Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceutical chemistry. P.Ravisankar Vignan Pharmacy College Vadlamudi, Guntur, Andhra Pradesh, India.

1. Cephalosporin
s Prof.P.Ravisankar
Vignan Pharmacy College
Vadlamudi
Guntur (Dist)
Andhra Pradesh, India.
banuman35@gmail.com
Phone: 9059994000

2. CephalosporinsCephalosporins
 What are cephalosporins?What are cephalosporins?
Cephalosporins are the second major groupCephalosporins are the second major group
ofof β-lactum,broadspectrum,Penicillinaaseβ-lactum,broadspectrum,Penicillinaase
resistance antibiotics derived from theresistance antibiotics derived from the
micro organism ‘Acrimoniummicro organism ‘Acrimonium
chrysogenum. These are closely related tochrysogenum. These are closely related to
the penicillins in both structure and modethe penicillins in both structure and mode
of action and are used to treat bacterialof action and are used to treat bacterial
infection.infection.

3. Why Cephalosporins?Why Cephalosporins?
 Broad spectrum of activityBroad spectrum of activity
 Stability toStability to ββ-lactamase-lactamase
 Oral and parenteralOral and parenteral
preparationspreparations
 Widely acceptedWidely accepted
 Treats ‘day to day’ as well asTreats ‘day to day’ as well as
‘serious infections’‘serious infections’
 High safety profileHigh safety profile

4. Introduction:
The cephalosporins are β-Lactam antibiotics that are
closely related both structurally and functionally to the
penicillins.
 Mechanism of action, mechanism of resistance and
some other properties of cephalosporins are identical
to penicillins
 Cephalosporins are one of the most widely used
antibiotics and are equal in importance to penicillin.

5. • The cephalosporins are isolated from:
- Cephalosprium species
- Prepared semisynthetically.
• In 1945
Giuseppe Brotzu`s discovered that cultures
of Cephalosporium acremonium inhibited
the growth of a wide variety of Gram-positive
and Gram-negative bacteria.

6. In 1948
Abraham and his colleagues have been supplied cultures
of the fungus and was isolated three principal antibiotic
components:
- Cephalosporin P, (a steroid antibiotic that resembles fusidic
acid) with minimal antibacterial activity, obtained from
fusidium coccineum.
- Cephalosporin N, later discovered to be identical with
synnematin N (a penicillin derivative now called penicillin N)
-It was found tobe derivative of 6-amino penicillanic acid.It is
greater activity against gram-ve bacteria, which is due to
its amino acid side chain. Salmonella typhi causative
organism of typhoid fever was successful.

7. • Penicillin N (Cephalosporin N)
*Most of the antibiotics introduced since 1965 have been
semisynthetic cephalosporins.

8. Cephalosporin C:
It is an analogue of 7-amino cephalosporanic acid abbrevatd as 7-ACA.
Cephalosporin C contains a dihydrothiazine ring A and a diamino adipoyl side
Chain.
7-amino cephalosporanic acid ie. 7-ACA is still serving as a lead nucleus
In the development of various agents belonging to the cephalosporin family.
1964 the first semi synthetic cephalosporin i.e. cefalothin was launched in the
Market by Eli Lilly and company.
From then onwards therewas no looking back and various cephallosporins are
Still being synthesized by making suitable modifications in the lead nucleus.
N
S
NH
H H
O
HO O
O
CH3OO
OH
NH2 O
Cephalosporin C
N
S
O
HO O
O
CH3ONH2
7- aminocephalosporinic acid
1
2
3
4
5
6
7
5
4
3
2
1
67
Cephalosporin C can be hydrolyzed by acid to 7-aminocephalosporanic
acid. Compounds containing 7-aminocephalosporanic acid are:
- Relatively stable in dilute acid.
- Highly resistant to penicillinase, regardless of the nature
of their side chains and their affinity for the enzyme.
Cephalosporin C

9. Historical background ofHistorical background of
cephalosporinscephalosporins
 Cephalosporin compounds were first isolated from cultures ofCephalosporin compounds were first isolated from cultures of
Cephalosporium acremoniumCephalosporium acremonium from a sewer infrom a sewer in SardiniaSardinia in 1948in 1948
by Italian scientistby Italian scientist Giuseppe BrotzuGiuseppe Brotzu..
 He noticed that these cultures produced substances that wereHe noticed that these cultures produced substances that were
effective againsteffective against Salmonella typhiSalmonella typhi, the cause of, the cause of typhoid fevertyphoid fever,,
which hadwhich had beta-lactamasebeta-lactamase..
 Guy NewtonGuy Newton andand Edward AbrahamEdward Abraham at theat the
Sir William Dunn School of PathologySir William Dunn School of Pathology at theat the
University of OxfordUniversity of Oxford isolatedisolated cephalosporin Ccephalosporin C..
 The cephalosporin nucleus, 7-aminocephalosporanic acid (The cephalosporin nucleus, 7-aminocephalosporanic acid (
7-ACA7-ACA), was derived from.), was derived from.
 Modification of the 7-ACA side-chains resulted in theModification of the 7-ACA side-chains resulted in the
development of useful antibiotic agents, and the first agentdevelopment of useful antibiotic agents, and the first agent
cephalothin (cephalothin (cefalotincefalotin) was launched by) was launched by Eli LillyEli Lilly in 1964in 1964

10.  1945 - Cephalosporins were first1945 - Cephalosporins were first detecteddetected in cephalosporium acremonium.in cephalosporium acremonium.
 1948 - Cephalosporins are semisynthetic antibiotic derivatives of1948 - Cephalosporins are semisynthetic antibiotic derivatives of
cephalosporin C . Brotzucephalosporin C . Brotzu publishedpublished his results in 1948.his results in 1948.
 1964 - Alarmed by the need to keep ahead of rapidly mutating bacterial1964 - Alarmed by the need to keep ahead of rapidly mutating bacterial
strains, researchers since then have developedstrains, researchers since then have developed 44 generation cephalosporins.generation cephalosporins.
 1971 -In january 19711971 -In january 1971 Eli Lilly introduced KeflexEli Lilly introduced Keflex, generic name Cephalexin, generic name Cephalexin
 1996 - In jan 1996 a progressive reintroduction of cephalosporins was1996 - In jan 1996 a progressive reintroduction of cephalosporins was
including the novelincluding the novel 44thth
generation cephlalosporin cefepinegeneration cephlalosporin cefepine..
 2003 - Feb 11, 2003-2003 - Feb 11, 2003- RanbaxyRanbaxy laboratories has rolled out its high-endlaboratories has rolled out its high-end
cephalosporin orcephalosporin or cefprozilcefprozil under the brand name Refzil.under the brand name Refzil.
Cephalosporins have an estimated RsCephalosporins have an estimated Rs 1000-crore in india1000-crore in india..
 2005 - Infact the risk that a patient with a history of penicillin allergy2005 - Infact the risk that a patient with a history of penicillin allergy
will experience a reaction to a first generation cephalosporin notwill experience a reaction to a first generation cephalosporin not
more than 0.5%, second generation cephalosporin not more than 0.2% and a thirdmore than 0.5%, second generation cephalosporin not more than 0.2% and a third
generation cephalosporin practicallygeneration cephalosporin practically nil in at least 25 studiesnil in at least 25 studies....
 2010 - Feb 28,2010 Most patients who have a history of penicillin allergy can safely take2010 - Feb 28,2010 Most patients who have a history of penicillin allergy can safely take
antibiotics called cehalosporinsantibiotics called cehalosporins,US,US researchers say.researchers say.

11. Biological sourcesBiological sources
 Cephalospoium acremonium is the most important source for theCephalospoium acremonium is the most important source for the
production of cephalosporins.production of cephalosporins.
Presently major source for the production of cephalosporins include..Presently major source for the production of cephalosporins include..
CephalosporinCCephalosporinC
PenicillinVPenicillinV
CephamycinCCephamycinC
Cephalosporins are semisynthetically prepared from 7-aminoCephalosporins are semisynthetically prepared from 7-amino
cephalosporanic acid(7-ACA) which is obtained fromcephalosporanic acid(7-ACA) which is obtained from
cephalosporinC and also prepared from (7-ADCA) i.e. 7-amino 3-cephalosporinC and also prepared from (7-ADCA) i.e. 7-amino 3-
deacetoxy cephalosporanic acid.deacetoxy cephalosporanic acid.

12. Mechanism of action
Mode of action
Cephalosporins are bactericidal and have the same mode of action as other
beta-lactam antibiotics (such as penicillins) but are less susceptible to penicillinases.
Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls.
The peptidoglycan layer is important for cell wall structural integrity. The final
transpeptidation step in the synthesis of the peptidoglycan is facilitated by
transpeptidases known as penicillin binding proteins (PBPs). PBPs bind to the D-Ala-
D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the
peptidoglycan. Beta-lactam antibiotics mimic this site and competitively inhibit PBP
crosslinking of peptidoglycan

13. Mechanism of actionMechanism of action
•Some PBP have
transpeptidase activity.
• Transpeptidase activity is
essential in cell wall
synthesis.
•cephalosporins and β-lactums
bind PBP (Penicillin Binding
Proteins).

14. The meChanism of resisTanCe of m.o
- Alteration of binding site.
- Decrease permeability.
- Production of β–lactamase enzymes (enzymatic inactivation).

15.  Classification of cephalosporins:-Classification of cephalosporins:-
1ST
Genaration
Parenteral
Cephalothin
Cephaloridine
Cefazolin
Oral
Cephalexin
(Keflex)
Cephadroxil
(Durecef)
Oral and parenteral
Cephradine
2nd
Gen.
Parenteral
CefamycinC
Cefoxitin
Cefotitan
Cefmetazole
Cefuroxime
Oral:
Cefachlor
Cefprozil
3rd
Gen
Parenteral
Cefotaxime
Ceftazidime
Ceftriaxone
Oral
Cefixime
Cefdinir
Ceftibuten
4th
Gen.
Parenteral
Cefepime
Cefpyrome
5th
Gen.
ceftobiprole
Generations of cephalosporins ,parenteral and oral..

17. The CephalosporinsThe Cephalosporins (generalized)(generalized)
11stst
GenerationGeneration Gram (+)Gram (+)
22ndnd
GenerationGeneration
Decreasing Gram (+)Decreasing Gram (+)
and Increasing Gram (-)and Increasing Gram (-)
33rdrd
GenerationGeneration
Gram (-), but also someGram (-), but also some
GPCGPC
44thth
GenerationGeneration Gram (+) and Gram (-)Gram (+) and Gram (-)
*Not effective vs. Enterococcus or Listeria

18. Structures of some important cephalosporins andStructures of some important cephalosporins and
cephamycinscephamycins
11STST
GENARATION CEPHALOSPORINSGENARATION CEPHALOSPORINS::
11stst
generation cephalosporins offer advantageous over penicillinsgeneration cephalosporins offer advantageous over penicillins
They have greaterstability to acid,They have greaterstability to acid,ββ-lactamases,good ratio of activity-lactamases,good ratio of activity
Against Gram+ve and Gram-ve bacterial. How ever they are genarally poor inAgainst Gram+ve and Gram-ve bacterial. How ever they are genarally poor in
Oral availability and are generally lower in activity.Oral availability and are generally lower in activity.
Prototypical Early cephalosporin: Cephalothin
1. Less antibiotic activity than Penicillin G against Gram positive bacteria
2. More activity than Pen G against Gram negative bacteria
3. Can be used on patients who are allergic to penicillin
4. Side chain acetoxy group is hot point for metabolic inactivation
Disadvantage of cephalosporin is the fact
That the acetyloxy group at position 3 is
Readily hydrolysed by esterase enzyme to
Give less active alcohol

19. The acetoxy group is important to the mechanism of inhibition and acts as a good
Leaving group where as the alcohol is much poorer leaving group.
Replacing the ester with a metabolically stable pyridinium group gives cephaloridine.
Pyridine can still act as a good leaving group for the inhibition mechanism but not
Cleaved by esters.
Exists as a zwitterion and is
soluble in water.

20. * Cefazolin
N
S
O
NH
C
CCH2
O
O OH
Cefazolin
N
N
N NN
S
CH3CH2S
*Cephalexin
N
S
O
NH
CH3
C
CCH
O
O OH
NH2
Cephalexin
Good for absorption
and bad for activity.
Since it is not a good
leaving group, it
Prevents the
Deactivation of
Cephalexin upto some
Extent.
It is not much clear that why 3- methyl group is so advantageous.
Although the methyl group at position is bad for activity the presence
Of hydrophilic amino group at the α-carbon of the acylamino side
Chain helps to compensate.

21. * Cephradine
N
S
O
NH
CH3
C
CCH
O
O OH
NH2
Cephradine
* Cefadroxil
N
S
O
NH
CH3
C
CCH
O
O OH
HO
NH2
Cefadroxil
(Velosef)

22. • Most cephalosporins are produced semisynthetically by the chemical
attachment of side chains to 7-aminocephalosporanic acid.
• Cephalosporins (7α-H) and cephamycins (7α-OCH3):
Cephalosporins
1
2
3
4
5
6
N
S
O
HO O
X
NH
H
R
O
7
Cephamycin
1
2
3
4
5
6
N
S
O
HO O
X
NH
OCH3
R
O
7
Most natural cephalosporin and cephamycin are not used
clinically for side effects, but semi-synthetic products are used.
Second Genaration cephalosporins:
Cephamycins:
`A methoxy substituent at position 7 of the
cephalosporin skeleton has proved
Advantageous. Compounds such as these are
known as cephamycins.
The parent compound cephamycin C was isolated
from a culture of
Streptomyces clavuligerus.
stabilizes

23. Second generation:
* Cefoxitin
N
S
OCH3
O
NH
C
CH2OCNH2
CCH2
S
O
O
O OH
Cefoxitin
N
S
O
NH
C
CH3O
C
O
O OH
Cefmetazole
NCCH2SCH2
N
N
NN
CH2S
CH3
N
S
O
NH
C
CH3O
C
O
O OH
Cefotetan
N
N
NN
CH2S
CH3
S
S
C
C
C
O
O
H2N
HO
Cefotetan
Cefmetazole
(Structures of some important cephamycins)

24. * Cefaclor
N
S
O
NH
Cl
C
CCH
O
O OH
NH2
Cefachlor
* Cefuroxime
N
S
O
NH
C
CH2OCNH2
C
O
O OH
Cefuroxime
C
NOCH3
O
O

25. * Cefuroxime axetil
N
S
O
NH
C
CH2OCNH2
C
O
O
Cefuroxime axetil
C
NOCH3
O
O
O CHOCCH3
O
CH3
* Cefonicid
N
S
O
NH
C
C
O
O OH
Cefonicid
N
NN
N
CH2S
CH2SO3H
CH
OH

26. * Ceforanide
N
S
O
NH
C
C
O
O OH
Ceforanide
N
NN
N
CH2S
CH2CO2H
CH2
CH2NH2
N
S
O
NH
C
C
O
O OH
Cefamandole
N
NN
N
CH2S
CH3
CH
OH
Cefamandole

27. Third generation:
*Cefotaxime
N
S
CH2OCCH3
C
O
NH
OHO
OCC
O
NOCH3
S
NH2N
Cefotaxime
*Ceftizoxime
N
S
O
NH
C
H
C
O
O OH
Ceftizoxime
C
NOCH3
S
N
H2N

28. N
S
O
NH
C
C
O
O OH
Ceftriaxone
C
NOCH3
S
N
H2N N
N
N OH
CH2S O
CH3
*Ceftriaxone
*Cefixime
N
S
NH
C
CH=CH2
O
CC
S
N
H2N
O
O OH
Cefixime
NOCH2CO2H

29. *Cefpodoxime proxetil
N
S
NH
CH2OCH3
C
O
C
O
O
NOCH3
Cefpodoxime proxetil
S
N
H2N C
O CHOCOCH(CH3)2
O
CH3

30. Third generation cephalosporins with good activity against
Pseudomonas:
*1-Cefoperazone
N
S
O
NH
C
CH2S
C
O
O OH
Cefoperazone
C
S
N
H2N
NH
C
N
N
O
O
O
C2H5
N
N
N
N
CH3
*2-Ceftazidime
N
S
O
NH
C
C
O
O OH
Ceftazidime
C
S
N
H2N
N
O
C CO2HCH3
CH3
N
CH2
+

31. Fourth Generation Cephalosporins:
* Cefpirome
NN
S
HN
O
H H
CO2
CC
N
S
H2N
N
O
-
OCH3
Cefpirome
+3
N
S
HN
O
H H
CO2
N
CC
N
S
H2N
N
O
-
OCH3
Cefepime
H3C
+
* Cefepime

32. 55thth
Generation cephalosporinGeneration cephalosporin
 CeftobiproleCeftobiprole ((ZefteraZeftera//ZevteraZevtera) is a 5th generation) is a 5th generation cephalosporincephalosporin antibioticantibiotic
with activity againstwith activity against methicillin-resistantmethicillin-resistant Staphylococcus aureusStaphylococcus aureus, penicillin-, penicillin-
resistantresistant Streptococcus pneumoniaeStreptococcus pneumoniae,, Pseudomonas aeruginosaPseudomonas aeruginosa, and, and
EnterococciEnterococci. It was discovered by. It was discovered by Basilea PharmaceuticaBasilea Pharmaceutica[6][6] and wasand was
developed bydeveloped by
Johnson & Johnson Pharmaceutical Research and DevelopmentJohnson & Johnson Pharmaceutical Research and Development..
 Ceftobiprole cannot be given by mouth and so is given intravenouslyCeftobiprole cannot be given by mouth and so is given intravenously
 Ceftobiprole inhibits the 2aCeftobiprole inhibits the 2a penicillin-binding proteinpenicillin-binding protein (pbp) of(pbp) of
Methicillin-resistant Staphylococcus aureusMethicillin-resistant Staphylococcus aureus and the 2x pbp ofand the 2x pbp of
Streptococcus pneumoniaeStreptococcus pneumoniae as well as the classic PBP-2 of MSSA.as well as the classic PBP-2 of MSSA.
Ceftobiprole is resistant to staphylococcalCeftobiprole is resistant to staphylococcal β-lactamaseβ-lactamase..

34. Pharmacokinetics
1- Administration:
All cephalosporins except cefadroxil, cephalexin, cephradine,
cefaclor, cefuroxime axetil, cefdinir, cefixime and ceftibuten
must be administered intravenously because of their poor oral
absorption.
2- Distribution:
- All of cephalosporins distribute very well into body fluids.
However, several cephalosporins penetrate into CSF in sufficient
concentration to be useful for the treatment of meningitis.
These include:
Cefuroxime (2nd
gen.), ceftriaxone, cefotaxime and
ceftizoxime (3rd
gen.).

35. 3- Fate:
- Elimination occurs through tubular secretion and/or glomerular
filtration.
Cefoperazone are excreted through the bile and are frequently
used in patients with renal insufficiency.

36. Adverse reactions
The most common adverse reactions are:
1- Allergic and hypersensitivity reactions
2- A disulfiram-like effect
3-Bleeding:
- Bleeding can occur with cefamandole, cefotetan, cefmetazole
moxalactam and cefoperazone (containing an N-methyl-5-
thiotetrazole moiety at the 3 position) b/c of antivitamin K
effects, administration of the vitamin corrects the problem.
4- Nephrotoxicity.

37. Therapeutic uses
- When Gm +ve bacteria is involved a 1st
generation agents is
preferable.
- When the pathogen is gm –ve and the infection is serious
parentral use of a 3rd
generation agent is recommended.
First generation cephalosporins are:
• Excellent agents for skin and soft tissue infections due to
S. aureus and S. Pyogenes.
• A single dose of cefazolin just before surgery is the preferred
as prophylaxis

39. Clinical uses of first gen.Clinical uses of first gen.
cephalosporinscephalosporins

40. Second-generation cephalosporins
• The second generation agents have inferior activity against
penicillin-resistant S. pneumoniae compared to either the 3rd
generation agents or ampicillin and therefore should not be
used for treatment of meningitis or pneumonia.
• In case where Gm -ve bacteria and anaerobes are involved
such as intraabdominal infections, pelvic inflammatory
disease and diabetic foot infection, cefoxitin and cefotetan have
been shown to be effective.
• For colorectal surgery where prophylaxis for intestinal
anaerobes is desired, cefoxitin or cefotetan (2nd
generation)
are preferred.

42. 3rd generation cephalosporins3rd generation cephalosporins
Clinical usesClinical uses

43. Third generation cephalosporins
• Third generation cephalosporins have been considered to be
the drugs of choice for serious infections caused by:
Klebsiella, Enterobacter, Proteus, Haemophilus species.
• Ceftriaxone is now the drug of choice for all form of gonorrhea.
• Cefotaxime or ceftriaxone (as part of a 3-drug combination with
vancomycin and ampicillin) are used for the initial treatment of
meningitis in nonimmunocompromised adults and children
older than 3 months.

44. • Ceftazidime + aminoglycoside is the drug of choice for
Pseudomonas meningitis.
• The antimicrobial spectrum of cefotaxime and ceftriaxone is
excellent for the treatment of community acquired pneumonia,
i.e. that caused by pneumococci, H. influenzae, S. aureus.
Third generation cephalosporins (Cont.)

45. The fourth generation
• The fourth generation are indicated for the empirical treatment
of nosocomial infections where antibiotic resistance due to
extended spectrum β-lactamases are anticipated.
e.g. cefepime has superior activity against nosocomial
isolates of Enterobacter, Citrobacter compared to
ceftazidime and piperacillin

49. 55thth
Genaration cephalosporinsGenaration cephalosporins
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[6] and was developed by Johnson & Johnson Pharmaceutical Research
and Development.
Ceftobiprole cannot be given by mouth and so is given intravenously
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

50. This compound has been modified by the addition of different
side chains to create a whole family of cephalosporin antibiotics.
Structural features of cephalosporins:

51. Structure-activity relation ship of cephalosporin CStructure-activity relation ship of cephalosporin C
There is a limited number of placesThere is a limited number of places
where modifications can be made butwhere modifications can be made but
there are more Possibilities than withthere are more Possibilities than with
penicillins…penicillins…
 Variations at the 3-Variations at the 3-
acylamino side chain.acylamino side chain.
 Variations at the 3-Variations at the 3-
acetoxymethyl side chain.acetoxymethyl side chain.
 Extra substitution at carbon.Extra substitution at carbon.
1
2
22
4
4
55
6
8
8 8

53. Cephalosporins advantages over penicillinsCephalosporins advantages over penicillins
 Increased acid stability compare to penicillinsIncreased acid stability compare to penicillins
 Most of the drugs better absorption thanMost of the drugs better absorption than
penicillin.penicillin.
 Broad antimicrobial spectrum.Broad antimicrobial spectrum.
 Increased activity against resistantIncreased activity against resistant
microorganisms.microorganisms.
 Decreased alleregenicity.Decreased alleregenicity.
 Increased tolerence than penicillins.Increased tolerence than penicillins.