2. What we gonna discuss here in Part 1
History
Breif Introduction
Chemistry
Generations
Pharmacokinetics (PK)
Pharmacodynamics (PD)
3. History
First chemical compounds of the cephalosporin isolated from
Cephalosporium acremonium-a cephalosporin producing
Fungus first discovered by Brotzu in 1948 from a sewage outfall
off the Sardinian coast.
Crude filtrates of the C. acremonium culture gave new
antibacterial activity.
Crude filtrate could inhibit the growth of S. aureus.
Isolation of culture fluids from the Sardinian fungus yielded
cephalosporin P, N and C.
Chemical methods and removal of the natural side chain
produced 7-aminocephalosporanic acid (7-ACA)- an analogue
to 6-aminopenicillanic acid (6-APA).
4. Cephalothin, a first generation Cephalosporin for parenteral use was the
first cephalosporin to become available for patients in the US which was
marketed by the pharmaceutical company Eli-lilly in 1964.
The second cephalosporin for parenteral use became available little
later and was marketed in the US under the name Cephaloridine.
Today thousands of semisynthesized analogues of natural
cephalosporin compounds based on the knowledge gained by intensive
research on the chemistry of those two starting materials.
5.
6. Structural Defination
Semi-synthetic antimicrobial agents
which are derivatives of 7-amino
cephalosporanic acid
closely related in structure to
penicillin have a beta-lactam ring.
stable in dilute acid
highly resistant to penicillinase
some bacteria can produce a beta-
7.
8.
9.
10. Anti-Infection Spectrum
All cephalosporins are active against most G+ cocci,
including penicillinase-producing
staphylococci and many strains of G- bacilli, but relatively
ineffective against enterococci.
Divided into 4 major groups called “Generations”
Are divided into Generations based on
parallel their chronological development
their antimicrobial spectrum
11. Wall synthesis description
Achieved through inhibition of the bacterial cell wall synthesis.
cell wall of both Gram-positive and Gram-negative bacteria is a tight covalently bound and cross-
linked peptidoglycan network, essential for bacterial growth, cell division and cellular structure.
The cell wall of bacteria is built up in two steps from the outside of the cell.
First step- disaccharide units linked with peptides and joined together on the outside of the wall
by a transglycolase
second step-a transpeptidase links together long polysaccharide chains which are linked together
through peptide bonds.
12. Mode od Action (MOD):
Transpeptidation-inhibited by cephalosporins.
Because of this inhibition
antibiotics are most effective when the bacteria are in the logarithmic phase of
growth, were then they are synthesizing the cell wall. If the bacteria are in the
stationary phase of growth then there is no wall synthesizing in progress and the
antibiotics have much lower effect.
To exert their mechanism of action by mimicking the structure of the transition state
of the chemical reaction when the transpeptidase is bound to the D-alanyl-D-alanine
sequence- (PBPs).
13. Opening of the β-lactam ring by a serine residue in the enzyme binding site
leads to covalent binding of the antibiotic molecule with the active site of the
enzyme.
Inactive irreversibly bound enzyme-complex which is incapable of further
cell wall synthesis and the cell will die from osmotic-lysis.
14. Antimicrobial resistance
Three mechanisms:
1. Modifications in target PBP
2. Drug inactivation by bacterial β-lactamases
3. Drug not being able to reach target PBP in the bacterial cell
Pneumococci and Meningococci acquire exogenous genetic material, and
incorporate it into their own chromosomes- leads to antimicrobial resistance.
The bacteria can also replace the PBP- vulnerable to B lactam antibiotics with
PBP that is less vulnerable.
15. Enzymes hydrolyze the bond between the carbon and nitrogen atom of the β-lactam
ring.
The enzymes active site is easily regenerated hydrolytically so it is re-usable
many times, in that way can a comparatively small amount of beta-lactamases
destroy a large amount of drug.
Gram+ve bacteria have a high release of beta-lactamases into their extracellular
space, where they meet the drug outside the cell wall.
Gram-ve bacteria secrete beta-lactamases into the periplasmic space between the
inner and outer membrane so they can't easily escape into the extracellular space,
and don't have to be biosynthesized in high quantities.
16. General Discussion on it Pharmacokinetics (PK)
Cephalosporins are given parenterally and orally.
Extent of binding to plasma protein vary from one to another.
e.g. Cefazolin is 80% protein bound ( hence, long t1/2 )
Cephalexin is 10-15% protein bound
Relatively lipid insoluble ( like penicillins )
Hence,do not penetrate cells or the CNS, except for third generations.
Mostly excreted unchanged by the kidney (glomerular & tubular
secretion ), except, ceftazidime & cefoperazone( glomerular)
Probenecid slows their elimination and prolong their half-live ( except
Ceftazidime & cefoperazone)
Half-life 30-90 min; ceftriaxone 4-7 hr
17. CLASSIFICATION BY
GENERATION
First Generation Cephalosporins.
Second Generation Cephalosporins.
Third Generation Cephalosporins.
Fourth Generation Cephalosporins.
18. FIRST GENERATION -
First generation cephalosporins- the first cephalosporins on
the market.
good antimicrobial activity against gram-positive bacteria than
gram-negative species.
Chemical structures are simple e.g. (Cephalexin, Cephradine
and Cefadroxil) have a single methyl group at position C-3.
The common side groups at C-3 are small uncharged groups
like methyl.
Methyl group at position C-3 gives low affinity for common
19. PHARMACOKINETICS
Do not penetrate the CNS.
Excretion is via the kidney and dose
adjustments must be made for
impaired renal function.
20. THERAPEUTIC USES
Parenteral agents are used primarily for prophylaxis in
various surgical procedures.
Oral drugs used for minor staph infections or some
polymicrobial infections.
Occasionally for gram negative infections.
21. SECOND GENERATION-
does not have the normal dihydrothiazin ring
The 7-phenyl-glycine makes it orally available and the chlorine at position C-3
makes it as active as Cefaclor.
An important structural change- the introduction of an α-iminomethoxy group to
the C-7 side chain- gave an increased resistance to β-lactamases due to
stereochemical blocking of the beta-lactam ring.
Cefuroxime was the first cephalosporin to incorporate this side chain.
Another very important group- aminothiazole ring to the C-3 side chain.
This development increases the binding affinity to PBP and increased antimicrobial
activity.
The aminothiazole ring can be seen in the structure of Cefotiam.
22. PHARMACOKINETICS
Several orally and parenterally available (cefoxitin-IV).
Poor penetration into the CNS.
Dosage adjustments must be made in renal failure.
Variety of gram negative infections.
23. THIRD GENERATION
Have the aminothiazole group at position C-7.
Different groups are found at the 7-α-position like 7-α-iminohydroxy and 7-α-
iminomethoxy.
Ceftibuten possesses an 7-α-ethylidene group.
This group gives ceftibuten higher resistance to enhanced spectrum β-lactamases. Many
of the oral have esters in parenteral forms and are hydrolysed by esterases in the
digestive tract (Cefteram-pivoxil).
Some can be absorbed orally without the need of esterification. This is done with
Cefixime and Cefdinir by putting a vinyl group in the C-3 position.
24. PHARMACOKINETICS
Cross the blood brain barrier well.
Half-lives and the necessary dosing
intervals vary greatly (ceftriaxone once
every 24h).
Most are excreted by the kidney and
require dosage adjustment (cefoperazone
and ceftriaxone are exceptions).
25. THERAPEUTIC USES
A wide variety of serious infections caused by organisms
resistant to other drugs.
• Gonorrhea
• Meningitis
• In neutropenic febrile immunocompromised patients
(with an aminoglycoside)
26. FOURTH GENERATION
Have greater activity against gram-negative bacteria than the second
and third generation- dipolar ionic zwitter ion compounds.
C-7 side chain is similar to 3rd generation containing iminomethoxy-
aminothiazole group and in Cefclidine aminothiadiazole.
Positively charged quaternary nitrogen in the C-3 side chain can
diffuse through the G-ve bacterial membrane more readily- positive
charge orients the drug molecule to the entrance of the porin
channel.
27. PHARMACOKINETICS
Good penetration into the CSF.
Cleared mainly by the kidneys.
THERAPEUTIC USES
Similar to the third generation cephalosporins.
28. 5th Generation Cephalosporines
Ceftobiprole and Ceftaroline.
Effective against methicillin-resistant-Staphylococcus-aureus (MRSA).
Ceftobiprole is a pyrrolidinone-3-ylidenemethyl cephem.
The C-3 side chain- have a strong binding affinity to PBP2a and PBP2x. PBP2a is
known to give staphylococci resistance to other β-lactam drugs and PBPx does the
same for pneumococci.
Ceftobiprole has a aminothiazoylhydroxyimino side chain at the C-7 position-
resistance to β-lactamase from S. aureus.
Ceftobiprole has poor water solubility and is therefor administered intravenously as
a ester prodrug called Ceftobiprole medocaril. It is rapidly broken down into active
Ceftobiprole by plasma esterases.
