Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients

Abstract

Colistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS); however, differences between the intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients have not been precisely documented. In this study, CMS and colistin concentrations were measured on two separate occasions within the plasma and epithelial lining fluid (ELF) of critically ill patients (n = 12) who had received 2 million international units (MIU) of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations. The ELF colistin concentrations varied considerably (9.53 to 1,137 mg/liter), but they were much higher than those in plasma (0.15 to 0.73 mg/liter) after aerosol delivery but not after intravenous administration of CMS. Following CMS aerosol delivery, typically, 9% of the CMS dose reached the ELF, and only 1.4% was presystemically converted into colistin. PK-PD analysis concluded that there was much higher antimicrobial efficacy after CMS aerosol delivery than after intravenous administration. These new data seem to support the use of aerosol delivery of CMS for the treatment of pulmonary infections in critical care patients.

FIG 1

CMS (top panels) and colistin (bottom panels) concentrations in ELF (open squares) and plasma (filled triangles) following a single dose via aerosol or i.v. administration at steady state.

FIG 2

Structural pharmacokinetic model. V_ELF, volume of distribution in lung compartment; F_aero, fraction of the aerosol dose that reaches systemic circulation; CL_{OUT_CMS}, clearance of CMS from central to lung compartments; CL_{IN_CMS}, clearance of CMS from lung to central compartments; CL_{ps_CMS}, clearance of CMS presystemic conversion in colistin; CL_{OUT_COLI}, clearance of colistin from central to lung compartments; CL_{IN_COLI}, clearance of colistin from lung to central compartments; V_CMS, volume of distribution of CMS; CL_{R_CMS}, renal clearance of CMS; CL_{NR_CMS}, nonrenal clearance of CMS; V_COL, volume of distribution of colistin; CL_COL, total clearance of colistin; f_m, fraction of the CMS dose not excreted unchanged that is converted into colistin.

FIG 3

Observed colistin and CMS concentrations in ELF and plasma with model predictions (as medians [solid lines] and 90% prediction intervals [gray shaded areas]) using parameter estimates.

FIG 4

Time-kill curves for P. aeruginosa exposed to colistin at concentrations (Conc.) ranging from 0 to 4 mg/liter for a starting inoculum of 5 × 10⁶ CFU/ml. The results (dots and error bars) are the means and standard deviations of the results from four replicates. Included are the model predicted curves (lines) with mean parameter estimates.

FIG 5

Predicted bacterial count over time after CMS aerosol delivery (2 MIU followed by 2 MIU i.v. at 8 h and 16 h) or i.v. administration (2 MIU every 8 h). The median (solid line), 25th to 75th percentile (dark grey area), and 5th to 95th percentile (light grey area) of the predicted counts are illustrated.