Plasmid-mediated colistin resistance in a patient infected with Klebsiella pneumoniae

Abstract

It is alarming that the plasmid-mediated mcr-1-encoded colistin resistance discovered by Yi-Yun Liu and colleagues,1Liu YY Wang Y Walsh TR et al.Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.Lancet Infect Dis. 2016; 16: 161-168Summary Full Text Full Text PDF PubMed Scopus (3334) Google Scholar probably selected in cows and pigs as discussed by Marisa Haenni and colleagues2Haenni M Poirel L Kieffer N et al.Co-occurrence of extended spectrum β lactamase and MCR-1 encoding genes on plasmids.Lancet Infect Dis. 2016; 16: 281-282Summary Full Text Full Text PDF PubMed Scopus (164) Google Scholar and Surbhi Malhorta-Kumar and colleagues,3Malhotra-Kumar S Xavier BB Das AJ Lammens C Butaye P Goossens H Colistin resistance gene mcr-1 harboured on a multidrug resistant plasmid.Lancet Infect Dis. 2016; 16: 283-284Summary Full Text Full Text PDF PubMed Scopus (121) Google Scholar is now spreading globally in Gram-negative pathogens.4Zeng KJ Doi Y Patil S Huang X Tian GB Emergence of plasmid-mediated mcr-1 gene in colistin-resistant Enterobacter aerogenes and Enterobacter cloacae.Antimicrob Agents Chemother. 2016; 60: 3862-3863Crossref PubMed Scopus (79) Google Scholar Moreover, colistin-resistant Escherichia coli without the canonical mcr-1 gene suggest that other (transferable) colistin-resistant mechanisms exist.3Malhotra-Kumar S Xavier BB Das AJ Lammens C Butaye P Goossens H Colistin resistance gene mcr-1 harboured on a multidrug resistant plasmid.Lancet Infect Dis. 2016; 16: 283-284Summary Full Text Full Text PDF PubMed Scopus (121) Google Scholar Here we present initial evidence for such non-mcr-1, plasmid-mediated colistin resistance in a patient treated unsuccessfully at the University Hospital in Basel, Switzerland, in 2010.5Babouee B Widmer AF Dubuis O et al.Emergence of four cases of KPC-2 and KPC-3-carrying Klebsiella pneumoniae introduced to Switzerland, 2009–10.Euro Surveill. 2011; 16: 19817Crossref PubMed Scopus (27) Google Scholar A blood isolate of Klebsiella pneumoniae expressing KPC-3, obtained within days of the initial meropenem and piperacillin-tazobactam treatment, was multidrug-resistant but colistin-sensitive (minimum inhibitory concentration [MIC]=0·25 mg/L). Treatment was switched to include twice-daily intravenous injections of 2·4 million colistin units, but a second blood isolate obtained 18 days later had acquired colistin resistance (MIC=16 mg/L). Whole-genome sequencing of this second strain with a combination of Pacific Biosciences and Illumina miSEQ sequencers revealed a chromosome of 5·4 Mb (National Center for Biotechnology Information [NCBI] reference CP015822) and three plasmids (CP015823, CP015824, and CP015825). Resequencing of the colistin-sensitive strain by miSEQ detected two of the plasmids, of 103 Kb (CP015824) and 43 Kb (CP015825), including genes for ampicillin resistance (KPC-3 and SHV-1). Only two nucleotide substitutions in the chromosome leading to aminoacid changes were found, which were in pullulanase and DNA-binding protein HU-β. Although regions of increased coverage and gaps in resequencing suggested some rearrangements and duplication events, none of the mutations detected provided satisfactory explanations for the change in colistin resistance. The main genetic difference detected between the strains that might explain colistin resistance was a plasmid of 205 Kb (CP015823), present only in the second strain. This IncFIIk-related plasmid does not harbour mcr-1, but carries genes related to metal transport, detoxification, virulence, and antibiotic resistance, including streptomycin adenylyltransferase. Sequence analysis did not reveal known candidates for lipopolysaccharide modification, such as any additional copies of arnB, although genes encoding putative phospholipases, acyl transferases, histidine kinases, and others were found. This plasmid shares more than 99% identity over large regions with many other reported plasmids, largely from Italy and the USA, including NCBI references CP010393.1, JX442974.1, CP007729.1, JN233704.1, CP009777.1, and CP006657.1, which do not themselves confer colistin resistance. Because all regions of the plasmid share a strong identity with plasmids isolated from colistin-sensitive strains, it is unclear how novel resistance determinants are encoded. In summary, these data point to colistin-resistance conferred by an unidentified mcr-1-independent mechanism associated to a plasmid, which we fear could be spreading undetected around the globe.3Malhotra-Kumar S Xavier BB Das AJ Lammens C Butaye P Goossens H Colistin resistance gene mcr-1 harboured on a multidrug resistant plasmid.Lancet Infect Dis. 2016; 16: 283-284Summary Full Text Full Text PDF PubMed Scopus (121) Google Scholar We hope to be proven wrong. SN is funded by a grant from the Swiss National Science Foundation, Transfer Project SystemsX.ch. MP reports personal fees from Basilea Pharmaceutica Limited; MC received grants from Swiss National Science Foundation, Transfer Project SystemsX.ch, and from Basilea Pharmaceutica Limited. We declare no competing interests. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological studyThe emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria. Full-Text PDF Co-occurrence of extended spectrum β lactamase and MCR-1 encoding genes on plasmidsFindings reported by Yi-Yun Liu and colleagues1 identified the plasmid-borne gene mcr-1 encoding resistance to colistin with a high prevalence in Escherichia coli isolates from animals, foodstuff, and human beings in China. The same gene was then reported in Europe (Denmark) among extended-spectrum β lactamase (ESBL) and AmpC-producing E coli isolates from chicken meat and human infections, but at a very low prevalence.2 Full-Text PDF Colistin resistance gene mcr-1 harboured on a multidrug resistant plasmidIn The Lancet Infectious Diseases, Yi-Yun Liu and colleagues reported, for the first time, plasmid-mediated colistin resistance in Escherichia coli isolated from animals, food, and patients in China.1 These data bring to the fore an as yet unknown facet of colistin resistance and yet again show the effect of antibiotic use in animal farming on human health.2,3 We screened a selection of 105 colistin-resistant E coli strains (sensititre minimum inhibitory concentration of colistin ≥4 mg/L) isolated during 2011–12 from passive surveillance of E coli diarrhoea in 52 calves from Wallonia and 53 piglets from Flanders, both regions of Belgium. Full-Text PDF Intrinsic colistin resistanceThe global dissemination of colistin resistance has received a great deal of attention recently. The mechanism of colistin resistance can be generally classified as mcr-1-independent (intrinsic) or mcr-1-dependent (acquired). In The Lancet Infectious Diseases, Stefan Nicolet and colleagues1 presented a case in which a blood isolate of Klebsiella pneumoniae developed colistin resistance after receiving colistin treatment. Neither the mcr-1 gene nor any known mutations associated with colistin resistance were found in the genome, but an additional mcr-1-null plasmid was found to be acquired when it was compared with the parental susceptible isolate. Full-Text PDF Plasmid-mediated or chromosomally mediated colistin resistance in Klebsiella pneumoniae?Stefan Nicolet and colleagues1 described a pair of sequential KPC-producing Klebsiella pneumoniae isolates from the same patient, including a colistin-susceptible isolate and a colistin-resistant isolate selected after 18 days of colistin treatment. Comparative genome analysis revealed that the two isolates differed by two missense mutations in chromosomal genes, plus some rearrangements and duplications, none of which could explain the acquisition of the colistin-resistant phenotype by the second isolate. Full-Text PDF