Colistin
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Colistin
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| Systematic (IUPAC) name | |
| N-(4-amino-1-(1-(4-amino-1-oxo-1-(3,12,23-tris(2-aminoethyl)- 20-(1-hydroxyethyl)-6,9-diisobutyl-2,5,8,11,14,19,22-heptaoxo- 1,4,7,10,13,18-hexaazacyclotricosan-15-ylamino)butan-2-ylamino)- 3-hydroxybutan-2-ylamino)-1-oxobutan-2-yl)-N,5-dimethylheptanamide | |
| Identifiers | |
| CAS number | |
| ATC code | J01 A07AA10 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C52H98N16O13 |
| Mol. mass | 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 and Burkholderia cepacia, and is used as a polypeptide antibiotic.
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[edit] Administration and posology
[edit] Forms
There are two forms of colistin available commercially: colistin sulfate and colistimethate sodium (colistin methanesulfonate sodium, colistin sulfomethate sodium). Colistin sulfate is cationic, colistimethate sodium is anionic; colistin sulfate is stable, but colistimethate sodium is readily hydrolysed to a variety of methanesulfonated derivatives. Colistin sulfate and colistimethate sodium 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.
- Colistimethate sodium may be used to treat Pseudomonas aeruginosa infections in cystic fibrosis patients and it has come into recent use for treating multidrug-resistant Acinetobacter infection, although resistant forms have been reported.[1][2] Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumanii and Pseudomonas aeruginosa meningitis/ventriculitis [3][4][5][6] Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii.[2]
- 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.
[edit] Dosage
Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated. Colistimethate sodium manufactured by Dumex-Alpharma (Colomycin injection) is prescribed in international units, but colistimethate sodium manufactured by Parkdale Pharmaceuticals (Coly-Mycin M Parenteral) is prescribed in milligrams of colistin base:
- Colomycin 1,000,000 units is 80mg colistimethate;[7]
- Coly-mycin M 150mg "colistin base" is 360mg colistimethate or 4,500,000 units.[8]
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 intravenous 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 to 12 mg/kg colistimethate sodium per day. For a 60kg man, therefore, the recommended dose for Colomycin is 240 to 480mg of colistimethate sodium, yet the recommended dose for Coly-Mycin is 360 to 720mg of colistimethate sodium. Likewise, the recommended "maximum" dose for each preparation is different (480mg for Colomycin and 720mg 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,[9][10] and the combination has been used successfully in patients.[11] There is also in-vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics [12].
Colistimethate sodium aerosol (Promixin; Colomycin Injection) is used to treat pulmonary infections, especially in cystic fibrosis. In the UK, the recommended adult dose is 1 - 2 million units (80 - 160mg) nebulised colistimethate twice daily.[13][14]
[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.[15][16]
[edit] Adverse reactions
The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves),[17][18][19][20] 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. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose [21].
At a dose of 160mg colistimethate IV every eight hours, very little nephrotoxicity is seen.[22][23] 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.[24]
The main toxicity described with aerosolised treatment is bronchospasm [25] which can be treated or prevented with the use of beta2-agonists such as salbutamol [26] or following a desensitisation protocol[27].
[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. doi:.
- 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. doi:.
[edit] References
- ^ Reis AO, Luz DAM, Tognim MCB, Sader HS, and Gales AC (2003). "Polymyxin-Resistant Acinetobacter spp. Isolates: What Is Next?". Emerg Infect Dis 9: 1025–7.
- ^ a b Towner K J (2008). "Molecular Basis of Antibiotic Resistance in Acinetobacter spp.", Acinetobacter Molecular Biology. Caister Academic Press. ISBN 978-1-904455-20-2.
- ^ Benifla M, Zucker G, Cohen S and Alkan M (2004). "Successful treatment of Acinetobacter meningitis with intrathecal polymyxin". J Antimicrobial Chemotherapy 54: 290–293.
- ^ Yagmur et al., (2006). "Intrathecal colistin for treatment of Pseudomonas aeruginosa ventriculitis: report of a case with successful outcome". Critical Care 10: 428. doi:.
- ^ Motaouakkil et al., (2006). "Colistin and rifampicin in the treatment of nosocomial infections from multiresistant Acinetobacter baumannii". Journal of Infection 53: 274–278. doi:.
- ^ Karakitsos et al., (2006). "Is intraventricular colistin an effective and safe treatment for post-surgical ventriculitis in the intensive care unit?". Acta Anaesthesiol Scand. 50: 1309–1310. doi:.
- ^ Colomycin injection [Summary of product characteristics]. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=1590
- ^ http://www.emea.europa.eu/pdfs/vet/mrls/081502en.pdf; NB. Colistin base has an assigned potency of 30 000 IU/mg
- ^ Giamarellos-Bourboulis EJ, Sambatakou H, Galani I, Giamarellou H. (2003). "In vitro interaction of colistin and rifampin on multidrug-resistant Pseudomonas aeruginosa". J Chemother 15: 235–38.
- ^ 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. doi:.
- ^ 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. doi:.
- ^ MacGowan AP, Rynn C, Wootton M, Bowker KE, Holt HA, Reeves DS. (1999). "In vitro assessment of colistin's antipseudomonal antimicrobial interactions with other antibiotics". Clin Microbiol Infect. 5: 32–36.
- ^ Promixin [Summary of Product Characteristics] http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=13532
- ^ Colomycin Injection [Summary of Product Characteristics] http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=1590
- ^ 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: 837. doi:.
- ^ 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. doi:.
- ^ Wolinsky E, Hines JD. (1962). "Neurotoxic and nephrotoxic effects of colistin in patients with renal disease". N Engl J Med 266: 759–68.
- ^ 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.
- ^ 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. doi:.
- ^ 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. doi:.
- ^ Beringer P. (2001). "The clinical use of colistin in patients with cystic fibrosis". Current Opinion in Pulmonary Medicine 7: 434–440. doi:.
- ^ 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. doi:.
- ^ Littlewood JM, Koch C, Lambert PA , et al. (2000). "A ten year review of Colomycin". Respir Med 94: 632–40. doi:.
- ^ Stein A, Raoult D. (2002). "Colistin: an antimicrobial for the 21st century?" 35: 901–2.
- ^ Maddison J, Dodd M, Webb AK. (1994). "Nebulized colistin causes chest tightness in adults with cystic fibrosis". Respir Med. 88: 145–147. doi:.
- ^ Kamin W, Schwabe A, Kramer I. (2006). "Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers". J Cyst Fibros. 5: 205–213. doi:.
- ^ Dominguez-Ortega J, Manteiga E, Abad-Schilling C, Juretzcke MA, Sanchez-Rubio J, Kindelan C. (2007). "Induced tolerance to nebulized colistin after severe reaction to the drug". J Investig Allergol Clin Immunol. 17: 59–61.
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