2: B-lactams

Question 1

G(+) vs. G(-): color on gram stain

Answer 1

G(+): dark purple (crystal violet)

G(-): light pink (safranin)

Question 2

G(+) vs. G(-): can drugs penetrate the outer layer?

Answer 2

G(+): drugs penetrate outer layer

G(-): drugs can’t penetrate outer layer, but some use porins

Question 3

G(+) vs. G(-): where are B-lactamases located?

Answer 3

G(+): excrete B-lactamases through cell wall (need more)

G(-): B-lactamases confined to periplasmic space

Question 4

G(+) vs. G(-): thickness of PG layer?

Answer 4

G(+): thick PG

G(-): thin PG

Question 5

G(+) vs. G(-): number of membranes?

Answer 5

G(+): one membrane

G(-): two membranes (more lipoidal)

Question 6

G(+) vs. G(-): L-Lys or DAP in PG?

Answer 6

G(+): L-Lys

G(-): DAP

Question 7

B-lactam MOA

Answer 7

penicillin resembles D-Ala-D-Ala -> acylates Ser of PBP to form a stable product, inactivating PBP

Question 8

what gives B-lactam ring its reactivity? 2 reasons

Answer 8

1. carbonyl: tetrahedral intermediate 90* compressed angle -> 109* angle
2. B-lactam carbonyl is more like a ketone carbonyl (N lone pair doesn’t overlap with C=O) -> more reactive

Question 9

why don’t bacterial PBPs react with host protein?

Answer 9

bacteria have D-Ala; human proteins do not

Question 10

4 mechanisms of resistance to B-lactmas

Answer 10

1. decreased cell uptake
2. mutant PBPs
3. efflux pump
   * *4. bacterial B-lactamases (hydrolyze B-lactam ring)

Question 11

what percent of people are allergic to B-lactams?

Answer 11

6-8% of US

Question 12

cause of B-lactam allergenicity

Answer 12

due to drug acting as hapten and acylating host proteins

Question 13

range of sx from B-lactam allergy

Answer 13

rash (urticaria) to anaphylaxis

Question 14

why can’t B-lactams be structurally altered to reduce allergenicity?

Answer 14

b/c allergenicity originates in pharmacophore

Question 15

how can you test for B-lactam allergy?

Answer 15

topical wheal and flare test

Question 16

is penicillin degradation in acid reversible or not? what can catalyze degradation?

Answer 16

irreversible

-catalyzed by heavy metal ions

Question 17

3 major degradation products of penicillin and mechanism of degradation

Answer 17

1. benzylpenicillenic acid (eliminate a sulfhydryl from 2nd intermediate)
2. Benzylpenillic acid (complex hydrolysis w/ ankemeric assistance)
3. Benzylpenicilloic acid (basic solution (-OH))

Question 18

how can penicillins be stabilized against degradation?

Answer 18

make R group more electronegative -> nucleophilicity of carbonyl is reduced

Question 19

effect of serum protein binding on penicillins

Answer 19

• reduces bioavailability b/c less [free drug]
• protects from degradation b/c degradation occurs on drugs in solution
• does not change half life b/c fast dissociation rates/ renal excretion rate = limiting factor

Question 20

how does lipophilicity of R group change serum protein binding?

Answer 20

more lipophilic R = more highly protein bound

Question 21

excretion of penicillin

Answer 21

rapid:
- biliary
- renal: 10% glomerular filtration, 90% tubular secretion via anionic mechanism

Question 22

what happens to half life of penicillin if administered to patient with kidney disease?

Answer 22

increase half life

Question 23

how can one target the anionic mechanism of penicillin excretion to increase its half life?

Answer 23

administer penicillin with probenecid

Question 24

Benzylpenicillin (Pen G): R group

Answer 24

-benzyl R group

Question 25

Benzylpenicillin (Pen G): B-lactamase sensitive?

Answer 25

yes

Question 26

Benzylpenicillin (Pen G): activity

Answer 26

G(+) cocci + N. gonorrhea, H. influenzae

drug of choice for treatment of more stuff than any other antibiotic

Question 27

Benzylpenicillin (Pen G): admin

Answer 27

p.o. - large dose

parenteral = most effective

Question 28

Benzylpenicillin (Pen G): toxicity/contraindications

Answer 28

• acute allergic reaction

- don’t give with significant history of asthma/allergies

Question 29

Methichillin: R group

Answer 29

ortho methoxy groups

Question 30

Methichillin: B-lactamase sensitive?

Answer 30

no - steric hindrance of methoxyls prevents nucleophilic attack on C=O

Question 31

Methichillin: admin

Answer 31

injection only (unstable in acid, so no oral)

Question 32

Methichillin: activity

Answer 32

narrow - mostly for B-lactamase producing S. aureus

Question 33

Methichillin: toxicity/contraindications

Answer 33

-inducer of B-lactamase, so only use when required

Question 34

Methichillin: resistance mechanism

Answer 34

PBP2 (mutation in gene mecA)

Question 35

Cephapirin: structure

Answer 35

cephalosporin w/ 6-member ring w/ S

-acetate at position 3

Question 36

Imipenem: structure

Answer 36

carbapenem

-S replaced by methylene (greater ring strain)

Question 37

Imipenem: B-lactamase sensitive? sensitive to anything else?

Answer 37

no - inhibits B lactamases

but, hydrolyzed by renal dehydropeptidase-1 (can be overcome when given w/ cilastatin)

Question 38

Imipenem: activity

Answer 38

G(+) and G(-)
-serious infections of gut, GU tract, bone, skin, endocardium

“magic bullet” - combo w/ cilastatin has broader activity than any other US antibiotic

Question 39

Imipenem: admin

Answer 39

parenteral

Question 40

Imipenem: toxicity/contraindications

Answer 40

good B-lactamase inducer, so only use when required

Question 41

aztreonam: structure

Answer 41

• synthetic monobactam

- sulfamic acid in place of C=O

Question 42

aztreonam: activity

Answer 42

almost completely G(-) - especially those by penicillin resistant dudes acquired in hospitals

Question 43

aztreonam: toxicity/contraindications

Answer 43

-cross allergenicity only reported with ceftazidime (same R group)

Question 44

aztreonam: what makes the B-lactam ring more reactive?

Answer 44

electronegativity of sulfamic acid