Colistin

Background

• A member of the polymyxin class also known as polymyxin E
• Active against most gram-negatives except for Proteus species and several others (see Resistance, below)
• Currently reserved for resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae

Mechanism of Action

• Given as a prodrug, which is converted in vivo into the active drug (compared to polymixin B, which is given in its active form)
• Disrupt membranes by interacting with membrane phospholipids to displace divalent cations
• Also bind lipid A in the cell wall lipopolysaccharide

Mechanisms of Resistance

• Conferred by alterations in lipid A, either reducing its charge or eliminating it altogether
• May be chromosomal (e.g. pmrC, pmrF, pmrAB, lpxA, lpxC, lpxD, OprH) or plasmid-mediated (e.g. mcr-1 gene)

Spectrum of Activity

• Broadly active against Gram-negative bacteria, including Enterobacterales and afermentative Gram-negative bacilli
• Not active against Gram-positive bacteria, given that they don't have lipopolysaccharide
• Resistance often seen in:
  • Brucella
  • Burkholderia
  • Inquilinus limosus
  • Morganellaceae (Proteus, Providencia, Morganella)
  • Neisseria
  • Pandoraea
  • Serratia

PK/PD

• Concentration-dependent activity
• Poor distribution into pleural fluid, joints, and CSF

Dosing

Intravenous Dosing

• Dosing is a mess, with a number of different units used by different people, despite having a standardized international unit, usually in millions (MIU)
  • 1 MIU = 80 mg colistimethate (CMS) in Europe
  • 1 MIU = 30 mg colistin base activity (CBA) in the US
• For European dosing, using IU of CMS:
  • Weight ≤60 kg: 50-75 kIU/kg/day divided q8h
  • Weight >60 kg: 1-2 MIU q8h, dose-adjusted to q12-18h for CrCl 10-20 and q18-24h for CrCl <10
• For US dosing, using mg of CBA:
  • 2.5-5 mg/kg ideal body weight daily divided q12h to q6h
  • E.g. 300 mg CBA (10 IU) daily for a 60 kg patient, compared to 3 to 4.5 MIU daily in Europe
• Critically ill patients may benefit from a loading dose of 300 mg CBA followed by regular maintanance dosing in 12 to 24 hours
• Per Mandell:
  • 5 mg CBA/kg IBW as loading dose (max 300 mg) followed by 5 mg CBA/kg IBW daily divided q8h
  • Maintenance is renally adjusted to 3.5 mg/kg/day divided q12h for CrCl 30-49, 2.5 mg/kg/day divided q12h for CrCl 10-29, and 1.5 mg/kg q24h for CrCl <10 or hemodialysis

Intrathecal Dosing

• Exists.

Safety

Adverse Effects

• Prominent and common nephrotoxicity, which is dose-related and usually reversible
• Rarely, neuromuscular blockage, which can cause weakness and apnea
• Other neurological effects include peripheral paresthesia, tingling of tongue, dizziness, vertigo, blurred vision, slurred speech, ataxia

Further Reading

• International Consensus Guidelines for the Optimal Use of the Polymyxins. Pharmacotherapy. 2019;39(1):10-39. doi: 10.1002/phar.2209