‘Fifth generation’* Cephalosporins

Ceftobiprole

Ceftaroline

*At present, CLSI has placed both in a separate & unnamed subclass of parenteral cephem

Bad bugs, no drugs: No ESKAPECID 2009; 48: 1 - 12

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nterococcus faecium

taphylococcus aureus

lebseilla pneumoniae

cinetobacter baumanii

seudomonas aeruginosa

nterobacter species

Clostridium difficile & E. coli

6 APA

Ernest Boris Chain Sir Howard Florey 1940

Penicillin was a chance discovery

Sir Alexander Fleming 1929

Cephalosporium acremoniumGreek: branches with head like seeds

Acremonium chrynogeniumGold producing branches

Cephalosporin C7 Amino cephalosporinic Acid

1945

7ACA

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

Drug Administration

Cefadroxil Oral

Cefazolin Parenteral

Cephalexin Oral

Cephradine Oral

GenerationFirst generation

Attributes

Acid stable

Stable to TEM & SHV β lactamases

Active against GPC: MSSA, S.pyogenes

Moderately active against a few GNB

Not active against PenR S.pyogenes or enterococci or MRSA

Drug Administration

Cefoclor Oral

Cefprozil Oral

Cefuroxime Oral & Parenteral

Loracarbef Oral

GenerationSecond generation

Attributes

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 1st generation

No activity against Pseudomonas

Drug Administration

Cefdinir Oral

Cefixime Oral

Cefotaxime Parenteral

Ceftriaxone Parenteral

Ceftazidime Parenteral

Cefopera-zone

Parenteral

GenerationThird generation

Attributes

Very important development

Stable against most TEM & SHV beta lactamases

Very potent against GNB

Some had excellent activity against Pseudomonas

Slightly less active than 1st Gen against GPC

Modest activity against anaerobes

Drug Administration

Cefepime Parenteral

Cefpirome Parenteral

Cefoselis Parenteral

Cefclidin Parenteral

GenerationFourth generation

Attributes

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

‘Fifth generation’Cephalosporins

Ceftobiprole

Ceftaroline

Cell Membrane

Peptidoglycan

Cell Membrane

Peptidoglycan

MRSA & DRSPPBP 2’ PBP 2X

}Not active against MRSA

} Not active against MRSA

}Not active against MRSA

} Active against MRSA

Ceftobiprole (ceftobiprole medocaril) Zeftera

Ceftobiprole

• Roche Basilea Janssen Ortho BAL 5788 Zeftera

• Approved in Canada and EU

Ceftaroline• TAK 599 Cerexa Forest Labs

• Agreement with Aztra Zaneca

• Favourable opinion by US FDA (Sept’10)

SAR of CeftarolineStarting point: cefozopran

Ceftaroline fosamil acetate(Teflaro)

In Vitro Activity of Ceftaroline Against Gram-Positive Organisms

StaphylococcusOrganism No. of

isolatesMIC50 (ug/ml) MIC90 (ug/ml) MIC range

(ug/ml)

S. aureus MSSA

MRSA

CA MRSA

VISA & hVISA

VRSA

2199 0.12- 0.25 0.25 – 0.5 <0.008 - 1

2082 0.5 – 1 1 - 2 0.12 - 4

244 0.5 0.5 – 1 0.25 - 1

123 1 2 0.25 - 4

9 - - 0.12 - 1

CONS MSSE

MRSE251 0.06 – 0.12 0.12 – 0.25 <0.16 – 0.5

379 0.25 – 0.5 0.5 - 1 <0.016 - 2

In Vitro Activity of Ceftaroline Against Gram-Positive Organisms

StreptococcusOrganism No. of

isolatesMIC50 (ug/ml)

MIC90

(ug/ml)

MIC range (ug/ml)

S. pneumoniae PenS

PenI

PenR

CephR

LevoNS

997 - 0.008 – 0.016 <0.008 – 0.25

253 0.015 – 0.03

0.06 <0.008 – 0.5

494 0.12 0.12 – 0.25 <0.008 – 0.5

136 0.25 – 0.5 0.25 – 0.5 0.125 - 2

22 <0.016 0.12 <0.016 - 0.12

S. pyogenes EryS

EryNS

91 <0.008 <0.008 <0.008 – 0.03

10 <0.008 0.015 <0.008 – 0.03

In Vitro Activity of Ceftaroline Against Gram-Positive Organisms

Streptococcus & EnterococcusOrganism No. of

isolatesMIC50

(ug/ml)

MIC90

(ug/ml)

MIC range (ug/ml)

S. agalactiae EryS

EryNS

viridans PenS

PenNR

59 0.015 0.015 <0.008 – 0.06

42 0.015 0.015 <0.008 – 0.12

235 <0.008 – 0.03 0.03 – 0.06 <0.008 – 1

56 0.03 – 0.12 0.5 <0.008 – 1

Enterococcus faecalis

faecium767 2 4 - 16 0.12 - >32

39 16 - 32 16 - 32 4 to > 32

In Vitro Activity of Ceftaroline Against Gram-Negative Organisms

Organism No. of isolates

MIC50 ug/ml MIC90 ug/ml MIC range (Ug/ml)

Morexella catarrhalis

Neisseria sppHaemophilus influenzae β lac –ve

β lac +ve

127 0.06 0.12 – 0.25 <0.016 – 0.5

13 0.016 – 0.125 <0.016 – 0.25

621 <0.008 – 0.016

<0.008 – 0.016 <0.008 – 1

150 <0.008 – 0.016

0.03 – 0.12 <0.008 – 2

E.coli wild type

ESBL +20 0.06 0.12 <0.016 – 0.25

15 >32 >32 > 32

In Vitro Activity of Ceftaroline Against Gram-Negative Organisms

Organism No. of isolates

MIC50 ug/ml MIC90 ug/ml MIC range (Ug/ml)

Non fermentors

Pseudomonas

aeruginosa

Acinetobacter spp

Stenotrophomonas maltophilia

20 16 >32 4 - >32

20 16 >32 2 to >32

10 >32 >32 >32

K.pneumoniae wild type

ESBL +21 0.06 0.5 0.03 – 4

15 >32 >32 > 32

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

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.

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

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

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

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.

Enzyme profile No. CPT MIC50

CPT MIC90

CXL MIC50 CXL MIC90

Reduction in CPT MIC

SHV 47 >32 >32 <0.06 1 > 64 fold

TEM 7 Range : 4 - > 32 Range: 0.12 – 0.5

CTX-M 537 >32 >32 <0.06 0.25 > 256 fold

KPC 9 Range : > 32 Range : 0.06 - 4

SHV +TEM 1 Range : > 32 Range : 0.12

SHV + CTX-M 28 >32 >32 <0.6 0.25 >256 fold

SHV + KPC 18 >32 >32 1 4 >16 fold

AmpC + CTX-M 41 >32 >32 0.25 2 >32 fold

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.

VancomycinLinezolid

DaptomycinCeftaroline

MRSA

Bad bugs, no drugs: No ESKAPECID 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

Antibiotic EraNew Sun rise or Final Sun set ?