Chapter: Modern Pharmacology with Clinical Applications: Bacitracin, Glycopeptide Antibiotics, and the Polymyxins

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The Polymyxins

The polymyxins are a group of antibiotics produced by Bacillus polymyxa. Polymyxin B (Aerosporin) and co-listin (polymyxin E, Coly-Mycin) are used in the treat-ment of bacterial diseases.

THE POLYMYXINS

 

 

The polymyxins are a group of antibiotics produced by Bacillus polymyxa. Polymyxin B (Aerosporin) and co-listin (polymyxin E, Coly-Mycin) are used in the treat-ment of bacterial diseases.

 

Structure and Mechanism of Action

 

The polymyxins are polypeptide antibiotics that contain both hydrophilic and lipophilic regions. These antibi-otics accumulate in the cell membrane and probably in-teract with membrane phospholipids. Most likely the fatty acid portion of the antibiotic penetrates the hy-drophobic portion of the membrane phospholipid and the polypeptide ring binds to the exposed phosphate groups of the membrane. Such an interaction would dis-tort the membrane, impair its selective permeability, produce leakage of metabolites, and inhibit cellular processes. In the laboratory polymyxin B can neutralize the effects of bacterial lipopolysaccharide (LPS) of gram-negative organisms and may stimulate the biosyn-thesis of complement component C3, factor B, inter-leukin (IL) 6, and granulocyte-macrophage colony stimulating factor (GM-CSF). Its clinical use in gram-negative sepsis has not been established. These antibi-otics also are toxic to mammalian cells.

 

Antimicrobial Spectrum

 

The polymyxins are active against facultative gram-neg-ative bacteria, P. aeruginosa in particular.

 

Absorption, Distribution, and Excretion

 

Polymyxin B and colistin are not well absorbed from the gastrointestinal tract. An intramuscular injection of the polymyxins results in high drug concentrations in the liver and kidneys, but the antibiotic does not enter the cerebrospinal fluid (CSF), even in the pres-ence of inflammation.

 

The polymyxins are slowly excreted by glomerular filtration; the slow elimination rate is due to binding in tissues. Elimination is decreased in patients with renal disease, and drug accumulation can lead to toxicity. Sodium colistimethate, the parenteral preparation, binds less to tissue and is excreted faster than the free base.

 

Clinical Uses

 

With the advent of potent broad-spectrum antibiotics, such as the quinolones and third-generation cephalo-sporins, the indications for the use of the polymyxins, with their serious potential for toxicity, are few. Their only justifiable use may be as topical agents.

 

In combination with neomycin, polymyxin B can be used as a bladder irrigant to reduce the risk of catheter-associated infections, although this use remains contro-versial. It also can be used as topical therapy in external otitis caused by P. aeruginosa.

 

Adverse Effects

 

Colistin and polymyxin B can cause extreme nephro-toxicity when used parenterally, and any preexisting re-nal insufficiency will potentiate the nephrotoxicity caused by these antibiotics.

 

Neurotoxicity is a rare adverse reaction that can be recognized by perioral paresthesia, numbness, weak-ness, ataxia, and blurred vision. These drugs may pre-cipitate respiratory arrest both in patients given muscle relaxants during anesthesia and in persons with myas-thenia gravis.

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