resistance is also conferred upon other species that carry different genes resistant to antibiotics. The emergence of the mcr-9 gene is quite remarkable. Use of colistin to treat Acinetobacter baumannii infections has led to the development of resistant bacterial strains. They have also developed resistance to the antimicrobial compounds LL-37 and lysozyme, produced by the human immune system. This cross-resistance is caused by gain-of-function mutations to the pmrB gene, a phosphoethanolamine transferase (similar to mcr-1) located on the bacterial chromosome. Not all resistance to colistin and some other antibiotics is due to the presence of resistance genes. Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a range of resistance to an antibiotic, has been observed in some species of Enterobacter since at least 2016 and was observed in some strains of Klebsiella pneumoniae in 2017–2018. In some cases this phenomenon has significant clinical consequences. Inherently resistant Brucella Burkholderia cepacia Chryseobacterium indologenes Edwardsiella Elizabethkingia meningoseptica Francisella tularensis spp. Gram-negative cocci Helicobacter pylori Moraxella catarrhalis Morganella spp. Neisseria gonorrhoeae and Neisseria meningitidis Proteus Providencia Serratia Some strains of Stenotrophomonas maltophilia Variable resistance Aeromonas Vibrio Prevotella Fusobacterium Escherichia coli Adverse reactions The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves), but this may reflect the very high doses given, which are much higher than the doses currently recommended by any manufacturer and for which no adjustment was made for pre-existing renal disease. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose. At a dose of 160 mg colistimethate IV every eight hours, very little nephrotoxicity is seen. Indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and it has been used for extended periods up to six months with no ill effects. Colistin-induced nephrotoxicity is particularly likely in patients with hypoalbuminemia. The main toxicity described with aerosolised treatment is bronchospasm, which can be treated or prevented with the use of β2-adrenergic receptor agonists such as salbutamol or following a desensitisation protocol. Mechanism of action Colistin is a polycationic peptide and has both hydrophilic and lipophilic moieties. These cationic regions interact with the bacterial outer membrane by displacing magnesium and calcium bacterial counter ions in the lipopolysaccharide. The hydrophobic and hydrophilic regions interact with the cytoplasmic membrane just like a detergent, solubilizing the membrane in an aqueous environment. This