Colistin


Colistin, also known as polymyxin E, is an antibiotic used as a last-resort for multidrug-resistant Gram negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in a form which can be injection into a vein or muscle or inhaled, known as colistimethate sodium and one which is applied to the skin or taken by mouth, known as colistin sulfate. Resistance to colistin is beginning to appear as of 2017.
Common side effects of the injectable form include kidney and neurological problems. Other serious side effects may include anaphylaxis, muscle weakness, and Clostridium difficile-associated diarrhea. The inhaled form may result in constriction of the bronchioles. It is unclear if use during pregnancy is safe for the baby. Colistin is in the polymyxin class of medications. It works by breaking down the cytoplasmic membrane which generally results in bacterial cell death.
Colistin was discovered in 1947 and colistimethate sodium was approved for medical use in the United States in 1970. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system. It is available as a generic medication. In the United Kingdom it costs the NHS about £5.40 per day for the injectable form as of 2018. In the United States this amount costs about US$47 as of 2019. It is derived from bacteria of the genus Paenibacillus.

Medical uses

Antibacterial spectrum

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:
For example, colistin 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 and colistin is highly effective in this environment. However, P. aeruginosa reside in the top layers of the biofilm, where they remain metabolically active. This is because surviving tolerant cells migrate to the top of the biofilm via pili motility and form new aggregates via quorum sensing.

Administration and dosage

Forms

Two forms of colistin are available commercially: colistin sulfate and colistimethate 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.
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 is prescribed in international units, but colistimethate sodium manufactured by Parkdale Pharmaceuticals is prescribed in milligrams of colistin base:
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. 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 is used to treat pulmonary infections, especially in cystic fibrosis. In the UK, the recommended adult dose is 1–2 million units nebulised colistimethate twice daily. Nebulized colistin has also been used to decrease severe exacerbations in patients with chronic obstructive pulmonary disease and infection with Pseudomonas aeruginosa.

Resistance

Resistance to colistin is rare, but has been described. The first colistin-resistance gene in a plasmid which can be transferred between bacterial strains was found in 2011 in China and became publicly known in November 2015. The presence of this plasmid-borne mcr-1 gene was confirmed starting December 2015 in South-East Asia, several European countries and the United States. It is produced by certain strains of the bacteria Paenibacillus polymyxa.
, no agreement exists about how to look for colistin resistance. The 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.
The plasmid-borne mcr-1 gene has been found to confer resistance to colistin. The first colistin-resistance gene in a plasmid which can be transferred between bacterial strains was found in 2011 and became publicly known in November 2015. This plasmid-borne mcr-1 gene has since been isolated in China, Europe and the United States.
India reported the first 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 more frequent in the Mediterranean and South-East Asia, where colistin resistance rates are continually increasing. Colistin-resistant E. coli was identified in the United States in May 2016.
Use of colistin to treat Acinetobacter baumannii infections has led to the development of resistant bacterial strains. which have also developed resistance to antimicrobial compounds LL-37 and lysozyme, produced by the human immune system.
It's worth noting that not all resistance to colisin and some other antibiotics is due to the presence of resistance genes. Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a range of resistance to an antibiotic, has been observed in some species of Enterobacter since at least 2016 and in some strains of Klebsiella pneumoniae in 2017-2018. In some cases this phenomenon has significant clinical consequences.

Inherently resistant

The main toxicities described with intravenous treatment are nephrotoxicity and neurotoxicity, 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 colistin-induced nephrotoxicity is particularly favoured in patients with hypoalbuminemia.
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.

Mechanism of action

Colistin is a polycationic peptide and has both hydrophilic and lipophilic moieties. These cationic regions interact with the bacterial outer membrane, by displacing magnesium and calcium 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 isosmolar environment.

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 that are as of yet not characterised.

History

Colistin was first isolated in Japan in 1949 from a flask of fermenting Bacillus polymyxa var. colistinus by the Japanese scientist Koyama and became available for clinical use in 1959.
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 prevalent in the 1990s, colistin started to get a second look as an emergency solution, in spite of toxic effects.

Biosynthesis

The biosynthesis of colistin requires the use of three amino acids threonine, leucine, and 2,4-diaminobutryic acid. It is important to synthesis the linear form of colistin before cycliziation. Elongation of non ribosomal peptide biosynthesis begins by a loading module and then the addition of each subsequent amino acid. The subsequent amino acids are added with the help of an adenylation domain, a peptidyl carrier protein domain, an epimerization domain, and a condensation domain. Cyclization is accomplished by utilizing a thioesterase. The first step is to have a loading domain, 6-methyl-heptanoic acid, associate 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 last module will have a thioesterase to complete the cyclization and form the product colistin.