Colistin
|
| 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 |
| Clinical data |
| Trade names |
Coly-mycinm |
| Pregnancy cat. |
C |
| Legal status |
PoM (UK), not available in US |
| Routes |
topical, oral, intravenous |
| Pharmacokinetic data |
| Bioavailability |
0% |
| Half-life |
5 hours |
| Identifiers |
| CAS number |
1264-72-8 Y |
| ATC code |
A07AA10 J01XB01 QJ51XB01 |
| PubChem |
CID 5311054 |
| DrugBank |
DB00803 |
| ChemSpider |
4470591 Y |
| UNII |
WP15DXU577 N |
| KEGG |
D02138 Y |
| ChEMBL |
CHEMBL501505 N |
| Chemical data |
| Formula |
C52H98N16O13 |
| Mol. mass |
1155,4495 g/mol |
SMILES
- O=C(N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H]1C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)NCC1)[C@H](O)C)CCN)CCN)CC(C)C)CC(C)C)CCN)CCN)[C@H](O)C)CCN)CCCC(C)CC
|
InChI
-
InChI=1S/C52H98N16O13/c1-9-29(6)11-10-12-40(71)59-32(13-19-53)47(76)68-42(31(8)70)52(81)64-35(16-22-56)44(73)63-37-18-24-58-51(80)41(30(7)69)67-48(77)36(17-23-57)61-43(72)33(14-20-54)62-49(78)38(25-27(2)3)66-50(79)39(26-28(4)5)65-45(74)34(15-21-55)60-46(37)75/h27-39,41-42,69-70H,9-26,53-57H2,1-8H3,(H,58,80)(H,59,71)(H,60,75)(H,61,72)(H,62,78)(H,63,73)(H,64,81)(H,65,74)(H,66,79)(H,67,77)(H,68,76)/t29?,30-,31-,32+,33+,34+,35+,36+,37+,38+,39-,41+,42+/m1/s1 Y
Key:YKQOSKADJPQZHB-QNPLFGSASA-N Y
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N (what is this?) (verify)
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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 most Gram-negative bacilli and is used as a polypeptide antibiotic.
Colistin is a decades-old drug that fell out of favor due to its nephrotoxicity. It remains one of the last-resort antibiotics for multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter.[1] NDM-1 metallo-β-lactamase multidrug-resistant Enterobacteriaceae have also shown susceptibility to Colistin.[2]
Contents
- 1 History
- 2 Administration and dosage
- 3 Mode of action
- 4 Resistance
- 4.1 Exceptional (inherently colistin resistant) Gram-negative bacteria
- 4.2 Gram-negative organisms with variable resistance to colistin
- 5 Pharmacokinetics
- 6 Adverse reactions
- 7 References
History[edit]
Colistin was derived from a flask of fermenting bacteria by a Japanese researcher in 1949.[3]
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This section requires expansion. (August 2012) |
Administration and dosage[edit]
Forms[edit]
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.[4][5] Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumanii and Pseudomonas aeruginosa meningitis/ventriculitis [6][7][8][9] Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii.[5]
- 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.
Dosage[edit]
Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated. The very different labeling of the parenteral products of colistin methanesulfonate in different parts of the world was first revealed by Li et al. [10] Colistimethate sodium manufactured by Xellia (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 80 mg colistimethate;[11]
- Coly-mycin M 150 mg "colistin base" is 360 mg colistimethate or 4,500,000 units.[12]
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 three times daily for patients weighing 60 kg or more with normal renal function. Coly-Mycin has a recommended dose of 2.5 to 5 mg/kg colistin base a day, which is equivalent to 6 to 12 mg/kg colistimethate sodium per day. For a 60 kg man, therefore, the recommended dose for Colomycin is 240 to 480 mg of colistimethate sodium, yet the recommended dose for Coly-Mycin is 360 to 720 mg of colistimethate sodium. Likewise, the recommended "maximum" dose for each preparation is different (480 mg for Colomycin and 720 mg 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 difficult for any physician.[citation needed]
Colistin has been used in combination with rifampicin, and there is in-vitro evidence of synergy,[13][14] and the combination has been used successfully in patients.[15] There is also in-vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics.[16]
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 – 160 mg) nebulised colistimethate twice daily.[17][18]
Mode of action[edit]
Colistin is polycationic and has both hydrophilic and lipophilic moieties. These poly-cationic regions interact with the bacterial outer membrane, by displacing bacterial counter ions in the lipopolysaccharide. Hydrophobic/hydrophillic regions interact with the cytoplasmic membrane just like a detergent, solubilizing the membrane in an aqueous environment. This effect is bactericidal even in an isosmolaric environment.
Resistance[edit]
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 2 mg/l, whereas the British Society for Antimicrobial Chemotherapy sets a cutoff of 4 mg/l or less as sensitive, and 8 mg/ml or more as resistant. There are not currently any US standards for measuring colistin sensitivity.
Use of colistin to treat Acinetobacter baumannii infections has, as with other antibiotics, led to the development of resistant bacterial strains. These resistant strains have also been shown to develop resistance to antimicrobial compounds, including LL-37 and lysozyme, produced as part of the human host's immune system.[19]
Exceptional (inherently colistin resistant) Gram-negative bacteria[edit]
- Brucella
- Burkholderia cepacia
- Chryseobacterium indologenes
- Edwardsiella
- Elizabethkingia meningoseptica
- Francisella tularensis spp.
- Gram-negative cocci
- Helicobacter pylori
- Moraxella catarrhalis
- Neisseria gonorrheae and Neisseria meningitidis
- Proteus
- Providencia
- Serratia
- Some strains of Stenotrophomonas maltophilia[20]
Gram-negative organisms with variable resistance to colistin[edit]
- Aeromonas
- Vibrio
- Prevotella
- Fusobacterium
Pharmacokinetics[edit]
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.[21][22]
Adverse reactions[edit]
The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves),[23][24][25][26] 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.[27]
At a dose of 160 mg colistimethate IV every eight hours, very little nephrotoxicity is seen.[28][29] 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.[30]
The main toxicity described with aerosolised treatment is bronchospasm,[31] which can be treated or prevented with the use of beta2-agonists such as salbutamol [32] or following a desensitisation protocol.[33]
References[edit]
- ^ Falagas, ME, Grammatikos, AP, Michalopoulos, A (October 2008). "Potential of old-generation antibiotics to address current need for new antibiotics". Expert review of anti-infective therapy 6 (5): 593–600. doi:10.1586/14787210.6.5.593. PMID 18847400.
- ^ Kumarasamy et al.; Toleman, Mark A; Walsh, Timothy R; Bagaria, Jay; Butt, Fafhana; Balakrishnan, Ravikumar; Chaudhary, Uma; Doumith, Michel et al. (2010). "Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study". The Lancet Infectious Diseases 10 (9): 597–602. doi:10.1016/S1473-3099(10)70143-2. PMC 2933358. PMID 20705517.
- ^ Vastag, Brian (2012), "NIH Superbug Outbreak Shows Lack of Antibiotics", The Washington Post, Saturday, 25 August 2012; pg A2.
- ^ 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 0-306-43902-6. [http://www.horizonpress.com/acineto.
- ^ Benifla M, Zucker G, Cohen S and Alkan M (2004). "Successful treatment of Acinetobacter meningitis with intrathecal polymyxin". J Antimicrobial Chemotherapy 54 (1): 290–293. doi:10.1093/jac/dkh289. PMID 15190037.
- ^ Yagmur et al.,; Esen, F (2006). "Intrathecal colistin for treatment of Pseudomonas aeruginosa ventriculitis: report of a case with successful outcome". Critical Care 10 (6): 428. doi:10.1186/cc5088. PMC 1794456. PMID 17214907.
- ^ Motaouakkil et al.,; Charra, B; Hachimi, A; Nejmi, H; Benslama, A; Elmdaghri, N; Belabbes, H; Benbachir, M (2006). "Colistin and rifampicin in the treatment of nosocomial infections from multiresistant Acinetobacter baumannii". Journal of Infection 53 (4): 274–278. doi:10.1016/j.jinf.2005.11.019. PMID 16442632.
- ^ Karakitsos et al.,; Paramythiotou, E; Samonis, G; Karabinis, A (2006). "Is intraventricular colistin an effective and safe treatment for post-surgical ventriculitis in the intensive care unit?". Acta Anaesthesiol Scand. 50 (10): 1309–1310. doi:10.1111/j.1399-6576.2006.01126.x. PMID 17067336.
- ^ Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, Paterson DL. (2006). "Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections". Lancet Infect Dis 6 (9): 589–601. PMID 16931410.
- ^ 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 (4): 235–38. doi:10.1159/000069498. PMID 12686786.
- ^ 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 (4): 494–95. doi:10.1093/jac/41.4.494.
- ^ 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 (8): 682–83. doi:10.1111/j.1469-0691.2005.01198.x. PMID 16008625.
- ^ 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. doi:10.1111/j.1469-0691.1999.tb00095.x.
- ^ 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
- ^ Napier, B. A.; Burd, E. M.; Satola, S. W.; Cagle, S. M.; Ray, S. M.; McGann, P.; Pohl, J.; Lesho, E. P.; Weiss, D. S. (21 May 2013). "Clinical Use of Colistin Induces Cross-Resistance to Host Antimicrobials in Acinetobacter baumannii". mBio 4 (3): e00021–13–e00021–13. doi:10.1128/mBio.00021-13.
- ^ Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients; Nikolaos Markou , Haralampos Apostolakos, Christiana Koumoudiou, Maria Athanasiou, Alexandra Koutsoukou, Ioannis Alamanos and Leonidas Gregorakos; Critical Care 2003, 7:R78-R83 doi:10.1186/cc2358
- ^ 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 (5): 837–40. doi:10.1093/jac/dkh167. PMID 15044428.
- ^ 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 (5): 1766–70. doi:10.1128/AAC.47.5.1766-1770.2003. PMC 153303. PMID 12709357.
- ^ Wolinsky E, Hines JD. (1962). "Neurotoxic and nephrotoxic effects of colistin in patients with renal disease". N Engl J Med 266 (15): 759–68. doi:10.1056/NEJM196204122661505. PMID 14008070.
- ^ 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". Annals of Internal Medicine 72 (6): 857–68. PMID 5448745.
- ^ 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 (3): 592–94. doi:10.1183/09031936.98.12030592. PMID 9762785.
- ^ 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 (1): 11–25. doi:10.1016/j.ijantimicag.2004.10.001. PMID 15620821.
- ^ Beringer P. (2001). "The clinical use of colistin in patients with cystic fibrosis". Current Opinion in Pulmonary Medicine 7 (6): 434–440. doi:10.1097/00063198-200111000-00013.
- ^ 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". Annals of Pharmacotherapy 34 (11): 1238–42. doi:10.1345/aph.19370. PMID 11098334.
- ^ Littlewood JM, Koch C, Lambert PA , et al. (2000). "A ten year review of Colomycin". Respir Med 94 (7): 632–40. doi:10.1053/rmed.2000.0834. PMID 10926333.
- ^ Stein A, Raoult D. (2002). "Colistin: an antimicrobial for the 21st century?". Clin Infect Dis 35 (7): 901–2. doi:10.1086/342570. PMID 12228836.
- ^ Maddison J, Dodd M, Webb AK. (1994). "Nebulized colistin causes chest tightness in adults with cystic fibrosis". Respir Med. 88 (2): 145–147. doi:10.1016/0954-6111(94)90028-0.
- ^ 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 (4): 205–213. doi:10.1016/j.jcf.2006.03.007. PMID 16678502.
- ^ 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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Antidiarrheals, intestinal anti-inflammatory/anti-infective agents (A07)
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| Rehydration |
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| Intestinal anti-infectives |
- Antibiotics
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- Colistin
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drug (J1p, w, n, m, vacc)
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