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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
Aminoglycosides dosing
For most infections Aminoglycosides are dosed using a high dose once daily administration
26
Aminoglycosides spectrum of activity
* 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)
27
Explain Resistance mechanisms of Aminoglycosides
* 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
28
What determines potency of Aminoglycosides
Charge determines potency, toxicity and resistance
29
Question
30
Question
31
Tetracyclines MOA
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
32
Tetracyclines route of administration
Good oral bioavailability
33
Tetracyclines t1/2
various Doxycyline \> minocycline \> tetracycline
34
Tetracyclines distribution
* Large volume of distribution * Bone, tissue \> plasma
35
Tetracycline metabolism and elimination
* 1o glomerular filtration * 2o biliary secretion
36
Doxycycline elimination
1o biliary secretion
37
Minocycline elimination
1o biliary secretion
38
Tetracyclines toxicities
* 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
Tetracyclines and color changes
40
Question
41
Tetracyclines spectrum of activity
Broad * GPC \> GNR, anaerobes; intracellular organisms * Chlamydia * H. pylori * Mycoplasma pneumonia * Bacillus anthracis * Actinomyces * Spirochetes (Borrelia burgdorferi) * Rickettsia (RMSF)
42
Tetracyclines Mechanisms of resistance
* 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
"New 'Tetracyclines'" AKA
Glycylcyclines: Tigecycline
44
Glycylcyclines
Tigecycline
45
Tigecycline MOA
* Binds to 16S rRNA of the 30S ribosomal subunit and blocks the A site * Structurally similar to minocycine
46
Tigecycline route of administration
Parenteral (IV)
47
Tigecycline half-life
t1/2=36 hours
48
Tigecycline elimination
* 1o biliary secretion of unchanged drug * 2o glucuronidation before urinary elimination
49
Tigecycline spectrum of activity
GPC including * MRSA * VRSA * VRE GNR (NOT pseudomonas) * Anaerobes
50
Tigecycline and evidence on fatality
Although Tigecycline demonstrated significant improvements in a number of clinically relevant cases, unexpected fatalities may occur
51
Macrolides MOA
Inhibitors of bacterial 50S ribosomal subunit * Bind to 23S rRNA of the bacterial 50S ribosomal subunit and inhibits transpeptidation and translocation
52
Macrolides
* Erythromycin * Clarithromycin * Telithromycin * Azithromycin
53
Erythromycin t1/2
t1/2​ = 1.5 hours
54
Clarithromycin t1/2​
t1/2​ = 4 hours
55
Telithromycin t1/2​
t1/2​ = 10 hours
56
Azithromycin t1/2​
t1/2​ = 68 hours
57
Macrolides elimination
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
Macrolides distribution
Higher concentrations in tissue (including phagocytes) and secretion than in plasma but INADEQUATE CNS levels
59
Macrolides toxicities
* 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
Macrolides spectrum
* 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
Macrolides mechanisms of resistance
* 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
Lincosamides
Clindamycin
63
Clindamycin MOA
* 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
Clindamycin distribution
Large volume of distribution except CNS
65
Clindamycin metabolism & Elimination
Hepatic metabolism by CYP450 enzymes and biliary secretion
66
Considerations of using multiple 50S ribosomal subunit inhibitors
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
Clindamycin Toxicities
* Diarrhea * Classical causation of Pseudomembranous colitis (Clostridium difficile superinfection, increasingly community acquired)
68
Clindamycin spectrum of activity
* GPC * Staph aureus * Strep pyogenes * Strep viridans * Anaerobes above the diaphragm * Used as synergystic bacteriostatic agent in necrotizing infections to reduce toxin expression
69
Clindamycin Mechanisms of resistance
rRNA methyltransferases
70
What is Pseudomembranous Colitis?
* from C. diff * Can be seen with antibiotic use, especially clindamycin, cephalosporins and fluoroquinolones
71
Oxazolidinones
* Linezolid * Tedizolid
72
Oxazolidinones MOA
* 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
Oxazolidinones route of administration
oral bioavailability is 100%
74
Linezolid t1/2
t1/2 = 4-6 hours
75
Tedizolid t1/2
t1/2 = 12 hours
76
Oxazolidinones metabolism and elimination
Broken down primarily be non-enzymatic oxidation so no renal or hepatic dosing adjustment is necessary
77
Oxazolidinones distribution
Large volume of distribution (including CNS for Linezolid)
78
Oxazolidinones spectrum of activity
GPC only including MRSA & VRE
79
Oxazolidinones mechanisms of resistance
Mutations in 23S rRNA and rRNA methyltransferases
80
Oxazolidinones toxicities
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
Chloramphenicol MOA
* Binds bacterial 50S ribosomal subunit and inhibits peptidyl transferase activity * Time-dependent killing
82
Chloramphenicol route of administration
Oral or IV
83
Chloramphenicol distribution
Widely distributed, including CNS & bone
84
Chloramphenicol half-life
t1/2 = 3 hours
85
Chloramphenicol metabolism and elimination
Hepatic metabolism primarily by glucuronidation, followed by urinary secretion
86
Chloramphenicol toxicities
* CYP450 inhibitor resulting in multiple drug-interactions * Mitochondrial toxicity * Reversible bone-marrow suppression * "Gray Baby Syndrome" * Rare idiosyncratic aplastic aneia * Rare leukemia
87
Chloramphenicol spectum of activity
Broad * GPC * GNR * Many anaerobes * Intracellular bacteria * Chlamydia * Rickettsia * Mycoplasma
88
Chloramphenicol mechanisms of resistance
* Reduced uptake and binding, plasmid-mediated CAM acetyltransferase * The Cfr rRNA methyltransferase confers global resistance to phenicols, lincosamides, streptogramins, oxazolidinones
89
The Cfr rRNA methyltransferase confers global resistance to
* phenicols * lincosamides * streptogramins * oxazolidinones
90
Question

Infectious Disease (82 decks)

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