ReviewUse of colistin-containing products within the European Union and European Economic Area (EU/EEA): development of resistance in animals and possible impact on human and animal health
Introduction
Colistin (polymyxin E) is a cationic, multicomponent, lipopeptide antibacterial agent discovered soon after the end of the Second World War (1949). An antibiotic originally named ‘colimycin’ was first isolated from the broth of Paenibacillus (Bacillus) polymyxa var. colistinus in 1950 [1]. Colistin has been used for decades in veterinary medicine, mainly to treat Gram-negative infections of the intestinal tract. For the treatment of human infections, colistin was restricted initially to ophthalmic and topical use [2], [3] owing to its systemic toxicity [2], [4], [5]. A recent global increase in Gram-negative bacteria that are multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) [6] has forced clinicians to re-introduce systemic colistin treatment in the form of its inactive prodrug, colistin methanesulfonate (CMS), as a last-resort drug for infections with such bacteria, which are frequently the cause of healthcare-associated infections [7]. Human infections with such highly resistant bacteria are associated with higher patient morbidity and mortality, higher costs and longer length of hospital stay [8], [9].
Due to its importance in human medicine, the public health impact of current or future use of colistin products in animals needs to be re-assessed at this time. The use of colistin in human and veterinary medicine is reviewed here, including a description of its toxicity profile, antibacterial spectrum, resistance mechanisms that render bacteria non-susceptible to polymyxin products, issues related to susceptibility testing, as well as the relationship between its use and antimicrobial resistance.
Section snippets
Human medicine
Colistin belongs to the antimicrobial class of polymyxins. In human medicine, colistin-containing products are commercially available in two forms, colistin sulphate and the prodrug CMS (syn. colistin methanesulphate, colistin sulphonyl methate, pentasodium colistimethanesulphate). CMS is microbiologically inactive [10] and is less toxic than colistin sulphate [11]. It is administered predominantly as parenteral formulations and via nebulisation [3]. Following administration, CMS is hydrolysed
Spectrum of antimicrobial activity and resistance mechanisms
The bactericidal effect of colistin (and polymyxin B) is the result of an interaction with divalent cations of the outer bacterial membrane, which causes a disruption of the cell structure, leakage of the cell contents and thereby cell lysis [12], [63]. The broad-spectrum activity of colistin against Gram-negative bacteria involves binding to lipid A, the anchor for lipopolysaccharide (LPS) and the main constituent of the outer membrane of many bacteria [64]. Polymyxins are active particularly
Possible links between the use of polymyxins and other antimicrobials and colistin resistance, in particular in bacteria of animal origin
Despite the abundant use of colistin in veterinary medicine for over 50 years, few studies have been performed looking at the possible transmission of colistin-resistant bacteria from animals to humans. Furthermore, there are limited surveillance data available on colistin resistance in animals, similarly to the surveillance situation in humans. To date no reports have been published demonstrating horizontal transfer of colistin resistance determinants or horizontal transmission of resistant
Conclusions on the impact on human and animal health of the use of colistin in food-producing animals
In recent years, colistin has become a last-resort antimicrobial for the treatment of severe human infections caused by MDR and XDR Gram-negative bacteria, despite its high toxicity. The major concern today is that the hospital outbreak strains developing stepwise colistin resistance are already MDR, XDR and even PDR. An example of this is K. pneumoniae sequence type (ST) 258 strains, resistant to all β-lactams, cephalosporins, carbapenems (KPC/class A; non-metallo), fluoroquinolones,
Funding
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Competing interests
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