Chapter 8: Colistin and Polymyxin B

INTRODUCTION

Antimicrobial resistance has become a worldwide health care crisis with many pathogens showing limited or no susceptibility to currently available antimicrobial treatments. Gram-negative infections are of even more concern because of the lack of currently effective treatments, as well as the lack of new antibiotics in development to treat these potentially lethal pathogens. It is currently estimated that no new antibiotics with activity against multiresistant gram-negative bacteria will be released within the next five years, emphasizing the need for last-line options, such as colistin, in cases where pathogens are resistant to all other antibiotics. in the last two decades, the paucity of novel antibiotics with which to treat drug-resistant infections, especially those caused by gram-negative pathogens, has led to their reconsideration as a therapeutic option.¹

Polymyxins are a group of polypeptide antibiotics that consists of five chemically different compounds (polymyxins A–E) discovered in 1947. Only polymyxin B and polymyxin E (colistin) have been used in clinical practice. They differ by a single amino acid change (D-phenylalanine in polymixin B replaces D-leucine in colistin). Polymyxins have been used extensively worldwide in topical otic and ophthalmic solutions for decades.² The mechanism behind colistin's bactericidal ability is considered to be identical to that of polymyxin.¹

Colistin was discovered in 1949 and was nonribosomally synthesized by Bacillus polymyxa subspecies colistinus Koyama.^3-4 Colistin was initially used therapeutically in Japan and in Europe during the 1950s and in the United States in the form of colistimethate sodium in 1959.⁵ However, the intravenous formulations of colistin and polymyxin B were gradually abandoned in most parts of the world in the early 1980s because of the reported high incidence of nephrotoxicity.^{6, 7, and 8}

This chapter review focuses on colistin, rather than polymyxin B, because of its wider use in current clinical practice.

MECHANISM OF ACTION

The initial target of the antimicrobial activity of polymyxins is the lipopolysaccharide (LPS) component of the outer membrane. The polymyxins have a strong positive charge and a hydrophobic acyl chain that give them a high binding affinity for LPS molecules. They interact electrostatically with these molecules and competitively displace divalent cations (Mg²⁺⁺ and Ca²⁺⁺) from them, causing disruption of the membrane. The result of this process is an increase in the permeability of the cell envelope, leakage of cell contents, and, subsequently, cell death. The exact mechanism by which the polymyxins induce bacterial killing is still unknown, and multiple bacterial cell targets may be involved. Polymyxins also bind to the lipid A portion of LPS and, in animal studies, block many of the biological effects of endotoxin.⁹

FORMULATIONS, DOSAGE, AND ROUTE OF ADMINISTRATION

Colistin is composed of at least 30 different polymyxin compounds, mainly colistin A and B. Two forms of colistin are available: ...