1
Q
What is the cause of most complicated skin and skin-structure infections?
A
MRSA
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
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
4
Q
What is the IV tx for serious infections w/ known or presumed MRSA?
A
- Glycopeptides
- New 5th gen cephalosporins (ceftobiprole, ceftaroline)
5
Q
How does MRSA have resistance?
A
Very low affinity of al penicillin’s, carbapenems, and almost all cephalosporins for PBP 2a
6
Q
What do 5th gen cephalosporins have high affinity for?
A
PBP 2a
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
8
Q
How is ceftaroline fosamil administered?
A
- As pro-drug converted by plasma phosphatases to active drug
- Administered IV only
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
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
11
Q
What is vancomycin?
A
Glycopeptide
12
Q
What does loss of the sugar portion of vancomycin cause?
A
Loss of about 1/4 of antibiotic potency
13
Q
What is the importance of aromatic chlorine substitutions of vancomycin?
A
- Prevent aromatic ring rotation
- Potency decreases if not present
14
Q
What is the significance of the hepta-peptide of vancomycin?
A
Required for activity
15
Q
How is vancomycin synthesized?
A
Heptapeptide portion is not made via ribosomal synthesis, so unusual amino acids like beta-hydroxytyrosine are incorporated
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
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
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)
19
Q
Does vancomycin have oral bioavailability?
A
No, given as IV infusion usually over 1 hour
20
Q
What is the spectrum of vancomycin?
A
- Gram pos and some gram pos anaerobes (esp clostridium species)
- No gram neg
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
22
Q
How is vancomycin given if it is used to treat clostridium difficile associated diarrhea?
A
Orally to act locally in gut
23
Q
What are side effects of vancomycin?
A
- Nephrotoxicity (rare at normal doses)
- Ototoxicity
- Upper body rash mediated by histamine release
24
Q
What is teicoplanin?
A
Group of at least 5 related chemicals that differ at the alkyl chain
25
What occurs at the alkyl chain of teicoplanin?
Does not dimerize, but alkyl chain inserts into the bacterial membrane which concentrates the antibiotic at the site of action
26
Why does teicoplanin distribute into fatty tissue better than vancomycin?
Higher lipid solubility
27
Describe the mechanism of teicoplanin
- 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
28
The mechanism of vancomycin resistance also confers ____ resistance
Teicoplanin
29
Does teicoplanin have oral bioavailability?
No, given as IV infusion or can be given by IM
30
What is the spectrum of activity of teicoplanin?
(Same as vancomycin)
- Gram pos and clostridium species
- No gram neg
31
What are the uses of teicoplanin?
Same to vancomycin but no oral formulation for Clostridium difficile associated diarrhea
32
What is a side effect of teicoplanin?
Nephrotoxicity
33
Which organisms have shown glycopeptide resistance?
- Enterococci species (vancomycin-resistant enterococci)
| - Staph aureus strains
34
How does vancomycin resistance arise?
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
Does changing D-Ala to D-Luc have an effect on cell wall synthesis?
No, it is just a leaving group from transpeptidation
36
What are the tx for VRE and VRSA?
- Quinupristin/dalfopristin
- Daptomycin
- Linezolid
- Ceftaroline fosamil or ceftobiprole medocaril
* *All of these are also effective for MRSA and MSSA
37
How linezolid work?
Inhibits bacterial protein synthesis by preventing N-formyl-methionine-tRNA (fMet-tRNA) ribosomal complex from forming, so inhibits initiation of protein synthesis
38
Does linezolid have oral bioavailability?
Yes
39
What is the spectrum of activity of linezolid?
- 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
What limits the use of linezolid?
Many serious side effects, so only used in emergency situations
41
What are the side effects of linezolid?
- 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
What is the spectrum of activity of daptomycin?
- Almost all clinically important gram pos infections (strep pyogenes, staph epidermidis, staph aureus, MSSR, MRSA, VRSA)
- VRE
- No anaerobes and no gram neg
43
How is daptomycin administered?
IV
44
What is daptomycin classified as?
Cyclic lipophilic peptide
45
Which antibiotics are protein synthesis inhibitors?
- Macrolides
- Aminoglycosides
- Tetracyclines
- Linezolid
46
What are aminoglycosides composed of?
- 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
How are aminoglycosides administered?
IV or IM (no oral absorption)
48
What are aminoglycosides often combined w/ and why?
Penicillins b/c of synergistic activity against gram pos (not combined in the same IV bag)
49
What is the spectrum of activity of aminoglycosides?
- 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
What is the mechanism of aminoglycosides?
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
What are the interactions of aminoglycosides?
1) Ion pair btwn 16S phosphate backbone and amines or guanidines
2) Ion dipole
3) H-bond
52
How are aminoglycosides taken up into bacteria?
Positively charged, so displace Ca2+ and Mg2+ ions that hold OM LPS together, which facilitates their diffusion across the OM
53
How do anaerobic bacteria have resistance to aminoglycosides?
Aminoglycosides require an active transport mechanism to cross the inner plasma membrane, which anaerobic bacteria do not have = resistance
54
What is gentamycin often used w/?
Penicillins or other beta-lactams b/c of its synergistic killing of gram pos enterococcus species
55
What are side effects of gentamycin?
- Nephrotoxicity (major)
- Ototoxicity
- Neuromuscular blockade (only w/ pre-existing condition such as myasthenia gravis or co-administration w/ neuromuscular blockers)
56
How is tobramycin administered?
IV solutions, eye drops, or ointment
57
What is different btwn gentamycin and tobramycin?
Same spectrum and side effects by tobramycin is more potent as an anti-pseudomonal
58
How is amikacin administered?
IV or IM solutions only
59
What is the spectrum of activity of amikacin?
Similar to gentamycin but slightly more gram neg
60
What is the spectrum of activity of gentamycin?
- Gram pos enterococcus species
- MSSA, but not MRSA
- Many gram neg including pseudomonas aeruginoase
- No anaerobes
61
Which aminoglycoside is less susceptible to resistance mechanisms?
Amikacin
62
How do bacteria develop resistance to aminoglycosides?
Produce enzymes that chemically modify the drug (ex: aminoglycoside phosphorylating enzyme, aminoglycoside adenylating enzymes, and aminoglycoside acetylating enzymes)
63
What do aminoglycoside phosphorylating enzymes do?
- Add phosphate to OH group on aminoglycoside, which disrupts interaction w/ ribosome
- Requires ATP
64
What do aminoglycoside adenylating enzymes do?
- Add adenyl to OH group on aminoglycoside, which sterically hingers the modified aminoglycoside from binding to 30S ribosome
- Requires ATP
65
What do aminoglycoside acetylating enzymes do?
- Add acetyl to NH2 or NH groups on aminoglycoside, which neutralizes positive charge and reduces potency
- Requires acetyl-CoA
66
What are some chemical incompatibilites of aminoglycosides?
Have chemical instabilities when given through the same IV line, Y site, or if mixed w/ other medications
67
What happens when heparin and aminoglycosides are mixed? How is this avoided?
Heparin decreases aminoglycoside blood levels, so flush lines are used to administer heparin
68
What happens when aminoglycosides are mixed w/ some beta-lactams (esp. pen G and cloxacillin)?
Interact w/ each other to make both antibiotic inactive
Medicinal Chemistry
flashcards
Decks in class (14)
# Cards
-
Lecture 1 - Intro115
-
Lecture 2 - Drug Solubility68
-
Lecture 3 - Drug Absorption/Isomers68
-
Lecture 4 - Drug Metabolism88
-
Lecture 5 - Drug Receptor Interactions57
-
Lecture 6 - Drug Targets63
-
Lecture 7 - Nicotinic and Muscarinic Receptors67
-
Lectures 8, 9, 10, and 11138
-
Lectures 12, 13, 14, and 15170
-
Lectures 16, 17, 18, and 19141
-
Lecture 20, 21, and 22127
-
Lecture 2368
-
Lecture 2446
-
Lecture 2517
