CEPHALOSPORINS

07.12.2022

hhu.de
 Table of contents

 Discovery of Cephalosporins
 Structure Activity Relationship
 Structure Optimizations and Synthesis
 Mechanism of Action
 Resistance to the Cephalosporins
 Important Pharmacokinetics Aspects
 Current First Choice
 Future aspects of Cephalosporins

2 hhu.de
 Discovery of Cephalosporins

In 1945, the Italian scientist Brotzu obtained various antibiotics

that inhibited the development of Staphylococcus aureus from
Cephalosporium acremonium cultures.

Cephalosporin C, which is first isolated from

compounds called CEPHALOSPORINS.
Giuseppe Brotzu

In Oxford in 1948 three major antibiotics were

isolated from cultures of such fungi by Abraham
and Newton.
1- Cephalosporin P
2-Cephalosporin N (Penicillin N)
3-Cephalosporin C Edward Abraham and Guy Newton

3 reference 1 hhu.de
 Cephalosporin C

In cephalosporin C, there is a dihydrothiazine ring

instead of the thiazolidine ring in Penicillin N and a
diamino adipoyl side Chain. The main core of cephalosporins is 7-
ACA (7-amino cephalosporanic acid).

Core structure of peniicilins (1) and cephalosporins (2)

In 1964 the first semi synthetic cephalosporin i.e.

cefalothin was launched in the Market by Eli Lilly
and company.

4 reference 1 hhu.de
 Cont.

In 1971: Eli Lilly introduced Keflex, generic name Cephalexin

In 1996 : a progressive reintroduction of cephalosporins

including the novel 4th generation cephalosporin cefepime.

In 2003: Ranbaxy laboratories rolled out its high-end

cephalosporin or cefprozil under the brand name Refzil

In 2010: “Most patients who have a history of penicillin allergy

can safely take antibiotics called cehalosporins”
US researchers .

5 reference 1 hhu.de
 SAR of Cephalosporins

6 reference 2 hhu.de
 Optimizations and generations

1st generation cephalosporins offer advantages over penicillins :

greater stability to acid, β-lactamases
good ratio of activity Against Gram+ve and Gram-ve bacterial
However, they are generally poor in Oral availability and are generally lower in activity.

Disadvantage of cephalosporin
the acetyloxy group at position 3 is Readily
hydrolyzed by esterase enzyme to Give less
active alcohol
Prototypical Early cephalosporin Cephalothin

1. Less antibiotic activity than Penicillin G against Gram positive bacteria

2. More activity than Pen G against Gram negative bacteria
3. Can be used on patients who are allergic to penicillin
4. Side chain acetoxy group is hot point for metabolic inactivation

7 reference 2 hhu.de
 Cont.

The acetoxy group is important to the mechanism of

inhibition and acts as a good Leaving group where as
the alcohol is a much poorer leaving group.

Replacing the ester with a metabolically stable

pyridinium group gives cephaloridine. Pyridine can
still act as a good leaving group for the inhibition
Cephaloridine
Exists as a zwitterion and is soluble in water. mechanism but not Cleaved by esters.

8 reference 2 hhu.de
 Cont.

CH3 Good for absorption and bad

for activity. Since it is not a good
leaving group, it Prevents the
Deactivation of Cephalexin up to
some extent.

Cephalexin structure

It is not much clear that why 3- methyl group is so advantageous.

Although the methyl group at position is bad for activity the presence Of hydrophilic
amino group at the α-carbon of the acylamino side Chain helps to compensate.

9 reference 2 hhu.de
 Second Generation
Stabilizes
neighboring
carbonyl group Cephamycins
A methoxy substituent at position 7 of the
cephalosporin skeleton has proved
Advantageous. The parent compound
cephamycin C was isolated from a culture of
Most natural cephalosporin and cephamycin are not Streptomyces clavuligerus.
used clinically for side effects,
but semi-synthetic products are used.

cefoxitin cefmetazole
cefotetan
10 reference 2,3 hhu.de
 Third generation

ceftizoxime, cefotaxime,
cefmenoxime, and ceftriaxone have
the identical 7-acyl group containing a
methoxyimino function and differ only in the
3-substituent, A.

11 reference 2,3 hhu.de

 Fourth Generation

They are chemically closely related to third-generation cephems.

They differ by having a C-3' quaternary ammonium group in position 3 of the cephem nucleus.
These molecules are zwitterionic compounds, by virtue of a positive charge on the nitrogen of
the C-3' group and a negative charge on the C-4 carboxylic group of the cephem nucleus.
Due to these zwitterionic properties, they penetrate the outer membrane of Gram-negative
bacteria rapidly.

cefpirome cefepime

12 reference 2,3,4 hhu.de

 Fifth generation

Ceftobiprole (Zeftera/Zevtera) is a 5th generation

cephalosporin antibiotic with activity against
methicillin-resistant Staphylococcus aureus,
penicillin-resistant Streptococcus pneumoniae,
Pseudomonas aeruginosa, and Enterococci.
Ceftobiprole

It was discovered by Basilea Pharmaceutical and was

developed by Johnson & Johnson Pharmaceutical
Research and Development.

13 reference 3,4 hhu.de

 Synthesis of Cephalosporins

(Z)-(2- aminothiazol-4- (Z)-(2-amino-thiazol-4-

yl)methoxyiminoacetic yl)methoxy-iminoacetic acid
acid Commercial antibiotic drugs :
cefotaxime , cefepime ,
The amidation process is based on the use of 4-toluenesulfonyl cefpodoxime, and ceftriaxone
chloride as an economically attractive coupling reagent in
combination with methanol or ethyl acetate as a preferred
solvent component.

14 reference 2 hhu.de
 Cephalosporins Coverage

+++ ++ + ++ ++
- -- --- --- ---

15 reference 5 hhu.de
 Mechanism of Action

 Bactericidal Antimicrobials

 Binds to the Penicillin Binding Protein (PBP)

 Inhibits the transpeptidase enzyme, which inhibits the crosslinking

of peptide chain strands

 Cell death due to compromised cell wall structure

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534636/figure/Fig1/

16 reference 6 hhu.de
 Important Pharmacokinetics Aspects
Oral Cephalosporins
 Absorption
 Absorb rapidly
 Cephalexin, cefadroxil are completely
absorbed while cefuroxime and cefixime are
absorbed to lesser extent
 Distribution
 Achieve therapeutic concentrations in most
tissues – pleural and synovial fluids
 Cannot cross the blood brain barrier
 Elimination
 Eliminated by the kidney except Cefixime
17 reference 7,8
Parenteral Cephalosporins
 Distribution
 Well distribution in tissues and fluids – CSF,
synovial and pleural fluid
 Small quantity of 1st and 2nd generation diffuse
CSF
 3rd generation Cephalosporins achieve
therapeutic concentrations in CSF
 Elimination
 Eliminated mostly by the kidney
 Only few cephalosporins have high biliary
elimination e.g. cefoperazone appears 70% in
bile
 Cefmenoxime, Ceftriaxone, Cefbuperazone
also exhibit high biliary elimination
hhu.de
 Current First Choice

◼ Sexually Transmitted Infection

 Gonorrhoea- Ceftriaxone in combination with azithromycin

◼ Pelvic Inflammatory Disease

 Ceftriaxone in combination with metronidazole and doxycycline

◼ Meningitis
 Ceftriaxone

https://www.indiamart.com/proddetail/ceftriaxone-injection-ip-23677850473.html

18 reference 9 hhu.de
 Resistance to the Cephalosporins

◼ S. Aureus can develop resistance by changing structure of PBP

 The bacteria that develops this resistance is called Methicillin resistance S. Aureus
(MRSA)
 5th generation Cephalosporins are effective against MRSA

◼ Another resistance mechanism is β-lactamase enzyme

 β- lactamase inhibitors are co-formulated with cephalosporins

19 reference 10 hhu.de
 Future aspects of Cephalosporins

Cefoperazone, Ceftaroline and Ceftobiprole have Ceftazidime is a potential drug to

potential as first-line treatments for gonorrhea and inhibit SARS-CoV-2 infection in vitro
provide a framework for the future design of by blocking spike protein–ACE2
cephalosporins with improved activity against ESC- interaction
resistant N. gonorrhea.
Although our knowledge of cephalosporin hypersensitivity and management is advancing, there are still
several areas that need further research. The lack of knowledge regarding cephalosporin antigenic
determinants is a hindrance to the development of improved in vivo and in vitro diagnostic tests.
20 reference 4,11 hhu.de
 References
1. Tilli Tansey; Lois Reynolds, eds. (2000). Post Penicillin Antibiotics: From acceptance to resistance?. Wellcome Witnesses to Contemporary Medicine.
History of Modern Biomedicine Research Group.
2. https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/ejoc.201900277
3. https://www.nature.com/articles/s41392-021-00619-y
4. https://pubmed.ncbi.nlm.nih.gov/31495420/
5. EZmed. Cephalosporin Antibiotic Drug Coverage by Generation Made Easy —. Ezmed. https://www.ezmedlearning.com/blog/
cephalosporins(accessed 2022-12-04).
6. Elsevier Enhanced Reader. https://www.sciencedirect.com/science/article/pii/B9780323393072000333/pdfft?isDTMRedir=true&download=true
(accessed 2022-12-06). https://doi.org/10.1016/B978-0-323-39307-2.00033-3.
7. Bergan, T. Pharmacokinetic Properties of the Cephalosporins. Drugs 2012, 34 (2), 89–104.
8. Kalman, D.; Barriere, S. L. Review of the Pharmacology, Pharmacokinetics, and Clinical Use of Cephalosporins. Tex. Heart Inst. J. 1990, 17 (3), 203.
9. Appropriate use of cephalosporins. https://bpac.org.nz/bpj/2011/december/cephalosporins.aspx (accessed 2022-12-04).
10. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK551517/.(accessed 2022-12-04).
11. Cephalosporins – Infectious Diseases – Merck Manuals Professional Edition". Merck Manuals Professional Edition. Retrieved 14 June 2018.

21 hhu.de
 ◼ Questions are welcome

Thank you 

22 hhu.de