Source: Health Products and Food Branch (CA) Revision Year: 2011
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.
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.
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.
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 Table 2 below.
Table 2. 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 (See DETAILED PHARMACOLOGY).
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 (See DETAILED PHARMACOLOGY).
No data is available on the use of polymyxin B sulphate in patients receiving peritoneal dialysis. Polymyxins are not effectively removed by hemodialysis.
Safety pharmacology studies on delayed ventricular repolarization (QT/QTc), respiratory and central nervous system are not available.
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.
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. Tissue diffusion is poor and the drug does not penetrate well into cerebrospinal fluid, pleural fluid or joints.
At therapeutic dosages, polymyxin B sulphate has been reported to cause nephrotoxicity as shown by slight tubular damage.
Following a 50 mg intramuscular dose, a peak concentration of 8 µg/mL was achieved in approximately 2 hours and serum half life was approximately 6 hours. Following multiple 2-4 mg/kg/day intramuscular polymyxin B sulphate, in divided doses, blood serum levels were reported to be 1-8 µg/mL. The peak levels occurred within 30 minutes to 2 hours after injection, the half-life was about 4.5 to 6 hours and the drug remained detected up to 12 hours. When Polymyxin B sulphate was given at a dose of 2.5 mg/kg/day for 7 days, drug accumulation was reported and peak serum concentrations reached 15-30 µg/mL.
The primary route of polymyxin B sulphate excretion is via the kidney. After an initial dose of polymyxin B sulphate there was a 12 to 24 hour lag period with only a small amount of drug (<1%) being recovered in the first 12 hours after injection. As therapy continues, the urinary concentration increases and eventually 60% of the dose can be accounted for in the urine and urinary concentrations of 10 to 100 µg/mL are attained. The fate of the remaining 40% was unclear, as polymyxins are not excreted in bile.
The limited data available on the use of polymyxin B sulphate in children suggests that the pharmacokinetics are similar in children (>2 years) and adults. The limited data available on the use of polymyxin B sulphate in infants (<2 years) suggests a possibility of higher peak serum levels and prolonged half-life in infants and neonates.
Plasma and urine levels 1 hour following a single intramuscular dose of 0.8 mg/kg in children (n=6) demonstrated considerable drug level variation, i.e., 0.4-19.0 (average 8.6) µg/mL and 0.2-48.0 (average 19.5) µg/mL in plasma and urine respectively, however these drug levels decreased to 0.6-9.2 (average 3.8) µg/mL and <0.2 µg/mL in plasma and urine, respectively, after 4 hours of polymyxin B sulphate administration.
Patients with renal dysfunction demonstrated an increased accumulation of polymyxin B sulphate. When a dose of 20 mg of polymyxin B was given intramuscularly every 8 hours, patients with renal dysfunction maintained serum levels at 2-5 µg/mL. Following a 50 mg dose, the serum half-life of approximately 6 hours reported in patients with normal kidney function increased to 2-3 days in patients who were anuric.
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.
Critically ill patients with renal impairment report lower than effective plasma concentrations after a few doses and frequently even at steady state. Based upon these findings, a higher first loading dose has been suggested.
Polymyxin B sulphate is isolated from Bacillus polymyxa. Polymyxins are rapidly bactericidal and target the bacterial cell membrane.
Lipopolypeptide polymyxins (polymyxin B/colistin) are surface active amphipathic agents, which interact strongly with phospholipids within the cell membrane and act in a detergent-like fashion to disrupt the structure of the cell membrane. The initial association of the polymyxin B/colistin with the bacterial membrane occurs through interactions between the cationic polypeptide (polymyxin B/colistin) and the anionic lipopolysaccharide within the outer membrane of the gram-negative bacteria, leading to derangement of cell membrane. Polymyxin displaces magnesium and calcium (ions that normally stabilize the lipopolysaccharide molecules) from the negatively charged lipopolysaccharide, leading to a loss of integrity of the membrane, an increase in the permeability of the cell envelope, leakage of cell contents, and subsequently, cell death. Polymyxins also avidly bind to the lipid A portion of the endotoxin in the outer membrane of gram-negative bacteria and inactivate the molecule.
Resistance to polymyxins can develop through adaptive or mutational mechanisms. Isolates with intrinsic resistance to polymyxins have alterations in lipid A that account for reduced binding. Acquired resistance to polymyxins has been reported in Escherichia coli and Salmonella spp. by substitution of phosphate groups in lipopolysaccharides.
Esterification of the lipid A moieties 4'-phosphate (with 4 amino-4-deoxy-L-arabinopyronase) and the glycosidic diphosphate (with 2-aminoethanol) results in a decrease in anionic charges. The change in surface charge can cause a decrease in polymyxin B binding site. For Klebsiella pneumoniae, lipopolysaccharide-related phosphate substitution with 4-amino-4-deoxy-Larabinopyronase has also been linked to polymyxin resistance. The development of resistance in Pseudomonas aeruginosa is due to increased production of the outer membrane protein H1.
Complete cross-resistance to other polymyxins including colistin has been reported.
Polymyxins are active for gram-negative bacteria only. Polymyxin B sulphate has been shown to be active against most strains of the following gram-negative bacteria both in vitro and in clinical infections as described in the INDICATIONS AND CLINICAL USE section. Table 3 contains information on the in vitro activity of clinical isolates from surveillance studies.
Table 3. In vitro activity of polymyxin B sulphate against gram-negative bacteria for which the clinical efficacy of polymyxin B sulphate has been demonstrated:
| Organism / Pathogen | Number of clinical isolates | MIC (μg/mL) | % susceptible | ||
|---|---|---|---|---|---|
| Range | 50% | 90% | |||
| Pseudomonas aeruginosa | 8705 | ≤1->8 | ≤1 | 2 | 98.7 |
| Enterobacter spp. | 4693 | ≤1->8 | ≤1 | >8 | 83.3 |
| Escherichia coli | 18325 | ≤1->8 | ≤1 | ≤1 | 99.5 |
| Klebsiella spp. | 8188 | ≤1->8 | ≤1 | ≤1 | 98.2 |
Clinical isolates collected from Asia-Pacific region, Europe, Latin America and North America, 2001-2004.
Table 4 contains information on the in vitro activity of clinical isolates from surveillance studies. However clinical significance of these bacterial isolates is unknown.
Table 4. In vitro activity of polymyxin B sulphate against organisms for which the clinical efficacy of polymyxin B sulphate has not been established:
| Organism / Pathogen | Number of clinical isolates | MIC (μg/mL) | % susceptible | ||
|---|---|---|---|---|---|
| Range | 50% | 90% | |||
| Acinetobacter spp. | 2621 | ≤1->8 | ≤1 | 2 | 97.9 |
| Aeromonas spp. | 368 | ≤1->8 | ≤1 | >8 | 71.7 |
| Alcaligenes spp. | 121 | ≤1->8 | 2 | >8 | 63.6 |
| Burkholderia cepacia | 153 | 0.5->8 | >8 | >8 | 11.8 |
| Pseudomonas spp. (non aeruginosa) | 282 | ≤1->8 | ≤1 | 2 | 98.7 |
| Stenotrophomonas maltophilia | 1256 | ≤0.12->8 | 1 | 8 | 72.4 |
| Citrobacter spp. | 895 | ≤1->8 | ≤1 | ≤1 | 99.1 |
| Proteus spp. | 895 | ≤1->8 | >8 | >8 | 1.3 |
| Proteus mirabilis | 1931 | ≤1->8 | >8 | >8 | 0.7 |
| Salmonella spp. | 2909 | ≤1->8 | ≤1 | 4 | 76.0 |
| Shigella spp. | 828 | ≤1->8 | ≤1 | ≤1 | 99.0 |
| Serratia spp. | 1919 | 0.25->8 | >8 | >8 | 5.4 |
Clinical isolates collected from Asia-Pacific region, Europe, Latin America and North America, 2001-2004.
Cation concentrations have been known to affect the activity of polymyxins.
Quantitative methods are used to determine antibacterial minimum inhibitory concentrations (MIC). These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. Standardized procedures are based on the dilution method (broth or agar) or equivalent using standardized inoculums and concentrations of polymyxin B sulphate. The MIC values should be interpreted according to the criteria provided in Table 5.
Table 5. Susceptibility Interpretive Criteria:
| Pathogen | Minimum Inhibitory Concentrationb | ||
|---|---|---|---|
| S | I | R | |
| PA | ≤2 | 4 | ≥8 |
| Acinetobacter spp. | ≤2 | - | ≥4 |
b S = Susceptible, I = Intermediate, R = Resistant
Please note discrepancies in susceptibility criteria from various guidance documents as the clinical outcome of patients infected with above-mentioned gram-negative organisms with MIC of 4 µg/ml is not available.
Studies suggest that peak serum conc. after repeated dosing can reach 15 µg/ml. More clinical data is needed to define optimal susceptibility breakpoints.
A report of susceptible (S) indicates that polymyxin B sulphate is likely to inhibit the growth of the pathogen if polymyxin B sulphate in the blood reaches the concentrations usually achievable. A report of intermediate (I) indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of resistant (R) indicates that polymyxin B sulphate is not likely to inhibit the growth of the pathogen if polymyxin B sulphate in the blood reaches the concentrations usually achievable and other therapy should be selected.
Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard polymyxin B sulphate powder should provide the MIC values noted in Table 6.
Table 6. Acceptable Quality Control Ranges for Susceptibility Testing:
| QC Organisms | Minimum Inhibitory Concentrations (µg/mL) |
|---|---|
| Escherichia coli ATCC 25922 | 0.25-2 |
| Pseudomonas aeruginosa ATCC 27853 | 1-4 |
Information not available.
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