73. Tetracyclines, aminoglycosides

Tetracyclines

Tetracyclines are a group of antibiotics. The most important ones are tetracycline, doxycycline, demeclocycline, minocycline, lymecycline and oxytetracycline. Tigecycline is technically not a tetracycline but is similar enough that it is mentioned here.

Mechanism of action

Tetracyclines bind to the 30S ribosomal subunit in bacteria and prevent elongation of the peptide chain. This elicits a bacteriostatic effect.

Mechanisms of resistance

Tetracyclines were previously widely used, which caused extensive resistance to develop. Resistance has receded recently and so their use has become more popular.

There are three main mechanisms of resistance. Expression of an efflux pump, enzymatic inactivation and expression of a “protection protein”, which protects the ribosomes from the antibiotic.

The efflux pump and protection protein don’t work against tigecycline, meaning that tigecycline is effective against many tetracycline-resistant infections.

Pharmacokinetics

Tetracycline and oxytetracycline are only 60 – 70% absorbed, while doxycycline and minocycline are 100% absorbed. This makes gastrointestinal symptoms more common in tetracycline and oxytetracycline. Tigecycline is not orally absorbed and must be given parenterally.

Tetracycline and oxytetracycline form chelates with metal ions, which decreases their absorption. For this reason, these drugs shouldn’t be taken with milk, antacids or iron preparations.

Tetracyclines accumulate intracellularly and extracellularly. They penetrate the placenta and are excreted in breast milk, but don’t enter the CNS. Because they accumulate intracellularly they’re especially effective against intracellular pathogens like Chlamydia and Rickettsia.

We should only know the excretion of doxycycline, which is the most used drug. It is mostly excreted by bile and therefore good for treating gallbladder infections.

Oxytetracycline and tetracycline have short half-lives and must be taken 2 – 4 times daily. Doxycycline, minocycline and tigecycline have long half-lives and can be taken only once daily.

Adverse effects

GI symptoms are most common in tetracycline and oxytetracycline, but all tetracyclines can directly irritate GI mucosa and even cause ulcers. These drugs should be taken with plenty of water.

Photosensitivity can occur. Both the drug itself and the person taking it should avoid sunlight to avoid dermatitis.

Tetracycline forms complexes with calcium in bones and teeth, causing deformities in growing bones and discoloration of teeth. For this reason, tetracyclines are contraindicated during pregnancy and under 8 years of age.

In high doses hepatotoxicity can occur.

Clinical use

Tetracyclines are mostly used for atypical bacteria like Borrelia, Mycoplasma, Rickettsia, Chlamydia, Vibrio cholerae etc. They are especially effective against intracellular bacteria. They’re also used to treat acne, as they decrease the colonization of Propionibacterium acnes. They may be used to treat H. pylori as well but are currently not part of the first-line regimen.

Tigecycline is used for complicated soft tissue infections and abdominal infections, especially when there is resistance toward the first-choice antibiotics. It’s even effective against MRSA, VRE and penicillin-resistant Strep. pneumoniae (PRSP).

Aminoglycosides

Compounds

• Gentamycin
• Streptomycin
• Tobramycin
• Neomycin
• Spectinomycin
• Amikacin

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.

Pharmacokinetics

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.

Adverse effects

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.

Dosing

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.

Clinical use

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.