Colistin sulfate

Chemical Properties

White or almost white, hygroscopic powder.

Uses

Colistin sulfate A Polymyxin potent antibiotic and apoptosis inducer. This compound induces apoptosis through interaction with the cytoplasmic membrane. Colistin is a key microbiological component in Colistin Oxolinic Acid Blood Agar utilized in the cultivation of Aminobacter aminovorans, Bacillus species, Hyphomicrobium species and Methylobacterium species. It is also a critical component is VCN Inhibitor & VCNT Inhibitor growth media used in the isolation of Neisseria species.

Uses

Cyclic polypeptide antibiotic produced by Bacillus polymyxa. Complex mixture of at least 30 components, primarily colistins A and B. [a]D= -65?(c= 1, Water) LOD: 3%

Uses

antibacterial

Uses

neuromuscular blocker

brand name

Coly-Mycin (Monarch).

Antimicrobial activity

All the polymyxins have a similar antibacterial spectrum, although there are slight quantitative differences in their activity in vitro. They are inactive against Gram-positive organisms, but nearly all enterobacteria, except Proteus spp., Burkholderia cepacia and Ser. marcescens, are highly susceptible. The MIC of polymyxin B or colistin sulfate for Esch. coli and Klebsiella spp. is 0.01–1 mg/L; the corresponding concentration for Ps. aeruginosa is 0.03–4 mg/L. Bacteroides fragilis is resistant, but other Bacteroides spp. and fusobacteria are susceptible. Resistance of V. cholerae eltor to polymyxin B distinguishes it from the classic vibrio.
The sulfomethyl derivatives are generally 4–8 times less active than the sulfates, but their activity is difficult to measure precisely since on incubation they spontaneously decay to the parent compound, with a corresponding progressive increase in antibacterial activity.
Binding of polymyxins to the bacterial cell membrane can increase permeability to hydrophilic compounds, including sulfonamides and trimethoprim, producing significant synergy. Synergy with ciprofloxacin is also described. Calcium ions exert a strong pH-dependent competition for membrane binding sites, and the presence of calcium and magnesium ions in certain culture media adversely affects the bactericidal activity, notably against Ps. aeruginosa.

Acquired resistance

There is complete cross-resistance between the polymyxins, but stable acquired resistance in normally susceptible species is very rare. Adaptive resistance, probably due to changes in cell-wall permeability, is readily achieved by passage of a variety of enterobacteria in the presence of the agents in vitro.

General Description

In 1950, Koyama et al. isolated an antibiotic fromAerobacillus colistinus (B. polymyxa var. colistinus) thatwas given the name colistin (Coly-Mycin S). It was used inJapan and in some European countries for several years beforeit was made available for medicinal use in the UnitedStates. It is recommended especially for the treatment of refractory urinary tract infections caused by Gram-negativeorganisms such as Aerobacter, Bordetella, Escherichia,Klebsiella, Pseudomonas, Salmonella, and Shigella spp.
Chemically, colistin is a polypeptide, reported by Suzukiet al. whose major component is colistin A. They proposedthe structure for colistin A differs from polymyxin B only by the substitution of D-leucine for D-phenylalanine as one of the amino acid fragments inthe cyclic portion of the structure. Wilkinson and Lowehave corroborated the structure and have shown that colistinA is identical with polymyxin E1.
Two forms of colistin have been prepared, the sulfate andmethanesulfonate, and both forms are available for use in theUnited States. The sulfate is used to make an oral pediatricsuspension; the methanesulfonate is used to make an intramuscularinjection. In the dry state, the salts are stable, andtheir aqueous solutions are relatively stable at acid pH from 2to 6. Above pH 6, solutions of the salts are much less stable.

Hazard

A poison by ingestion.

Pharmaceutical Applications

Polymyxin B and colistin (polymyxin E); mixtures of sulfates of polypeptides produced by strains of B. polymyxa and B. polymyxa var. colistinus. Colistimethate sodium (colistin sulfomethate sodium). Molecular weights: polymyxin B ₁ 1203; polymyxin B ₂ 1189; colistimethate sodium 1748.
A group of basic polypeptide antibiotics with a side chain terminated by characteristic fatty acids. Five polymyxins (A–E) were originally characterized and others have since been added. Polymyxin B and colistin (polymyxin E) sulfates have been commercially developed.
By treatment with formalin and sodium bisulfite, five of the six diaminobutyric acid groups of the polymyxins can be modified by sulfomethyl groups to form undefined mixtures of the mono-, di-, tri-, tetra- and penta-substituted derivatives. Sulfomethyl polymyxins differ considerably in their properties from the parent antibiotics: they are less active antibacterially, less painful on injection, more rapidly excreted by the kidney and less toxic. Only colistimethate sodium is now commercially available for systemic use, but polymyxin B and colistin sulfates are found as ingredients of several topical formulations.

Biochem/physiol Actions

Mode of Action: Binds to lipids on the cell cytoplasmic membrane of Gram-negative bacteria and disrupts the cell wall integrity. Antimicrobial spectrum: Gram-negative bacteria. It is proposed that renal reabsorption of colistin may involve organic cation transporters and peptide transporters and that the process is sensitive to pH .

Pharmacokinetics

Oral absorption: Negligible
C_max (colistimethate sodium) 2 mega-units: 6–7 mg/L after 2–3 h
(c. 16 mg colistin base) i.m.
Plasma half-life (colistimethate sodium): c.4–6 h
Plasma protein binding: Very low
Absorption
Polymyxins are not absorbed from the alimentary tract or mucosal surfaces, but can be absorbed from denuded areas or large burns.
Distribution
After parenteral administration of the sulfates, blood levels are usually low (1–4 mg/L 2 h after a 500 000 unit intramuscular dose). Substantially higher plasma levels are obtained from intramuscular injections of sulfomethyl polymyxins. There is some accumulation in patients receiving 120 mg every 8 h. In patients treated intravenously with a priming dose of 1.5–2.5 mg/kg followed by continuous infusion of 4.8–6.0 mg/h for 20–30 h, steady state levels were around 5–10 mg/L. The volume of distribution is unknown, but polymyxins diffuse poorly into tissue fluids and penetration to cerebrospinal fluid is poor. As a result of binding to mammalian cell membranes (sulfomethates less so), they persist in the tissues, where they accumulate on repeated dosage, although they disappear from the serum. Polymyxin crosses the placenta, but the levels achieved are low. A small amount appears in the breast milk.
Metabolism and excretion
The sulfates are excreted almost entirely by the kidney, but after a considerable lag, with very little of the dose appearing in the first 12 h. The sulfomethyl derivatives are much more rapidly excreted, accounting for their shorter half-lives. Around 80% of a parenteral dose of colistimethate sodium is eventually found in the urine, with concentrations reaching around 100–300 mg/L at 2 h. The fate of the remainder is unknown, but no metabolic products have been described and none is excreted in the bile. Polymyxins accumulate in renal failure and are not removed by peritoneal dialysis.

Clinical Use

Colistimethate sodium
Infections due to Ps. aeruginosa and other Gram-negative rods resistant to less toxic agents
Cystic fibrosis (inhalation therapy for pseudomonas infection)
Polymyxin B and colistin sulfate
Component of preparations for local application
Superficial infections with Ps. aeruginosa and to prevent the colonization of burns
Selective decontamination of the gut and as a paste for control of upper respiratory tract colonization in patients on prolonged mechanical ventilation (in combination with other agents)

Side effects

Pain and tissue injury can occur at the site of injection of the sulfates, but this is less of a problem with the sulfomethyl derivatives. Neurological symptoms such as paresthesia with typical numbness and tingling around the mouth, dizziness and weakness are relatively common, and neuromuscular blockade, sometimes severe enough to impede respiration, occurs. Evidence of nephrotoxicity is observed in about 20% of patients, leading to acute tubular necrosis in about 2%. Damage is more likely in patients with pre-existing renal disease. The appearance of any evidence of deterioration of renal function or of neuromuscular blockade calls for immediate cessation of treatment. All the toxic manifestations appear to be reversible, but complete recovery may be slow.
Although less toxic than the sulfate, untoward effects have been observed in up to one-quarter of those treated with colistimethate sodium. Nephrotoxicity is common, with an increase in urea and creatinine over the first few days of treatment. Acute tubular necrosis is heralded by the appearance of proteinuria, hematuria and casts, sometimes without prior evidence of functional impairment. Renal damage usually continues to progress for up to 2 weeks after withdrawal of therapy. Renal damage is likely to increase with the dose and with the simultaneous administration of other potentially nephrotoxic agents. Manifestations of central and peripheral neurotoxicity occur particularly in patients with impaired renal function. Neuromuscular blockade is seen principally in patients also receiving anesthetics or other agents that impair neuromuscular transmission. Complete flaccid paralysis with respiratory arrest and subsequent complete recovery has been seen in a patient with myasthenia gravis. Allergy is occasionally seen, and nebulized colistin has caused bronchial hyperreactivity with tightness in the chest in adults with cystic fibrosis. Application of colistin or polymyxin B ear drops can lead to ototoxicity.

Safety Profile

A poison by ingestion, intraperitoneal, subcutaneous, and intravenous routes. When heated to decomposition it emits toxic vapors of NOx and SOx.