Poliz-B Mechanism of Action

Pharmacotherapeutic group: Antibacterials for systemics use, polymyxins. ATC code: J01XB02.
Pharmacology: Pharmacodynamics: Mechanism of action: The antibiotic lipopeptide polymyxin is a large molecular weight detergent. Polymyxin acts by way of three known mechanisms. Polymyxins interact electrostatistically with the outer membranes of gram-negative bacteria and competitively displace divalent cations from the membrane lipids, specifically calcium and magnesium that stabilize the lipopolysaccharide molecule. This disrupts the outer membrane and releases lipopolysaccharides. The change in the permeability of the bacterial membrane leads to leakage of the cell content and subsequently cell lysis and death. Polymyxins are surface-active amphipathic agents containing both lipophilic and lipophobic groups. They penetrate into cell membranes and interact with phospholipids in the membranes, leading to permeability changes that quickly disrupt cell membranes and cell death. Polymyxins also bind to the lipid A portion of endotoxin or LPS molecules.
Polymyxins are active for gram-negative bacteria only. Acinetobacter spp., Pseudomonas aeruginosa, E. coli, Klebsiella spp., Citrobacter spp., Enterobacter spp. (formerly called Aerobacter), Haemophilus influenzae are commonly susceptible to polymyxins. However, Proteus spp., Providencia spp., Morganella spp., Serratia spp., Burkholderia spp., Moraxella spp., Neisseria spp., all gram-positive bacteria and most anaerobes are less active/naturally resistant to polymyxins.
Mechanism(s) of Resistance: Resistance to polymyxins can develop through mutational or adaptive mechanisms, with almost complete cross resistance with other polymyxins. Polymyxin resistance has been reported by various mechanisms; (1) by modification of the phosphate groups of lipopolysaccharides due to substitution with ethanolamine or aminoarabinose; (2) increased production of the outer membrane protein H1.
Naturally resistant gram-negative bacteria such as Proteus mirabilis and Burkholderia cepacia, show complete substitution of the lipid phosphate by ethanolamine or aminoarabinose.
Cross-Resistance: Complete cross-resistance has been reported with colistin (polymyxin E).
Safety Pharmacology: Data on delayed ventricular repolarization (QT/QTc) and convulsion potential are not available.
Pharmacodynamics: Polymyxins are bactericidal targeting the bacterial cell membrane. The pharmacodynamics of polymyxin B sulphate are concentration dependent. The ratio of the area under the plasma concentration-time curve to the bacterial minimum inhibitory concentration (AUC/MIC) is the most predictive efficacy index.
Pharmacokinetics: Polymyxin B sulphate is not absorbed from the gastrointestinal tract. After intravenous infusion of polymyxin B in critically ill patients, the median human protein binding is 58% (range, 36%-74%). Low volume of distribution of polymyxin B (approximately 0.09 L/kg) is reported. The biotransformation of the intravenous polymyxin B is incompletely characterized. Polymyxin B is low urinary recovery (median 4.04%; range, 0.98%-17.4%), suggesting that renal route is not a major pathway of polymyxin B elimination. Half-life of intravenous polymyxin B in critically ill patients is reported to be around 11.9 hours, with a mean total body clearance, scaled by TBW of approximately 0.03 L/h/kg.
Pharmacokinetics in special population: Renal insufficiency: Pharmacokinetic of polymyxin B was evaluated in patients with renal insufficiency (estimated creatinine clearance <80 mL/min) and patients with normal renal function (estimated creatinine clearance ≥80 mL/min). The adjusting AUC for daily dose (in IU/kg of TBW) was determined and reported that polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable, suggesting that polymyxin B clearance did not depend on creatinine clearance. Therefore, polymyxin B dose adjustment should not be necessary in patients with impaired renal function (see Dosage & Administration).
Toxicology: Preclinical safety data: No studies of preclinical safety data have been available.