Colistin
The other polymyxin, given as an inactive prodrug that converts to active colistin in the body, revived as salvage therapy for carbapenem-resistant Acinetobacter, Pseudomonas and Klebsiella.
Also known as polymyxin E, colistimethate sodium, CMS, colistin base activity, Coly-Mycin M, Colomycin, Promixin
Approved drug — Licensed by a major regulator for human use, with phase-3 trial data behind it.
Approved in the 1960s under pre-modern standards. Modern dosing comes from population pharmacokinetic work published from 2011 onward, and randomised trials (AIDA, OVERCOME) have generally shown high mortality with colistin-based regimens and no clear benefit from adding a carbapenem. It survives as a salvage agent because resistant organisms leave few alternatives, not because it performs well.
How it works
Colistin differs from polymyxin B by a single amino acid (D-leucine in place of D-phenylalanine) and kills by the same detergent mechanism. The clinically important difference is formulation: intravenous colistin is given as colistimethate sodium, an inactive sulfomethylated prodrug that must hydrolyse in plasma to liberate active colistin. Conversion is slow and incomplete, so plasma colistin rises over many hours and a loading dose is essential in serious infection. Colistimethate is cleared renally while formed colistin is not, which creates the counterintuitive situation where renal impairment increases colistin exposure. Because the prodrug is renally excreted and converts in the urinary tract, colistin performs relatively better in urinary infection and relatively worse in bacteraemia than polymyxin B. mcr-1 plasmid-mediated resistance, first reported in 2015, is now global.
Targets: Lipid A / lipopolysaccharide, Gram-negative outer membrane, Bacterial inner membrane
Dosing
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| Loading dose for systemic infectionInfused over 30 to 60 minutes as the first dose. | 300 mg | once, at the start of therapy | intravenous |
| Maintenance therapyStarting 12 hours after the loading dose. | 300 mg – 360 mg | divided every 12 hours | intravenous |
| Nebulised colistin for pulmonary infectionVia jet or vibrating-mesh nebuliser, usually after bronchodilator. | 30 mg – 150 mg | twice daily | inhaled |
- · 300 mg of colistin base activity (about 9 million international units), given regardless of renal function. Colistin dosing is a units minefield: 1 mg CBA equals about 30,000 IU and about 2.4 mg of colistimethate sodium. Confusing these three units has killed people.
- · 300-360 mg CBA per day (roughly 9-10.9 million IU) divided into two doses in patients with normal renal function. Unlike polymyxin B, this maintenance dose IS reduced in renal impairment because the prodrug is renally cleared.
- · 1-2 million IU (roughly 33-66 mg CBA) twice or three times daily is typical for cystic fibrosis Pseudomonas suppression and as adjunct in ventilator-associated pneumonia. Must be reconstituted immediately before use — pre-mixed colistimethate that has converted to colistin in the syringe has caused fatal chemical pneumonitis.
Titration
Maintenance dose is adjusted downward by creatinine clearance while the loading dose is not. Patients on continuous renal replacement therapy need higher, not lower, maintenance doses because colistimethate is efficiently dialysed.
Cycling
Courses of 7-14 days for systemic infection. Chronic inhaled suppression in cystic fibrosis runs on alternating months for years, which is a different risk calculation entirely.
Pharmacology
- Half-life
- Formed colistin has a half-life of roughly 9 to 18 hours in critically ill adults, commonly cited around 14 hours; the colistimethate prodrug itself clears much faster.
- Onset
- Slow to reach therapeutic concentrations without a loading dose — plasma colistin can take 2 to 3 days to reach steady state, which is exactly why loading is mandatory.
- Routes
- intravenous, inhaled
- Molecule
- Natural-product cyclic cationic lipopeptide, decapeptide with a fatty acyl tail; administered as the methanesulfonate prodrug
- Sequence length
- 10 amino acids
- Molecular weight
- 1169.5 Da
Handling
- Diluent
- Sterile water for injection or 0.9% sodium chloride
- Typical mix
- 2 or 10 mL
- Vial sizes
- 150 mg
- Lyophilised
- Room temperature, 20-25°C.
- Reconstituted
- Refrigerated and used within 24 hours for IV use; used immediately for inhalation.
Mixing
Swirl gently to avoid foaming. For nebulisation, reconstitute immediately before use and never store a prepared nebuliser solution — spontaneous conversion to active colistin in the container is directly linked to fatal respiratory events.
Side effects
- very commonNephrotoxicity— Acute kidney injury in roughly 30-60% of patients depending on the definition used, dose and duration. The single biggest limitation of the drug.
- commonNeurotoxicity - paraesthesia, dizziness, confusion— Dose-related and reversible.
- commonBronchospasm with nebulised administration— Pre-treatment with a bronchodilator and a test dose under supervision are standard.
- rareNeuromuscular blockade— Can cause respiratory arrest, particularly with concomitant neuromuscular blockers or in myasthenia gravis.
- rareChemical pneumonitis from degraded nebuliser solution— Documented fatalities from pre-mixed colistimethate that converted to colistin before inhalation. Mix fresh, every time.
Do not use if
- Myasthenia gravis and other neuromuscular disorders.
- Known polymyxin hypersensitivity.
- Pre-mixed or stored nebuliser solutions must never be used.
- Should not be used when a newer agent such as ceftazidime-avibactam, meropenem-vaborbactam or cefiderocol has documented in vitro activity, since randomised data favour those agents on both efficacy and toxicity.
Combining it
- cautionaminoglycosides — Additive nephrotoxicity and neuromuscular blockade.
- cautionvancomycin — Higher combined rate of acute kidney injury.
- conflictneuromuscular blocking agents — Potentiated and prolonged paralysis.
- redundantpolymyxin-b — Same drug class and mechanism; there is no scenario requiring both.
- synergymeropenem — In vitro and some clinical synergy against carbapenem-resistant Acinetobacter, though the OVERCOME and related randomised trials did not show a mortality benefit for the combination.
What to monitor
- · Daily serum creatinine, urine output and electrolytes.
- · Neurological status, especially in patients who cannot report paraesthesia.
- · Spirometry or symptom check after the first nebulised dose to catch bronchospasm.
- · Confirm the units on every order — CBA milligrams, international units and colistimethate milligrams are three different numbers.
Legal status
Prescription-only injectable, approved in the US, EU and most markets. Inhaled colistimethate is licensed in Europe for cystic fibrosis and used off-label for that purpose in the US.
References
- Tsuji et al. 2019, international consensus guidelines for the optimal use of the polymyxins (guideline)
- Paul et al. 2018, AIDA trial of colistin versus colistin plus meropenem in carbapenem-resistant gram-negative infection (trial)
- Coly-Mycin M Parenteral (colistimethate for injection) US prescribing information (label)
Mechanism in depth
Polymyxin E - a cationic cyclic lipopeptide that binds the lipid A phosphate groups of Gram-negative lipopolysaccharide, displaces the stabilising divalent cations, and permeabilises the outer membrane. It is given as colistimethate sodium, an inactive sulfomethylated prodrug that must hydrolyse in vivo to release colistin, and that conversion is slow and incomplete.
What usually goes wrong
Dose unit confusion is a genuine and repeatedly documented hazard: colistimethate is expressed as colistin base activity in some countries and as international units in others, and the two differ by roughly a factor of thirty. A prescription transcribed across that boundary without conversion has caused real overdoses. Beyond that, the prodrug's slow conversion means a loading dose is needed, and omitting it leaves the patient subtherapeutic for the first day of a life-threatening infection.
Bloodwork worth running
| Marker | When | Why it matters |
|---|---|---|
| Serum creatinine and eGFR | Baseline then daily to every other day. | Nephrotoxicity is dose-limiting and common - historically the reason the polymyxins were abandoned, and the reason they are reserved now.Act if: A rising creatinine on therapy usually forces a dose reduction or a switch; there is often no safer alternative, which is the whole problem. |
| Neurological observation | Clinically, throughout. | Neurotoxicity presents as perioral paraesthesia, dizziness and, rarely, neuromuscular blockade - the last is dangerous alongside neuromuscular blocking agents.Act if: Any new weakness or paraesthesia warrants review. |
Pharmacokinetics
- Crosses blood-brain barrier
- no
- Accumulates
- Yes — doses stack before steady state
- Elimination
- Mixed
Receptor targets
- Lipid A of Gram-negative LPS — Electrostatic, cation-displacing
Outer membrane permeabilisation and rapid killing
What to expect, and when
Rapid bactericidal action once active drug is formed, but the prodrug conversion delays effective concentrations by several hours without a loading dose.
Stacking and comparisons
Polymyxin B is the closely related alternative and reaches active concentrations more predictably because it is given as the active drug; colistin remains preferred for urinary infection because polymyxin B achieves poor urinary levels.
Genuinely uncertain
- Optimal dosing in renal replacement therapy remains poorly defined and varies substantially between published regimens.
- Whether polymyxin B should replace colistin for systemic infection - it needs no prodrug conversion - is argued but not resolved.