Beta Lactams (Cushman lecture 1)

Question 1

Beta lactamase excretion in gram+ vs gram-

Answer 1

• gram +: excreted through cell wall to external environment, so have to be produced in larger quantities compared to gram -
• gram -: confined to periplasmic space

Question 2

Gram - peptidoglycan structure/function

Answer 2

• the peptidoglycan contains a meso-diaminopimelic acid (DAP)
• peptidoglycan is cross-linked by a bridge between a DAP strand and D-Ala strand.
• linkage is vital for bacterial cell wall

Question 3

Gram + peptidoglycan structure/function

Answer 3

• peptidoglycan contains L-lysine residue instead of DAP
• crosslinking occurs between L-lys to D-Ala
• linkage vital for bacterial cell wall

Question 4

Beta lactam antibiotic mechanism of action (related to peptidoglycan crosslinking)

Answer 4

• inhibit transpeptidases that “glue” peptidoglycan strands together by crosslinking
• B-lactam acylate the transpeptidase Ser residue in enxyme active site to form a stable product, which inactivates the enzyme thus inhibiting the crosslinking— deactivates bacterial cell wall (cell death)

Question 5

Resistance to beta lactam antibiotics (4 ways)

Answer 5

• decreased cellular uptake of the drug
• mutation of PBP to decrease affinity for penicillins
• efflux pumps
• induction of bacterial beta lactamases

Question 6

Beta lactamase (overview)

Answer 6

• catalyze hydrolysis of beta lactam moiety
• hydrolysis of acylated B-lactamase intermediate is fast, so enzyme rapidly hydrolyzed drug molecules
• hydrolysis of beta lactams is IRREVERSIBLE

Question 7

Under acidic conditions, degradation products of Pen G are:

Answer 7

• benzylphenicillenic acid
• benzylpenillic acid
• benzylpenicilloic acid

Question 8

Under basic conditions, degredation products of penicillin:

Answer 8

• A penicilloic acid

Question 9

Penicillin hydrolysis products have no antibiotic activity. (t/f)

Answer 9

True

Question 10

Why is Pen V more stable to hydrolysis in the stomach than Pen G

Answer 10

• the electronegativity of the ether oxygen decreases the nucleophilicity of the amide carbonyl
  (less nucleophilic, less reactive, so more stable in acidic conditions)

Question 11

Effect of using penicillin with probenecid

Answer 11

• increases duration of action (t1/2 increased)

Question 12

Penicillin G (Benzylpenicillin) use/properties

Answer 12

• gram + cocci
• beta lactamase sensitive
• parenteral administration
• acute allergic rxns (vary)

Question 13

Penicillin V

Answer 13

• more stable (than G) in acid
• given orally

Question 14

Methicillin

Answer 14

• not beta lactamase sensitive
• administered by injection
• lot of resistance (so discontinued)

Question 15

Nafcillin

Answer 15

• beta lactamase resistant
• not really used due to resistance
• clinically identical to methicillin

Question 16

Oxacillin, Cloxacillin, Dicloxacillin

Answer 16

• isoxazoles
• not beta lactamase sensitive
• dicloxacillin still available for oral use

Question 17

Ampicillin

Answer 17

• ## gram - organisms are sensitive to ampicillin

Question 18

Amoxicillin

Answer 18

• significantly better oral activity (than ampicillin)

Question 19

Use of beta lactamase inhibitors

Answer 19

• used in combination with beta lactamase sensitive penicillins
• acylate the serine hydroxyl group in active site of beta lactamase, which inactivates the Beta lactamase (making the beta lactam it’s given with work)

Question 20

Beta lactam+beta lactamase inhibitors:

Answer 20

• potassium clavulanate + amoxicillin = Augmentin
• sulbactam + ampicillin = Unasyn
• tazobactam + pipericillin = Zosyn
• avabactam + ceftazidime = Avcaz

Question 21

Piperacillin

Answer 21

• activity against gram + bacteria and some gram -
• added side chain fragment resembles a longer section of peptidoglycan chain than ampicillin – enhanced potency
• used parenterally

Question 22

cephalosporins (overview)

Answer 22

• inhibit crosslinking. 6 membered rings. hydrolyzed by B-lactamases.
• generally less allergenicity than penicillins. use in caution if penicillin allergy.

Question 23

1st gen cephalosporins

Answer 23

• primarily active against gram + cocci (staph aureus and staph pyogenes; strepto agalactiae and strepto pneumoniae)
• cephazolin – parenteral (bc reactive side chain)
• cephalexin – oral (C-3 not chemically reactive)

Question 24

2nd gen cephalosporins

Answer 24

• anti gram + activity (same as 1st gen + Haemophilus influenzae)
• activity against gram - bacteria (acinetobacter, citrobacter, enterobacter, E coli, Klebsiella, Neisseria, Proteus, Providencia, and Serratia)
• cefuroxime – parenteral and oral (carbamate side chain not a good leaving group)

Question 25

3rd gen cephalosporins

Answer 25

• more activity vs gram - bacteria
• useful against nosocomial multidrug-resistant strains
• aminothiazole substituent and oxime either at 7 position
• parenterally active (charged pyridinium ring – good leaving group – too reactive to be orally given)

Question 26

4th gen cephalosporins

Answer 26

• same activity as 3rd gens + pseudomonas aeruginosa
• more active against gram +
• cefepime – parenterally active (N-methylpyrrolidine good leaving group so increases reactivity)

Question 27

5th gen cephalosporins

Answer 27

• active vs MRSA and community acquired bacterial pneumonia
• ceftaroline - IV infusion (ceftaroline fosamil is prodrug hydrolyzed to ceftaroline by plasma phosphatase)