Beta-lactamase inhibition: A potted history of beta lactamase and lessons from recent development of betalactamase inhibiter combinations

Transcription

1 Beta-lactamase inhibition: A potted history of beta lactamase and lessons from recent development of betalactamase inhibiter combinations Dr Shampa Das, Senior Lecturer, Molecular and Clinical Pharmacology, University of Liverpool

2 !-lactamase inhibition: A potted history of! lactamase and lessons from recent development of!- lactamase inhibitor combinations Shampa Das Shampa Das PKPD Ltd/ Senior Lecturer, University of Liverpool BSAC, January 15 th,

3 Outline Brief overview of!-lactams (BLs) and!-lactamase inhibitors (BLIs) Challenges of developing BL-BLI combinations Thoughts on why we develop BL-BLI combinations rather than a standalone inhibitor 3

4 What are!-lactam antibiotics? There are 5 basic mechanisms by which antibiotics act: Inhibition of cell wall synthesis Inhibition of protein synthesis Alteration of cell membranes Inhibition of nucleic acid synthesis Anti-metabolite activity 4

5 What are!-lactam antibiotics? There are 5 basic mechanisms by which antibiotics act: Inhibition of cell wall synthesis Inhibition of protein synthesis Alteration of cell membranes Inhibition of nucleic acid synthesis Anti-metabolite activity!-lactams bind to penicillin binding proteins (PBP) PBP enzymes cross-link the peptidoglycan layer of the cell wall Inhibition of this slows cell wall synthesis eventually resulting in cell lysis 5

6 !-lactams are one of the most commonly used antibiotics Well used because they have bactericidal effect, well tolerated and broad spectrum Account for majority of parenteral prescriptions in the US There are many different PBPs and thus a diverse range of!-lactams with different spectrum of activity: Penicillins Cephalosporins Carbapenems Monobactams As monotherapy, cephalosporins and carbapenems account for the most use 6

7 Resistance to!-lactam antibiotics!-lactams are becoming less effective due to emerging resistance, of which there are several mechanisms: Inactivation by!-lactamase enzymes Changes in active site of PBPs which reduces the affinity of!-lactam antibiotics Alteration or loss of porin, reducing access of!-lactams in Gram-negative bacteria Production of efflux pumps 7

8 Hydrolysis by!-lactamases is the primary resistance mechanism to affect the activity of!- lactams!-lactamases hydrolyse the!-lactam ring thus inactivating the!-lactam There has been a rapid and growing emergence of!-lactamases since the 1960 s 8

9 !-lactamases Serine!-lactamses Metallo-!-lactamses Class A Class C Class D Class B E. coli, Klebsiella, Pseudomonas ESBLs TEM, SHV, CTX-M Amp C Enterobacter, Citrobacter, Proeus, Serratia, Pseudomonas OXA carbapenameses Eg. OXA-48 Acinetobacter, E. coli, Pseudomonas carbapenamases NDM-1, VIM-1 IMP Pseudomonas, Acinetobacter E. coli, Klebsiella carbapenamases KPC Different types of!-lactamases which have different affinity to!-lactams 9

10 Impact on!-lactam antibiotics Penicillins limited utility as monotherapy now due to!-lactamases Cephalosporins generally broad spectrum, but use is being limited by extended spectrum!-lactamases (ESBLs) and metallo-!- lactamases (MBLs) Monobactams only Aztreonam licensed, labile to ESBLs and most carbapenemases but stable to MBLs Carbapenems broad spectrum and not susceptible to ESBLs but are susceptible to carbapenemases (KPC, some OXA and MBLs) 10

11 !-lactamase inhibitors (BLIs) Developed to be co-admistered with!-lactam antibiotics BLIs bind to!-lactamases, preventing hydrolysis of the!-lactam Used in combination with a!-lactam to extend its spectrum of activity Generally little inherent antibiotic activity 11

12 Early!-lactamase inhibitors Contain!-lactam ring in structure Some!-lactam activity Inhibit non-carbapenamse Class A enzymes (i.e. not KPC) 12

13 BL-BLI combinations Clavulanic acid was developed with amoxycillin as the first BL-BLI combination Subsequently tazobactam and sulbactam developed with similar spectrum of activity Sulbactam is generally combined with ampicillin Tazobactam is combined with piperacillin More recently tazobactam has been approved in combination with ceftolozane AAI101 is a new BLI currently in development with extended activity 13

14 Non-!-lactam-!-lactamase inhibitors Within the last 10 years, new classes of BLIs have been developed One class is based on a diazabicyclooctane structure which does not contain the!-lactam ring avibactam Tend to have a broader spectrum of activity including some of the Class A carbapenemases (KPC), Class C and some Class D Avibactam in combination with ceftazidime is approved Others such as relebactam and nacubactam in development 14

15 Other BLI s Vaborbactam is boronic acid and also doesn t contain the!-lactam ring Developed to target KPC carbapenemases Recently approved in combination with meropenem 15

16 Activity of recently approved BL/BLI combinations Class A Class B Class C Class D BL/BLI ESBL KPC MBL Amp C OXA - carbapenemases Ceftazidime-avibactam Ceftolozane-tazobactam Meropenem-vaborbactam Different BL/BLI combinations have different spectrum of activity 16

17 Challenge of metallo-!-lactamases (MBLs) Broad substrate specificity and can hydrolise most!-lactams apart from monobactams NDM-1 is a metallo-!-lactamase Treatment options are more limited to agents such as colistin and tigecycline which are associated with more toxicity Aztreonam-avibactam is currently in clinical development Novel MBL inhibitors are in development 17

18 Development of BL-BLI combinations Developed as combination agent Need to demonstrate that the combination provides activity that the single agent doesn t Can t compare BL-BLI to!-lactam partner alone, as this would exclude patients for which the!-lactam is resistant Regulatory pathway is to conduct a non-inferiority study However, this can provide limited information on activity of the BLI 18

19 Limitations with data from the non-inferiority study Ceftazidime-avibactam compared to meropenem and meropenem vaborbactam compared to piperacillin-tazobactam in Phase 3 This precludes the recruitment of patients with carbapanemases (KPC) Comparator arm not efficacious against KPC Stringent requirements about prior use of antibiotics Impacts the type of patient recruited less likely to be infected with resistant pathogens Percentage of patients with resistant pathogens in randomisedcontrol trials is low (<20%) 19

20 Resistant pathogen studies In both the ceftazidime-avibactam and meropenem-vaborbactam programmes a resistant pathogen study was conducted Comparator arm was best available therapy Studies very difficult to recruit especially in US and central Europe Trying to develop drugs for emerging problem 20

21 Dose selection Correct dose selection is critical Under-dosing will lead to emergence of resistance BLI doesn t have activity: Need quantify dose of BLI through the activity of the BL partner Dose ranging in clinical studies will not help dose selection of the BLI Understanding the pharmacokinetic-pharmacodynamic (PK-PD) relationship becomes more critical 21

22 Pharmacodynamics of BLI Need to understand the pharmacodynamics (PD) of the BLI PD may be different to the partner!-lactam Aim is to convert infecting bacteria to!-lactamase-negative phenotype Due to lack of inherent activity, PD measurement is impact on activity of the!-lactam partner Experiments must be in!-lactam-resistant organisms with a background of!-lactam which is ineffective alone, but efficacious in combination with the BLI More challenging than experiments to understand the PD of a single agent 22

23 Further considerations with dose selection Ideally the pharmacokinetics of the!-lactam should be comparable to the BLI The BLI is needed at a pharmacodynamically active level for as long as the!-lactam Free β-lactam conc Activity of!-lactam BLI needed to support the pharmacodynamic effect of!- lactam MIC of bacterium dosing interval 23

24 Challenges with PK of both agents BL-BLIs developed as combination agents: Designed to be administered from a single vial Eg. if!-lactam with long half life partnered with BLI with short half-life Difficult it will be difficult to adjust the dosing of each to administer together Concentration!-lactam Need to consider on dose adjustments, eg. renal impairment, DDI, hepatic impairment, paediatric dosing etc Time!-lactamase inhibitor 24

25 Partnering BLIs with multiple!-lactams Because of the heterogeneity of!-lactamases, they bind to different!-lactams and BLI s with different affinity Thus there is a difference to how labile different!-lactams are to the presence of!-lactamases This in turn impacts the amount of BLI that is required The amount of BLI required for one!-lactam partner may differ from other!-lactam partners, which will impact the dose and regimen i.e. PD may be different 25

26 An example of this is avibactam Avibactam is a BLI which is approved for use in combination with ceftazidime (CAZ-AVI): Avibactam dose designed to achieve PD target of ft> threshold concentration of 1mg/L Approved dose is 2g CAZ/500mg AVI, 2h infusion, q8h Avibactam is also currently in development with aztreonam (ATM-AVI) However the PD target in combination with aztreonam is different Threshold target is higher at 2.5mg/L Thus dosing needs to be different ATM-AVI tested in Phase 3 trials at 500mg ATM /167mg AVI 30min infusion loading dose, with maintenance doses of 1500 ATM/500mg AVI 3h infusion, q6h 26

27 Why don t we develop a standalone BLI? Dosing is the biggest challenge: Different requirements with different!-lactam partners due to different binding affinity Accounting for differences in PK Incorrect and inadequate dosing is a significant risk and threat to emergence of resistance Currently there is no regulatory pathway What clinical evidence would be required? Clinical trials with at least one!-lactam partner would be needed Clinical programme with multiple partners would be costly and challenging 27

28 Conclusions!-lactams are a vital and commonly used antibiotic but emergence of resistance is threatening their utility Development of BL-BLI combinations has been critical to the continued use of!-lactams Clinical development is challenging Currently a development path for standalone BLI s is not apparent 28