Hubbry Logo
ColistinColistinMain
Open search
Colistin
Community hub
Colistin
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Colistin
Colistin
Colistin
View on Wikipedia
from Wikipedia
Colistin
Clinical data
Trade namesXylistin, Coly-Mycin M, Colobreathe, others
AHFS/Drugs.comMonograph
MedlinePlusa682860
License data
Routes of
administration		Topical, by mouth, intravenous, intramuscular, inhalation
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability0%
Elimination half-life5 hours
Identifiers
  • 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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.012.644 Edit this at Wikidata
Chemical and physical data
FormulaC52H98N16O13
Molar mass1155.455 g·mol−1
3D model (JSmol)
  • 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=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 checkY
  • Key:YKQOSKADJPQZHB-QNPLFGSASA-N checkY
 ☒NcheckY (what is this?)  (verify)

Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia.[7][8] These may involve bacteria such as Pseudomonas aeruginosa, carbapenem-resistant Klebsiella pneumoniae (CRKP), or Acinetobacter.[9] It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin 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 addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions, it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as 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 serious side effects may include anaphylaxis, muscle weakness, and Clostridioides difficile-associated diarrhea.[8] The inhaled form may result in constriction of the bronchioles.[8] It is unclear if use 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 medical 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 medicine.[15] It is available as a generic medication.[16] It is derived from bacteria of the genus Paenibacillus.[10]

Medical uses

[edit]

Antibacterial spectrum

[edit]

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: 0.12–128 μg/mL
  • Klebsiella pneumoniae: 0.25–128 μg/mL
  • Pseudomonas aeruginosa: ≤0.06–16 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 dosage

[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 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.

Dosage

[edit]

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 80 mg colistimethate;[29]
  • Coly-mycin M 150 mg colistin base is 360 mg 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 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 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 1–2 million units (80–160 mg) 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]

Resistance

[edit]

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 2 mg/L, whereas the British Society for Antimicrobial Chemotherapy sets a MIC cutoff of 4 mg/L or less as sensitive, and 8 mg/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 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]

A recent review from 2016 to 2021 fount that E. coli is the dominant species harbouring mcr genes. Plasmid - mediated colistin resistance is also conferred upon other species that carry different genes resistant to antibiotics. The emergence of the mcr-9 gene is quite remarkable.[45]

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, which controls the expression of lipid A phosphoethanolamine transferases (similar to mcr-1) located on the bacterial chromosome.[46] Similar results have been obtained with mcr-1 positive E. coli, which became better at surviving a mixture of animal antimicrobial peptides in vitro and more effective at killing infected caterpillars.[47]

Not all resistance to colistin and some other antibiotics is due to the presence of resistance genes.[48] Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a range of resistance to an antibiotic,[49] has been observed in some species of Enterobacter since at least 2016[48] and was observed in some strains of Klebsiella pneumoniae in 2017–2018.[50] In some cases this phenomenon has significant clinical consequences.[50]

Inherently resistant

[edit]

Variable resistance

[edit]

Adverse reactions

[edit]

The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves),[52][53][54][55] 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 pre-existing renal disease. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose.[56]

At a dose of 160 mg colistimethate IV every eight hours, very little nephrotoxicity is seen.[57][58] 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.[59] Colistin-induced nephrotoxicity is particularly likely in patients with hypoalbuminemia.[60]

The main toxicity described with aerosolised treatment is bronchospasm,[61] which can be treated or prevented with the use of β2-adrenergic receptor agonists such as salbutamol[62] or following a desensitisation protocol.[63]

Mechanism of action

[edit]

Colistin is a polycationic peptide and has both hydrophilic and lipophilic moieties.[64] 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 outer cell membrane of Gram-negative bacteria. It competitively displaces divalent cations (Ca2+ and Mg2+) from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents and bacterial death.

Colistin has also been reported to target tubulin, favorizing its polymerization.[65]

Pharmacokinetics

[edit]

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 eliminated by non-renal mechanism(s) that are as of yet not characterised.[66][67]

History

[edit]

Colistin was first isolated in Japan in 1949 by Y. Koyama, from a flask of fermenting Bacillus polymyxa var. colistinus,[68] and became available for clinical use in 1959.[69]

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 toxicity.[70]

Colistin has also been used in agriculture, particularly in China from the 1980s onwards. Chinese production for agriculture exceeded 2700 tons in 2015. China banned colistin use for livestock growth promotion in 2016.[71]

Biosynthesis

[edit]

The biosynthesis of colistin requires the use of three amino acids: threonine, leucine, and 2,4-diaminobutryic acid. The linear form of colistin is synthesized before cyclization. Non-ribosomal peptide biosynthesis begins with 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), a peptidyl carrier protein domain (PCP), an epimerization domain (E), and a condensation domain (C). Cyclization is accomplished by a thioesterase.[72] The first step is to have a loading domain, 6-methylheptanoic 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.

The loading domain 6-methylheptanoic acid is shown in salmon; yellow is 2,4-diaminobutryic acid; light blue is threonine; magenta is leucine.

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Colistin

View on Grokipedia
from Grokipedia
Colistin, also known as polymyxin E, is a cationic derived from the soil bacterium polymyxa var. colistinus, renowned for its bactericidal activity against multidrug-resistant (MDR) . Discovered in in the late , it was introduced clinically in 1959 but largely abandoned by the 1970s due to high rates of nephro- and , only to resurge in the late 1990s as a last-resort amid the global crisis of . Administered primarily as its inactive colistimethate sodium (CMS), which converts to active colistin , it exhibits a narrow-spectrum action targeting pathogens such as , , and carbapenem-resistant (CRE), including . Its mechanism involves electrostatic binding to lipopolysaccharides (LPS) in the outer membrane of , displacing divalent cations like Ca²⁺ and Mg²⁺, which destabilizes the membrane and leads to rapid cell death through permeabilization and leakage of intracellular contents. Clinically, colistin is indicated for severe infections including , bloodstream infections, urinary tract infections, and caused by MDR Gram-negatives, often in (ICU) settings or cystic fibrosis patients, with routes of administration encompassing intravenous, inhaled, intrathecal, or topical applications. Pharmacodynamically, it demonstrates concentration-dependent killing and a significant post-antibiotic effect, with the free area under the curve to (fAUC/MIC) ratio serving as the primary efficacy predictor, typically targeting ratios of 20–57 for optimal outcomes against susceptible strains. However, its use is tempered by emerging resistance mechanisms, primarily involving chromosomal mutations in regulatory systems like PmrAB or PhoPQ that modify LPS with positively charged moieties (e.g., 4-amino-4-deoxy-L-arabinose or phosphoethanolamine), reducing colistin's binding affinity; via the mcr genes further exacerbates this threat globally. Additionally, colistin carries substantial toxicity risks, with nephrotoxicity affecting 20–45% of patients—manifesting as through tubular damage and —and neurotoxicity in up to 7% of cases, including , neuromuscular blockade, and apnea, though both are often reversible upon discontinuation. Despite these challenges, ongoing research explores combination therapies (e.g., with or rifampicin) and optimized dosing strategies to enhance efficacy while mitigating adverse effects, underscoring colistin's critical role in modern infectious disease management.

Chemical properties

Structure

Colistin is a cyclic produced by the bacterium Paenibacillus polymyxa subsp. colistinus, consisting primarily of two closely related components: colistin A and colistin B. It features a heptapeptide cyclic ring formed by seven residues, connected via bonds, acylated at its by a chain. This configuration imparts a distinctive amphipathic character to the molecule, with the cyclic portion providing rigidity and the acyl chain contributing hydrophobicity. The composition includes D-leucine, L-threonine, and multiple L-α,γ-diaminobutyric acid (Dab) residues, totaling five Dab units across the structure. Specifically, the cyclic heptapeptide ring comprises the sequence Dab-Thr-Dab-Dab-Dab-D-Leu-Dab, where the ring is closed between the γ-amino group of the first Dab and the carboxyl group of the last Dab. The N-terminal Dab is acylated with a 6-methyloctanoyl chain in colistin A or a 6-methylheptanoyl chain in colistin B, which together form the commercial colistin mixture. The Dab residues, each bearing a primary amino group on their γ-carbon, confer multiple positive charges to the , resulting in its overall cationic nature at physiological . The structural formula of colistin can be depicted as follows, with the cyclic ring highlighted for clarity:

Cyclic Heptapeptide Ring: Dab¹ - Thr² - Dab³ - Dab⁴ - Dab⁵ - D-Leu⁶ - Dab⁷ (cyclized via γ-NH₂ of Dab¹ to COOH of Dab⁷) N-Terminal Acyl Chain: Fatty Acid attached to NH of Dab¹

Cyclic Heptapeptide Ring: Dab¹ - Thr² - Dab³ - Dab⁴ - Dab⁵ - D-Leu⁶ - Dab⁷ (cyclized via γ-NH₂ of Dab¹ to COOH of Dab⁷) N-Terminal Acyl Chain: Fatty Acid attached to NH of Dab¹

This representation underscores the positions of the key residues, where superscripts denote standard numbering in polymyxin nomenclature. The positive charges primarily arise from the free ε-amino groups of the five Dab residues, enhancing the molecule's interaction with negatively charged surfaces. In comparison to the related polymyxin B, colistin differs mainly in the substitution of D-phenylalanine with at position 6 of the cyclic ring, which subtly alters its hydrophobicity while maintaining the overall scaffold of five Dab residues, one , and the N-terminal fatty acyl . Polymyxin B typically features a 6-methyloctanoyl similar to colistin A, but the leucine substitution in colistin contributes to its distinct spectrum of activity against certain .

Physical and chemical properties

Colistin appears as a to off-white or slightly yellow fine powder that is odorless. The molecular weight of colistin A, the primary component, is approximately 1155 Da. Colistin exhibits high in (approximately 564 g/L) and acidic solutions, but it is poorly soluble in organic solvents such as acetone and , with slight in . This amphipathic nature arises from its structural features, including hydrophobic and hydrophilic moieties. It demonstrates optimal stability in the range of 2 to 8, showing resistance to enzymatic degradation by (at 2.2–4.8) and (at 4.4–7.5) due to the presence of D-amino acids in its polypeptide chain. However, colistin undergoes in alkaline conditions, with degradation appearing dependent on concentration, while remaining stable in acidic even at elevated temperatures up to 100 °C. In its dry powder form, colistin is stable indefinitely at when protected from , and reconstituted aqueous solutions maintain stability for up to two weeks at 2–15 °C. Clinically, it is formulated as colistin sulfate, suitable for oral and topical applications due to its direct activity, or as colistimethate sodium, a with methanesulfonate groups attached to reduce toxicity and enable parenteral administration via slower to active colistin.

Uses

In human medicine

Colistin serves as a last-resort antibiotic in human medicine for treating infections caused by multidrug-resistant (MDR) Gram-negative bacteria, particularly carbapenem-resistant strains such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae that are unresponsive to other available therapies. It is primarily indicated for severe infections including bacteremia, sepsis, and nosocomial pneumonia in critically ill patients, where it has demonstrated clinical success rates of approximately 50-70% in observational studies and small clinical trials. The antibacterial spectrum of colistin is limited to aerobic Gram-negative bacteria, with potent activity against most Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter species, but it shows no efficacy against Gram-positive bacteria, anaerobes, or most fungi. Susceptibility is defined by minimum inhibitory concentration (MIC) breakpoints of ≤2 mg/L for key pathogens like A. baumannii, P. aeruginosa, and K. pneumoniae according to both CLSI and EUCAST guidelines, with resistance indicated at ≥4 mg/L (CLSI) or >2 mg/L (EUCAST). For susceptible strains, colistin achieves bactericidal effects at these concentrations, though emerging resistance poses challenges in treatment outcomes. In clinical practice, colistin is administered intravenously as colistimethate sodium (CMS), the form, for systemic infections, with a recommended dosage of 2.5-5 mg/kg/day of colistin base activity (CBA), divided into 2-4 doses, and adjusted for renal function to avoid accumulation in patients with creatinine clearance below 50 mL/min. , using 150-300 mg CMS (approximately 1-2 million IU) twice daily, is employed for pulmonary infections such as those in patients or (VAP), often as adjunctive to IV . Topical or of colistin sulfate is utilized for gut in selective digestive tract protocols or for localized infections like urinary tract infections (UTIs) via intravesical instillation, with doses typically ranging from 1-2 million IU every 8-12 hours, though systemic absorption is minimal in these routes. Intrathecal or intraventricular administration is used for infections such as , with doses of 1-10 mg/day adjusted based on levels. Specific applications include its role in managing VAP due to MDR A. baumannii or P. aeruginosa, where inhaled colistin has shown bacteriological and clinical response rates of up to 83% in small cohorts. For complicated UTIs caused by resistant Gram-negatives, intravesical administration provides with high local concentrations and low systemic exposure. In and bloodstream infections, intravenous colistin is used as monotherapy or in combination, with evidence from clinical trials indicating improved survival when paired with other agents like , particularly in ICU settings where MDR prevalence is high. is advised to optimize dosing and mitigate resistance development during prolonged use.

In veterinary medicine

Colistin is primarily indicated in veterinary medicine for the treatment of enteric infections caused by susceptible Gram-negative bacteria in livestock, such as non-invasive Escherichia coli in pigs and calves, and other Enterobacteriaceae in poultry and cattle. Historically, it has also been used prophylactically as a feed additive to prevent gastrointestinal infections and promote growth in food-producing animals, including pigs, poultry, and swine. Its spectrum of activity remains focused on Gram-negative pathogens, similar to human applications, but administration in veterinary settings often involves oral routes via feed or water to target intestinal sites effectively. Dosing regimens for colistin in animals are tailored to species and body weight, with higher concentrations typically required for large compared to use; for example, feed supplementation at 75,000–100,000 IU/kg body weight per day is common for and pigs to achieve therapeutic levels in the . In , veterinary guidelines have restricted its use to metaphylaxis and treatment of confirmed susceptible infections, emphasizing targeted application to minimize overuse. Globally, colistin usage in animal agriculture has been widespread, particularly in and , where it was commonly incorporated into feeds until regulatory restrictions began in the mid-2010s due to concerns over . In , for instance, its role as a growth promoter was banned in 2017 following the discovery of the mobile colistin resistance gene mcr-1, which highlighted the implications of resistance transmission through the from animals to humans. European surveys indicate a significant decline, with over 50% of veterinarians ceasing or reducing colistin prescriptions by 2022; as of 2025, sales continue to decline with 29 countries globally prohibiting colistin use in food-producing animals, driven by national bans and stewardship programs. The phase-out of colistin in veterinary practice has prompted shifts toward alternatives such as vaccines against enteric pathogens like E. coli and Salmonella, probiotics, and other antibiotics like tetracyclines or florfenicols, which have shown efficacy in maintaining animal health without exacerbating polymyxin resistance. Studies correlating reduced colistin usage with lower resistance rates in livestock pathogens, such as decreased prevalence of mcr-1-positive E. coli in European farms post-restrictions, underscore the benefits of these transitions for sustainable agriculture.

Pharmacology

Mechanism of action

Colistin exerts its antibacterial effects primarily through interaction with the outer membrane of . The positively charged colistin molecule binds electrostatically to the negatively charged phosphate groups and components of (LPS) in the outer membrane, displacing stabilizing divalent cations such as Mg²⁺ and Ca²⁺. This displacement disrupts the cross-bridging of LPS molecules, leading to destabilization of the outer membrane structure and an increase in its permeability. The hydrophobic acyl tail of colistin then inserts into the , further expanding the membrane and facilitating self-promoted uptake into the periplasmic space. Secondary effects contribute to the overall bactericidal activity. The increased permeability allows colistin to reach and disrupt the inner cytoplasmic membrane, causing leakage of essential cellular contents such as potassium ions, nucleotides, and proteins, which ultimately leads to osmotic imbalance and cell lysis. Additionally, colistin inhibits vital respiratory processes by binding to and suppressing the activity of enzymes like NADH-quinone oxidoreductase in the electron transport chain, particularly in pathogens such as Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Upon entering the cytoplasm, colistin interacts with intracellular targets, including anionic phospholipids, promoting their loss from the membrane; it also induces oxidative stress through the generation of reactive oxygen species (ROS) via the Fenton reaction, resulting in damage to DNA, RNA, proteins, and lipids. At therapeutic concentrations, colistin is fully bactericidal, rapidly killing susceptible without exhibiting bacteriostatic effects. It shows no significant cross-resistance with other classes, except for the closely related polymyxins, due to its unique membrane-targeting mechanism. Colistin and polymyxin B have similar spectra of activity against aerobic , with colistin incorporating 6-methyloctanoic acid in its A component and 6-methylheptanoic acid in its B component.

Pharmacokinetics

Colistin is administered primarily via intravenous, intramuscular, or routes due to its poor oral , which is negligible (<1%) as it is not significantly absorbed from the gastrointestinal tract. The active form, colistin, is not directly administered systemically; instead, the prodrug colistimethate sodium (CMS) is used, which undergoes partial conversion to colistin in vivo through hydrolysis, with the fraction converted ranging from 0.14 to 0.45 depending on patient factors such as renal function and dosing duration. This conversion occurs systemically but is relatively slow, leading to delayed attainment of steady-state colistin plasma concentrations, often exceeding 36 hours with standard intermittent dosing. Pharmacokinetic parameters exhibit high variability, particularly in critically ill patients influenced by augmented renal clearance, renal replacement therapy, and other factors; therapeutic drug monitoring is recommended when available to optimize dosing. Following intravenous administration of CMS, colistin exhibits limited distribution to tissues, characterized by a volume of distribution of approximately 0.2–0.6 L/kg in adults, reflecting its polar nature and restricted penetration beyond the . Plasma protein binding of colistin is moderate, around 50%, which contributes to its relatively low free fraction and further limits tissue access. While systemic administration results in poor penetration into the (CSF), with ratios of 5–11% relative to plasma levels, inhalation delivers high local concentrations in the lungs (6–13 mg/L in sputum), making it preferable for pulmonary infections. Metabolism of colistin is minimal, as the prodrug CMS is primarily converted to the active drug via hydrolysis by non-specific esterases in plasma and tissues, without involvement of hepatic cytochrome P450 enzymes. This process does not generate significant metabolites beyond colistin itself, and there is no evidence of extensive hepatic biotransformation. Excretion of CMS occurs predominantly via the kidneys through glomerular filtration, with 60–70% of the dose recovered unchanged in urine over 24 hours in individuals with normal renal function. In contrast, formed colistin undergoes extensive tubular reabsorption, resulting in low renal clearance (<2 mL/min) and minimal urinary excretion (<5% of the dose). The elimination half-life of CMS is short, approximately 2–3 hours, in patients with normal renal function (creatinine clearance >80 mL/min), while colistin's is longer, around 4 hours under similar conditions; both are markedly prolonged (up to 14–18 hours) in renal impairment due to reduced CMS clearance. Dosage adjustments are recommended for renal dysfunction, such as reducing the maintenance dose by 50% when creatinine clearance is <50 mL/min to avoid accumulation.

Bacterial resistance

Intrinsic resistance

Colistin demonstrates no intrinsic activity against Gram-positive bacteria, as these organisms lack the lipopolysaccharide (LPS)-containing outer membrane that serves as the antibiotic's primary target for disrupting bacterial cell integrity. Instead, Gram-positive bacteria possess a thick peptidoglycan layer in their cell wall, which prevents colistin from effectively accessing and permeabilizing the cytoplasmic membrane. Representative examples include Staphylococcus aureus and Enterococcus faecalis, where the absence of an outer membrane renders colistin ineffective without any need for adaptive mutations. Certain anaerobic bacteria and specific Gram-negative species also exhibit intrinsic resistance to colistin, often attributable to the absence of a typical outer membrane or reduced LPS content that limits the antibiotic's binding and uptake. Anaerobes, such as those in the Bacteroides genus, lack the aerobic conditions or membrane dynamics required for colistin's self-promoted uptake mechanism. Among Gram-negatives, genera like Proteus, Serratia, and Burkholderia show natural non-susceptibility; for instance, Proteus mirabilis and Serratia marcescens maintain low LPS levels or structural variations that evade colistin's electrostatic interactions. Fungi and mycobacteria are similarly unaffected by colistin due to fundamentally different cell wall compositions that do not feature the LPS targets essential for the antibiotic's action. Fungal cell walls, rich in chitin and β-glucans, provide a barrier incompatible with colistin's membrane-disrupting mode, rendering it inactive against eukaryotic microbes. In mycobacteria, such as Mycobacterium tuberculosis, the presence of mycolic acids in a waxy lipid-rich envelope further impedes colistin's penetration and efficacy. This spectrum of intrinsic resistance confines colistin's therapeutic application to infections by susceptible aerobic Gram-negative pathogens, such as Pseudomonas aeruginosa and certain Enterobacteriaceae, without reliance on acquired genetic changes in resistant taxa.

Acquired resistance

Acquired resistance to colistin in susceptible Gram-negative bacteria primarily arises through genetic mutations that alter the lipopolysaccharide (LPS) component of the outer membrane, reducing the drug's ability to bind and disrupt the membrane. The most common mechanism involves the addition of positively charged groups, such as phosphoethanolamine (pEtN), to the lipid A moiety of LPS, which neutralizes the negative charge and repels the cationic colistin molecule. This modification is regulated by two-component systems like PmrAB (also known as BasRS) and ParRS (also known as CrrAB), where mutations in the sensor kinase genes (e.g., pmrB or parR) activate downstream effectors such as the pEtN transferase PmrC, leading to increased pEtN incorporation. In some isolates, particularly of Acinetobacter baumannii and Escherichia coli, complete loss of LPS occurs due to mutations in lipid A biosynthesis genes like lpxA, lpxC, or lpxD, preventing colistin from targeting the outer membrane altogether, though this often comes at a fitness cost to the bacterium. A significant driver of acquired resistance is the plasmid-mediated dissemination of mobile colistin resistance (mcr) genes, which encode enzymes that catalyze similar lipid A modifications, primarily through pEtN addition or other acylation changes that decrease colistin affinity. Since the discovery of mcr-1 in 2015 in China, nine additional variants (mcr-2 to mcr-10) have been identified between 2016 and 2023, with mcr-2 reported in Belgian pigs, mcr-3 to mcr-5 in various European and Asian livestock sources, mcr-6 to mcr-8 in the UK and China, mcr-9 globally in clinical and environmental samples, and mcr-10 in Chinese clinical isolates. These genes are often carried on conjugative plasmids like IncI2 or IncHI2, facilitating horizontal transfer among Enterobacterales, and their global spread has been strongly linked to agricultural use of colistin in livestock, though prevalence has declined in regions with bans (e.g., post-2018 in China). As of 2025, mcr-9 and mcr-10 continue to disseminate widely in Enterobacteriaceae, contributing to ongoing resistance threats. Surveillance data indicate low to moderate colistin resistance rates among Gram-negative bacilli in clinical settings as of 2024-2025, with a pooled global prevalence of approximately 5-9% overall, varying by species and region; for example, rates are lower in E. coli and P. aeruginosa (around 1%) but higher in Klebsiella spp. and carbapenem-resistant isolates (up to 15% or more in some areas). The emergence of mcr-9 has been notable, often co-occurring with carbapenemase genes like blaNDM-5 in multidrug-resistant Enterobacter cloacae complex isolates from ICU patients, enabling concurrent transfer of colistin and carbapenem resistance via IncHI2 plasmids and increasing minimum inhibitory concentrations (MICs) by ≥8-fold upon induction. Studies from 2024 and 2025 have further characterized novel lipid A variants, including those induced by magnesium depletion or mutations leading to distinct pEtN or L-Ara4N modifications, which confer resistance by altering colistin binding in E. coli and K. pneumoniae without mcr involvement. Acquired colistin resistance is associated with higher treatment failure rates and increased mortality in infections caused by extensively drug-resistant (XDR) Gram-negative strains where colistin serves as a last-resort option. To address this, combination therapies have shown promise; for instance, 2024 findings demonstrate that valnemulin, a pleuromutilin antibiotic, synergizes with colistin to restore susceptibility in MDR E. coli and K. pneumoniae isolates, reducing bacterial loads by ~10^9-fold in vitro and improving survival by 60% in mouse models of infection through enhanced membrane permeabilization and ATP depletion.

Adverse effects

Nephrotoxicity and neurotoxicity

Colistin is associated with significant nephrotoxicity, primarily manifesting as acute kidney injury (AKI) through acute tubular necrosis. The primary mechanism involves oxidative stress and mitochondrial damage, where colistin disrupts mitochondrial membrane permeability, leading to reduced membrane potential, decreased ATP production, and increased reactive oxygen species (ROS) generation. This triggers apoptosis via the mitochondrial pathway (upregulation of Bax, cytochrome C release, and caspase-3/9 activation), death receptor pathway (Fas/FasL upregulation and caspase-8 activation), and endoplasmic reticulum stress (ATF6 and CHOP upregulation). The incidence of colistin-induced nephrotoxicity with intravenous use ranges from 20% to 60%, with recent studies reporting rates around 45-52% in critically ill patients. AKI typically develops 5-10 days after initiation, with risk factors including high doses (>4 mg/kg/day), (proximal to inotropic support needs), , concomitant NSAID use, , advanced age, and pre-existing renal impairment. In patients with renal impairment, pharmacokinetic accumulation exacerbates toxicity due to prolonged half-life. Neurotoxicity from colistin is less common, occurring in 1-7% of cases, though rates may rise in patients with due to exacerbated neuromuscular weakness. It primarily involves neuromuscular blockade through presynaptic inhibition of release and postsynaptic receptor blockade, leading to prolonged depolarization, calcium efflux, and mitochondrial dysfunction with ROS accumulation. Manifestations include , vertigo, , confusion, and rarely apnea or respiratory , often linked to high doses, hypoxia, or concurrent neuromuscular blockers. Monitoring for both toxicities involves regular serum creatinine assessments (every 2-3 days initially) and checks, with hydration to mitigate dehydration-related risks. is reversible in approximately 50-60% of cases upon discontinuation or dose adjustment, though severe AKI may require dialysis in 8-30% and rarely leads to permanent damage. Recent 2023 studies indicate lower AKI rates with optimized dosing regimens, such as twice-daily administration compared to thrice-daily, emphasizing the importance of weight-based adjustments to minimize peak exposures.

Other adverse reactions

When administered via inhalation, particularly in patients with cystic fibrosis, colistin can induce bronchospasm and cough, reported in up to 10% of recipients, with severe cases leading to discontinuation in approximately 7%. These respiratory effects are often transient and can be mitigated through pretreatment with bronchodilators such as beta-2 agonists. In clinical settings, a challenge dose is sometimes used to assess tolerance prior to regular nebulization. For topical or oral applications, colistin is associated with allergic reactions ranging from mild skin rashes to rare instances of , with an overall incidence of below 2%. Prolonged oral use, due to its poor systemic absorption, may lead to superinfections such as difficile-associated or fungal overgrowth in the . Anaphylactic events, though uncommon (less than 1%), have been documented primarily with parenteral but occasionally with non-intravenous routes. Systemic administration of colistin carries risks of reactions, including urticaria and pruritus, occurring in about 2% of cases based on historical data. Electrolyte imbalances, such as hypomagnesemia, , and , have been observed, sometimes manifesting as a Bartter-like with . These disturbances are linked to tubular dysfunction and may require monitoring and supplementation. Regarding , colistin is classified as FDA category C, indicating showing teratogenic and embryotoxic effects, with limited human data advising use only if benefits outweigh risks. Colistin exhibits drug interactions that can exacerbate adverse effects, notably enhanced nephrotoxicity when co-administered with nonsteroidal anti-inflammatory drugs (NSAIDs) or . Concomitant use with , observed in up to 26% of treated patients in some cohorts, heightens renal risk through additive mechanisms. Similarly, NSAIDs contribute to this interaction by impairing renal . Close monitoring of renal function is recommended during such combinations.

Society and culture

Regulations and bans

The (WHO) has emphasized the critical importance of colistin for human , classifying it as a highest priority critically important (HPCIA) since 2016 and recommending against its use for growth promotion in veterinary settings from 2017 onward to preserve efficacy and curb resistance. These guidelines urge reductions in overall use in food-producing animals, prioritizing alternatives for disease prevention and treatment. Several countries have implemented specific bans on colistin in to align with these recommendations. In the , restrictions began in 2006 with a ban on antimicrobial growth promoters, including colistin, in , followed by updated advice in 2016 to minimize its veterinary sales and limit use to therapeutic or metaphylactic purposes only. prohibited colistin as a feed additive and growth promoter in 2016, with the ban taking effect in May 2017, targeting its widespread prior use in production. In , the banned the manufacture, sale, and distribution of colistin for food-producing animals in 2019, with enforcement strengthened through Food Safety and Standards Authority of India (FSSAI) amendments effective April 1, 2025, prohibiting its use in meat, poultry, eggs, and production. Globally, 29 countries had initiated measures by 2023–2025 to phase out colistin in food-producing animals, including full bans, usage restrictions, or never authorizing it for veterinary purposes, as part of broader efforts to combat . These policies have shown positive impacts, such as a decline in colistin resistance and the prevalence of the mcr-1 gene in both animals and s following China's ban, with colonization rates dropping dramatically from 2017 onward. Enforcement remains challenging, particularly in , where black market trade and unauthorized use persist despite bans, as evidenced by ongoing detection of colistin in samples in 2023. The WHO Global and Use (GLASS) supports monitoring through standardized detection and reporting of colistin resistance in key pathogens like , aiding global tracking of these trends.

One Health implications

Colistin resistance, particularly mediated by mobilized colistin resistance (mcr) , exemplifies the paradigm by demonstrating interconnected transmission dynamics across human, animal, and environmental compartments. The initial discovery of the mcr-1 in 2015 in revealed its presence in such as pigs and chickens, retail , and human clinical isolates, underscoring the risk of zoonotic transfer through contaminated and water sources. Subsequent investigations have confirmed zoonotic transmission pathways, including direct spread from swine farms to farmers and nearby human populations via fecal-oral routes and environmental exposure on farms. These findings highlight how agricultural use of colistin in promotes the selection and dissemination of resistant , potentially entering human populations through the or direct contact. Environmental reservoirs further amplify the global spread of colistin resistance, with mcr genes persisting in , systems, and agricultural soils contaminated by runoff from operations. Studies from 2023 detected multiple mcr variants, including mcr-3.12, mcr-4.3, mcr-5.1, and mcr-9.1, in samples from County, illustrating urban environmental hotspots for resistance dissemination. More recent 2025 research in identified mcr-1 and mcr-10 in urban , linking these reservoirs to broader ecological cycles influenced by human and animal waste discharge. Similarly, investigations into soil environments have shown elevated mcr prevalence in areas receiving agricultural runoff, facilitating among and contributing to the persistence of resistance beyond clinical settings. To address these interconnected threats, approaches emphasize integrated surveillance that combines veterinary, human health, and environmental monitoring data for early detection of colistin resistance trends. For example, a 2024 study in utilized a multisectoral sampling strategy to track colistin-resistant across humans, animals, and wastewater, revealing shared resistance mechanisms. A parallel 2025 effort in examined mcr genes in from human, animal, and retail meat sources, demonstrating the value of unified data integration for informing policy. Within these frameworks, alternatives such as bacteriophage therapy are gaining traction as targeted interventions against colistin-resistant pathogens, offering a non-antibiotic strategy that aligns with reducing selective pressure across sectors. Looking ahead, 2025 analyses have issued urgent calls for unified global policies under the umbrella to avert pan-drug resistance, advocating for coordinated restrictions on colistin in , enhanced cross-border , and in sustainable alternatives to mitigate the escalating . Such strategies aim to break transmission cycles by addressing root causes at their interfaces, ensuring the preservation of colistin as a last-resort for .

History

Discovery and early development

Colistin was first isolated in 1949 by Japanese microbiologist Yūji Koyama and colleagues from a strain of Bacillus polymyxa var. colistinus (now classified as Paenibacillus polymyxa subsp. colistinus), a spore-forming bacterium sourced from a sample in . The antibiotic was named "colistin" after the colistinus variant; the research was conducted at the Kitasato Institute for Infectious Diseases in . This discovery was formally reported in 1950, marking colistin as a member of the polymyxin family of polypeptide produced by bacteria. Early characterization efforts in the late 1940s and 1950s focused on its basic properties and composition. Preliminary studies identified colistin as a basic polypeptide with strong activity against , including and , through disruption of bacterial cell membranes. Its chemical structure—a cyclic decapeptide with a tail—was gradually elucidated through , analysis, and enzymatic degradation in the 1950s and early 1960s, primarily by researchers like T. Suzuki at the . Initial and animal trials during the 1950s confirmed its bactericidal effects against a range of Gram-negative pathogens, positioning it as a potential treatment for infections resistant to earlier antibiotics like penicillin. Colistin entered clinical use in the late 1950s, with introductions in and around 1959 for topical and systemic treatment of Gram-negative infections. In the United States, the more stable and less toxic derivative colistimethate sodium (CMS) received FDA approval in 1959 for intravenous and intramuscular administration, addressing concerns over the parent compound's instability and side effects. Early clinical trials demonstrated efficacy in urinary tract infections, Pseudomonas-related conditions, and , but reports of significant and —such as and —emerged quickly. By the 1970s and , colistin's use declined sharply due to these toxicity issues and the availability of safer alternatives like aminoglycosides (e.g., gentamicin) and third-generation cephalosporins, which offered broader spectra with lower risk profiles. This led to its near-abandonment in many Western countries by the early , relegating it primarily to topical applications for minor infections.

Resurgence and modern use

The resurgence of colistin began in the mid-1990s amid the escalating crisis of multidrug-resistant (MDR) Gram-negative bacterial infections, particularly those caused by pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii, which rendered many conventional antibiotics ineffective. This revival positioned colistin as a vital last-line option in intensive care units (ICUs) for treating severe infections, such as ventilator-associated pneumonia and bloodstream infections. In recognition of its critical role, the World Health Organization (WHO) included colistin in its inaugural List of Critically Important Antimicrobials for Human Medicine in 2005, classifying it in the highest-priority category due to its unique mechanism against Gram-negative bacteria and limited alternatives. Key events further amplified colistin's prominence and highlighted emerging challenges. The discovery of the plasmid-mediated mcr-1 gene in 2015, which confers transferable colistin resistance and was initially identified in Escherichia coli from livestock and humans in , triggered global alarm over the potential collapse of this as a therapeutic option. Concurrently, colistin consumption in human medicine rose significantly across , increasing approximately 1.8-fold between 2000 and 2010, driven by the need to combat carbapenem-resistant in hospital settings. This uptick underscored the antibiotic's indispensable status but also fueled concerns about accelerating resistance. Recent milestones reflect concerted efforts to mitigate resistance through policy and innovation. In 2016, banned colistin as a feed additive in animal to curb the spread of mcr-1-like genes from livestock to pathogens, a move that demonstrated short-term reductions in resistance prevalence among E. coli isolates. By 2023, frameworks gained traction in policy analyses, emphasizing integrated across , animal, and environmental sectors to address colistin resistance dissemination, as outlined in reviews tracing regulatory impacts on antimicrobial stewardship. Emerging combination therapies have shown promise; for instance, a 2024 study demonstrated that valnemulin synergizes with colistin to restore susceptibility in MDR Gram-negative pathogens by targeting proton motive force, improving bacterial clearance in preclinical models. In 2025, further research has explored colistin's role as an inhibitor and synergies with agents like , alongside studies on modification mechanisms contributing to resistance, highlighting ongoing efforts to extend its utility. Today, colistin remains restricted to last-resort use for life-threatening MDR infections, guided by antimicrobial stewardship programs to preserve efficacy. Ongoing clinical trials focus on optimized formulations, such as nebulized or fixed-dose combinations, to enhance and minimize while combating resistance.

Biosynthesis and production

Biosynthetic pathway

Colistin, also known as polymyxin E, is naturally produced by the Gram-positive bacterium polymyxa (formerly classified as polymyxa), a soil-dwelling, growth-promoting rhizobacterium. The occurs via a non-ribosomal peptide synthetase (NRPS) pathway, a modular enzymatic that enables the synthesis of complex independent of ribosomal machinery. This pathway constructs the cyclic decapeptide structure of colistin, incorporating unusual such as L-α,γ-diaminobutyric acid (Dab), L-threonine (Thr), and L-leucine (Leu), along with a fatty acyl chain for enhanced membrane activity. The core of the biosynthetic machinery is encoded by the pmxABCDE gene cluster, spanning approximately 40.6 kb in the P. polymyxa genome. The synthetases PmxA, PmxB, and PmxE drive the peptide assembly through their adenylation (A), condensation (C), and peptidyl carrier protein (PCP) domains organized into modules specific for each amino acid. Biosynthesis initiates with the attachment of a fatty acid (typically 6-methyloctanoic acid) to the N-terminal Dab residue via the starter C-domain in PmxE. The linear peptide chain is then elongated sequentially: PmxE incorporates five modules (Dab-Thr-Dab-Dab-Dab), followed by PmxA (Leu-Thr-Dab-Dab), and PmxB (Thr), resulting in a 10-amino-acid chain with the sequence Dab-Thr-Dab-Dab-Dab-Leu-Thr-Dab-Dab-Thr. Cyclization occurs through the thioesterase (TE) domain in PmxB, which catalyzes the formation of a lactam ring between the γ-amino group of the N-terminal Dab and the C-terminal Thr carboxyl group, yielding the mature cyclic structure. The accessory genes pmxC and pmxD encode ABC transporter components that facilitate secretion of the product. Biosynthesis of colistin is regulated by environmental cues, particularly carbon source availability, which influences gene expression in the cluster. Glucose represses production through carbon catabolite repression (CCR), limiting yields, whereas starch enhances it by reducing residual sugars and promoting amylase activity, leading to up to twofold higher colistin titers. The transition state regulator AbrB acts as a negative controller by binding directly to the promoter region upstream of pmxA, repressing transcription; its downregulation under favorable conditions like starch utilization relieves this inhibition. Variations within the polymyxin family arise from subtle differences in NRPS A-domain specificities across P. polymyxa strains—for instance, colistin features all-Dab residues, while polymyxin B incorporates a phenylalanine at position 6 due to altered substrate recognition in the corresponding module. Evolutionarily, the pmx NRPS gene cluster exhibits hallmarks of (HGT), including low and genomic island localization, facilitating its dissemination among Paenibacillus species and related genera. This mobility contributes to the diversification of polymyxin analogs and may underpin the emergence of resistance mechanisms, as similar NRPS modules can generate structural variants that mimic or evade host defenses, paralleling the HGT-driven spread of mobilized colistin resistance (mcr) genes in clinical pathogens.

Industrial production

Colistin is produced on an industrial scale through submerged fermentation using strains of Paenibacillus polymyxa (formerly Bacillus polymyxa), the natural producer of the . The process employs large-scale bioreactors where the are cultivated under controlled conditions of (typically 28–32°C), (6.5–7.5), and to maximize yield. Optimized fermentation media include carbon sources such as glucose or starch, nitrogen sources like or , and mineral salts, with fed-batch strategies often applied to sustain growth and production phases. Reported yields from such processes range from approximately 0.3 g/L in engineered strains to up to 0.01 g/L in conventional fermentations (with units often reported in IU/L; typical conversion: 12,500–20,000 IU/mg colistimethate sodium). Downstream processing begins with separation of the fermentation broth, typically involving acidification to precipitate the colistin base followed by or to recover the crude product. Purification proceeds through a series of steps, including adsorption onto resins and , often utilizing to remove impurities like proteins and pigments, achieving high selectivity based on the cationic nature of colistin. Further refinement may employ reverse-phase for into components like colistin A and B. The purified colistin base is then chemically converted to colistimethate sodium, the preferred parenteral form, by reacting with and to form methanesulfonate derivatives on the amino groups, followed by neutralization and drying. This conversion enhances solubility and reduces toxicity for clinical use. Quality control adheres to stringent pharmacopoeial standards set by regulatory authorities such as the FDA and WHO, requiring colistin sulfate or colistimethate sodium to exhibit a potency of at least 90–95% of the labeled activity and purity levels exceeding 95% by chromatographic analysis, with limits on related substances (e.g., <5% for minor polymyxins). Endotoxin levels must be below 0.5 EU/mg to ensure safety for injectable formulations. Challenges include managing batch variability from biological sources, addressed through in-process monitoring of potency via microbiological assays and HPLC for purity. Recent advances focus on of P. polymyxa to enhance yields and purity, with recombinant modifications to biosynthetic pathways achieving titers up to 0.65 g/L in engineered strains as of 2024. Additionally, sustainable production strategies incorporate agro-industrial wastes like corn steep liquor or as low-cost media components, reducing environmental impact from conventional nutrient sourcing and generation in . These improvements aim to meet rising demand amid while complying with green manufacturing principles.

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC2869076/
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC4410713/
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC7241451/
  4. https://academic.oup.com/cid/article/40/9/1333/371785
  5. https://pubs.acs.org/doi/full/10.1021/jacsau.5c00587
  6. https://journals.asm.org/doi/10.1128/aac.02378-18
  7. https://pubchem.ncbi.nlm.nih.gov/compound/Colistin
  8. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2016.01789/full
  9. https://www.sciencedirect.com/topics/chemistry/colistin-b
  10. https://onlinelibrary.wiley.com/doi/10.1155/2015/624316
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC7692639/
  12. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1625595/full
  13. https://journals.asm.org/doi/10.1128/aac.00868-15
  14. https://www.eucast.org/
  15. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050108s033lbl.pdf
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC7437259/
  17. https://www.ema.europa.eu/en/documents/scientific-guideline/updated-advice-use-colistin-products-animals-within-european-union-development-resistance-and-possible-impact-human-and-animal-health_en.pdf-0
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC7602861/
  19. https://www.mdpi.com/2076-2607/8/11/1716
  20. https://onehealthadv.biomedcentral.com/articles/10.1186/s44280-023-00029-5
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC9697203/
  22. https://www.openveterinaryjournal.com/index.php?fulltxt=227387&fulltxtj=100&fulltxtp=100-1730741579.pdf
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC11974320/
  24. https://pubmed.ncbi.nlm.nih.gov/21544080/
  25. https://link.springer.com/article/10.1007/s40262-025-01488-2
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC5154767/
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC2772309/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC3910712/
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC4775947/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC3224467/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC6519339/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC9248837/
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC8605564/
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC180136/
  35. https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.677720/full
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC5955468/
  37. https://www.cell.com/trends/microbiology/abstract/S0966-842X(23)00295-0
  38. https://www.nature.com/articles/s43856-025-01109-w
  39. https://onlinelibrary.wiley.com/doi/10.1111/apm.13508
  40. https://ann-clinmicrob.biomedcentral.com/articles/10.1186/s12941-025-00799-3
  41. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1477836/full
  42. https://www.mdpi.com/1420-3049/30/14/2950
  43. https://pubmed.ncbi.nlm.nih.gov/39912656/
  44. https://www.mdpi.com/2079-6382/14/10/958
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC11390741/
  46. https://journals.asm.org/doi/10.1128/aac.00070-14
  47. https://pmc.ncbi.nlm.nih.gov/articles/PMC9686878/
  48. https://www.dovepress.com/comprehensive-assessment-of-colistin-induced-nephrotoxicity-incidence--peer-reviewed-fulltext-article-IDR
  49. https://pmc.ncbi.nlm.nih.gov/articles/PMC10198178/
  50. https://annalsofintensivecare.springeropen.com/articles/10.1186/2110-5820-1-14
  51. https://www.mdpi.com/1420-3049/26/24/7456
  52. https://www.atsjournals.org/doi/10.1164/rccm.201312-2208OC
  53. https://ec.europa.eu/health/documents/community-register/2016/20160926135752/anx_135752_en.pdf
  54. https://healthonline.washington.edu/sites/default/files/record_pdfs/Inhaled-Colistin.pdf
  55. https://www.medicinenet.com/colistin/article.htm
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC9841843/
  57. https://ccforum.biomedcentral.com/articles/10.1186/cc3995
  58. https://pmc.ncbi.nlm.nih.gov/articles/PMC8857716/
  59. https://pubmed.ncbi.nlm.nih.gov/33535401/
  60. https://www.drugs.com/pregnancy/colistimethate.html
  61. https://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-13-380
  62. https://www.jidc.org/index.php/journal/article/download/32084017/2136/90463
  63. https://reference.medscape.com/drug/firvanq-vancocin-vancomycin-342573
  64. https://www.who.int/news/item/07-11-2017-stop-using-antibiotics-in-healthy-animals-to-prevent-the-spread-of-antibiotic-resistance
  65. https://aricjournal.biomedcentral.com/articles/10.1186/s13756-017-0294-9
  66. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30328-2/fulltext
  67. https://thebetterindia.com/192452/fssai-rules-bans-colistin-animal-feed-antibiotic-resistance-health-india/
  68. https://www.sciencedirect.com/science/article/pii/S0167587725001199
  69. https://fssai.gov.in/upload/notifications/2024/10/67178d79690b3antibiotic%20gazette.pdf
  70. https://www.cidrap.umn.edu/antimicrobial-stewardship/study-finds-short-term-impact-chinas-ban-colistin-animals
  71. https://wwwnc.cdc.gov/eid/article/27/9/20-3642_article
  72. https://www.cidrap.umn.edu/antimicrobial-stewardship/study-suggests-colistin-still-being-widely-used-animal-feed
  73. https://www.who.int/publications/i/item/glass-the-detection-and-reporting-of-colistin-resistance-2nd-ed
  74. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00424-7/fulltext
  75. https://wwwnc.cdc.gov/eid/article/23/3/16-1553_article
  76. https://pmc.ncbi.nlm.nih.gov/articles/PMC5382726/
  77. https://pubs.acs.org/doi/10.1021/acs.estlett.3c00080
  78. https://pmc.ncbi.nlm.nih.gov/articles/PMC11847452/
  79. https://www.nature.com/articles/s41467-025-61606-3
  80. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0298096
  81. https://journals.asm.org/doi/10.1128/spectrum.02156-24
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC8503728/
  83. https://www.biosocialhealthjournal.com/FullHtml/bshj-55
  84. https://www.nature.com/articles/s43856-025-01090-4
  85. https://pubmed.ncbi.nlm.nih.gov/14056349/
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC2772240/
  87. https://encyclopedia.pub/entry/8139
  88. https://apps.who.int/iris/handle/10665/255027
  89. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00541-1/fulltext
  90. https://www.researchgate.net/publication/267518706_Trends_in_Colistin_Use_in_60_Countries_2000-2010
  91. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30329-2/fulltext
  92. https://pubmed.ncbi.nlm.nih.gov/36640846/
  93. https://www.nature.com/articles/s42003-024-06805-2
  94. https://www.nature.com/articles/s41598-025-18206-4
  95. https://pmc.ncbi.nlm.nih.gov/articles/PMC12561702/
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC8698549/
  97. https://pmc.ncbi.nlm.nih.gov/articles/PMC2687177/
  98. https://pmc.ncbi.nlm.nih.gov/articles/PMC6204185/
  99. https://pubmed.ncbi.nlm.nih.gov/26059516/
  100. https://www.nature.com/articles/srep21329
  101. https://hub.hku.hk/bitstream/10722/344150/1/FullText.pdf
  102. https://www.tandfonline.com/doi/pdf/10.1080/00021369.1984.10866169
  103. https://www.unmc.edu/intmed/divisions/id/asp/protected-antimicrobials/colistin.html
  104. https://patents.google.com/patent/WO2011051070A1/en
  105. https://www.diaion.com/en/application/pharmaceutical/pdf/antibiotics_fermentation_products_small_molecules_apis.pdf
  106. https://patents.google.com/patent/CN102161694B/en
  107. https://patents.google.com/patent/EP2470555B1/en
  108. https://www.fao.org/fileadmin/user_upload/vetdrug/docs/2-2006-colistin.pdf
  109. https://www.sciencedirect.com/science/article/abs/pii/S1096717624000958
Add your contribution
Related Hubs
User Avatar
No comments yet.