Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria.

A N Kristoffersson, V Rognås, M J E Brill, Y Dishon-Benattar, E Durante-Mangoni, V Daitch, A Skiada, J Lellouche, A Nutman, A Kotsaki, R Andini, N Eliakim-Raz, R Bitterman, A Antoniadou, M O Karlsson, U Theuretzbacher, L Leibovici, G L Daikos, J W Mouton, Y Carmeli, M Paul, L E Friberg

Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 2021;26(12):1644-1650

PMID: 32213316

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Abstract

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.

Address: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.; Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel; The Cheryl Spencer Institute for Nursing Research, University of Haifa, Israel.; Department of Precision Medicine, University of Campania 'L Vanvitelli' and AORN dei Colli-Monaldi Hospital, Napoli, Italy.; Infectious Diseases University Research Centre, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, and Department of Medicine E, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel.; First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece.; National Centre for Infection Control and Antibiotic Resistance, Tel Aviv Medical Centre, Tel Aviv, Israel; National Laboratory for Antibiotic Resistance and Investigation of Outbreaks in Medical Institutions, Tel Aviv Medical Centre, Tel Aviv, Israel.; National Centre for Infection Control and Antibiotic Resistance, Tel Aviv Medical Centre, Tel Aviv, Israel.; 4th Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, University General Hospital Attikon, Athens, Greece.; Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Techion - Israel Institute of Technology, Haifa, Israel.; Centre for Anti-Infective Agents, Vienna, Austria.; Sackler Faculty of Medicine, Tel-Aviv University, and Department of Medicine E, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel; Department of Medicine E, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel.; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands.; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. Electronic address: [email protected].

DOI: 10.1016/j.cmi.2020.03.016

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MeSH Terms: Anti-Bacterial Agents, Bacteria, Carbapenems, Colistin, Critical Illness, Drug Resistance, Bacterial, Gram-Negative Bacterial Infections, Humans