Exam 1 Lecture 7 and 8 Flashcards
Principles of Antimicrobials
1
Q
What is the effect of timing antibiotics on survival?
A
In sepsis patients, early antimicrobial initiation correlated with higher survival fraction. Every hour counts!
2
Q
Potential antibiotic targets
A
- Cell wall
- Cell membrane
- DNA replication
- Transcription
- Protein Synthesis
3
Q
Which bacterial target is least toxic to humans?
A
Cell wall
4
Q
Selective toxicity
A
Increasing toxicity to bacteria while having the least effect on our cells
5
Q
Selective toxicity contributes to:
A
Side effects and therapeutic index
6
Q
What is therapeutic index?
A
Toxic dose/therapeutic dose
7
Q
Therapeutic index for penicillins:
A
High (low toxicity and can be administered in high amounts)
8
Q
Therapeutic index for aminoglycosides:
A
Low (lower dose can be toxic, so blood level of aminoglycosides must be monitored actively)
9
Q
Therapeutic drug monitoring must be done for:
A
(example) Aminoglycosides and Vancomycin
10
Q
Sources of antimicrobials
A
Naturally occurring, semi-synthetic, synthetic
11
Q
Absorption
A
Oral vs IV
12
Q
Oral (absorption)
A
Not all becomes bioavailable, not absorbed as well as a result
13
Q
IV (absorption)
A
Becomes available to all sites at a high rate, including blood and soft tissues
14
Q
Pharmacology impacts on drug choice (5 things)
A
- Absorption
- tissue distribution
- metabolism/excretion
- time-dependent killing (half life)
- concentration-dependent killing
15
Q
What does a bactericidal drug do?
A
Inhibits growth and kill bacterial cells
16
Q
Examples of bactericidal drug
A
Beta lactams, aminoglycosides
17
Q
When would you want to administer a bactericidal drug?
A
- immunocompromised patient (who would have decreased response to bacteriostatic)
- Very severe infection
Overall, if there’s a choice, often go for bactericidal
18
Q
What does a bacteriostatic drug do?
A
Inhibits bacterial growth but does not kill; relies on host immune system to help clear out the bacteria
19
Q
Examples of bacteriostatic drug
A
Macrolides, tetracyclines
20
Q
What is MIC?
A
Minimum inhibitory concentration; clinically, all susceptibility testing goes back to MIC
21
Q
What is combination therapy?
A
Administering 2 (or possibly more) drugs at the same time
22
Q
Why is combination therapy helpful sometimes?
A
Helps to reduce chance of developing resistance over time
23
Q
When do you want to give combination therapy?
A
- Empiric therapy
- Polymicrobial Infection
- Prevent resistance
- Enhanced efficacy (synergy, additive)
24
Q
What is empiric therapy?
A
Used when the exact causative agent is not known or are hard to predict, yet antimicrobials are administered to cover those potential bacteria; “educated guess”
25
How do providers make antimicrobial decisions before we give them a final report?
Physician sees patient; makes clinical diagnosis; and prescribes empiric antimicrobials
26
1st generation cephalosporins are great for...
MSSA
27
Example of 1st generation cephalosporin
Cefazolin
28
Vancomycin is great for...
Emperic coverage (both MSSA and MRSA are susceptible)
29
In vitro susceptibility testing examples
1. Broth Dilution
2. Diffusion tests (Kirby-Bauer, ETEST)
3. Beta lactamase test
4. Molecular test
30
Broth or ETEST provides ____
MIC
31
Kirby Bauer provides ___
mm inhibition
32
MIC and KB must be ______
correlated with clinical breakpoints
33
What are the three clinical breakpoints?
Resistant, Intermediate, Susceptible
34
Names of cell wall antibiotics
1. Beta lactams (penicillins and cephalosporins)
| 2. Glycopeptides (vancomycin)
35
Name of cell membrane antibiotics
Polymixins
36
Name of DNA antibiotics
1. [Fluoro]quinolones (e.g. ciprofloxacin)
| 2. Sulfonamides and trimethoprim (e.g. Bactrim)
37
Name of transcription antibiotics
Rifampin
38
Name of protein synthesis antibiotics (4 classes)
1. Aminoglycosides (e.g. gentamycin)
2. Macrolides (e.g. azithromycin, "Z-pack")
3. Tetracyclines
4. Lincosamides (e.g. clindamycin)
39
Lincosamide drug name example
Clindamycin
40
Aminoglycosides drug name example
Gentamycin
41
Macrolides drug name example
Azithromycin
42
General mechanisms of resistance
1. Efflux
2. Target site alterations
3. Inactivating enzymes
4. Restricted access to target
43
What is meant by restricted access to target?
Inherent structures in the bacteria that makes it harder for drug penetration (e.g. physical barrier, porins)
44
What is the biggest concern for infection control?
Mobile genetic elements that contribute to transformation of bacterial populations, allowing them to acquire resistance genes and for resistance mechanism to spread
45
How are resistance determinants encoded/expressed?
1. Intrinsic (chromosomal)
2. De novo mutations
3. Acquired (plasmids, transposons, integrons, natural transformation, bacteriophage)
46
Why are infections of mechanical heart valves and prosthetic joints "surgical solutions"?
1. biofilms provide physical barriers to antimicrobials
| 2. organisms are often not rapidly growing, reducing the efficacy of many antimicrobials
47
What does a mucoid isolate imply?
slows diffusion and ability of drugs to get into the cell
48
2 examples of restricting access to target
1. biofilms
| 2. impermeability (porins, LPS)
49
Direct interactions with antibiotics
1. Inactivation by hydrolysis (ex. beta lactamase)
| 2. Inactivation by steric hindrance (ex. aminoglycoside-modifying enzymes)
50
Mutation of target site example
Mutations in topoisomerase confer fluoroquinolone resistance
51
Target site protection example
Methylation of 16S rRNA alters binding of erythromycin to ribosome
52
Upregulation of efflux pumps can lead to:
Multidrug resistance
53
True or false: efflux pumps can be broad or narrow spectrum
true
54
How do we end up with multi-drug resistant strains?
1. encode multiple genes (ex. on a plasmid)
2. encode a gene that can target multiple antibiotics
3. selective pressure
55
Beta lactams are ____ cell ____ agents
cidal; wall
56
4 categories of beta lactams:
1. penicillin
2. cephalosporins
3. monobactams
4. carbapenems
57
Beta lactams bind ____ which _____ cell growth
PBPs (penicillin binding proteins); inhibits
58
Why are beta lactams cidal?
weakens integrity of cell wall, leading to osmotic instability and lyses the cell
59
Lower generations of cephalosporins generalizations:
narrow spectrum (primarily gram positives); not as good for resistant strains
60
Which cephalosporin covers MRSA?
Ceftaroline (5th generation)
61
Ceftriaxone is a ____ cephalosporin
3rd generation
62
What are 3 general mechanisms of resistance to Beta lactams?
1. decreased penetration to the target site
2. Inactivation of antibiotic by bacterial enzyme
3. alteration of target site
63
Where are beta lactamases localized in Gram - cells?
periplasmic space (higher level resistance)
64
Where are beta lactamases localized in Gram + cells?
secreted (often lower level resistance)
65
AmpC beta lactamases are ______ encoded and _____ for several Enterobactericeae
chromosomally; inducible
66
When does AmpC become a problem?
When it is overexpressed
67
AmpC
encodes for beta-lactamase enzyme
68
AmpR
repressor
69
AmpD
regulator that detects small cell wall fragments
70
True or false: you must treat a SPICEM organism with a 1st, 2nd, or 3rd generation cephalosporin
False --> this can lead to quick resistance
71
Carbapenem mechanism of resistance (3 things)
1. decreased penetration to the target site (efflux)
2. inactivation of the antibiotic by a bacterial enzyme (carbapenemase in KPC)
3. Enzymatic degradation plus decreased uptake (beta lactamase AmpC plus porin mutation)
72
Alterations of ____ may influence their binding affinity for beta lactam antibiotics. This mechanism is responsible for ___ ____ ____.
PBP's; methicillin resistance in staphylococci (MRSA)
73
How is PBP2a acquired?
Through mobile element called SCCmec, mecA gene encodes for PBP2a
74
What are some lab methods to detect methicillin resistance?
1. susceptibility to methicillin, cefoxitin, or oxacillin (disc diffusion, MICs)
2. detection of mecA gene through PCR
3. detection of PBP2a through lateral flow/latex agglutination
75
Vancomycin blocks peptidoglycan crosslinks of _____ only.
gram positive bacteria
76
What forms hydrogen bonds with D-ala-D-ala?
vancomycin
77
Vancomycin is used for ____ treatment against ____.
empiric; MRSA
78
True or false: vancomycin can treat C. diff and can be administered orally
True
79
True or false: vancomycin can be nephrotoxic
True; MIC and therapeutic drug monitoring are used together to facilitate dosing and prevent toxicity
80
True or false: In MSSA, vancomycin works better than a beta lactam
False: vancomycin be suboptimal
81
Vancomycin acquired resistance:
Altered peptidoglycan precursors, tolerance
82
Vancomycin resistance mechanism in Enterococci?
Altered terminal peptide is D-lactate, therefore vancomycin cannot H bond
83
What is the most common mechanism for E. faecalis and E. faecium resistance?
Van A and Van B; transferable due to being encoded on mobile genetic elements
84
Best therapy for E. faecalis
Ampicillin
85
True or false: E. faecalis is usually resistant to vancomycin
False; rarely resistant
86
True or false: E. faecium is frequently resistant to ampicillin and vancomycin
True
87
Which antibiotic targets cell membrane?
Polymyxins
88
Polymyxins are ____ polypeptides with ___ ___ effect
large; cationic detergent
89
True or false: Polymyxins are relatively toxic
true; primarily for multi-drug resistant Gram -
90
DNA replication antibiotics
Fluoroquinolones, sulfas/trimethoprim, metronidazole
91
Fluoroquinolones that are targeted towards Gram -:
1. Ciprofloxacin
| 2. Levofloxacin
92
Fluoroquinolones that are targeted towards Gram +:
Moxifloxacin
93
How do fluoroquinolones work?
Inhibit DNA gyrase +/- topoisomerase IV
| therefore inhibits chromosomal replication -> cidal
94
Fluoroquinolones stand out for:
high bioavailability (oral almost as good as IV)
95
How do sulfas/trimethoprim work?
Inhibits folate synthesis, thereby inhibiting purine metabolism
96
Do mammals synthesize folic acid?
No
97
Sulfas/trimethoprim spectrum
Broad spectrum against many G+ and G-, also some parasites
98
Sulfonamides target:
dihydropteroate synthetase
99
Trimethoprim targets:
Dihydrofolate reductase
100
Metronidazole requires reduction of ___ ___ under ____ conditions
nitro group; anaerobic
101
Metronidazole only effective against ___ and ___
Anaerobes; protozoa
102
True or false: metronidazole causes breaks in the RNA
false --> DNA
103
Transcription antibiotic name
Rifampin
104
Rifampin inhibits ____ ____, and therefore inhibits _____
RNA polymerase; transcription
105
In ribosomes, resistance can be conferred by __ __ in ___
point mutations; rpoB
106
T or F: With rare exceptions, rifampin must be used in combination therapy
Tru; rapid selection for resistance
107
Antibiotics against protein synthesis names
1. Aminoglycosides
2. Tetracyclines
3. Macrolides
4. Clindamycin
108
How do aminoglycosides work?
1. Binds irreversibly to bacterial 30S and 50S
2. prevents formation of initiation complexes
3. Cidal
109
What are aminoglycosides effective against?
Gram negatives
110
Aminoglycosides are ___ with beta lactams
synergistic
111
Tetracyclines spectrum
Broad
112
Tetracycline mechanism
bind irreversibly to 30S ribosomal subunits, preventing attachment of aminoacyl-tRNAs to ribosomal acceptor
113
True or false: tetracyclines are bactericidal
false; bacteriostatic
114
Macrolides drug names examples
erythromycin, azithromycin, clarithryomycin
115
Macrolides mechanism
bind reversibly to 23S, blocks translocation of tRNA acceptor to donor site
116
Macrolides spectrum
Broad -
1. gram +, some gram -
2. anaerobes
3. Atypical mycobacteria
4. atypical respiratory pathogens
117
Clindamycin mechanism
1. binds 50S ribosomal subunit, prevents elongation of peptide chains
2. Bacteriostatic or bactericidal
118
Clindamycin has poor penetration into the ___
CSF
119
Clindamycin is frequently used for ____ ____ and ____
gram + cocci; anaerobes
120
_____ can be used to suppress toxin formation and can cause inducible resistance
Clindamycin
121
Erythromycin & Clindamycin mechanisms of action (3 things)
1. inhibit protein synthesis at 50S ribosome
2. prevent transpeptidation and chain elongation
3. have a common binding site at 23S rRNA component of the 50S ribosome
122
Erythromycin mechanisms of resistance
Efflux, Methylation of ribosome
123
Clindamycin mechanisms of resistance
Methylation of ribosome
124
What coverage difference is there between ciprofloxacin/levofloxacin and moxifloxacin?
Moxifloxacin is mainly for G+
| Cipro/levofloxacin is mainly for G-
125
Name two drugs where both MIC and therapeutic drug monitoring are used
Vancomycin and Aminoglycosides
126
What are 4 general categories of resistance?
1. Efflux
2. Target site alteration
3. Drug alteration/degradation
4. Physical barrier
127
How would you treat a patient with an Enterococci infection prior to having susceptibility results back?
E. faecium = vancomycin
| E. faecalis = ampicillin
128
What 2 drugs have the same target and are concerning for cross resistance?
Erythromycin and Clindamycin
129
Why do you not want to treat Enterobacter with ceftriaxone?
It's a 3rd gen cephalosporin (need 4th or 5th gen) - resistance can quickly develop, especially AmpC resistance
130
What are the 2 most common mechanisms for resistance to beta-lactams?
1. Beta lactamase
| 2. PBP2A (altered target site)
131
Name 2 classical side effects that can occur with both vancomycin and aminoglycosides
1. Ototoxicity (ear)
| 2. Nephrotoxicity (kidney)
132
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Which of the following is the best drug for mycoplasma?
A. Penicillin
B. Ceftriaxone
C. Vancomycin
D. Azithromycin
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D - Azithromycin
133
Name 2 drugs commonly used for anaerobes
Clindamycin and metronidazole
