The verdict
Our read at a glance.
Whether colistin is understood as a toxic, last-resort antibiotic for multidrug-resistant Gram-negative infections, rather than a routine or broadly safe antimicrobial, and how its old, mostly non-randomized evidence base is weighed.
- The signal
- Colistin reliably kills many multidrug-resistant Gram-negative bacteria in the lab and is used clinically when other antibiotics fail, but much of its evidence is old and observational rather than from modern randomized trials, and getting the dose right is difficult.
- The unknown
- The best dosing to balance effectiveness against kidney damage, when to combine it with other antibiotics, and how fast transferable resistance (the mcr genes) will erode its usefulness.
- Our read
- An old antimicrobial peptide brought back as a last resort against drug-resistant Gram-negative superbugs. Colistin works by tearing open the bacterial membrane, but its serious kidney and nerve toxicity, awkward dosing, and largely historical evidence base make it a reserve drug, used when the alternatives have run out, and a stark reminder that the antibiotic pipeline matters.
The mechanism
How it works.
Gram-negative bacteria are wrapped in an extra outer membrane studded with a greasy, negatively charged molecule (LPS) held together by metal ions. Colistin is a ring-shaped peptide with a fatty tail and several positive charges; it latches onto that outer membrane, elbows out the stabilizing metal ions, and acts like a detergent, punching through both the outer and inner membranes. The bacterium's contents leak out and it dies. The injected form is given as an inactive prodrug (colistimethate) that slowly turns into active colistin in the body, which is part of why dosing it well is so tricky.
Safety & regulatory boundary
The consequential part.
Colistin commonly damages the kidneys and can affect the nerves and, rarely, breathing muscles, which is why it was set aside when safer antibiotics existed and why it is now reserved for serious resistant infections under specialist care. Its dosing is tricky because the injected form is an inactive prodrug. It is a last-resort hospital antibiotic, not a routine or take-home drug, and plasmid-borne resistance (mcr genes) is an emerging threat to it.
What's next
What we're watching.
Better dosing and pharmacokinetic guidance, combination strategies, the spread of mcr-mediated colistin resistance, and newer agents that could replace it for resistant Gram-negative infections.
Context
Why this is discussed.
Colistin is a 1950s antibiotic that was largely shelved for its toxicity, then revived out of necessity as resistant Gram-negative 'superbugs' outran newer drugs. It is now a real-world example of an approved antimicrobial peptide standing as one of the last lines of defense.
The evidence base
13 cited references.
Registered trials5
ClinicalTrials.gov · NA · RECRUITING · 2025-07-15
ClinicalTrials.gov · PHASE3 · RECRUITING · 2026-03-27
ClinicalTrials.gov · PHASE4 · COMPLETED · 2016-08-26
ClinicalTrials.gov · PHASE2 · NOT_YET_RECRUITING · 2026-04-01
ClinicalTrials.gov · PHASE2 · NOT_YET_RECRUITING · 2026-04
Indexed literature (PubMed)8
Kaye KS et al. · Lancet Infect Dis · 2023
Ardebili A et al. · Expert Rev Anti Infect Ther · 2023
Shields RK et al. · Clin Infect Dis · 2023
Scudeller L et al. · Int J Antimicrob Agents · 2021
Lee J et al. · Antimicrob Agents Chemother · 2025
Ungthammakhun C et al. · Int J Infect Dis · 2024
Wilson BM et al. · Clin Infect Dis · 2020
Fritzenwanker M et al. · Dtsch Arztebl Int · 2018
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