Evaluation of Pharmacokinetic and Pharmacodynamic Properties of Intravenous Colistimethate Sodium

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.

Inclusion Criteria:

- Patients ≥ 18 years old receiving intravenous colistimethate sodium for the treatment
of infection

- Have cystic fibrosis and/or are critically ill (admitted to a critical care unit)

Exclusion Criteria:

- Pregnancy

- Breastfeeding

- Prisoners