Cephalosporins, Why Cephalosporins? Advantages of cephalosporins over penicillin, Mechanism of action of cephalosporins, Classification of cephalosporins, Structures of some important cephalosporins and cephamycins, Oximinocephalosporins, SAR of cephalosporins,Hydrolytic reactions, degradation and stability of cephalosporins, Uses of cephalosporins, Comparison between 6-APA and 7-ACA and penam and cepham.

1. Cephalosporins
Cephalosporins
Prof. Dr. P. Ravisankar Ph.D
Vignan Pharmacy College
Vadlamudi
Guntur (Dist)
Andhra Pradesh, India.
banuman35@gmail.com
Phone: +919000199106

2. Cephalosporins
• The second major group of β-lactam antibiotics to be discovered were the cephalosporins.
• The first cephalosporin (Cephalosporin-C) was derived from a fungus called
Cephalosporium Acremonium now called Acremonium chrysogenum.
• This fungus was obtained in the 1945s from sewer waters on the island of Sardina. By
Giuseppe Brotzu’s.
• Abraham and Newton at Oxford University, having been supplied cultures of the fungus in
1948, isolated 3 principal antibiotic compounds
• Cephalosporin C; Cephalosporin N (penicillin N); Cephalosporin P (a steroid with minimal
antibacterial activity)
• This was the work of an Italian professor, who noticed that the waters surrounding the
sewage outlet were periodically cleaned of microorganisms.
• Biological sources
• Giuseppe Brotzu’s: Cephalosporin isolated a fungus called Cephalosporium acremonium
(now called Acremonium chrysogenum. Inhibited the growth of a wide variety of Gram-
positive and Gram-negative bacteria.

3. Why Cephalosporins? Advantages of cephalosporins over penicillins
➢ Increased acid stability compared to penicillins.
➢ Improved pharmacokinetic properties, particularly better oral absorption than
penicillins.
➢ Cephalosporins are highly potent with broad-spectrum activity than penicillins.
➢ Increased activity against resistant microorganisms
- As a result of resistance to enzymatic destruction,
- improved penetration, Increased receptor affinity, etc
➢ Decreased allergenicity, Increased tolerance after parenteral administration.
➢ Widely accepted, Treats ‘day-to-day as well as ‘serious infections’, High safety
profile., cephalosporins are prescribed safely for penicillin-allergic patients.
➢ Cephalosporins are more resistant to beta-lactamases than penicillins.
➢ Cephalosporins are much more stable in acids compared to penicillins.
➢ 5th generation cephalosporins ceftobiprole had powerful antipseudomonal
characteristics.
➢ Most of the doctors and authors recommended cephalosporins are dugs of the first
choice in pediatrics.

4. 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.
The Mechanism by which cephalosporins inhibit the transpeptidase enzyme

5. Cephalosporin C
It is not potent compared to penicillins (1/1000 the activity of Penicillin G)
But it has antibacterial activity against Gram +ve and Gram –ve bacteria.
It has greater resistance to acid hydrolysis and beta-lactamase enzymes.
It has fewer allergic reactions. Therefore, Cephalosporin C was seen as a useful
lead compound for the Development of broad-spectrum antibiotics.
The aim was to produce analogs with increased potency while retaining the
The breadth of activity.
Cephalosporin C itself has been used in the treatment of UTI infections.
SAR of cephalosporin C:
Betalactum ring + dihydrothiazine ring
A bicyclic ring is essential 2. Ionized carboxylate group at position 4.
Acyl amino side chain at position 7.
The strain effect of a six-membered ring fused to a four-membered ring is less than
For penicillin.
The Acetyloxy group at position 3 is imp. It is a good leaving group. In the inhibition
Mechanism.
There is a limited number of places where
modifications can be made, but there are more
possibilities than with penicillins. These are as follows;
• variations of the 7-acylamino side chain;
• variations of the 3-acetoxymethyl side chain;
• extra substitution at carbon 7.

7. • 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..

8. Parenteral:
1st Genaration:
Cephalothin
Cephaloridine
Cephapirin
Cefazolin
Oral:
Cephalexin( Keflex)
Cephadroxil ( Duricef)
Both oral and parenteral:
Cephradine ( Velosef)
2nd Genaration:
Cephamycin C
Cefoxitin
Cefmetazole
Cefotitan
Cefchlor
Cefuroxime (Zinnat)
1st generation.
Actie against Striptococci
Staphylococci
PEcK
P= Proteus mirabilis
Ec = Escherichia Coli
K= Klebsiella
2nd genaration:
HEN PEcK
H= Haemophilus influenzae
E= Enterobacter
N= Neisseria.
P= Proteus mirabilis
Ec= Escherichia Coli
K= Klebsiella

9. The Cephalosporins (generalized)
1st Generation Gram (+)
2nd Generation
Decreasing Gram (+)
and Increasing Gram (-)
3rd Generation
Gram (-), but also some
Gram (+ve)
4th Generation Gram (+) and Gram (-)

10. Structures of some important cephalosporins and cephamycins
1ST GENARATION CEPHALOSPORINS:
1st generation cephalosporins have lower activity than penicillins but better range.
They have greater stability to acid, β - lactamases, good ratio of activity than
penicillins. Most are poorly absorbed through gut wall.
A disadvantage with cephalothin is infact the
acetyloxy group at position 3 is readily
hydrolysed by esterase enzymes to give less
active alcohol.
(pareneral)
N
S
O
COOH
H
H
O CH3
O
N
H
C
O
S
Cephalothin

11. 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. It is poorly absorbed through gut wall and has to be injected.
Exists as a zwitterion and is
soluble in water.
-
(parenteral)
N
S
O
COOH
H
H
O CH3
O
N
H
C
O
S
Cephalothin
Metabolism
N
S
O
COOH
H
H
OH
N
H
C
O
S
Less active alcohol and has
decreased activity
Esterase
enzymes
N
S
O
COO
H
H
N
N
H
C
O
S
Cephaloridine.

12. * Cefazolin
*Cephalexin
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.
(parenteral)
Keflex
(oral)
(Ancef)
N
S
O
COOH
H
H
S S
N
H
C
O
N
Cephazolin
N N
CH3
N
N
N
Thiadiazole
Tetrazole
N
S
O
COOH
H
H
CH3
N
H
C
O
7

H2N H
Good for absorption
and usually bad for activity
3
1 2
4
5
Cefalexin
D-Phenyl glycyl cephalosporins

13. Cephadroxil
(durecef)
•Both cephalexin and cefadroxil cause diarrhea due to amino and -COOH groups.
But the effect of cefadroxil is less compared to cephalexin.
In general 1st generation cephalosporins are advantageous over penicillins in that
they have Greater stability to acid and beta-lactamases.
They have a good ratio of activity against Gram +ve and Gram-ve bacteria. However
They have poor oral availability and are generally lower in activity.
Cephradine
(Velosef)
Both oral and parenteral
cephalosporin
N
S
O
COOH
H
H
CH3
N
H
C
O
7

H2N H
Good for absorption
and usually bad for activity
3
1 2
4
5
Cefadroxil
HO
N
S
O
COOH
H
H
CH3
N
H
C
O
7

H2N H
3
1 2
4
5
Cephradine
cyclohexadiene

14. In Cephalosporins 7α-H present and in
cephamycins 7α-OCH3 is present.
Most natural cephalosporin and cephamycin are not used
clinically for side effects, but semi-synthetic products are used.
2nd Genaration cephalosporins:
Cephamycins: cephamycins are Cephalosporins containing a –OCH3 substituent
at 7-position.
The parent compound cephamycin C was isolated from a culture of Streptomyces clavuligerus
And was the first betalactum tobe isolated from a bacterial source.
Due to steric hindrance provided by the extra –OCH3 group
at C-7α rather than hydrogen atom.
then greater resistance to beta lactamase and show
Broad spectrum of activity than 1st generation
cephalosporins.
N
S
O
COOH
N
H
C
O
7
3
1 2
4
5
Cephamycin C
O NH2
O
Urethane or carbamate
NH2
H
HOOC H
OCH3
Stabilizes neighbouring
carbonyl gruop

15. Second generation:
* Cefoxitin (available parenteral)
Cefotetan
Cefmetazole
(Structures of some important cephamycins)
Cefoxitin show good metabolic stability
To esterases due to the presence of
Urethance group rather than ester at
Position 3.
N
S
O
COOH
N
H
C
O
7
3
1 2
4
5 O NH2
O
H
OCH3
Cefoxitin
S
Thiophen
N
S
O
COOH
N
H
C
O
7
3
1 2
4
5 S
S
H
OCH3
Cefmetazole
C
N
N N
N
N
CH3
N-Methyl 5-thio-tetrazole
(MTT)
N
S
O
COOH
N
H
C
O
7
3
1 2
4
5 S
H
OCH3
Cefotitan
N N
N
N
CH3
C3 position incorporates a N-methyl
thio tetrazole moiety (MTT)
H2NOC
HOOC
C7 alpha position- OCH3 group which gives
sufficient resistance towards beta lactamase.
The presence of MTT moiety (group) at C-3 position decreases Prothrombin levels
thereby prolonging the clotting time. The MTTgroup also producing disulfiran, like
effects.
These 3 drugs are used in
1. Diabetic foot
2. Septicemia
3. Abdominal infections

16. N
S
O
COOH
N
H
C
O
7
3
1 2
4
5
CH
C
H
H2N H H
Cefprozil
HO
CH CH3
Cefprozil
Oral second generation:
N
S
O
COOH
N
H
C
O
7
3
1 2
4
5
Cl
C
H
H2N H H
Cefaclor
N
S
O
COOH
H
H
O NH2
O
N
H
C
O
O
Cefuroxime
N
O
CH3
Cefuroxime:
In general 2nd generation cephalosporins have variable activity against Gram+ve Cocci, but increased activity against Gram-ve bacteria.
•Zinnat trade name
Hydroxyl phenylglycyl moiety
At its acylamino side chain

17. OXIMINOCEPHALOSPORINS:
A major advance in cephalosporin research has been the development of the
oximinocephalosporins. These contain an iminomethoxy group at the a-position of the
acyl side chain(C=N-O-CH3), which significantly increases the stability of cephalosporins against
the (beta-lactamases produced by some organisms (e.g. Haemophilus influenza).
Third generation cephalosporins:
Replacing the furan ring of the aforesaid oxyimino cephalosporins
with an aminothiazole ring enhances the penetration of cephalosporins
through the outer membrane of Gram-negative bacteria and may also
increase affinity for the transpeptidase enzyme. As a result, third-
generation cephalosporins containing this ring have a marked increase
in activity against these bacteria.
Oral 3rd generation cephalosporins:
N
S
O
COOH
H
H
N
H
C
O
S
N
Cefdinir
N
OH
H2N

18. N
S
O
COOH
H
H
N
H
C
O
S
N
Cefdinir
N
OH
H2N
N
S
O
COOH
H
H
N
H
C
O
S
N
Cefixime
N
OCH2COOH
H2N
Vinyl or ethinyl group
N
S
O
COOH
H
H
N
H
C
O
S
N
Ceftibuten
HC
CH2COOH
H2N
vinyl or ethenyl is the functional
group −CH=CH2, namely
the ethylene molecule (H2C=CH2) minus
one hydrogen atom
Trade name:Suprax
Corboxy methoxy imino
2-amino- 1,3 thiazole

19. Third and fourth-generation cephalosporins:
Replacing the furan ring of the oximinocephalosporins with an aminothiazole ring
enhances the penetration of cephalosporins through the outer membrane of Gram-
negative bacteria and may also increase affinity for the transpeptidase enzyme.
A variety of such structures have been prepared such as
ceftazidime, cefotaxime, ceftizoxime and ceftriaxone
N
S
O
COOH
H
H
N
H
C
O
S
N
Ceftazidime
N
H2N
N
O
C
H3C
CH3
COOH
N
S
O
COOH
H
H
N
H
C
O
S
N
Ceftizoxime
N
OCH3
H2N
N
S
O
COOH
H
H
N
H
C
O
S
N
N
H2N
O
CH3
S N
N
N
O
OH
CH3
Ceftriaxone
N
S
O
COOH
H
H
N
H
C
O
S
N
Ceftaxime
N
OCH3
H2N
O CH3
O
This is eliminated by hepatic
excretion

20. 4th Generation cephalosporins
• Cefepime and cefpirome: oxyimino cephalosporins which have been classed as
fourth-generation cephalosporins. They are zwitterionic compounds having a
positively charged substituent at position 3 and a negatively charged
carboxylate group at position 4. This property appears to radically enhance the
ability of these compounds to penetrate the outer membrane of Gram-
negative bacteria. They are also found to have a good affinity for the
transpeptidase enzyme and a low affinity for a variety of β-lactamases.
N
S
O
COOH
H
H
N
H
C
O
S
N
N
H2N
O
CH3
N
Cefepime
H3C
N
S
O
COOH
H
H
N
H
C
O
S
N
N
H2N
O
CH3
N
Cefpirome
Amino thiazole
1-methyl pyrrolin
The C3 position of cefepime is occupied by a quaternary N-methyl pyrrolidine
Group which is responsible for the antibacterial activity.
Cyclopenta pyridinium
2-amino
1,3thiadiazole

21. 5th Generation cephalosporin
• 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.

22. N
S
COOH
O
H
N
C
O
R1
H
H
1
2
3
4
5
6
7
8
-Lactam ring is
vital forantibacterial activity
any modification results
in compounds with decreased
activity.
Corboxyl group at C2 position helps
converting the drug into its salt form.
estarification of the -COOH group results
in formation of ester prodrugs.This facilitates
in oral administration of cephalosporins and
also enhances their bioavailability profiles.
Double bond b/n C3 and C4 isimp. for antibacterial
activity. Shifting the saturation b/n C2 andC3 results
in decreased antibacterial activity.
S atom at 1st positionpossess appreciable antibacterial activity.and
shows reduced resistance towords -Lactamases.
If S is replaced by O,but the reverse is true when stability toward
betalactamase is considered.
Ar
The 6 hydrogen
is essential for
biological activity
antibacterial acitivity is improved when R1 is a
5 membered heteroccle versus a 6 membered
heterocycle
The follwoing changes improved betalactamase resistance
1, The L- isomer of and  amino ' hydrogen derivative of a
cephalosporin wa 30 -40 times more stable than D- isomer.
2. The addition of methoxyoxime to the  and ' positions increased
stability nearly 100 times.
The z-oxime was as much as 20,000 fold more stable than the E- oxime.

'
7 methoxy group improves
the drug stability(greater
resistance) towords
 lactamase and improves
the antibacterial activity.(due to
steric hindrance provided by
extra methoxy group
7  amino group is essential
for antimicrobial activity
The addition of amino and hydrogen to the  and ' position respectively, results in a
basic compounds that is protonated under acidic conditions of the stomach. The amonium
ion improves the stability of the beta lactam ring of cephalosporin, leading to orally active
drugs.
C3 acetoxymethyl group is good leaving group.
Deacetylation produces metabolically inactive compounds. Metabolism
can be blocked to prolong activity by stablegroups such as pyridinium
group ( cephaloridine)
Methyl substitution at position 3 is good for
absorption but bad for activity unless a hydrophilic group is present at the
alpha position of acyl side chain.
7- Aminoadipic side
chain
7-amino cephalosporinic acid
7-ACA
Oximinocephalosporins have resulted
in 2nd and 3 rd 4th geeneration cephalosporins
which increases the stability, potency and
broder spectra of activity perticularly gram -ve
bacteria. (Haemophilus influnza.)
Presence of oximino
cephalosporin with
aminothiazole ring
enhances the penetration
of cephalosporins through
outer membrane of gram-ve
bacteria and also increase the
affinity for the transpeptidase
enzyme
Variations at 7-
acyl amino side chain
changes anitimicrobial
activity.
Variation of the side chain at position3
alters the metabolic and pharmacokinitic
properties of the compound.
Cefepime and cefpirome are Oximinocephalosporins
whcih are zwitterionic compounds having positively
charged subtituent (pyrrolidinium group ) at position 3
and negatively charged coboxylate at position 4. This
property appears to penetrate the outer memembrane
of gram -ve bacteria. They have good affinity for
transpeptidase enzyme. They have activity against
gram-ve cocci,gram-ve bacilli, P.aeruginosa, and also
enterobacterial species.
SAR
of Cephalosporins

25. Clinical uses of 1st generation cephalosporins
Impetigo
• Caused by: Staphylococcus aureus and Streptococcus
pyogenes
Celullitis
• Group A streptococcus bacterium (Streptococcus
pyogenes, GAS) and Staphylococcus aureus
Prophylaxis of surgical wound infections
• Mainly produced by Gram positive bacteria

26. Second-generation cephalosporins uses:
• 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 the treatment of meningitis or pneumonia.
• In cases 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 are desired, cefoxitin or cefotetan (2nd generation)
are preferred.

27. 3rd generation cephalosporins
Clinical uses
Bacterial
meningitis:
Gérmenes más
frecuentes en
adultos: S.
Pneumoniae,
N.
meningitidis
Gonorrhea
Neisseria
Pneumonia:
only in some
cases
Only ceftazidime
P. Aeruginosa
infections.

28. Uses of 3rd generation cephalosporins
•Sexually transmitted infections (gonorrhea, pelvic inflammatory disease, epididymitis, proctitis).
•Moderate-to-severe diabetic foot infections.
•Empiric therapy for acute lower respiratory infections
•Empiric treatment for suspected infection in Human Immunodeficiency Virus (HIV) patients (outpatients).
•Lyme disease with CNS involvement and with or without parenchymal involvement.
•Mild to severe intraabdominal infections.
•Encephalitis and meningitis. In general, meningitis caused by Haemophilus influenzae, meningococci, and
Enterobacteriaceae can be treated with cefotaxime, ceftriaxone, ceftazidime, or ceftizoxime. Pseudomonas
aeruginosa meningitis can be treated with ceftadizime. Pneumococcal meningitis can be treated with cefotaxime,
ceftizoxime, or ceftriaxone.
•Febrile neutropenia (ceftazidime).
•Alternative treatment options include syphilis, gonorrhea, acute bacterial rhinosinusitis, endometritis, pharyngitis,
uncomplicated cystitis, infectious diarrhea, and combat wounds.
•Endoscopic urologic procedures with mucosal trauma, vertebral osteomyelitis, skin and soft tissue infections
•Cefotaxime is the most commonly used third-generation cephalosporin over an aminoglycoside in neonatal early-onset
sepsis due to its wider therapeutic index.
•Uses of the fourth generation
• The fourth-generation cephalosporins (e.g., cefepime), while retaining their activity
against gram-negative like third-generation, also have improved gram-positive activity.
•Cefepime is active on many gram-positive and gram-negative strains and is used to
treat severe infections such as ICU pneumonia, abdominal infections, sepsis, and
meningitis.