Colate Mechanism of Action

Pharmacology: Pharmadynamics: Mode of action: Colistimethate sodium is a cyclic polypeptide antibiotic derived from Bacilus polymyxa var. colistinus and belongs to the polymyxin group. The polymyxin antibiotics are cationic agents that work by damaging the cell membrane, the resulting physiological affects are lethal to the bacterium. Polymyxins are selective for Gram-negative bacteria that have a hydrophobic outer membrane.
Resistance: Resistant bacteria are characterized by modification of the phosphate groups of lipopolysaccharide that become substituted with ethanolamine or aminoarabinose. Naturally resistant Gram-negative bacteria, such as Proteus mirabilis and Burkholderia cepacia, show complete substitution of their lipid phosphate by ethanolamine or aminoarabinose.
Cross resistance: Cross resistance between colistimethate sodium and polymyxin B would be expected. Since the mechanism of action of the polymyxins is different from that of other antibiotics, resistance to colistin and polymixin by the previously mentioned mechanism alone would not be expected to result in resistance to other drug classes.
Breakpoints: The suggested general MIC breakpoint to identify bacteria susceptible to colistimethate sodium is <4 mg/L. Bacteria for which the MIC of colistimethate sodium is >8 mg/L should be considered resistant.
Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Pharmacokinetics: Absorption: The information on the pharmacokinetics of colistimethate sodium (CMS) and colistin is limited. There are indications that pharmacokinetics in critically ill patients differ from those in patients with less severe physiological derangement and from those in healthy volunteers. The following data are based on studies using HPLC to determine CMS/colistin plasma concentrations.
After infusion of colistimethate sodium the inactive pro-drug is converted to the active colistin. Peak plasma concentrations of colistin have been shown to occur with a delay of up to 7 hours after administration of colistimethate sodium in critically ill patients.
Distribution: The volume of distribution of colistin in healthy subjects is low and corresponds approximately to extracellular fluid (ECF). The volume of distribution is relevantly enlarged in critically ill subjects. Protein binding is moderate and decreases at higher concentrations. In the absence of meningeal inflammation, penetration into the cerebrospinal fluid (CSF) is minimal, but increases in the presence of meningeal inflammation.
Both CMS and colistin display linear PK in the clinically relevant dose range.
Biotransformation: Colistimethate sodium is converted to the base in vivo. As 80% of the dose can be recovered unchanged in the urine, and there is no biliary excretion, it can be assumed that the remaining drug is inactivated in the tissues. The mechanism is unknown.
Elimination: It is estimated that approximately 30% of colistimethate sodium is converted to colistin in healthy subjects, its clearance is dependent on creatinine clearance and as renal function decreases, a greater portion of CMS is converted to colistin. In patients with very poor renal function (creatinine clearance <30 mL/min), the extent of conversion could be as high as 60 to 70%. CMS is eliminated predominantly by the kidneys via glomerular filtration. In healthy subjects, 60% to 70% of CMS is excreted unchanged in the urine within 24 hours.
70% CMS is eliminated predominantly by the kidneys via glomerular filtration. In healthy subjects, 60% to 70% of CMS is excreted unchanged in the urine within 24 hours.
Half-life of colistin in healthy subjects and those with cystic fibrosis is reported to be around 3 h and 4 h, respectively, with a total clearance of around 3 L/h. In critically ill patients, half-life has been reported to be prolonged to around 9-18 h.