Ceftaroline is a fifth-generation cephalosporin antibiotic active against methicillin-resistant Staphylococcus aureus (MRSA) and other resistant pathogens. It has excellent in vitro activity against gram-positive cocci including MRSA and is administered intravenously or intramuscularly. When combined with the beta-lactamase inhibitor NXL104, ceftaroline's activity may be extended to include some ESBL-producing gram-negative bacilli, though it remains inactive against non-fermenters like Pseudomonas aeruginosa. Ceftaroline is approved to treat complicated skin and skin structure infections and community-acquired bacterial pneumonia.

1. ‘ Fifth generation’* Cephalosporins Ceftobiprole Ceftaroline *At present, CLSI has placed both in a separate & unnamed subclass of parenteral cephem

3. 6 APA Ernest Boris Chain Sir Howard Florey 1940 Penicillin was a chance discovery Sir Alexander Fleming 1929

4. Cephalosporium acremonium Greek: branches with head like seeds Acremonium chrynogenium Gold producing branches Cephalosporin C 7 Amino cephalosporinic Acid 1945

6. 7ACA Deresinski SC. Ceftibiprole: breaking therapeutic dogmas of the beta lactam class. Diag Micro Infect Dis 2008; 61: 82 – 85.

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

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

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

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

11. ‘ Fifth generation’ Cephalosporins Ceftobiprole Ceftaroline

12. Cell Membrane Peptidoglycan

13. Cell Membrane Peptidoglycan MRSA & DRSP PBP 2’ PBP 2X

14. } Not active against MRSA } Not active against MRSA } Not active against MRSA } Active against MRSA

15. Ceftobiprole (ceftobiprole medocaril) Zeftera

18. SAR of Ceftaroline Starting point: cefozopran

19. Ceftaroline fosamil acetate (Teflaro)

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

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

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

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

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

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

43. MRSA Vancomycin Linezolid Daptomycin Ceftaroline

45. Antibiotic Era New Sun rise or Final Sun set ?