The Beta-lactams- Cephalosporins, Carbapenems & Monobactams

Question 1

The Cephalosporins generations 1-5

Answer 1

Large family of broad spectrum beta-lactams
Classified into generations based loosely on spectrum of activity. 1st gen: active vs aerobic G +ve cocci. 2nd gen: better lactamase stability, more G-ve stability with some anaerobe activity. 3rd gen: better lactamase stability, enhanced intrinsic activity and vs serious G-ve. 4th gen: diffuse more readily into G-ve , lower affinity for their b-lactamases, extended spectrum for both G+ and G-. 5th gen: anti-MRSA e.g. ceftobiprole + ceftaroline.

Question 2

Prototypic cephalosporin: Cephalosporin C structure

Answer 2

7-ACA cephem nucleus

six-membered dihydrothiazine ring responsible for penicilinase stability.

Question 3

SARS of cephalosporin C at sites

Answer 3

Substitution at R1 site usually increases stability against B-lactamases. R2 modifications may extend serum half-life of compound.

Question 4

Pharmacological properties of cephalosporins;

Answer 4

oral and parenteral formulations.

Antimicrobial effects depend on sustained concs of drug above MIC of infecting organism.

Question 5

Adverse effects of cephalosporins:

Answer 5

Generally well tolerated.
Adverse effects include GI upset, hypersensitivity reactions and superinfections.
rate of cross-reactive allergy in patients with penicillin allergy may not be as high as first thought.

Question 6

Activity and use of cephalosporins:

generations 2, 3/4, 4, 5

Answer 6

2nd gen: some enterobacteriaceae, RTIs, otitis media. 3rd + 4th gen: many gram +ves + some STIs, meningitis categorized by WHO as critically and highly important respectively..
4th gen: nosocomal infections + immunocompromised.
5th gen: anti-MRSA

Question 7

Carbapenems

Answer 7

derivatives of thienamycin , natural product of streptomyces cattleya.
differ from penicillins by substitution of C for S and addition of double bond to five-membered ring of penicillin nucleus
carbapenems in use include imipenem, meropenem and doripenem.

Question 8

Imipenem:

Answer 8

A carbapenem
inactivated by enzyme of renal brush border so is administered with cilastatin
Serum t1/2 of 1hr
resistant to range of b-lactamses
adverse reactions include infusion site problems, nausea & vomiting, rash, fever.
Very active against most aerobic and anaerobic G+ve pathogens including staphs and streps and vs most G-ve aerobic pathogens incl neisseria, enterobacteriaceae.
Treatment of severe nosocomal infections and polymicrobial infections including septicaemia, skin infections and complicated UTIs

Question 9

Meropenem;

Answer 9

Resistant to dihydropeptidase
Slightly more active against aerobic G-ve bacilli, slightly less active vs aerobic G=ve bacilli. active vs Burkholderia cepacia.
Fewer adverse reactions than imipenem, wider therapeutic window.

Question 10

Relative activity of carbapenems:

Answer 10

Imipenem has slightly more Gram +ve activity, Ertapenem, meropenem and doripenem are more gram -ve, with the latter two even more so.

The carbaps are important broad spectrum drugs, mainly reserved for life-threatening infections.

Question 11

Monobactams: Aztreonam

Answer 11

First isolated from chromobacterium violaceum
active vs G-ve aerobic
clinical importance because of toxicity profile.
no affinity for PBPs of G+ves or anaerobes.
affected by B-lactamases but weak inducer.
Non-nephrotoxic alternative to aminoglycosides.
Uses include: UTIs, infections in cancer, neutropenic and burns patients.