Old and Novel Polymyxins Against Serious Gram-Negative Infections

Abstract

Polymyxins (polymyxin B and colistin) are bactericidal pentacationic cyclic lipodecapeptides that act specifically on Gram-negative bacteria. They were largely abandoned because of their toxicity to kidney proximal tubuli. Now they have been reinstated, in spite of their toxicity, in the therapy of severe infections caused by extremely multiresistant strains. Such strains are now rapidly emerging and spreading. The nephrotoxicity of polymyxins does complicate the therapy, may even require its discontinuation, and must be weighed against the beneficial effects on patient survival. Furthermore, in the recent years it has become increasingly clear that the current dosage regimens are suboptimal in critically ill patients. Clinicians are advised to use larger doses, but this further increases nephrotoxicity. Since there is notably synergy between polymyxins and several other antibiotics, combination therapies may be useful, and clinical evidence for their advantages is currently accumulating. Novel, less nephrotoxic compounds that have strong antibacterial activity would be very welcome. The nephrotoxicity of polymyxins might be related to their very highly cationic nature. In contrast to the old polymyxins, which carry five positive charges, NAB739 carries three positive charges only. The activity of NAB739 against Escherichia coli and Klebsiella pneumoniae is quite close to that of polymyxin B. Pieces of indirect evidence suggest that NAB739 might be less nephrotoxic than the old polymyxins. Ongoing studies compare the efficacy and nephrotoxicity of NAB739 and polymyxin B in animal models. Useful compounds might also include NAB7061 and NAB741, both carrying three positive charges. They lack potent direct action but sensitize Gram-negative bacteria to other antibiotics by facilitating their entry inside the cell.