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Pharm > 2: Vancomycin + Macrolides > Flashcards

2: Vancomycin + Macrolides Flashcards

1
Q

what type of drug is vancomycin? how many of this type of drug are there?

A

non-ribosomal glycopeptide

-only 2 (this and teicoplanin)

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2
Q

vancomycin MOA

A

inhibits G(+) cell wall synthesis by covering D-Ala-D-Ala terminus, so PG can’t react w/ neighboring PG

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3
Q

what dose of vancomycin is bacteriocidal

A

1-5 ug/mL

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4
Q

resistance to vancomycin associated with what?

A

VRE connected to avoparcin use (livestock feed additive), but reversible (decreased resistance when stopped avoparcin use)

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5
Q

mechanism of vancomycin resistance?

A

D-Ala-D-Ala replaced by D-Ala-D-Lac (1000x reduced affinity)

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6
Q

toxicity/side effects of vancomycin

A
  • hypersensitivity: red skin rash + some anaphylaxis

- rare: nephrotoxicity/ototoxicity (associated with high [circulating drug])

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7
Q

macrolide structure

A

macrocyclic lactone, 14-member ring, polyketide

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8
Q

how are polyketides produced? what pattern does it produce?

A

sequential addition of propionate groups to growing chain -> results in methyl groups on alternating C’s

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9
Q

where does erythromycin A come from?

A

most from Streptomyces fermentation -> erythronolide intermediate

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10
Q

how can you make erythromycin more soluble?

A

pka is 8.8, so can form more soluble salts:

  • glucoheptonic acid
  • lactobiononic acid
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11
Q

macrolide MOA

A
  • inhibit bacterial protein synthesis: bind reversibly to P site, preventing peptidyl-tRNA translocation (or bind b/w A and P sites, inhibiting peptide bond formation)
  • binds on 23S RNA of 50S subunit
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12
Q

bacteriostatic or bacteriocidal?

A

bacteriostatic mostly, but can be bacteriocidal in high concentration

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13
Q

where do macrolides accumulate and why is this important?

A

in leukocytes -> transported directly to infection

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14
Q

4 mechanisms of macrolide resistance

A
  1. lactone ester hydrolase (hydrolyzes ring)
  2. methylated A2058 on 23S RNA (inhibits binding to 23S)
  3. A2058 -> G2058 (10,000x reduction in binding)
  4. efflux pump
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15
Q

what hypothesis did the discovery of methylation of A2058 as a macrolide resistance mechanism provide?

A

resistance may originate in the producing organism and then transfer to other bacteria

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16
Q

resistance to what other bug is associated with macrolide use?

A

S. pneumoniae

17
Q

what two bugs have inherent macrolide resistance? what is the mechanism of their resistance?

A

Pseudomonas and Enterobacter

-don’t allow entry of drug

18
Q

describe acid inactivation of macrolides - how does this affect oral administration of macrolides?

A

intramolecular acid-catalyzed ketal formation at 6-OH -> causes GI cramping
-oral erythromycin must be enteric coated or as a stable salt/ester

19
Q

2 ways in which acid inactivation is overcome?

A
  1. Clarithromycin: 6-OCH3 instead of 6-OH blocks ketal formation
  2. Azithromycin: N-methylated methyleneamino instead of C9 ketone blocks ketal formation
20
Q

describe macrolide metabolism

A

mainly demethylation in liver by CYP3A4

21
Q

half life of erythromycin

A

1.5h

22
Q

elimination of macrolides

A

mostly bile, small bit in urine

23
Q

DDIs with each of the following macrolides:

  • erythromycin
  • clarithromycin
  • azithromycin
A

erythro, clarithro inhibit CYP3A4 -> probs w/:

  • carbamazepine
  • cyclosporin
  • disopyramide
  • midazolam
  • quinidine
  • rifampicin
  • rifabutin
  • theophylline
  • triazolam
  • zidovudine

no reported cases with azithromycin

others: ergotamine, digoxin, methylprednisone

24
Q

macrolide side effects:

  • general
  • rare
  • long term use
  • preg/nursing moms
A
  • stimulate GI -> vomit, nausea, diarrhea, cramps, pain
  • rashes (minor to severe)
  • rare Stevens Johnson syndrome, toxic epidermal necrolysis
  • long term use: reversible cholestatic hepatitis (jaundice + cramps, nausea, fever)
  • late preg/nursing moms: increase risk of pyloric stenosis in kids
25
Q

Erythromycin estolate (Ilosone): structure

A

propionyl ester, lauryl sulfate prodrug of erythro - makes it more lipophilic -> increases oral absorption, serum levels

26
Q

Erythromycin estolate (Ilosone): side effects

A

some cholestatic jaundice: granular bile blocks duct -> bile salts in serum

27
Q

Erythromycin estolate (Ilosone): contraindications

A

pre-existing liver disease

28
Q

Erythromycin estolate (Ilosone): activity

A
  • GABHS
  • primary syphilis
  • amebic dysentery
  • endocarditis (surgery prophylaxis for viridans)
29
Q

erythromycin ethyl succinate: structure

A

ethyl succinate ester prodrug of erythro - makes it more lipophilic -> increase oral absorption

30
Q

erythromycin ethyl succinate: admin

A

flavored oral suspension or coated tabs

31
Q

clarithromycin: structure

A

C6 methyl ether of erythro - blocks ketal formation, better oral absorption, less GI upset

32
Q

clarithromycin: metabolism

A

bioactivation: 14-(R)-hydroxy metabolite has increased activity

33
Q

clarithromycin: admin

A
  • oral suspensions
  • tablets
  • extended release pills
34
Q

azithromycin (zithromax, z pak): structure

A

15 member lactone ring w/ N-CH3 b/w C9 and C10 - blocks ketal formation

35
Q

azithromycin (zithromax, z pak): half life, cause of this length?

A

68h -> once a day admin (due to extensive uptake and subsequent release of drug from tissues)

36
Q

azithromycin (zithromax, z pak): contraindications

A

coordinates with Mg or Al (antacids) -> prevents absorption

37
Q

azithromycin (zithromax, z pak): excretion

A

biliary excretion, predominately unchanged

38
Q

azithromycin (zithromax, z pak): activity

A

G(-)

39
Q

azithromycin (zithromax, z pak): side effects

A

GI:

  • diarrhea
  • nausea
  • abdominal pain
  • vomit

Pharm (19 decks)

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