Fifth generation cephalosporins 2011

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Fifth generation cephalosporins 2011

  1. 1. ‘ Fifth generation’* Cephalosporins Ceftobiprole Ceftaroline *At present, CLSI has placed both in a separate & unnamed subclass of parenteral cephem
  2. 2. Bad bugs, no drugs: No ESKAPE CID 2009; 48: 1 - 12 <ul><li>E </li></ul><ul><li>S </li></ul><ul><li>K </li></ul><ul><li>A </li></ul><ul><li>P </li></ul><ul><li>E </li></ul>nterococcus faecium taphylococcus aureus lebseilla pneumoniae cinetobacter baumanii seudomonas aeruginosa nterobacter species Clostridium difficile & E. coli
  3. 3. 6 APA Ernest Boris Chain Sir Howard Florey 1940 Penicillin was a chance discovery Sir Alexander Fleming 1929
  4. 4. Cephalosporium acremonium Greek: branches with head like seeds Acremonium chrynogenium Gold producing branches Cephalosporin C 7 Amino cephalosporinic Acid 1945
  5. 6. 7ACA Deresinski SC. Ceftibiprole: breaking therapeutic dogmas of the beta lactam class. Diag Micro Infect Dis 2008; 61: 82 – 85.
  6. 7. Generation First generation Oral Cephradine Oral Cephalexin Parenteral Cefazolin Oral Cefadroxil Administration Drug Acid stable Stable to TEM & SHV β lactamases Active against GPC: MSSA, S.pyogenes Moderately active against a few GNB Not active against Pen R S.pyogenes or enterococci or MRSA Attributes
  7. 8. Generation Second generation Oral Loracarbef Oral & Parenteral Cefuroxime Oral Cefprozil Oral Cefoclor Administration Drug More potent against some GNB: E.coli , Kleb., Proteus Some had good activity against respiratory pathogens: H.influenzae & Neisseria spp. Slightly less active against GPC than 1 st generation No activity against Pseudomonas Attributes
  8. 9. Generation Third generation Parenteral Cefopera- zone Parenteral Ceftazidime Parenteral Ceftriaxone Parenteral Cefotaxime Oral Cefixime Oral Cefdinir Administration Drug Very important development Stable against most TEM & SHV beta lactamases Very potent against GNB Some had excellent activity against Pseudomonas Slightly less active than 1 st Gen against GPC Modest activity against anaerobes Attributes
  9. 10. Generation Fourth generation Parenteral Cefclidin Parenteral Cefoselis Parenteral Cefpirome Parenteral Cefepime Administration Drug More balanced spectra Reduced affinity for class 1 beta lactamases Increased outer membrane permeability Active against GPC & GNB Modest activity against anaerobes Not active against MRSA Attributes
  10. 11. ‘ Fifth generation’ Cephalosporins Ceftobiprole Ceftaroline
  11. 12. Cell Membrane Peptidoglycan
  12. 13. Cell Membrane Peptidoglycan MRSA & DRSP PBP 2’ PBP 2X
  13. 14. } Not active against MRSA } Not active against MRSA } Not active against MRSA } Active against MRSA
  14. 15. Ceftobiprole (ceftobiprole medocaril) Zeftera
  15. 16. Ceftobiprole <ul><li>Roche  Basilea  Janssen Ortho </li></ul><ul><li>BAL 5788  Zeftera </li></ul><ul><li>Approved in Canada and EU </li></ul>
  16. 17. Ceftaroline <ul><li>TAK 599  Cerexa  Forest Labs </li></ul><ul><li>Agreement with Aztra Zaneca </li></ul><ul><li>Favourable opinion by US FDA (Sept’10) </li></ul>
  17. 18. SAR of Ceftaroline Starting point: cefozopran
  18. 19. Ceftaroline fosamil acetate (Teflaro)
  19. 20. In Vitro Activity of Ceftaroline Against Gram-Positive Organisms Staphylococcus <0.016 - 2 0.5 - 1 0.25 – 0.5 379 <0.16 – 0.5 0.12 – 0.25 0.06 – 0.12 251 CONS MSSE MRSE 0.12 - 1 - - 9 0.25 - 4 2 1 123 0.25 - 1 0.5 – 1 0.5 244 0.12 - 4 1 - 2 0.5 – 1 2082 <0.008 - 1 0.25 – 0.5 0.12- 0.25 2199 S. aureus MSSA MRSA CA MRSA VISA & hVISA VRSA MIC range (ug/ml) MIC 90 (ug/ml) MIC 50 (ug/ml) No. of isolates Organism
  20. 21. In Vitro Activity of Ceftaroline Against Gram-Positive Organisms Streptococcus <0.008 – 0.03 0.015 <0.008 10 <0.008 – 0.03 <0.008 <0.008 91 S. pyogenes Ery S Ery NS <0.016 - 0.12 0.12 <0.016 22 0.125 - 2 0.25 – 0.5 0.25 – 0.5 136 <0.008 – 0.5 0.12 – 0.25 0.12 494 <0.008 – 0.5 0.06 0.015 – 0.03 253 <0.008 – 0.25 0.008 – 0.016 - 997 S. pneumoniae Pen S Pen I Pen R Ceph R Levo NS MIC range (ug/ml) MIC 90 (ug/ml) MIC 50 (ug/ml) No. of isolates Organism
  21. 22. In Vitro Activity of Ceftaroline Against Gram-Positive Organisms Streptococcus & Enterococcus 4 to > 32 16 - 32 16 - 32 39 0.12 - >32 4 - 16 2 767 Enterococcus faecalis faecium <0.008 – 1 0.5 0.03 – 0.12 56 <0.008 – 1 0.03 – 0.06 <0.008 – 0.03 235 <0.008 – 0.12 0.015 0.015 42 <0.008 – 0.06 0.015 0.015 59 S. agalactiae Ery S Ery NS viridans Pen S Pen NR MIC range (ug/ml) MIC 90 (ug/ml) MIC 50 (ug/ml) No. of isolates Organism
  22. 23. In Vitro Activity of Ceftaroline Against Gram-Negative Organisms > 32 >32 >32 15 <0.016 – 0.25 0.12 0.06 20 E.coli wild type ESBL + <0.008 – 2 0.03 – 0.12 <0.008 – 0.016 150 <0.008 – 1 <0.008 – 0.016 <0.008 – 0.016 621 <0.016 – 0.25 0.016 – 0.125 13 <0.016 – 0.5 0.12 – 0.25 0.06 127 Morexella catarrhalis Neisseria spp Haemophilus influenzae β lac –ve β lac +ve MIC range (Ug/ml) MIC 90 ug/ml MIC 50 ug/ml No. of isolates Organism
  23. 24. In Vitro Activity of Ceftaroline Against Gram-Negative Organisms > 32 >32 >32 15 0.03 – 4 0.5 0.06 21 K.pneumoniae wild type ESBL + >32 >32 >32 10 2 to >32 >32 16 20 4 - >32 >32 16 20 Non fermentors Pseudomonas aeruginosa Acinetobacter spp Stenotrophomonas maltophilia MIC range (Ug/ml) MIC 90 ug/ml MIC 50 ug/ml No. of isolates Organism
  24. 25. Ceftaroline PK <ul><li>Dose 600 mg IV 600 mg IM </li></ul><ul><li>Cmax (ug/ml) 19.7 11.6 </li></ul><ul><li>Tmax (h) 0.98 2 </li></ul><ul><li>AUC (h.ug/ml) 45 55.3 </li></ul><ul><li>T ½ (h) 2.13 2.5 </li></ul><ul><li>CLr (ml/min) 108 110 </li></ul><ul><li>% excreted unchanged 69 </li></ul>
  25. 26. Cefaroline PD <ul><li>Bactericidal agent </li></ul><ul><li>Time dependent, concentration independent killing </li></ul><ul><li>T > MIC best predictor of efficacy </li></ul><ul><li>% free drug T> MIC was </li></ul><ul><ul><li>43.9% for S.pneumoniae </li></ul></ul><ul><ul><li>33.9% for S.aureus </li></ul></ul><ul><ul><li>41.11% for GNB </li></ul></ul><ul><li>Free drug %T >MIC necessary for efficacy was slightly reduced for animals with normal neutrophil counts. </li></ul>
  26. 27. Adverse effects / drug interactions <ul><li>Ceftaroline is well tolerated </li></ul><ul><li>No serious or dose limiting toxicities identified </li></ul><ul><li>No clinically significant changes in biochemical, haematology, coagulation or urinalysis </li></ul><ul><li>ECG data suggests no QT interval prolongation </li></ul><ul><li>Nausea and infrequent injection site tenderness </li></ul><ul><li>Little interaction with human liver microsomes </li></ul>
  27. 38. Conclusions <ul><li>Ceftaroline is a fifth generation cephalosporin with excellent activity against GPCs including MRSA & DRSP </li></ul><ul><li>Affinity for all PBPs including PBP 2’ and PBP 2X </li></ul><ul><li>Not ESBL stable, Not active against Non fermentors </li></ul><ul><li>Administer prodrug as slow IV infusion 600 mg IV BID </li></ul><ul><li>Ceftaroline fosamil acetate (water solubility 100 mg/ml) rapidly converts to active ceftaroline in vivo </li></ul><ul><li>Well tolerated, predictable PK </li></ul><ul><li>T > MIC predicts for clinical efficacy, concentration independent or time dependent killing </li></ul><ul><li>Indicated for: </li></ul><ul><ul><li>Complicated skin & soft tissue infections </li></ul></ul><ul><ul><li>Community acquired pneumonia </li></ul></ul>
  28. 39. Future <ul><li>NXL 104 is a non β lactam β lactamase inhibitor developed by Novexel </li></ul><ul><li>Under phase II clinical trials in combination with CTZ </li></ul><ul><li>Forest & Novexel have an understanding to develop it for Ceftaroline </li></ul>
  29. 40. Impact of Nxl-104 on Ceftaroline MICs of Bacteria Producing Extended-Spectrum, AmpC, or KPC Beta-Lactamases R. BADAL , S. BOUCHILLON , M. HACKEL , D. HOBAN , S. HAWSER , G. WILLIAMS ; IHMA, Inc., Schaumburg, IL, IHMA, Inc., Epalinges, Switzerland, Cerexa, Inc., Oakland, CA. >32 fold 2 0.25 >32 >32 41 AmpC + CTX-M >16 fold 4 1 >32 >32 18 SHV + KPC >256 fold 0.25 <0.6 >32 >32 28 SHV + CTX-M Range : 0.12 Range : > 32 1 SHV +TEM Range : 0.06 - 4 Range : > 32 9 KPC > 256 fold 0.25 <0.06 >32 >32 537 CTX-M Range: 0.12 – 0.5 Range : 4 - > 32 7 TEM > 64 fold 1 <0.06 >32 >32 47 SHV Reduction in CPT MIC CXL MIC 90 CXL MIC 50 CPT MIC 90 CPT MIC 50 No. Enzyme profile
  30. 42. Carry Home Message <ul><li>Ceftaroline is an injectable cephalosporin active against MRSA & MSSA [ & RTI pathogens] </li></ul><ul><li>It is approved for use in cSSSI & CABP </li></ul><ul><li>Its use may be extended when combined with NXL 104 to include ESBL +ve GNB strains </li></ul><ul><li>It is inactive against Non fermentor GNB & Carbapenemase producers. </li></ul>
  31. 43. MRSA Vancomycin Linezolid Daptomycin Ceftaroline
  32. 44. Bad bugs, no drugs: No ESKAPE CID 2009; 48: 1 - 12 <ul><li>E </li></ul><ul><li>S </li></ul><ul><li>K </li></ul><ul><li>A </li></ul><ul><li>P </li></ul><ul><li>E </li></ul>nterococcus faecium taphylococcus aureus lebseilla pneumoniae cinetobacter baumanii seudomonas aeruginosa nterobacter species Clostridium difficle & E. coli
  33. 45. Antibiotic Era New Sun rise or Final Sun set ?

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