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

Abstract

The emerging resistance of Gram-negative bacteria is a growing problem worldwide. Together with the financial cost, limited efficacy, and local unavailability of newer antibiotics or their combinations, it has led to the reintroduction of colistin as a therapeutic alternative. Despite its protracted development and availability on the market, there is now a complex maze of questions surrounding colistin with a more or less straightforward relationship to its safety and efficacy. This review aims to offer a way to navigate this maze. We focus on summarizing the available literature regarding the use of colistin in critically ill patients, particularly on stability, pharmacokinetics, methods for determining plasma concentrations, and therapeutic drug monitoring benefits and limitations. Based on these data, we then highlight the main gaps in the available information and help define directions for future research on this drug. The first gap is the lack of data on the stability of intravenous and nebulization solutions at clinically relevant concentrations and under external conditions corresponding to clinical practice. Furthermore, pharmacokinetic-pharmacodynamic parameters should be validated using standardized dosing, including a loading dose. Based on the pharmacokinetic data obtained, a population model for critically ill patients should be developed. Finally, the interference of colistin with extracorporeal methods should be quantified.

An evolution of therapies to treat sepsis caused by carbapenem-resistant Enterobacteriaceae (CRE)

“…The ring structure contains alternating D-and L-amino acids, and its sidechain is covalently bonded to a fatty acid via the acyl group (Figure 7) [26]. With five diaminobutyrate residues attached to the ring structure, free amines can give the molecule an overall positive charge at the physiological pH (around 7.4) [27]. The ionic property in addition to its polar functional groups all contributes to colistin's water solubility: the polar groups, such as amino and carboxyl groups, interact with water molecules through hydrogen bonding, whereas the positively charged molecules improve solubility by interacting with negatively charged oxygen atoms in water molecules.…”

“…This remodeling is driven by changes in two-component regulatory systems, PhoPQ and PmrAB. The alterations in these systems lead to a less anionic lipid A, which reduces the interaction with colistin [27][28][29][30]. They do so by adding ethanolamine to the lipid A region of LPS, which makes the bacterial membrane less negatively charged, reducing its binding to positively charged colistin.…”

At the Intersection of Critical Care and Infectious Diseases: The Year in Review

“…In addition, the optimal dosing paradigm remains unclear. Although various simulations and pharmacokinetic analyses suggest potential optimized regimens, no RCT-based evidence truly supports the currently recommended doses for these agents [ 47 ]. Finally, these antibiotics are major nephrotoxins.…”

Sepsis Stewardship: The Puzzle of Antibiotic Therapy in the Context of Individualization of Decision Making

“…Colistin, with a known nephrotoxic potential and a narrow therapeutic index, was formerly recommended in antibiotic therapy association schemes to treat carbapenemaseproducing GNB or Pseudomonas aeruginosa MDR, but the availability of the new BL-BLI and the growing increase in resistance to colistin due to its use in recent years have contributed to this practice being advised against. Currently, colistin is practically relegated to the treatment of Acinetobacter baumannii infections and for those cases of resistance or intolerance to the new BL-BLI [62].…”