Dosing guidance for intravenous colistin in critically-ill patients

Abstract

Background: Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large inter-patient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (C_ss,avg) of 2mg/L.

Methods: Plasma concentration-time data from 214 adult critically-ill patients (creatinine clearance 0-236mL/min; 29 receiving renal replacement therapy (RRT)) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based upon the relationship between the dose of colistimethate that would be needed to achieve a desired C_ss,avg and creatinine clearance. The increase in colistin clearance when patients were on RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for C_ss,avg ≥2 and <30% for C_ss,avg ≥4mg/L.

Results: When algorithm doses were applied back to individual patients not on RRT (including patients prescribed intermittent dialysis on a non-dialysis day), >80% of patients with creatinine clearance <80mL/min achieved C_ss,avg ≥2mg/L; but for patients with creatinine clearance ≥80mL/min target attainment was <40%, even with the maximum allowed daily dose of 360mg colistin base activity. For patients receiving RRT, target attainment rates were >80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained C_ss,avg ≥4mg/L.

Conclusions: The project has generated clinician-friendly dosing algorithms and pointed to circumstances where intravenous monotherapy may be inadequate.

Keywords: Intravenous colistin; critically-ill patients; dosing guidance; influence of renal impairment and renal replacement modalities; population pharmacokinetics.

Figure 1.

Steady-state plasma concentrations of colistimethate (A) and formed colistin (B) across a dosage interval in 215 critically ill patients. Patients were receiving colistimethate either every 8, 12, or 24 hours.

Figure 2.

Linear-linear (A) and log-linear (B) plots of the relationship between the daily dose of colistin base activity (CBA) needed for each 1 mg/L of the average steady-state plasma concentration of colistin (C_ss,avg) and creatinine clearance. The regression equation in panel B with the intercept adjusted from 1.667 to 1.825 is the renally based dosing algorithm (Equation 2 in Table 2).

Figure 3.

Percentage of patients in each creatinine clearance cluster achieving average steady-state plasma concentrations of colistin (C_ss,avg) of ≥0.5, ≥1, ≥1.5, ≥2, and ≥4 mg/L using the daily dose of colistimethate in Table 3 relevant to the actual creatinine clearance of each patient.