Clinical relevance and plasmid dynamics of mcr-1-positive Escherichia coli in China: a multicentre case-control and molecular epidemiological study

Abstract

Background Although the emergence of the plasmid-mediated colistin resistance gene, mcr-1, caused global concern, little is known about its clinical implications and transmission characteristics over time. We aimed to investigate the clinical relevance of infection with mcr-1-positive Escherichia coli isolates and to investigate long-term plasmid dynamics. MethodsWe did a multicentre case-control study and molecular epidemiological survey of mcr-1-positive E coli infections. E coli isolates from four hospitals in China in 2008 to 2017 were collected and screened for mcr-1 by PCR and Sanger sequencing. Patients with mcr-1-positive E coli infections and matched controls with mcr-1-negative E coli infections were included in a 1:4 ratio, considering age, sex, living environment, comorbidities, antimicrobials used, and clinical sample type as potential risk factors in a regression model. 28-day mortality was also observed. The genomes of all mcr-1-positive E coli were sequenced to explore their genetic background and map ISApl1 elements. Plasmids carrying mcr-1 were characterised by their resistance profile and incompatibility group. Findings 29 100 isolates were collected across all hospitals and during the study period, 300 (1•03%) of which were mcr-1-positive E coli. The overall proportion of mcr-1-positive isolates significantly increased from 0•42% (1 of 240) in 2008 to 1•39% (66 of 4748; p<0•0001) in 2017. Factors related to health-care contact, including receiving cancer care, indwelling central venous catheter, and hospitalisation in the past 3 months, and some sample types (pus secretion and sputum) were significantly associated with mcr-1-positive E coli infection. 28-day mortality was low in both mcr-1positive (11 [4•4%] of 248 patients) and mcr-1-negative (39 [3•8%] of 1030 patients) groups and did not significantly differ. Although the genetic background of mcr-1-positive E coli was diverse, most of the mcr-1-encoding plasmids occurred in three dominant Inc groups (IncX4, IncI2, and IncHI2). Only the large IncHI2 plasmids conferred multiple resistances and probably integrated with other resistance plasmids. In 205 (68%) of 300 mcr-1-positive E coli isolates, mcr-1 genes lost their capacity for mobilisation because of loss of flanking ISApl1 elements.Interpretation The prevalence of mcr-1-positive E coli infection among patients increased over the study period, although it remained low. Health-care contact was the most probable risk factor. Plasmids are likely to have played a critical role in mcr-1 transmission, rather than clone dissemination and lateral transfer of ISApl1. Our findings underscore the importance of continued surveillance of E coli strains positive for mcr-1 and potentially other resistanceassociated genes, particularly in hospital settings.

Genomic patterns and characterizations of chromosomally-encoded mcr-1 in Escherichia coli populations

“…1 ). The most common ST among chromosomally-encoded mcr - 1 -positive E. coli isolates was ST10 (n = 10, 18.5%), which is consistent with the main host for plasmid-mediated mcr - 1 on E. coli species [ 3 , 4 , 12 ]. The phylogeny demonstrated two sequence clusters (SCs), except for two isolates which were distinct from two SCs as the outgroup (Fig.…”

“…Accumulated evidence showed that banning of colistin in animal feed efficiently restricted mcr-1 prevalence, not only in animals but also in humans and the whole ecosystem in China [2][3][4]. However, our previous study showed that a low proportion of Escherichia coli carrying chromosomally-encoded mcr-1 continually existed in the ecosystem [4], which was sporadically reported by other studies as well [9][10][11].…”

“…The emergence and rapid dissemination of plasmidmediated mobile colistin resistance gene (mcr-1) have become a severe threat to public health [1]. The predominant carriers of mcr-1 were IncX4, IncI2, and IncHI2 plasmids, which are transferable and adaptive plasmid types with broad host range and contributed to the spread of mcr-1 among various sources and bacterial species [2][3][4]. Besides, recombination of transposons, especially Tn6330 (ISApl1-mcr-1-pap2-ISApl1), the primary vehicle for transmission of mcr-1, and phage-like sequences enable mcr-1 to transfer across plasmids and isolates.…”

“…We identified 33 plasmid Inc types among all isolates, and the results showed that the most common Inc type was IncFIB(K) (45.8%, n = 22), followed by IncColRNAI (43.8%, n = 21), IncHI1 (33.3%, n = 16), IncX1 (31.3%, n = 15), IncFIB (AP001918) (27.1%, n = 13), and IncY (20.8%, n = 10). Remarkably, the common Inc types of mcr - 1 -harboring plasmids, such as IncX4, IncI2, IncHI2, and IncpO111 [ 1 , 3 , 4 , 12 ], were rarely detected among these isolates (Fig. 1 ), indicating that the chromosomally-encoded mcr - 1 may derive from IS Apl1 /Tn 6330 through transposition, but not from the plasmid.…”

Global distribution of mcr gene variants in 214,095 metagenomic samples

“…To date, mcr-1 is the most studied mcr gene variant, and the dissemination has been described in detail. Multiple studies agree that even though mcr-1 has been detected in a few isolates from the 1980s 18 , it has been appearing with increasing frequencies in samples between 2011 and 2017 and decreasing in later years 8,18,19,47 . We see a similar trend in the mcr-1 positive frequencies, but the levels seem to increase from 2008 with the highest levels in 2015; the year of mcr-1 being reported 4 (Figure 1).…”