CSE in critically ill patinets with mdr infection. Pptx

CEFOPERAZONE SULBACTAM

1. Ceftriaxone Sulbactam EDTA

2. AMR – Global concern 10 million more people would be expected to die every year due to AMR by 2050 2 million deaths are projected to occur in India due to AMR by the year 2050

3. AMR – Global Threat - Carbapenems Resistance Rates in India 72 % resistant 30 % resistant 69 % resistant 42 % resistant The State of World’s Antibiotics 2019 Report CDDEP

4. AMR – Resistance rates to third generation cephalosporins 93 % resistant 93 % resistant 83 % resistant The State of World’s Antibiotics 2019 Report CDDEP 93 % resistant

5. https://dbtindia.gov.in/sites/default/files/IPPL_final.pdf last accessed Oct 2021 Indian Critical Priority Pathogen Enterobacteriaceae (Klebsiella pneumoniae and Esherichia coli) Carbapenem-R Tigecycline-R Colistin-R Non-fermenting bacteria (Acinetobacter baumannii and Pseudomonas aeruginosa) Carbapenem-R Colistin - R WHO Priority Pathogen List Global Critical Priority Pathogen

6. Key Highlights Bacterial AMR is a health problem whose magnitude is at least as large as major diseases such as HIV and malaria, and potentially much larger. There were an estimated 4·95 million (3·62–6·57) deaths associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911–1·71) deaths attributable to bacterial AMR. Lower RTI accounted for more than 1·5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. Lancet 2022; 399: 629–55

7. The six leading pathogens for deaths associated with resistance (E. coli, followed by S. aureus, K. pneumoniae, S. pneumoniae, A. baumannii, and P. aeruginosa) were responsible for 9,29,000 deaths attributable to AMR and 3·57 million (2·62–4·78) deaths associated with AMR in 2019. Global deaths attributable to and associated with bacterial AMR by pathogen, 2019 Lancet 2022; 399: 629–55

8. Antibiotic resistance is increasing at an alarming rate and is now widely recognised as a global issue that requires urgent attention. Despite several strategies being deployed, resistance levels are still of huge concern. ARBs represent a promising avenue of research to counter Antibiotic Resistance Breaker

9. Antibiotic Resistance Breaker Antibiotic resistance breakers (ARBs) capable of re- sensitising resistant bacteria to antibiotics

10. Ceftriaxone sulbactam EDTA EDTA as Resistance breaker Zn Ion Chelation in MBLs 1 ( Reduces expression of efflux pumps) 2 3 (Increases permeability by chelating Mg ion) Disrupts biofilm formation Inhibits horizontal transfer of resistance by plasmids 4 5 Ceftriaxone sulbactam EDTA may be useful option for the treatment of MDR GNB infection Chaudhary Manu. African Journal of Microbiology (2012) Research Vol. 6(39), pp. 6799-6804 Finnegan S. 2015 Probable Mechanisms

11. Mechanism of Action

12. Patented in countries Chelate the Zn Ions in MBLs

13. Indication

14. ELORES INDICATION Presenter’s Name DD-MM-YEAR Slide No.

15. DOSAGE

16. The usual adult daily dose is 1.5 g to 3.0 g every 24 hr or twice daily, which could be increased as per severity of infection to maximum dosage of 6.0 g per day In two divided doses ( 3.0 g bd). Renal and hepatic impairment: Under following conditions dosage needs to be adjusted: Pre-terminal renal failure (Creatinine clearance < 10 mL/min): Daily dosage should be limited to < 3 g

17. Spectrum of Activity Acinetobacter E. coli Pseudomonas Aeruginosa Klebsiella Activity against a wide range of ESBL and MBL producing Gram-negative pathogens and is used as a treatment option for a multitude of bacterial infections.

18. Breakpoints Summary

19. Clinical Evidence

20. The primary objective To show the noninferiority of CSE to meropenem at the test-of-cure visit (8–12 days after the end of therapy), with a noninferiority margin of 10%. Patient population Eligible patients were randomized 1:1 to CSE 1000 mg/500 mg/37 mg every 12 hours or meropenem 1000 mg every 8 hours. Both CSE and meropenem were administered for 5–14 days as 30-minute intravenous infusions. Study Design and Study Population PLEA was a phase 3 , prospective, randomized, multicenter, double-blind, double-dummy, parallel-group, noninferiority trial designed and conducted in accordance with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance for cUTI trials. (n=230) The primary objective To show the noninferiority of CSE to meropenem at the test-of-cure visit (8–12 days after the end of therapy), with a noninferiority margin of 10%. Patient population Eligible patients were randomized 1:1 to CSE 1000 mg/500 mg/37 mg every 12 hours or meropenem 1000 mg every 8 hours. Both CSE and meropenem were administered for 5–14 days as 30-minute intravenous infusions. Study Design and Study Population PLEA was a phase 3 , prospective, randomized, multicenter, double-blind, double-dummy, parallel-group, noninferiority trial designed and conducted in accordance with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance for cUTI trials. (n=230)

21. Primary Endpoints: The primary efficacy endpoints of this study were defined separately to adhere to the varying regulatory guidelines of the FDA and EMA. The FDA coprimary endpoints were 1. The proportion of patients with clinical cure at TOC in the microbiologic modified intent-to-treat ( mMITT ) population and 2. The proportion of patients with clinical cure and microbiological eradication at TOC in the mMITT population. The EMA primary endpoint 1. Microbiological eradication at TOC in the mMITT population Secondary Endpoints: Per-patient and per-pathogen clinical and microbiological response at EOT and LFU; Per patient and per-pathogen clinical and microbiological response at EOT, TOC, and LFU in patients infected with an ESBL producing pathogen. Safety and tolerability were assessed by monitoring reported adverse events (AEs).

22. Results

23. Key Pointers Ceftriaxone Sulbactam EDTA is a novel antibiotic resistance breaker, approved by DCGI and has activity against NDM as well as ESBL. It has undergone complete drug development which is a major challenge in Indian scenario. It is safe and well tolerated drug Used as a combination with polymyxin in severe infection such as VAP and BSI. In phase 3 evaluation, ceftriaxone sulbactam EDTA has shown non inferiority against meropenem in the treatment of patients with cUTI, including AP.

24. Thank You