Mechanism of Action
LPS Disruption (Same as Polymyxin B)
Colistin has the identical mechanism to polymyxin B: Dab residues bind lipid A phosphates, displacing membrane-stabilizing divalent cations, followed by outer membrane permeabilization and inner membrane disruption by the lipid tail insertion. The mechanism is bactericidal through rapid membrane depolarization and loss of cytoplasmic contents. The Gram-negative selectivity is absolute, Gram-positive bacteria lack LPS outer membrane structure and are intrinsically resistant.
MCR Resistance Mechanism
The mcr-1 gene (and subsequent mcr-2 through mcr-9) encodes a phosphoethanolamine (PEA) transferase that adds PEA to lipid A phosphate groups, reducing the net negative charge of the LPS. This reduces colistin binding affinity by reducing electrostatic attraction. MCR genes are on mobile plasmids that can transfer between Enterobacteriaceae species, raising the nightmare scenario of combining colistin resistance with carbapenem resistance (creating truly pan-resistant bacteria). MCR strains have been isolated from human patients globally since 2015.
Research Summary
CRE Last-Resort Treatment
FDA ApprovedColistin (or polymyxin B) combined with fosfomycin, meropenem (high-dose extended infusion), or rifampicin represents the standard of care for carbapenem-resistant K. pneumoniae and CRE infections. SYNERGY trial data supports combination over monotherapy for mortality outcomes, despite the toxicity. For MCR-positive strains without other resistance, colistin retains activity and should still be used, MCR alone does not fully abrogate killing, just raises MIC.
MCR Global Emergence (2015-Present)
Emerging Resistance CrisisLiu et al. (2015) identified mcr-1 in animal-source E. coli in China, rapidly followed by global detection in food animals, food products, and clinical isolates in over 50 countries. The plasmid-borne nature allows rapid spread. WHO designated MCR resistance as a critical priority resistant organism. Surveillance programs track MCR prevalence; fortunately, clinical outcomes in MCR-positive infections have not yet been catastrophically different from susceptible strains when combination therapy is used, but the trend is alarming.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| CRE/MDR Gram-negative (IV) | Loading: 9 MIU CMS; Maintenance: 3-4.5 MIU every 8h | Every 8-12 hours | IV (as colistimethate) |
| Inhaled (VAP) | 1-2 MIU every 8 hours | Every 8 hours | Nebulized inhalation |
Dosing as colistimethate (CMS); requires conversion factor to colistin base activity (CBA). TDM recommended.
Interactions
Safety Profile
Nephrotoxicity (AKI in 40-60%) and neurotoxicity (dizziness, paresthesias, respiratory muscle weakness) are the primary dose-limiting toxicities. CMS prodrug has more predictable PK than polymyxin B for IV use. TDM is recommended where available. The risk/benefit equation strongly favors use in life-threatening pan-resistant infections despite significant toxicity. Inhaled colistin for VAP has lower systemic exposure and better tolerability.
References
- [1]Liu YY, et al. (2016). Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis, 16(2), 161-168.
- [2]Tsuji BT, et al. (2019). International consensus guidelines for the optimal use of the polymyxins: endorsed by the American College of Clinical Pharmacy (ACCP). Pharmacotherapy, 39(1), 10-39.