Colistin
Encyclopedia
Colistin 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 lingerdoodle. It is one of the last-resort antibiotics
for multidrug-resistant Pseudomonas aeruginosa
, and Acinetobacter
. New Delhi metallo-β-Lactamase multidrug-resistant Enterobacteriaceae have also shown susceptibility to Colistin.
, colistimethate is the inactive prodrug of colistin. The two drugs are not interchangeable .
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 thrice 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.
Colistin has been used in combination with rifampicin
, and there is in-vitro evidence of synergy, 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.
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.
Colistimethate is eliminated by the kidneys, but colistin is supposed to be eliminated by non-renal mechanism(s) that are as yet not characterised.
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 colistin has been used for extended periods of 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.
Polymyxin
Polymyxins are antibiotics, with a general structure consisting of a cyclicpeptide with a long hydrophobic tail. They disrupt the structure of thebacterial cell membrane by interacting with its phospholipids...
antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
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
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacilli and is used as a lingerdoodle. It is one of the last-resort antibiotics
Drug of last resort
Drugs of last resort are drugs only used when all other options are exhausted. Many of the best known are antibiotics, antivirals, or chemotherapy agents. In those cases, they have the most potent antibiotic, antiviral, or anticancer effects, and/or are drugs for which no resistant strains are...
for multidrug-resistant Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
, and Acinetobacter
Acinetobacter
Acinetobacter [asz−in−ée−toe–back−ter] is a genus of Gram-negative bacteria belonging to the Gammaproteobacteria. Acinetobacter species are non-motile and oxidase-negative, and occur in pairs under magnification....
. New Delhi metallo-β-Lactamase multidrug-resistant Enterobacteriaceae have also shown susceptibility to Colistin.
Forms
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 aeruginosaPseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
, 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 fibrosisCystic fibrosisCystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
patients, and it has come into recent use for treating multidrug-resistant AcinetobacterAcinetobacterAcinetobacter [asz−in−ée−toe–back−ter] is a genus of Gram-negative bacteria belonging to the Gammaproteobacteria. Acinetobacter species are non-motile and oxidase-negative, and occur in pairs under magnification....
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 baumanniiAcinetobacter baumanniiAcinetobacter baumannii is a species of pathogenic bacteria, referred to as an aerobic gram-negative bacterium, that is resistant to most antibiotics. As a result of its resistance to drug treatment, some estimates state the disease is killing tens of thousands of U.S...
.
- Colistin sulfate may be used to treat intestinal infections, or to suppress colonColon (anatomy)The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
ic flora. Colistin sulfate is also used as topical creams, powders, and otic solutions.
Dosage
Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated. Colistimethate sodium manufactured by Axellia (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 thrice 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.
Colistin has been used in combination with rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
, and there is in-vitro evidence of synergy, 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 lipophilicLipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
moieties
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
. These poly-cationic regions interact with the bacterial outer membrane, by displacing bacterial counter ions in the lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
. 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
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.Exceptional (inherently colistin resistant) Gram-negative bacteria
- Gram-negative cocci
- ProteusProteus (bacterium)Proteus is a genus of Gram-negative Proteobacteria.-Clinical significance:Three species—P. vulgaris, P. mirabilis, and P. penneri—are opportunistic human pathogens. Proteus includes pathogens responsible for many human urinary tract infections. P. mirabilis causes wound and urinary...
- ProvidenciaProvidencia (bacterium)Providencia is a Gram negative, motile bacterium of the family Enterobacteriaceae. Some strains are opportunistic pathogens in humans and can cause urinary tract infections, particularly in patients with long-term indwelling urinary catheters or extensive severe burns. Other strains Providencia...
- SerratiaSerratiaSerratia is a genus of Gram-negative, facultatively anaerobic, rod-shaped bacteria of the Enterobacteriaceae family. The most common species in the genus, S. marcescens, is normally the only pathogen and usually causes nosocomial infections. However, rare strains of S. plymuthica, S. liquefaciens,...
- EdwardsiellaEdwardsiellaEdwardsiella is a Gram negative, fermentative bacteria of the family Enterobacteriaceae. It was first discovered in snakes in 1962.----Associated persons:Philip R. EdwardsDescription:...
- Neisseria gonorrheae and Neisseria meningitidisNeisseria meningitidisNeisseria meningitidis, often referred to as meningococcus, is a bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life threatening sepsis. N. meningitidis is a major cause of morbidity and mortality during childhood in industrialized countries...
- Moraxella catarrhalisMoraxella catarrhalisMoraxella catarrhalis is a fastidious, nonmotile, Gram-negative, aerobic, oxidase-positive diplococcus that can cause infections of the respiratory system, middle ear, eye, central nervous system and joints of humans.-History:...
- Helicobacter pyloriHelicobacter pyloriHelicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
- BrucellaBrucellaBrucella is a genus of Gram-negative bacteria. They are small , non-motile, non-encapsulated coccobacilli, which function as facultative intracellular parasites....
- Elizabethkingia meningoseptica
- Chryseobacterium indologenes
- Burkholderia cepacia
- Some strains of Stenotrophomonas maltophiliaStenotrophomonas maltophiliaStenotrophomonas maltophilia is an aerobic, nonfermentative, Gram-negative bacterium. It is an uncommon bacterium and human infection is difficult to treat. Initially classified as Pseudomonas maltophilia, S. maltophilia was also grouped in the genus Xanthomonas before eventually becoming the type...
Gram-negative organisms with variable resistance to colistin
- AeromonasAeromonasAeromonas is a gram-negative, facultative anaerobic rod that morphologically resembles members of the family Enterobacteriaceae. Fourteen species of Aeromonas have been described, most of which have been associated with human diseases. The most important pathogens are A. hydrophila, A. caviae, and...
- VibrioVibrioVibrio is a genus of Gram-negative bacteria possessing a curved rod shape, several species of which can cause foodborne infection, usually associated with eating undercooked seafood. Typically found in saltwater, Vibrio are facultative anaerobes that test positive for oxidase and do not form...
- PrevotellaPrevotellaPrevotella is a genus of bacteria.Bacteroides melaninogenicus has recently been reclassified and split into Prevotella melaninogenica and Prevotella intermedia....
- FusobacteriumFusobacteriumFusobacterium is a genus of filamentous, anaerobic, Gram-negative bacteria, similar to Bacteroides.Fusobacterium contribute to several human diseases, including periodontal diseases, Lemierre's syndrome, and topical skin ulcers...
Pharmacokinetics
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.
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 colistin has been used for extended periods of up to six months with no ill effects.
The main toxicity described with aerosolised treatment is bronchospasm
Bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...
, which can be treated or prevented with the use of beta2-agonists such as salbutamol
Salbutamol
Salbutamol or albuterol is a short-acting β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It is marketed as Ventolin among other brand names....
or following a desensitisation protocol.