The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium,
which was previously known as “Cephalosporium”.
The aerobic mold which yielded cephalosporin C was found in the sea near a sewage outfall in SuSiccu, by
Cagliari harbour in Sardinia (Italy), by the Italian pharmacologist Giuseppe Brotzu in 1945.Researchers at
the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C, which had
resistance to β-lactamases but was not sufficiently potent for clinical use.
Cephalosporin compounds were first isolated from cultures of Acremonium strictum from a sewer in
Sardinia in 1948 by Italian scientist Giuseppe Brotzu. He noticed these cultures produced substances that
were effective against Salmonella typhi, the cause of typhoid fever, which had β-lactamase. Cephalosporins
were first sold in 1964 (Cephalothin) by Eli Lilly.
1945 - Cephalosporins were firstdetected in Cephalosporium acremonium
1948 - Cephalosporins are semisynthetic antibiotic derivatives ofcephalosporin C
1948 - Brotzu published his results in 1948
1964 - Alarmed by the need to keep ahead of rapidly mutating bacterialstrains, researchers since then have
developed 4 generation cephalosporins.
1971 -In January 1971Eli Lilly introduced Keflex, generic name Cephalexin
1996 -In January 1996 a progressive reintroduction of cephalosporinsincluding the novel4th
2003-In February 2003 Ranbaxy laboratories has rolled out its high-endcephalosporin orcefprozilunder the
brand name Refzil.Cephalosporins have an estimated Rs 1000-crore in India
2005 - Infact the risk that a patient with a history of penicillin allergywill experience a reaction to a first-
generation cephalosporin notmore than 0.5%, second generation cephalosporin not more than 0.2% and a
third-generation cephalosporin practicallynil in at least 25 studies
2010 -In October 2010 Ceftarolin (a fifth-generation cephalosporin) - was approved by the food and drug
Cephalosporins are semisynthetic derivatives of Cephalosporin C. Cephalosporin C is an analogue of 7-
aminocephalosporanic acid (7-ACA):
1. First generation: First generation cephalosporins were the first cephalosporins on the market. They
have good antimicrobial activity against gram-positive bacteria but limited activity against gram-
Gram-positive: Activity against penicillinase-producing, methicillin-susceptible staphylococci and
streptococci (though they are not the drugs of choice for such infections). No activity against methicillin-
resistant staphylococci or enterococci.
Gram-negative: Activity against Proteus mirabilis, some Escherichia coli, and Klebsiella pneumoniae,
but have no activity against Bacteroides fragilis, Pseudomonas, Acinetobacter, Enterobacter, indole-
positive Proteus, or Serratia.
2. Second generation: Early second generation cephalosporins are very similar in basic structure to the
Gram-positive: Less than first-generation.
Gram-negative: Greater than first-generation:Haemophilus influenzae, Enterobacter aerogenes and
some Neisseria + Proteus mirabilis, some Escherichia coli, and Klebsiella pneumoniae.
3. Third generation:The majority of third generation cephalosporins have the aminothiazole group at
Gram-positive: Some members of this group have decreased activity against gram-positive
organisms.Activity against Staphylococci and Streptococci is less with the third-generation compounds
than with the first- and second-generation compounds.
Gram-negative: Third-generation cephalosporins have a broad spectrum of activity and further
increased activity against gram-negative organisms. They are also able to penetrate the central nervous
system, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae,
and susceptible E. coli, Klebsiella, and penicillin-resistant N. gonorrhoeae.
4. Fourth generation:The fourth generation cephalosporins have greater activity against gram-negative
bacteria than the second and third generation.This difference is attributed to them being dipolar ionic
Gram-positive: They are extended-spectrum agents with similar activity against Gram-positive
organisms as first-generation cephalosporins.
Gram-negative: Fourth-generation cephalosporins are zwitter-ions that can penetrate the outer
membrane of Gram-negative bacteria. They also have a greater resistance to β-lactamases than the third-
generation cephalosporins. Many can cross the blood-brain barrier and are effective in meningitis. They
are also used against Pseudomonas aeruginosa.
5. Fifth generation: These new drugs are the only β-lactam antibiotics that are effective against
Mechanism of action
Cephalosporins are bactericidal and are less susceptible to hydrolysis by β-lactamases compared to
Cephalosporins disrupt the synthesis of the peptidoglycan layer forming the bacterial cell wall.The
peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the
synthesis of the peptidoglycan is facilitated by 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 the D-Ala-D-Ala site, thereby irreversibly inhibiting the PBP mediated crosslinking of the
a. The addition of amino group and a hydrogen to α and α1 position produces basic compound, which is
protonated under acidic conditions of stomach. The ammonium ion improves the stability of β-lactum of
cephalosporins and make active orally. Activity against positive bacteria is increased and gram negative is
decreased by acylation of amino group.
b. When the new acyl groups are derived from carboxylic acids, it shows good spectrum of antibacterial
action for gram-positive bacteria.
c. Substitutions on the aromatic ring phenyl that increase lipophilicity provide higher gram-positive activity
and generally lower gram-negative activity.
d. The phenyl ring in the side chain can be replaced with other heterocycles with improved spectrum of
activity and pharmacokinetic properties; these include thiophene, tetrazole, furan, pyridine, and
e. The L-isomer of an α-amino α1 -hydrogen derivative of cephalosphorins was 30–40 fold stable than D-
isomer. Addition of methoxy oxime to α and α1increases the stability to nearly 100-fold. The presence of
catechol grouping can also enhance activity, particularly, against Pseudomonas aeruginosa, and also retain
some gram-positive activity, which is unused for a catechol cephalosporin.
Modiﬁcation in the C-3 substitution: The pharmacokinetic and pharmacodynamics depends on C-3
substituents. Modiﬁcation at C-3 position has been made to reduce the degradation (lactone of desacetyl
cephalosporin) of cephalosporins.
a.The benzoyl ester displayers improved gram-positive activity, but lowered gram-negative activity.
b. Pyridine, imidaozle replaced acetoxy group by azide ion yields derivative with relatively low
c. Displacement with aromatic thiols of 3-acetoxy group results in an enhancement of activity against gram-
negative bacteria with improved pharmacokinetic properties.
d. Orally active compounds are produced by replacement of acetoxy group at C-3 position with CH3 and Cl.
a. Methoxy group at C-7, shows higher resistance to hydrolysis by β-lactamase.
b. Oxidation of ring spectrum to sulphoxide or sulphone greatly diminishes or destroys antibacterial activity.
c. Replacement of sulphur with oxygen leads to oxacepam (latamoxet) with increased antibacterial activity,
because of its enhanced acylating power. Similarly, replacement of sulphur with methylene group
(loracavet) has greater chemical stability and a longer half-life.
d. The carboxyl group position-4 has been converted into ester prodrugs to increase bioavailability of
cephalosporins, and these can be given orally as well.
e. The antibacterial activity depends on the oleﬁnic linkage at C-3 and C-4 position and their activity is lost
due to the ionization of double bond to 2nd and 3rd positions.
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