUCAST fixe les concentrations critiques (Breakpoints), Associations inhibiteurs de ß-lactamases et ß-lactamines Nouvelles molécules L. Dubreuil Maître de conférences en Pharmacologie Professeur de Bactériologie clinique

2 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 Ceftolozane/tazobactam = Zerbaxa 1.5 g q8h ou 3 g q8h Previous names: CXA-101, CXA-201, FR

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4 Log 10 CFU/thigh at 24 h The Efficacy of Ceftolozane Correlates Best With %Time > MIC (%T>MIC) = Zerbaxa 4 Neutropenic mouse thigh infection model used to establish ceftolozane parameters 1 %T>MIC is the PK/PD measure most correlated with the in vivo efficacy of ceftolozane 10 9 R 2 = 20.0% R 2 = 45.9% R 2 = 61.0% C max /MIC h AUC/MIC Time>MIC R 2 represents the percentage of variance in colony forming unit (CFU)/thigh that can be attributed to each PK/PD index. AUC, area under the curve; MIC, minimum inhibitory concentration. Organism used: Klebsiella pneumoniae Craig and Andes. Antimicrob Agents Chemother. 2013;57: For Internal Training Purposes Only 4

5 In vitro PD model: Ceftolozane 5 Relationship between ft>mic and log reduction in 24 hr viable counts

6 Summary Pharmacodynamic Ceftolozane Targets 6 Stasis %T > MIC target of < 30% derived from neutropenic mouse thigh models for ceftolozane was lower than other cephalosporins %T>MIC does not change based on MIC Mean Stasis %T>MIC 1-log kill %T>MIC 2-log kill %T>MIC S. pneumoniae P. aeruginosa Enterobacteriaceae (wild-type) NA Enterobacteriaceae (ESBL producers) NA %T>MIC, percentage of time that the drug concentration exceeds minimum inhibitory concentration; ESBL, extended spectrum β-lactamase. 1. Lepak et al. Antimicrob Agents Chemother. 2014;58(10): Craig and Andes. Antimicrob Agents Chemother. 2013;57:

7 Change in Log 10 (CFU/mL) In Vitro Efficacy of Tazobactam Correlates Best With %Time > Threshold 7 Dose fractionation studies used to establish pharmacokinetic/pharmacodynamic (PK/PD) parameters of tazobactam in combination with ceftolozane The %Time > threshold concentration was the exposure measure most associated with tazobactam efficacy, regardless of enzyme expression CTX-M-15 producing Escherichia coli 2 0 R 2 = R 2 = R 2 = Dose fractionation schedule Control q24h q12h q8h q6h Construct of enzyme expression High β-lactamase Moderate β-lactamase Low β-lactamase AUC (mg/l h) C max (µg/ml) %Time > Threshold a a The threshold concentration was 0.05 mg/l for the low- and moderate-β-lactamase genetic constructs and 0.25 mg/l for the high-β-lactamase genetic constructs AUC, area under the plasma concentration-time curve; C max, maximum (peak) plasma drug concentration. VanScoy et al. Antimicrob Agents Chemother. 2013;57: For Internal Training Purposes Only 7

8 METHODS Monte Carlo Simulation 8

9 METHODS Monte Carlo Simulation 9

10 10 CEFTOLOZANE/TAZOBACTAM Monte Carlo Simulations Population PK parameters from the analysis were input into Pharsight Clinical Trial Simulator 1000 subjects were simulated Dosing regimen =1000 mg ceftolozane Q8h as a 1-hr infusion Intensive plasma sampling simulated on Day 7 Target attainment rates were determined for MICs ranging from mg/l Probability of target attainment by MIC MIC (mg/l) 30% T>MIC (%)

11 11 Probability of Target Attainment Against P. aeruginosa 1.0-g CEFTOLOZANE dose PTA is 94.7% for the 1 log 10 kill target against Pseudomonas with an MIC value up to 8 mg/l in plasma for the 1 g ceftolozane dose Melhem et al. ECCMID Poster P1743. T >CMI 40% For Internal Training Purposes Only 11

12 Probability of Target Attainment Against Enterobacteriaceae 1.5-g CEFTOLOZANE/TAZOBACTAM dose 12 PTA is 80.9% for the 1 log 10 kill target against Enterobacteriaceae with an MIC value up to 4 mg/l in plasma for the 1.5 g ceftolozane/tazobactam dose %T>MIC, percentage of time that the drug concentration exceeds minimum inhibitory concentration. Rubino et al. ICAAC Poster A

13 Probability of Target Attainment Against Enterobacteriaceae 1.5-g CEFTOLOZANE/TAZOBACTAM dose 13 PTA is 80.9% for the 1 log 10 kill target against Enterobacteriaceae with an MIC value up to 4 mg/l in plasma for the 1.5 g ceftolozane/tazobactam dose %T>MIC, percentage of time that the drug concentration exceeds minimum inhibitory concentration. Rubino et al. ICAAC Poster A

14 % of Isolates CEFTOLOZANE/TAZOBACTAM PACTS 2011: Comparative Activity Against Enterobacteriaceae Ceftolozane/tazobactam Ceftolozane Ceftazidime Piperacillin-Tazobactam MIC (mg/l) MIC (mg/l) Range MIC 50 MIC 90 % > 8 Ceftolozane/tazobactam Ceftolozane Ceftazidime Piperacillin/tazobactam 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)

15 15 Allure anormale de la courbe ceftolozane-tazobactam, Le problème n apparaît pas avec ceftazidime-avibactam

16 T >CMI 50% 2log Avibactam ft >1 mg/l 16

17 Simulated Target Attainment Data CAZ MIC (µg/ml) *C T =1 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 Zavicefta 2000mg CAZ/500mg NXL104 2-h infusion (Proposed Phase 3 dose) 50% T>MIC & T>*C T Thus a dose of 2000mg CAZ/500mg NXL104 given as a 2h infusion is intended for Phase 3

18 929 Shields novel ST258, clade II sublineage, which are not hypermutators

19 Tremendous new!

20 bicyclo-acyl hydrazide = BCH diazabicyclooctanes= DBO Nacubactam = Vaborbactam Relebactam VNRX 5133

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22 Pharmacodynamics of Ceftazidime and Avibactam in Neutropenic Mice with Thigh or Lung Infection Johanna Berkhout, Maria J. Melcherset al. Antimicrobial Agents and Chemotherapy January 2016 Volume 60 1 We conclude that the effect of avibactam in combination with ceftazidime is dependent on the time above threshold %ft>ct 1mg/liter. The results found in this study are proposed to be applicable to designing and assessing human dosing regimens. %ft>ct 0,5 1 4

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24 M. J. Melchers, E. et al. Ceftolozane-tazobactam AAC (12) The main PDI (pharmacokinetic/pd index (PDI)-response) that correlated with the effect of tazobactam was the ftct achieved with a CT of 0.5 mg/liter tazobactam.

25 The Relationship Between Tazobactam %T>Threshold and Change in Log 10 CFU PK/PD In Vitro Infection Model Ceftolozanetazobactam Seuil de tazobactam The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. Vanscoy B, Mendes RE, McCauley J, Bhavnani SM, Bulik CC, Okusanya OO, Forrest A, Jones RN, Friedrich LV, Steenbergen JN, Ambrose PG. Pharmacological basis of β-lactamase inhibitor therapeutics: tazobactam in combination with Ceftolozane. Antimicrob Agents Chemother For Internal Training Purposes Only Dec;57(12):

26 CT = ½ CMI The enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates was the product of the individual isolate s ceftolozane-tazobactam MIC value (determined with a tazobactam concentration of 4 mg/liter) and 0.5. The tazobactam %Timethresholds associated with net bacterial stasis and 1- and 2- log10 CFU reductions in bacteria at 24h were 65.9, 77.3, and 90.2% of the dosing interval

27 Aztréonam-Avibactam

28 aztréonam

29 Johan W. Mouton Antimicrobial Agents and Chemotherapy 2017 Volume 61 Issue 9 Pharmacodynamics of Cefepime Combined with Tazobactam against Clinically Relevant Enterobacteriaceae in a Neutropenic Mouse Thigh Model Exposure-response relationships (ERRs) of tazobactam A sigmoidal maximum-effect (Emax) model was fitted to the data Time-dependent activity of tazobactam. The cumulative percentage that freedrug concentrations are above the threshold concentration over a period of 24 h [%ftct], The threshold concentration (CT) best correlating with tazobactam efficacy was 0.25 mg/ liter, as evidenced by the best fit of the percentage of time above the threshold concentration (%ftct) and response. A mean %ftct of 24.6% (range, 11.4 to 36.3%) for a CT of 0.25 mg/liter was required to obtain a bacteriostatic effect.

30 Dose fixe de cépépime on fait varier: les concentrations de Tazobactam les rythmes d administration du tazobactam Abaissement logarithmique de la charge bactérienne [Δlog10 CFU] dans la cuisse de souris The first approach was to determine the relationship between exposure and efficacy for a range of threshold levels and by visual inspection to decide which looked best.

31 To quantify these relationships, the R 2 for each of the plots was plotted against the concentration threshold value, and a fourth-order polynomial was fitted to the data points to allow calculation of the optimum value. ax 4 + bx 3 + cx 2 + dx + e = 0 Ferrari ( ) The calculated CT with the highest R 2 was subsequently used as the tazobactam threshold for each strain. 0,25mg/L

32 If CT is indeed the PK/PD index that best predicts efficacy, there should be a CT at which the %ftct response relationships of the q2h, q4h, and q6h regimens do not differ significantly from each other. Indépendance du régime d administration

33 Synthèse des concentrations seuils des inhibiteurs Agent Inhibiteur seuil d activité Antibiotique associé ft > CT T > CT T > CMI Ceftolozane-Tazobactam 0,5 (½ CMI) > 90% 35-50% Ceftazidime-Avibactam 1 50% 50% Aztréonam-Avibactam 2,5 50% 50% Céfépime-tazobactam 0,25 25% bactériostase Nacubactam-méropenem ¼ CMI L. Dubreuil 2018

34 MIC (mg/l) 30% T>MIC (%) La pharmaco vous dis je! Le Monte Carlo! Et la distribution des CMI? et la clinique?

35 cssti: clinical & microbiological success by MIC Gram-positive pathogens MIC (mg/l) S. aureus (all) n/n(%) MRSA n/n(%) MSSA n/n(%) β Streptococci n/n(%) /64 (100.0) /19 (94.7) /12 (100.0) 11/12 (91.7) /5 (100.0) /3 (100.0) - 3/3 (100.0) /79 (91.1) 73/79 (92.4) 148/156 (94.9) 149/156 (95.5) - 18/18 (100.0) 72/79 (91.1) 73/79 (92.4) 130/138 (94.2) 131/138 (94.9) /109 (93.6) 101/108 (93.5) 1/1 (100.0) /11 (100.0) 11/11 (100.0) /4 (50.0) 2/4 (50.0) - Total* 338/362 (93.4) 340/362 (93.9) 132/141 (93.6) 206/221 (93.2) 208/221 (94.1) /100 (99.0) 98/100 (98.0) Microbiological success n/n(%), Clinical or clinical and microbiological success n/n(%) (per isolate response, not per patient) *For isolates with susceptibility results available 35

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37 The Novel β-lactamase Inhibitor, ETX-2514, (DBO)in Combination with Sulbactam Effectively Inhibits Acinetobacter baumannii

38 Activités comparées des inhibiteurs de ß-lactamases Agent KPC A MDL B ampc C Oxa D Pseudomonas aeruginosa MDR Acinetobacter baumannii MDR Avibactam-ceftazidime X N X v X N Aztreonam-Avibactam X X* X N N Relebactam-imipenem X X X Vaborbactam-Meropenem X N X N VNRX Céfépime X X X X X Zidebactam--Céfépime X X X X X X Nacubactam-Méropenem X X X v X X ETX Sulbactam X X X X * Entérobactérales L. Dubreuil 2018

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40 Cefiderocol (S ), A Siderophore Cephalosporin,

41 Cumulative percentage (%) Antibacterial activity against CRE Carbapenem resistant Enterobacteriaceae (n=149) S CAMHB+apo-T Chelex-treated ISB CAMHB S Ceftazidime Meropenem MIC ( g/ml) The test strains include both KPC- and NDM-producers Ceftazidime, Meropenem: MIC was determined in CAMHB Influence du chélateur sur les valeurs de CMI de la sidérophore-céphalosporine S

42 Relationships between %T f>mic and Efficacy in Rat RTI Models Efficacy against MDR P. aeruginosa and A. baumannii Chelex treated ISB Test strains Results of rat infusion study MIC (µg/ml) %T f>mic 1-hour infusion P. aeruginosa ATCC hour infusion P. aeruginosa SR hour infusion (IMP-1 producer, MDRP) 3-hour infusion hour infusion A. baumannii hour infusion A. baumannii hour infusion (MDRA, CC92) 3-hour infusion hour infusion A. baumannii hour infusion A. baumannii hour infusion (MDRA) 3-hour infusion :Change from baseline control log 10 CFU/lung : -ca 2 log 10 reduction Conclusion: The probability of achieving a PK/PD exposure based on 75% of T f>mic in plasma is recommended to be the appropriate target to demonstrate the clinical efficacy of S

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45 Triazaacénaphthylène Spiropyrimidénétrione No cross-resistance has been described

46 Polymyxin Spero Therapeutics is developing SPR 741, a lead potentiator candidate, a cationic peptide and a derivative of the compound polymyxin B, which interacts with.

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