intro ! (updated)[1]

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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References:

intro ! (updated)[1]

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