Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials, polymyxins ATC code: J01XB01
General properties
Mechanism of action
Colistin is a cyclic polypeptide antibacterial agent belonging 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 aerobic 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
Susceptible (S)        Resistant (R) a
Acinetobacter                                    S<2                      R>2mg/L Enterobacteriaceae                               S<2                      R>2mg/L Pseudomonas spp                                  S<4                      R>4mg/L a
Breakpoints apply to dosage of 2-3 MIU x 3. A loading dose (9 MIU) may be needed.
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.

Commonly susceptible species
Acinetobacter baumannii
Haemophilus influenzae
Klebsiella spp
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

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
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.
Absorption
Absorption of colistimethate sodium from the gastrointestinal tract does not occur to any appreciable extent in the normal individual.
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
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.

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 nonrenally 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.