Colistin

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; Coly-monas(India)
Pregnancy category	C
Legal status	PoM (UK), not available in US
Routes of administration	topical, oral, intravenous, inhaled
Pharmacokinetic data
Bioavailability	0%
Biological half-life	5 hours
Identifiers
CAS Number	1264-72-8 Y
ATC code	A07AA10 (WHO) J01XB01 QJ51XB01 (WHO)
PubChem	CID: 5311054
DrugBank	DB00803 Y
ChemSpider	4470591 Y
UNII	WP15DXU577 N
KEGG	D02138 Y
ChEMBL	CHEMBL501505 N
Chemical data
Formula	C52H98N16O13
Molecular 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
NY (what is this?)  (verify)

Colistin (polymyxin E) is a polymyxin antibiotic produced by certain strains of Paenibacillus 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. NDM-1 metallo-β-lactamase multidrug-resistant Enterobacteriaceae have also shown susceptibility to colistin. Resistance to colistin has been identified in the Escherichia coli strain SHP45, carried by the mcr-1 gene, as the first plasmid-mediated polymyxin resistance mechanism.

History

Colistin was derived from a flask of fermenting bacteria by a Japanese researcher in 1949.

Administration and dosage

Forms

Two forms of colistin are 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. Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumanii and Pseudomonas aeruginosa meningitis/ventriculitis Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii.

• 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 A (polymyxin E1) and colistin B (polymyxin E2) can be purified individually to research and study their effects and potencies as separate compounds.

Dosage

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. 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;
• Coly-mycin M 150 mg "colistin base" is 360 mg colistimethate or 4,500,000 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 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 depends on the manufacturer. This complete absence of any regulation or standardisation of dose makes intravenous colistin dosing difficult for any physician.

Colistin has been used in combination with rifampicin, and evidence of in-vitro synergy exists, and the combination has been used successfully in patients. There is also in-vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics.

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.

Mode of action

Colistin is polycationic and has both hydrophilic and lipophilic moieties. These polycationic regions interact with the bacterial outer membrane, by displacing bacterial counter ions in the lipopolysaccharide. Hydrophobic/hydrophilic 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.

Spectrum of bacterial susceptibility

Colistin has been effective in treating infections caused by Pseudomonas, Escherichia, and Klebsiella species. The following represents MIC susceptibility data for a few medically significant microorganisms.

• Escherichia coli: 0.12–128 μg/ml
• Klebsiella pneumoniae: 0.25–128 μg/ml
• Pseudomonas aeruginosa: ≤0.06–16 μg/ml

Colestin in combination with other drugs are used to attack P. aeruginosa biofilm infection in lungs of CF patients. Biofilms have a low oxygen environment below the surface where bacteria are metabolically inactive. Colestin is highly effective in this environment. However, P. aeruginosa in the outer layers where they are metabolically active can develop resistance to colestin. Consequently, a drug combination attacking both the inactive and active forms of P. aeruginosa is highly effective.

Resistance

Resistance to colistin is currently rare, but is described. At present, no agreement exists 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. No standards for measuring colistin sensitivity are given in the US.

India reported the first clear and detailed colistin-resistance study which mapped 13 colistin-resistant cases recorded over 18 months. It concluded that pan-drug resistant infections, particularly those in the blood stream, have a higher mortality. Multiple other cases were reported from other Indian hospitals. Although resistance to polymyxins is generally less than 10%, it is higher in the Mediterranean and South-East Asia (Korea and Singapore), where colistin resistance rates are continually increasing.

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.

Exceptional (inherently colistin-resistant) Gram-negative bacteria

• Brucella
• Burkholderia cepacia
• Chryseobacterium indologenes
• Edwardsiella
• Elizabethkingia meningoseptica
• Francisella tularensis spp.
• Gram-negative cocci
• Helicobacter pylori
• Moraxella catarrhalis
• Morganella spp.
• Neisseria gonorrheae and Neisseria meningitidis
• Proteus
• Providencia
• Serratia

• Some strains of Stenotrophomonas maltophilia

Gram-negative organisms with variable resistance to colistin

• Aeromonas
• Vibrio
• Prevotella
• Fusobacterium

Pharmacokinetics

No clinically useful absorption of colistin occurs in 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.

Adverse reactions

The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves), 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.

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

The main toxicity described with aerosolised treatment is bronchospasm, which can be treated or prevented with the use of beta2-agonists such as salbutamol or following a desensitisation protocol.

Further reading

Resistance

•