Estimation of the Difference in Colistin Plasma Levels in Critically Ill Patients with Favorable or Unfavorable Clinical Outcomes

Abstract

In recent decades, antimicrobial resistance (AMR) has led to an increased use of therapeutic alternatives. Among these options, colistin continues to be an option for the treatment of multi-resistant (MDR) Gram-negative bacterial infections. However, due to its high toxicity (nephrotoxicity and neurotoxicity) and narrow therapeutic window, colistin treatment must be utilized carefully. Colistin-treated patients have been observed to have higher mortality due to inadequate therapeutic levels. The objective of this study was to estimate the difference in colistin plasma levels in critically ill patients, and its relationship to favorable or unfavorable clinical outcomes. This prospective observational study was conducted between September 2017 and June 2020 at the Universidad de La Sabana Clinic, in patients who had been treated with colistimethate sodium (CMS) for at least 72 h until day 7 of drug treatment in the critical care unit of a university hospital. There were no statistically significant differences in colistin levels between groups with favorable or unfavorable clinical outcomes (0.16 SD vs. 0.54 SD p-value = 0.167). There was higher mortality in patients with subtherapeutic levels (18% vs. 0%), and additionally, there was a greater rate of renal failure in the group with higher therapeutic levels (50% vs. 20.7%). Due to the loss of power of the study, we were unable to demonstrate a possible difference between colistin levels related to favorable or unfavorable clinical outcomes at day 7. However, we recommend further studies to evaluate the impact of measuring levels in terms of mortality and security.

Challenges of Colistin Use in ICU and Therapeutic Drug Monitoring: A Literature Review

“…The omission of a loading dose substantially delays the achievement of therapeutic levels and can be the reason for a suboptimal clinical response [ 39 , 57 , 87 ]. Future studies, including the pharmacokinetic profile of CMS and colistin and defined clinical markers of efficacy and safety, may clarify and update the target PK/PD parameters and confirm the relationship between colistin plasma levels and the effectiveness and safety of the therapy [ 86 ]. The key to this is the implementation of TDM into routine clinical practice, including a validated method suitable for the daily determination of such a specific substrate and taking into account all the above-mentioned limitations.…”

“…TDM is a useful tool for guaranteeing drug safety and efficacy, especially for agents with a narrow therapeutic window and the expected correlation between efficacy or safety and plasma concentration. Colistin fulfills these conditions, and its physicochemical properties allow us to anticipate changes in plasma concentrations in critically ill patients alone or with concomitant extracorporeal methods such as RRT and ECMO [ 86 ]. There are only a few papers available on the real impact of extracorporeal methods on colistin pharmacokinetics.…”

“…Another limitation of colistin TDM is the issue of its actual target concentration. Although the PK/PD parameter is defined, most of the available data are insufficient to fully confirm the relationship between plasma levels and the efficacy and safety of colistin treatment [ 86 ].…”