Clinical outcomes of colistin methanesulfonate sodium in correlation with pharmacokinetic parameters in critically ill patients with multi-drug resistant bacteria-mediated infection: A systematic review and meta-analysisoa mark
Background: Colistin is a viable option for multidrug resistant gram-negative bacteria emerged from inappropriate antibiotic use. Nonetheless, suboptimal colistin concentrations and nephrotoxicity risks hinder its clinical use. Thus, the aim of this study is to investigate clinical outcomes in correlation with pharmacokinetic differences and infection types in critically ill patients on intravenous colistin methanesulfornate sodium (CMS). Methods: A systematic literature search of Embase, Google Scholars, and PubMed was performed to identify clinical trials evaluating pharmacokinetic parameters along with clinical outcomes of CMS treatment from inception to July 2023. The pooled analyses of clinical impact of CMS on nephrotoxicity, mortality, clinical cure, and colistin concentration at steady state (Css,avg) were performed. This study was registered in the PROSPERO (CRD 42023456120). Results: Total of 695 critically ill patients from 17 studies were included. The mortality was substantially lower in clinically cured patients (OR 0.05; 95% CI 0.02 – 0.14), whereas the mortality rate was statistically insignificant between nephrotoxic and non-nephrotoxic patients. Inter-patient variability of pharmacokinetic parameters of CMS and colistin was observed in critically ill patients. The standard mean differences of Css,avg were statistically insignificant between clinically cure and clinically failure groups (standard mean difference (SMD) −0.25; 95% CI −0.69 – 0.19) and between nephrotoxic and non-nephrotoxic groups (SMD 0.67; 95% CI −0.27–1.61). The clinical cure rate is substantially lower in pneumonia patients (OR 0.09; 95% CI 0.01 – 0.56), and pharmacokinetic parameters pertaining to microbiological cure were different among strains. Conclusion: The mortality rate was substantially lower in clinically cured patients with CMS. However, no significant differences in Css,avg of colistin were examined to determine the impact of pharmacokinetic differences on clinical outcomes including mortality rate and nephrotoxicity risk. Nevertheless, the clinical cure rate is substantially lower in patients with respiratory infection than patients with urinary tract infection.
This study was supported by National Research Foundation Korea, funded by Ministry of Education (2021R1I1A1A01044500) and Ministry of Science and ICT (2021R1C1C1003735), and Ministry of Food and Drug Safety in 2023 (21153MFDS 601). Y.J. Choi received funds from Ministry of Education and Ministry of Food and Drug Safety. S. Shin received funds from Ministry of Science and ICT.This study was supported by National Research Foundation Korea, funded by Ministry of Education (2021R1I1A1A01044500) and Ministry of Science and ICT (No. 2021R1C1C1003735), Mistry of Food and Drug Safety in 2023 (No. 21153MFDS 601), and Kyung Hee University in 2022 (KHU-20222123)This study was supported by National Research Foundation Korea, funded by Ministry of Education [grant number 2021R1I1A1A01044500] and Ministry of Science and ICT [grant number 2021R1C1C1003735], and Ministry of Food and Drug Safety in 2023 [grant number 21153MFDS 601].