Resistance polymyxins

Some polymyxins are sold for second-line systemic therapy. Polymyxin B sulfate and colistimethate sodium can be used for intravenous, intramuscular, or intrathecal administration, especially for Pseudomonas aerupinosa mP QXiosis, but also for most other gram-negative organisms, such as those resistant to first-line antibiotics. Nephrotoxicity and various neurotoxicities are common in parenteral, but not in topical, use. Resistance to polymyxins develops slowly, involves mutation and, at least in some bacteria, adaptation, a poorly understood type of resistance that is rapidly lost on transfer to a medium free of polymyxin. Resistance can involve changes in the proteins, the lipopolysaccharides, and lipids of the outer membrane of the cell (52). Polymyxin and colistin show complete cross-resistance. 

Breazeale, S.D., Ribeiro, A.A., McClerren, A.L., Raetz, C.R.H. A formyltransferase required for polymyxin resistance in Escherichia coli and the modification of lipid A with 4-amino-4-deoxy-L-arabinose. Identification and function of UDP-4-deoxy-4-formamido-L-arabinose. J Biol Chem 280 (2005) 14154-14167. 

Gunn, J.S., Lim, K.B., Krueger, J., Kim, K., Guo, L., Hackett, M., Miller, S.I. PmrA-PmrB-regulated genes necessary for 4-aminoarabinose lipid A modification and polymyxin resistance. Mol Microbiol 27 (1998) 1171-1182. 

Lee, H., Hsu, F.F., Turk, J., Groisman, E.A. The PmrA-regulated pmrC gene mediates phos-phoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica. J Bacteriol 186 (2004) 4124—4133. 

Trent, M.S., Ribeiro, A.A., Doerrler, W.T., Lin, S., Cotter, R.J., Raetz, C.R.H. Accumulation of a polyisoprene-linked amino sugar in polymyxin resistant mutants in Salmonella typhimurium and Escherichia coli structural characterization and possible transfer to lipid A in the periplasm. J Biol Chem 276 (2001a) 43132-43144. 

Helander, I., Kilpelainen, I., Vaara, M. Increased substitution of phosphate groups in lipopolysac-charides and lipid A of the polymyxin-resistant pmrA mutants of Salmonella typhimurium a 31P-NMR study. Mol Microbiol 11 (1994) 481—487. 

Vaara, M., Vaara, T., Sarvas, M. Decreased binding of polymyxin by polymyxin-resistant mutants of Salmonella typhimurium. J Bacteriol 139 (1979) 664-667. 

Yan, A., Guan, Z., Raetz, C. An undecaprenyl phosphate-aminoarabinose flippase required for polymyxin resistance in Escherichia coll 1 Biol Chem 282 (2007) 36077-36089. 

In polymyxin-resistant clinical isolates, in addition to constitutive aminoarabi-nosylation, loss of the lipid A modifying enzyme LpxO, an oxygenase required for the synthesis of 2-OH fatty acids (Gibbons et al., 2000) appears to contribute to CAP resistance, as many such isolates exhibit relative or absolute deficiency... 

Moskowitz, S.M., Bums, J.L., Nguyen, C.D., Hftiby, N., Ernst, R.K., Miller, S.I. Polymyxin resistance and lipid A structure of Pseudomonas aeruginosa isolated from colistin-treated and colistin-naive cystic fibrosis patients. Pediatr Pulmonol Suppl 20 (2000) 272. 

Resistance to penicillins and cephalosporins Resistance to polymyxins Resistance to tetracyclines Resistance to sulphonamides Mutation... 

Resistance to colistin has been analysed in 44 adults with cystic fibrosis treated with inhaled colistin. Five developed polymyxin resistance (31). After therapy P. aeruginosa became sensitive to polymyxins within a few months, enabling the reintroduction of colistin for antibacterial treatment. 

In the laboratory, chelating agents have been used to overcome resistance in bacteria. For example, ethylenediaminetetra-acetic acid (EDTA) restored susceptibility in polymyxin-resistant strains of Pseudomonas, presumably by removing calcium and magnesium from the plasma membrane (Brown and Richards, 1965). EDTA also restored susceptibility to hospital-isolated strains of penicillin-resistant Staphylococcus aureus (Rawal, 1969). Further, oxytetra-... 

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