Polymyxins Flashcards
MOA
Polymyxins are cationic detergents that bind to the anionic lipopolysaccharide molecules of the outer cell membrane of Gram-negative bacteria causing displacement of calcium and magnesium, which normally stabilize the cell membrane. This action leads to changes in cell wall permeability, leakage of cellular contents, and subsequent cell death.
Polymyxins display concentration-dependent bactericidal activity.
MOR
A.Alteration of the outer cell membrane – decreased lipopolysaccharide content, reduction in calcium and magnesium content, decreased outer membrane proteins
B.Cross-resistance exists between polymyxin B and colistin
Spectrum of activity
Gram negative aerobes:
PEEACKSSS
Acinetobacter spp. (including MDR strains)
Pseudomonas aeruginosa (including MDR strains)
Citrobacter spp.
Enterobacter spp.
Escherichia coli
Haemophilus influenzae
Klebsiella spp.
Salmonella spp.
Shigella spp.
Stenotrophomonas maltophilia (83-88% susceptible)
pharmacology
Colistin displays extensive interpatient variability and a narrow therapeutic window – TDM
adsorption
Polymyxins are not absorbed from the gastrointestinal tract; minimal systemic absorption has been reported after inhalation therapy.
distribution
Vd of colistin = 0.17 L/kg; Vd polymyxin B = 0.4 L/kg (indicating limited extravascular distribution)
Older literature suggests that colistin demonstrates poor penetration into the pleural cavity, lung parenchyma, bone, and the CSF (5%); penetration of polymyxin B into the CSF is not well described
Adverse effects
1.Nephrotoxicity
2.Neurotoxicity
elimination
Polymyxin B and colistin are primarily eliminated by nonrenal routes and do not require dosage adjustment in renal dysfunction.
HOWEVER
50% of CMS(IV formulation of colistin) is excreted unchanged in the urine by glomerular filtration
Dosing Polymixin B IV
Most current references do NOT recommend dosage adjustment in the presence of renal insufficiency (although the manufacturer labeling does)
