Ineffectiveness of carbapenems in real-world clinical practice according to therapeutic drug monitoring data and Roszdravnadzor AIS reports

Abstract

Relevance. The use of carbapenems is associated with significant variability in pharmacokinetics/pharmacodynamics (FC/PD) parameters, particularly in critically ill patients. The combination of variability in these parameters and standardized dosing regimens can lead to irrational dosing, excessively high or low doses, and consequently less effective treatment and resistance. Optimal management of these factors is essential for combating the development of resistance, particularly for reserve antibiotics.The aim of this study was to evaluate the achievement of the target levels of carbapenems (imipenem/cilastatin) in plasma concentrations in patients with burn injury based on therapeutic drug monitoring and to analyze spontaneous reports registered in the AIS Roszdravnadzor database regarding the effectiveness of therapy.Methods. The analysis included patients receiving antibiotic therapy with imipenem/cilastatin in the burn unit for adults at the University Hospital of the Volga Region Research Medical University for burn trauma who were hospitalized from 01.03.2023 to 30.06.2023. The study was conducted without correcting the trade name of imipenem/cilastatin. Therapeutic drug monitoring was performed after the 4th administration of imipenem/cilastatin. Blood was drawn at 3 h (1st sample), 5 h (2nd sample), and 8 h (3rd sample) after infusion in a clotting activator tube. The analysis was performed using a liquid chromatograph "LC-20 Prominance" (Shimadzu, Japan) in reversed-phase mode with a matrix photodiode detector for UV and visible spectra. Data processing was performed using the LCsolution program. Spontaneous reports regarding the use of carbapenems recorded in the AIS of Roszdravnadzor from January 2020 to November 2023 were also analyzed as the object of the study.Results. The results of the study of carbapenems (imipenem/cilastatin) concentration level achievement in the plasma of patients with burn injury showed that the effective imipenem concentration exceeding the MPC value in relation to the isolated Gram-negative pathogen was found only in 1 out of 5 patients included in the study. Two patients showed dynamically changing IPC values during treatment, indicating the necessity of therapeutic drug monitoring, as well as the probability of failure to achieve target concentrations and optimal FC/FD values. In another two patients, imipenem concentrations were insufficient to maintain optimal FC/PD values, indicating that the antimicrobial regimen was ineffective. An analysis of spontaneous reports registered in the AIS of Roszdravnadzor regarding identified cases of the ineffectiveness of carbapenems (imipenem/cilastatin, meropenem) revealed 5,2% of reports regarding meropenem and 1.4% regarding imipenem/cilastatin in the total structure of reports.Conclusion. The implementation of therapeutic drug monitoring procedures can reduce therapy ineffectiveness and antibiotic resistance through personalized antimicrobial dosing.