Colistin Dosing Recommendations and Formulary Guidelines

Colistin is a polymyxin antibiotic administered as the prodrug colistimethate. Due to poor pharmacokinetics, administration of colistin intravenously is only recommended for urinary tract infections or as inhalation therapy for multi-drug resistant bacteria.1 Polymyxin B is the preferred agent from this class for most systemic infections. After being originally introduced in the late 1950’s, colistin’s association with adverse effects including nephrotoxicity and neurotoxicy led to a decline in use.2-4 There has been a resurgence in use of the polymyxin class of antibiotics driven by the increasing prevalence of difficult-to-treat multi-drug resistant (MDR) Gram-negative pathogens (e.g. P. aeruginosa, Acinetobacter sp., and carbapenem-resistant Enterobacteriaceae).

While optimal colistin dosing is not entirely clear, international guidelines have been published to clarify best practices.1 Initial experiences with the drug occurred before the advent of modern pharmacokinetics, pharmacodynamics, and toxicodynamics. Thus only limited dosing data exists.5-8 To complicate the matter, vials are labeled colistimethate for injection but the strength of all FDA-approved products in the US are dosed in terms of colistin base, not the prodrug colistimethate.9 International units are often referred to in literature from around the world. This regularly leads to confusion in clinical practice and represents a potential for medication errors as highlighted in a recent alert from the National Coordinating Council on Medication Error Reporting and Prevention.10

Colistin dose conversion:

  1. 12,500 IU = 1 mg of colistimethate
  2. 2.67 mg colistimethate = 1 mg colistin base
  3. Thus 2 million IU = 160 mg colistimethate = 60 mg colistin base

Due to the unique place colistin holds in the antibiotic armamentarium as salvage therapy for patients infected with multi-drug resistant Gram-negative pathogens, plus the complexities of dosing and significant toxicity risk, the following recommendations to its use are recommended:

Restrictions:

  1. Colistin use will be restricted to Infectious Disease and Pulmonary Services
    1. Applies to both intravenous and inhaled formulations
    2. Use by other services requires formal consultation by Infectious Disease or Pulmonary
      1. The drug will be dispensed for 24 hours only unless one of those groups has been formally consulted and approved the use
  2. Colistimethate orders at Nebraska Medicine are placed for “colistin” as base activity
    1. Example: Colistin (base) 150 mg IV divided q12h

Suggested Dosing Guidelines 1, 7, 12

  1. Intravenous with normal renal function:
    1. Use loading dose of 300mg IV; start maintenance dose 12h after loading dose 
      CrCl (mL/min) Dose
      >90 180mg q12h
      80 to <90 170mg q12h
      70 to <80 150mg q12h
  2. Intravenous with abnormal renal function
    1. Use loading dose of 300 mg IV; start maintenance dose 24 hours after loading dose in patients with CrCl≤40 ml/min
    2. Doses <300 mg may be given q24h 
      CrCl (mL/min) Dose
      60 to <70 275 mg/d
      50 to <60 245 mg/d
      40 to <50 220 mg/d
      30 to <40 195 mg/d
      20 to <30 175 mg/d
      10 to <20 160 mg/d
      5 to <10 145 mg/d
      0 130 mg/d
  3. Intravenous dosing for patients on renal replacement therapy
    1. HD: 130mg/d + 50 mg on dialysis days after typical 4-hr HD
      1. 40mg supplemental if 3-hr HD session instead
    2. CRRT: 220mg q12h
    3. Sustained low-efficiency dialysis (SLED)
      1. Usual dose per CrCL (typically 130mg/d) + 10%/hr.
        1. E.g. 10 hr nocturnal dialysis requires 130mg supplemental dose
  4. Inhalation Dosing: 8, 11, 12 Inhaled colistin base should not be used as monotherapy for pneumonia, but may be the sole treatment of tracheobronchitis or colonization with MDR bacteria (pulmonary exacerbation of cystic fibrosis). It should be combined with an IV antimicrobial agent for serious infections. IV colistin can be used in conjunction with inhaled colistin given that the inhaled drug is not substantially absorbed systemically.
    1. Adults: 75 mg or 150 mg colistin base inhaled q12h
      1. For ventilator-associated pneumonia: 150mg q8h may be used 13
    2. Children <13 years of age: 30 mg or 75 mg colistin base inhaled q12h

References:

  1. Tsuji BT, Pogue JM, Zavascki AP, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019 Jan;39(1):10-39. doi: 10.1002/phar.2209.
  2. Lim L, et al. Pharmacotherapy 2010;30(12):1279–1291)
  3. Hartzell JD, et al. Clin Infect Dis. 2009 Jun 15;48(12):1724-8.
  4. Molina J, et al. Expert Opin Pharmacother 2009;10:2811–28.
  5. Markou N, et al. Clin Ther. 2008 Jan;30(1):143-51.
  6. Plachouras D, et al. Antimicrob Agents Chemother. Aug. 2009, p. 3430–3436
  7. Garonzik SM, et al. Antimicrob Agents Chemother. 2011 Jul;55(7):3284-94.
  8. Ratjen F, et al. J Antimicrob Chemother 2006; 57: 306–311
  9. Monarch Pharmaceuticals, Inc. 5/2009. Colistimethate. Package Insert. Monarch Pharmaceuticls, Inc. Bristol, TN
  10. https://www.nccmerp.org/sites/default/files/NANAlertJune2011.pdf
  11. Rattanaumpawan P, et al. J Antimicrob Chemother 2010; 65: 2645–2649
  12. Kofteridis DP, et al. Clinical Infectious Diseases 2010; 51(11):1238–1244
  13. https://www.medscape.com/viewarticle/848388