Dr. Zhanel's Lectures Flashcards
1
Q
What does the ideal antimicrobial do?
A
Eradicates the infectious organism without damaging the host
2
Q
Are antibiotic and antimicrobial synonymous?
A
Yes
3
Q
What are antibiotics?
A
Drugs naturally produced by bacteria and fungi
4
Q
Which species produce the majority of available antibiotics?
A
- Streptomyces species
- Bacillus species
- Molds
5
Q
What is selective toxicity?
A
The ability of an antimicrobial to selectively act on the pathogen and not on the human cell
6
Q
What is selective toxicity often expressed as?
A
Therapeutic index, ratio, or window
7
Q
What does a large therapeutic window indicate?
A
Safe
8
Q
What does a small therapeutic window indicate?
A
Toxic
9
Q
When would you use a drug with a small therapeutic window?
A
When nothing else works
10
Q
What does broad spectrum mean?
A
Antimicrobials that work against different kinds of pathogens
11
Q
When are broad spectrum antimicrobials used?
A
When you don’t know what is causing an infection
12
Q
When are narrow spectrum antimicrobials used?
A
When you know what is causing the infection
13
Q
Why aren’t broad spectrum antimicrobials used all the time?
A
Because they kill pathogens as well as normal flora
14
Q
What does bactericidal mean?
A
The ability of an antibiotic to kill (more than 3 logs in 24 hours) an organism
15
Q
When are bactericidal antibiotics used?
A
- Immunocompromised individuals
- Infections in the brain
- Infections of the heart valves/tissues
16
Q
In immunocompotent patients, are bactericidal or bacteriostatic antibiotics better and why?
A
They are the same because the immune system works with the antibiotic
17
Q
What does bacteriostatic mean?
A
Reversibly inhibiting growth (less than 3 logs in 24 hours)
18
Q
Are the majority of antibiotics bacteriostatic or bactericidal?
A
Bacteriostatic
19
Q
What is MIC?
A
- Minimum inhibitory concentration
- The lowest concentration of an antibiotic that prevents growth of the pathogen
20
Q
Do you want a low or high MIC?
A
As low as possible
21
Q
What is MBC?
A
- Minimum bactericidal concentration
- Lowest concentration that kills an organism
22
Q
Do you want the MBC/MIC ratio to be small or large?
A
Small
23
Q
What is the typical MBC/MIC ratio of a bactericidal agent?
A
2-4
24
Q
What is the typical MBC/MIC ratio of a bacteriostatic agent?
A
Very high, if it kills at all
25
How is antibiotic susceptibility determined?
Dilution or diffusion tests
26
What is a dilution test?
- A series of test tubes with broth or plates with agar with different antibiotic concentrations are set up
- The lowest concentration of antibiotic that inhibits growth after 16-24 hours is the MIC
27
What are disk tests?
- Antibiotic-impregnated disks are placed on freshly streaked plates containing the organism
- A zone of inhibition occurs are the disk, and the zone width is the MIC
28
What does a big zone of inhibition mean?
The antibiotic is good for that pathogen
29
What does a small zone of inhibition mean?
The pathogen is resistant to that antibiotic
30
What are the 4 common methods of action of antibiotics?
- Damage bacterial cell wall (peptidoglycan) synthesis
- Inhibit microbial protein and nucleic acid synthesis
- Disrupt microbial membrane structure and function
- Block metabolic pathways through inhibition of enzymes
31
When would 2 antibiotics be used together?
If you don't know what the pathogen is and a secondary infection is possible
32
What are the 3 possible outcomes of antimicrobial combination and which is the most important in practice?
- Indifference (most important)
- Synergy
- Antagonism
33
What is indifference?
Slightly more killing than one antibiotic alone
34
What is synergy?
Way more killing together than each separately
35
What is antagonism?
Less killing together than each separately
36
Which outcome is the most common in antimicrobial combination?
Indifference or additivity
37
Where are NAM and NAG synthesized?
In the cytoplasm
38
How is the pentapeptide chain formed?
Amino acids are sequentially added to UDP-NAM
39
____ is added to UDP-NAM as a dipeptide
2 terminal D-alanines
40
Where is the NAM-pentapeptide transported?
From UDP to a bactoprenol phosphate carrier at the cell membrane surface
41
What is the function of UDP-NAG?
Add NAG to the NAM-pentapeptide to form the peptidoglycan repeat unit
42
What is special about the peptidoglycan repeat unit in gram positives?
A pentaglycine interbridge is required, so glycines are added by glycyl-tRNA molecules
43
Where is the NAM-NAG peptidoglycan repeat unit transported?
Across the cell membrane to the outer surface by the bactoprenol pyrophosphate carrier
44
What are the last few steps of peptidoglycan synthesis, after all transportation has occurred?
- New peptidoglycan unit is attached to the existing peptidoglycan chain
- Bactoprenol carrier returns to inside of cell
- Phosphate is released to bactoprenol phosphate so it can accept a new NAM-pentapeptide
45
What does transpeptidation create?
Peptide cross-links between the peptidoglycan chains
46
What enzyme performs transpeptidation?
Transpeptidase
47
What is transpeptidase called in gram negatives and positives?
Penicillin binding protein (PBP)
48
What are the categories of cell wall active antibiotics?
- Penicillins
- Cephalosporins
- Glycopeptides/lipopeptdes
- Bacitracin
49
What are penicillins and cephalosporins referred to as?
Beta-lactams
50
Are penicillins broad or narrow spectrum?
Both
51
Do penicillins have a small or large therapeutic window?
Large
52
Do cephalosporins have a small or large therapeutic index?
Large
53
Are cephalosporins broad or narrow spectrum?
Broad
54
Are glycopeptides broad or narrow spectrum?
Narrow
55
Do glycopeptides have a small or large therapeutic index?
Small
56
Which type of cell wall active antibiotics inhibit cell wall synthesis?
- Beta lactams and beta-lactam like agents
- Glycopeptides
- Bacitracin
57
What does inhibition of cell wall synthesis cause?
Osmotic instability, which causes cell death
58
Are beta-lactams bactericidal or bacteriostatic?
Bactericidal
59
Are glycopeptides bactericidal or bacteriostatic?
Bactericidal
60
Is bacitracin bactericidal or bacteriostatic?
Bactericidal
61
What are the terminal AA residues on the precursor NAM/NAG peptide subunits?
D-alanyl-D-alanine
62
What facilitates the binding of beta-lactams to the active serine site of PBPs?
D-alanyl-D-alanine
63
What prevents the final crosslinking of a new peptidoglycan layer?
The binding of the beta-lactam nucleus to the serine residue of the PBP active site
64
What is the consequence of beta-lactams binding to PBPs?
Inhibition of peptidoglycan synthesis, which causes autolysin activation, which breaks down existing peptidoglycan, causing cell death
65
Where do glycopeptides bind to an peptidoglycan?
The terminal D-ala-D-ala residues
66
How does bacitracin work as an antibiotic?
Blocks the dephosphorylation of bactoprenol pyrophosphate
67
What is important to note about bacitracin?
- Very toxic, so only used topically
| - Good at killing staph and strep, which are most common in skin infections
68
What are mechanisms of resistance that pathogens use?
- Beta-lactamases
- Alteration of PBPs
- Reduction in antibiotic uptake
- Antibiotic efflux
69
What do beta-lactamases do?
Break the beta-lactam ring
70
How can beta-lactamases be inhibited?
By binding irreversibly to beta-lactamase inhibitors
71
Do beta-lactamases cause a large or small increase in MIC?
Large
72
Does alteration of PBPs cause a large or small increase in MIC?
Small
73
What type of ribosomes do prokaryotic cells have?
70S ribosomes, with 50S and 30S units
74
What type of ribosomes do eukaryotes have?
80S ribosomes, with 60S and 40S units
75
What does the ribosomal structural difference between prokaryotic and eukaryotic cells account for?
The selective toxicity of antibiotics that affect protein synthesis
76
What type of ribosomes are mitochondrial ribosomes?
70S
77
How do antibiotics that inhibit protein synthesis generally work?
Interacting with the prokaryotic ribosome at the 30S site or the 50S site
78
Which types of antibiotics interact with the 30S site of a prokaryotic ribosome?
- Aminoglycosides
| - Tetracyclines
79
Which types of antibiotics interact with the 50S site of a prokaryotic ribosome?
- Chloramphenicol
- Clindamycin
- Macrolides
- Ketolides
- Oxazolidinones
80
Are antibiotics that inhibit protein synthesis bacteriostatic or bactericidal?
Bacteriostatic, except aminoglycosides are bactericidal
81
What is the most important aminoglycoside?
Gentamicin
82
Are aminoglycosides bactericidal or bacteriostatic and why?
Bactericidal because they bind to mRNA
83
Are aminoglycosides broad or narrow spectrum?
Broad
84
Do aminoglycosides have a large or small therapeutic index?
Small
85
When are aminoglycosides used?
When other things aren't working
86
What are the 2 most important macrolides?
- Erythromycin
| - Clindamycin
87
Are macrolides bacteriostatic or bactericidal?
Bacteriostatic
88
Are macrolides broad or narrow spectrum?
Broad
89
Do macrolides have a large or small therapeutic index?
Large
90
What are macrolides used to treat?
RTI's
91
What is the most important tetracycline?
Tetracycline
92
Are tetracyclines bacteriostatic or bactericidal?
Bacteriostatic
93
Are tetracyclines broad or narrow spectrum?
Very broad
94
Do tetracyclines have a large or small therapeutic index?
Medium
95
What is important to note about tetracyclines?
Can't be used in women that can potentially become pregnant
96
Do oxazolidinones have a large or small therapeutic index?
Medium
97
Are oxazolidinones broad or narrow spectrum?
Very narrow, only staph and strep
98
What is the general mechanism of resistance in gram-negative bacteria?
Reduce antibiotic uptake
99
What is the mechanism of resistance against aminoglycosides?
- Plasmid and chromosomally encoded inactivating enzymes modify the antibiotic so that it can't bind to ribosomal sites
- Alteration in bacterial ribosomes
100
What is the mechanism of resistance against macrolides?
Plasmid mediated mono or di-methylation of adenine of the 23S rRNA, causing reduced affinity between the antibiotic and ribosome
101
What is the mechanism of resistance against tetracyclines?
Tetracycline efflux across the cytoplasmic membrane
102
How can resistance to tetracyclines be overcome?
Using tigecycline
103
What is the mechanism of resistance against chloramphenicol?
Plasmid or chromosomally encoded enzyme (chloramphenicol acetyltransferase) modifies the antibiotic
104
What is the mechanism of mechanism against oxazolidinones?
Mutations of 23S rRNA
105
What do fluoroquinolones contain?
A 4-quinolone ring
106
Are fluoroquinolones bacteriostatic or bactericidal?
Bactericidal
107
What is the mechanism of action of fluoroquinolones?
Inhibition of bacterial DNA gyrase
108
What is DNA gyrase?
An enzyme that introduces negative twists in DNA and helps separates its strands
109
What is a generalization about fluoroquinolones?
They disrupt all cell processes that involve DNA
110
What are the 3 mechanisms of resistance against fluoroquinolones and which is the most important?
- Reduced uptake through altered outer-membrane proteins or LPS
- Spontaneous single step mutations involving DNA gyrase leading to reduced antibiotic binding (*most important)
- Antibiotic efflux across the cell membrane
111
Which mechanism of resistance against fluoroquinolones occurs in gram-negatives?
Reduced uptake through altered outer-membrane proteins or LPS
112
What do sulfonamides do?
Interfere with different steps of the metabolic pathways that synthesize folic acid
113
What are sulfonamides structurally similar to and why is this important?
- Para-aminobenzoic acid (PABA)
| - PABA is required by bacteria for folic acid synthesis
114
What is the outcome of sulfonamide action of inhibiting folic acid synthesis?
Decrease in bacterial purines, which subsequently inhibits bacterial growth
115
What are the 3 mechanisms of resistance against sulfonamides?
- Reduced accumulation (preventing uptake of the drug or effluxing the drug out of the cell)
- Drug inactivation through chemical modification
- Target site modification
