Last updated on December 6, 2019 at 21:14
Mechanism of action:
Like all antibiotics aminoglycosides must penetrate the bacterial cell envelope. They passively permeate the outer membrane of Gram-negatives through porin channels. The penetration of the cytoplasmic membrane is secondary active transport, which depends on oxygen and pH. This transport is therefore inhibited in hypoxic and acidic environments.
When inside the bacterial cells aminoglycosides they bind to the 30S ribosomal subunit. They then inhibit the initiation of protein synthesis, and they induce misreading, causing the cell to produce faulty proteins. This effect is bactericidal and concentration-dependent, so a higher dose kills more bacteria. There is also a significant postantibiotic effect, which means that there is a suppression of bacterial growth even after the antibiotic has been removed from the system.
Mechanisms of resistance:
The most common mechanism of resistance to aminoglycosides is enzymatic inactivation of the aminoglycosides. Cytoplasmic enzymes catalyse adenylation, acetylation or phosphorylation of the antibiotic, which inactivates it.
Resistance can also occur due to decreased penetration or by changing the binding sites of the aminoglycoside on the 30S ribosomal subunit.
Aminoglycosides are highly polar molecules and are therefore not orally absorbed. They don’t enter the CNS. They accumulate in the inner ear and the kidney.
These drugs are eliminated by glomerular filtration in unchanged form. The half-life is 2 – 3 hours.
Aminoglycosides are highly toxic, with a narrow therapeutic window. The adverse effects depend on the plasma concentration and the exposure time.
The two main adverse effects are nephrotoxicity and ototoxicity. The former is reversible, and renal function often recovers after the aminoglycoside treatment. It is more likely to occur in people with pre-existing renal disease. Due to their renal elimination any nephrotoxicity of aminoglycosides can decrease the elimination and potentiate the side effects further.
The ototoxicity is irreversible. The aminoglycosides irreversibly damage the vestibulocochlear nerve. This can cause tinnitus, hearing impairment, dizziness or ataxia.
Even a single dose of aminoglycoside can cause neuromuscular blockade with paralysis. This occurs mostly in people who also take calcium channel blockers or peripheral muscle relaxants, or in people with myasthenia gravis.
Studies have shown that the effectiveness of aminoglycosides depends more on the maximum serum concentration than the average serum concentration. This is partly due to the postantibiotic effect. Because of this and the fact that the side effects are exposure-over-time-related, giving a single daily dose causes fewer side effects while still being effective.
The dose to be given is calculated based on the body weight. In people with renal failure the dose should be reduced proportionally with the decrease in GFR. Continuous plasma level monitoring is recommended, and the dose should be adjusted accordingly.
Aminoglycosides are generally used for severe gram-negative bacilli infections like sepsis. Gentamycin and beta-lactams combined is one of the first choices for sepsis with unknown microbe and focus, as it’s effective against those bacteria that most commonly cause sepsis. They’re not effective against anaerobes (due to the O2 requirement to enter the bacteria).
Tobramycin is more effective against pseudomonas and is preferred over gentamycin in pseudomonas infections. It is often given in inhaled form to treat pseudomonas infections in cystic fibrosis patients.
Neomycin is very toxic and is therefore not given parenterally. It’s not absorbed and can therefore be given orally to eliminate the gut flora before abdominal surgery. Nowadays it’s more commonly used topically.
Streptomycin is a second-line drug in the treatment of tuberculosis.
Amikacin is resistant to bacterial enzymes which inactivate other aminoglycosides and can therefore be used to treat aminoglycoside-resistant bacteria.
Spectinomycin is used to treat resistant cases of gonorrhoea. It is not ototoxic or nephrotoxic.
Mechanism of action:
Macrolides bind to the 50S subunit of bacterial ribosomes, inhibiting translocation. This effect is bacteriostatic.
Mechanism of resistance:
Resistance is often encoded by a plasmid. It can be mediated by drug efflux, enzymatic inactivation or changing the binding-site of macrolides on the ribosomes.
Macrolides are orally absorbed. Erythromycin is acid-labile and is therefore administered in a special enterosolvent formulation or as an ester prodrug. Food intake interferes with the absorption of erythromycin, but not the newer macrolides, which are acid-stable.
They penetrate well into tissues, but they don’t enter the CNS. Azithromycin accumulates in macrophages while clarithromycin accumulates in the middle ear. This is beneficial as azithromycin is “carried” to the site of infection while clarithromycin becomes very effective in treating otitis media.
All three are partially metabolized in the liver and mainly excreted by bile. Erythromycin and clarithromycin are CYP3A4 inhibitors, while azithromycin is not.
Erythromycin has half-life of 2h, clarithromycin of 6h and azithromycin of 12h. However, azithromycin accumulates in tissues, and its tissue half-life is 72 hours. This means that azithromycin only needs to be taken once daily. Clarithromycin can be given 2 times daily.
GI symptoms are common, especially for erythromycin. Long QT and hepatotoxicity are rare, but less rare for erythromycin.
The antimicrobial spectrum of erythromycin is similar to that of penicillin, so it’s often used as an alternative for penicillin-sensitive patients.
Macrolides are important in the treatment of atypical pneumonia, as they’re effective against mycoplasma, legionella and Chlamydophila.
71. Glycopeptide antibiotics, polymixins, gramicidins, nitroimidazoles
73. Tetracyclines. Chloramphenicol, clindamycin, linezolid, streptogramins