Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Zambon S.p.A., Via Lillo del Duca 10, 20091 Bresso (MI) - Italy
Pharmacotherapeutic group: other antibacterials, Polymyxins
ATC code: J01XB01
Colistimethate sodium is a prodrug of colistin, a polymyxin antibiotic , (belonging to the polymyxin E group). It is a polypeptide structure and is derived from Bacillus polymyxa var. colistinus.
The polymyxin antibiotics are surface active agents and act by binding to and changing the permeability of the bacterial cell membrane causing bacterial cell death. Polymyxins are bactericidal against Gram-negative bacteria with a hydrophobic outer membrane.
Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria.
Resistance develops due to modifications of lipopolysaccharide (LPS) or other components in the bacterial cell membrane.
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.
Commonly susceptible species:
Acinetobacter species
Haemophilus influenzae
Klebsiella species
Pseudomonas aeruginosa
Species for which acquired resistance may be a problem:
Stenotrophomonas maltophilia
Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans)
Inherently resistant organisms:
Burkholderia cepacia and related species
Proteus spp
Providencia spp
Serratia spp
Colistimethate sodium acquired resistance in mucoid Pseudomonas aeruginosa has been reported to be approximately 3%. However, local rates of resistance may vary including higher rates (see Section 4.4).
The resistance to polymyxins is not crossed with other antibiotic families.
Gastrointestinal absorption is negligible hence the swallowing of colistimethate sodium deposited in the nasopharynx is unlikely to add to the systemic exposure.
Absorption following lung administration is influenced by the nebuliser system, aerosol droplet size and disease state of the lungs.
A study in healthy volunteers, who inhaled colistimethate sodium, demonstrated the Cmax of polymyxin E1 (the active moiety) varied between 40.0 and 69.9 ng/mL and the AUC varied between 350 and 668 ng/mL/h depending on the nebuliser and the fill volume and concentration, which varied the dose from 0.3 million IU to 2 million IU. The half-life was approximately 5.2 hours. The absolute bioavailability was calculated to vary between 5% and 18% depending on the nebuliser. The AUC following an intravenous dose of 0.5 million IU was 3,352 ng/mL/h and the Cmax was 1,232 ng/mL.
Colistimethate sodium undergoes conversion to its base in vivo.
There is no information on the elimination of colistimethate sodium following nebulisation.
Following i.v. administration excretion is primarily renal with 62% of a parenteral dose recovered in the urine within 8 hours and around 80% in 24 hours.
Animal studies with colistimethate do not indicate adverse effects on fertility or embryo-foetal development. Peri-postnatal studies have not been conducted.
Data on potential genotoxicity and carcinogenicity for colistimethate sodium are lacking. Colistin has been shown to induce chromosomal aberrations in human lymphocytes in vitro an effect that might be related to a reduction in mitotic index, which was also observed. Colistin was not mutagenic in a set of other tests.
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