Antibacterial spectrumEdit
Colistin has been effective in treating infections caused by Pseudomonas, Escherichia, and Klebsiella species. The following represents minimum inhibitory concentration [MIC] susceptibility data for a few medically significant microorganisms:[17][18]
- Escherichia coli: 0.12128 μg/ml
- Klebsiella pneumoniae: 0.25128 μg/ml
- Pseudomonas aeruginosa: 0.0616 μg/ml
For example, 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 reside in the top layers of the biofilm, where they remain metabolically active.[20] This is because surviving tolerant cells migrate to the top of the biofilm via pili and form new aggregates via quorum sensing.[21]
Administration and dosageEdit
FormsEdit
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 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 patients with cystic fibrosis, and it has come into recent use for treating multidrug-resistant Acinetobacter infection, although resistant forms have been reported.[22][23] Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumannii and Pseudomonas aeruginosa meningitis and ventriculitis[24][25][26][27] Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii.[23]
- 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.
DosageEdit
Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated. The different labeling of the parenteral products of colistin methanesulfonate in different parts of the world was noted by Li et al.[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 80mg colistimethate;[29]
- Coly-mycin M 150mg colistin base is 360mg colistimethate or 4,500,000 units.[30]
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 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 12mg/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 depends on the manufacturer. This complete absence of any regulation or standardisation of dose makes intravenous colistin dosing difficult for the physician.[citation needed]
Colistin has been used in combination with rifampicin; evidence of in vitro synergy exists,[31][32] and the combination has been used successfully in patients.[33] There is also in vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics.[34]
Colistimethate sodium aerosol [Promixin; Colomycin Injection] is used to treat pulmonary infections, especially in cystic fibrosis. In the UK, the recommended adult dose is 12 million units [80160mg] nebulised colistimethate twice daily.[35][29] Nebulized colistin has also been used to decrease severe exacerbations in patients with chronic obstructive pulmonary disease and infection with Pseudomonas aeruginosa.[36]
ResistanceEdit
Resistance 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[fr] uses a MIC cut-off of 2mg/l, whereas the British Society for Antimicrobial Chemotherapy sets a MIC cutoff of 4mg/l or less as sensitive, and 8mg/l or more as resistant. No standards for describing colistin sensitivity are given in the United States.
The first 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 pig farm where colistin is routinely used 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 detailed colistin-resistance study, 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 mortality. Multiple other cases were reported from other Indian hospitals.[41][42] Although resistance to polymyxins is generally[where?] less than 10%,[specify] 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 development of resistant bacterial strains. They have also developed resistance to the antimicrobial compounds LL-37 and lysozyme, produced by the human immune system. 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 other antibiotics is due to the presence of resistance genes.[46] Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a range 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 20172018.[48] In some cases this phenomenon has significant clinical consequences.[48]