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Medicinal Chemistry > Lecture 23 > Flashcards

Lecture 23 Flashcards

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1
Q

What is the cause of most complicated skin and skin-structure infections?

A

MRSA

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2
Q

What are complicated skin and skin-structure infections?

A

Severe skin infections of deep soft tissue (fascia and/or muscle layers) that require surgical intervention or are in combination w/ underlying disease that makes tx difficult

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3
Q

What is the oral tx for skin infections where MRSA culture and sensitivity are known?

A
  • Trimethoprim/sulfamethoxazole
  • MInocycline or doxycycline
  • Fusidic acid
  • Rifampin
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4
Q

What is the IV tx for serious infections w/ known or presumed MRSA?

A
  • Glycopeptides

- New 5th gen cephalosporins (ceftobiprole, ceftaroline)

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5
Q

How does MRSA have resistance?

A

Very low affinity of al penicillin’s, carbapenems, and almost all cephalosporins for PBP 2a

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6
Q

What do 5th gen cephalosporins have high affinity for?

A

PBP 2a

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7
Q

What is ceftaroline fosamil used to treat?

A
  • Many gram pos infections resistant to most antibiotics, including MRSA, MSSA, and VRSA
  • Shown in vitro activity against some types of VRE and S aureus resistant to daptomycin and linezolid
  • Shown in vitro activity against multi-drug resistant Strep pneumoniae
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8
Q

How is ceftaroline fosamil administered?

A
  • As pro-drug converted by plasma phosphatases to active drug
  • Administered IV only
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9
Q

What is ceftobiprole medocaril used to treat?

A
  • Many gram pos infections resistant to most antibiotics, including MRSA, MSSA, and VRSA
  • Shown in vitro activity against S aureus resistant to daptomycin, tigecycline, and linezolid
  • Shown in vitro activity against multi-drug resistant Strep pneumoniae
  • Broad gram neg spectrum
  • Anti-pseudomonal activity
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10
Q

How is ceftobiprole medocaril administered?

A
  • As a pro-drug converted to active drug by esterase or happens non-enzymatically in aqueous environment like blood
  • Administered IV only
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11
Q

What is vancomycin?

A

Glycopeptide

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12
Q

What does loss of the sugar portion of vancomycin cause?

A

Loss of about 1/4 of antibiotic potency

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13
Q

What is the importance of aromatic chlorine substitutions of vancomycin?

A
  • Prevent aromatic ring rotation

- Potency decreases if not present

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14
Q

What is the significance of the hepta-peptide of vancomycin?

A

Required for activity

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15
Q

How is vancomycin synthesized?

A

Heptapeptide portion is not made via ribosomal synthesis, so unusual amino acids like beta-hydroxytyrosine are incorporated

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16
Q

Why don’t glycopeptide antibiotics have activity against gram neg bacteria?

A

Have a large size, so can’t penetrate through the outer membrane of gram neg cells and is not taken up by the gram neg porin

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17
Q

What does vancomycin interact w/?

A
  • Peptidoglycan building block formed from Parks nucleotide

- Extensive interaction takes place btwn second D-ala and vancomycin via a specific H-bond network

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18
Q

How and why does vancomycin dimerize?

A
  • In an antiparallel orientation w/ building blocks of peptidoglycan
  • Prevents transglycosidation and transpeptidation (can also bind to growing peptidoglycan after transglycosidation and before transpeptidation)
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19
Q

Does vancomycin have oral bioavailability?

A

No, given as IV infusion usually over 1 hour

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20
Q

What is the spectrum of vancomycin?

A
  • Gram pos and some gram pos anaerobes (esp clostridium species)
  • No gram neg
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21
Q

What is vancomycin used to treat?

A
  • Skin infections and complicated skin infections
  • Endocarditis caused by gram positive
  • Clostridium difficile (anaerobic) associated diarrhea
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22
Q

How is vancomycin given if it is used to treat clostridium difficile associated diarrhea?

A

Orally to act locally in gut

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23
Q

What are side effects of vancomycin?

A
  • Nephrotoxicity (rare at normal doses)
  • Ototoxicity
  • Upper body rash mediated by histamine release
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24
Q

What is teicoplanin?

A

Group of at least 5 related chemicals that differ at the alkyl chain

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25
Q

What occurs at the alkyl chain of teicoplanin?

A

Does not dimerize, but alkyl chain inserts into the bacterial membrane which concentrates the antibiotic at the site of action

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26
Q

Why does teicoplanin distribute into fatty tissue better than vancomycin?

A

Higher lipid solubility

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27
Q

Describe the mechanism of teicoplanin

A
  • Binds to parks nucleotide attached to phospholipid in membrane
  • Can bind to D-Ala-D-Ala portion as w/ vancomycin
  • Long alkyl chain anchors it to the membrane, concentrating it where it is needed, preventing transglycosidation and transpeptidation
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28
Q

The mechanism of vancomycin resistance also confers ____ resistance

A

Teicoplanin

29
Q

Does teicoplanin have oral bioavailability?

A

No, given as IV infusion or can be given by IM

30
Q

What is the spectrum of activity of teicoplanin?

A

(Same as vancomycin)

  • Gram pos and clostridium species
  • No gram neg
31
Q

What are the uses of teicoplanin?

A

Same to vancomycin but no oral formulation for Clostridium difficile associated diarrhea

32
Q

What is a side effect of teicoplanin?

A

Nephrotoxicity

33
Q

Which organisms have shown glycopeptide resistance?

A
  • Enterococci species (vancomycin-resistant enterococci)

- Staph aureus strains

34
Q

How does vancomycin resistance arise?

A

Strains change the peptidoglycan building block such that D-Ala-D-Ala is replaced w/ D-Ala-D-Luc, which vancomycin cannot bind to

35
Q

Does changing D-Ala to D-Luc have an effect on cell wall synthesis?

A

No, it is just a leaving group from transpeptidation

36
Q

What are the tx for VRE and VRSA?

A
  • Quinupristin/dalfopristin
  • Daptomycin
  • Linezolid
  • Ceftaroline fosamil or ceftobiprole medocaril
  • *All of these are also effective for MRSA and MSSA
37
Q

How linezolid work?

A

Inhibits bacterial protein synthesis by preventing N-formyl-methionine-tRNA (fMet-tRNA) ribosomal complex from forming, so inhibits initiation of protein synthesis

38
Q

Does linezolid have oral bioavailability?

A

Yes

39
Q

What is the spectrum of activity of linezolid?

A
  • All clinically relevant gram pos infection (strep pyogenes, staph epidermidis, staph aureus, MSSR, MRSA, and VRSA)
  • VRE
  • Limited spectrum against anaerobes
  • No activity against gram neg
40
Q

What limits the use of linezolid?

A

Many serious side effects, so only used in emergency situations

41
Q

What are the side effects of linezolid?

A
  • Myelosuppression (anemia, thrombocytopenia, neutropenia)
  • Peripheral or otic neuropathy
  • Inhibits MAO => dietary restrictions and contraindication w/ pseudoephedrine; may also lead to serotonin syndrome w/ SSRIs
42
Q

What is the spectrum of activity of daptomycin?

A
  • Almost all clinically important gram pos infections (strep pyogenes, staph epidermidis, staph aureus, MSSR, MRSA, VRSA)
  • VRE
  • No anaerobes and no gram neg
43
Q

How is daptomycin administered?

A

IV

44
Q

What is daptomycin classified as?

A

Cyclic lipophilic peptide

45
Q

Which antibiotics are protein synthesis inhibitors?

A
  • Macrolides
  • Aminoglycosides
  • Tetracyclines
  • Linezolid
46
Q

What are aminoglycosides composed of?

A
  • Amino sugars that are linked w/ glycosidic bonds
  • Amino substitutions on sugars can be guanidino groups, primary or secondary amines
  • Sugars are 5 or 6 membered rings
47
Q

How are aminoglycosides administered?

A

IV or IM (no oral absorption)

48
Q

What are aminoglycosides often combined w/ and why?

A

Penicillins b/c of synergistic activity against gram pos (not combined in the same IV bag)

49
Q

What is the spectrum of activity of aminoglycosides?

A
  • Gram pos enterococcus species
  • Stap epidermidis
  • MSSA
  • Not MRSA, VRE, or VRSA
  • Broad activity against gram neg including E. coli and pseudomonas aeruginosa
  • No activity against anaerobes
50
Q

What is the mechanism of aminoglycosides?

A

Bind to 16S rRNA w/in 30S subunit of the ribosome, causing mis-reading of codons and incorporation of inappropriate amino acids (at low doses) => increased permeability of the membrane and increased [ ] of aminoglycosides
- At high doses, inhibit translocation prematurely, terminating translation

51
Q

What are the interactions of aminoglycosides?

A

1) Ion pair btwn 16S phosphate backbone and amines or guanidines
2) Ion dipole
3) H-bond

52
Q

How are aminoglycosides taken up into bacteria?

A

Positively charged, so displace Ca2+ and Mg2+ ions that hold OM LPS together, which facilitates their diffusion across the OM

53
Q

How do anaerobic bacteria have resistance to aminoglycosides?

A

Aminoglycosides require an active transport mechanism to cross the inner plasma membrane, which anaerobic bacteria do not have = resistance

54
Q

What is gentamycin often used w/?

A

Penicillins or other beta-lactams b/c of its synergistic killing of gram pos enterococcus species

55
Q

What are side effects of gentamycin?

A
  • Nephrotoxicity (major)
  • Ototoxicity
  • Neuromuscular blockade (only w/ pre-existing condition such as myasthenia gravis or co-administration w/ neuromuscular blockers)
56
Q

How is tobramycin administered?

A

IV solutions, eye drops, or ointment

57
Q

What is different btwn gentamycin and tobramycin?

A

Same spectrum and side effects by tobramycin is more potent as an anti-pseudomonal

58
Q

How is amikacin administered?

A

IV or IM solutions only

59
Q

What is the spectrum of activity of amikacin?

A

Similar to gentamycin but slightly more gram neg

60
Q

What is the spectrum of activity of gentamycin?

A
  • Gram pos enterococcus species
  • MSSA, but not MRSA
  • Many gram neg including pseudomonas aeruginoase
  • No anaerobes
61
Q

Which aminoglycoside is less susceptible to resistance mechanisms?

A

Amikacin

62
Q

How do bacteria develop resistance to aminoglycosides?

A

Produce enzymes that chemically modify the drug (ex: aminoglycoside phosphorylating enzyme, aminoglycoside adenylating enzymes, and aminoglycoside acetylating enzymes)

63
Q

What do aminoglycoside phosphorylating enzymes do?

A
  • Add phosphate to OH group on aminoglycoside, which disrupts interaction w/ ribosome
  • Requires ATP
64
Q

What do aminoglycoside adenylating enzymes do?

A
  • Add adenyl to OH group on aminoglycoside, which sterically hingers the modified aminoglycoside from binding to 30S ribosome
  • Requires ATP
65
Q

What do aminoglycoside acetylating enzymes do?

A
  • Add acetyl to NH2 or NH groups on aminoglycoside, which neutralizes positive charge and reduces potency
  • Requires acetyl-CoA
66
Q

What are some chemical incompatibilites of aminoglycosides?

A

Have chemical instabilities when given through the same IV line, Y site, or if mixed w/ other medications

67
Q

What happens when heparin and aminoglycosides are mixed? How is this avoided?

A

Heparin decreases aminoglycoside blood levels, so flush lines are used to administer heparin

68
Q

What happens when aminoglycosides are mixed w/ some beta-lactams (esp. pen G and cloxacillin)?

A

Interact w/ each other to make both antibiotic inactive

Medicinal Chemistry (14 decks)

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