ORBLICEF -Antimicrobial Training slides.pptx

Antimicrobial Drugs Description

1. OR BLI CEF ™ Moving From Trials to Clinical practice

2. Approved Indications: Indicated in adult patients (≥18 years) in following conditions caused by susceptible pathogens: Complicated urinary tract infections ( cUTIs ) including acute pyelonephritis. Hospital-acquired and ventilator-associated pneumonia (HAP/VAP). Bacteraemia occurring in association with above two indications. Cefepime and Enmetazobactam should be used only to treat or prevent infections that are culture proven or strongly suspected to be caused by susceptible bacteria

3. Spectrum of Activity: Demonstrated clinical efficacy: Gram-negative microorganisms: Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Proteus mirabilis Enterobacter cloacae complex In vitro susceptible microorganisms: Gram-negative microorganisms: Klebsiella aerogenes Klebsiella oxytoca Serratia marcescens Citrobacter freundii Citrobacter koseri Providencia rettgeri Providencia stuartii Acinetobacter baumannii   Gram-positive microorganisms: Staphylococcus aureus (methicillin-susceptible strains only) Species not susceptible to cefepime-enmetazobactam : Enteroccocus spp.

4. Recommended Dosage and Duration: Standard Dosage: 2 grams of Cefepime combined with 0.5 gram Enmetazobactam 8 hourly. Infusion Time: 2 hours for cUTI including Acute Pyelonephritis and associated bacteraemia 4 hours for HAP including VAP and associated bacteraemia Treatment Duration: cUTIs including AP: 7–10 days depending on severity. HAP/VAP: 7–10 days based on clinical response. Associated bacteraemia: Up to 14 days

5. Recommended Dosage Table: Indications Dosages Dosing interval Infusion duration Treatment duration complicated Urinary Tract Infections (cUTI) including pyelonephritis 2.5 grams (2 grams Cefepime and 0.5 grams Enmetazobactam ) 8 hourly 2 hours 7-10 days Hospital-acquired Pneumonia (HAP) including Ventilator Associated Pneumonia (VAP) 2.5 grams (2 grams Cefepime and 0.5 grams Enmetazobactam) 8 hourly 4 hours 7-10 days Bacteraemia associated with/suspected to be associated with cUTI , HAP or VAP 2.5 grams (2 grams Cefepime and 0.5 grams Enmetazobactam) 8 hourly 2 or 4 hours (depending on association with cUTI , HAP or VAP) Up to 14 days

6. Renal Impairment Dosage: Dose adjustment is recommended in patients with renal impairment who have an absolute estimated glomerular filtration rate (eGFR) less than 60 mL/min. Absolute eGFR (mL/min) Recommended dose of ORBLICEF™ Dosing Interval Mild (60 to <90) 2.5 grams (2 grams Cefepime and 0.5 grams Enmetazobactam ) Every 8 hours Moderate (30 to <60) 1.25 grams (1 gram Cefepime and 0.25 grams Enmetazobactam ) Every 8 hours Severe (15 to <30) 1.25 grams (1 gram Cefepime and 0.25 grams Enmetazobactam ) Every 12 hours End stage renal disease (<15) 1.25 grams (1 gram Cefepime and 0.25 grams Enmetazobactam ) Every 24 hours Patients requiring hemodialysis Loading dose of 1.25 grams (1 gram Cefepime and 0.25 grams Enmetazobactam ) on the first day of treatment, followed by 0.625 grams (0.5 grams Cefepime and 0.125 grams Enmetazobactam ) thereafter every 24 hours but after the haemodialysis session on haemodialysis days Every 24 hours Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) 2.5 grams (2 grams Cefepime and 0.5 grams Enmetazobactam) Every 48 hours

7. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Hypersensitivity to any cephalosporin antibacterial agent. Severe hypersensitivity (e.g., anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g., penicillins , carbapenems or monobactams).

8. Adverse effects: Common Adverse Effects: The most common adverse reactions that occurred in the Phase 3 study were: Alanine aminotransferase (ALT) increased (4.8%) Aspartate aminotransferase (AST) increased (3.5%) Diarrhoea (2.9%) Infusion site phlebitis (1.9%). A serious adverse reaction of Clostridioides difficile colititis occurred in 0.2% (1/516). Serious Adverse Effects: Anaphylaxis, Stevens-Johnson syndrome, Clostridioides difficile-associated diarrhea , neurotoxicity (e.g., seizures).

9. Mechanism of Action and Resistance: Mechanism of Action: Cefepime: Cefepime exerts bactericidal activity by inhibiting peptidoglycan cell wall synthesis as a result of binding to and inhibition of penicillin-binding proteins (PBPs). Enmetazobactam: It is a penicillanic acid sulfone β-lactamase inhibitor structurally related to penicillin against class A ESBLs. Enmetazobactam binds to β-lactamases and prevents the hydrolysis of cefepime. Cefepime-enmetazobactam : Demonstrates in vitro activity against Enterobacterales in the presence of some β-lactamases and extended-spectrum β-lactamases (ESBL) of the following groups: CTX-M, SHV, TEM, and VEB. Cefepime is inherently stable to hydrolysis by some AmpC cephalosporinases and OXA- 48. Cefepime-enmetazobactam is not active against bacteria that produce some KPCs (except KPC-2&3), metallo -β-lactamases (MBLs) or some oxacillinases (OXA except OXA-48). Mechanisms of Resistance: Production of carbapenemases . Efflux pumps and mutations in PBPs.

10. Clinical Breakpoints defined by EUCAST: S = Susceptible; R = Resistant; ATU = Area of technical uncertainity 1 For MIC determination, the concentration of enmetazobactam is fixed at 8 mg/L. 2 Susceptibility interpretive criterion are based on a dose of 2 grams cefepime and 0.5 g enmetazobactam every 8 hours by intravenous infusion over 2 hours. 3 For disk diffusion, use paper disks impregnated with 30/20 mcg cefepime-enmetazobactam. 4/A The beta-lactamases produced by the organisms either do not modify the parent cephalosporin or are insufficiently inhibited by the inhibitor. Therefore, the addition of the beta-lactamase inhibitor is not expected to add clinical benefits. Source: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Addenda/Cefepime-enmetazobactam_addendum_22_May_2024.pdf Minimum Inhibitory Concentrations (mcg/mL) 1,2 Disk Diffusion (zone diameter in mm) 3 Pathogen S R S R ATU Enterobacterales ≤4 >4 ≥22 <22 21-22 Pseudomonas aeruginosa Note 4 Note 4 Note A Note A  

11. Clinical Breakpoints defined by USFDA: S = Susceptible; SDD = susceptible-dose dependent; I = Intermediate; R = Resistant a Susceptibility interpretive criterion are based on a dose of 2 grams cefepime and 0.5 g enmetazobactam every 8 hours by intravenous infusion over 2 hours in patients with an estimated glomerular filtration rate from 60 mL/min to less than 130 mL/min. b For disk diffusion, use paper disks impregnated with 30/20 mcg cefepime-enmetazobactam. c Among Enterobacterales species, clinical efficacy was shown for  Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae complex. Source: https://www.fda.gov/drugs/development-resources/cefepime-and-enmetazobactam-injection Minimum Inhibitory Concentrations (mcg/mL) a Disk Diffusion b (zone diameter in mm) Pathogen S SDD I R S SDD I R Enterobacterales c < 8/8 - - > 16/8 ≥21 - - ≤20 Pseudomonas aeruginosa < 8/8 - - > 16/8 ≥18 - - ≤17

12. Disk Diffusion QC Ranges – CLSI: QC strain recommended for routine QC. Test one of these agents by a disk diffusion or MIC method to confirm the integrity of the respective QC strain b,c Footnotes: ATCC® is a registered trademark of the American Type Culture Collection. Per ATCC ® convention, the trademark symbol is used after “BAA” in each catalog number, in conjunction with the registered ATCC ® name. Careful attention to organism maintenance ( eg , minimal subcultures) and storage ( eg , −60°C or below) is especially important for these QC strains because spontaneous loss of the plasmid encoding the β-lactamase has been documented. If stored at temperatures above −60°C or if repeatedly subcultured , these strains may lose their resistance characteristics and QC results may be outside the acceptable ranges. To confirm the integrity of the QC strain, test one of the single β-lactam agents highlighted in orange by either a disk diffusion or MIC test method when the strain is first subcultured from a frozen or lyophilized stock culture. In some cases, only MIC ranges are available to accomplish this confirmation (see Table 5A-2). In-range results for the single agent indicate the QC strain is reliable for QC of β-lactam combination agents. It is not necessary to check the QC strain again with a single agent until a new frozen or lyophilized stock culture is put into use, providing recommendations for handling QC strains as described in M021 and M072 are followed. Strain may demonstrate two colony morphologies: 1) opaque and cream colored and 2) translucent. Both colony morphologies can be used. QC ranges were established using data from only one disk manufacturer. Disks from other manufacturers were not available at the time of testing.   References: CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests. 13th ed. CLSI standard M02. Clinical and Laboratory Standards Institute; 2018. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. 11th ed. CLSI standard M07. Clinical and Laboratory Standards Institute; 2018. Antimicrobial Agent Disk Content QC Organisms and Characteristics Escherichia coli ATCC ®a 25922 Pseudomonas aeruginosa ATCC ® 27853 Staphylococcus aureus ATCC ® 25923 Escherichia coli ATCC ® 35218 c,d Klebsiella pneumoniae ATCC ® 700603 b,c,d Escherichia coli NCTC 13353 b,c Klebsiella pneumoniae ATCC ® BAA-1705 ™ b,c Klebsiella pneumoniae ATCC ® BAA- 2814 ™ Acinetobacter baumannii NCTC 13304 b,c β- lactamase negative Inducible AmpC β-lactamase negative, mecA negative TEM-1 SHV-18 OXA-2 Mutations in OmpK35 and OmpK37 TEM-1 CTX-M-15 OXA-1 KPC-2 SHV KPC-3 SHV-11 TEM-1 OXA-27 Zone Diameter QC Ranges, mm Cefepime 30 µg 31–37 25-31 23-29 31–37 23-29 6-15 f – – 6-15 f Cefepime- enmetazobactam e 30/20 µg 32–38 26–32 – 32–38 26–32 27–33 – – –

13. MIC QC Ranges – CLSI a : QC strain recommended for routine QC. Test one of these agents by a disk diffusion or MIC method to confirm the integrity of the respective QC strain b,c Footnotes: Unsupplemented Mueller-Hinton medium (cation-adjusted if broth). See Table 5A-1 for QC ranges for combination agents from other drug classes. ATCC® is a registered trademark of the American Type Culture Collection. Per ATCC® convention, the trademark symbol is used after “BAA” in each catalog number, in conjunction with the registered ATCC® name. Careful attention to organism maintenance ( eg , minimal subcultures) and storage ( eg , −60°C or below) is especially important for these QC strains because spontaneous loss of the plasmid encoding the β-lactamase has been documented. If stored at temperatures above −60°C or if repeatedly subcultured , these strains may lose their resistance characteristics and QC results may be outside the acceptable ranges. To confirm the integrity of the QC strain, test one of the single β-lactam agents highlighted in orange by either a disk diffusion or MIC test method when the strain is first subcultured from a frozen or lyophilized stock culture. In-range results for the single agent indicate the QC strain is reliable for QC of β-lactam combination agents. It is not necessary to check the QC strain again with a single agent until a new frozen or lyophilized stock culture is put into use, providing recommendations for handling QC strains as described in M021 and M072 are followed. If the highest concentration tested on a panel is lower than the QC range listed for the particular antimicrobial agent and the MIC result obtained for the QC strain is interpreted as resistant, the QC strain can be considered reliable for QC of β-lactam combination agents ( eg , ampicillin panel concentrations 1–16 μg /mL; ampicillin Enterobacterales breakpoints [ μg /mL]: ≤ 8 [S], 16 [I], ≥ 32 [R]; MIC of > 16 μg /ml [R] would be acceptable for K. pneumoniae ATCC® 700603). Strain may demonstrate two colony morphologies: 1) opaque and cream colored and 2) translucent. Both colony morphologies can be used. Either strain highlighted in green may be used for routine QC of this antimicrobial agent. NOTE 1: MIC ranges apply to both broth microdilution and agar dilution unless otherwise specified. References: CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests. 13th ed. CLSI standard M02. Clinical and Laboratory Standards Institute; 2018. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. 11th ed. CLSI standard M07. Clinical and Laboratory Standards Institute; 2018. Antimicrobial Agent QC Organisms and Characteristics Escherichia coli ATCC ®b 25922 Pseudomonas aeruginosa ATCC ® 27853 Staphylococcus aureus ATCC ® 29213 Enterococcus faecalis ATCC ® 29212 Escherichia coli ATCC ® 35218 c,d Klebsiella pneumoniae ATCC ® 700603 c,d,e Escherichia coli NCTC 13353 c,d Klebsiella pneumoniae ATCC ® BAA-1705 ™c,d Klebsiella pneumoniae ATCC ® BAA-2814 ™ Acinetobacter baumannii NCTC 13304 c,d  β-lactamase negative  Inducible Amp C Weak β-lactamase mecA negative   TEM-1 SHV-18 OXA-2 Mutations in OmpK35 and OmpK37 CTX-M-15 OXA-1 KPC-2 TEM SHV KPC-3 SHV-11 TEM-1 OXA-27 MIC QC Ranges, µg/mL Cefepime 0.016–0.12 0.5–4 1–4 – 0.008–0.06 0.5–2 ≥ 64 – 32 16–128 Cefepime-enmetazobactam 0.03/8–0.12/8 0.5/8–2/8 – – 0.008/8–0.06/8 0.12/8–0.5/8 0.03/8–0.12/8 – – –

14. Pharmacokinetics: Absorption After 2 g cefepime and 0.5 g enmetazobactam IV infusion over 2 hours to 8 hourly, C max on Day 1 and Day 7 were 87–100 mcg/ml and 17–20 mcg/ml for cefepime and enmetazobactam respectively. There was no significant difference in C max and AUC between healthy volunteers and cUTI patients. Distribution Well distributed in bodily fluids and tissues including bronchial mucosa. The total volume of distribution was 16.9 L for cefepime and 20.6 L for enmetazobactam . Serum protein binding: Cefepime ~20% independent of its concentration in serum. Enmetazobactam the serum protein binding is negligible. An epithelial lining fluid (ELF) study showed that cefepime and enmetazobactam have similar lung penetration up to 73% and 62% at 8 hours post start of infusion. Biodistribution coefficient fAUC (ELF/plasma) over the entire 8h dosing interval of 47% for cefepime and 46% for enmetazobactam .  Biotransformation Cefepime is minimally metabolized in the liver (~7% of the administered dose). Enmetazobactam undergoes minimal hepatic metabolism. Elimination Both cefepime and enmetazobactam are primarily excreted via kidneys as unchanged substance. Elimination half-life of cefepime 2 g and enmetazobactam 0.5g are 2.7 hours and 2.6 hours, respectively. Urinary recovery of unchanged cefepime accounts for approximately 85% and for enmetazobactam , approximately 90% over a 24-hour period. Mean renal clearance for enmetazobactam was 5.8 L/h and mean total clearance was 7.6 L/h. There is no accumulation following multiple IV infusions.

15. Pharmacokinetics Pharmacokinetic Parameters Cefepime Enmetazobactam C max (µg/mL) 99.8 (26.4) 19.8 (6.3) AUC last ( μg•h /mL) 379.5 (123.3) 75.3 (30.8) % Bound to human plasma protein 20% Negligible V ss (L) 20.02 (6.44) 25.26 (9.97) CL (L/h) 5.8 (1.9) 7.6 (2.9) T 1/2 (h) 2.7 (1.1) 2.6 (1.1) Metabolism 2 Minimally m etabolized Route of elimination Renal % Excreted unchanged in urine 85% 90% Proportionality Exposure approximately proportional to dose following IV administration Accumulation Similar pharmacokinetics following single and multiple dosing Pharmacokinetic/pharmacodynamic relationship: The antimicrobial activity of cefepime has been shown to best correlate with the percentage of time of the dosing interval in which the free active substance concentration was above the cefepime-enmetazobactam MIC (% fT >MIC). For enmetazobactam , the pharmacokinetic/pharmacodynamic (PK-PD) index is the percentage of time of the dosing interval in which the free active substance concentration was above a threshold concentration (% fT >CT).

16. Advantage over Piperacillin-Tazobactam: Enhanced Efficacy Against Resistant Organisms: Cefepime-Enmetazobactam demonstrates higher efficacy against ESBL-producing E. coli and K. pneumoniae compared to Piperacillin-Tazobactam. Clinical Trial Data: In a Phase 3 ALLIUM trial, overall success was 79.1% for cefepime-enmetazobactam vs. 58.9% for piperacillin/tazobactam (adjusted stratified difference, 21.2% (95% stratified Newcombe CI, 14.3% to 27.9%). The superiority of cefepime-enmetazobactam versus piperacillin/tazobactam in overall response at TOC was also confirmed in the sub-group of patients with ESBL-producing uropathogens with a 30.2 % difference (95% stratified Newcombe CI, 13.4% to 45.1%). Lower Resistance Potential: Cefepime-enmetazobactam can overcome wider spectrum of beta-lactamases, including: Class A - CTX-M and SHV (ESBL), TEM and VEB (Penicillinases), KPC- 2 & 3 ( Carbapenemases ) Class C - AmpC (Penicillinases and most cephalosporinases) Class D - OXA- 48 ( carbapenemases ) In Vitro Data: Cefepime-Enmetazobactam is associated with lower MIC values (≤1 µg/mL for 90% of ESBL strains), compared to Piperacillin-Tazobactam, which often requires higher MICs (≥16 µg/mL) for the same effect. Favourable Safety Profile: Piperacillin-Tazobactam has been associated with a higher incidence of acute kidney injury (AKI) compared to Cefepime-Enmetazobactam. Clinical Safety Data: The incidence of AKI was 3.8% with Cefepime-Enmetazobactam vs. 7.5% with Piperacillin-Tazobactam in comparative studies. Source: https://journals.asm.org/doi/10.1128/aac.00105-19

17. Reason for Approval in HAP/VAP: The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the AUC in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains of K pneumoniae. The dose fractionation study suggested both  fT  > threshold and   f AUC:MIC are relevant PD indices. Cefepime alone, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v. ), had minimal antimicrobial effect. When cefepime was combined with enmetazobactam , a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The AUC ELF :AUC plasma  ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively with a biodistribution coefficient fAUC (ELF/plasma) over the entire 8h dosing interval of 47% for cefepime and 46% for enmetazobactam . ≥2-log kill (99%) in the lung was achieved with a plasma and ELF cefepime  fT  > MIC of ≥20% and enmetazobactam   f T  > 2 mg/l of ≥20% of the dosing interval. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269479/

18. Drug exposure targets for plasma and epithelial lining fluid (ELF) are shown in the left and right panels, respectively. The panels provide a way of identifying pairs of drug exposure targets for cefepime and enmetazobactam in plasma and ELF associated with various degrees of logarithmic killing in the lung.

19. Reason for 4 hour Infusion in HAP/VAP: Pharmacokinetics and Pharmacodynamics (PK/PD): HAP/VAP often involves more resistant pathogens and higher bacterial loads in a complex structure like the lungs. A prolonged infusion of 4 hours helps maintain higher plasma concentrations over time, ensuring better drug penetration into lung tissues and maximizing bacterial killing. Severity and Complexity of Infection: HAP/VAP is a more severe and complex infection, often associated with multidrug-resistant organisms. The extended 4-hour infusion ensures sustained drug levels, which is crucial for treating these severe infections, particularly in critically ill patients who may have altered drug distribution and clearance. Bacterial Resistance and MIC Considerations: The pathogens in HAP/VAP, in general have higher MICs. The prolonged infusion helps maintain drug concentrations above the MIC (% f T > MIC) for a longer period, improving the chances of successful treatment.

20. Why L-arginine? L-Arginine is used in the formulation of Cefepime-Enmetazobactam as a buffering agent (excipient). Its primary functions are: pH Stabilization: L-Arginine helps maintain the pH of the formulation within a suitable range (typically around pH 4.0-6.0), which is essential for the stability of the active ingredients. This prevents degradation of Cefepime and Enmetazobactam, ensuring the drug remains effective throughout its shelf life and during administration. Solubility Enhancement: L-Arginine can increase the solubility of Cefepime and Enmetazobactam in the formulation, facilitating their delivery into the bloodstream when administered intravenously. Minimization of Irritation: The use of L-Arginine as a buffering agent helps reduce the potential for local irritation at the injection site, which can occur if the solution’s pH is too acidic or too alkaline. Overall, L-Arginine plays a crucial role in optimizing the formulation of Cefepime-Enmetazobactam, contributing to its stability, efficacy, and patient tolerability.

21. Conclusion: Cefepime-enmetazobactam is indicated in Adult (≥18 years) in following conditions the caused by susceptible pathogens (culture proven ): cUTI including Acute Pyelonephritis HAP including VAP Bacteraemia associated with above two indications Key Takeaways: Cefepime-enmetazobactam is superior than Piperacillin-Tazobactam in achieving clinical cure and microbiological eradication overall and in the sub-group of patients with ESBL-producing pathogens. Cefepime-enmetazobactam enhanced activity against resistant Gram-negative bacteria, including ESBL and some carbapenemase producers, makes it effective in treating serious infections where resistance is a concern as a Carbapenem Sparing agent. Cefepime-enmetazobactam was approved for HAP including VAP on the basis of pathogen profiles and Intrapulmonary Pharmacokinetic study of Cefepime and Enmetazobactam in Healthy Volunteers. A ≥2-log kill (99% kill rate) in the lung was achieved with a plasma and ELF cefepime fT > MIC of ≥20% and enmetazobactam fT  > 2 mg/l of ≥20% of the dosing interval.