Global colistin use: a review of the emergence of resistant Enterobacterales and the impact on their genetic basis

Abstract

The dramatic global rise of MDR and XDR Enterobacterales in human medicine forced clinicians to the reintroduction of colistin as last-resort drug. Meanwhile, colistin is used in the veterinary medicine since its discovery, leading to a steadily increasing prevalence of resistant isolates in the livestock and meat-based food sector. Consequently, transmission of resistant isolates from animals to humans, acquisition via food and exposure to colistin in the clinic are reasons for the increased prevalence of colistin-resistant Enterobacterales in humans in the last decades. Initially, resistance mechanisms were caused by mutations in chromosomal genes. However, since the discovery in 2015, the focus has shifted exclusively to mobile colistin resistances (mcr). This review will advance the understanding of chromosomal-mediated resistance mechanisms in Enterobacterales. We provide an overview about genes involved in colistin resistance and the current global situation of colistin-resistant Enterobacterales. A comparison of the global colistin use in veterinary and human medicine highlights the effort to reduce colistin sales in veterinary medicine under the One Health approach. In contrast, it uncovers the alarming rise in colistin consumption in human medicine due to the emergence of MDR Enterobacterales, which might be an important driver for the increasing emergence of chromosome-mediated colistin resistance.

Keywords: mcr; One Health; antimicrobial use; chromosome; lipid A; polymyxin.

Figure 1.

Comparison of changes in sales and consumption of polymyxin in veterinary and human medicine within the European Union. Left: Averaged percentages of sales of polymyxin relative to total sales (in tons of active ingredient) in five European countries for the period 2005–2009 using the data from the first ESVAC report (European Medicines Agency 2011). The period 2010–2017 shows the averaged percentage of sales of polymyxin relative to the total sales (in mg of active ingredient by Population Correction Unit (PCU)) of the reporting countries for each year (European Medicines Agency ; European Medicines Agency ; European Medicines Agency ; European Medicines Agency ; European Medicines Agency ; European Medicines Agency ; European Medicines Agency ; European Medicines Agency ; European Medicines Agency 2020). Right: Annual average consumption of polymyxin [in Defined Daily Doses (DDD) per 1000 inhabitants per day] in the community and hospital sector in Europe, including Switzerland, using data provided by the ESAC-Net interactive database (https://www.ecdc.europa.eu/en/antimicrobial-consumption/surveillance-and-disease-data/database, accessed October 2020). For both sectors, polymyxins include colistin (polymyxin E) and polymyxin B.

Figure 2.

Global trends in colistin resistance in human clinical Enterobacterales. Data were obtained from the ATLAS database (https://atlas-surveillance.com, accessed February 2021), which includes data from the TEST (Tigecycline Evaluation Surveillance Trial) surveillance program, the AWARE (Assessing Worldwide Antimicrobial Resistance Evaluation) as well as INFORM (International Network for Optimal Resistance Monitoring) program. Resistance is shown as percentage from Enterobacter spp., Klebsiella spp. and E. coli using the data from all surveillance programs (ATLAS data source) and MIC values >2 mg/L according to the EUCAST breakpoint. (A) Global trend of colistin resistance among clinical Enterobacter spp., Klebsiella spp. and E. coli as well as combined genera from 2014 to 2019. B: Trends of colistin resistance in clinical Enterobacterales in different continents from 2014 to 2019. (A and B) Data reporting countries were: Europe: Austria, Belgium, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Netherlands, Poland, Portugal, Romania, Russia, Spain, Sweden, Switzerland, Turkey, Ukraine and United Kingdom; North America: Canada, United States; Latin America: Argentina, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Guatemala, Mexico, Panama and Venezuela; Asia: China (incl. Hong Kong and Taiwan), Japan, Korea, South, Malaysia, Philippines and Thailand; Africa: Israel, Jordan, Kenya, Kuwait, Morocco, Nigeria, Qatar, Saudi Arabia and South Africa; Oceania: Australia and New Zealand.

Figure 3.

Regulatory network of LPS-modifying proteins involved in colistin resistance in Enterobacterales. The PhoPQ TCS is activated by low Mg²⁺ concentrations, low pH and the presence of antimicrobials peptides, such as colistin, leading to the expression of the regulator MgrB, the adaptor protein PmrD and the sRNA mgrR. MgrB exerts negative feedback on PhoQ, while mutations in MgrB typically result in the constitutive activation of the PhoPQ TCS. The sRNA mgrR impedes the expression of EptB. The adaptor protein PmrD activates the PmrAB TCS leading to the expression of multiple target genes responsible for LPS biosynthesis and modification. PmrA also becomes activated by the CrrAB TCS via the adaptor protein CrrC. Gain-of function mutations in CrrB can also result in the activation of gene expression of the pmrHFIJKLM operon without involvement of the PmrAB TCS. In addition, mutations in the proteins YciM and LpxM have been found to confer colistin resistance. The plus symbol indicates positive regulation and the yellow star highlights alterations in proteins/genes, which may lead to colistin resistance.

Figure 4.

Possible transmission routes of colistin-resistant Enterobacterales. Colistin-resistant Enterobacterales emerge as a result of the use of colistin in the livestock sector, in animal clinics and the hospitals. Resistant isolates can disseminate between different areas of life, which is indicated by the red arrows.

Figure 5.

Landscape of Enterobacterales sequence types associated with chromosomal mutations leading to colistin resistance. Worldwide prevalence of chromosomal-mediated colistin resistance in different sequence types from E. coli, K. pneumoniae, Enterobacter spp. and Salmonella spp. isolated from human, animal, food and wildlife. Detailed information is given in Table S2 (Supporting Information) in addition with information regarding sequence types of each species associated with mcr-gene