The Beta-lactam family: The Penicillins

Question 1

Beta-lactam family members: (4)

Mode of action:

Common features to all members:

Answer 1

Penicillins
Cephalosporins
Carbapenems
Monobactams

Inhibition of bacterial cell-wall synthesis

Beta-lactam ring and carboxyl group, leading to similar pharmacokinetics and mode of action.

Question 2

Beta-lactam ring system:

Answer 2

• Highly strained + reactive
• Penicillins and related compounds susceptible to degradation.
• Sensitive to acid, so clinical solutions are buffered.
• Allergenic haptens are formed In vivo.
• Many bacteria produce penicillinases which degrade and inactivate beta-lactams –> beta- lactamases are most common type.
  They are chromosomally or plasmid encoded.
• beta-lactamase inhibitors developed to sustain action of beta-lactams.

Question 3

By what reaction does the beta-lactamase cause the beta-lactam to lose its function?
Penicillin G is converted to which inactive reagent by a beta-lactamase?

Answer 3

Hydrolysis

Penicilloic acid

Question 4

Peptidoglycan cell wall synthesis:

Growth and multiplication of bacterial cell wall synthesis involves…

Peptidoglycan synthesis overview: (3 steps)

Name 3 bacterial enzymes that catalyse final stage of PG synthesis, and where they’re located.

Answer 4

Cell wall expansion, septum formation, daughter cell separation.

• Precursor synthesis in cytoplasm from amino acid glutamine.
• Transferred to lipid carrier in cell membrane called bactoprenol + transports the precursors outside.
• polymerization of subunits: new PG attached to existing PG by transglycosylation reactions.

-Transpeptidase
-carboxypeptidase
- endopeptidase
(located beneath cell wall)

Question 5

Mode of activity: ‘Substrate-analogue’ model:

1. ) The bacterial enzymes are also known as…
2. ) Spatial arrangement…
3. ) Acylation is …
4. ) Bacterial growth is …

Answer 5

Penicillin Binding proteins

Spatial arrangement of beta-lactam ring resembles D-Alanyl-D-alanine portion of PG

The acylation is irreversible

Bacterial growth is inhibited

Question 6

Why are penicillins considered bactericidal:

What is the unbalanced growth hypothesis?

What is the triggering hypothesis is pneumococci?

What is lipoteichoic acid and why is it important?

Answer 6

PG hydrolases act on the cell wall which weaken it and cause It to lyse.

Inhibition of cell wall synthesis by any means triggers bacterial autolytic enzymes (de-inhibits them)

It acts as regulator of autolytic wall enzymes (muramidases). It has antigenic properties being able to stimulate specific immune response and is released from the bacterial cells mainly after bacteriolysis induced by lysozyme, cationic peptides from leucocytes, or beta-lactam antibiotics.

Question 7

Persisters + Tolerance:

Persisters:

Tolerance:

Answer 7

Proportion of bacterial population may survive exposure to penicillin (both G+ve and G-ve)
Cell wall remains intact, perhaps the biosynthesis of PG halts while penicillin is present (dormancy).

Some strains of staph and strep tolerate b-lactams and are killed more slowly than usual.
They have the same minimum inhibitory concentration as other cells, but a higher minimum bactericidal concentration.

Question 8

Name 2 natural penicillins:

Name 4 peniclllinase-resistant penicillins:

Why are they resistant?

Answer 8

Penicillin G
Penicillin V

Methicillin
Oxacillin
Cloxacillin
Dicloxacillin

Acyl side chain prevents disruption of b-lactam ring
(Use detail from med chem, e- withdrawing)

Question 9

Aminopenicillins:

Answer 9

Ampicillin
Amoxicillin
These are extended spectrum penicillins

Question 10

Anti-pseudomonal penicillins: (carboxypenicillins)

Answer 10

These are called carboxypenicillins
Carbenicillin- effective against UTI, high dose -> bleeding
Ticarcillin- Injection vs gram -ve. used in combination with clavulanate as Timentin
Azlocillin- broad spectrum, great in vitro potency

Question 11

Penicillins + b-lactamse inhibitors:

Answer 11

Amoxicillin-clavulanic acid –> Augmentin

Ticarcillin- clavulanic acid –> restored efficacy against ticarcillin-resistant bacteria.

Question 12

Pharmacological properties of penicillins: (7)

Answer 12

-Many destroyed by stomach acid, so administered parenterally.
- those not destroyed by stomach acid are absorbed in duodenum, peak levels in 1-2h.
- Short serum half-life
- rapid excretion, mainly by kidneys
distributed widely, mostly in extracellular space
- Need sustained concentrations of penicillin above MIC of infecting organism.
Slow release, but stays above MIC long enough to have effect

Question 13

Methods for prolonging serum levels of penicillin: (4)

Answer 13

Give huge doses
Mix with oily/waxy excipients for slow release
use insoluble derivatives of penicillins (procaine)
Give probenicid orally at same time as penicillin. Probenicid blocks renal excretion.

Question 14

Natural penicillins:

Answer 14

• Pen G effective primarily against gram +ves including anaerobes.
• PenG/Procaine used for when serum levels needed for hours (how does it do this)
• PenG benthazine used for prolonged low levels, e.g. for early and latent stages of syphilis

Question 15

Penicillinase-resistant penicillins (antistaphylococcal penicillins):

Answer 15

• Acyl side chain sterically inhibits action of penicillinase
• active against streptococci and staphylococci but not gram -ves
• Methicillin + Oxacillin

Question 16

Extended spectrum penicillins

Answer 16

Extended activity against gram -ve bacilli
Increased penetration through outer membrane and higher affinity for plasma binding proteins.
Aminopenicillins:
Ampicillin- active against E.coli + salmonella with parenteral admin
Amoxicillin- oral admin only, used for UTIs and RTI
Antipseudomonal penicillins e.g. Carbenicillin + piperacillin. Mainly used against P. aeruginosa and often given with an aminoglycoside for invasive infections, neutropenic patients, sepsis

Question 17

Beta-lactamase inhibitors:

Two ways of action:

Clavulanic acid, tazobactam and sulbactam:

Answer 17

1. ) high-affinity irreversible binding to catalytic site of b-lactamase which prevents hydrolytic action
2. ) Bind directly to bacterial PBPs, increasing antibacterial activity of the penicillin.

These primarily inhibit plasma-encoded beta-lactamases.
Augmentin was the first oral combination
Ticarcillin-clavulanic acid –> first parenteral administration
Avibactam - non b-lactam b-lactamse inhibitor, used for complicated UTIs

Question 18

Adverse reaction to penicillins:

Answer 18

Generally well-tolerated

• allergic reactions
• electrolyte abnormalities
• gastrointestinal
• hepatic
• Renal