Mechanism
Polymyxin B is a cyclic decapeptide produced by the soil bacterium Bacillus polymyxa. The molecule has a fatty acid (6-methyl-heptanoyl) tail attached to the N-terminus and a cyclic structure formed by an amide bond between the terminal diaminobutyric acid and the side chain of an internal diaminobutyric acid.
The mechanism of action targets the outer membrane of Gram-negative bacteria:
- The cationic peptide structure binds the negatively-charged lipid A portion of lipopolysaccharide (LPS) in the outer membrane
- This displaces divalent cations (Mg²⁺, Ca²⁺) that normally stabilize LPS
- The hydrophobic fatty acid tail inserts into the membrane
- Membrane integrity is disrupted; cellular contents leak; the bacterium dies
The mechanism is largely specific to Gram-negative bacteria because Gram-positive organisms lack the outer membrane and LPS that polymyxin B targets.
The mechanism also explains both the spectrum (broad activity against Gram-negative pathogens) and the resistance profile (intrinsic resistance in Proteus, Serratia, Burkholderia spp. due to LPS modifications; acquired resistance via mcr-type genes that modify LPS to reduce polymyxin binding).
What the evidence shows
Historical use (1950s–1970s): Polymyxin B was widely used as a systemic antibiotic until concerns about nephrotoxicity and the availability of safer alternatives (later-generation cephalosporins, aminoglycosides, fluoroquinolones) reduced clinical use to topical and ophthalmologic applications.
Modern resurrection (2000s onward): The emergence of carbapenem-resistant Gram-negative pathogens — particularly Acinetobacter baumannii, carbapenemase-producing Enterobacterales (CRE), and MDR Pseudomonas aeruginosa — has driven re-adoption of polymyxin B and colistin as last-resort options.
Evidence base: Mostly observational and from case series rather than RCTs. The major MDR pathogen contexts where polymyxin B is used (carbapenem-resistant infections in critically ill patients) make controlled trials ethically and practically difficult — randomization to non-active alternatives in life-threatening infections is not feasible. Multiple retrospective cohort studies and a few prospective comparative studies inform contemporary use.
Comparative effectiveness: Polymyxin B and colistin have similar antibacterial spectra. Polymyxin B has somewhat better pharmacokinetics for systemic infections (rapidly bactericidal, no metabolism to active prodrug); colistin is administered as colistin methanesulfonate (CMS), a prodrug requiring conversion. Practice varies regionally.
Dosing literature
Approved dosing (intravenous):
- Loading dose: 2.5 mg/kg (≈25,000 units/kg) IV over 30–60 minutes
- Maintenance: 1.25–1.5 mg/kg every 12 hours, adjusted for renal function
- Pediatric: Weight-based equivalent
Renal dose adjustment is critical and complex; therapeutic drug monitoring (where available) is increasingly standard practice.
Inhaled administration for ventilator-associated pneumonia is used in some settings as an adjunct to systemic therapy, though evidence for efficacy is mixed.
Topical and ophthalmic preparations — the historical mainstay — are still widely used (Neosporin Ophthalmic, etc.).
Risks and adverse events
Major (systemic IV use):
- Nephrotoxicity — dose-related, occurs in 20–60% of patients depending on definition and population. Reversible in many cases but can require dialysis. Major reason for therapeutic-window concerns.
- Neurotoxicity — paresthesia, ataxia, vertigo, peripheral neuropathy; dose- and concentration-related
- Respiratory paralysis — rare but reported, particularly with neuromuscular blockade co-administration
Less common:
- Hypersensitivity reactions
- Drug fever
- Eosinophilia
- Bronchospasm with inhaled administration
Drug interactions:
- Other nephrotoxic drugs (vancomycin, aminoglycosides, contrast media) — significant interaction
- Neuromuscular blocking agents — potentiation of paralysis
Antimicrobial resistance concern:
- Acquired resistance via plasmid-borne mcr genes (first described 2015) is a critical public health concern
- Heteroresistance (subpopulation with elevated MICs) is common and can drive treatment failure
- Stewardship implications: every unnecessary use of polymyxin B accelerates resistance and erodes the drug’s last-resort utility
Regulatory status
| Region | Status | Notes |
|---|---|---|
| United States | Approved | Multiple generic IV preparations; topical preparations widely available. |
| European Union | Approved | Colistin (polymyxin E) is more commonly used in EU systemic practice. |
| United Kingdom | Approved | |
| Most major markets | Approved |
The drug is on the WHO Model List of Essential Medicines and classified as a WHO “Reserve” antimicrobial — meaning it should be used selectively and with stewardship oversight.
Where to get it
Through hospital infectious-disease consultation in the systemic-IV use case. Not a candidate for outpatient prescription or any self-sourcing pathway — this is critical-care, hospital-administered therapy.
Topical preparations (neomycin/polymyxin/bacitracin combinations) are over-the-counter for minor skin abrasions and similar uses; that’s a different product entirely from systemic IV polymyxin B.
We have no fulfillment partner for polymyxin B. (See How we make money.)
References (selected)
- Tsuji BT et al. International Consensus Guidelines for the Optimal Use of the Polymyxins. Pharmacotherapy 2019. PubMed
- Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care 2006.
- Liu YY et al. Emergence of plasmid-medi
Quick Facts
| Also Known As | Polymyxin B sulfate, Aerosporin |
|---|---|
| Sequence | Dab-Dab-Dab-Dab-Dab-Dab-Dab-Dab-Dab-Dab (Note: Polymyxin B is a mixture of closely related compounds, primarily Polymyxin B1 and B2, with the decapeptide ring attached to a fatty acyl tail. The sequence shown is the common polymyxin core of 10 diaminobutyric acid (Dab) residues in the cyclic portion; the full structure includes a tripeptide side chain (Dab-Thr-Dab) and a 6-methyloctanoyl or 6-methylheptanoyl fatty acid tail.) |
| Molecular Formula | Variable mixture; Polymyxin B1: C56H98N16O13 |
| Molecular Weight | Approximately 1200-1300 Da for the various components (Polymyxin B1 sulfate: ~1385.6 Da). |
Research Parameters
| Half-Life | Approximately 4-6 hours in patients with normal renal function; prolonged in renal impairment. |
|---|---|
| Stability | Lyophilized powder is stable at recommended storage conditions. After reconstitution for intravenous use, solutions are typically stable for 24-48 hours at 2-8°C, though specific product labeling should be consulted. |
| Solubility | Sterile Water for Injection, 0.9% Sodium Chloride Injection. |
| Vial Size | 500000 mg |
| Storage (Lyophilized) | Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F). Protect from light. |
| Storage (Reconstituted) | Store at 2-8°C (36-46°F) for up to 72 hours, or as per specific product instructions. |
| Typical Research Dose | 1.5-2.5 mg/kg/day intravenously (equivalent to 1,500,000-2,500,000 mcg/kg/day). |
| Cycle Parameters | Administered in divided doses (usually every 12 hours) intravenously over 60-120 minutes. Treatment duration is typically 7 14 days, based on clinical response, and is not used in cyclical 'on/off' protocols. |
| Amino Acid Count | 14 |
Mechanism of Action
Polymyxin B exerts its bactericidal effect primarily by disrupting the outer membrane of Gram-negative bacteria. Its cationic peptide region binds electrostatically to the anionic lipopolysaccharide (LPS) in the outer membrane, while its hydrophobic fatty acyl tail inserts into the membrane bilayer.
Membrane Disruption and Permeabilization: The initial binding to LPS displaces divalent cations (Mg2+, Ca2+) that stabilize the outer membrane. This destabilization allows the lipopeptide to insert into the membrane, leading to increased permeability and leakage of intracellular contents, ultimately causing cell death.
Endotoxin Neutralization: By binding tightly to the lipid A component of LPS, Polymyxin B can neutralize bacterial endotoxin. This can mitigate the pro-inflammatory effects of LPS release during antibiotic treatment, although this effect is secondary to its direct killing activity.
Secondary Intracellular Effects: Some evidence suggests that after permeabilizing the outer membrane, Polymyxin B may also interact with the cytoplasmic membrane and potentially inhibit vital respiratory enzymes, contributing to cell death.
Research Applications
Antimicrobial Resistance Research: Polymyxin B is a critical tool for studying mechanisms of resistance in Gram-negative bacteria, including plasmid-mediated mcr genes and other modifications to LPS that reduce binding. Research focuses on understanding resistance epidemiology and developing combination therapies to overcome it.
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling: Due to its narrow therapeutic window, extensive research is conducted to define optimal dosing regimens. Studies investigate its complex PK in critically ill patients, including those on renal replacement therapy, to minimize toxicity while maximizing efficacy.
Inhalation Therapy Development: Research explores the administration of Polymyxin B via inhalation for the treatment of respiratory infections like ventilator-associated pneumonia and cystic fibrosis exacerbations. This route aims to deliver high local concentrations to the lungs while minimizing systemic exposure and associated nephrotoxicity.
Combination Therapy Synergy: A major research area investigates Polymyxin B in combination with other antibiotics (e.g., carbapenems, rifampin) to enhance killing, prevent resistance emergence, and allow for lower, less toxic doses of polymyxin.
Safety & Side Effects
The primary dose-limiting toxicity is nephrotoxicity (acute kidney injury), reported in up to 60% of patients in older studies, though modern, careful dosing may reduce this incidence. Neurotoxicity (dizziness, ataxia, paresthesia, and rarely neuromuscular blockade leading to respiratory failure) is a well-documented risk, particularly with high doses or in patients with renal impairment. Other reported side effects include hypersensitivity reactions, pain at the injection site, and fever. Anecdotal reports and theoretical concerns include the potential for superinfection or colonization with resistant organisms due to its narrow spectrum.
Dosage Information
Disclaimer: The following information is derived from clinical and preclinical research literature and is not a recommendation for use.
In clinical research and treatment, dosing is highly individualized based on renal function and infection severity. Typical intravenous doses range from 1.5 to 2.5 mg/kg per day (often divided into two doses), with adjustments for renal impairment. For inhalation therapy in research, doses of 25-75 mg (of Polymyxin B base activity) administered twice daily have been studied. The primary routes are intravenous and intramuscular; inhalation is an area of active investigation. Duration of therapy is typically 7-14 days but can be extended for difficult-to-treat infections.
References
Zavascki, A.P., Goldani, L.Z., Li, J., Nation, R.L. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. Current Opinion in Infectious Diseases, 2007.
Nation, R.L., Velkov, T., Li, J. Colistin and polymyxin B: peas in a pod, or chalk and cheese? Clinical Infectious Diseases, 2014.
Bergen, P.J., Landersdorfer, C.B., Zhang, J., et al. Pharmacokinetics and pharmacodynamics of 'old' antibiotics: polymyxins, aminoglycosides, and glycopeptides. Current Opinion in Pharmacology, 2012.
Poirel, L., Jayol, A., Nordmann, P. Polymyxins: Antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clinical Microbiology Reviews, 2017.
Sandri, A.M., Landersdorfer, C.B., Jacob, J., et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clinical Infectious Diseases, 2013.
Kwa, A.L., Lim, T.P., Low, J.G., et al. Pharmacokinetics of polymyxin B1 in patients with multidrug-resistant Gram-negative bacterial infections. Diagnostic Microbiology and Infectious Disease, 2008.