Recent Research provided advances for Colistin TDM
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| Year of publication | 2024 |
| Type | Conference abstract |
| MU Faculty or unit | |
| Citation | |
| Description | Introduction: Colistin maintains its position in critically ill patients and the therapy of infections caused by multidrug-resistant Gram-negative bacteria. The increasing resistance of pathogens and the need to achieve higher plasma concentrations on the one hand and concentration-dependent nephrotoxicity and neurotoxicity on the other make colistin an antibiotic with a narrow therapeutic window. The target PK/PD parameter is the fAUC/MIC. Currently, we target colistin AUCSS,24h approximately 50 mg.h/L or css 2 mg/L. However, nephrotoxicity has been observed at concentrations only slightly higher. The defined therapeutic target is countered by the large interindividual variability of the concentrations achieved and the generally complex pharmacokinetics of colistin, which is compounded by the fact that it is administered as a prodrug. TDM appears to be a way of ensuring the safety and efficacy of treatment. However, is it available and reliable? Can it really help us? Objectives: Summarize the gaps in the TDM of colistin and summarize lessons learned from several follow-on projects that can help fill these gaps. Methods: A literature review on practical aspects of colistin TDM. Second phase: Development of a method suitable for determining colistin/CMS in plasma and TDM. Short-term stability tests of colistin and CMS. Preliminary results of a prospective, non-randomized, single-center phase IV pharmacokinetic clinical trial to assess the effect of ECMO on the pharmacokinetics of colistin and CMS (COL-ECMO2022 trial). Data are presented as mean±SD. Results: We consider the main gaps in TDM of colistin to be the unavailability of a method for the determination of colistin (and CMS) in daily practice and the lack of stability data on collected plasma samples, although general stability studies suggest that CMS is prone to spontaneous conversion to colistin. As no facility in the Czech Republic performed plasma colistin and CMS determinations, we introduced and validated a rapid LC-MS method with a total analysis time of 5 min. To fill the second gap, we conducted a short-term stability study. After 24 h at room temperature (RT), the degradation of colistin samples reached almost 10%. Similar rates of CMS conversion were observed after only 2 hours at RT. The degradation of both colistin and CMS was more significant at 37 °C. Preliminary results of the pharmacokinetic study (7 patients analyzed, 6 males, age 49±24 years, weight 94±27 kg and height 175±5 cm, creatinine clearance 1.99±1.59 ml/s/1.73 m2) show a high exposure to colistin despite the use of standard dosage. Colistin AUCSS,24h was 165±128 mg.h/L, cSS corresponds to 6.9±5.3 mg/L. Considering the variable relationship between CMS concentration and achieved colistin concentrations, the determination of colistin itself, especially trough concentration, seems to be crucial; the determination of CMS is not essential. Conclusion: There are some obstacles to introducing routine TDM, but some seem surmountable. The stability data emphasize the need for quality transport and rapid sample processing. Preliminary data from a pharmacokinetic study show significantly higher exposure to colistin despite standard dosage. Real-time TDM appears to be a fundamental condition for the rational use of colistin. |
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