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MICRO > L2: Antimicrobial Agents > Flashcards

L2: Antimicrobial Agents Flashcards

1
Q

Antibiotics and antimicrobial agents are different from disinfectants how?

A

They are specific for certain bacteria or microbes

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2
Q

Many antibiotics come from what?

What does this help explain?

A

Natural compounds made by bacteria or fungi to gain an evolutionary advantage in natural environments.

High resistance to some antibiotics since bacteria have been exposed to these compounds for millions of years

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3
Q

3 characteristics of the ideal antibiotic

A
  1. Target a variety of pathogens but spare normal flora
  2. Prohibit rapid development of resistance
  3. Selective for bacteria and does not damage host
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4
Q

What is the ideal antibiotic?

A

No such thing

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5
Q

Antibiotics are generally targeted against what?

A

Systems in all bacteria

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6
Q

The broader the spectrum of an antibiotics, the more likely what will happen?

A

The antibiotic will be more likely to attack normal flora

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7
Q

Do all antibiotics have resistance somewhere?

A

Yes

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8
Q

Limiting resistance to a drug has more to do with what? 2

A
  1. Prescribing practices of physicians

2. compliance of patients

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9
Q

Are all antibiotics toxic to the host?

Why or why not?

A

Yes

Since mitochondria are evolutionarily related to bacteria, many broad spectrum drugs affect mitochondria function

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10
Q

What are 4 of the main adverse effects of antibiotics?

A
  1. Allergic reactions (penicillin)
  2. Toxic (aplastic anemia, ototoxicity)
  3. Suppression of normal flora: (colon)
  4. Antimicrobial resistance
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11
Q

Antibiotics are split into what two categories?

A
  1. Bacteriostatic

2. Bactericidal

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12
Q

What is difference between bacteriostatic and bactericidal?

A 
bacteriostatic = inhibit growth
bacteriocidal = kill
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13
Q

Bacteriostatic drugs rely on what to eliminate pathogen?

A

Host immunity

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14
Q

Bactericidal drugs are useful when?

A

situations when host defenses cannot be relied upon to control the pathogen

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15
Q

What are the five main targets of an antibiotic?

A
  1. Cell wall
  2. protein synthesis
  3. nucleic acid synthesis
  4. metabolic pathways
  5. Cytoplasmic membrane
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16
Q

Which is the least toxic target of an antibiotic?

Why?

A

Cell wall

Mitochondria do not make peptidoglycan so it doesn’t attack them.

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17
Q

What is one side effect of a cell wall antibiotic?

A

Allergic reaction to peptidoglycan fragments

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18
Q

In terms of protein synthesis what is targeted in antibiotics? What will also be targeted?

A

Bacterial ribosomes

Mitochondrial ribosomes are inhibited leading to side effects

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19
Q

How useful are the antibiotics against nucleic acids?

A

Not very because there aren’t many conserved bacterial enzymes.

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20
Q

How useful are antibiotics against metabolic pathways?

A

Average, there are some unique bacterial metabolic enzymes

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21
Q

How are antibiotics used against cytoplasmic membranes?

WHy?

A

In a topical manner

Bacterial membranes are similar to eukaryotic membranes.

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22
Q

3 parts of cell wall synthesis?

A
  1. Cell wall subunits are made in cell cytoplasm
  2. Bactoprenol transports the subunits from inside the cell to ouside the cell
  3. Penicillin binding proteins link the subunits together into the existing cell wall
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23
Q

What anti-biotic attacks cytoplasmic synthesis of cell wall subunits?

A

Fosfomycin

Cycloserine

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24
Q

What anti-biotic attacks BACTOPRENOL and the transport of subunits?

A

Bacitracin

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25
Q

What do Beta-lactams do?

A

Attack PBP

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26
Q

What antibiotic is used against crosslinking?

A

Vancomycin

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27
Q

Beta-lactams contain a 4 membered ring called the what?

What does it mimic?

A

lactam ring

the terminal D-ala-D-ala of peptidoglycan side chains.

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28
Q

Where can beta-lactams bind?

A

transpeptidases and carboxypeptidases and inhibit their function.

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29
Q

Transpeptidases and carboxypeptidases are collectively known as what?

A

penicillin binding proteins or PBPs

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30
Q

inhibition of PBP inhibits what?

A

cross-linking of peptidoglycan chains weakening the mesh

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31
Q

What bacteria are not affected by Beta-lactams

A

Cell wall-free forms (e.g. Mycoplasmas and L-forms

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32
Q

Besides having a cell wall, what is the requirement for penicillin to inhibit a cell

A

Cells must be actively synthesizing cell walls

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33
Q

Natural penicillins have what spectrum?
What are they effective against? (2)
What are they sensitive to?

A

Narrow

Gram +
Gram - cocci

Acid

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34
Q

Penicillinase-resistant penicillin has side chains that prevent what?

A

inactivation from penicillinase enzymes

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35
Q

broad spectrum penicillins have what that give them their broad spectrum?
What are they effective against?

A

Modified side chains

Gram + and Gram -

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36
Q

Extended spectrum penicillins have greater effectiveness against what species of bacteria?
What else is it okay against?

A

Pseudomonas

Gram + organisms

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37
Q

Penicillin and Beta lactamase inhibitor are combination of what?

A

Penicillin drug and enzyme inhibitor

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38
Q

Augmentin is blend of what?

A

Amoxicillin + clavulanic acid

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39
Q

Tazoscin, Zosyn, Piprataz are what blended together?

A

Piperaccilin and tazobactam

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40
Q

In general, later generations of cephalosporins have greater effectiveness against what?

A

gram negative bacteria

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41
Q

Where has the basic structure of penicillin been modified? (2)

A
  1. Second ring structure

2. Altering R groups

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42
Q

What are the four goals of modifying Beta-lactams?

A
  1. Increase spectrum
  2. Increase stability in acid
  3. Bypass resistance mechanism
  4. Bypass allergic reactions
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43
Q

Why is it important to increase beta lactam acid stability?

A

Lactam ring is normally broken down by stomach acid so most penicillins must be administered parenterally

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44
Q

What percentage of the population is allergic to penicillin?

A

20%

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45
Q

What makes amoxicillin special?

A

Resistant to stomach acid

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46
Q

What makes clavulanic acid special?

A

Beta-lactamase inhibitor

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47
Q

amoxicillin + clavulanic acid = what?

A

Augmentin

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48
Q

What is the largest problem now in antibiotic resistance?

A

Extended spectrum Beta-lactamases

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49
Q

What are the three main ways beta-lactam is resisted?

A

Enzyme degradation
Reduced affinity PBP’s
Reduced membrane pemeability

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50
Q

Mutations to PBP genes result in what?

How does this happen?

A

Lower affinity of PBP’s for penicillin

  1. within the normal complement of PBPs in the cell
  2. the cell may acquire a low affinity PBP as an extra enzyme that can function when the antibiotic is present.
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51
Q

How does strep get reduced affinity PBP’s?

A

Mutation

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52
Q

How does MRSA get reduced affinity PBP’s?

A

Acquisition

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53
Q

How does reduced membrane permeability affect resistance to penicillin?

A

Loss of porins in the outer membrane of Gram-negative bacteria reduces the ability of penicillin to penetrate the cell

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54
Q

Penicillin is degraded by what enzyme?

A

Beta-lactamase

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55
Q

What inhibits beta-lactamase?

A

Clavulanic acid

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56
Q

Glycopeptides such as vancomycin inhibit what?

A

peptidoglycan cross-linking by binding to the terminal D-ala-D-ala of the peptide chain

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57
Q

Are glycopeptides effective against gram-negative bacteria?

A

No, because they cannot penetrate the outer membrane, too large to pass through the porins

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58
Q

Resistance to vancomycin is most commonly due to what?

A

substitution of the terminal D-ala with D-lac leading to loss of the central hydrogen bond with the amino group and a 1000-fold decrease in affinity

59
Q

What is the relative size of vancomycin?

A

Huge

60
Q

What exactly reduces vancomycin’s affinity with its target?

A

Change to oxgen in D-lac reduces affinity 1000x

61
Q

Other cell wall antibiotics include?

A

Fosphomycin
Cycloserine
Bacitracin

62
Q

Fosphomycin has what effect?

A

Blocks conversion of glucosamine to muramic acid

63
Q

Cycloserine has what effect?

A

Acts as a D-alanine analog blocking incorporation

64
Q

Bacitracin has what effect?

How is this primarily used?

A

Interferes with transfer of peptidoglycan precursors across the cell membrane.

Used primarily in topical ointments to inhibit Gram-positives

65
Q

The majority of protein synthesis inhibitors bind to what?

A

Ribosomal RNA

66
Q

What provides the selectivity of protein synthesis inhibitors?

A

Bacterial rRNA is different from eukaryotic rRNA

67
Q

Drugs in the inhibition of protein synthesis group include? 7

A 
Aminoglycosides
Tetracyclins
Macrolides
Chloramphenicol
Lincosamides
Oxazolidinones
Streptogramins
68
Q

Aminoglycoside structure is what?

A

di, tri, and tetra-amine (amino) containing sugars (glycan

69
Q

What is the mechanism of action of aminoglycosides?
In simple terms?
What does this cause?

A

Bind irreversibly to the 30S subunit of the bacterial ribosome and prevent binding of fmet-tRNA

(blocks initiation of translation and causes mis-reading of mRNA)

Cause codon misreading by 70S ribosomes

70
Q

What are common aminoglycosides used? 5

A 
Streptomycin
gentamicin, 
tobramycin, 
amikacin 
netilimicin
71
Q

Side effects of aminoglycosides? 2

A

Nephrotoxic

Ototoxic: damages the 8th cranial nerve required for inner ear function) causing nephrotoxic

72
Q

Resistance mechanism to aminoglycosides mainly?

A

modification of the drug by specific enzymes such as acetylase, adenylase, and phosphorylase

73
Q

Tetracycline structure?

A

planar molecules with 4 (tetra) six-member rings (cycline)

74
Q

Mechanism of tetracycline action?
Is this binding irreversible?
What does that make tetracycline?

A

Binds reversibly to the 30S subunit and prevents binding of tRNAs to the acceptor site of the ribosome.

No, reversible

Bacteriostatic

75
Q

Spectrum of tetracyclin?

A

Very broad

76
Q

Common tetracyclines in use? (4)

A

Doxycycline
Minocycline
oxytetracycline
Chlortetracycline

77
Q

Resistance mechanism to tetracyclines?

A

efflux, the ability to pump the antibiotic back out of the cell after it has entered

78
Q

Side effects of tetracyclines? (2)

A
  1. Broad spectrum leads to suppression of natural intestinal flora causing stomach upset and diarrhea
  2. Interference with bone development and permanent staining of teeth in children
79
Q

What population should not get tetracycline?

A

Children under 8 years of age

80
Q

Structure of chloramphenicol?

A

modified nitrobenzene ring

81
Q

Mechanism of chloramphenicol?
Does it bind irreversibly?
What does that make this?

A

Binds to the peptidyl transferase center of 23S rRNA in the 50S subunit inhibiting peptide bond formation

No

Bacteriostatic

82
Q

Resistance mechanism to chloramphenicol? (3)

A
  1. Mainly enzymatic modification of the drug by acetylation at the OH group by enzyme CAT.
  2. Target modification
  3. Change in permeability
83
Q

Side effects of chloramphenicol? 2

A
  1. bone marrow suppressant

2. Irreversible aplastic anemia

84
Q

Macrolides, Lincosamides, and Streptogramins (MLS) have what mechanism of action?

A

bind to the same region of the 23S rRNA preventing translocation or some other aspect of translation. (prevent continuation of protein synthesis)

85
Q

MLS has what for resistance?

A

target modification by methylation of a specific nucleotide of the 23S rRNA

86
Q

Side effects of MLS? 1

A

Clindamycin severely alters the balance of natural flora in the intestines and is not effective against C dif allowing it to flourish and cause pseudomembranous colitis

87
Q

Examples of MLS antibiotics?

A
  1. Erythromycin
  2. Azithromycin (Z-pak)
  3. Clindamycin
  4. Synercid (quinupristin/dalfopristin)
88
Q

Osazolidinones have what method of action? (2)

A
  1. target 23S rRNA

2. prevent joining of the 50S to the 30S subunit of the ribosome

89
Q

Oxazolidinones are used for what type of infections?

A

multi-resistant Gram-positive infections

90
Q

Example of oxazolidinone?

A

Linezolid (Zyvox)

91
Q

Fusidic acid has what mechanism of action?

What is it used most for?

A

Inhibits the function of EF-G

used primarily for Staph infections

92
Q

Nucleic acid synthesis inhibitors drugs include? (5)

A
  1. Quinolones
  2. Rifampicin
  3. Sulfonamides
  4. Trimethoprim
  5. Metronidazole (Flagyl)
93
Q

Quinolones include what four drugs?

A

1st generation: Nalidixic acid
2nd generation: Fluorquinolone/Ciprofloxacin
3rd generation: Levofloxacin
4th generation: Gemifloxacin

94
Q

Is the structure of quinolones natural or synthesis?

A

Synthetic

95
Q

Mechanism of quinolone action? 2

A
  1. Interferes with the function of the two bacterial type II topoisomerases, gyrase and topoisomerase IV
  2. Traps the DNA-enzyme complex in the cleaved state
96
Q

Quinolone action is similar to what?

A

anticancer drugs that inhibit human type II topoisomerase

97
Q

Quinolone resistance is because of what?

A

Chromosomal mutations in a highly conserved region of all topoisomerases that lower affinity for the drug

98
Q

Mutations that make bacterial enzymes resistance to bacterial topoisomerase inhibitors actually has what other effect?

A

make them sensitive to eukaryotic inhibitors

99
Q

Quinolone is not recommended for who? (2)

Why?

A

children or lactating women

because of possible effects on cartilage development

100
Q

Rifampicin has what mechanism of action?

A

Blocks the initiation of transcription by binding selectively to bacterial RNA polymerase.

101
Q

Rifampicin is used primarily for what infection?

A

Mycobacterial infections (TB).

102
Q

Rifampcin resistance is due to what?

A

Chromosomal mutations in the target

103
Q

Side effects of rifampicin? (2)

A

Rash

Jaundice

104
Q

What are the two inhibitors of folic acid synthesis that also inhibit bacterial nucleic acid synthesis?

A
  1. sulfonamides

2. trimethoprim

105
Q

Structure of sulfonamides

A

Synthetic analogs of PABA

106
Q

Sulfonamides have what mechanism of action?

A

Interferes with the synthesis of nucleic acid bases (purines and pyrimidines) by competing with PABA in the first step on the pathway to synthesis of folic acid.

107
Q

Selectivity of sulfonamides against bacteria and not host is because of what?

A

the fact that humans do not synthesize folic acid but require it as a nutrient

108
Q

Sulfonamides are used to treat what?

A

Urinary tract infections

109
Q

How is resistance acquired in sulfonamides?

A

Acquisition of a second enzyme with lower affinity for the drug

110
Q

Side effects of sulfonamides? 2

A
  1. rashes

2. bone marrow suppression

111
Q

Trimethoprim has what for structure?

A

Analog of the aminohydroxypyrimidine moiety of folic acid

112
Q

Mechanism of trimethoprim action?

A

Inhibition of folic acid synthesis at a later stage by inhibition of dihydrofolate reductase

113
Q

What gives trimethoprim its selectivity despite dihydrofolate reductase being in all mammalian cells?

A

trimethoprim has a higher affinity for the bacterial version

114
Q

what is trimethoprim frequently given in addition to?

For what infections?

A

sulfamethoxazole

urinary tract

115
Q

Resistance to trimethoprim is done how?

A

Acquisition of a second DHFR enzyme with lower affinity for the drug

116
Q

Side effects to trimethoprim are worse in what patients?

A

in AIDS patients

117
Q

Mechanism of action of metronidazole/flagyl?

What must happen first?

A

Results in DNA breaks

Pro-drug must be reduced to active drug within the bacterial cell

118
Q

Flagyl/metronidazole is only effective on what?

A

anaerobic bacteria because only they can supply the necessary reducing environment

119
Q

Resistance to metronidazole/flagyl is due to what? (2)

A

decreased uptake or decreased reduction

120
Q

Side effects of metronidazole/flagyl?

A

Rare CNS effects

121
Q

What is the reducing agent of metronidazole?

A

Ferredoxin

122
Q

Antibiotics against the plasma membrane include? 2

A
  1. polymixins

2. daptomycin (cubicin)

123
Q

Structure of polymixins?

A

large cyclic polypeptides

124
Q

Mechanism of polymixin action?

How is it used?

A

disrupt bacterial membranes

topically

125
Q

Resistance to polymixins is due to what?

A

reduced uptake

126
Q

Daptomycin/Cubicin has what structure?

A

lipopeptide

127
Q

Daptomycin/Cubicin has what mechanism of action?

A

Inserts into bacterial membrane by lipid portion and disrupts membrane potential which stops everything else

128
Q

Use of Daptomycin/Cubicin is when? (3)

A

to severe skin infections,
bacteremia
endocarditis caused by multiply resistant Gram-positive organisms.

129
Q

Side effects of Daptomycin/Cubicin 2

A

Renal impairment,

effects on skeletal muscle

130
Q

Is there resistance to Daptomycin/Cubicin

A

Yes but not defined

131
Q

Mycobacteria are tough to make drugs for because of what? (4)

A
  1. the waxy outer layer prevents penetration of many antibiotics
  2. they are frequently intracellular
  3. they grow extremely slowly requiring long term treatment
  4. common in immuno-compromised patients
132
Q

Treatment for mycobacteria typically involves what?

A

cocktail of drugs including rifampicin, streptomycin, isoniazid, ethambutol, and pyrazinamide

133
Q

What is a problem with cocktail mycobacterial treatment?

A

Compliance

134
Q

Mechanism of isoniazid?

What does it require first?

A

Prevents mycolic acid synthesis

conversion to active form by catalase function so catalase mutants are resistant to the drug.

135
Q

Mechanism of ethambutol?
Resistance occurs when?
Side effect?

A

Inhibits synthesis of arabinoglycans

if it is not part of a cocktail

optic neuritis.

136
Q

Pyrazinamide has what structure?

A

A nicotinamide analog

137
Q

Dapsone is what type of molecule?

What is it used for?

A

sulfonamide

M. leprae infections

138
Q

5 mechanisms of antibiotic resistance?

A
  1. Enzymatic modification of the antibiotic.
  2. Modification of target
  3. Decreased permeability
  4. Loss of transport system
  5. Reverse transport out of cell
139
Q

Acquisition of resistance can be due to what? (2)

Which is major cause?

A
  1. Spontaneous mutation

2. Acquisition of new genes: Major

140
Q

What is the alteration of existing genes called?

A

Vertical evolution

141
Q

Acquisition of new genes for resistance is called what?

A

Horizontal transfer

142
Q

Resistance plasmids are transmitted between who? (2)

A
  1. same bacterial species

2. different bacterial species

143
Q

What is wrong with antibiotics right now?

A
  1. We have made two new ones since the 1960’s.
  2. Bacteria are so good at evolving resistance
  3. Bacteria can share resistance
  4. No incentives for pharm companies to make new antibiotics
144
Q

Based on the current state of antibiotics, what is it important for us physicians to know?

A

What we’ve got is probably what we’ll have for the foreseeable future, so it is incumbent upon physicians to prescribe them wisely to retain their effectiveness as long as possible.

MICRO (22 decks)

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