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Cefiderocol - Dr. ANCY GEORGE

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Ancy George
Ancy George

Cefiderocol is a novel siderophore cephalosporin antibiotic being developed for the treatment of infections caused by carbapenem-resistant Gram-negative bacteria. A phase 2 clinical trial found intravenous cefiderocol to be non-inferior to imipenem-cilastatin for treating complicated urinary tract infections caused by multidrug-resistant Gram-negative pathogens. Cefiderocol utilizes bacterial iron transport systems to penetrate the outer membrane of Gram-negative bacteria and is highly stable against various carbapenemase enzymes. Its pharmacokinetics and safety profile support a dosage of 2g administered intravenously every 8 hours. These results provide a basis for submitting cefiderocol for FDA approval to treat serious Gram-negative

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NEW DRUG CEFIDEROCOL Dr. Ancy George JR Pharmacology
Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial Simon Portsmouth, David van Veenhuyzen, Roger Echols, Mitsuaki Machida, Juan Camilo Arjona Ferreira, Mari Ariyasu, Peter Tenke, Tsutae Den Nagata Lancet Infect Dis 2018 October 25, 2018
Objective To assess the efficacy and safety of Cefiderocol vs Imipenem Cilastatin for treatment of complicated UTI in patients with risk of multidrug resistant Gram negative infections Methods Phase 2, multicenter, double blind, parallel group, non- inferiority trailat 67 hospitals in 5 countries
Inclusion criteria Adults admitted with clinical diagnosis of complicated UTI (cUTI) with or without pyelonephritis or thoses with acute uncomplicated pyelonephritis. Randomly assigned as 2:1 into Cefiderocol (2g) and Imipenem- Cilastatin ( 1g each) Q8H for 7-14 days Exclusion Baseline urine culture with more than 2 uropathogens Fungal UTI Carbepenem resistant uropathogen
Primary endpoint Composite of clinical and microbiological outcomes at test of cure (7 days after treatment cessation), which was used to establish non-inferiority (15% and 20% margins) of cefiderocol versus imipenem-cilastatin.
Results 1 year study Cefiderolcol Assigned 303 Got treatment 300 GN uropathogen 252 Effective treatment 183 (73%) (p value = 0.0004) Adverse effects 122(41%) Imipenem-cilastatin Assigned 149 Got treatment 148 GN uropathogen 119 Effective treatment 65 (55%) Adverse effects 76(51%)
Inference Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration.
Cefiderocol - Dr. ANCY GEORGE
CEFIDEROCOL Phase III drug Cefiderocol is a novel catechol substituted siderophore cephalosporin INDICATIONS It is against Gram negative bacteria including Carbapenem- resistant strains of Enterobacteriaceae Acinetobacter baumannii Pseudomonas aeruginosa Stenotrophomonas maltophilia
USES Cefiderocol is being developed as a therapeutic drug for the treatment of carbapenem-resistant Gram-negative bacterial infections, including nosocomial pneumonia, bloodstream infections, complicated urinary tract infection (cUTI).
Structural similarity with Cefepime Bactericidal Inhibition of bacterial cell wall synthesis by binding to penicillin binding proteins CEFEPIME CEFIDEROCOL
Cefiderocol - Dr. ANCY GEORGE
TROJAN HORSE It form a chelating complex with ferric iron and utilize the bacterial iron transport system to penetrate the outer membrane of GN organisms.
Highly stable to various types of carbapenemase KPC, OXA, IMP, VIM and NDM Potent activity against Gram-negatives including CR strains Acinetobacter baumannii Pseudomonas aeruginosa Escherichia coli Klebsiella pneumoniae Stenotrophomonas maltophilia Not active against Gram positives or anaerobes APEKS
STABILITY OF CEFIDEROCOL TO CARBEPENEMASES
Pharmacokinetics Terminal elimination half-life -1.98 to 2.74 hr. in healthy subjects. Cefiderocol is excreted mainly via the kidneys, with 60 to 70% of the dose in urine as the unchanged parent drug. The total clearance (CL) of cefiderocol was dependent on renal Dose adjustment required in renal failure No accumulation was observed at the 2 g every 8 hours dose intravenous infusion, and this dose was well tolerated when administered over 10 days.
Dosage and administration 2-g q8h dosing with a 3-h intravenous infusion was selected as the standard dose regimen
Diarrhoea (4%) Hypertension (4%) Constipation (3%) Infusion site pain (3%) Headache (2%) Nausea (2%) Cough (2%) Vomiting (2%) Hypokalaemia (2%) Insomnia (1%) Renal cyst (1%) Infusion site erythema (1%) Abdominal pain upper (1%) Cardiac failure (1%) Clostridium difficile colitis (<1%) Vaginal infection
Adverse Effect Single dose effects Diarrhea Contact dermatitis Rash Abdominal pain Blood in urine WBC in urine Increased total counts Multiple dose effect Increased TSH Elevated AST, ALT
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Cefiderocol - Dr. ANCY GEORGE

  • 1. NEW DRUG CEFIDEROCOL Dr. Ancy George JR Pharmacology
  • 2. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial Simon Portsmouth, David van Veenhuyzen, Roger Echols, Mitsuaki Machida, Juan Camilo Arjona Ferreira, Mari Ariyasu, Peter Tenke, Tsutae Den Nagata Lancet Infect Dis 2018 October 25, 2018
  • 3. Objective To assess the efficacy and safety of Cefiderocol vs Imipenem Cilastatin for treatment of complicated UTI in patients with risk of multidrug resistant Gram negative infections Methods Phase 2, multicenter, double blind, parallel group, non- inferiority trailat 67 hospitals in 5 countries
  • 4. Inclusion criteria Adults admitted with clinical diagnosis of complicated UTI (cUTI) with or without pyelonephritis or thoses with acute uncomplicated pyelonephritis. Randomly assigned as 2:1 into Cefiderocol (2g) and Imipenem- Cilastatin ( 1g each) Q8H for 7-14 days Exclusion Baseline urine culture with more than 2 uropathogens Fungal UTI Carbepenem resistant uropathogen
  • 5. Primary endpoint Composite of clinical and microbiological outcomes at test of cure (7 days after treatment cessation), which was used to establish non-inferiority (15% and 20% margins) of cefiderocol versus imipenem-cilastatin.
  • 6. Results 1 year study Cefiderolcol Assigned 303 Got treatment 300 GN uropathogen 252 Effective treatment 183 (73%) (p value = 0.0004) Adverse effects 122(41%) Imipenem-cilastatin Assigned 149 Got treatment 148 GN uropathogen 119 Effective treatment 65 (55%) Adverse effects 76(51%)
  • 7. Inference Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration.
  • 9. CEFIDEROCOL Phase III drug Cefiderocol is a novel catechol substituted siderophore cephalosporin INDICATIONS It is against Gram negative bacteria including Carbapenem- resistant strains of Enterobacteriaceae Acinetobacter baumannii Pseudomonas aeruginosa Stenotrophomonas maltophilia
  • 10. USES Cefiderocol is being developed as a therapeutic drug for the treatment of carbapenem-resistant Gram-negative bacterial infections, including nosocomial pneumonia, bloodstream infections, complicated urinary tract infection (cUTI).
  • 11. Structural similarity with Cefepime Bactericidal Inhibition of bacterial cell wall synthesis by binding to penicillin binding proteins CEFEPIME CEFIDEROCOL
  • 13. TROJAN HORSE It form a chelating complex with ferric iron and utilize the bacterial iron transport system to penetrate the outer membrane of GN organisms.
  • 14. Highly stable to various types of carbapenemase KPC, OXA, IMP, VIM and NDM Potent activity against Gram-negatives including CR strains Acinetobacter baumannii Pseudomonas aeruginosa Escherichia coli Klebsiella pneumoniae Stenotrophomonas maltophilia Not active against Gram positives or anaerobes APEKS
  • 15. STABILITY OF CEFIDEROCOL TO CARBEPENEMASES
  • 16. Pharmacokinetics Terminal elimination half-life -1.98 to 2.74 hr. in healthy subjects. Cefiderocol is excreted mainly via the kidneys, with 60 to 70% of the dose in urine as the unchanged parent drug. The total clearance (CL) of cefiderocol was dependent on renal Dose adjustment required in renal failure No accumulation was observed at the 2 g every 8 hours dose intravenous infusion, and this dose was well tolerated when administered over 10 days.
  • 17. Dosage and administration 2-g q8h dosing with a 3-h intravenous infusion was selected as the standard dose regimen
  • 18. Diarrhoea (4%) Hypertension (4%) Constipation (3%) Infusion site pain (3%) Headache (2%) Nausea (2%) Cough (2%) Vomiting (2%) Hypokalaemia (2%) Insomnia (1%) Renal cyst (1%) Infusion site erythema (1%) Abdominal pain upper (1%) Cardiac failure (1%) Clostridium difficile colitis (<1%) Vaginal infection
  • 19. Adverse Effect Single dose effects Diarrhea Contact dermatitis Rash Abdominal pain Blood in urine WBC in urine Increased total counts Multiple dose effect Increased TSH Elevated AST, ALT