Pharmacology: Pharmacodynamics: Colistimethate sodium is a polymyxins antibiotic. It is inactive until hydrolyzed to colistin; this hydrolysis occurs in vitro in aqueous solutions of the drug and in vivo. Colistin has bactericidal activity against gram-negative bacilli. Colistin acts as a cationic detergent which damages the bacterial cytoplasmic membrane causing leaking of intracellular substances and cell death.
Colistin is active in vitro against many strains of Acinetobacter spp., Citrobacter spp., Escherichia coli, Enterobacter spp., Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Shigella spp. and some strains of Bordetella spp. and Vibrio spp.
Most strains of Proteus spp., Providencia spp., Serratia spp., Neisseria gonorrhoeae, Neisseria meningitidis, and Bacteroides fragilis are resistant to colistin. The drug is inactive against gram-positive bacteria, fungi, and viruses.
Pharmacokinetics: Absorption: Colistimethate sodium is poorly absorbed from the gastrointestinal tract of adults and must be given parenterally. The drug is not absorbed through mucous membranes, or intact or denuded skin. Peak plasma concentrations usually occur 2 to 3 hours after an intramuscular injection and 10 minutes after an intravenous injection of colistimethate sodium.
Distribution: Following IM or IV administration of colistimethate sodium, the drug is widely distributed into body tissues, but only negligible concentrations of antimicrobial activity are attained in synovial, pleural, or pericardial fluids. Colistin crosses the placenta and is distributed into breast milk but diffusion into the CSF is negligible. Plasma protein binding of colistin is reported to be more than 50%.
Metabolism and Elimination: Colistimethate sodium is hydrolyzed in vivo to colistin and possibly other metabolites with fewer substituted amino groups. The serum half-life of colistimethate sodium is 2 to 3 hours but is prolonged in renal impairment; values of 10 to 20 hours have been reported in patients with a creatinine clearance of less than 20 mL/minute. Following administration of colistimethate sodium in a few anuric patients, half-life of antimicrobial activity reportedly ranged up to 2-3 days.
Colistimethate is mainly excreted by glomerular filtration as changed and unchanged drug and up to 80% of a parenteral dose may be recovered in the urine within 24 hours. Excretion is more rapid in children than in adults; it is reduced in patients with renal impairment.