Beta-Lactams

Question 1

What are the beta lactams

Answer 1

penicillins, cephalosporins, carbapenems, monobactams

Question 2

Chemical structure of penicillins

Answer 2

1. All penicillins share the same basic structure of a 5-membered thiazolidine ring connected to a beta-lactam ring. The side chains differ among the penicillins, providing different antibacterial spectrums and PK properties, as well as greater beta-lactamase stability.

Question 3

Chemical structure of cephalosporins

Answer 3

2. Cephalosporins contain a beta-lactam ring where the 5-membered thiazolidine ring of the penicillins is replaced by a 6-membered dihydrothiazine ring. This structural difference provides stability against some beta-lactamase enzymes that may render the penicillins inactive.
3. Cephamycins are cephalosporins with a methoxy group at position 7 of the beta-lactam ring, which confers activity against anaerobes such as Bacteroides spp.

Question 4

Chemical structure of carbapenems

Answer 4

4. Carbapenems are beta-lactam antibiotics with a carbapenem nucleus. Contain a beta-lactam ring fused to a 5-memebered ring, like the penicillins, but the 5-memebered ring of the carbapenem contains a carbon atom at position one instead of a sulfur atom. All contain a hydroxyethyl group in the trans configuration at position 6 as compared to an acylamino group in the cis configuration of the penicillins and cephalosporins. This results in increased antibacterial activity and greater stability against most beta-lactamase enzymes.

Question 5

Chemical structure of monobactams

Answer 5

5. Monobactam: synthetic monocyclic beta-lactam antibiotics, only contains a beta-lactam ring with side chains.

Question 6

Beta-lactam mechanism of action

Answer 6

1. Same mechanism of action: inhibitors of cell wall synthesis – interfere with bacterial cell wall synthesis by binding to and inhibiting enzymes called penicillin binding-proteins (PBPs) which are located in the cell wall of bacteria and are primarily expressed during cell division. Inhibit cross-linking of the cell wall. Inhibition of PBPs by beta-lactam antibiotics leads to inhibition of the final transpeptidation step of peptidoglycan synthesis, exposing a less osmotically stable cell membrane that leads to decreased bacterial growth, bacterial cell lysis, and death.

Question 7

Beta-lactam mechanisms of resistance

Answer 7

1. destruction by beta-lactamase enzymes – hydrolyzes the cyclic amide bond of the beta-lactam ring, inactivating the antibiotic’ beta-lactamase enzymes produced by gram-negative bacteria reside in the periplasmic space, making it a very efficient mechanism of resistance.
2. Cephalosporins are resistant to degradation by beta-lactamases of some bacteria.
3. Inducible beta-lactamases: bacteria product beta-lactamase enzymes when exposed to antibiotics (such as during treatment of Enterobacter spp. Infections with ceftazidime).
4. alteration in penicillin binding proteins (PBPs) – decreased binding affinity of penicillin to PBPs ex. MRSA, PRSP
5. decreased permeability of outer cell membrane in gram-negative bacteria – altered porin proteins

Question 8

Pharmacodynamic properties of beta-lactams

Answer 8

display time-dependent (T>MIC) bactericidal activity (except enterococcus spp)

Question 9

Elimination half-life of beta-lactams

Answer 9

4. Short elimination half-life (<2 hrs): repeated, frequent dosing is needed for most beta-lactams to maintain serum concentrations above the MIC of the infecting bacteria for an adequate amount of time (except ceftriaxone, cefotetan, cefixime, ertapenem)

Question 10

Route of elimination of beta-lactams

Answer 10

5. Renal elimination: primarily eliminated unchanged by glomerular filtration and tubular secretion (except nafcillin, oxacillin, ceftriaxone, cefoperazone)

Question 11

Potential for cross-allergenicty of beta-lactams

Answer 11

6. Cross-allergenicity: all except aztreonam