New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale

Abstract

Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

FIG 1

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 the central to lung compartments; CL_{in_CMS}, clearance of CMS from the lung to central compartments; CL_{ps_CMS}, presystemic clearance of CMS biotransformation 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_RCMS, renal clearance of CMS; CL_NRCMS, 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 2

CMS and colistin plasma concentrations (Conc.) observed (x) in 73 critically ill patients after first CMS dose and at steady state.

FIG 3

Normalized prediction distribution errors (NPDE) as a function of time and typical predictions (PRED) for CMS plasma concentrations (A), colistin plasma concentrations (B), and CMS urine concentrations (C).

FIG 4

Typical colistin plasma profiles predicted from present results (full black line), along with 90% confidence intervals (gray shaded area), from those of a healthy volunteer (full gray line) (6) and the work of Plachouras et al. (dashed black line) (2) after a single 3-MIU CMS dose administered as a 60-min infusion. The colistin plasma concentrations (Conc.) observed in the present study and normalized to a 3-MIU dose are also shown (X).

FIG 5

Colistin concentrations (Conc.) following a 3-MIU dose of CMS infused over 60 min every 8 h in a typical Plachouras patient (i.e., CL_CR, 82 ml/min, and body weight, 80 kg), predicted without a loading dose from our results (black solid line) and those of Plachouras et al. (black dashed line) (2) and Garonzik et al. (gray dashed line) (17) and with a 9-MIU loading dose from our results (gray solid line).