Fifth generation cephalosporins 2011

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

2. Bad bugs, no drugs: No ESKAPE
CID 2009; 48: 1 - 12
•E
•S
•K
•A
•P
•E
nterococcus faecium
taphylococcus aureus
lebseilla pneumoniae
cinetobacter baumanii
seudomonas aeruginosa
nterobacter species
Clostridium difficile & E. coli

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
194
5

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

7. OralCephradine
OralCephalexin
ParenteralCefazolin
OralCefadroxil
Administration
Drug
Generation
First generation
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. OralLoracarbef
Oral &
Parenteral
Cefuroxime
OralCefprozil
OralCefoclor
Administration
Drug
Generation
Second generation
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. ParenteralCefopera-
zone
ParenteralCeftazidime
ParenteralCeftriaxone
ParenteralCefotaxime
OralCefixime
OralCefdinir
Administration
Drug
Generation
Third generation
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. ParenteralCefclidin
ParenteralCefoselis
ParenteralCefpirome
ParenteralCefepime
Administration
Drug
Generation
Fourth generation
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

16. Ceftobiprole
•Roche  Basilea  Janssen Ortho
BAL 5788  Zeftera
•Approved in Canada and EU

17. Ceftaroline
•TAK 599  Cerexa  Forest Labs
•Agreement with Aztra Zaneca
•Favourable opinion by US FDA (Sept’10)

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 - 20.5 - 10.25 – 0.5379
<0.16 – 0.50.12 – 0.250.06 – 0.12251
CONS
MSSE
MRSE
0.12 - 1--9
0.25 - 421123
0.25 - 10.5 – 10.5244
0.12 - 41 - 20.5 – 12082
<0.008 - 10.25 – 0.50.12- 0.252199
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 – 0.030.015<0.00810
<0.008 – 0.03<0.008<0.00891
S. pyogenes
Ery
S
Ery
NS
<0.016 - 0.12 0.12<0.01622
0.125 - 20.25 – 0.50.25 – 0.5136
<0.008 – 0.50.12 – 0.250.12494
<0.008 – 0.50.060.015 –
0.03
253
<0.008 – 0.250.008 – 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 > 3216 - 3216 - 3239
0.12 - >324 - 162767
Enterococcus
faecalis
faecium
<0.008 – 10.50.03 – 0.1256
<0.008 – 10.03 – 0.06<0.008 – 0.03235
<0.008 – 0.120.0150.015 42
<0.008 – 0.060.0150.01559
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>3215
<0.016 – 0.250.120.0620
E.coli
wild type
ESBL +
<0.008 – 20.03 – 0.12<0.008 –
0.016
150
<0.008 – 1<0.008 – 0.016<0.008 –
0.016
621
<0.016 – 0.250.016 – 0.12513
<0.016 – 0.50.12 – 0.250.06127
Morexella
catarrhalis
Neisseria spp
Haemophilus
influenzae β lac –ve
β lac +ve

MIC range
(Ug/ml)
MIC
90
ug/mlMIC
50
ug/mlNo. of
isolates
Organism

24. In Vitro Activity of Ceftaroline Against
Gram-Negative Organisms
> 32>32>3215
0.03 – 40.50.0621
K.pneumoniae
wild type
ESBL +
>32>32>3210
2 to >32>321620
4 - >32>321620
Non fermentors

Pseudomonas

aeruginosa
Acinetobacter spp
Stenotrophomonas
maltophilia

MIC range
(Ug/ml)
MIC
90
ug/mlMIC
50
ug/mlNo. of
isolates
Organism

25. Ceftaroline PK
•Dose 600 mg IV 600 mg IM
•Cmax (ug/ml) 19.7 11.6
•Tmax (h) 0.98 2
•AUC (h.ug/ml) 45 55.3
•T ½ (h) 2.13 2.5
•CLr (ml/min) 108 110
•% excreted unchanged 69

26. Cefaroline PD
•Bactericidal agent
•Time dependent, concentration independent killing
•T > MIC best predictor of efficacy
•% free drug T> MIC was
–43.9% for S.pneumoniae
–33.9% for S.aureus
–41.11% for GNB
•Free drug %T >MIC necessary for efficacy was
slightly reduced for animals with normal neutrophil
counts.

27. Adverse effects / drug interactions
•Ceftaroline is well tolerated
•No serious or dose limiting toxicities identified
•No clinically significant changes in biochemical,
haematology, coagulation or urinalysis
•ECG data suggests no QT interval prolongation
•Nausea and infrequent injection site tenderness
•Little interaction with human liver microsomes

38. Conclusions
•Ceftaroline is a fifth generation cephalosporin with
excellent activity against GPCs including MRSA & DRSP
•Affinity for all PBPs including PBP 2’ and PBP 2X
•Not ESBL stable, Not active against Non fermentors
•Administer prodrug as slow IV infusion 600 mg IV BID
•Ceftaroline fosamil acetate (water solubility 100 mg/ml)
rapidly converts to active ceftaroline in vivo
•Well tolerated, predictable PK
•T > MIC predicts for clinical efficacy, concentration
independent or time dependent killing
•Indicated for:
–Complicated skin & soft tissue infections
–Community acquired pneumonia

39. Future
•NXL 104 is a non β lactam β lactamase
inhibitor developed by Novexel
•Under phase II clinical trials in
combination with CTZ
•Forest & Novexel have an understanding
to develop it for Ceftaroline

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 fold20.25>32>3241AmpC + CTX-M
>16 fold41>32>3218SHV + KPC
>256 fold0.25<0.6>32>3228SHV + CTX-M
Range : 0.12Range : > 321SHV +TEM
Range : 0.06 - 4 Range : > 329KPC
> 256 fold0.25<0.06>32>32537CTX-M
Range: 0.12 – 0.5Range : 4 - > 327TEM
> 64 fold1<0.06>32>3247SHV
Reduction in
CPT MIC
CXL
MIC
90
CXL MIC
50
CPT
MIC
90
CPT
MIC
50
No.Enzyme profile

42. Carry Home Message
•Ceftaroline is an injectable cephalosporin
active against MRSA & MSSA [ & RTI
pathogens]
•It is approved for use in cSSSI & CABP
•Its use may be extended when combined
with NXL 104 to include ESBL +ve GNB
strains
•It is inactive against Non fermentor GNB &
Carbapenemase producers.

43. Vancomycin
Linezolid
Daptomycin
Ceftaroline
MRSA

44. Bad bugs, no drugs: No ESKAPE
CID 2009; 48: 1 - 12
•E
•S
•K
•A
•P
•E
nterococcus faecium
taphylococcus aureus
lebseilla pneumoniae
cinetobacter baumanii
seudomonas aeruginosa
nterobacter species
Clostridium difficle & E. coli

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