Which sequence correctly describes how a polymyxin kills a gram-negative bacterium?

The cationic drug binds the phosphate groups of anionic lipid A, displaces stabilising calcium and magnesium, and makes the outer membrane permeable — The action is physical rather than enzymatic. Electrostatic attraction pulls the positively charged molecule onto the negatively charged lipid A of lipopolysaccharide, and the divalent cations that bridge adjacent lipopolysaccharide molecules are pushed aside. The outer membrane then leaks its contents and the organism dies, a detergent-like effect that needs neither bacterial growth nor protein synthesis to work.

It inhibits lipopolysaccharide synthesis, so the outer membrane cannot be assembled

It is transported into the cytoplasm and inhibits ribosomal protein synthesis

It cross-links peptidoglycan strands, leaving a rigid wall the cell cannot expand

Why does the polymyxin class have no useful activity against gram-positive organisms?

Gram-positive bacteria have no outer membrane and therefore no lipopolysaccharide target — Every step of the mechanism depends on lipid A sitting in an outer membrane. Organisms built without that membrane simply present nothing for a cationic detergent antibiotic to attack, so the gap is absolute rather than a matter of degree. Being reserved as a last-line agent says nothing about breadth of spectrum, and confusing the two is a common examination error.

The thick peptidoglycan layer of gram-positives destroys the drug enzymatically

Gram-positive organisms pump the drug out through constitutive efflux systems

Gram-positive ribosomes differ too much for the drug to bind them

Which statement about the two systemically used polymyxins is correct?

Polymyxin B is given in active form, while colistin is administered parenterally as the inactive prodrug colistimethate sodium — Colistimethate sodium has to hydrolyse in the body before any active colistin exists, and that conversion delays and blurs the achievement of useful drug concentrations. Polymyxin B needs no such conversion, which is why it is favoured for intravenous therapy: levels arrive sooner and more predictably, and nephrotoxicity by that route is lower.

Both are administered as inactive prodrugs requiring hydrolysis

Colistin is given intravenously in active form, whereas polymyxin B is the prodrug

Colistimethate sodium is a different drug from colistin, with a different molecular target

Which adverse effect has the highest incidence with polymyxins and constrains their use most?

Nephrotoxicity — Renal toxicity is the most frequent adverse effect of the class and the reason colistin was largely abandoned after its introduction, returning to practice only when resistance closed off gentler alternatives. It can present with blood or protein in the urine, reduced urine output and, at worst, renal failure, so urea, creatinine and urine output are followed throughout treatment. Therapy is stopped if renal impairment appears, though the tubular injury commonly recovers afterwards with supportive fluid and electrolyte care.

Hypersensitivity rash and urticaria

A patient on a polymyxin develops neuromuscular blockade progressing towards respiratory failure. Which statement is correct?

Cholinesterase inhibitors are of no benefit; the drug is stopped and ventilation supported mechanically if apnoea develops — Neurological toxicity affects roughly seven in every hundred treated patients, most often as paresthesia, with dizziness, numbness, tingling and vertigo also described; mild symptoms usually settle once the drug is withdrawn. At the severe end the blockade can shut down respiration, and an anticholinesterase does nothing to reverse it — mechanical ventilation is what supports the patient if apnoea occurs. This behaviour is what distinguishes it from blockade produced by competitive neuromuscular blocking agents.

Neostigmine reliably reverses the blockade, as it does for competitive neuromuscular blocking drugs

Neurotoxicity from this class is confined to paresthesia and never threatens ventilation

The blockade indicates an allergic reaction and is managed with adrenaline

A blood culture grows a gram-negative organism. Which group should not be assumed susceptible to colistin, because it is resistant before any exposure?

Proteus, Serratia, Morganella, Providencia and Burkholderia — These genera constitutively decorate their lipid A with cationic substituents such as L-Ara4N and phosphoethanolamine, through the arnBCADTEF operon and the eptB gene. The resulting loss of negative charge leaves the cationic drug with nothing to bind, so resistance is built into the organism rather than acquired under pressure. Identifying the genus is therefore enough to rule the class out.

Klebsiella pneumoniae and Escherichia coli

Why is mcr-1 regarded as a more serious development than chromosomal colistin resistance?

It sits on a plasmid and so can move horizontally between gram-negative species — Mutations in regulatory systems such as pmrAB, phoPQ or mgrB stay locked inside the lineage that acquired them. A plasmid-carried gene travels laterally instead, and mcr-1 has done so worldwide since it was first described in Escherichia coli from pigs and meat in China in November 2015, with further variants following. Agricultural use in pig and poultry farming dominates global colistin consumption and sustains the reservoir, so this is an agricultural problem as much as a hospital one.

It inactivates the drug enzymatically rather than altering the membrane target

It confers resistance to every antibiotic class simultaneously

It arises only in organisms that are already carbapenem-resistant

Pharmacology · Cell membrane–active antibiotics

Polymyxins

Cationic detergent antibiotics that tear open the gram-negative outer membrane — last-line therapy for multidrug-resistant organisms, limited by nephrotoxicity and neurotoxicity.

Quick revision

Polymyxins are positively charged detergents that bind the negatively charged lipid A of gram-negative LPS, displace calcium and magnesium and blow a hole in the outer membrane — bactericidal, gram-negative only, and reserved as a last line because of nephrotoxicity and neurotoxicity.

Mechanism: the positively charged polymyxin binds the phosphate groups of negatively charged lipid A, displacing divalent calcium and magnesium and disrupting the outer membrane. (1)
Bactericidal, and because the target is the outer membrane the class is active against gram-negative organisms only. (1)
Two agents are used clinically: polymyxin B and polymyxin E, which is colistin. (1)
Colistin is given parenterally as the inactive prodrug colistimethate sodium; polymyxin B is given in its active form. (1) (3)
Last line of treatment for infections resistant to other antibiotics, especially carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. (1)
Nephrotoxicity has the highest incidence of the adverse effects and is the dose-limiting problem. (1)
Neurotoxicity occurs in around 7% of patients; paresthesia is the most common manifestation, and neuromuscular blockade can cause respiratory failure. (1)
Proteus, Serratia, Morganella, Providencia and Burkholderia are intrinsically resistant. (2)
mcr-1 is a plasmid-borne, horizontally transferable colistin resistance gene first reported in E. coli from pigs and meat in China in November 2015 — a global concern because it moves between species. (2) (3)

Overview

Polymyxins are cationic polypeptide antibiotics of which two members are used in clinical practice: polymyxin B and polymyxin E, better known as colistin. They are approved for serious infections caused by multidrug-resistant gram-negative bacteria, particularly Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, and are often the only effective agent left against carbapenem-resistant Enterobacteriaceae. (1)

The mechanism is physical rather than biochemical. The positively charged drug is drawn to the phosphate groups of the negatively charged lipid A of lipopolysaccharide, displaces the calcium and magnesium that stabilise the outer membrane, and increases permeability until the cell leaks and dies. Because that target exists only in the gram-negative outer membrane, the class has no gram-positive activity. The same binding also neutralises free lipopolysaccharide released when bacteria die. (1)

Colistin was approved by the FDA in 1959 and then largely abandoned because of its nephrotoxicity; it returned to practice only because resistance closed off the safer alternatives. Nephrotoxicity still has the highest incidence of its adverse effects, and neurotoxicity affects around 7% of patients, ranging from paresthesia to neuromuscular blockade with respiratory failure. Prescribing a polymyxin is a decision made when the alternatives have run out. (1) (3)

Resistance has followed the revival. The plasmid-borne mcr-1 gene, first reported in Escherichia coli from pigs and meat in China in November 2015, transfers horizontally between gram-negative species and has since been found worldwide alongside further variants. Because polymyxins sit at the end of the treatment line, their loss has no obvious successor. (2) (3)

Classification and drug examples

A small class. The clinically meaningful split is between the two systemic agents — which differ in whether the drug arrives active or as a prodrug — and the topical and inhaled preparations used for local effect.

Systemic agent given in active form

Preferred for intravenous use because it delivers faster and more reliable drug levels with lower nephrotoxicity than the colistin prodrug. (1)

Polymyxin B (Polymyxin B sulfate) · IV — Administered parenterally in its active form; also used intrathecally or intraventricularly in preservative-free formulations. (1)

Systemic agent given as a prodrug

Colistimethate sodium is inactive until hydrolysed to colistin, which delays and complicates the achievement of active drug levels. (1) (3)

Colistin (Polymyxin E, Colistimethate sodium (CMS)) · IV/inhaled — Given parenterally as the inactive prodrug colistimethate sodium; hydrolysis releases active colistin. (1) (3)

Topical and inhaled preparations

Used where a local effect is wanted and systemic exposure — with its nephrotoxicity — is best avoided. (1) (4)

Polymyxin B, topical · Ophthalmic/otic/skin — Used in otitis externa, bacterial conjunctivitis and minor skin infection, usually in combination preparations. (1)
Colistimethate sodium, inhaled (Nebulised colistimethate, Colistimethate dry powder for inhalation) · Inhaled — Used for chronic Pseudomonas aeruginosa lung infection in cystic fibrosis; a dry-powder inhaler formulation exists alongside nebulised delivery. (4) (1)

Mechanism of action

Positively charged polymyxin binds the phosphate groups of the negatively charged lipid A of gram-negative lipopolysaccharide, displaces stabilising calcium and magnesium, increases outer membrane permeability and kills the organism; it also binds free lipopolysaccharide released on cell death.

Molecular target: Lipid A of lipopolysaccharide in the gram-negative outer membrane
Killing effect: bactericidal
Kill kinetics: concentration-dependent

Electrostatic attraction to lipid A
The positively charged polymyxin molecule is drawn to the phosphate groups of the negatively charged lipid A component of lipopolysaccharide in the gram-negative outer membrane. (1)
Divalent cations are displaced
Binding displaces the calcium and magnesium ions that bridge and stabilise adjacent lipopolysaccharide molecules. (1)
The outer membrane becomes permeable
Loss of those stabilising cations disrupts the outer membrane and increases its permeability — the detergent-like action that defines the class. (1)
Cell contents leak and the organism dies
Cellular contents escape through the disrupted membrane and the bacterium is killed. The effect is bactericidal and does not depend on bacterial growth or protein synthesis. (1)
Released endotoxin is neutralised
Polymyxins also bind lipopolysaccharide released as a result of cellular death, neutralising its endotoxin effects. (1)
Gram-positives are unaffected throughout
Every step depends on lipopolysaccharide in an outer membrane. Organisms without one present no target, which is why the spectrum is gram-negative only. (1)

Spectrum of activity

A narrow, strictly gram-negative spectrum whose value lies in what it retains against multidrug-resistant organisms rather than in its breadth.

Spectrum by subclass

Subclass	Gram-positive	Gram-negative	Anaerobes	Atypicals	Notable gaps
class-wide	—	Enterobacteriaceae, including carbapenem-resistant strains, Pseudomonas aeruginosa, including multidrug-resistant strains, Acinetobacter baumannii, Klebsiella pneumoniae	—	—	All gram-positive organisms — no outer membrane, no target, Proteus mirabilis and Proteus vulgaris (intrinsic resistance), Serratia marcescens (intrinsic resistance), Morganella morganii and Providencia species (intrinsic resistance), Burkholderia species (intrinsic resistance) (1) (2) (3)

Major clinical uses

Read each row as drug → organism → indication. Therapy is always directed by local susceptibility data and the treating clinician.

Drug	Organism	Indication	Role	Note
Polymyxins as a class	Carbapenem-resistant Enterobacteriaceae	Serious infection where the organism is resistant to other available antibiotics	reserve	Often the only effective agent remaining, which is the whole basis of the class's continued use. (1)
Polymyxins as a class	Multidrug-resistant Pseudomonas aeruginosa	Systemic infection caused by susceptible multidrug-resistant strains	reserve	Susceptibility must be confirmed; intrinsic resistance elsewhere in the gram-negatives makes empiric assumptions unsafe. (1)
Polymyxins as a class	Acinetobacter baumannii	Serious multidrug-resistant infection	reserve	One of the three organism groups named in the approved indications. (1)
Polymyxin B	Multidrug-resistant gram-negative bacteria	Intravenous therapy where a polymyxin is indicated	reserve	Preferred over colistimethate intravenously for faster, more reliable drug levels and lower nephrotoxicity. (1)
Colistimethate sodium, inhaled	Pseudomonas aeruginosa	Chronic Pseudomonas lung infection in cystic fibrosis	targeted	Delivered by nebuliser or dry-powder inhaler; dry-powder colistimethate was found non-inferior to nebulised tobramycin on lung function measures. (4)
Polymyxin B, topical	Susceptible gram-negative organisms	Otitis externa, bacterial conjunctivitis and minor skin infection	adjunct	Local application avoids the systemic toxicity that constrains the class. (1)

Pharmacokinetics

Drug	Route	Absorption	CSF penetration	Metabolism	Elimination	Half-life	Adjust in
Polymyxin B	IV	Not absorbed orally; given parenterally in active form	Poor — intrathecal or intraventricular preservative-free administration is used when CNS therapy is needed	Not a significant hepatic substrate	See prescribing reference	See prescribing reference	Renal function monitoring required; therapeutic drug monitoring is used (1)
Colistin (as colistimethate sodium)	IV	Not absorbed orally; given parenterally as an inactive prodrug requiring hydrolysis to active colistin	Poor — intraventricular or intrathecal routes used for CNS infection	Colistimethate is hydrolysed to active colistin	See prescribing reference	See prescribing reference	Renal function monitoring required (1) (3)
Colistimethate sodium, inhaled	Inhaled	Delivered directly to the airway; systemic exposure limited compared with intravenous use	Not applicable	Hydrolysis to active colistin	Not clinically framed by this route	Not clinically relevant by this route	See prescribing reference (4) (1)

The prodrug distinction is the pharmacokinetic headline of this class. Polymyxin B arrives active; colistimethate sodium must hydrolyse first, and that conversion is why intravenous polymyxin B achieves faster and more reliable drug levels with lower nephrotoxicity. (1) (3)
Therapeutic drug monitoring is used alongside renal function monitoring — BUN, creatinine and urine output — because nephrotoxicity has the highest incidence of the class's adverse effects. (1)
Aerosolised administration is given with bronchodilator pre-treatment because of the risk of bronchospasm, and only preservative-free formulations may be used intrathecally or intraventricularly. (1)
This page gives no dose regimens by design. Doses depend on indication, organism, renal function, formulation and the unit of measurement used for the particular preparation, and belong in a prescribing reference used by the treating clinician.

Adverse effects

Common

Nephrotoxicity: The adverse effect with the highest incidence and the factor that historically limited clinical use of the class. Presents with haematuria, proteinuria, oliguria and, at its worst, acute renal failure. (1) (3)
Paresthesia and other mild neurological symptoms: Paresthesia is the most common neurotoxic manifestation; dizziness, numbness, tingling and vertigo also occur. Mild neurological symptoms typically resolve after the drug is stopped. (1)
Hypersensitivity reactions: Rash, urticaria and fever. (1)
Skin hyperpigmentation: A recognised effect of the class. (1)

Serious adverse effects

Neuromuscular blockade with respiratory failure: Part of the neurotoxicity spectrum, which affects around 7% of patients overall. Blockade can progress to respiratory failure and apnoea. Stop the drug and support ventilation mechanically if apnoea develops. Cholinesterase inhibitors such as neostigmine are of no benefit for the resulting respiratory depression. (1)
Acute renal failure: The severe end of the nephrotoxicity spectrum, which is why renal parameters are monitored throughout therapy. Discontinue therapy if renal impairment develops and give supportive care with fluid and electrolyte monitoring. (1)
Bronchospasm: Associated with aerosolised administration. Bronchodilator pre-treatment before nebulised therapy, and monitor for signs of bronchospasm. (1)
Superinfection: A recognised consequence of therapy, since the drug leaves gram-positive and intrinsically resistant gram-negative organisms untouched. Surveillance for superinfection is part of routine monitoring. (1)

Drug-specific effects

Colistin (colistimethate sodium), intravenous: Higher nephrotoxicity than intravenous polymyxin B, which is one reason polymyxin B is preferred for the intravenous route. (1)
Colistimethate sodium, inhaled: Bronchospasm on aerosolisation, mitigated by bronchodilator pre-treatment. (1)

Contraindications, precautions and interactions

Contraindications

Hypersensitivity to polymyxin B, colistimethate sodium, colistin or any component of the formulation. (1)

Precautions

Existing renal impairment, given that nephrotoxicity is the adverse effect with the highest incidence and therapy is discontinued if renal impairment develops. (1)
Myasthenia gravis and other disorders of neuromuscular transmission, because the class causes neuromuscular blockade that can progress to respiratory failure — and because cholinesterase inhibitors do not reverse it. (1)
Airway disease when the inhaled route is used, because aerosolisation can provoke bronchospasm. (1)
Intrathecal or intraventricular administration requires preservative-free formulations only. (1)

Drug interactions

Other nephrotoxic agents: Additive risk of renal injury on top of a drug whose principal toxicity is already nephrotoxicity. (1)
Neuromuscular blocking agents and other drugs impairing neuromuscular transmission: Compounded neuromuscular blockade, with the risk of respiratory failure. (1)

Resistance mechanisms

Intrinsic resistance through constitutive lipid A modification

Several gram-negative genera permanently modify their lipopolysaccharide with cationic substituents such as L-Ara4N and phosphoethanolamine, via the arnBCADTEF operon and eptB gene. This reduces the negative charge the cationic drug needs to bind, so these organisms are resistant before any exposure. (2)

Examples: Proteus mirabilis and Proteus vulgaris, Serratia marcescens, Morganella morganii, Providencia species, Burkholderia cepacia

Recognise the genus and choose a different class; do not treat these organisms empirically with a polymyxin.

Chromosomal two-component system mutation

Mutations activating the PmrAB and PhoPQ regulatory systems switch on the same lipid A modifications in organisms that are normally susceptible. In Klebsiella pneumoniae, inactivation of the mgrB gene upregulates the phoPQ operon and produces resistance. (2)

Examples: Klebsiella pneumoniae with mgrB inactivation, Enterobacteriaceae with pmrAB or phoPQ mutations

Susceptibility testing on the individual isolate rather than assumption from species identity.

Plasmid-mediated mcr genes

mcr-1 was first reported in Escherichia coli isolated from pigs and meat in China in November 2015. Because it is plasmid-borne it transfers horizontally between gram-negative species and has since been identified across multiple continents, with variants now described through mcr-10; mcr-1 accounts for the large majority of positive isolates globally. (2) (3)

Examples: Escherichia coli, Other Enterobacteriaceae acquiring mcr-carrying plasmids

Surveillance, restriction of agricultural colistin use and stewardship of the remaining clinical supply.

Polymyxins are what is left when carbapenems have failed, so resistance here has no obvious successor class. The pressure driving it is not mainly clinical: veterinary use in pig and poultry farming dominates global colistin consumption and sustains a livestock reservoir of mcr-carrying plasmids that can move into human pathogens.

Comparison tables

Polymyxin B versus colistin

The two clinically used polymyxins differ chiefly in whether the administered drug is already active. Local susceptibility data and a prescribing reference govern actual therapy.

Feature	Polymyxin B	Colistin (polymyxin E)
Form administered parenterally	Active drug	Inactive prodrug, colistimethate sodium (1) (3)
Speed and reliability of drug levels	Faster and more reliable	Delayed by the need for hydrolysis (1)
Nephrotoxicity by the IV route	Lower	Higher (1)
Inhaled use	Not the usual inhaled agent	Nebulised or dry-powder colistimethate in cystic fibrosis (4)
Preferred IV choice	Preferred	Second choice intravenously (1)

Three routes to colistin resistance

All three converge on the same endpoint — a less negatively charged lipid A that the cationic drug cannot bind.

Type	Genetic basis	Can it spread between species?	Example
Intrinsic	Constitutive arnBCADTEF / eptB lipid A modification	No — inherent to the genus	Proteus, Serratia, Burkholderia (2)
Acquired chromosomal	pmrAB, phoPQ, mgrB mutations	No — confined to the lineage	Klebsiella pneumoniae with mgrB inactivation (2)
Plasmid-mediated	mcr-1 and related mcr genes encoding phosphoethanolamine transferase	Yes — horizontal transfer, global spread	Escherichia coli, first reported China 2015 (2) (3)

High-yield exam pearls

Polymyxins are detergents, not enzyme inhibitors. (1) (2) They work by electrostatic attraction between the cationic drug and the anionic phosphate groups of lipid A, displacing calcium and magnesium and physically increasing membrane permeability. Nothing about it depends on a bacterial enzyme, which is why resistance is about changing the membrane charge rather than destroying the drug.
Gram-positive organisms are untouchable by this class. (1) The target is lipopolysaccharide in the gram-negative outer membrane. Gram-positives have no outer membrane and therefore no target at all.
Colistin is a prodrug when given systemically; polymyxin B is not. (1) (3) Colistimethate sodium is an inactive precursor that must hydrolyse to active colistin, which is why polymyxin B is preferred intravenously for faster and more reliable drug levels and lower nephrotoxicity.
Polymyxins also bind free LPS released by dying bacteria. (1) This neutralises endotoxin as well as killing the organism — a mechanistic feature unique to this class among antibacterials.
Some gram-negatives are resistant before they ever meet the drug. (2) Proteus mirabilis, Serratia marcescens, Morganella morganii, Providencia species and Burkholderia cepacia modify lipid A with L-Ara4N and phosphoethanolamine, reducing the negative charge the drug needs to bind. This is intrinsic resistance, not acquired.
mcr-1 changed the resistance picture because it sits on a plasmid. (2) (3) Chromosomal colistin resistance stays in one lineage; a plasmid gene can be transferred horizontally between gram-negative species and has been found on multiple continents.
Neostigmine does not reverse polymyxin neuromuscular blockade. (1) Cholinesterase inhibitors provide no benefit for the resulting respiratory depression; management is mechanical ventilation if apnoea develops. This distinguishes it from blockade by competitive neuromuscular blocking drugs.

Common exam traps

Trap: "Polymyxins are broad-spectrum because they are last-line agents." Actually: Last-line and broad-spectrum are different things. Polymyxins act on the gram-negative outer membrane and have no gram-positive activity at all; they are reserved because few other options remain against MDR gram-negatives. (1)
Trap: "Colistin and colistimethate are the same drug." Actually: Colistimethate sodium is an inactive prodrug that hydrolyses to active colistin. The distinction matters clinically: it is why IV polymyxin B reaches reliable levels faster than IV colistin. (1) (3)
Trap: "A gram-negative isolate should respond to colistin." Actually: Not if it is Proteus, Serratia, Morganella, Providencia or Burkholderia — these are intrinsically resistant through constitutive lipid A modification. (2)
Trap: "Polymyxin nephrotoxicity means the drug can never be restarted." Actually: Nephrotoxicity is the dose-limiting toxicity and therapy is discontinued if renal impairment develops, but the injury is a tubular one that commonly recovers after withdrawal with supportive fluid and electrolyte care. It is a monitoring problem, not an automatic permanent contraindication. (1)
Trap: "Colistin resistance is a hospital problem only." Actually: Veterinary use in pig and poultry farming dominates global colistin consumption and creates the selective pressure behind the mcr reservoir. The resistance story is an agricultural one as much as a clinical one. (3)

Self-test questions

Answers are hidden until you open them. These questions are written from this page's cited content and are for study only — they are not clinical guidance.

Which sequence correctly describes how a polymyxin kills a gram-negative bacterium?
- It inhibits lipopolysaccharide synthesis, so the outer membrane cannot be assembled
- It is transported into the cytoplasm and inhibits ribosomal protein synthesis
- The cationic drug binds the phosphate groups of anionic lipid A, displaces stabilising calcium and magnesium, and makes the outer membrane permeable
- It cross-links peptidoglycan strands, leaving a rigid wall the cell cannot expand
Show answer
Answer: The cationic drug binds the phosphate groups of anionic lipid A, displaces stabilising calcium and magnesium, and makes the outer membrane permeable
The action is physical rather than enzymatic. Electrostatic attraction pulls the positively charged molecule onto the negatively charged lipid A of lipopolysaccharide, and the divalent cations that bridge adjacent lipopolysaccharide molecules are pushed aside. The outer membrane then leaks its contents and the organism dies, a detergent-like effect that needs neither bacterial growth nor protein synthesis to work. (1)
Why does the polymyxin class have no useful activity against gram-positive organisms?
- Gram-positive bacteria have no outer membrane and therefore no lipopolysaccharide target
- The thick peptidoglycan layer of gram-positives destroys the drug enzymatically
- Gram-positive organisms pump the drug out through constitutive efflux systems
- Gram-positive ribosomes differ too much for the drug to bind them
Show answer
Answer: Gram-positive bacteria have no outer membrane and therefore no lipopolysaccharide target
Every step of the mechanism depends on lipid A sitting in an outer membrane. Organisms built without that membrane simply present nothing for a cationic detergent antibiotic to attack, so the gap is absolute rather than a matter of degree. Being reserved as a last-line agent says nothing about breadth of spectrum, and confusing the two is a common examination error. (1)
Which statement about the two systemically used polymyxins is correct?
- Both are administered as inactive prodrugs requiring hydrolysis
- Colistin is given intravenously in active form, whereas polymyxin B is the prodrug
- Colistimethate sodium is a different drug from colistin, with a different molecular target
- Polymyxin B is given in active form, while colistin is administered parenterally as the inactive prodrug colistimethate sodium
Show answer
Answer: Polymyxin B is given in active form, while colistin is administered parenterally as the inactive prodrug colistimethate sodium
Colistimethate sodium has to hydrolyse in the body before any active colistin exists, and that conversion delays and blurs the achievement of useful drug concentrations. Polymyxin B needs no such conversion, which is why it is favoured for intravenous therapy: levels arrive sooner and more predictably, and nephrotoxicity by that route is lower. (1) (3)
Which adverse effect has the highest incidence with polymyxins and constrains their use most?
- Skin hyperpigmentation
- Nephrotoxicity
- Bronchospasm
- Hypersensitivity rash and urticaria
Show answer
Answer: Nephrotoxicity
Renal toxicity is the most frequent adverse effect of the class and the reason colistin was largely abandoned after its introduction, returning to practice only when resistance closed off gentler alternatives. It can present with blood or protein in the urine, reduced urine output and, at worst, renal failure, so urea, creatinine and urine output are followed throughout treatment. Therapy is stopped if renal impairment appears, though the tubular injury commonly recovers afterwards with supportive fluid and electrolyte care. (1) (3)
A patient on a polymyxin develops neuromuscular blockade progressing towards respiratory failure. Which statement is correct?
- Neostigmine reliably reverses the blockade, as it does for competitive neuromuscular blocking drugs
- Neurotoxicity from this class is confined to paresthesia and never threatens ventilation
- Cholinesterase inhibitors are of no benefit; the drug is stopped and ventilation supported mechanically if apnoea develops
- The blockade indicates an allergic reaction and is managed with adrenaline
Show answer
Answer: Cholinesterase inhibitors are of no benefit; the drug is stopped and ventilation supported mechanically if apnoea develops
Neurological toxicity affects roughly seven in every hundred treated patients, most often as paresthesia, with dizziness, numbness, tingling and vertigo also described; mild symptoms usually settle once the drug is withdrawn. At the severe end the blockade can shut down respiration, and an anticholinesterase does nothing to reverse it — mechanical ventilation is what supports the patient if apnoea occurs. This behaviour is what distinguishes it from blockade produced by competitive neuromuscular blocking agents. (1)
A blood culture grows a gram-negative organism. Which group should not be assumed susceptible to colistin, because it is resistant before any exposure?
- Klebsiella pneumoniae and Escherichia coli
- Acinetobacter baumannii
- Pseudomonas aeruginosa
- Proteus, Serratia, Morganella, Providencia and Burkholderia
Show answer
Answer: Proteus, Serratia, Morganella, Providencia and Burkholderia
These genera constitutively decorate their lipid A with cationic substituents such as L-Ara4N and phosphoethanolamine, through the arnBCADTEF operon and the eptB gene. The resulting loss of negative charge leaves the cationic drug with nothing to bind, so resistance is built into the organism rather than acquired under pressure. Identifying the genus is therefore enough to rule the class out. (2)
Why is mcr-1 regarded as a more serious development than chromosomal colistin resistance?
- It inactivates the drug enzymatically rather than altering the membrane target
- It confers resistance to every antibiotic class simultaneously
- It sits on a plasmid and so can move horizontally between gram-negative species
- It arises only in organisms that are already carbapenem-resistant
Show answer
Answer: It sits on a plasmid and so can move horizontally between gram-negative species
Mutations in regulatory systems such as pmrAB, phoPQ or mgrB stay locked inside the lineage that acquired them. A plasmid-carried gene travels laterally instead, and mcr-1 has done so worldwide since it was first described in Escherichia coli from pigs and meat in China in November 2015, with further variants following. Agricultural use in pig and poultry farming dominates global colistin consumption and sustains the reservoir, so this is an agricultural problem as much as a hospital one. (2) (3)

Frequently asked questions

Why do polymyxins only work against gram-negative bacteria?

Their target is lipid A, part of the lipopolysaccharide found in the gram-negative outer membrane. Gram-positive organisms have no outer membrane and therefore nothing for the drug to bind, so the class is inactive against them entirely. (1)

What is the difference between colistin and colistimethate sodium?

Colistimethate sodium is an inactive prodrug that must be hydrolysed in the body to release active colistin. Polymyxin B, by contrast, is given in its active form, which is why it is preferred intravenously for faster and more reliable drug levels and lower nephrotoxicity. (1) (3)

Why are polymyxins described as last-resort antibiotics?

Because they are often the only agent still effective against multidrug-resistant gram-negative organisms, particularly carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Their nephrotoxicity had pushed them out of use until resistance removed the safer alternatives. (1) (3)

Which gram-negative organisms are naturally resistant to colistin?

Proteus mirabilis and Proteus vulgaris, Serratia marcescens, Morganella morganii, Providencia species and Burkholderia species. They constitutively modify lipid A with cationic sugars and phosphoethanolamine, reducing the negative charge the drug needs in order to bind. (2)

Why is mcr-1 such a concern?

Because it sits on a plasmid rather than the chromosome. First reported in Escherichia coli from pigs and meat in China in November 2015, it can transfer horizontally between gram-negative species and has since been found on multiple continents, with further variants described. Resistance that spreads laterally erodes a last-line class far faster than lineage-bound mutation does. (2) (3)

Can polymyxin-induced muscle weakness be reversed with neostigmine?

No. Cholinesterase inhibitors such as neostigmine provide no benefit for the respiratory depression caused by polymyxin neuromuscular blockade. Management is to stop the drug and support ventilation mechanically if apnoea develops. (1)

Why is colistin given by inhalation in cystic fibrosis?

Inhalation delivers the drug straight to the airway for chronic Pseudomonas aeruginosa lung infection, using nebulised or dry-powder colistimethate. Dry-powder colistimethate was found non-inferior to nebulised tobramycin on lung function measures. Bronchodilator pre-treatment is used because aerosolisation can cause bronchospasm. (4) (1)

References

Polymyxin (StatPearls) StatPearls Publishing / NCBI Bookshelf, 2023
Molecular mechanisms related to colistin resistance in Enterobacteriaceae Infection and Drug Resistance / PubMed Central, 2019
A Review on Colistin Resistance: An Antibiotic of Last Resort Microorganisms / PubMed Central, 2024
Colistimethate sodium powder and tobramycin powder for inhalation for the treatment of chronic Pseudomonas aeruginosa lung infection in cystic fibrosis: systematic review and economic model NIHR Journals Library, Health Technology Assessment No. 17.56 / NCBI Bookshelf, 2013