From the Guidelines
Colistin, also known as polymyxin E, is an antibiotic that works by disrupting bacterial cell membranes, primarily targeting gram-negative bacteria by binding to lipopolysaccharide (LPS) molecules in their outer membrane, and its use is recommended with caution due to potential resistance mechanisms and side effects, as highlighted in recent studies 1.
Mechanism of Action
The mechanism of action of colistin involves binding to LPS molecules in the outer membrane of gram-negative bacteria through electrostatic interactions between its positively charged peptide rings and the negatively charged phosphate groups of lipid A in LPS. This binding displaces calcium and magnesium ions that normally stabilize the outer membrane, causing increased permeability. Colistin then inserts its fatty acid tail into the membrane, creating pores that lead to leakage of cellular contents and ultimately bacterial cell death. Additionally, colistin can bind and neutralize bacterial endotoxin (LPS), potentially reducing inflammatory responses during infection.
Resistance to Colistin
Resistance to colistin occurs through several mechanisms, with the most common being modifications to lipid A that reduce its negative charge, thereby decreasing colistin's binding affinity. These modifications typically involve addition of phosphoethanolamine or 4-amino-4-deoxy-L-arabinose to lipid A, mediated by chromosomal mutations in regulatory systems like PmrAB, PhoPQ, or through plasmid-mediated mcr genes. The plasmid-mediated resistance is particularly concerning as it can spread horizontally between bacterial species. Other resistance mechanisms include efflux pumps that remove colistin from bacterial cells, capsule formation that creates a physical barrier, and complete loss of LPS in some bacteria. Heteroresistance, where subpopulations of bacteria display different susceptibility levels, further complicates treatment with colistin.
Clinical Considerations
Recent studies have highlighted the importance of monitoring renal function during polymyxin treatment and avoiding combination with ototoxic and nephrotoxic drugs 1. The use of colistin in combination with other antibiotics, such as carbapenems, has been assessed in several studies, with mixed results 1. However, the most recent and highest quality study suggests that combination therapy may not be beneficial for CRAB infections, and colistin monotherapy may be sufficient 1. Therefore, colistin should be used with caution and in accordance with recent guidelines and studies, taking into account the potential risks and benefits of combination therapy and the need for close monitoring of renal function and potential side effects.
From the Research
Mechanism of Action of Colistin
- Colistin is a positively charged deca-peptide antibiotic that disrupts the integrity of the outer membrane of the cell wall of gram-negative bacteria by binding to the lipid A moiety of lipopolysaccharides, resulting in cell death 2.
- The endotoxic activity of lipopolysaccharides is simultaneously inhibited by colistin 2.
- Colistin exerts bactericidal activity by targeting lipopolysaccharide (LPS) in the cytoplasmic membrane (CM) 3.
- The disruption of the outer membrane by colistin leads to the release of calcium ions into the aqueous phase, resulting in membrane disruption 4.
Resistance to Colistin
- Resistance to colistin can emerge through various mechanisms, including intrinsic, mutational, and transferable mechanisms 5.
- The emergence of plasmid-mediated mobile colistin resistance (mcr) poses a significant challenge to the treatment of multidrug-resistant infections 4.
- The modification of lipid A in the outer membrane of mcr-1 bacteria with a covalently attached phosphoethanolamine group enables the formation of a large number of hydrogen bonds, resulting in an electrostatic net on the membrane and enhancing membrane stability 4.
- MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than outer membrane 3.
Strategies to Overcome Resistance
- Combining colistin with other antibiotics can help to overcome resistance 2.
- The use of LPS transport inhibitors, such as murepavadin, can increase the susceptibility of bacteria to colistin by causing LPS accumulation in the cytoplasmic membrane 3.
- The combination of polymyxins with curcumin has shown synergistic inhibitory effects on bacterial growth and can help to minimize the unwanted side effects of polymyxins 6.