Colistin
Antimicrobial / ClinicalAlso known as: Polymyxin E, Colistimethate, Coly-Mycin
Mechanism
Another last-resort antibiotic closely related to Polymyxin B, critical for fighting extremely drug-resistant gram-negative superbugs. Given as a prodrug (colistimethate sodium) that converts to active colistin in the body. Can be given IV for bloodstream infections or nebulized directly into the lungs for resistant pneumonia. Critical for XDR Acinetobacter and Pseudomonas infections.
Technical detail
Cyclic cationic lipopeptide (Polymyxin E) from Paenibacillus polymyxa var. colistinus. Same LPS-binding mechanism as Polymyxin B: displaces divalent cations from lipid A, disrupts outer membrane, inserts into inner membrane causing lysis. Key difference: administered as inactive prodrug colistimethate sodium (CMS) — sulfomethylated derivative with reduced toxicity during distribution. CMS spontaneously hydrolyzes to active colistin in vivo (variable conversion). Formulations: IV (CMS), nebulized (CMS for pulmonary infections — achieves high lung concentrations), intrathecal (for CNS infections). Active against XDR Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae (CRE). Nephrotoxicity: 30-60% incidence with IV use.
Effects
ANTIMICROBIAL MECHANISM: Cyclic lipopeptide antibiotic (polymyxin E). Binds lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria via electrostatic interaction between positively charged Dab (diaminobutyric acid) residues and negatively charged lipid A phosphate groups. This displaces divalent cations (Ca2+, Mg2+) that stabilize LPS, disrupting outer membrane integrity. Inserts fatty acyl chain into the hydrophobic domain, causing membrane permeabilization and cell death. Also has an "endotoxin-neutralizing" effect by binding free LPS (clinically relevant in Gram-negative sepsis). SPECTRUM: Gram-negative aerobes including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae (including carbapenem-resistant strains, CRE), Enterobacter spp., E. coli, Citrobacter spp. Intrinsically resistant: Proteus spp., Providencia spp., Morganella morganii, Serratia marcescens, Burkholderia cepacia complex, Neisseria spp. No Gram-positive or anaerobic activity. MIC BREAKPOINTS: CLSI (2024): Susceptible ≤2 μg/mL for P. aeruginosa and Acinetobacter. EUCAST: Susceptible ≤2 μg/mL. Resistance breakpoint >2 μg/mL. MIC creep being observed globally. RESISTANCE MECHANISMS: Chromosomal: modification of lipid A phosphate groups via phosphoethanolamine transferase (mcr genes, PmrABC, PhoPQ two-component systems) — reduces electrostatic binding affinity. Plasmid-mediated: mcr-1 through mcr-10 genes (first reported 2015, Liu et al., Lancet Infectious Diseases) — particularly concerning due to horizontal gene transfer potential. Loss of LPS (rare, seen in A. baumannii — becomes colistin-resistant but fitness-impaired). Efflux pumps (minor role). PHARMACOKINETICS: Colistin is administered as the inactive prodrug colistimethate sodium (CMS) intravenously, which is hydrolyzed to active colistin in vivo. Conversion is slow and variable (Cmax achieved 4-7 hours after CMS dose). Poor lung penetration from IV route (motivating inhaled colistin for pneumonia). Renal elimination of CMS; active colistin has minimal renal clearance. Vd ~0.34 L/kg. Half-life of CMS ~2-3 hours; formed colistin half-life ~5-7 hours. Protein binding ~50%. CSF penetration poor. NEPHROTOXICITY: Major dose-limiting toxicity. Occurs in 20-60% of patients depending on definition and risk factors (RCT data, meta-analyses). Mechanism: colistin directly damages renal tubular epithelial cells via D-amino acid oxidase and oxidative stress. Usually reversible upon discontinuation. Risk factors: concurrent nephrotoxins, pre-existing renal impairment, high trough levels, prolonged therapy, older age. NEUROTOXICITY: Less common than nephrotoxicity (2-7%). Paresthesias, dizziness, visual disturbances, confusion, neuromuscular blockade (rare but serious — can cause respiratory failure). Apneic events described historically when colistin was dosed higher than current protocols.
Practitioner Guide
CLINICAL PEARLS — INFECTIOUS DISEASE SPECIALIST PERSPECTIVE: DOSING: CMS (colistimethate sodium) dosing is confusing due to different international formulations. In US: labeled as colistin base activity (CBA). In Europe: labeled as international units (IU) of CMS. 1 mg CBA ≈ 2.4 mg CMS ≈ 30,000 IU CMS. Standard IV: Loading dose 300 mg CBA (9 million IU CMS) followed by maintenance 150 mg CBA (4.5 million IU) q12h (for CrCl ≥90 mL/min). CRITICAL: Must renally adjust. Use ABW (actual body weight) for dosing. THE LOADING DOSE IS CRITICAL — steady-state colistin concentrations take >48 hours without loading due to slow CMS→colistin conversion. Target AUC/MIC ratio >50 (emerging PK/PD target). Traditional target: Css,avg 2 μg/mL (but this associates with significant nephrotoxicity). INHALED COLISTIN: For Gram-negative pneumonia (VAP/HAP), add nebulized CMS 75-150 mg CBA q8-12h to IV therapy. Use vibrating mesh nebulizer (not jet) for optimal particle size. Administer via inline nebulizer in ventilated patients. Bronchospasm is a risk — pretreat with bronchodilator. RENAL MONITORING: Check Cr/BUN daily in ICU patients. Rise typically occurs days 5-7. Hold or reduce dose if creatinine doubles. Consider TDM (therapeutic drug monitoring) where available — target trough colistin 1-2 μg/mL (challenging to measure clinically). COMBINATION THERAPY: Almost always used in combination for serious infections. Common partners: meropenem (synergy demonstrated in vitro/animal, conflicting RCT data — AIDA trial showed no benefit of colistin + meropenem vs. colistin alone for A. baumannii BSI), rifampin (synergistic in vitro, limited clinical data), tigecycline, ampicillin-sulbactam (for Acinetobacter), fosfomycin (synergistic, increasing evidence). WHEN TO USE: Last resort for extensively drug-resistant (XDR) and pandrug-resistant (PDR) Gram-negatives. Most common scenario: CRE, CRAB (carbapenem-resistant A. baumannii), MDR P. aeruginosa. Being replaced where possible by ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, and imipenem-relebactam for CRE. Still essential for CRAB (few alternatives). AVOID if susceptibility to any less toxic agent exists. STORAGE: CMS vials at room temperature. Reconstituted solution: use within 24 hours (CMS continues hydrolyzing to colistin in solution — so freshly prepared is more controlled). Some institutions use pre-diluted continuous infusion over 24 hours.
Research Summary
TIER 1 (Gold Standard): Paul et al., 2018 (AIDA trial) — RCT comparing colistin + meropenem vs. colistin monotherapy for severe A. baumannii infections: no benefit of combination (NEJM, PMID: 29897866). Garonzik et al., 2011 — population PK model for colistin/CMS dosing (Antimicrobial Agents and Chemotherapy, PMID: 21911565). Plachouras et al., 2009 — PK of colistin after IV CMS in critically ill patients (PMID: 19721065). Nation et al., 2017 — updated dosing recommendations (Clinical Infectious Diseases, PMID: 27986673). FDA-approved 1959; Safety communications regarding nephrotoxicity. TIER 2 (Strong): Li et al., 2006 — colistin pharmacology and clinical utility review (Lancet Infectious Diseases, PMID: 17008173). Liu et al., 2016 — discovery of plasmid-mediated colistin resistance (mcr-1) (Lancet Infectious Diseases, PMID: 26603172 — landmark paper). DrugBank DB01141. Examine.com: N/A (clinical antibiotic). International Society of Anti-Infective Pharmacology consensus guidelines. TIER 3 (Moderate): Clinical experience from ID specialists managing XDR infections. ICU-based case series and cohort studies. International data: high colistin resistance rates in parts of Asia, Middle East, and South America. Surveillance data (SENTRY, EARS-Net) tracking resistance trends. WHO Essential Medicines List (Reserve category). Conference presentations at IDWeek, ECCMID. KEY FINDINGS: (1) Colistin is the last-resort agent for XDR Gram-negatives but is being displaced by newer agents where possible. (2) Loading dose is essential for timely therapeutic levels. (3) Nephrotoxicity is the main limitation — occurs in 20-60%. (4) Plasmid-mediated resistance (mcr genes) is a global emergency. (5) Combination therapy rationale is debated (AIDA trial was negative). GAPS: Optimal AUC/MIC targets in humans. Whether TDM-guided dosing improves outcomes. Optimal combination partners. How to manage mcr-positive infections. ACTIVE TRIALS: Multiple ongoing for inhaled colistin, combination regimens, and comparisons with newer agents.