Abstract
Following their initial discovery in the 1940s, polymyxin antibiotics fell into disfavor due to their potential clinical toxicity, especially nephrotoxicity. However, the dry antibiotic development pipeline, together with the rising global prevalence of infections caused by multidrug-resistant (MDR) Gram-negative bacteria have both rejuvenated clinical interest in these polypeptide antibiotics. Parallel to the revival of their use, investigations into the mechanisms of action and resistance to polymyxins have intensified. With an initial known effect on biological membranes, research has uncovered the detailed molecular and chemical interactions that polymyxins have with Gram-negative outer membranes and lipopolysaccharide structure. In addition, genetic and epidemiological studies have revealed the basis of resistance to these agents. Nowadays, resistance to polymyxins in MDR Gram-negative pathogens is well elucidated, with chromosomal as well as plasmid-encoded, transferrable pathways. The aims of the current review are to highlight the important chemical, microbiological, and pharmacological properties of polymyxins, to discuss their mechanistic effects on bacterial membranes, and to revise the current knowledge about Gram-negative acquired resistance to these agents. Finally, recent research, directed towards new perspectives for improving these old agents utilized in the 21st century, to combat drug-resistant pathogens, is summarized.
Highlights
The progressive global rise and dissemination of multidrug-resistant (MDR) bacteria represent an enormous threat to humans today, and a main concern to public health and modern health care systems [1]
Polymyxin B is used with bacitracin as an opthalmic ointment, while it is available with neomycin as a urinary bladder irrigant for short-term use in abacteriuric patients to help prevent bacteriuria and Gram-negative rod septicemia associated with the use of indwelling catheters
Considering the further limitations of the antimicrobial options available for the management of infections caused by MDR Enterobacteriaceae, there is no doubt that the recent reports of polymyxin resistance in these pathogens raises major concerns, and stresses the need for better surveillance and infection control
Summary
The progressive global rise and dissemination of multidrug-resistant (MDR) bacteria represent an enormous threat to humans today, and a main concern to public health and modern health care systems [1] Given their distinctive cellular features, Gram-negative bacteria are said to develop and acquire dynamic resistance patterns and cause significant morbidity and mortality worldwide. Against such pathogens, polymyxins represent one of the last-resort antibiotics that is still effective [3], among few others, including fosfomycin, ceftazidime/avibactam and the recently approved meropenem–vaborbactam [4,5].
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