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Pharmacology Infectious Disease > Antibacterials: Cell Wall Inhibitors > Flashcards

Antibacterials: Cell Wall Inhibitors Flashcards

1
Q

Why do gram positive bacteria typically have to produce larger quantities of beta-lactamases to confer beta-lactam resistance?

A

Gram + don’t have an outer membrane = beta lactamases are secreted vs. Gram - beta lactamases are confined to the periplasmic space.

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2
Q

What do drugs need to be able to do to enter Gram - bacteria?

A

Pass through porins in the outer membrane

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3
Q

What is the difference in Gram + vs. Gram - peptidoglycan?

A

Gram - –> Meso-diaminopimelic acid (DAP)

Gram + –> L-lysine (COOH of DAP replaced by H)

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4
Q

What are the general chemical constituents of pepditoglycan?

A

Polymer of N-acetylglucosamine (G) and N-Acetylmuramic acid (M) with L-ala, D-Glu, L-Lys (G+) or DAP (G-) attached to TWO D-Ala.

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5
Q

What forms the cross bridge in peptidoglycan synthesis?

A

transpeptidases

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6
Q

Between what do transpeptidases form the peptidoglycan cross bridge?

A

G- = 4th residue - D-Ala and DAP

G + = 4th residue - D-Ala and L-Lys

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7
Q

Briefly describe the mechanism of transpeptidation.

A

2 Addition Elimination Reactions:
Serine of Transpeptidase attacks + attaches to one peptidoglycan molecule
Second peptidoglycan molecule displaces the Transpeptidase
Form Peptide bond

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8
Q

How do beta lactams inhibit peptidoglycan synthesis? How does this lead to bacterial death?

A

Acylate the transpeptidase serine residue - blocks peptidoglycan cross linking.

Weak peptidoglycan = osmotic stress, cell lysis

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9
Q

What 2 things make penicillin highly reactive?

A

1) Ring strain of 4 membered ring (90 degrees)

2) Penicillin ring folding (to reduce ring strain) prevents N –> carbonyl resonance stabilization

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10
Q

Why do we see heterogeneity of responses of different bacteria to penicillin?

A

Many different transpeptidases (penicillin-binding proteins) in different bacteria.

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11
Q

What prevents bacterial transpeptidases from catalyzing reactions with host alanine residues?

A

Bacterial peptidoglycan substrate contains unnatural D-Ala residues.

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12
Q

What are 4 mechanisms of resistance to beta lactam antibiotics?

A

1) Reduced cellular uptake
2) Efflux pumps
3) Transpeptidase mutations - decreased affinity
4) Elaboration or induction of Transpeptidases

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13
Q

How do beta-lactamases inactivate beta lactam antibiotics?

A

1) serine of beta lactamase acylates beta lactam (addition elimination)
2) Water added to regenerate enzyme (addn elimin)

FAST REACTION - many drug molecules quickly inactivated

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14
Q

How do beta-lactamases cause allergic reactions? How do you test for allergenicity?

A

Drug is hapten - acylates host proteins.

Test w/ prick test - wheel and flare.

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15
Q

What reduces the bioavailability of penicillins? What can facilitate this reduced bioavailability?

A

IRREVERSIBLE Degradation/hyrdolysis to penicillenic acids reduces bioavailability:
Acidic (i.e. in stomach) - Enchomerid - side chain participates
Basic - Nucleophilic attack of carbonyl in beta lactam ring

Heavy metal ions catalyze penicillin degradation

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16
Q

Why is Penicillin V able to be taken orally but not PenG?

A

Electronegative O side group stabilizes the carbonyl group so it can’t participate in the acidic hydrolysis reaction in the stomach.

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17
Q

How does protein binding affect penicillins (what causes binding, bioavailability, degradation, half life)?

A

Liphophilic side chains = more protein bound
Protein binding = decreased bioavailability (free drug), degradation protection
No affect on half life - fast dissociation rates

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18
Q

Two ways for penicillin excretion. What is most common?

A

Renal, Biliary

Renal tubular secretion predominates

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19
Q

How can you increase the half life of penicillins?

A

Add a competitor for tubular secretion:
anion route - add an anion (e.g. PROBENECID)
cation - add a cation

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20
Q

What two actions contribute to antibiotic resistance?

A

Widespread livestock use

Lack of judicious use by healthcare workers

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21
Q

Why is methicillin not beta lactamase sensitive?

A

Two methoxy substituents attached ortho to the amide - steric hinderance prevents beta-lactamase nucleophilic attack of the beta lactam carbonyl.

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22
Q

How has Staph aureus developed Methicillin resistance?

A

Mutation in the transpeptidase - mecA gene coding for PBP2

23
Q

What differentiates cephalosporins structurally from penicillins?

A

6 membered ring attached to the beta lactam ring vs the 5 membered ring in penicillins

24
Q

How is cefepime inactivated?

A

Host esterases –> inactive lactone.

25
Q

How does Aztreonam’s structural difference affect it’s reactivity?

A

Sulfur group electronegativity activates beta lactam ring for hydrolysis and PBP interaction.

26
Q

How do penicillins work?

A

acylate transpeptidases - prevent peptidoglycan/cell wall cross linking/synthesis

27
Q

Name 5 drugs/drug classes that have broad spectrum activity against G+ organisms. What are the unique characteristics of each?

A

Penicillin G - IV
Penicillin V - ORAL
Aminopenicillins (Ampicillin, amoxicillin) - Used in combo w/ beta-lactamase inhibitor
Cephalosporins - Less susceptible to penicillinases
Carbapenems - Imipenem/cilastatin - penicillinase resistant; meropenem - stable to DHP1 & less toxicity

28
Q

Name 5 drugs/drug classes that have broad spectrum activity against G- organisms.

A 
Aminopenicillins (ampicillin, amoxicillin)
Ticarcillin, piperacillin, carbenicillin
3rd generation cephalosporins
Carbepenems
Aztreonam
29
Q

What drugs can be used to treat pseudomonas?

A

Ticarcillin, piperacillin, carbenicillin
3rd (Ceftazidime) & 4th Generation cephalosporins
Aztreonam

30
Q

In addition to G+ organisms, what can PenG and PenV be used to treat?

A

N. gonorrhoeae, H. influenza, spirochetes

31
Q

What are Methicillin, oxacillin/nafcillin/dicloxacillin primarily used to treat? How is methicillin given and why?

A

Staph aureus (NOT MRSA)

Methicillin - IV only - not acid stable.

32
Q

Name 4 drugs resistant to beta-lactamases and one group that is less susceptible to penicillinases.

A
  1. Methicillin
  2. Oxacillin/Nafcillin/Dicloxacillin
  3. Imipenem/cilastatin
  4. Aztreonam

Cephalosporins - less susceptible

33
Q

What is the difference in coverage of the different generations of cephalosporins?

A

1st. G+ mostly; PEcKS - Proteus, E. coli, Klebsiella, Serratia
2nd. G+ mostly; HEN PEcKS - H. influenzae, Enterobacter, Neisseria, PEcKS
3rd. G- mostly
4th. G+ and pseudomonas

34
Q

What is used to treat infant vs. adult meningitis?

A

Infant - Cefotaxime

Adult - Ceftriaxone

35
Q

How do carbapenems differ from penicillin? When should they be used?

A

“Carb” = carbon analogs of penicillin; S replaced with a C = more reactive

“magic bullets” - use judiciously - broadest spectrum available

36
Q

How does aztreonam differ from penicillin? When should Aztreonam be used?

A

C2 replaced with sulfamic acid.

Use with G- infections; good for penicillin allergic patients and renal insufficient patients.

37
Q

What drugs should be used with penicillinase inhibitors?

A

Aminopenicillins & Antipseudomonals (Ticarcillin, piperacillin, carbenicillin)

38
Q

What are the three penicillinase inhibitors? What are the drug names when they are used in combination with aminopenicillins?

A

Unasyn - Sulbactam + Ampicillin
Zoxyn - Tazobactam + Piperacillin
Augmentin - Amoxicillin + Clavulanic Acid

39
Q

What is Dehydropeptidase-1? What medication does this affect, and what needs to be done to mediate its affects?

A

DHP-1 = renal peptidase that hydrolyzes Imipenem. Must give Imipenem with cilastatin = a DHP-1 inhibitor.

40
Q

What is the major concern with penicillin family use?

A

Hypersensitivity and cross-reactive hypersensitiviey.

41
Q

What are some toxicities of cephalosporins?

A

Hypersensitivity, vitamin K deficiency, increased nephrotoxicity of aminoglycosides.

42
Q

What is Vancomycin used for?

A

G+ - serious only - resistance development; MRSA, C. Diff

43
Q

How does Vancomycin inhibit cell wall synthesis?

A

Inhibits transpeptidation: Binds the D-ala-D-ala terminus of peptidoglycan precursor.

44
Q

How does Vanco mechanism relate to and differ from that of penicillin?

A

Both inhibit transpeptidation.
Vanco surrounds precursor
Penicillin binds transpeptidases/PBPs

45
Q

What toxicities are associated with Vancomycin?

A

Nephrotoxicity, Ototoxicity, Thrombophlebitis, Red Man Syndrome (diffuse flushing - directly activates mast cells)

46
Q

What is Red Man Syndrome? What causes this and why?

A

Diffuse facial flushing. Vancomycin directly activates mast cells.

47
Q

Why is vanco use restricted to only serious G+ infections, resistant organisms, and C. diff?

A

Toxicity

Resistance develops quickly.

48
Q

How does resistance to Vancomycin form?

A

D-ala D-ala changes to D-ala D-lac on bacteria. Change can undergo transpeptidation but does not bind drug.

49
Q

How do beta lactamase inhibitors work?

A

Acylate the beta lactamase serine OH in the active site.

50
Q

What is the mechanism of action of Fosphomycin?

A

Inhibits enzyme (MurA) responsible for catalyzing production of activated NAG for cell wall synthesis. MurA SH group opens Fosphomycin epoxide ring.

51
Q

What are Repository Penicillins used for and how are they administered? Name three.

A

Used for longer duration of action in URI and susceptible Strep infections. Given deep IM injection only.

Benzylpenicillin, Benzathine, Benzylpenicillin Procaine

52
Q

What toxicities are associated with Repository Penicillins?

A

Cardiac arrest and permanent neurological damage if administered into the blood stream or near nerves.

53
Q

Why should methicillin use be limited to only when absolutelly necessary?

A

Induces beta lactamase - contributes to development of resistance.

Pharmacology Infectious Disease (8 decks)

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