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Week 1: Protein synthesis inhibitor antibiotics Flashcards

1
Q

Learning objectives

A
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2
Q

Classes of bacterial protein synthesis inhibitors

A
  • Aminoglycosides
  • Tetracyclines
  • Glycylcyclines
  • Chloramphenicol
  • Macrolides
  • Lincosamines
  • Oxazolidinones
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3
Q

Aminoglycosides

A
  • Gentamicin
  • Tobramycin
  • Amikacin
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4
Q

Tetracyclines

A
  • Tetracycline
  • Doxycycline
  • Minocycline
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5
Q

Glycylcyclines

A

Tigecycline

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6
Q

Macrolides

A
  • Erythromycin
  • Clarithromycin
  • Azithromycin
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7
Q

Lincosamines

A

Clindamycin

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8
Q

Oxazolidinones

A
  • Linezolid
  • Tedizolid
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9
Q

Possible targets for protein synthesis inhibitors

A
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10
Q

Classes of drugs that inhibit Bacterial 30S ribosomal subunit

A
  • Aminoglycosides
  • Tetracyclines
  • Glycylcyclines
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11
Q

Classes of drugs that inhibit bacterial 50s ribosomal subunit

A
  • Chloramphenicol
  • Macrolides
  • Lincosamines
  • Oxazolidinones
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12
Q

Aminoglycosides MOA

A

Effects on binding the the 30S bacterial ribosomal subunit A site blocking the initiation of protein synthesis

  • Fixed positive charge at all physiological pHs
  • Binds to the 16S rRNA at the A site on 30S ribosomal subunit and arrests translation in the initiation phase or causes premature termination of the protein
  • At lower doses, induces misreading of mRNA
  • Impairs bacterial oxidative phosphorylation
  • Selectivity due to higher affinity for prokaryotic ribosomal RNA and lack of uptake by most Eukaryotic cells
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13
Q

Aminoglycosides selectivity

A

Selectivity due to higher affinity for prokaryotic ribosomal RNA and lack of uptake by most Eukaryotic cells

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14
Q

Aminoglycosides route of administration

A
  • Parenteral (IV) dosing only
    • usually requires therapeutic drug monitoring to ensure safety and efficacy
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15
Q

Aminoglycosides distribution

A
  • Charged drug is confined to extracellular water
  • Not active in acidic environments (ie abscess)
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16
Q

Aminoglycosides metabolism and elimination

A
  • eliminated by renal glomerular filtration
    • dose adjustment in renal dysfunction
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17
Q

Aminoglycosides half-life

A

t1/2~ 2-3 hours

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18
Q

Aminoglycosides dose adjustment

A

Dose adjustment necessary in renal dysfunction

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19
Q

Aminoglycosides characteristic which is unlike other protein synthesis inhibitors

A

IS bactericidal

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20
Q

Aminoglycosides effect

A
  • Bactericidal (unlike other protein synthesis inhibitors)
  • Concentration-dependent killing with PAE
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21
Q

PAE AKA

A

Post-antibiotic Effect

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22
Q

Aminoglycosides toxicities

A

from fixed positive charge

  • Nephrotoxicity
  • Ototoxicity
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23
Q

Aminoglycosides nephrotoxicity

A
  • Dose-dependent
  • Augmented by concurrent diuretics (eg furosemide) and other nephrotoxins (eg vancomycin)
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24
Q

Aminoglycosides Ototoxicities

A
  • High-frequency hearing-loss and vestibular dysfunction
  • Genetic predisposition due to mutations in mitochondrial rRNA
  • Augmented by diuretics e.g. furosemide
  • Blockade of neuromuscular junction
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25
Q

Aminoglycosides dosing

A

For most infections Aminoglycosides are dosed using a high dose once daily administration

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26
Q

Aminoglycosides spectrum of activity

A
  • Primarily used against aerobic GNR, including Pseudomonas
  • Has synergysitc activity with cell wall active antibiotics in treating Staph aureus and Enterococcus (used for serious infections like endocarditis)
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27
Q

Explain Resistance mechanisms of Aminoglycosides

A
  • Plasmid exchange of aminoglycoside metabolizing enzymes can confer resistance to specific Aminoglycosides
  • Arises from phosphorylation, adenylation, acetylation, rRNA methyltransferase and decreased uptake
  • Charge determines potentcy, toxicity and resistance
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28
Q

What determines potency of Aminoglycosides

A

Charge determines potency, toxicity and resistance

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29
Q

Question

A
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30
Q

Question

A
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31
Q

Tetracyclines MOA

A

Inhibitors of the bacterial 30S ribosomal subunit by

  • binds to 16S rRNA and/or proteins at the acceptor (A) site on 30S ribosomal subunit, blocking tRNA access

&

  • Chelator of Ca++, Mg++, Fe+++ and other ions
  • Is actively transported into bacterial cells
  • Bacteristatic
  • Time-dependent killing
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32
Q

Tetracyclines route of administration

A

Good oral bioavailability

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33
Q

Tetracyclines t1/2

A

various

Doxycyline > minocycline > tetracycline

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34
Q

Tetracyclines distribution

A
  • Large volume of distribution
  • Bone, tissue > plasma
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35
Q

Tetracycline metabolism and elimination

A
  • 1o glomerular filtration
  • 2o biliary secretion
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36
Q

Doxycycline elimination

A

1o biliary secretion

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37
Q

Minocycline elimination

A

1o biliary secretion

38
Q

Tetracyclines toxicities

A
  • Binding to teeth and bones; avoid use in pregnancy, childhood
  • GI intolerance (NVD)
    • rare cases esophageal ulceration
  • Photosensitivity caused by free radical generation upon irradiation
39
Q

Tetracyclines and color changes

40
Q

Question

41
Q

Tetracyclines spectrum of activity

A

Broad

  • GPC > GNR, anaerobes; intracellular organisms
  • Chlamydia
  • H. pylori
  • Mycoplasma pneumonia
  • Bacillus anthracis
  • Actinomyces
  • Spirochetes (Borrelia burgdorferi)
  • Rickettsia (RMSF)
42
Q

Tetracyclines Mechanisms of resistance

A
  • TET-A gene encodes protein which pumps tetracyclines out of the bacteria (ABC transporter efflux pump) or rRNA methylase
  • Ribosomal mutations prevents tetracycline binding
43
Q

“New ‘Tetracyclines’” AKA

A

Glycylcyclines: Tigecycline

44
Q

Glycylcyclines

A

Tigecycline

45
Q

Tigecycline MOA

A
  • Binds to 16S rRNA of the 30S ribosomal subunit and blocks the A site
  • Structurally similar to minocycine
46
Q

Tigecycline route of administration

A

Parenteral (IV)

47
Q

Tigecycline half-life

A

t1/2=36 hours

48
Q

Tigecycline elimination

A
  • 1o biliary secretion of unchanged drug
  • 2o glucuronidation before urinary elimination
49
Q

Tigecycline spectrum of activity

A

GPC including

  • MRSA
  • VRSA
  • VRE

GNR (NOT pseudomonas)

  • Anaerobes
50
Q

Tigecycline and evidence on fatality

A

Although Tigecycline demonstrated significant improvements in a number of clinically relevant cases, unexpected fatalities may occur

51
Q

Macrolides MOA

A

Inhibitors of bacterial 50S ribosomal subunit

  • Bind to 23S rRNA of the bacterial 50S ribosomal subunit and inhibits transpeptidation and translocation
52
Q

Macrolides

A
  • Erythromycin
  • Clarithromycin
  • Telithromycin
  • Azithromycin
53
Q

Erythromycin t1/2

A

t1/2​ = 1.5 hours

54
Q

Clarithromycin t1/2​

A

t1/2​ = 4 hours

55
Q

Telithromycin t1/2​

A

t1/2​ = 10 hours

56
Q

Azithromycin t1/2​

A

t1/2​ = 68 hours

57
Q

Macrolides elimination

A

Erythromycin, clarithromycin and telithromycin are metabolized by (and inactivate) CYP450 and are excreted in the bile

Azithromycin is excreted largely unchanged in biles and is relatively free of drug interactions

58
Q

Macrolides distribution

A

Higher concentrations in tissue (including phagocytes) and secretion than in plasma but INADEQUATE CNS levels

59
Q

Macrolides toxicities

A
  • GI complaints
    • NVD
    • Cholestatic jaundice
  • Erythromycin and Clarithromycin are strong inhibitors of CYP450 enzumes, resulting in may potential drug-interactions (generally an increase of the interacting agent (eg Ca2+ channel blocker (Nifedipine, Felodipine, amlodipine) levels can rise to 5x therapeutic, increasing risk of renal injury, hypotension and death)
  • Complete medication history and evaluation for drug-interactions should be considered when using macrolides
60
Q

Macrolides spectrum

A
  • GPC > GNR, anaerobes; intracellular organisms
  • Strep pneumo
  • Chlamydia
  • mycoplasma
  • legionella
  • some protozoa (Toxoplasma, Cryptosporidium, Plasmodium)
  • Concentration-dependent killing and PAE (Azithromycin) and time-dependent, concentration enhanced killing (erythromycinn, clarithromycin) without PAE
  • Particularly helpful in respiratory infections given high tissue-penetration and activitty against intracellular organisms
61
Q

Macrolides mechanisms of resistance

A
  • Increased efflux (mefE gene)
  • Plasmid acquired rRNA methyltransferase (Erm gene; erythromycin resistance methylases) which reduces or eliminates binding of macrolides to the site of action or mutation in rRNA
  • Hydrolysis
62
Q

Lincosamides

A

Clindamycin

63
Q

Clindamycin MOA

A
  • Binds to the 23S rRNA in the bacterial 50S ribosomal subunit inhibiting translication, formation of the initiation complex and occupation of the A site
  • Time-dependent killing
64
Q

Clindamycin distribution

A

Large volume of distribution except CNS

65
Q

Clindamycin metabolism & Elimination

A

Hepatic metabolism by CYP450 enzymes and biliary secretion

66
Q

Considerations of using multiple 50S ribosomal subunit inhibitors

A

Note that 50S inhibitors interfere with the binding of eachother limiting their use in combination and also making them subject as a group to particular rRNA methyltransferases that can shield the binding site(s) on rRNA with a methyl group

67
Q

Clindamycin Toxicities

A
  • Diarrhea
  • Classical causation of Pseudomembranous colitis (Clostridium difficile superinfection, increasingly community acquired)
68
Q

Clindamycin spectrum of activity

A
  • GPC
  • Staph aureus
  • Strep pyogenes
  • Strep viridans
  • Anaerobes above the diaphragm
  • Used as synergystic bacteriostatic agent in necrotizing infections to reduce toxin expression
69
Q

Clindamycin Mechanisms of resistance

A

rRNA methyltransferases

70
Q

What is Pseudomembranous Colitis?

A
  • from C. diff
  • Can be seen with antibiotic use, especially clindamycin, cephalosporins and fluoroquinolones
71
Q

Oxazolidinones

A
  • Linezolid
  • Tedizolid
72
Q

Oxazolidinones MOA

A
  • Binds to the 23S rRNA at the peptidyl (P) site of the bacterial 50S ribosomal subunit interfering with formation of the initiation (f-Met-tRNA-ribosome-mRNA ternary) complex, arresting the bacterial ribosome at initiation (cf. aminoglycoside action at the A site of the 30S ribosomal subunit causing arrest at initiation)
  • Bacteristatic or bactericidal depending on organism
  • Time-dependent killing
73
Q

Oxazolidinones route of administration

A

oral bioavailability is 100%

74
Q

Linezolid t1/2

A

t1/2 = 4-6 hours

75
Q

Tedizolid t1/2

A

t1/2 = 12 hours

76
Q

Oxazolidinones metabolism and elimination

A

Broken down primarily be non-enzymatic oxidation so no renal or hepatic dosing adjustment is necessary

77
Q

Oxazolidinones distribution

A

Large volume of distribution (including CNS for Linezolid)

78
Q

Oxazolidinones spectrum of activity

A

GPC only including MRSA & VRE

79
Q

Oxazolidinones mechanisms of resistance

A

Mutations in 23S rRNA and rRNA methyltransferases

80
Q

Oxazolidinones toxicities

A

More commonly associated with Linezolid than Tedizolid

  • Myelosuppression, especially thrombocytopenia
  • Long-term therapy: potentially irreversible optical and peripheral neuropathy
  • Serotonin syndrome with concurrent SSRIs or diets rich in tyramine due to non-selective MAO inhibition, which can progress to fever, tachycardia and arrhythmia, seizure, loss of consciousness
81
Q

Chloramphenicol MOA

A
  • Binds bacterial 50S ribosomal subunit and inhibits peptidyl transferase activity
  • Time-dependent killing
82
Q

Chloramphenicol route of administration

A

Oral or IV

83
Q

Chloramphenicol distribution

A

Widely distributed, including CNS & bone

84
Q

Chloramphenicol half-life

A

t1/2 = 3 hours

85
Q

Chloramphenicol metabolism and elimination

A

Hepatic metabolism primarily by glucuronidation, followed by urinary secretion

86
Q

Chloramphenicol toxicities

A
  • CYP450 inhibitor resulting in multiple drug-interactions
  • Mitochondrial toxicity
  • Reversible bone-marrow suppression
  • “Gray Baby Syndrome”
  • Rare idiosyncratic aplastic aneia
  • Rare leukemia
87
Q

Chloramphenicol spectum of activity

A

Broad

  • GPC
  • GNR
  • Many anaerobes
  • Intracellular bacteria
  • Chlamydia
  • Rickettsia
  • Mycoplasma
88
Q

Chloramphenicol mechanisms of resistance

A
  • Reduced uptake and binding, plasmid-mediated CAM acetyltransferase
  • The Cfr rRNA methyltransferase confers global resistance to phenicols, lincosamides, streptogramins, oxazolidinones
89
Q

The Cfr rRNA methyltransferase confers global resistance to

A
  • phenicols
  • lincosamides
  • streptogramins
  • oxazolidinones
90
Q

Question

Infectious Disease (82 decks)

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