Colistin, besides known as polymyxin E, is an antibiotic medicine used as a last-resort treatment for multidrug-resistant gram-negative infections including pneumonia. [ 7 ] [ 8 ] These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. [ 9 ] It comes in two forms : colistimethate sodium can be injected into a vein, injected into a muscleman, or inhaled, and colistin sulfate is chiefly applied to the clamber or taken by mouth. [ 10 ] Colistimethate sodium [ 11 ] is a prodrug ; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the summation of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergo hydrolysis to form a building complex mix of partially sulfomethylated derivatives, arsenic well as colistin. resistance to colistin began to appear as of 2015. [ 12 ] common side effects of the injectable form include kidney problems and neurological problems. [ 8 ] other unplayful english effects may include anaphylaxis, muscle helplessness, and Clostridium difficile -associated diarrhea. [ 8 ] The inhale shape may result in constriction of the bronchioles. [ 8 ] It is unclear if habit during pregnancy is safe for the fetus. [ 13 ] Colistin is in the polymyxin class of medications. [ 8 ] It works by breaking down the cytoplasmic membrane, which generally results in bacterial cell death. [ 8 ] Colistin was discovered in 1947 and colistimethate sodium was approved for checkup use in the United States in 1970. [ 9 ] [ 8 ] It is on the World Health Organization ‘s List of Essential Medicines. [ 14 ] The World Health Organization classifies colistin as critically important for human music. [ 15 ] It is available as a generic medication. [ 16 ] It is derived from bacteria of the genus Paenibacillus. [ 10 ]
Reading: Colistin – Wikipedia
aesculapian uses [edit ]
antibacterial spectrum [edit ]
Colistin has been effective in treating infections caused by Pseudomonas, Escherichia, and Klebsiella species. The follow represents minimum inhibitory concentration ( MIC ) susceptibility data for a few medically significant microorganisms : [ 17 ] [ 18 ]
- Escherichia coli: 0.12–128 μg/ml
- Klebsiella pneumoniae: 0.25–128 μg/ml
- Pseudomonas aeruginosa: ≤0.06–16 μg/ml
For case, colistin in combination with other drugs is used to attack P. aeruginosa biofilm infection in lungs of patients with cystic fibrosis. [ 19 ] Biofilms have a low-oxygen environment below the surface where bacteria are metabolically inactive, and colistin is highly effective in this environment. however, P. aeruginosa occupy in the top layers of the biofilm, where they remain metabolically active. [ 20 ] This is because surviving kind cells migrate to the clear of the biofilm via pili and form raw aggregates via quorum sensing. [ 21 ]
administration and dose [edit ]
Forms [edit ]
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, whereas colistimethate sodium is promptly hydrolysed to a kind of methanesulfonated derivatives. Colistin sulfate and colistimethate sodium are eliminated from the soundbox by different routes. With respect to Pseudomonas aeruginosa, colistimethate is the nonoperational prodrug of colistin. The two drugs are not interchangeable .
- Colistimethate sodium may be used to treat Pseudomonas aeruginosa infections in patients with cystic fibrosis, 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 baumannii and Pseudomonas aeruginosa meningitis and 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 in 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.
dose [edit ]
Colistin sulfate and colistimethate sodium may both be given intravenously, but the dose is complicated. The different pronounce of the parenteral products of colistin methanesulfonate in different parts of the global was noted by Li et alabama. [ 28 ] Colistimethate sodium manufactured by Xellia ( Colomycin injection ) is prescribed in international units, whereas 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 national to the regulations that modern drugs are discipline to, and consequently there is no standardize drug of colistin and no detailed trials on pharmacology or pharmacokinetics. The optimum drug of colistin for most infections is therefore nameless. Colomycin has a recommended intravenous drug of 1 to 2 million units three times casual for patients weighing 60 kilogram or more with normal nephritic function. Coly-Mycin has a recommended dose of 2.5 to 5 mg/kg colistin basal a day, which is equivalent to 6 to 12 mg/kg colistimethate sodium per day. For a 60 kilogram serviceman, therefore, the recommended venereal disease for Colomycin is 240 to 480 milligram of colistimethate sodium, yet the recommended dose for Coly-Mycin is 360 to 720 magnesium of colistimethate sodium. Likewise, the recommended “ utmost ” venereal disease for each readiness is different ( 480 magnesium for Colomycin and 720 milligram 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 standardization of dose makes intravenous colistin dosing difficult for the doctor. [ citation needed ] Colistin has been used in combination with rifampicin ; attest of in vitro synergy exists, [ 31 ] [ 32 ] and the combination has been used successfully in patients. [ 33 ] There is besides in vitro tell of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics. [ 34 ] Colistimethate sodium aerosol ( Promixin ; Colomycin Injection ) is used to treat pneumonic infections, specially in cystic fibrosis. In the UK, the recommended adult drug is 1–2 million units ( 80–160 magnesium ) nebulised colistimethate doubly daily. [ 35 ] [ 29 ] Nebulized colistin has besides been used to decrease severe exacerbations in patients with chronic clogging pneumonic disease and infection with Pseudomonas aeruginosa. [ 36 ]
resistance [edit ]
immunity to colistin is rare, but has been described. As of 2017, no agreement exists about how to define colistin resistance. The Société Française de Microbiologie [ francium ] uses a MIC cut-off of 2 mg/l, whereas the british Society for Antimicrobial Chemotherapy sets a MIC cutoff of 4 mg/l or less as medium, and 8 mg/l or more as tolerant. No standards for describing colistin sensitivity are given in the United States. The beginning known colistin-resistance gene in a plasmid which can be transferred between bacterial strains is mcr-1. It was found in 2011 in China on a hog farm where colistin is routinely use and became publicly known in November 2015. [ 37 ] [ 38 ] The presence of this plasmid-borne gene was confirmed starting December 2015 in South-East Asia, several european countries, [ 39 ] and the United States. [ 40 ] It is found in certain strains of the bacteria Paenibacillus polymyxa. [ citation needed ] India reported the first detail colistin-resistance cogitation, which mapped 13 colistin-resistant infections recorded over 18 months. It concluded that pan-drug-resistant infections, particularly those in the bloodstream, have a higher deathrate. Multiple other cases were reported from other amerind hospitals. [ 41 ] [ 42 ] Although underground to polymyxins is by and large less than 10 %, it is more frequent in the Mediterranean and South-East Asia ( Korea and Singapore ), where colistin resistance rates are increasing. [ 43 ] Colistin-resistant E. coli was identified in the United States in May 2016. [ 44 ] Use of colistin to treat Acinetobacter baumannii infections has led to the growth of tolerant bacterial strains. They have besides developed resistance to the antimicrobial compounds LL-37 and lysozyme, produced by the homo immune arrangement. This cross-resistance is caused by gain-of-function mutations to the pmrB gene, a phosphoethanolamine transferase ( similar to mcr-1 ) located on the bacterial chromosome. [ 45 ] not all resistance to colistin and some early antibiotics is due to the presence of resistance genes. [ 46 ] Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a roll of resistance to an antibiotic, [ 47 ] has been observed in some species of Enterobacter since at least 2016 [ 46 ] and was observed in some strains of Klebsiella pneumoniae in 2017–2018. [ 48 ] In some cases this phenomenon has significant clinical consequences. [ 48 ]
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inherently repellent [edit ]
variable resistance [edit ]
adverse reactions [edit ]
The independent toxicities described with intravenous treatment are nephrotoxicity ( damage to the kidneys ) and neurotoxicity ( damage to the nerves ), [ 50 ] [ 51 ] [ 52 ] [ 53 ] but this may reflect the very high doses given, which are a lot higher than the doses presently recommended by any manufacturer and for which no allowance was made for preexistent nephritic disease. Neuro- and nephrotoxic effects appear to be ephemeral and subside on discontinuance of therapy or reduction in dose. [ 54 ] At a acid of 160 mg colistimethate IV every eight hours, identical little nephrotoxicity is seen. [ 55 ] [ 56 ] indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and it has been used for extended periods improving to six months with no ill effects. [ 57 ] Colistin-induced nephrotoxicity is peculiarly likely in patients with hypoalbuminemia. [ 58 ] The main toxicity described with aerosolized treatment is bronchospasm, [ 59 ] which can be treated or prevented with the use of β2-adrenergic receptor agonists such as salbutamol [ 60 ] or following a desensitization protocol. [ 61 ]
mechanism of action [edit ]
Colistin is a polycationic peptide and has both hydrophilic and lipophilic moieties. [ 62 ] These cationic regions interact with the bacterial outer membrane by displacing magnesium and calcium bacterial counter ions in the lipopolysaccharide. [ citation needed ] The hydrophobic and hydrophilic regions interact with the cytoplasmic membrane just like a detergent, solubilizing the membrane in an aqueous environment. [ citation needed ] This effect is bactericidal even in an isosmolar environment. [ citation needed ] Colistin binds to lipopolysaccharides and phospholipids in the out cell membrane of gram-negative bacteria. It competitively displaces bivalent cations ( Ca2+ and Mg2+ ) from the phosphate groups of membrane lipids, which leads to break of the extinct cell membrane, escape of intracellular contents and bacterial death .
Pharmacokinetics [edit ]
No clinically utilitarian absorption of colistin occurs in the gastrointestinal tract. For systemic infection, colistin must consequently be given by injection. Colistimethate is eliminated by the kidneys, but colistin is eliminated by non-renal mechanism ( s ) that are as of so far not characterised. [ 63 ] [ 64 ]
history [edit ]
Colistin was first base isolated in Japan in 1949 by Y. Koyama, from a flask of fermenting Bacillus polymyxa volt-ampere. colistinus, [ 65 ] and became available for clinical function in 1959. [ 66 ] Colistimethate sodium, a less toxic prodrug, became available for injection in 1959. In the 1980s, polymyxin use was widely discontinued because of nephro- and neurotoxicity. As multi-drug resistant bacteria became more prevailing in the 1990s, colistin started to get a irregular look as an emergency solution, in malice of perniciousness. [ 67 ] Colistin has besides been used in agribusiness, peculiarly in China from the 1980s onwards. chinese production for agriculture exceeded 2700 tons in 2015. China banned colistin use for livestock growth forwarding in 2016. [ 68 ]
biosynthesis [edit ]
The biosynthesis of colistin requires the use of three amino acids : threonine, leucine, and 2,4-diaminobutryic acid. The linear shape of colistin is synthesized before cycliziation. Non-ribosomal peptide biosynthesis begins with a load faculty and then the summation of each subsequent amino acerb. The subsequent amino acids are added with the aid of an adenylation domain ( A ), a peptidyl carrier protein domain ( PCP ), an epimerization sphere ( E ), and a condensation sphere ( C ). Cyclization is accomplished by a thioesterase. [ 69 ] The first base step is to have a loading world, 6-methylheptanoic acid, consort with the A and PCP domains. now with a C, A, and PCP domain that is associated with 2,4-diaminobutryic acid. This continues with each amino acid until the linear peptide chain is completed. The survive module will have a thioesterase to complete the cyclization and form the product colistin . The loading world 6-methylheptanoic acerb is shown in pink-orange ; yellow is 2,4-diaminobutryic acidic ; light blasphemous is threonine ; magenta is leucine .