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1.INTRODUCTION

•Beta-lactam antibiotics
•Bacterial cell wall synthesis inhibitors.
•These are bactericidal drugs
•Chemically related to penicillins
•High therapeutic index.
•Recognized by the inclusion of “cef” or
“ceph” in their official names.

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2.Source & Discovery:
Cephalosporium acremonium, the first source of the
cephalosporins, was isolated in 1948 by Italian scientist, Brotzu
from the sea near a sewer outlet off the Sardinian coast. Crude
filtrates from cultures of this fungus were found to inhibit the in
vitro growth of S. aureus and to cure staphylococcal infections
and typhoid fever in human beings. Culture fluids in which the
Sardinian fungus was cultivated were found to contain three
distinct antibiotics, which were named cephalosporin P, N, and
C. With isolation of the active nucleus of cephalosporin C, 7-
aminocephalosporanic acid, and with the addition of side chains,
it became possible to produce semisynthetic compounds with
antibacterial activity very much greater than that of the parent
substance

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•CHEMISTRY:
•Basic nucleus is 7-amino-cephalosporinic-acid
•Having the following main parts
•Dihydrothiazine ring
•Β-Lactam ring
•Two side chains i.e R & X
•R  changes in pharmakodynamics
X  changes in pharmacokinetics

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The nucleus of the cephalosporins, 7-aminocephalo-sporanic
acid, bears a close resemblance to 6-amino-penicillanic acid.
The intrinsic antimicrobial activity of natural cephalosporins
is low,but the attachment of various R1 and R2 groups
has yielded hundreds of potent compounds of low toxicity.
Cephalosporins can be classified into four major groups or
generations, depending mainly on the spectrum of their
antimicrobial activity.
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.

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7-Aminocephalosporanic acid nucleus

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 •CLASSIFICATION
Cephalosporins are similar to penicillins, but more stable to many bacterial beta-
lactamases and therefore have a broader spectrum of activity.
However, strains of E. coli and Klebsiella species expressing extended-spectrum beta-
lactamases that can hydrolyze most cephalosporins are becoming a problem.
Cephalosporins are not active against enterococci and L. monocytogenes.

Cephalosporins are classified (Generations/

Spectrum) as;

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•First generation cephalosporin.
•Narrow spectrum drugs  G+ve & Few G-ve bacteria’s.
•Can’t cross BBB except cephalothin
•Highly susceptible to beta- lactamases

•Drugs of this group are as follows (7 drugs)

•Oral;
•Cephalexin (ciporex)
•Cephradine (velosef)
•Cefadroxil (Duricef)
•Parental;
•Cefazolin
•Cephalothin
•Cephaloridin
•cephapirin
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 Second generation cephalosporin.
 Intermediate spectrum
 Can’t cross BBB
 Most susceptible to Beta-
lactamase except Cefuroxime
(11 drugs)
Oral Paraenteral

cefuroxime Cephamandol
cephaclor Cephonicid
cefuroxime axetil Cephoranide
loracarbef Cefuroxime sodium

Cephamycin
•Cefmetazole
•Cefotetan
•Cefoxitin 10
 Third generation cephalosporin.
 Extended/broad spectrum
 Most can cross BBB
 Most resistant to Beta-lactamases
 (10 drugs)
Paraenteral

Ceftriaxone
en Ceftazidime
xime proxetil Cefoperazone
Lactamoxcef
Moxalactam
Cefotaxime sodium

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Fourth generation cephalosporins.
 Extended/broad spectrum
 Cross BBB
 Highly resistant to Beta-lactamases
 (2 drugs)
Oral Paraenteral

NA Cefepime
cefpirome

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Summary with Brands

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Spectrum of first Generation

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 Spectrum of Second Generation
The second-generation display greater activity against three
additional gram-negative organisms. H. influenzae,
Enterobacter aerogenes, and some Neisseria species,
whereas activity against gram-positive organisms is weaker.

•First generation µ-organisms (SSPEK)+

•Moraxella catarrhallis
•H- influenza
•Anaerobes esp Bacteroid fragilis

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 Spectrum of Third Generation
•First generation (SSPEK) +
•Second generation (MEHN) +
•Pseudomonas aerogenosa
•Certain enteriobacteriacea
•Salmonella typhae
•Vibrio cholera

The third-generation cephalosporins have enhanced activity

against gram-negative bacilli, including those mentioned above,
as well as most other enteric organisms plus Serratia marcescens.
Ceftriaxone have become agents of choice in the treatment of
meningitis.

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 Spectrum of Fourth Generation
•First generation +
•Second generation +
•Third generation
Cefepime is classified as a fourth-generation
cephalosporin and must be administered
parenterally. Cefepime has a wide antibacterial spectrum
being active against streptococci and staphylococci.
Cefepime is also effective against aerobic gram-negative
organisms, such as enterobacter, E. coli, K. pneumoniae
P. mirabilis, and P. aeruginosa (mostly for resistant case

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 Cephalosporins:
Mechanisms of Resistance
•Mechanism  Same as that of penicillins

 i) Antibiotic Destruction by Beta-

lactamases (Enterobacteraciae)
 ii) Alteration in the PBP target resulting
in reduced binding affinity (MRSA)
 iii) Reduced penetration of the antibiotic
through the LPS membrane

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 Resistance Organisms
•Resistance to Cephem antibiotics.
L2AME
L2  Legionella pneumophila
Listeria monocytogenes
A  Atypical microbes
•Mycoplasma
•Mycobacterium
•Spirochetes
M  MRSA
E  Enterococci
•Fragilis
•Liquefaciens
•Durans
•Zymogen
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MOA

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COMPARATIVE STUDY OF CEPHALOSPORINS

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COMPARATIVE STUDY OF CEPHALOSPORINS

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ADRs

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 Cephalosporin prescribing in
Renal Impairment
 Most, apart from Ceftriaxone, need
dose adjustment.

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End

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Cephalosporins are group of broad spectrum
antibiotics, which are grouped into 4 generation
with increasing activity against gram – ve bacteria
and some what decreasing activity against gram +
bacteria.
They are more active against most streptococci except
enterococci spp (which are intrinsically
resistant).Importantly, they have no activity against
listeria and Methicillin resistant Staphylococci. Most
penicillin allergic patients will tolerate cephalosporins
but this group of antibiotics should be avoided if there
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is definitive history of anaphylaxis after penicillin
administration. In general third generation
cephalosporins are less active against staphylococci
than 1st and 2nd generation cephalosporins.
The intrinsic antimicrobial activity of cephalosporins
is low, but the attachment of various R1 and R2
groups yeilded drugs of good therapeutic activity.
The cephalosporins are a class of β-lactam antibiotics
originally derived from Acremonium, which was
previously known as "Cephalosporium".
Together with cephamycins they constitute a subgroup
of β-lactam antibiotics called cephems
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Chemistry:
All cephalosporins are semisynthetic derivatives of 7-
amino cephalosporanic acid.

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Classification
Cephalosporins are grouped into generations by their
antimicrobial properties. The cephalosporins were
designated first generation, while latter more extended
were classified as 2nd generation cephalosporins.
Significantly each newer generation has greater gram
– ve coverage than the preceding generation.
Conversely, The older generations of cepalosporins
have greater gram +ve coverage (Strep & Staph)
coverage than the newer generation.
1. Gram + ve coverage diminishes as gram -ve
Coverage im of cephalosporins.proves with successive
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generations of cephalosporins.
2.Total daily dosage of individual cephalosporins is
similar within each generation.
3.Frequency of dosing decreases with increase in
generation.
4.Palatibility increases with increase in generation.
5.Most 2nd and third generations are approved for use
in patients less than 6 month of age.

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The first cephalosporins were designated first
generation, whereas later, more extended spectrum
cephalosporins were classified as second-generation
cephalosporins. Each newer generation of
cephalosporins has significantly greater Gram
negative antimicrobial properties than the preceding
generation, in most cases with decreased activity
against Gram-positive organisms. Fourth-generation
cephalosporins, however, have true broad spectrum
activity.

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Classifiaction: (Lippon cots)
1.First generation cephalosporins
1. Cefadroxil 2. Cefazolin 3. Cephalexin
4. Cephapirin 5. Cephradine 6. Cephalothin
Spectrum:
Staphylococci (Except MRSA), Streptococci (Not
enterococci), E.Coli, Proteus, Klebsiella
2. Second generation cephalosporins
1. Cefaclor
2. Cefamandole
3. Cefmetazole
4. Cefonicid
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5.Cefotetan 6.Cefoxitin 7.Cefprozil
8.Cefuroxime 9.Cefuroxime axetil
10.Loracarbef (is a carbacepem class)
Spectrum:
As in first generation plus Haemophilus
(Beta lactamase producing bacteria)
6.Cefoxitin (As for 1st and 2nd generation +
Bacteroides)
3. Third generation
1.Cefdinir 2. Cefixime
3. Cefoperazone
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5. Cefotaxime 6. Cefpodoxime 7. Ceftazidime
8. Ceftibuten 9. Ceftizoxime 10. Ceftriaxone
11. Carbapenems 12. Imipenem
13. Meropenem 14. Monobactam
15. Aztreonam
Spectrum:
As for 2nd generation plus most gram –ve bacilli
except pseudomonas.
7. Ceftazidime
As for above plus pseudomonas.

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4th generation
1.Cefipime
2.Cefpirome
Spectrum:
As for above plus pseudomonas.

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Classifiaction: (Antibiotic guide)
1.First generation cephalosporins
1. Cefadroxil 2. Cefazolin 3. Cephalexin
4. Cephapirin 5. Cephradine 6. Cephalothin
Spectrum:
Staphylococci (Except MRSA), Streptococci (Not
enterococci), E.Coli, Proteus, Klebsiella
2. Second generation cephalosporins
1. Cefaclor
2. Cefoxitin
3.Cefprozil
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4.Cefuroxime
5.Cefuroxime axetil
6.Loracarbef (is a carbacepem class)
7.Cefamendole
Spectrum:
As in first generation plus Haemophilus
(Beta lactamase producing bacteria)
2.Cefoxitin (As for 1st and 2nd generation +
Bacteroides)
3. Third generation
1 Cefixime
2. Cefotaxime
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3. Cefpodoxime
4. Ceftazidime
5. Ceftibuten
6.Ceftriaxone
Spectrum:
As for 2nd generation plus most gram –ve bacilli
except pseudomonas.
4. Ceftazidime
As for above plus pseudomonas.

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4th generation
1.Cefipime
2.Cefpirome
Spectrum:
As for above plus pseudomonas.

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Classifiaction: (Bhattachyra)
1.First generation cephalosporins
1. Cefadroxil 2. Cefazolin 3. Cephalexin
4. Cephapirin 5. Cephradine 6. Cephalothin
7.Cephaloridine
2. Second generation cephalosporins
1. Cefaclor
2. Cefamandole 3. ceforanide
3. Cefmetazole
4. Cefonicid
5.Cefotetan 6.Cefoxitin 7.Cefprozil
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 8.Cefuroxime 9.Cefuroxime axetil
10.Loracarbef (is a carbacepem class)
3. Third generation
1.Cefdinir
2. Cefixime
3. Cefoperazone
4. Cefotaxime
5. Ceftriaxone
6. Cefpodoxime
7. Ceftazidime
8. Ceftibuten
9. Ceftizoxime 10.Moxalactam 11.Latamocef
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12. Proxetil 13. cefditoren 14. pivoxil
4th generation
1.Cefipime
Note:
The antibacterial spectrum of first generation
cephalosporins is similar to that of penicillinase
resistant pencillins with slightly greater gram – ve
coverage.
2. Cefazolin is the only first-generation parenteral
cephalosporin still in general use.

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PK
1.PK characteristics are similar to penicillins.
2.Some third generation Cephalosporins pass into CS
and are drug of choice for meningitis. Drugs are
eliminated in urine by glomerular filtration and tubular
secretion. Probenecid increases the plasma half life of
cephalosporins. Dose of cephalosporins should be
reduced in renal dysfunction.However two third
generation drugs (Cefoperazone and ceftriaxone) are
mainly excreted through bile, and hence no dose
adjustment is required in renal dysfuction.
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Antimicrobial spectrum:
1. First generation Cephalosporins
These cephalosporins are active against Gram + cocci,
some gram – ve bacteria-E.Coli, Klebsiella, proteus
and some anaerobes. Inactive against pseudomonas,
B.fragilis and in meningitis. They are used in UTI,
bronchitis and minor infections.
2. Second generation cephalosporins
They are effective against organisms affected by first
generation drugs but less potent aginst gram + ve
bacteria. Some of these are active against H.
Influenzae (cefuroxime, cefaclor, cefamendole), and
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Some others against B.fragilis and N.Gonorrhoea.
They are inactive against pseudomonas. They can be
used against beta lactamase producing bacteria and
anaerobes.
3.Third generation cephalosporins:
These drugs provide extended coverage against gram
-ve organisms and most of these reach CNS.They are
also active pseudomonas, Hemophilus and
nesseiria.Ceftizoxime and moxalactam act against
B.fragilis. They are used to treat meningitis caused by
pneumococci, meningococci and Hemophilus
influenzae, resistant UTI and penicillin resistant
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Gonococci.
4.Fourth generation cephalosporins:
Cefipime is more active against beta lactamase
producing
bacteria. It has good activity against enterobacter,
P.aeruginosa, S.aureus and S.pneumoniae.

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Mechanism of action;
All beta lactam antibiotics have similar mechanism of
action and inhibit bacterial cell wall synthesis by;
1.Attachment to specific penicillin-binding proteins
(PBPs) called transpeptidase enzyme of bacteria.
2. Blocking the Transpeptidation of peptidoglycan of
the bacterial cell wall and
3.Activation of autolytic enzyme of the cell wall.
B/C of the mode of action, Beta lactam antibiotics are
only effective against multiplying micro-organism
when the cell wall is being synthesized. Beta lactam
antibiotics are bactericial in nature.
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Clinical uses:
1. Septicemia (Cefuroxime, Cefoxitime)
2. Pneumonia due to susceptible organisms
3. Meningitis (Ceftrioxone and Cefotoxime)
4. Biliary tract infections
5. Urinary tract infections
6. Sinusitis (Cefadroxil)

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Adverse drug reactions:
1.Hypersensitivity reaction very similar to those that
occur with penicillins.
2.Blood dyscrasias:
(neutropenia and thrombocytopenia)
3.Nephrotoxicity (Cephradine)
4.Sometimes disufiram like reaction are seen on the
ingestion of alcohol.
5.Prolog use of 2nd and 3rd generation cephalosporins
may lead to superinfection with resistant
Staphylococci, enterococci and candida.
6.Nausea, diarrhoea, rashes, electtrolyte disturbance
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Pain at the site of injection
8.Others;
Pseudomembranous colitis, superinfection and
eosinophilia.
9. Certain cephalosporins (Cefamendole,
Cefoperazone) may cause disulfiram like reaction

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1.First generation cephalosporins
1. Cephalexin 0.25-1g q .i.d oral
2. Cefazolin 0.5-2g q .i.d i.v.
3. Cefadroxil 0.5-1g o.d/b.i.d oral

2. Second generation cephalosporins

1. Cefaclor 0.25-0.5 g t.i.d oral
2.Cefuroxime 0.25-0.5 g b.i.d i.v
3.Cefuroxime axetil0.25-0.5 g b.i.d oral

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3. Third generation
1. Cefixime 0.1-0.2 g o.d/b.i.d oral
2. Cefoperazone 1-2 g b.i.d im/i.v
3. Cefotaxime 1-2 g b.i.d im/iv
4. Ceftriaxone 1-2 g o.d/b.i.d i.v
5. Ceftazidime 0.5-2g t.i.d/b.i.d i.v

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4th generation
1.Cefipime 0.5-2g b.i.d i.v

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Mechanism of resistance:
1. Inability of the drug to reach the site of action i.e
poor penetration by the drug.
2.Alteration in the antibiotic binding proteins so that
interaction does not occur.
3.Degradation of the drug by Beta lactamases.
4.Failure of activation of autolytic enzymes in the cell
Wall.
.

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Septicemia:
It the presence of bacteria in the blood and is often
associated with severe disease.
Pneumonia:
It the inflammatory illness of the lungs. It is described
as lung alveolar inflammation and abnormal alveolar
filling with fluid.
Signs and Symptoms:
1. Cough producing yellow or greenish sputum or
Phelgm
2.High grade fever characterized by shaking chills.
3.Shortness of breath.
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Meningitis:
It is the inflammation of protective membrane
covering the brain and spinal cord, collectively known
as Meningitis.
Signs and symptoms:
1. Severe headach
2. Nuchal rigidity (Neck is stiff i.e unable to flex neck
forward)
3.High grade fever
4.Altered mental status
5.Photophobia (Unable to tolerate light)
6.Phonophobia ((Unable to tolerate loud noise)
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Sinusitis:
It is the inflammation of paranasal sinuses (Air filled
spaces communicating with nasal cavity within the
bones of skull and face)
Superinfection:
It is an infection following previous infection,
especially when caused by micro-organisms that are
resistant or become rsistant to antibiotic used earlier.It
is produced by sudden growth of type of bacterai etc.
different from original offenders in a wound or lesion
or area under treatment.
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Pseudomemranous colitis:
It is the infection of the colon caused by clostridium
difficile.
Signs and symptoms:
1.Offensive swelling diarrhoea
2.Fever
3.Abdominal pain
DD-Transpeptidase:
It is a bacterial enzyme that cross links the
peptidoglycan chains to form rigid cell wall.Also
known as DD-Peptidase, DD transPeptidase, D-alanyl
D-alanine,Carboxypeptidase, and serine type D-Ala
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D-Ala carboxypeptidase.
1.Narrow spectrum drugs:
As the name implies, these are only active against
relatively small number of micro-organisms. In
general narrow spectrum antibiotics are effective
against the gram +ve bacteria.
2.Moderate spectrum drugs:
These drugs are effective against gram +ve and most
systemic, enteric and urinary tract gram – ve bacteria.
3.Broad spectrum:
These are drugs that are effective against all
prokaraytes with two exceptions
1.Mycobacterium 2.Pseudomonas 65
4. Extended spectrum;
Effective against both Gram positive, Gram
negative bacteria and other bacteria such as
pseudomonas, clebsiella etc.

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Cephamycin
Cephamycins are a group of beta-lactam antibiotics.
They are very similar to cephalosporins, and the
cephamycins are sometimes classified as
cephalosporins. Like cephalosporins, cephamycins are
based upon the cephem nucleus. Cephamycins were
Originally produced by Streptomyces, but synthetic
ones have been produced as well. Cephamycins
possess a methoxy group at the 7-alpha position. &
Include 1. Cefoxitin
2.Cefotetan
3. Cefmetazole
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Note
1.Persons allergic to penicillins can be given
azreotenam with little likehood of allergic reactions.
2.As with the penicillins, the cephalosporin –lactam
Ring is the chemical group associated with
Antibacterial activity.
2. Cephalosporins have been associated with
superinfections with Clostridium difficile, enterococci,
MRSA, coagulasenegative staphylococci, P.
aeruginosa, and Candida albicans.
Overgrowth by toxigenic C. difficile occasionally
causes pseudomembranous colitis in patients treated
with cephalosporins. Some third-generation
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Cephalosporins induce production of extended
spectrum lactamases (ESBLs) in P. aeruginosa. The
ESBLs can transfer to various Enterobacteriaceae and
produce organisms resistant to almost all –lactam
antibiotics.
3. Drugs with the methylthiotetrazole ring can also
Cause severe disulfiram-like reactions; consequently,
Alcohol and alcohol-containing medications must be
avoided.

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Clinical Uses
The first-generation cephalosporins have activity
against most of the bacterial pathogens that colonize
skin and infect wounds. Consequently, first-generation
cephalosporins are useful in antimicrobial prophylaxis
before surgery. Second-generation cephalosporins are
used to treat infections caused by susceptible
organisms. For example, cefoxitin and cefotetan have
Good anaerobic activity, and they have utility in the
Treatment and prophylaxis of lower abdominal and
Gynecological infection. A broad spectrum of
antibacterial activity makes third-generation
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cephalosporins important in the treatment of a wide
range of infections, including Lyme disease,
pneumonia, peritonitis, and sepsis syndrome.

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BACITRACIN
Bacitracin is a cyclic peptide mixture first obtained
from the Tracy strain of Bacillus subtilis in 1943. It is
active against gram-positive microorganisms.
Bacitracin inhibits cell wall formation by interfering
with dephosphorylation in cycling of the lipid carrier
that transfers peptidoglycan subunits to the growing
cell wall. There is no cross-resistance between
bacitracin and other antimicrobial drugs.
Bacitracin is highly nephrotoxic when administered
systemically and is only used topically.
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Bacitracin is poorly absorbed. Topical application
results in local antibacterial activity without systemic
toxicity. Bacitracin, 500 units/g in an ointment base
(often combined with polymyxin or neomycin), is
indicated for the suppression of mixed bacterial flora
in surface lesions of the skin, in wounds, or on
mucous
membranes. Solutions of bacitracin containing 100-
200 units/mL in saline can be used for irrigation of
joints, wounds, or the pleural cavity.

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Others cell wall synthesis inhibitors
1.Cycloserine
2.Fosfomycin
3.Daptomycin
4.Teicoplanin

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