Colistin (Polymyxin E)

 Introduction

Last-line therapy (bactericidal) for multidrug-resistant (MDR) gram-negative infections.

  • Carbapenem-resistant Enterobacterales (CRE)
  • MDR Acinetobacter
  • MDR Pseudomonas
  • XDR gram-negative infections

Why only Gram-negative?

Because Gram-positive bacteria lack an outer LPS membrane.


Formulation

  • Available in two forms:
    • Colistin sulfate (topical/oral – not systemic)
    • Colistimethate sodium (CMS) – IV/inhalational form (prodrug)


IV colistin = Colistimethate sodium (CMS), which converts in vivo to active colistin.

This conversion is slow and incomplete → important pharmacokinetic implications.



 Spectrum of Activity

Active Against:

  • Carbapenem-resistant Enterobacterales (CRE)
  • ESBL producers
  • MDR Acinetobacter baumannii
  • MDR Pseudomonas aeruginosa
  • Some Klebsiella species

Not Active Against: Intrinsic resistance due to LPS modification.

  • Gram-positive organisms
  • Anaerobes
  • Proteus
  • Serratia
  • Morganella
  • Burkholderia cepacia
  • Providencia


 Pharmacokinetics 

1️⃣ Prodrug Nature

IV CMS → slowly hydrolyzed to active colistin.

  • Slow conversion
  • Delayed therapeutic levels
  • Hence loading dose mandatory
  • Colistin exhibits concentration-dependent killing


2️⃣ Distribution

  • Moderate tissue penetration
  • Poor CSF penetration
  • Limited lung epithelial lining fluid penetration (better with nebulized)


3️⃣ Elimination

  • CMS → Renal excretion
  • Active colistin → Non-renal elimination

Thus:

  • Renal impairment increases active colistin levels
  • High risk nephrotoxicity


 Dosing 

  • Million International Units (MIU)
  • mg of colistin base activity (CBA)

1 MIU ≈ 80 mg CMS ≈ 30 mg colistin base

Step

Recommendation

Renal impairment

Reduce maintenance, not loading

CRRT

Higher maintenance often needed

 Infusion

30–60 minutes IV infusion


 Loading dose should NOT be reduced in renal failure.Why?

Because:

  • Loading dose depends on volume of distribution
  • Not on clearance
  • Needed to achieve therapeutic plasma levels quickly

Maintenance dose → adjust according to CrCl.


 Adverse Effects 

1️⃣ Nephrotoxicity (Most Important)

Mechanism:Acute tubular necrosis

Usually reversible.

Adjust for renal function
Monitor creatinine every 48 hrs

2️⃣ Neurotoxicity

  • Paresthesia
  • Dizziness
  • Neuromuscular blockade
  • Respiratory depression (rare)

 May potentiate muscle relaxants (important in ICU/OR).


3️⃣ Electrolyte disturbances

  • Hypomagnesemia
  • Hypokalemia


 Resistance Mechanisms

  1. Modification of LPS
  2. mcr-1 gene (plasmid mediated)
  3. Adaptive resistance in heteroresistant populations

mcr gene → transferable colistin resistance → global concern.