Protein Synthesis Inhibitors
Last updated 12th Oct 2019 - Tom Heaton
The classes of antimicrobials which inhibit protein synthesis include:
- Aminoglycosides
- Macrolides
- Lincosamides
Aminoglycosides
E.g. gentamicin, tobramycin, neomycin, amikacin.
These are an important class of antibiotics with a wide gram negative cover.
They may have some gram positive cover, but no anaerobic activity as they enter the cell via an oxygen dependent mechanism.
As noted earlier, they have a synergistic effect with antibiotics that interfere with cell wall synthesis e.g. beta lactams.
This is a good video on them: https://www.youtube.com/watch?v=IPcbQddeJTw
These are an important class of antibiotics with a wide gram negative cover.
They may have some gram positive cover, but no anaerobic activity as they enter the cell via an oxygen dependent mechanism.
As noted earlier, they have a synergistic effect with antibiotics that interfere with cell wall synthesis e.g. beta lactams.
This is a good video on them: https://www.youtube.com/watch?v=IPcbQddeJTw
PD
They function by binding to the 30s subunit of bacterial ribosomes, inhibiting or disrupting their role in synthesising proteins from RNA.
This is bactericidal (a constant supply of proteins is needed for cell life).
Their efficacy is based upon their peak plasma concentration.
They are actively transported into bacterial cells and this may be impaired by electrolyte disturbances, acidosis or hypoxia, and hence their lack of efficacy in anaerobes.
These effects continue in the bacteria after drug levels fall, and they are described as having a significant post-antibiotic effect.
They function by binding to the 30s subunit of bacterial ribosomes, inhibiting or disrupting their role in synthesising proteins from RNA.
This is bactericidal (a constant supply of proteins is needed for cell life).
Their efficacy is based upon their peak plasma concentration.
They are actively transported into bacterial cells and this may be impaired by electrolyte disturbances, acidosis or hypoxia, and hence their lack of efficacy in anaerobes.
These effects continue in the bacteria after drug levels fall, and they are described as having a significant post-antibiotic effect.
PK
They have a low lipid solubility and are not absorbed from the gut, being given parenterally.
They are quite large polarised molecules which means they have quite a low distribution, being primarily limited to the extracellular space.
They have low protein binding.
They are not metabolised and excreted unchanged in the urine.
They half a plasma half life of 2-3 hours.
Their narrow therapeutic window and mechanism of action means that they are usually given as a single dose, with subsequent monitoring of levels.
They have a low lipid solubility and are not absorbed from the gut, being given parenterally.
They are quite large polarised molecules which means they have quite a low distribution, being primarily limited to the extracellular space.
They have low protein binding.
They are not metabolised and excreted unchanged in the urine.
They half a plasma half life of 2-3 hours.
Their narrow therapeutic window and mechanism of action means that they are usually given as a single dose, with subsequent monitoring of levels.
Adverse effects
Ototoxicity occurs due to accumulation of the drug within the perilymph.
It is usually related to peak drug levels and reduced clearance, and is therefore exacerbated by renal impairment or furosemide administration.
It more commonly affects the vestibular system (gentamicin and tobramycin) and is usually permanent.
Nephrotoxicity, with acute tubular necrosis, is a risk of aminoglycoside use, with the risk increasing with age.
ICU patients are also at high risk.
The injury tends to recover after discontinuation of treatment.
Muscular weakness occurs due to interference with prejunctional release and post junctional responsive to acetylcholine at the neuromuscular junction.
This prolongs the action of nondepolarizing neuromuscular blockers and makes them relatively contraindicated in patients with myasthenia gravis.
- Ototoxicity
- Nephrotoxicity
- Weakness
Ototoxicity occurs due to accumulation of the drug within the perilymph.
It is usually related to peak drug levels and reduced clearance, and is therefore exacerbated by renal impairment or furosemide administration.
It more commonly affects the vestibular system (gentamicin and tobramycin) and is usually permanent.
Nephrotoxicity, with acute tubular necrosis, is a risk of aminoglycoside use, with the risk increasing with age.
ICU patients are also at high risk.
The injury tends to recover after discontinuation of treatment.
Muscular weakness occurs due to interference with prejunctional release and post junctional responsive to acetylcholine at the neuromuscular junction.
This prolongs the action of nondepolarizing neuromuscular blockers and makes them relatively contraindicated in patients with myasthenia gravis.
Clinical use
There are 3 main mechanisms by which resistance to aminoglycosides may develop:
- Gram negative bacteria
- Some gram positive organisms
There are 3 main mechanisms by which resistance to aminoglycosides may develop:
- Transferase enzyme
- Impaired entry into cell
- Mutation of 30s subunit of ribosomes
Macrolides
E.g. erythromycin, clarithromycin, azithromycin
This is a good introductory video: https://www.youtube.com/watch?v=FeYDn6oU9II
Erythromycin was the initial drug of this class with clarithromycin and azithromycin being synthesised later.
This is a good introductory video: https://www.youtube.com/watch?v=FeYDn6oU9II
Erythromycin was the initial drug of this class with clarithromycin and azithromycin being synthesised later.
PD
These act by binding to the 50s unit of bacterial ribosomes, inhibiting protein synthesis.
Their actions are primarily bacteriostatic but can be bactericidal.
These act by binding to the 50s unit of bacterial ribosomes, inhibiting protein synthesis.
Their actions are primarily bacteriostatic but can be bactericidal.
PK
They generally have good oral bioavailability and can be given orally or IV.
Oral preparations are enterically coated or in other preparations as they are destroyed by gastric acid, and food can impair absorption.
CSF penetration is poor, but otherwise good for other tissues.
They undergo hepatic metabolism, but with a significant amount also excreted unchanged in the urine (requiring dose adjustment in renal failure and RRT).
Protein binding is variable between the drugs.
Azithromycin has a better bioavailability and prolonged half life and so is suitable for once daily dosing.
They generally have good oral bioavailability and can be given orally or IV.
Oral preparations are enterically coated or in other preparations as they are destroyed by gastric acid, and food can impair absorption.
CSF penetration is poor, but otherwise good for other tissues.
They undergo hepatic metabolism, but with a significant amount also excreted unchanged in the urine (requiring dose adjustment in renal failure and RRT).
Protein binding is variable between the drugs.
Azithromycin has a better bioavailability and prolonged half life and so is suitable for once daily dosing.
Side Effects
GI upset is a common feature of this class, including nausea, diarrhoea and hepatic dysfunction.
They have a prokinetic effect and erythromycin is used to this end in critical care.
Erythromycin has fewer adverse effects in this way.
They can increase the levels of certain drugs: warfarin, digoxin, theophylline, and alfentanil and midazolam in the case of erythromycin.
- GI upset
- QT prolongation
- Drug interactions
GI upset is a common feature of this class, including nausea, diarrhoea and hepatic dysfunction.
They have a prokinetic effect and erythromycin is used to this end in critical care.
Erythromycin has fewer adverse effects in this way.
They can increase the levels of certain drugs: warfarin, digoxin, theophylline, and alfentanil and midazolam in the case of erythromycin.
Clinical
They have a similar spectrum of effectiveness as the penicillins, and are commonly substituted in cases of allergy:
Their action against mycoplasma and legionella make it specifically indicated for these.
Clarithromycin has a better cover against streptococci and listeria.
Azithromycin has better gram negative cover.
They have a similar spectrum of effectiveness as the penicillins, and are commonly substituted in cases of allergy:
- Good gram positive effects
- Good atypical cover - mycoplasma, legionella
- Some anaerobic activity
- Some gram negative activity
Their action against mycoplasma and legionella make it specifically indicated for these.
Clarithromycin has a better cover against streptococci and listeria.
Azithromycin has better gram negative cover.
Links & References
- Varley, A. Sule, J. Absalom, A. Principles of antibiotic therapy. CEACCP. 2009. 9(6): 184-188. https://academic.oup.com/bjaed/article/9/6/184/378495
- Hasudungan, A. Microbiology - antibiotics mechanism of action. 2013. https://www.youtube.com/watch?v=IVBCrzjOl40
- Strong Medicine. Antibiotics. 2013. https://www.youtube.com/watch?v=GX3kYv42mcc&list=PLYojB5NEEakWCoWLnx0F1OxY6PXVaBkVT
- Lockwood, G. Antimicrobial drugs. e-LFH. 2019.
- Gillon, S. et al. Revision notes in intensive care medicine. 2016. Oxford University Press.
- Med Vids Made Simple. Aminoglycosides. Youtube. 2018. https://www.youtube.com/watch?v=IPcbQddeJTw
