Thursday, August 03, 2017

Eurosurveillance: Mcr-One, Two, Three And Counting




Almost two years ago (Nov 2015) the news broke (see MCR-1: The Return Of The Plasmids) of the discovery of a new antibiotic resistance gene in China - dubbed mcr-1 - that conveys resistance to Colistin. 
At that time the initial samples with the MCR-1 resistance gene were still susceptible to Carbapenems, meaning they could still be treated.
The concern is that eventually one or more of these resistant bacteria could eventually develop pandrug-resistance - where no effective treatment option remains.

Completely resistant infections have been - thankfully - rare, although in March of last year, in The Lancet's Emergence of the mcr-1 colistin resistance gene in carbapenem-resistant Enterobacteriaceae, we saw a report from China on two K pneumoniae isolates that carried the MCR-1 gene and the gene for NDM-5, providing it near pandrug resistance.  

Since then, MCR-1 has been found to exist globally, and joins the growing ranks of antimicrobial resistant organisms (MRSA, CRE, NDM-1, etc.) that threaten to overwhelm our dwindling arsenal of effective antibiotics.
Last summer, only 7 months after mcr-1 was identified, we learned of a variant dubbed mcr-2 (see Eurosurveillance: Identification Of A Novel Colistin-Resistant MRC-2 Gene In E Coli - Belgium, 2016).
Today the ECDC's Eurosurveillance Journal brings us an editorial, and 3 papers on the detection of a third mcr variant: mcr-3 . . .  followed by a paper on yet another variant; mcr-4.
Almost predictably, this mcr gene is following the same general pattern we've seen with NDM-1 (which now has variants including  NDM-2, NDM-4, NDM-5, NDM-7 and NDM-9.).
Some excerpts from the editorial, followed by links to all four papers.  This is definitely an issue of Eurosurveillance you'll want to read in its entirety.
 Plasmid-encoded colistin resistance: mcr-one, two, three and counting

by J Kluytmans

In November 2015, the first description of plasmid-mediated colistin resistance (mcr-1 gene) was reported from China in food animals, food and humans [1]. Many reports from all over the world have followed since. The reported rates vary considerably, ranging from sporadic findings up to 67% in Escherichia coli isolates fromTunisian chicken [2]. However, the rates have been consistently higher in livestock than in humans. This points to a reservoir in animals with spill over to humans.
Until recently, colistin use in humans has been limited but it has been used extensively in veterinary medicine for decades, both as curative treatment and for prevention of disease [3]. The amount of use in livestock varies enormously. In Europe, for example, in 2013, the annual colistin sales in some countries exceeded 20 mg per population corrected unit (PCU) while in other countries the sales were below 1 mg/PCU. Following the detection of mcr-1, the European Medicines Agency updated their advice on the use of colistin in humans and animals [3] with the aim of reducing the use in animals by 65% in the coming years. Quantitative targets of 5 mg/PCU and 1 mg/PCU have been set for a reduction in high and medium consuming countries, respectively.
In the summer of 2016, a group from Belgium reported a new variant of the plasmid-mediated colistin resistance gene, mcr-2 [3]. Xavier et al. studied colistin-resistant E. coli strains from pigs and calves and found mcr-2 more frequently than mcr-1. +In this issue of Eurosurveillance, there are three reports on a third variant, mcr-3. In one of the studies, mcr-3 was detected in an E. coli isolate from a patient with a bloodstream infection who had recently visited Thailand [4]. The travel history in combination with the extended-spectrum beta-lactamase (ESBL) marker in the same strain (CTX-M55) strongly suggests that the patient acquired this multi-resistant E. coli in Asia.
        (Continue . . . )
Not mentioned in the above editorial is the 4th Rapid Communications on today's list, describing yet another new mcr variant; mcr-4.  These articles just went live, and I've not  had time to read and absorb them, but I expect to spend time later today and tomorrow doing so.  

Follow the links to read:

Rapid communications
Novel mcr-3 variant, encoding mobile colistin resistance, in an ST131 Escherichia coli isolate from bloodstream infection, Denmark, 2014
by L Roer, F Hansen, M Stegger, UW Sönksen, H Hasman, AM Hammerum
A novel variant of the plasmid-borne colistin resistance gene mcr-3 was detected on an IncHI2 plasmid in an ST131 CTX-M-55-producing Escherichia coli isolate from a Danish patient with bloodstream infection in 2014. The discovery of novel plasmid-borne genes conferring resistance to colistin is of special interest since colistin has reemerged as an important drug in the treatment of infections with multidrug-resistant Gram-negative bacteria

Plasmid-borne colistin resistance gene mcr-3 in Salmonella isolates from human infections, Denmark, 2009–17

by E Litrup, K Kiil, AM Hammerum, L Roer, EM Nielsen, M Torpdahl
This report describes one Salmonella isolate harbouring both mcr-1 and mcr-3. We also found nine other Salmonella isolates positive for the plasmid-borne colistin resistance gene, mcr-3. The strains were isolated from patients in Denmark between 2009 and 2017 and five of the patients had travelled to Asia. In addition to mcr-3, all strains were found positive for blaTEM-1, strA, strB, sul2 and tet(A) or tet(B), and most strains were positive for blaCTX-M-55 and qnrS.

Co-occurrence of colistin-resistance genes mcr-1 and mcr-3 among multidrug-resistant Escherichia coli isolated from cattle, Spain, September 2015

by M Hernández, MR Iglesias, D Rodríguez-Lázaro, A Gallardo, NM Quijada, P Miguela-Villoldo, MJ Campos, S Píriz, G López-Orozco, C de Frutos, JL Sáez, M Ugarte-Ruiz, L Domínguez, A Quesada
 Colistin resistance genes mcr-3 and mcr-1 have been detected in an Escherichia coli isolate from cattle faeces in a Spanish slaughterhouse in 2015. The sequences of both genes hybridised to same plasmid band of ca 250 kb, although colistin resistance was non-mobilisable. The isolate was producing extended-spectrum beta-lactamases and belonged to serotype O9:H10 and sequence type ST533. Here we report an mcr-3 gene detected in Europe following earlier reports from Asia and the United States.

Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016
by A Carattoli, L Villa, C Feudi, L Curcio, S Orsini, A Luppi, G Pezzotti, CF Magistrali

A novel mcr colistin resistance gene was identified in a strain of Salmonella enterica, monophasic variant of serovar Typhimurium (4,5,12:i:- ), isolated from a pig at slaughter in Italy in 2013, and in Escherichia coli strains collected during routine diagnostic of post-weaning diarrhoea in pigs from Spain and Belgium in 2015 and 2016. Immediate implementation of mcr-screening including this novel gene variant is required for Salmonella and E. coli from humans and food-producing animals in Europe.

This issue also contains a detailed surveillance and outbreak report from Italy on  KPC-carbapenemase spreading among outpatients.

Surveillance and outbreak report

Evolving beta-lactamase epidemiology in Enterobacteriaceae from Italian nationwide surveillance, October 2013: KPC-carbapenemase spreading among outpatients

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