Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria

BACKGROUND:Polymyxin B sulfate and colistin, also known as colistimethate, have not been used for many years because less toxic antimicrobials are available. Gram-negative bacteria that are resistant to the aminoglycosides, β-lactams, and fluoroquinolones are becoming more common. These bacteria are often susceptible to the polymyxins.OBJECTIVE:To present a review of the chemistry, antibacterial spectrum, dosing, pharmacokinetics, toxicity, and indications for polymyxin B sulfate and colistin.DATA SOURCE:A MEDLINE search (1966–1998) of the English-language literature was performed to identify primary literature on the polymyxins. Older citations (1949–1965) were identified through the bibliographies of these articles.STUDY SELECTION:All available reports of in vitro antibacterial activity, animal and clinical trials, and case reports were reviewed.DATA SYNTHESIS:The polymyxins are amphipathic molecules that interact with lipopolysaccharide in the bacterial outer membrane. They have potent antiendotoxic pr...

Polymyxin B Sulfate and Colistin: Old Antibiotics for Emerging Multiresistant Gram-Negative Bacteria:

The emergence of multidrug-resistant Gram-negative bacteria that cause nosocomial infections is a growing problem worldwide. Colistin was first introduced in 1952 and was used until the early 1980s for the treatment of infections caused by Gram-negative bacilli. In vitro, colistin has demonstrated excellent activity against various Gram-negative rod-shaped bacteria, including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Recent clinical findings regarding colistin activity, pharmacokinetic properties, clinical uses, emerging resistance, toxicities and combination therapy have been reviewed. Recent approaches to the use of colistin in combination with other antibiotics hold promise for increased antibacterial efficacy. It is probable that colistin will be the 'last-line' therapeutic drug against multidrug-resistant Gram-negative pathogens in the 21st century.

Colistin: an update on the antibiotic of the 21st century.

Few discoveries in the history of medicine have had such a profound impact on human life and society as the discovery of antibiotics to combat bacterial infections. In the last few decades, there has been an observed exponential increase in the number of antibacterial compounds with diverse chemical structures introduced clinically to control infectious diseases. The most significant development in antibiotic research has been the ability to extend and improve the action of naturally occurring compounds by chemical modification. An example of this is the chemical modification of the penicillin molecule such that the new derivatives are immune to attack by bacterial enzymes (e.g., ,B-lactamases). Despite efforts in the search for new antibiotics as well as the improvement of existing antibiotic performance, bacterial resistance to antimicrobial agents remains a problem in the treatment of infections. Before a new antibiotic is introduced into clinical practice, extensive laboratory studies are performed to prove that the new compound is superior to existing compounds in killing the many species of pathogens for which the antibiotic is intended. These species of pathogens, which are grown planktonically in test tubes, are often used to test the effectiveness of the compound in their eradication. If the results are promising, then carefully designed in vivo animal models and clinical trials are used to obtain data regarding the efficacy of the compound. Undoubtedly, this approach has been extremely successful, and many new antibiotics are introduced into clinical practice annually. However, resistance to the antibiotic may be detected soon after its release for clinical use. We believe that this is partly due to the inadvertent use of sublethal concentrations of antibiotics in the treatment of chronic infections such as medical device-related infections. It is therefore of great importance to consider the strategies that are being used to deal with medical device-related infections. It is hoped that this minireview will help to stimulate the formulation of effective strategies to combat these chronic infections.

Establishment of aging biofilms: possible mechanism of bacterial resistance to antimicrobial therapy.

Spontaneous polymyxin-resistant mutants of Pseudomonas aeruginosa were isolated. The mutations responsible for this phenotype were mapped to a two-component signal transduction system similar to PmrAB of Salmonella enterica serovar Typhimurium. Lipid A of these mutants contained aminoarabinose, an inducible modification that is associated with polymyxin resistance. Thus, P. aeruginosa possesses a mechanism that induces resistance to cationic antimicrobial peptides in response to environmental conditions.

PmrAB, a two-component regulatory system of Pseudomonas aeruginosa that modulates resistance to cationic antimicrobial peptides and addition of aminoarabinose to lipid A.

Pseudomonas aeruginosa strain PA01, which is normally sensitive to 10 units/ml of polymyxin, was adapted in eight successive steps to be resistant to polymyxin at 6000 units/ml. The polymyxin-resistant variant was very sensitive to all other antibiotics with which it was challenged, including hydrophobic antibiotics such as erythromycin. This increased sensitivity implies that the acquired polymyxin resistance had disrupted the permeability barrier of the outer membrane. Changes in the outer membrane protein profile of PA01 were studied at each adaption step using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). At the third step (resistant to 80 units/ml) protein H1 was absent. At succeeding steps up to 6000 units/ml of polymyxin, protein H1 was still absent and the levels of OM proteins D, E, F (major porin) and G were all considerably reduced compared with the wild type. Overproduction of protein H1 by wild type P. aeruginosa under conditions of magnesium depletion has been proposed as a mechanism to explain polymyxin resistance. However, protein H1 remained absent from the outer membrane of the polymyxin-resistant variants even under magnesium depletion. Furthermore, protein H1 could not be induced by magnesium depletion when the resistant variant was repeatedly grown in concentrations of polymyxin as low as 10 units/ml yet, at this low concentration, the variant retained its resistance to 6000 units/ml. These observations make it unlikely that induction of protein H1 alone is a mechanism of polymyxin resistance in P. aeruginosa.

H. Anwar

Papers

Outer membrane proteins of polymyxin resistant Pseudomonas aeruginosa: effect of magnesium depletion