Chemical formula: C₅₆H₉₈N₁₆O₁₃ Molecular mass: 1,203.499 g/mol
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 lipopolysacchrides. 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. Acintobacter spp., Pseudomonas aeruginosa, E. coli, Klebsiella spp., Citrobacter spp., Enterobacter spp. (formerly called Aerobacter), Hemophilus 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.
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.
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 lipopolysacchrides 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.
Complete cross-resistance has been reported with Colistin (Polymyxin E).
Data on delayed ventricular repolarization (QT/QTc) and convulsion potential are not available.
Polymyxin B sulphate is not absorbed from the gastrointestinal tract. Serum polymyxin B sulphate concentrations are low because 79% to 92% of the drug loses its activity due to protein binding. The drug is excreted primarily by the kidneys. After an initial dose of polymyxin B sulphate there is a 12 to 24 hour lag period before significant amounts of drug are found in urine. Less than 1% of infused polymyxin B sulphate is recovered in the urine. At therapeutic dosages, polymyxin B sulphate has been reported to cause nephrotoxicity as shown by slight tubular damage.
Pharmacokinetic parameters of polymyxin B sulphate are shown in the table below.
Pharmacokinetic Parameters for Polymyxin B Sulphatea:
| Polymyxin B Sulphate | |
|---|---|
| Cmax | 8 mg/L |
| Time to Cmax | 2h |
| Half-life | 6h |
| Half-life with renal insufficiency | 48-72 h |
| Elimination | 60% recovered in urine |
| Volume of distribution | ND |
a Following a 50 mg intramuscular dose of polymyxin B sulphate
ND = Not Determined
Polymyxins are not effectively removed by hemodialysis and the effect of high-flux dialyzers is unknown. No information concerning the removal of polymyxin B sulphate by peritoneal dialysis is available.
The limited data available on the use of polymyxins in children suggests that the pharmacokinetics are similar in children and adults. The limited data available on the use of polymyxin B sulphate in neonates suggests a possibility of higher peak serum levels and prolonged half-life in infants and neonates.
Patients with impaired renal function demonstrated an increased accumulation of polymyxin B sulphate. Pharmacokinetic data in patients with renal insufficiency are scarce, therefore no definite dosing recommendations can be made in these patients.
No data is available on the use of polymyxin B sulphate in patients receiving peritoneal dialysis. Polymyxins are not effectively removed by hemodialysis.
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