lecture 10

Question 1

what are cephalosporin and cephamycin

Answer 1

alternative to β-lactam antibiotics, bind to pbps, often used in penicillin resistant infections, are made from penicillin N by Cephalosporium fungi and Streptomyces bacteria.
Semi-synthetic cephalosporins and cephamycins can also be made by using an acylase to remove the side-chain to give the cephem core.
Chemical acylation gives ‘semi-synthetic’ cephalosporins

Question 2

why is cephalosporin not used anymore

Answer 2

Cephalosporin C was not used clinically as more effective alternatives (cephalothin and cephaloridine) were quickly developed.
Cephalothin undergoes rapid metabolism (removal of acetyl group).
Cephaloridine causes nephrotoxicity (kidney toxicity).
Cephalexin is usually preferred as it is almost completely absorbed from the intestines despite having lower antibiotic activity.
Most cephalosporins given by mouth are cephalexin derivatives.

Question 3

what are the strategies for over-coming beta-lactamases(2)

Answer 3

Change the structure of the antibiotic:
This is often a temporary solution due to the rapid development of resistance.
Changing the structure of the antibiotic can substantially change the organisms against which the antibiotic is effective.
Co-administer a blocking antibiotic:
The level of protection can be poor and can result in resistance to multiple antibiotics, but sometimes successful e.g., co-fluampicil (Dr Ellis’ lecture).
Use a suicide inhibitor with the antibiotic e.g., clavulanic acid:
Inhibitors undergo catalysis to generate a reactive species that inactivates the β-lactamase.

Question 4

what is clavulanic acid

Answer 4

Clavulanic acid is an irreversible inhibitor of class A β-lactamases (penicillinases).
It has weak antibiotic activity on its own, but it potentiates the effect of penicillins (by preventing degradation by β-lactamases).
It is normally co-administered with amoxycillin (similar pharmacokinetics) – coamoxyclav, formerly known as AugmentinTM.
It is not effective against class B (metal-dependent) β-lactamases (e.g., NDM-1) as they do not use an active site residue behaving as a nucleophile.
It is not effective against class C (cephalosporinase) or D (extended spectrum) β-lactamases (does not bind to the enzyme).