Resurgence of Colistin: A Review of Resistance, Toxicity, Pharmacodynamics, and Dosing

Abstract

Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram-negative infections. After several years of clinical use, its popularity diminished because of reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last-line treatment option for multidrug-resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram-negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA-PmrB and PhoP-PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last-line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

“…Of increasing concern is the emergence of colistin resistance among Gram-negative bacteria. Colistin is often considered an antibiotic of "last resort, " and colistin-resistance is typically accompanied by high levels of resistance to other antibiotics [62,63] because colistin is peptide based and cationic, similar to AMPs, it is possible that colistin resistance translates into resistance to AMPs and ceragenins.…”

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

“…However, since levels of resistance to most available classes of antibiotics have been rapidly increasing in Gram-negative bacteria, there has been a resurgence of interest in polymyxins over the last decade. [4][5][6] Polymyxins have retained excellent activity against these multi-drug resistant (MDR) pathogens although a recent report of plasmid-mediated resistance is potentially worrisome. 7,8 Two forms of polymyxin are currently in use for systemic infections: colistin methane sulfonate and polymyxin B (PMB).…”

Intravenous polymyxins: Revival with puzzle

“…Colistin sulfate is for oral and topical use, while CMS is for parenteral and aerosol therapy; both forms may be given by inhalation (4)(5)(6)(7)(8)(9). CMS is hydrolyzed to colistin, which is the base component responsible for its antibacterial activity (10), and is less toxic than colistin sulphate (11). While colistin is more stable than colistimethate in human plasma (12).…”