5TH GENERATION

CEPHALOSPORINS

Dr.T.V.Rao MD

DR.T.V.RAO MD 1
 WHAT ARE CEPHALOSPORINS
• The cephalosporins
structurally related to
the penicillin's consist
of a –beta lactam ring
attached to a
dihydrothiazoline ring.
Substitutions of
chemical groups result
in varying
pharmacologic
properties and
antimicrobial activities .
DR.T.V.RAO MD 2
 HISTORY OF CEPHALOSPORINS
• Cephalosporin compounds were first isolated from cultures of
Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian
scientist Giuseppe Brotzu He noticed that these cultures produced
substances that were effective against Salmonella typhi, the cause of typhoid
fever, which had beta-lactamase. Guy Newton and Edward Abraham at the
Sir William Dunn School of Pathology at the University of Oxford isolated
cephalosporin C. The cephalosporin nucleus, 7-aminocephalosporanic acid
(7-ACA), was derived from cephalosporin C and proved to be analogous to
the penicillin nucleus 6-aminopenicillanic acid, but it was not sufficiently
potent for clinical use. Modification of the 7-ACA side-chains resulted in the
development of useful antibiotic agents, and the first agent cephalothin
(cefalotin ) was launched by Eli Lilly in 1964.

DR.T.V.RAO MD 3
 CEPHALOSPORINS
• are B-Lactam antibiotics isolated from Cephalosporium spp.

• inhibit wide variety of gram(+) and gram(-) bacteria

• Abraham and Newton, the suppliers of fungi cultures

isolated three principal antibiotic components:

Cephalosporin
- aPI
steroid with minimal antibacterial property
Cephalosporin N
- Identical with synnematin N ( also called penicillin N
Cephalosporin C
-Resistant to S. aureus B-lactamase; antibacterial
property is inferior to penicillin N.
DR.T.V.RAO MD 4
 Cephalosporins
• Cephalosporin N or Penicillin N
- the amino acid in the chain confers more activity against
gram(-) bacteria particularly Salmonella spp.
- less active against gram(+) organism -
contains thiazolidine ring

O
NH2
HO H H
S CH3
NH
N
O CH3
O
OH
O

DR.T.V.RAO MD 5
 Cephalosporins
• Cephalosporin C
- congener of Penicillin N
- contains dihydrothiazide ring

O
NH2
HO H H CH3
S O
NH
N O
O
O
OH O

DR.T.V.RAO MD 6
 NOMENCLATURE OF CEPHALOSPORINS
Chemical Abstracts
> fused ring is named 5-thia, 1-azabicyclo[4.2.0]oct-2-ene
> CEPHALOTHIN ( is an antibiotic of the cephalosporin class. It is related to the
penicillin drugs in how it kills bacteria, but cephalosporins have a much broader range of
activity against bacteria than penicillins. is 3-(acetoxymethyl)-7-[2-
(thienylacetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid.
> saturated bicyclic ring system is named as cepham
> all cephalosporins and cefamycins are named as 3-cephems, to designate the
position of the double bond in the structure.

DR.T.V.RAO MD 7
 SPECTRUM OF ACTIVITY
CEPHALOSPORINS
> are considered broad-spectrum antibiotics with
similar activities to that of ampicillin.

> more resistant to the inactivation by the beta-lactamases,

particularly those produced by gram(+) bacteria.

> exhibit potent activity against most species of Klebsiella

Different potencies are due to:

1. Different bacterial strains
2. Characteristics of individual bacterial species

3. Resistance to the inactivation of the beta-lactamases

4. Permeability of the bacterial cell

5. Intrinsic activity against bacterial enzymes involved

DR.T.V.RAO MD
in cell wall synthesis and cross linking. 8
 GENERATION OF CEPHALOSPORINS
• Cephalosporin drugs
fall into five classes
or generations. Each
subsequent
generation of these
drugs demonstrates
greater efficacy
against gram-
negative bacteria.
DR.T.V.RAO MD 9
 WHAT ARE 5TH GENERATION
CEPHALOSPORINS
• Fifth generation
cephalosporins were
developed in the lab to
specifically target against
resistant strains of
bacteria. In particular,
ceftobiprole is effective
against methicillin-resistant
Staphylococcus aureus
(MRSA).

DR.T.V.RAO MD 10
 CEFTRAROLINE, A 5TH. GENERATION
CEPHALOSPORIN

• Ceftaroline is a beta-lactam of
the cephalosporin class of
antimicrobials with activity
against aerobic and anaerobic
gram-positive and aerobic
gram-negative bacteria
associated with skin and
respiratory infections. It also
has activity against methicillin-
resistant Staphylococcus aureus
and Streptococcus pneumonia .

DR.T.V.RAO MD 11
 FDA APPROVES CEFTAROLINE FOSAMIL
• On October 29th, FDA has approved Ceftaroline Fosamil under the trade
name Teflaro. Ceftaroline Fosamil (previously known by the research code
TAK-599, the parent drug, Ceftaroline is also known as T-91,825) is an
antibiotic indicated for the treatment of adults with acute bacterial skin and
skin structure infections (ABSSSI) caused by susceptible Gram-positive and
Gram-negative microorganisms, such as Staphylococcus aureus (including
methicillin-susceptible and -resistant isolates), Streptococcus pyogenes
Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and
Klebsiella oxytoca, and also for the treatment of community-acquied bacterial
pneumonia (CABP) caused by susceptible Gram-positive and Gram-negative
bacteria, such as Streptococcus pneumoniae (including cases with
concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible
isolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella
oxytoca, and Escherichia coli.

DR.T.V.RAO MD 12
 THE STRUCTURE OF CEFTAROLINE FOSAMIL
RESEMBLES OTHER CEPHALOSPORINS
• (6R,7R)-7-{(2Z)-2-(ethoxyimino)-
2-[5-(phosphonoamino)-
1,2,4thiadiazol-3-yl]acetamido}-
3-{[4-(1-methylpyridin-1-ium-4-
yl)-1,3-thiazol-2-yl]sulfanyl}-8-
oxo-5-thia-1azabicyclo[4.2.0]oct-
2-ene-2-carboxylate contains a
cyclic amide (the beta-lactam
ring) fused with a six member
ring (the cephem ring). Another
notable feature of Ceftaroline
Fosamil is the thiazolylthio
group, which is thought to be
crucial for the activity against
MRSA.
DR.T.V.RAO MD 13
 HOW CEFTAROLINE WORKS
• Ceftaroline is a broad-spectrum
cephalosporin. Ceftaroline has
the ability to bind to penicillin-
binding protein (PBP) 2a , an
MRSA-specific PBP that has low
affinity for most other β-lactam
antibacterial. The high binding
affinity of ceftaroline to PBP 2a
(median inhibitory concentration
0.90 μg/mL) correlates well with
its low minimum inhibitory
concentration for MRSA.

DR.T.V.RAO MD 14
 CEFTAROLINE IS MODIFIED FROM CEFOZOPRAN
• Ceftaroline was developed by
modifying the structure of the
fourth-generation cephalosporin
cefozopran The prodrug,
ceftaroline fosamil, which
contains a phosphono group to
increase water solubility, is
rapidly converted in plasma into
the bioactive agent, ceftaroline
The 1,3-thiazole ring attached to
the 3-position of the
cephalosporin nucleus and the
oxime group in the C7 acyl
moiety are responsible for the
enhanced anti-MRSA activity
observed with ceftaroline.
DR.T.V.RAO MD 15
 ADVANTAGES OF CEFTAROLINE
• The high affinity of ceftaroline for penicillin-binding proteins is
responsible for the potent activity observed against clinically
relevant pathogens. With respect to the treatment of CABP, the
activity of ceftaroline against pathogens such as S. pneumoniae,
S. aureus, Haemophilus influenzae and Moraxella catarrhalis
demonstrates coverage across a broad range of pathogens
typically encountered in clinical practice. Ceftaroline is also very
active against common pathogens seen in ABSSSIs such as S.
aureus (methicillin-susceptible S. aureus and methicillin-
resistant S. aureus) and Streptococcus pyogenes.

DR.T.V.RAO MD 16
 MECHANISM OF ACTION OF
CEFTAROLINE
• Ceftaroline was developed by
modifying the structure of the
fourth-generation cephalosporin
cefozopran. The prodrug,
ceftaroline fosamil, which
contains a phosphono group to
increase water solubility, is
rapidly converted in plasma into
the bioactive agent, ceftaroline
The 1,3-thiazole ring attached to
the 3-position of the
cephalosporin nucleus and the
oxime group in the C7 acyl
moiety are responsible for the
enhanced anti-MRSA activity
observed with ceftaroline.
DR.T.V.RAO MD 17
 CEFTAROLINE IS ACTIVE ON
• Ceftaroline is active in vitro against Gram-positive
cocci, including MRSA, methicillin-resistant
Staphylococcus epidermidis , penicillin-resistant
Streptococcus pneumoniae and vancomycin-resistant
Enterococcus faecalis (not E. faecium). The broad-
spectrum activity of ceftaroline includes many Gram-
negative pathogens but does not extend to extended-
spectrum β-lactamase-producing or AmpC-derepressed
Enterobacteriaceae or most nonfermentative Gram-
negative bacilli.

DR.T.V.RAO MD 18
 CEFTAROLINE HAS SYNERGISTIC
ACTION
• Ceftaroline has been shown to have
synergistic activity against Gram-
negative species in combination with an
aminoglycoside. In an in vitro study,
ceftaroline plus amikacin was synergistic
against 90% of isolates tested, including
Pseudomonas aeruginosa, extended-
spectrum β-lactamase (ESBL)-producing
Escherichia coli, ESBL-producing
Klebsiella pneumoniae and AmpC-
derepressed Enterobacter cloacae.
Synergy was also demonstrated for
ceftaroline in combination with
meropenem against all E. coli isolates
tested

DR.T.V.RAO MD 19
 CEFTAROLINE HAS LIMITED ACTIVITY …….
• Ceftaroline
demonstrates limited
activity against
anaerobes such as
Bacteroides fragilis and
non-fragilis Bacteroides
spp. Limited data show
that ceftaroline has a
low propensity to select
for resistant
subpopulations.

DR.T.V.RAO MD 20
 ADVANTAGE OF CEFTAROLINE
• 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
fermentors GNB &
Carbapenemase producers.
DR.T.V.RAO MD 22
 FIFTH GENERATION CEFTOBIPROLE

• Fifth generation
• Ceftobiprole has been
described as "fifth generation",]
though acceptance for this
terminology is not universal.
• Ceftobiprole (and the soluble
prodrug medocaril) are on the
FDA fast-track. Ceftobiprole
has powerful antipseudomonal
characteristics and appears to
be less susceptible to
development of resistance.

DR.T.V.RAO MD 23
 CEFTOBIPROLE (ZEFTERA/ZEVTERA) IS A
• Ceftobiprole (Zeftera/Zevtera) is a 5th generation
cephalosporin antibiotic with activity against methicillin-
resistant Staphylococcus aureus , penicillin-resistant
Streptococcus pneumoniae , Pseudomonas aeruginosa,
and Enterococci It was discovered by Basilea
Pharmaceutica and was developed by Johnson &
Johnson Pharmaceutical Research and Development. It
has been shown to be statistically non-inferior to the
combination of vancomycin and ceftazidime for the
treatment of skin and soft tissue infections.

DR.T.V.RAO MD 24
 PHARMACOLOGY OF CEFTOBIPROLE
• Ceftobiprole inhibits the 2a
penicillin-binding protein
(pbp) of Methicillin-resistant
Staphylococcus aureus and
the 2x pbp of Streptococcus
pneumoniae as well as the
classic PBP-2 of MSSA.
Ceftobiprole is resistant to
staphylococcal β-lactamase

DR.T.V.RAO MD 25
 HOW CEFTOBIPROLE DIFFERS FROM OTHER
BETA LACTAMS
• Ceftobiprole can be distinguished from other beta-
lactams by its increased binding to penicillin-binding
protein 2a. Penicillin-binding proteins, the targets of
beta-lactam antibiotics, are enzymes found in the
membrane that are the last step of peptidoglycan
biosynthesis. Penicillin-binding protein 2a is the
enzyme most directly related to methicillin-resistant
staphylococci. Activity of ceftobiprole has been studied
against both the community-acquired MRSA strains
and hospital-acquired MRSA
DR.T.V.RAO MD 26
CLSI PUTS ON THE LIST OF UNNAMED CLASS
• Currently, ceftaroline
and ceftobiprole are
on an unnamed
subclass of
cephalosporins by
the Clinical and
Laboratory
Standards Institute
(CLSI).
DR.T.V.RAO MD 27
 5TH GENERATION CEPHALOSPORINS ARE NOT ULTIMATE
SOLUTIONS FOR ANTIBIOTIC RESISTANCE

• Antimicrobial stewardship programmes can be

implemented to reduce inappropriate use of
antimicrobials, thereby controlling the development of
resistance. These programmes are also useful in
limiting toxicity and overgrowth of pathogenic
organisms such as C. difficile. Typical stewardship
programmes target antimicrobials that pose a risk of
development of resistance, are associated with
significant toxicity, require therapeutic drug monitoring,
have the potential to select for pathogenic organisms or
have a high cost.
DR.T.V.RAO MD 28
 • Created by Dr.T.V.Rao MD for “ e ‘ learning
resources for Medical Microbiologists in
Developing World
• Email
• doctortvrao@gmail.com

DR.T.V.RAO MD 29