Protein Synthesis inhibitors Flashcards
What drugs are aminoglycosides?
Amikacin, gentamicin, neomycin, streptomycin
What is the spectrum for aminoglycosides?
- 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)
What are aminoglycosides administered with for anaerobic infections?
metronidazole or clindamycin
What can aminoglycosides be used with to treat staphylococci, streptococci and enterococci?
Penicillin
What is the MOA of aminoglycosides?
- 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
What causes resistance to aminoglycosides?
- Mutation of binding site on 30S ribosomal
subunit (streptomycin only) - Inhibition of transport into cell
- Inactivation by enzymes (acetyl transferases,
adenyl transferases & nucleotidyl transferases)
What is the absorption of amnioglycosides?
After IM administration → rapidly and completely
absorbed → distributed in the extracellular fluid
and tissues
What increases the half life of aminoglycosides?
Reduced renal capacity and during the use in neonates
How are aminoglycosides metabolised and excreted?
Excreted mainly unaltered (70-90%) within 24
hours in the urine
T or F - Bactericidal effect of aminoglycosides are concentration dependent?
True
Aminoglycosides exert a short post-antibiotic effect, T or F?
False, post-antibiotic effect is prolonged
What are the side effects of aminoglycosides?
- 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 - All are nephrotoxic and ototoxic (therapy > 5
days, ↑ doses, in elderly, renal insufficiency) - Neuromuscular blockage
What are the most nephrotoxic aminoglycosides?
Neomycin, tobramycin & gentamicin are most
nephrotoxic
Which aminoglycosides are the most ototoxic?
Neomycin & amikacin
Which aminoglycosides are the most vestibulotoxic?
Streptomycin & gentamicin
What happens if streptomycin is administered during pregnancy?
Streptomycin given during pregnancy cause
deafness in the child
What are the drug interactions of aminoglycosides?
- General anaesthetics
- Neuromuscular blocking agents
- Oto- or nephrotoxic agents (vancomycin,
amphotericin) - Loop diuretics
What are the cautions with aminoglycosides?
- Elderly
- Renal insufficiency
- Neonates
- Strong caution bordering on contraindication:
Pregnancy (Streptomycin) - Contraindicated: Myasthenia gravis
Are macrolides bacteriostatic or bacteriocidal?
They are Bacteriostatic. At high dosages → bactericidal
What drugs are macrolides?
erythromycin (prototype drug), azithromycin, clarithromycin
What are macrolides effective in the treatment of?
– Legionnaires disease (Leggionella
pneumophila)
– Whooping cough (Bordetella pertussis)
– Mycoplasma pneumoniae
– Diphtheria (Corynebacterium) infections
Macrolides can also be used as an alternative
drug by patients that are allergic to what drug?
Penicillin
What is the spectrum for erythromycin?
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)
What is the drug regime for a person allergic to penicillin with peptic ulcer disease?
Eradication of Helicobacter pylori in Peptic ulcer
disease (clarithromycin/azithromycin +
metronidazole + omeprezole) in penicillin allergy
When is erythromycin CI?
Erythromycin/azithromycin NOT TO BE USED for
syphilis in pregnant women allergic to penicillins
What drugs are used for rickettsial
infections (2nd line agent)?
Azithromycin/clarithromycin
What is the MOA of macrolides?
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
What causes resistance to macrolides?
- Reduced cell membrane permeability or active
efflux - Production of esterases that hydrolize
macrolides - Modification of the ribosomal binding site
What affects the absorption of erythromycin?
Erythromycin absorption effected by:
formulation, gastric acidity & food
* Administered orally as stearate salt or esterified
form (estolate)
* Erythromycin (base & stearate) → food ↓
absorption
How are macrolides metabolised and excreted?
Readily metabolised by the liver and excreted in
the bile
What are the side effects of microlides?
- GIT intolerance (abdominal pain, cramping,
nausea, vomiting, diarrhoea) - Allergic reactions (rare)
- Hepatotoxicity:
– When the estolate is, however, taken for more
than 10 days, cholestatic jaundice
(irreversible) can occur
– Benign elevation of serum transaminase - Erythromycin and clarithromycin → inhibit the
liver cytochrome P450 system & P-glycoprotein
What are the drug interactions of microlides?
- Serum concentrations of different drugs ↑
(e.g. theophylline, and warfarin) - Reduce efficacy of combined oral contraceptive
pill
What are the cautions for microlides?
- Liver disease
- Impaired biliary function
- C/I Porphyria (erythromycin)
- Heart disease (clarithromycin & azithromycin)
Are tetracyclines bacteriostatic or bacteriocidal?
Bacteriostatic
What drugs are tetracyclines?
Tetracycline, doxycycline, minocycline, Tigecycline
What is the use of tetracyclines?
Combination with other agents for treatment of
malaria
Chronic bronchitis
Acne
What bacteria are tetracyclines the drug of choice for?
– Rickettsia
– Chlamydia
– Brucellosis
– Mycoplasma
– Spirochaetal infections
What is the MOA of tetracyclines?
- 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
What causes resistance to tetracyclines?
- Decreased intracellular accumulation (decreased
influx or active efflux) → most important - Production of a protein that interferes with the
binding of tetracyclines on the ribosome - Enzymatic inactivation
What must tetracyclines be taken with?
Taken with adequate amount of fluid
What prevents absorption of tetracyclines?
Antacids and milk
How are Doxycycline and minocycline excreted?
Excreted mainly in bile (safer in renal
impairment)
What are the side effects of tetracyclines?
- Cause GIT disruptions e.g. nausea and vomiting
(dose related) - Destruction of normal gut flora →
superinfections with Candida - Pseudomembranous colitis → Clostridium
difficile can also occur - Elderly patients → hepatotoxic effects
- Photosensitivity
- Deposited in bone and teeth
- Causing bone growth retardation in children
- Discolouration of nails and teeth & occasional
enamel hypoplasia in children - Potentially nephrotoxic
- Reduced efficacy of the combined oral
contraceptive pill - Minocycline
– Blue-grey pigmentation of the skin &
pigmentation of acne scars
– Vestibular toxicity - Tiglecycline
– Increased mortality and treatment failure
noted
What are the drug interactions of tetracyclines?
- Carbamazepine, phenytoin, barbiturates,
rifampicin (serum levels of doxycycline ↓) - Vit A & other retinoids → enhanced risk of ↑
intracranial pressure - Combined oral contraceptive pill
What are the cautions with tetracyclines?
- Systemic lupus erythematosus (minocycline)
- Myasthenia gravis
- Hepatic impairment
- Porphyria
- Elderly
- C/I in pregnancy, Children < 8 - 12 yrs
Which antibiotic is rarely used as first choice treatment because of it’s potential toxicity?
Chloramphenicol. It is bacteriostatic
When is Chloramphenicol indicated?
Only reserved for severe infections by
susceptible organisms due to potential to cause
aplastic anaemia
What is the spectrum of Chloramphenicol?
- 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
What is the MOA of Chloramphenicol?
- Powerful inhibitor of bacterial protein synthesis
- Attaches reversibly to the 50S ribosomal-subunit
- Interferes with the mechanism of action of
peptidyltransferase
What causes resistance against Chloramphenicol?
- Production of chloramphenicol acetyltransferase that inactivates the drug
How is Chloramphenicol administered?
Orally.
How is Chloramphenicol metabolised?
Metabolised in the liver and after glucuronide
formation → urine
What are the side effects of Chloramphenicol?
- Serious irreversible bone marrow depression →
idiosyncratic → fatal aplastic anaemia (topical use) - Dose-related reversible bone marrow toxicity
- Efficacy of the combined oral contraceptive pill → reduced
- 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 - GIT effects, optic or peripheral neuritis
- Hypersensitivity reactions and jaundice
- Inhibits liver enzymes
What are the drug interactions of Chloramphenicol?
- Causes hepatic enzyme inhibition:
– ↑ concentrations of phenytoin, warfarin,
sulphonylurea antidiabetic agents - Used with hepatic enzyme inducers
(penobarbital, rifampicin) → efficacy of
chloramphenicol ↓ - Vit B, folic acid & iron → chloramphenicol may
interfere with haematological response - Combined oral contraceptive pill
What are the cautions/CI of chloramphenicol?
C/I :
– Allergy
– Porphyria
– Third trimester of pregnancy
– Neonates
– Lactation
Caution:
– Impaired hepatic function
– Bone marrow depression
What is the spectrum of Clindamycin?
- 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
What is the MOA of clindamycin?
- 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
What causes resistance to clindamycin?
- Mutation of ribosomal binding site
- Enzymatic inactivation
Where is clindomycin metabolised?
Liver
How is clindomycin excreted?
bile
What are the side effects of clindomycin?
- Common: diarrhoea, nausea (oral, IV & IM), skin reactions
- Transient ↑ liver enzymes & bilirubin
- Transient leucopenia, thrombocytopenia, agranulocytosis,
eosinophilia - Pseudomembranous colitis is a serious and potentially
fatal complication
– Toxin produced by Clostridium difficile - May reduce efficacy of combined oral contraceptive pill
What are the drug interactions of clindomycin?
Oral contraceptive
What are the cautions with clindomycin?
- GIT disease
- Severe hepatic impairment
- Porphyria
- Elderly
- Pregnancy/Lactation
What type of antibiotic is fusidic acid?
A steroid antibiotic
What is the spectrum of fusidic acid?
- 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
What is the MOA of fusidic acid?
- Mechanism of action similar to macrolides
(inhibiting translocation)
How is fusidic acid excreted?
Excreted as metabolites in bile
What are the side effects of fusidic acid?
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
What are the DI of fusidic acid?
- Hydrocortisone – decrease in AB activity of fusidic acid
- Statins - ↑ risk of rhabdomyolysis
What is the CI for fusidic acid?
Hepatic dysfunction
What is the spectrum of mupirocin?
Gram pos. bacteria, effective against
methicillin-resistant Staphylococcus aureus
What is the MOA of mupirocin?
– Reversibly binds to Isoleusine-tRNA
synthetase and prevents formation of
Isoleusine-tRNA
– Inhibits protein and RNA synthesis
– Bactericidal at high concentrations
How is mupirocin administered?
Topically only
What are the side effects of upirocin?
Mild stinging, burning, itching at site of
application
What is the caution with mupirocin?
Porphyria
What drug is a Ketolide?
Telithromycin
What is the spectrum of ketolides (telithromycin)?
– Similar spectrum to macrolides, H. influenzae
– Erythromycin–resistant strains of
pneumococcus
What is the MOA of ketolides (telithromycin)?
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)
How are ketolides (telithromycin) metabolised and excreted?
Metabolised in liver, Excretion: biliary and
urinary
What are the side effects of ketolides (telithromycin)?
- Inhibits liver enzymes
- Risk of potentially serious hepatotoxicity
- Respiratory failure → myasthenia gravis
patients - Visual disturbances
- Loss of consciousness
What drug is an Oxazolidinone?
Linezolid
What is the spectrum of oxazolidinones (linezolid)?
– 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
When is linezolid indicated?
Last resort where every other antibiotic therapy
has failed → should be reserved for this purpose
What is the MOA of linezolid (an oxazolidinone)?
– Prevents formation of ribosome complex
– Binds to 23S ribosomal RNA of the 50S
ribosomal subunit, inhibits protein synthesis
What causes resistance to linezolid?
Mutation of linezolid binding site on 23S
ribosomal RNA
What are the side effects of linezolid?
- Haemolytic toxicity (mild, reversible)
- Peripheral neuropathy (prolonged use)
- Reversible non-selective inhibitor of MAO
- Headache, moniliasis/fungal infection,
metallic taste, GIT effects, neurotoxicity
What are the drug interactions of linezolid?
– Sympathomimetic or adrenergic drugs
→ produces serotonin syndrome (fever,
flushing, sweating, tremors, and delirium)
What drugs are streptogramins?
Quinupristin-dalfopristin (fixed 30/70 combination)
– Each agent alone: bacteriostatic
– Combined: bactericidal
What is the spectrum of streptogramins (Quinupristin-dalfopristin)?
– 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
What is the MOA of streptogramins (Quinupristin-dalfopristin)?
– 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
What causes resistance to streptogramins?
– Quinupristin
* A ribosomal methylase that prevents binding
* Lactonases produced that inactivate the drug
– Dalfopristin
* Acetyltransferases produced that inactivate
the drug
* Increased efflux
When is the dose of streptogramins adjusted?
Dose adjustment with hepatic dysfunction
What are the side effects of streptogramins?
- Via peripheral vein → inflammation, pain,
oedema, infusion site reaction,
thrombophlebitis - Nausea, diarrhoea, vomiting
- Rash, pruritus
- Headache
- Pain
- Arthralgia, myalgia
- Asthenia
- Conjugated hyperbilirubinaemia
What are the drug interactions of streptogramins?
Warfarin
Diazepam
Terfenadine
Astemizole
Cisapride
NNRTI
Cyclosporine (ciclosporine)
What drug is a lipopeptide?
Daptomycin
What is the spectrum for daptomycin?
– 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
What is the MOA of daptomycin (a lipopeptide)?
– 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)
When is the dose of daptomycin reduced?
In renal impairment
What are the side effects of daptomycin?
- Cardiovascular, Central nervous system
- Rash, GIT effects, Electrolyte disturbances
- Haematological, Musculoskeletal & Hepatic effects
- Acute renal failure (2.2%), Dyspnea (2.1%)
- Hypersensitivity
- Possible myopathy & rhabdomyolysis (with statins)
What drugs cause disruption of the bacterial plasma membrane?
Polymyxin B and E (colistin)
What is the MOA of Polymyxin B and E (colistin)?
– Attach to phospholipids in bacterial plasma
membrane (disrupt membrane structure)
– Change membrane permeability
– Selectively bactericidal to Gram neg. bacteria
How is polymyxin B administered?
Topical use only
What is the spectrum of polymyxin B?
– Skin, eye & ear infections
– IV: combination “salvage” therapy in
exceptional cases of infections due to
multidrug-resistant Gram neg. pathogens (P.
aeruginosa, Actinobacter baumanii)
What are he side effects of polymyxin B?
Parenteral: nephrotoxic and neurotoxic
What is the spectrum for polymyxin E (colistin)?
– Severe resistant Gram negative infections
(carbapenems resistant)
– Last line treatment for multi-drug resistant
infections
What are the side effects of polymyxin E?
Reversible nephrotoxicity
