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8/4/2019 Intro ! (Updated)[1]
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Core structure of the cephalosporins
The cephalosporins are -Lactam
antibiotics that are closely related
both structurally and functionally tothe penicillins.
Mechanism of action, mechanism of resistance
and some other properties of cephalosporins areidentical to penicillins.
Cephalosporins are one of the most widely used
antibiotics and are equal in importance to
penicillin. The worlds largest antibiotic production
is around 5x107 kg/year, from which 3x107 kg
are represented by the group of
-Lactam.
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Classification of cephalosporinsCephalosporins have been classified as first, second, third and
fourth generation largely on the basis of bacterial susceptibilitypatterns and resistance to - lactamases:
First generation Second generation Third generation Fourth generationCephalothinCephapirinCefazolinCephalexin*Cephradine*Cefadroxil
CefamandoleCefuroximeCefonicidCeforanideCefaclor*CefoxitinCefotetanCefprozil*Cepuroxime axetil*Cefmetazole
CefotaximeCeftizoximeCeftriaxoneCeftazidimeCefoperazone
Cefixime*Cefpodoxime
proxetil*Ceftibuten*Cefdinir*
CefepimeCefpiromeCefclidin
* Oral agents
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Mechanism of Action of
Cephalosporin
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Peptidoglycan - heteropolymeric component of the cell wall
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Transpeptidase enzymes join the peptide of one monomer with
that of another in order to provide strength to the cell wall
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Cephalosporins bind to the transpeptidase enzyme
and block the formation of the peptide cross-links.
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Resulting in a weak cell wall and osmotic lysis of the bacterium
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Advances in Cephalosporin Production
1. Biochemie (Germany/Austria), a subsidiary of Novartis, has
developed an enzyme-catalysed process for manufacture of the
antibiotic cephalosporin. The efficiency of the enzymes was optimised
by genetically modifying the micro-organisms that produce the
enzymes. When compared to the conventional chemical process, the
enzymatic process produces 100 times less waste solvent to be
incinerated and, as a result, the cost of production and the potentialenvironmental impact of the process are both reduced.
2. Similarly, DSM (Netherlands) has used a metabolically engineeredmicro-organism to reduce the waste produced in the manufacture of
cephalexin by 3 to7-fold. This has allowed the company to reduce
production costs so that it can compete effectively in international
markets.
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Future Prospects
The semi-synthetic b-lactam a will retain a significant market
share.Their broad spectrum of activity, high potency, low toxicity, and
stability toward hydrolysis makes them a class preferred by
clinicians. New semisynthetic cephalosporins continue to be
developed in the pharmacology programs of different
companies and new generations of cephalosporins will beavailable in the future. As the pressure on the price remains
high, new developments are fuelled by the advances in
knowledge on the molecular biology of CPC biosynthesis.
Molecular biology has entered the strain improvement
programs of most companies and combined with a more
careful control of the fermentation process will lead to more
efficient processes.
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Future Prospects (contd.)
The introduction ofgreen routes to semi-synthetic b-lactams
has started in Europe and has much room for improvement
and expansion.
Changes will only gradually be implemented as margins are
low and products long off patent. Hence, most production
facilities are long depreciated and investment into upgrading a
facility is difficult to justify. However, emerging new
compounds and new companies have the opportunity to step
forward and implement new technologies.
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Recovery of antibioticsRecovery and purification of bio-products require
continuous research for the development of optimized and
economic operation.
Cephalosporin C, a b-lactam antibiotic is an exception in
that it is highly water soluble and non-extractable, yet it
can be effectively adsorbed onto neutral aromatic sorbents.
Thus although ion exchange recovery processes were
developed, a significant amount of commercially produced CPC
is still recovered using neutral aromatic adsorbents.
For large scale operations, the most commonly used
neutral polymeric adsorbents are copolymers of styrene (or
ethyl vinyl benzene) and divinyl benzene.
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Recovery and purification1. Commercially available neutral polymeric
sorbents are used for recovery of betalactam antibiotic cephalosporin C (CPC), fromaqueous solution. The objective of this workis to evaluate the separation of CPC fromfermentation broth during purification process.2. The neutral forms of CPC are preferentiallyadsorbed onto the neutral sorbents. Adsorptionof CPC was higher onto the aromatic ascompared to aliphatic ester sorbent. The kineticsof CPC adsorption on aromatic polymericadsorbent has been investigated. Isopropylalcohol solution was used to desorb CPC.
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Rajendrapur,gazipur plant forcephalosporin production
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PROCESS OF PURIFICATION
The process of purification consisted of three main
stages:
1. Adsorption on a column of charcoal (pH 6) and elution
with aqueous acetone.
2. Chromatography on acid-washed alumina from aqueous
acetone.
3. Countercurrent distribution at 30 in a system composed of
water,phenol,carbontetrachloride and2:4:6-trimethylpyridine sulphate at pH 6- 1.
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