Polypeptide antibiotics

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Polypeptide antibiotics:

These are low molecular weight polypeptides produced by various bacterial species.
They possess strong bactericidal action but not used systemically due to toxicity
These drugs include polymyxins, bacitracin, thiostrepton, tyrothricin and gramicidin.

Polymyxins:

It is generic name used for a group of six strong basic cyclic polypeptides namely polymyxins A,B,C,D,E & M. Of this polymyxins B and E are therapeutically used.

Polymyxin B:

It is bactericidal polypeptide antibiotics obtained from bacterium Bacillus polymyxa.
It is used only for topical application and oral administration
It is cationic detergent consisting of cyclic peptides with a long hydrophobic tail consisting of amino acid and fatty acid moiety.

Mechanism of action:

These are rapidly acting bactericidal agent with a detergent like action on the bacterial cell membrane.

Polymyxins, due to presence of positively charged cyclic peptides interacts with LPS in outermembrane of gram -ve bacteria

Alteration in membrane permeability of bacteria

Cellular constituents like ions, amino acids, purines and pyrimidines escape from protoplasm

Disruption of bacterial cell membrane

Death of bacteria

In addition to bactericidal action, polymyxin B may also inactivate endotoxins produced by gram -ve bacteria by binding to anionic lipid component of LPS of toxin.
It doesnot interact with cell membrane of gram +ve bacteria. So, its activity is mainly confined to gram -ve bacteria
Bactericidal activity is reduced by serum and tissues fluids and by soap and other surface-active agents

Antimicrobial spectrum:

It has narrow spectrum of activity with efficacy against gram -ve bacteria only
They are active against Enterobacter, Klebsiella, Salmonella, Pasteurella, Bordetella, Pseudomonas, E.coli and
Most Proteus and Serratia species are resistant to polymyxins.
It is used only when other drugs are not effective against gram -ve bacteria.

Bacterial resistance:

Pharmacokinetics:

These are not absorbed on topical application and little or no absorption takes place from GI tract
After parenteral administration, peak blood levels develop in 1-2 hours. However, blood levels of polymyxins remain low because of their interaction with cell membrane as well as to tissue debris and purulent exudates
These are metabolized and excreted in urine as inactive metabolites
Plasma half-lives of polymyxins ranges from 3-6 hours.

Side effects/Adverse effects:

Side effects on topical application and oral administration is low with occasional diarrhoea, nausea and vomiting.
Parenteral administration produces serious toxic effects, particularly nephrotoxicity and neurotoxicity.
Nephrotoxicity is manifested as albuminuria, renal cast and hematuria and is due to accumulation of drug in glomerular and renal epithelial cells
Neurotoxic effects include loss of balance and muscle weakness.
Ataxia, diplopia and ptosis may occur.
Neuromuscular paralysis
Parenteral administration can degranulate mast cell leading to histamine release.
Hypersensitivity
Pain at injection sites

Contraindications and precautions:

Clinical uses:

It is used topically to treat gram -ve infection of skin, eye and ear
In treatment of bovine mastitis caused by Pseudomonas aeruginosa and Klebsiella.
It is administered orally to cattle and swine for the treatment of gram -ve enteric infection
It is mainly indicated for life-threatening infections due to gram -ve bacteria particularly pseudomonas spp, which are not responding to other antibiotics.

Dose:

All species: 20,000 units/kg, PO, 2 times daily

5,000-10,000 units/kg, IM, 2 times daily

Cattle: 50,000-100,000 units (total), intramammary

100,000 units (total), intrauterine