Polymyxin B

Medical uses

Spectrum of susceptibility

PolymyxinB has been used to treat urinary tract infections and meningitis caused by Pseudomonas aeruginosa and Haemophilus influenzae, respectively. The following represents MIC susceptibility data for a few medically significant microorganisms.

• Haemophilus influenzae: ≥0.8 μg/mL
• Pseudomonas aeruginosa: 0.25–1 μg/mL

Endotoxin adsorption

Toraymyxin An effective use of polymyxinB is found in patients with refractory septic shock, that is, without positive outcome to the administration of standard treatments (increase in volemia and other antibiotics). The obstacle of the toxicity of polymyxinB is bypassed by extracorporeal circulation with perfusion of venous blood through a cartridge on whose fibers polymyxinB is covalently fixed; in this way the antibiotic exerts its bactericidal function but is not released into the blood since it remains fully attached to the fiber. Through this perfusion the cartridge retains the endotoxin, recognized as the trigger of septic shock. The treatment of the cartridge to polymyxinB (Toraymyxin, medical device designed and produced by the Japanese Toray), takes place in two sessions of two hours each, carried out at a distance of 24 hours.

Mechanism of action

1. Alters bacterial outer membrane permeability by binding to a negatively charged site in the lipopolysaccharide layer, which has an electrostatic attraction for the positively charged amino groups in the cyclic peptide portion (this site normally is a binding site for calcium and magnesium counter ions); the result is a destabilized outer membrane
2. Fatty acid portion dissolves in hydrophobic region of cytoplasmic membrane and disrupts membrane integrity
3. Leakage of cellular molecules, inhibition of cellular respiration
4. Binds and inactivates endotoxin
5. Relative absence of selective toxicity: nonspecific for cell membranes of any type, highly toxic.

Removal of the hydrophobic tail of polymyxinB yields polymyxin nonapeptide (PMBN), which still binds to LPS, but no longer kills the bacterial cell. However, it still detectably increases the permeability of the bacterial cell wall to other antibiotics, indicating that it still causes some degree of membrane disorganization.

Mixture composition

PolymyxinB is composed of polymyxins B1, B1-I, B2, B3, and B6. Polymyxins B1 and B2 are considered major components. These related components are structurally identical with the exception of a variable fatty acid group on each fraction. Results from in vitro studies have shown marginal differences in MIC data when comparing the fractions.

Research application

PolymyxinB is also used to induce envelope stress in order to study the organisms' response to such stress. Polymyxin envelope stress assays such as this have been used for the study of small RNA (sRNA) responses in Salmonella enterica.

References

References

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