Review
Use 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

https://doi.org/10.1016/j.ijantimicag.2015.06.005Get rights and content

Highlights

  • A multidisciplinary international review panel on colistin use in veterinary medicine.

  • There is extensive use of colistin in veterinary medicine.

  • There is no evidence for the transmission of colistin resistance in bacteria that have been spread from animals to humans.

  • There is a clear need to reinforce systematic monitoring of bacteria from food-producing animals for resistance to colistin (polymyxins).

  • Colistin should no longer be used for prophylaxis of diseases in animals.

Abstract

Since its introduction in the 1950s, colistin has been used mainly as a topical treatment in human medicine owing to its toxicity when given systemically. Sixty years later, colistin is being used as a last-resort drug to treat infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae), for which mortality can be high. In veterinary medicine, colistin has been used for decades for the treatment and prevention of infectious diseases. Colistin has been administered frequently as a group treatment for animal gastrointestinal infections caused by Gram-negative bacteria within intensive husbandry systems. Given the ever-growing need to retain the efficacy of antimicrobials used to treat MDR infections in humans, the use of colistin in veterinary medicine is being re-evaluated. Despite extensive use in veterinary medicine, there is limited evidence for the development of resistance to colistin and no evidence has been found for the transmission of resistance in bacteria that have been spread from animals to humans. Since surveillance for colistin resistance in animals is limited and the potential for such transmission exists, there is a clear need to reinforce systematic monitoring of bacteria from food-producing animals for resistance to colistin (polymyxins). Furthermore, colistin should only be used for treatment of clinically affected animals and no longer for prophylaxis of diseases, in line with current principles of responsible use of antibiotics.

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

None.

Competing interests

None declared.

Ethical approval

Not required.

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