Vaxcel Polymyxin E Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Colistimethate sodium is a cyclic polypeptide antibiotic derived from Bacillus 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 effects are lethal to the bacterium. Polymyxins are selective for Gram-negative bacteria that have a hydrophobic outer membrane.
Resistance: Resistant bacteria are characterised 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 polymyxin 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. (See Table 1.)

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Pharmacokinetics: Absorption: Absorption from the gastrointestinal tract does not occur to any appreciable extent in the normal individual. When given by nebulisation, variable absorption has been reported that may depend on the aerosol particle size, nebuliser system and lung status. Studies in healthy volunteers and patients with various infections have reported serum levels from nil to potentially therapeutic concentrations of 4 mg/l or more. Therefore, the possibility of systemic absorption should always be borne in mind when treating patients by inhalation.
Distribution: After the administration to patients with cystic fibrosis of 75 mg/kg/day in divided doses given as 30 min intravenous infusions to steady state the C_max was determined to be 23±6 mg/l and C_min at 8 hours was 4.5±4 mg/l. In another study in similar patients given 2 million units every 8 hours for 12 days the C_max was 12.9 mg/l (5.7-29.6 mg/l) and the C_min was 2.76 mg/l (1.0-6.2 mg/l). In healthy volunteers given a bolus injection of 150 mg (2 million units approx.) peak serum levels of 18 mg/l were observed 10 minutes after injection. Protein binding is low. Polymyxins persist in the liver, kidney, brain, heart and muscle. One study in cystic fibrosis patients gives the steady-state volume of distribution as 0.09 L/kg.
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: The main route of elimination after parenteral administration is by renal excretion with 40% of a parenteral dose recovered in the urine within 8 hours and around 80% in 24 hours. Because colistimethate sodium is largely excreted in the urine, dose reduction is required in renal impairment to prevent accumulation. After intravenous administration to healthy adults the elimination half-life is around 1.5 hrs. In a study in cystic fibrosis patients given a single 30-minute intravenous infusion the elimination half-life was 3.4±1.4 hrs. The elimination of colistimethate sodium following inhalation has not been studied. A study in cystic fibrosis patients failed to detect any colistimethate sodium in the urine after 1 million units were inhaled twice daily for 3 months. Colistimethate sodium kinetics appear to be similar in children and adults, including the elderly, provided renal function is normal. Limited data are available on use in neonates which suggest kinetics are similar to children and adults but the possibility of higher peak serum levels and prolonged half-life in these patients should be considered and serum levels monitored.