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Protein Synthesis inhibitors Flashcards

1
Q

What drugs are aminoglycosides?

A

Amikacin, gentamicin, neomycin, streptomycin

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2
Q

What is the spectrum for aminoglycosides?

A
  • Aerobic gram-negative infections
  • Pseudomonas aeruginosa (drug of choice)
  • Mycobacterial infections
  • Some Gram pos. bacteria
  • Topically for serious sight-threatening eye
    infections, otitis media, infection of the nasal
    vestibuli, skin infections (not recommended)
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3
Q

What are aminoglycosides administered with for anaerobic infections?

A

metronidazole or clindamycin

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4
Q

What can aminoglycosides be used with to treat staphylococci, streptococci and enterococci?

A

Penicillin

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5
Q

What is the MOA of aminoglycosides?

A
  • Penetrate via passive diffusion → porin channels
    across the outer membrane
  • Actively transported across the bacterial cell
    membrane → cytoplasm
    Inhibition of protein synthesis occurs in the
    following way:
    1. Preventing the formation of the initiation
    complex
    2. Polyribosomes are broken down to non-
    functional monosomes
    3. The mRNA is incorrectly “read” and incorrect
    amino acids are joint to form non-functional
    or toxic proteins
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6
Q

What causes resistance to aminoglycosides?

A
  1. Mutation of binding site on 30S ribosomal
    subunit (streptomycin only)
  2. Inhibition of transport into cell
  3. Inactivation by enzymes (acetyl transferases,
    adenyl transferases & nucleotidyl transferases)
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7
Q

What is the absorption of amnioglycosides?

A

After IM administration → rapidly and completely
absorbed → distributed in the extracellular fluid
and tissues

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8
Q

What increases the half life of aminoglycosides?

A

Reduced renal capacity and during the use in neonates

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9
Q

How are aminoglycosides metabolised and excreted?

A

Excreted mainly unaltered (70-90%) within 24
hours in the urine

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10
Q

T or F - Bactericidal effect of aminoglycosides are concentration dependent?

A

True

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11
Q

Aminoglycosides exert a short post-antibiotic effect, T or F?

A

False, post-antibiotic effect is prolonged

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12
Q

What are the side effects of aminoglycosides?

A
  1. Narrow therapeutic index, toxicity is directly
    dependent on:
    a. Plasma concentration
    b. The duration of exposure
    c. Dosages are in accordance with age, body
    weight and renal function
  2. All are nephrotoxic and ototoxic (therapy > 5
    days, ↑ doses, in elderly, renal insufficiency)
  3. Neuromuscular blockage
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13
Q

What are the most nephrotoxic aminoglycosides?

A

Neomycin, tobramycin & gentamicin are most
nephrotoxic

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14
Q

Which aminoglycosides are the most ototoxic?

A

Neomycin & amikacin

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15
Q

Which aminoglycosides are the most vestibulotoxic?

A

Streptomycin & gentamicin

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16
Q

What happens if streptomycin is administered during pregnancy?

A

Streptomycin given during pregnancy cause
deafness in the child

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17
Q

What are the drug interactions of aminoglycosides?

A
  1. General anaesthetics
  2. Neuromuscular blocking agents
  3. Oto- or nephrotoxic agents (vancomycin,
    amphotericin)
  4. Loop diuretics
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18
Q

What are the cautions with aminoglycosides?

A
  1. Elderly
  2. Renal insufficiency
  3. Neonates
  4. Strong caution bordering on contraindication:
    Pregnancy (Streptomycin)
  5. Contraindicated: Myasthenia gravis
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19
Q

Are macrolides bacteriostatic or bacteriocidal?

A

They are Bacteriostatic. At high dosages → bactericidal

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20
Q

What drugs are macrolides?

A

erythromycin (prototype drug), azithromycin, clarithromycin

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21
Q

What are macrolides effective in the treatment of?

A

– Legionnaires disease (Leggionella
pneumophila)
– Whooping cough (Bordetella pertussis)
– Mycoplasma pneumoniae
– Diphtheria (Corynebacterium) infections

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22
Q

Macrolides can also be used as an alternative
drug by patients that are allergic to what drug?

A

Penicillin

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23
Q

What is the spectrum for erythromycin?

A

Corynebacterium
diphtheriae infections
* Erythromycin → acne (2nd line agent)
* Respiratory, neonatal, ocular or genital
chlamydial infections
* Treatment of community-acquired pneumonia
(resistance ↑)
Prophylaxis against endocarditis during dental
procedures (2nd line agent)

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24
Q

What is the drug regime for a person allergic to penicillin with peptic ulcer disease?

A

Eradication of Helicobacter pylori in Peptic ulcer
disease (clarithromycin/azithromycin +
metronidazole + omeprezole) in penicillin allergy

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25
Q

When is erythromycin CI?

A

Erythromycin/azithromycin NOT TO BE USED for
syphilis in pregnant women allergic to penicillins

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26
Q

What drugs are used for rickettsial
infections (2nd line agent)?

A

Azithromycin/clarithromycin

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27
Q

What is the MOA of macrolides?

A

Attach to the bacterial 50S ribosomal subunit
* Bind to a site on the 50S subunit close to the
sites for chloramphenicol and clindamycin
– Can competitively inhibit the binding of these
agents when given together
* Inhibit translocation

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28
Q

What causes resistance to macrolides?

A
  1. Reduced cell membrane permeability or active
    efflux
  2. Production of esterases that hydrolize
    macrolides
  3. Modification of the ribosomal binding site
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29
Q

What affects the absorption of erythromycin?

A

Erythromycin absorption effected by:
formulation, gastric acidity & food
* Administered orally as stearate salt or esterified
form (estolate)
* Erythromycin (base & stearate) → food ↓
absorption

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30
Q

How are macrolides metabolised and excreted?

A

Readily metabolised by the liver and excreted in
the bile

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31
Q

What are the side effects of microlides?

A
  1. GIT intolerance (abdominal pain, cramping,
    nausea, vomiting, diarrhoea)
  2. Allergic reactions (rare)
  3. Hepatotoxicity:
    – When the estolate is, however, taken for more
    than 10 days, cholestatic jaundice
    (irreversible) can occur
    – Benign elevation of serum transaminase
  4. Erythromycin and clarithromycin → inhibit the
    liver cytochrome P450 system & P-glycoprotein
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32
Q

What are the drug interactions of microlides?

A
  1. Serum concentrations of different drugs ↑
    (e.g. theophylline, and warfarin)
  2. Reduce efficacy of combined oral contraceptive
    pill
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33
Q

What are the cautions for microlides?

A
  • Liver disease
  • Impaired biliary function
  • C/I Porphyria (erythromycin)
  • Heart disease (clarithromycin & azithromycin)
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34
Q

Are tetracyclines bacteriostatic or bacteriocidal?

A

Bacteriostatic

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35
Q

What drugs are tetracyclines?

A

Tetracycline, doxycycline, minocycline, Tigecycline

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36
Q

What is the use of tetracyclines?

A

Combination with other agents for treatment of
malaria
Chronic bronchitis
Acne

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37
Q

What bacteria are tetracyclines the drug of choice for?

A

– Rickettsia
– Chlamydia
– Brucellosis
– Mycoplasma
– Spirochaetal infections

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38
Q

What is the MOA of tetracyclines?

A
  • Crystalline amphoteric molecules with low
    solubility
  • Used as hydrochloride salts → more soluble
  • Move into micro-organisms via passive diffusion
    & energy-dependent process of active transport
  • Sensitive cells concentrate the drug
    intracellularly
  • Bind to 30S bacterial ribosomal subunit
  • Prevent formation of initiation complex
  • Inhibit codon-anticodon interaction
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39
Q

What causes resistance to tetracyclines?

A
  1. Decreased intracellular accumulation (decreased
    influx or active efflux) → most important
  2. Production of a protein that interferes with the
    binding of tetracyclines on the ribosome
  3. Enzymatic inactivation
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40
Q

What must tetracyclines be taken with?

A

Taken with adequate amount of fluid

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41
Q

What prevents absorption of tetracyclines?

A

Antacids and milk

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42
Q

How are Doxycycline and minocycline excreted?

A

Excreted mainly in bile (safer in renal
impairment)

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43
Q

What are the side effects of tetracyclines?

A
  1. Cause GIT disruptions e.g. nausea and vomiting
    (dose related)
  2. Destruction of normal gut flora →
    superinfections with Candida
  3. Pseudomembranous colitis → Clostridium
    difficile can also occur
  4. Elderly patients → hepatotoxic effects
  5. Photosensitivity
  6. Deposited in bone and teeth
  7. Causing bone growth retardation in children
  8. Discolouration of nails and teeth & occasional
    enamel hypoplasia in children
  9. Potentially nephrotoxic
  10. Reduced efficacy of the combined oral
    contraceptive pill
  11. Minocycline
    – Blue-grey pigmentation of the skin &
    pigmentation of acne scars
    – Vestibular toxicity
  12. Tiglecycline
    – Increased mortality and treatment failure
    noted
44
Q

What are the drug interactions of tetracyclines?

A
  1. Carbamazepine, phenytoin, barbiturates,
    rifampicin (serum levels of doxycycline ↓)
  2. Vit A & other retinoids → enhanced risk of ↑
    intracranial pressure
  3. Combined oral contraceptive pill
45
Q

What are the cautions with tetracyclines?

A
  1. Systemic lupus erythematosus (minocycline)
  2. Myasthenia gravis
  3. Hepatic impairment
  4. Porphyria
  5. Elderly
  6. C/I in pregnancy, Children < 8 - 12 yrs
46
Q

Which antibiotic is rarely used as first choice treatment because of it’s potential toxicity?

A

Chloramphenicol. It is bacteriostatic

47
Q

When is Chloramphenicol indicated?

A

Only reserved for severe infections by
susceptible organisms due to potential to cause
aplastic anaemia

48
Q

What is the spectrum of Chloramphenicol?

A
  • When standard treatment are C/I → use for
    rickettsial infections and bacterial meningitis
  • Typhoid fever
  • Used for bacterial eye infections
  • Not used for long-term or repeat treatment or for prophylactic use
  • Active against:
    – Chlamydia & Mycoplasma infections
    – Streptococci, staphylococci & Haemophilus
    infections & anaerobes
49
Q

What is the MOA of Chloramphenicol?

A
  • Powerful inhibitor of bacterial protein synthesis
  • Attaches reversibly to the 50S ribosomal-subunit
  • Interferes with the mechanism of action of
    peptidyltransferase
50
Q

What causes resistance against Chloramphenicol?

A
  • Production of chloramphenicol acetyltransferase that inactivates the drug
51
Q

How is Chloramphenicol administered?

A

Orally.

52
Q

How is Chloramphenicol metabolised?

A

Metabolised in the liver and after glucuronide
formation → urine

53
Q

What are the side effects of Chloramphenicol?

A
  1. Serious irreversible bone marrow depression →
    idiosyncratic → fatal aplastic anaemia (topical use)
  2. Dose-related reversible bone marrow toxicity
  3. Efficacy of the combined oral contraceptive pill → reduced
  4. Use with great care → babies → ineffective conjugation
    with glucuronic acid and excretion of the drug → “grey
    baby syndrome” (approximately 40% mortality)
    – Abdominal distension, cyanosis, vasomotor collapse,
    failure to feed
  5. GIT effects, optic or peripheral neuritis
  6. Hypersensitivity reactions and jaundice
  7. Inhibits liver enzymes
54
Q

What are the drug interactions of Chloramphenicol?

A
  1. Causes hepatic enzyme inhibition:
    – ↑ concentrations of phenytoin, warfarin,
    sulphonylurea antidiabetic agents
  2. Used with hepatic enzyme inducers
    (penobarbital, rifampicin) → efficacy of
    chloramphenicol ↓
  3. Vit B, folic acid & iron → chloramphenicol may
    interfere with haematological response
  4. Combined oral contraceptive pill
55
Q

What are the cautions/CI of chloramphenicol?

A

C/I :
– Allergy
– Porphyria
– Third trimester of pregnancy
– Neonates
– Lactation
Caution:
– Impaired hepatic function
– Bone marrow depression

56
Q

What is the spectrum of Clindamycin?

A
  • Susceptible Gram pos. infections in patients
    allergic to penicillins
  • Sensitive staphylococcal & anaerobic infections
  • Used for severe soft tissue infections
  • Lung abscesses
  • Quinsy (not responding to penicillin)
  • Inactive against enterococci
57
Q

What is the MOA of clindamycin?

A
  • Similar mechanism of action to macrolides
  • Inhibits protein synthesis:
    – Binds to the 50S subunit of the bacterial ribosome
    (binding site identical to macrolides)
    – Interferes with the formation of the initiation complex
    – Inhibits translocation
  • Bacteriostatic
  • Bactericidal at higher concentrations
58
Q

What causes resistance to clindamycin?

A
  1. Mutation of ribosomal binding site
  2. Enzymatic inactivation
59
Q

Where is clindomycin metabolised?

A

Liver

60
Q

How is clindomycin excreted?

A

bile

61
Q

What are the side effects of clindomycin?

A
  1. Common: diarrhoea, nausea (oral, IV & IM), skin reactions
  2. Transient ↑ liver enzymes & bilirubin
  3. Transient leucopenia, thrombocytopenia, agranulocytosis,
    eosinophilia
  4. Pseudomembranous colitis is a serious and potentially
    fatal complication
    – Toxin produced by Clostridium difficile
  5. May reduce efficacy of combined oral contraceptive pill
62
Q

What are the drug interactions of clindomycin?

A

Oral contraceptive

63
Q

What are the cautions with clindomycin?

A
  1. GIT disease
  2. Severe hepatic impairment
  3. Porphyria
  4. Elderly
  5. Pregnancy/Lactation
64
Q

What type of antibiotic is fusidic acid?

A

A steroid antibiotic

65
Q

What is the spectrum of fusidic acid?

A
  • Treatment of severe staphylococcal infections
    (osteomyelitis, pneumonia, septicaemia)
  • Combination with another anti-staphylococcal
    agent (e.g. cloxacillin) to prevent emergence of
    resistance is essential
  • Used topically for acute skin infections (5 days) & conjunctivitis
66
Q

What is the MOA of fusidic acid?

A
  • Mechanism of action similar to macrolides
    (inhibiting translocation)
67
Q

How is fusidic acid excreted?

A

Excreted as metabolites in bile

68
Q

What are the side effects of fusidic acid?

A

Side-effects, drug interactions and CI
1. Hepatotoxicity (reversible)
2. GIT effects (take with meals)
3. Risk of kernicterus in neonates
4. Avoid in pregnancy
5. IM: local tissue necrosis
6. Local hypersensitivity

69
Q

What are the DI of fusidic acid?

A
  1. Hydrocortisone – decrease in AB activity of fusidic acid
  2. Statins - ↑ risk of rhabdomyolysis
70
Q

What is the CI for fusidic acid?

A

Hepatic dysfunction

71
Q

What is the spectrum of mupirocin?

A

Gram pos. bacteria, effective against
methicillin-resistant Staphylococcus aureus

72
Q

What is the MOA of mupirocin?

A

– Reversibly binds to Isoleusine-tRNA
synthetase and prevents formation of
Isoleusine-tRNA
– Inhibits protein and RNA synthesis
– Bactericidal at high concentrations

73
Q

How is mupirocin administered?

A

Topically only

74
Q

What are the side effects of upirocin?

A

Mild stinging, burning, itching at site of
application

75
Q

What is the caution with mupirocin?

A

Porphyria

76
Q

What drug is a Ketolide?

A

Telithromycin

77
Q

What is the spectrum of ketolides (telithromycin)?

A

– Similar spectrum to macrolides, H. influenzae
– Erythromycin–resistant strains of
pneumococcus

78
Q

What is the MOA of ketolides (telithromycin)?

A

Can bind to 2 sites on the bacterial ribosome,
with higher affinity than macrolides (similar
effect as macrolides, may also inhibit
formation of newly forming ribosomes)

79
Q

How are ketolides (telithromycin) metabolised and excreted?

A

Metabolised in liver, Excretion: biliary and
urinary

80
Q

What are the side effects of ketolides (telithromycin)?

A
  1. Inhibits liver enzymes
  2. Risk of potentially serious hepatotoxicity
  3. Respiratory failure → myasthenia gravis
    patients
  4. Visual disturbances
  5. Loss of consciousness
81
Q

What drug is an Oxazolidinone?

A

Linezolid

82
Q

What is the spectrum of oxazolidinones (linezolid)?

A

– Gram positive bacteria (staphylococci,
streptococci, enterococci, Gram pos.
anaerobic cocci & Gram pos. rods)
– Cloxacillin-resistant staphylococci &
vancomycin-resistant enterococci, MRSA
– Mostly bacteriostatic
– Bactericidal against streptococci
– Drug resistant M. tuberculosis

83
Q

When is linezolid indicated?

A

Last resort where every other antibiotic therapy
has failed → should be reserved for this purpose

84
Q

What is the MOA of linezolid (an oxazolidinone)?

A

– Prevents formation of ribosome complex
– Binds to 23S ribosomal RNA of the 50S
ribosomal subunit, inhibits protein synthesis

85
Q

What causes resistance to linezolid?

A

Mutation of linezolid binding site on 23S
ribosomal RNA

86
Q

What are the side effects of linezolid?

A
  1. Haemolytic toxicity (mild, reversible)
  2. Peripheral neuropathy (prolonged use)
  3. Reversible non-selective inhibitor of MAO
  4. Headache, moniliasis/fungal infection,
    metallic taste, GIT effects, neurotoxicity
87
Q

What are the drug interactions of linezolid?

A

– Sympathomimetic or adrenergic drugs
→ produces serotonin syndrome (fever,
flushing, sweating, tremors, and delirium)

88
Q

What drugs are streptogramins?

A

Quinupristin-dalfopristin (fixed 30/70 combination)
– Each agent alone: bacteriostatic
– Combined: bactericidal

89
Q

What is the spectrum of streptogramins (Quinupristin-dalfopristin)?

A

– Most Gram pos. bacteria & most respiratory
pathogens (e.g. pneumococci, Mycoplasma pneumoniae,
Legionella pneumophilia, Chlamydia pneumoniae)
– 90% of Staph. aureus and coagulase neg.
staphylococci incl. methicillin resistant strains
– Penicillin resistant pneumococci
– Enterococcus faecium incl. strains which are
resistant to ampicillin, gentamicin and
vancomycin
– Not active against E. faecalis

90
Q

What is the MOA of streptogramins (Quinupristin-dalfopristin)?

A

– The two components are structurally unrelated
– They bind to distinct sites on the 50S
ribosomal subunit
– Interfere with peptidyl transferase enzyme
action
– They cooperate to inhibit protein synthesis

91
Q

What causes resistance to streptogramins?

A

– Quinupristin
* A ribosomal methylase that prevents binding
* Lactonases produced that inactivate the drug
– Dalfopristin
* Acetyltransferases produced that inactivate
the drug
* Increased efflux

92
Q

When is the dose of streptogramins adjusted?

A

Dose adjustment with hepatic dysfunction

93
Q

What are the side effects of streptogramins?

A
  1. Via peripheral vein → inflammation, pain,
    oedema, infusion site reaction,
    thrombophlebitis
  2. Nausea, diarrhoea, vomiting
  3. Rash, pruritus
  4. Headache
  5. Pain
  6. Arthralgia, myalgia
  7. Asthenia
  8. Conjugated hyperbilirubinaemia
94
Q

What are the drug interactions of streptogramins?

A

Warfarin
Diazepam
Terfenadine
Astemizole
Cisapride
NNRTI
Cyclosporine (ciclosporine)

95
Q

What drug is a lipopeptide?

A

Daptomycin

96
Q

What is the spectrum for daptomycin?

A

– Infections caused by multi-resistant bacteria
– Active against Gram pos. bacteria only, MRSA
and glycopeptide-resistant enterococci
– Skin and skin structure infections (Gram-pos.)
– S. aureus bacteraemia incl. right-sided infective
endocarditis

97
Q

What is the MOA of daptomycin (a lipopeptide)?

A

– Disrupting bacterial cell membrane function
– Bind to the membrane and cause rapid
depolarisation
– Cause a loss of membrane potential
– Inhibition of protein, DNA and RNA synthesis
– Bactericidal (concentration dependent)

98
Q

When is the dose of daptomycin reduced?

A

In renal impairment

99
Q

What are the side effects of daptomycin?

A
  1. Cardiovascular, Central nervous system
  2. Rash, GIT effects, Electrolyte disturbances
  3. Haematological, Musculoskeletal & Hepatic effects
  4. Acute renal failure (2.2%), Dyspnea (2.1%)
  5. Hypersensitivity
  6. Possible myopathy & rhabdomyolysis (with statins)
100
Q

What drugs cause disruption of the bacterial plasma membrane?

A

Polymyxin B and E (colistin)

101
Q

What is the MOA of Polymyxin B and E (colistin)?

A

– Attach to phospholipids in bacterial plasma
membrane (disrupt membrane structure)
– Change membrane permeability
– Selectively bactericidal to Gram neg. bacteria

102
Q

How is polymyxin B administered?

A

Topical use only

103
Q

What is the spectrum of polymyxin B?

A

– Skin, eye & ear infections
– IV: combination “salvage” therapy in
exceptional cases of infections due to
multidrug-resistant Gram neg. pathogens (P.
aeruginosa, Actinobacter baumanii)

104
Q

What are he side effects of polymyxin B?

A

Parenteral: nephrotoxic and neurotoxic

105
Q

What is the spectrum for polymyxin E (colistin)?

A

– Severe resistant Gram negative infections
(carbapenems resistant)
– Last line treatment for multi-drug resistant
infections

106
Q

What are the side effects of polymyxin E?

A

Reversible nephrotoxicity

Pharmacology (11 decks)

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