Colistin Resistance: From Laboratory Research to Modern Clinical Management

<b>Background/Objectives:</b> Colistin, a polymyxin antibiotic introduced in the mid-20th century, has regained clinical importance as a last-resort agent for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria. The global dissemination of carbapenem-resistant pathogens has intensified colistin use, leading to a concerning rise in resistance. This review aims to provide a comprehensive and up-to-date synthesis of colistin's pharmacological characteristics, resistance mechanisms, epidemiology, and current and emerging therapeutic strategies. <b>Methods:</b> A narrative review of the literature was conducted, encompassing studies on the chemistry, mechanism of action, pharmacodynamics, clinical use, dosing, and resistance to colistin. Data on chromosomal and plasmid-mediated resistance mechanisms, detection methodologies, epidemiological trends, and clinical outcomes were examined. In addition, evidence on colistin-based treatment strategies and novel non-antibiotic approaches was analyzed. <b>Results:</b> Colistin remains active against many MDR Gram-negative pathogens, including <i>Klebsiella pneumoniae</i>, <i>Pseudomonas aeruginosa</i>, and <i>Acinetobacter baumannii</i>; however, resistance is increasingly reported worldwide. Both chromosomally mediated modifications of lipid A and plasmid-mediated mcr genes contribute to resistance, with heteroresistance posing diagnostic and therapeutic challenges. Carbapenem resistance has emerged as a major driver of colistin use and subsequent resistance selection. Combination therapies, inhaled formulations, and guideline-directed use may improve outcomes, while emerging alternatives such as antimicrobial peptides, bacteriophages, nanoparticles, photodynamic therapy, and CRISPR-based technologies show promise. <b>Conclusions:</b> The escalating prevalence of colistin resistance threatens the effectiveness of this critical last-line antibiotic. Optimized use, robust resistance surveillance, accurate detection methods, and the development of innovative therapeutic strategies are essential to preserve colistin's clinical utility and address the growing burden of MDR Gram-negative infections.