Evaluation of Pharmacokinetic and Pharmacodynamic Properties of Intravenous Colistimethate Sodium
Condition: Colistin
MeSH terms: Cystic Fibrosis
Study type: Observational

Summary: 
      Colistin is a polymixin antibiotic used in the treatment of multidrug-resistant gram-negative
      infections. Given the limited use of colistin and previous challenges with laboratory assays
      to determine plasma concentrations, there is a lack of knowledge of the pharmacokinetic
      profile of colistin. The purpose of the investigators observational prospective
      pharmacokinetic cohort study is to examine the steady-state pharmacokinetic and
      pharmacodynamic properties of intravenous colistimethate sodium in cystic fibrosis and
      critically ill patients.
    

Detailed description: 
      Colistin, also known as polymixin E, is a peptide antibiotic that demonstrates
      concentration-dependent bactericidal killing against gram-negative pathogens including
      Pseudomonas and Acinetobacter. Originally discovered in the 1950s, its use has been limited
      due to the concern for its systemic toxicities including nephrotoxicity and neurotoxicity.
      However, a revival of colistin use has been seen in recent years due to the increased
      emergence of multidrug-resistant (MDR) gram-negative pathogens and a lack of alternative
      antimicrobial therapies.

      Colistin is administered intravenously as colistimethate sodium (CMS), an inactive prodrug
      that lacks antibacterial activity, and is hydrolyzed into its active form in plasma as
      colistin A and colistin B. Prior pharmacokinetic studies have demonstrated a wide range of
      pharmacokinetic/pharmacodynamics (PK/PD) findings for colistin. Variability in results have
      been attributed to an unreliable differentiation between colistin and CMS plasma
      concentrations with the use of microbiological assays, in addition to procedures that
      resulted in substantial in vitro hydrolysis of CMS to colistin during sample preparation.
      Refined laboratory methods such as high-performance liquid chromatography (HPLC) have
      circumvented such issues and provided opportunities for further pharmacokinetic profiling.

      Given the scarcity of its use and challenges with quantitative assays, the pharmacokinetic
      and pharmacodynamic profile of colistin has been poorly characterized particularly amongst
      cystic fibrosis and critically ill patients. Determination of such parameters in these
      patient populations is vital to optimize the maximum concentration to minimum inhibitory
      concentration (Cmax:MIC) ratio for maximal efficacy, minimize adverse effects and to reduce
      the development of bacterial resistance. Previous studies examining the steady-state
      pharmacokinetics of colistin in cystic fibrosis and critically ill patients have concluded
      that based on the in vitro pharmacodynamics against Pseudomonas aeruginosa, current dose
      recommendations may be inadequate to achieve desirable Cmax:MIC ratios and dose escalations
      may be warranted.

      The investigators study aims to determine steady-state colistin A and colistin B
      concentrations in cystic fibrosis and critically ill patients, evaluate pharmacodynamic
      parameters and relationship to microbiologic success, and monitor for the incidence of
      nephrotoxicity. The findings of this pilot study will be used to develop dosing
      recommendations for future pharmacokinetic studies of colistimethate sodium in cystic
      fibrosis and critically ill patients.
    

Intervention name(s): colistimethate sodium
Intervention type(s): Drug
Other intervention name(s): colistin; CMS
Intervention MeSH terms: Colistin
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Inpatients at the University of Colorado Hospital
      
Biospecimen description: 
      Plasma
    
Keywords: pharmacokinetics; cystic fibrosis; critical illness