72. Glycopeptide antibiotics. Daptomycin, fosfomycin, bacitracin, polymyxins, gramicidins

Page created on September 25, 2019. Last updated on January 7, 2022 at 22:50

Glycopeptide antibiotics

The important glycopeptide antibiotics are vancomycin and teicoplanin.

Mechanism of action:

Glycopeptide antibiotics inhibit cell wall synthesis by inhibiting the transpeptidation process which is essential for cell wall synthesis. They bind to the D-Ala-D-Ala residue of the substrate for the transpeptidation reaction.

They are mainly effective against Gram positive bacteria. They are bactericidal.

Pharmacokinetics and dosing:

These drugs have poor oral absorption, so they’re not used orally for systemic treatment. This property makes them very good for treating GI-tract infections, as the drug will remain in the GI tract.

Glycopeptide antibiotics are distributed well in the EC space, and they only enter the CNS when the meninges are inflamed. They’re eliminated unchanged by the kidneys. Vancomycin has a shorter half-life (4 – 6 hours) while teicoplanin has a long half-life (45 – 70 hours).

Adverse effects:

If the infusion is not given slowly enough the drugs can trigger non-specific mast cell degranulation and histamine release. This gives red flushing of the skin, dyspnoea and hypotension.

These drugs can increase the nephrotoxicity of other nephrotoxic drugs like aminoglycosides or NSAIDs.

Clinical use:

Glycopeptides, especially vancomycin, is the first-line treatment of MRSA infections. They are the first-line treatment of C. difficile colitis when given orally (according to uptodate. The lecture is not up to date and says that metronidazole is the first-line).

Lipopeptide antibiotics

Daptomycin is the only important lipopeptide antibiotic.

Mechanism of action:

Daptomycin integrates into the cell membrane and increases its permeability. This depolarizes it by causing efflux of ions, which kills the bacterium.

Pharmacokinetics:

It is not absorbed orally, and it is eliminated by the kidneys. Daptomycin is inactivated by the surfactant in the lungs.

Adverse effects:

Reversible myopathy and potentially rhabdomyolysis. Eosinophilic pneumonia.

Clinical use:

Daptomycin is usually reserved for multi-resistant bacteria like vancomycin-resistant enterococci and MRSA. It can’t be used to treat pneumonia, due to the surfactant thing.

Fosfomycin

Fosfomycin is an epoxide antibiotic.

Mechanism of action:

It inhibits the cell wall synthesis by inhibiting an enzyme called MurA.

Pharmacokinetics and dosing:

It is orally absorbed and is eliminated unchanged by the kidneys.

Clinical use:

Fosfomycin has a wide antibiotic spectrum, including MRSA, ESBL and VRE. Even then it is mostly used to treat uncomplicated urinary tract infections, but only if there is resistance against first-choice antibiotics. A single dose of 3g is often sufficient.

Bacitracin

Bacitracin is a mix of polypeptides.

Mechanism of action:

It inhibits the lipid barrier which transports the building blocks of the cell wall through the cell membrane.

Pharmacokinetics:

It is not orally absorbed. It is eliminated unchanged by the kidneys.

Clinical use:

Bacitracin is mostly used topically for skin infections. It is rarely used systemically because it is highly nephrotoxic.

Polymyxins

Polymyxin B or polymyxin E (also called colistin) are antibiotics mostly used topically. They can be used systemically for severe gram-negative infections like pseudomonas, but these antibiotics cause severe nephrotoxicity and neurotoxicity and are therefore not commonly used on this indication.

They kill bacteria by disrupting the structure of the outer cell membrane. They have no effect on Gram-positive bacteria.

Gramicidin

Gramicidin is a mixture of peptides with antibiotic activity. It causes haemolysis of RBCs, so it cannot be used systemically. It’s instead used topically, in eye or ear drops.

They kill bacteria by forming ion channels in the membrane, disrupting the ion gradient.

Nitrofurans

The only important nitrofuran is nitrofurantoin.

Mechanism of action:

Like nitroimidazoles nitrofurantoin is reduced to active metabolites that damage DNA and proteins.

Pharmacokinetics:

Unlike nitroimidazoles nitrofurantoin doesn’t penetrate tissues well. It is rapidly absorbed in the GI tract and rapidly excreted unchanged by the kidneys.

Adverse effects:

Nausea and hypersensitivity reactions are the most common. Pneumonitis and pulmonary fibrosis are rarer, more severe side effects.

Clinical use:

Thanks to its pharmacokinetics nitrofurantoin is effective in treating lower urinary tract infections. It is one of the first choices for treating uncomplicated cystitis and in prophylaxis.