Τίτλος:
Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Objectives: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. Methods: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis. Results: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14–1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03–1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19–1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. Discussion: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival. © 2020 The Authors
Συγγραφείς:
Kristoffersson, A.N.
Rognås, V.
Brill, M.J.E.
Dishon-Benattar, Y.
Durante-Mangoni, E.
Daitch, V.
Skiada, A.
Lellouche, J.
Nutman, A.
Kotsaki, A.
Andini, R.
Eliakim-Raz, N.
Bitterman, R.
Antoniadou, A.
Karlsson, M.O.
Theuretzbacher, U.
Leibovici, L.
Daikos, G.L.
Mouton, J.W.
Carmeli, Y.
Paul, M.
Friberg, L.E.
Περιοδικό:
Clinical Microbiology and Infection
Λέξεις-κλειδιά:
carbapenem; colistin; colistin methanesulfonate sodium; creatinine; prodrug; unclassified drug; antiinfective agent; carbapenem derivative; colistin, Acinetobacter; antibiotic sensitivity; Article; carbapenem resistance; clinical trial; controlled study; creatinine clearance; critically ill patient; death; drug blood level; drug clearance; drug dose reduction; Gram negative infection; hemodialysis; human; kidney function; loading drug dose; major clinical study; minimum inhibitory concentration; morning dosage; pharmacokinetic parameters; priority journal; Pseudomonas; Pseudomonas aeruginosa; randomized controlled trial; Sequential Organ Failure Assessment Score; survival; survival analysis; antibiotic resistance; bacterium; blood; critical illness; drug effect; Gram negative infection; microbiology; mortality, Anti-Bacterial Agents; Bacteria; Carbapenems; Colistin; Critical Illness; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans
DOI:
10.1016/j.cmi.2020.03.016
