Colistimethate Other names: Colistimethate sodium

Colistimethate sodium (CMS) is a cyclic polypeptide antibacterial active substance that is derived from Bacillus polymyxa var. colistinus and belongs to the polymyxin group. Polymyxins work by damaging the cell membrane and 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, which 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 between colistin (polymyxin E) and polymyxin B is expected. Since the mechanism of action of the polymyxins is different from that of other antibacterial agents, resistance to colistin and polymyxin by the above mechanism alone would not be expected to result in resistance to other drug classes.

PK/PD relationship

Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria. fAUC/MIC is considered to be correlated with clinical efficacy.

EUCAST Breakpoints:

^a Breakpoints apply to dosage of 2-3 MIU x 3. A loading dose (9 MIU) may be needed.

Absorption

Colistimethate is not significantly absorbed from the lung after inhalation. After administration of 1,662, 500IU twice daily for 7 days in adult, adolescent and paediatric cystic fibrosis patients mean C_max values of total colistimethate of up to 455ng/ml (adult mean) were observed. T_max for total colistimethate occurred between 0.5 and 1 hour post-dose. Although the population PK analysis showed that age is a statistically significant covariate, the AUC_0-6 and dose adjusted AUC_0-6 (AUC_0-6/D) for total CMS and total free colistin were similar between children and adolescents, while higher AUC_0-6 was observed in the adult group. When AUC_0-6 was adjusted by dose and body weight, a slightly higher AUC_0-6/D/W for total CMS and total free colistin was observed in children. High PK variability was observed in all three groups. Therefore, dose adjustment in low age groups is considered not necessary.

High concentrations of total free colistin (mean 23.5mg/L) and total colistimethate (mean 178mg/L) were observed in sputum at 1 hour post-dose on Day 8 following BID dosing for 7 days across all age groups.

Absorption of colistimethate from the gastro-intestinal tract does not occur to any appreciable extent in the normal individual.

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.

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 a parenteral 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.

The elimination of the active colistin is incompletely characterised. Colistin undergoes extensive renal tubular reabsorption and may either be cleared non-renally or undergo renal metabolism with the potential for renal accumulation. Colistin clearance is decreased in renal impairment, possibly due to increased conversion of CMS.

Half-life of colistin in healthy subjects and those with cystic fibrosis is reported to be around 3h and 4h, respectively, with a total clearance of around 3L/h. In critically ill patients, half-life has been reported to be prolonged to around 9-18h.

Data on potential genotoxicity are limited and carcinogenicity data for colistimethate sodium are lacking. Colistimethate sodium has been shown to induce chromosomal aberrations in human lymphocytes in vitro. This effect may be related to a reduction in mitotic index, which was also observed.

Reproductive toxicity studies in rats and mice do not indicate teratogenic properties. However, colistimethate sodium given intramuscularly during organogenesis to rabbits at 4.15 and 9.3 mg/kg resulted in talipes varus in 2.6 and 2.9% of foetuses respectively. These doses are 0.5 and 1.2 times the maximum daily human dose. In addition, increased reabsorption occurred at 9.3mg/kg.