74. Macrolide antibiotics, clindamycin, chloramphenicol, oxazolidinones, streptogramins

Page created on September 27, 2019. Last updated on January 7, 2022 at 22:47

Macrolides

Compounds:

  • Erythromycin
  • Clarithromycin
  • Azithromycin

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.

Pharmacokinetics:

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.

Adverse effects:

GI symptoms are common, especially for erythromycin. Long QT and hepatotoxicity are rare, but less rare for erythromycin.

Clinical use:

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.

Chloramphenicol

Mechanism of action:

Chloramphenicol binds to the 50S ribosomal subunit and inhibits elongation of the peptide chain. This effect is bacteriostatic against most bacteria it is effective against, but is bactericidal against H. influenzae, Neisseria and Bacteroides fragilis.

Mechanism of resistance:

Resistance against chloramphenicol is common among Gram-positives and Gram-negatives. It is mediated by enzymatic inactivation or by decreased cell envelope penetration.

Pharmacokinetics:

Chloramphenicol is orally absorbed, and it is broadly distributed, including in the CNS.

It is metabolized in the liver, mostly by conjugation with glucuronic acid by the enzyme UGT. It is excreted by the kidney and has a short half-life (3 – 5 hours).

Adverse effects:

This drug is toxic, with three significant adverse effects. It can inhibit mitochondrial protein synthesis in cells in the bone marrow, causing bone-marrow suppression. This effect is reversible in that it will be normalized after cessation of the drug. It is also dose dependent.

However, chloramphenicol can cause aplastic anaemia as well. Unlike the aforementioned bone-marrow depression this aplastic anaemia is irreversible and not dose dependent. It can occur even after the smallest dose, and it usually occurs weeks or months after the last dose. It is fatal if not treated with bone marrow transplantation. The mechanism of this adverse effect is unknown.

Grey baby syndrome is the last significant adverse effect of chloramphenicol. It occurs when a pregnant mother receives chloramphenicol during the last trimester. Neonates, especially prematures, have decreased or no UGT activity. This causes chloramphenicol to accumulate, causing muscle weakness, cyanosis, vomiting, hypothermia and circulatory shock. The cyanosis gives the baby a grey appearance, hence the name.

Lastly, chloramphenicol causes some less severe side effects as well, like GI symptoms and oral and vaginal candidiasis.

Clinical use:

The toxicity of chloramphenicol limits its clinical use. Its systemic use is often limited to severe cases or when other safer antibiotics are unavailable. It’s more commonly used in developing countries, as it is relatively cheap.

Topical application is not associated with adverse effects. Chloramphenicol eyedrops are therefore often used in conjunctivitis.

It is sometimes used to treat bacterial meningitis, Rickettsia, Coxiella, Brucella and Salmonella typhi infections.

Clindamycin

Clindamycin is a semi-synthetic lincosamide.

Mechanism of action:

It binds to the 50S ribosomal subunit, inhibiting peptide translocation. This effect is bacteriostatic.

Pharmacokinetics:

The drug is completely orally absorbed. It is broadly distributed but does not enter the CNS. It accumulates in macrophages and in bones.

It is metabolized in the liver and excreted by the bile. The elimination is rapid, with a half-life of 3 hours.

Adverse effects:

Diarrhoea and C. difficile colitis are much more common with clindamycin than with other antibiotics. Rashes are relatively common, and metallic taste can also occur.

Clinical use:

Clindamycin is effective against most Gram-positive cocci, but not Enterococci. It is also effective against anaerobes, but not against aerobe Gram-negatives.

Clindamycin is used topically to treat acne. It is used systemically to treat soft tissue infections, bone infections, joint infections and abscesses.

Oxazolidinones

The important oxazolidinones are linezolid and tedizolid.

Mechanism of action:

These drugs bind to the 50S subunit of the bacterial ribosome and inhibit protein synthesis. The exact mechanism is unique for this class of drugs, and it inhibits protein synthesis at an earlier stage than other antibiotics.

Linezolid is a weak, reversible monoamine oxidase inhibitor.

Pharmacokinetics:

These drugs are completely absorbed (bioavailability 100%) from the GI tract and are broadly distributed. They penetrate the CNS.

They are 70% biotransformed and excreted by the kidney, while the remaining 30% are excreted unchanged.

Adverse effects:

Peripheral neuropathy and bone marrow suppression are the most significant side effects, but gastrointestinal side effects can also occur. The more severe side effects usually only occur in people who have been treated with the drugs for weeks.

Unique for linezolid is that it can cause serotonin syndrome, especially if taken with monoamine oxidase inhibitors or SSRIs. It can also cause the cheese reaction.

Clinical use:

Oxazolidinones are effective against Gram-positives and Mycobacteria. Both of these drugs are effective against multi-resistant bacteria like VRE, MRSA, VRSE and multi-resistant M. tuberculosis. These drugs are reserved for multi-resistant infections.

Streptogramins

The most important streptogramins are quinupristin and dalfopristin. These antibiotics are usually given in combination to yield a synergic action. When used alone they’re bacteriostatic but the combination is bactericidal.

Mechanism of action:

Streptogramins bind to the 50S subunit and inhibit elongation of the peptide chain, similarly to clindamycin and macrolides. Dalfopristin enhances the binding of quinupristin.

Pharmacokinetics:

These drugs are not absorbed and must be given IV. They accumulate in macrophages and don’t enter the CNS.

They’re metabolized in the liver by CYP450 and excreted with bile. They inhibit CYP3A4 and can therefore interact with many drugs.

Adverse effects:

The drug commonly has side effects (10 – 15%), including arthralgia, myalgia and pain at the infusion site.

Clinical use:

Quinupristin/dalfopristin is effective against multi-resistant Gram-positives like VRE, MRSA and VRSE. They’re reserved for multi-resistant infections, often as a last resort. Resistance toward quinupristin/dalfopristin is rare.


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Pharmacology 2

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