Colistin

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Colistin
Systematic (IUPAC) name
 ?
Identifiers
CAS number 1264-72-8
ATC code J01XB01
PubChem 5311054
DrugBank APRD00886
Chemical data
Formula C52H98N16O13
Mol. weight 2797.3193 g/mol
Pharmacokinetic data
Bioavailability 0%
Metabolism  ?
Half life 5 hours
Excretion  ?
Therapeutic considerations
Pregnancy cat.

C
Legal status

PoM (UK), not available in US
Routes topical, PO, IV

Colistin (polymyxin E) is a polymyxin antibiotic produced by certain strains of Bacillus polymyxa var. colistinus. Colistin is a mixture of cyclic polypeptides colistin A and B. Colistin is effective against Gram-negative bacilli, except Proteus.

Contents

[edit] Administration and posology

There are two forms of colistin (also known as 'the nuke bomb' of antibiotics) available commercially: colistin sulphate and colistimethate (colistin methanesulphonate sodium, colistin sulphomethate sodium). Colistin sulphate is cationic, colistimethate is anionic; colistin sulphate is stable, but colistimethate is readily hydrolysed to a variety of methanesulphonated derivatives. Colistin suphate and colistimethate are eliminated from the body by different routes. With respect to Pseudomonas aeruginosa, colistimethate is the inactive prodrug of colistin. The two drugs are not interchangeable.

Colistin sulfate may be used to treat intestinal infections, or to suppress colonic flora. Colistin sulfate is also used as topical creams, powders, and otic solutions.

Colistin sulfate and colistimethate may both be given intravenously, but the dosing is complicated and borders on nightmarish. Colistimethate manufactured by Dumex-Alpharma (Colomycin injection®) is prescribed in units, but colistimethate manufactured by Parkdale Pharmaceuticals (Coly-Mycin M Parenteral®) is prescribed in milligrams of colistin base:

  • Colomycin 500,000 units is 40mg colistimethate;[1]
  • Coly-mycin M 150mg "colistin base" is 400mg colistimethate or 5,000,000 units.

Because colistin was introduced into clinical practice over 50 years ago, it was never subject to the regulations that modern drugs are subject to, and therefore there is no standardised dosing of colistin and no detailed trials on pharmacology or pharmacokinetics: the optimal dosing of colistin for most infections is therefore unknown. Colomycin has a recommended dose of 1 to 2 million units thrice daily for patients weighing 60kg or more with normal renal function, Coly-Mycin has a recommended dose of 2.5 to 5mg/kg colistin base a day, which is equivalent to 6.67 to 13.3 mg/kg colistin base a day. For a 60kg man, therefore, the recommended dose for Colomycin is 240 to 480mg of colistimethate, yet the recommended dose for Coly-Mycin is 400 to 800mg of colistimethate. Likewise, the recommended "maximum" dose for each preparation is different (480mg for Colomycin and 800mg for Coly-Mycin). Each country has different generic preparations of colistin and the recommended dose will depend on the manufacturer. This complete absence of any regulation or standardisation of dose makes intravenous colistin dosing a nightmare for any physician.

Colistin has been used in combination with rifampicin, and there is in vitro evidence of synergy,[2][3] and the combination has been used successfully in patients.[4]

Colistimethate aerosol (Promixin®) is used to treat pulmonary infections, especially in cystic fibrosis. In the UK and Australia, the dose most commonly used is 40mg (1 million units) nebulised colistimethate thrice daily.

[edit] Mode of action

Colistin is polycationic and has both hydrophilic and lipophilic moieties. These interact with the bacterial cytoplasmic membrane, changing its permeability. This effect is bactericidal.

[edit] Resistance

Resistance to colistin is currently rare, but is described. At present there is no agreement about how to look for colistin resistance. The Société Française de Microbiologie uses a cut off of 2mg/l, whereas the British Society for Antimicrobial Chemotherapy sets a cutoff of 4mg/l or less as sensitive, and 8mg/ml or more as resistant. There are not currently any US standards for measuring colistin sensitivity.

[edit] Pharmacokinetics

There is no clinically useful absorption of colistin from the gastrointestinal tract. For systemic infection, colistin must therefore be given by injection. Colistimethate is eliminated by the kidneys, but colistin is supposed to be eliminated by non-renal mechanism(s) that are as yet not characterised.[5][6]

[edit] Adverse reactions

The main toxicities described are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves),[7][8][9][10] but this may reflect the very high doses given, which are much higher than the doses currently recommended by any manufacturer and for which no adjustment was made for renal disease.

At a dose of 160mg colistimethate IV every eight hours, very little nephrotoxicity is seen.[11][12] Indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and colistin has been used for extended periods of up to six months with no ill effects.[13]

[edit] Further reading

  • Li J, Nation RL, Tunridge JD, et al. (2006). "Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections". Lancet Infect Dis 6 (8): 589–601.
  • Li J , Nation RL, Milne RW, et al. (2005). "Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria". Int J Antimicrob Agents 25: 11–25.

[edit] References

  1. ^ Colomycin injection [Summary of product characteristics]. Bexley, Kent, UK: Forest Laboratories UK Ltd., 2004.
  2. ^ Giamarellos-Bourboulis EJ, Sambatakou H, Galani I, Giamarellou H. (2003). "{{{title}}}". J Chemother 15: 235–38.
  3. ^ Hogg GM, Barr JG, Webb CH. (1998). "In-vitro activity of the combination of colistin and rifampicin against multidrug-resistant strains of Acinetobacter baumannii". J Antimicrob Chemother 41: 494–95.
  4. ^ Petrosillo N, Chinello P, Proietti MF, et al. (2005). "Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii infections: clinical outcome and adverse events". Clin Microbiol Infect 11: 682–83.
  5. ^ Li J, Milne RW, Nation RL, et al. (2004). "Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonate". J Antimicrob Chemother. 53.
  6. ^ Li J, Milne RW, Nation RL, et al. (2003). "Use of high performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration". Antimicrob Agents Chemother 47: 1766–70.
  7. ^ Wolinsky E, Hines JD. (1962). "Neurotoxic and nephrotoxic effects of colistin in patients with renal disease". N Engl J Med 266: 759–68.
  8. ^ Koch-Weser J, Sidel VW, Federman EB, et al. (1970). "Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy". Ann Intern Med 72: 857–68.
  9. ^ Ledson MJ, Gallagher MJ, Cowperthwaite C, et al. (1998). "Four years' experience of intravenous colomycin in an adult cystic fibrosis unit". Eur Respir J 12: 592–94.
  10. ^ Li J, Nation RL, Milne RW, et al. (2005). "Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria". Int J Antimicrob Agents 25: 11–25.
  11. ^ Conway SP, Etherington C, Munday J, et al. (2000). "Safety and tolerability of bolus intravenous colistin in acute respiratory exacerbation in adults with cystic fibrosis". Ann Pharmacother 34: 1238–42.
  12. ^ Littlewood JM, Koch C, Lambert PA , et al. (2000). "A ten year review of Colomycin". Respir Med 94: 632–40.
  13. ^ Stein A, Raoult D. (2002). "Colistin: an antimicrobial for the 21st century?" 35: 901–2.
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