mcr1 – ETIDIoH

A #cluster of #colistin- and #carbapenem-resistant #Klebsiella pneumoniae carrying #blaNDM-1 and #mcr-8.2 (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

A cluster of colistin- and carbapenem-resistant Klebsiella pneumoniae carrying blaNDM-1 and mcr-8.2

Ke Ma, Yu Feng, Lu Liu, Zhihong Yao, Zhiyong Zong

The Journal of Infectious Diseases, jiz519, https://doi.org/10.1093/infdis/jiz519

Published: 11 December 2019

Abstract

Background

Klebsiella pneumoniae resistant to both carbapenems and colistin imposes severe challenges for management. Here we report a cluster of five carbapenem-resistant K. pneumoniae clinical strains belonging to ST1 and K57 types, four of which were also resistant to colistin, from two hospitals.

Methods

The five strains were subjected to whole genome sequencing (WGS) using the short-read Illumina HiSeq platform and two strains were also selected for long-read WGS using MinION. Clonal relatedness of the five strains was determined based on single nucleotide polymorphisms (SNPs). Conjugation experiments were performed to obtain self-transmissible plasmids.

Results

All five strains carried the carbapenemase-encoding gene blaNDM-1, whereas the four colistin-resistant strains also harbored a new variant of the mcr-8 colistin resistance gene, namely mcr-8.2. Mcr-8.2 differs from Mcr-8.1 by four amino acid substitutions (A51V, A232S, N365Y, and N480K). mcr-8.2 was located on a large, hybrid, non-self-transmissible plasmid containing IncQ, IncR, and IncFII replicons, whereas blaNDM-1 was carried by self-transmissible IncX3 plasmids. Phylogenetic analysis based on SNPs revealed that the five strains were likely to have a common origin.

Conclusion

Both the intra- and inter-hospital transfer of strains carrying mcr-8 and blaNDM-1 were identified, which represents an emerging threat for clinical management and infection control.

colistin resistance, mcr, plasmid, Klebsiella pneumoniae

Topic: plasmids – colistin – klebsiella pneumoniae – single nucleotide polymorphism – beta-lactamase ndm-1 – carbapenem resistance – whole genome sequencing

This content is only available as a PDF.

Author notes: These authors contributed equally.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

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Keywords: Antibiotics; Drugs Resistance; Colistin; Carbapenem; Klebsiella pneumoniae; Nosocomial outbreaks; NDM1.

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#Bloodstream #infections caused by #Escherichia coli carrying #mcr-1 gene in hospitalized patients in northern #Italy from 2012 to 2018 (Infection, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Infection. 2019 Nov 22. doi: 10.1007/s15010-019-01377-4. [Epub ahead of print]

Bloodstream infections caused by Escherichia coli carrying mcr-1 gene in hospitalized patients in northern Italy from 2012 to 2018.

Mariani B1, Corbella M2,3, Merla C1,4, Tallarita M1,4, Piralla A1, Girello A1, Castelli M5, Bracchi C6, Marone P1, Cambieri P1.

Author information: 1 UOC Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo, Piazzale Golgi 19, 27100, Pavia, Italy. 2 UOC Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo, Piazzale Golgi 19, 27100, Pavia, Italy. m.corbella@smatteo.pv.it. 3 Servizio Epidemiologia Clinica e Biometria, Direzione Scientifica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. m.corbella@smatteo.pv.it. 4 Scuola di Specializzazione in Microbiologia e Virologia, Università degli Studi di Pavia, Pavia, Italy. 5 Dipartimento di Bioscienze, Centro Romeo ed Enrica Invernizzi Ricerca Pediatrica, Università degli Studi di Milano, Milan, Italy. 6 Unità di analisi del rischio ed epidemiologia genomica, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia-Romagna, Parma, Italy.

Abstract

PURPOSE:

The recurrence of multi-drug resistant (MDR) pathogens to the latest antibiotics and the limited development of new antibacterial agents have reduced the options for the treatment of severe infections. The reintroduction of old antibiotics, such as colistin, represents an effective strategy, since the latest antibiotics are over-consumed and ineffective against MDR pathogens. In 2015, Liu (Lancet Infect Dis 16:161-168, 2016) reported Escherichia coli (E. coli) isolates carrying plasmid-mediated colistin resistance gene mcr-1. The first of mcr-1 positive colistin-resistant (col-R) E. coli from a human blood culture was observed in 2012 in Latin America, while in Italy was reported for the first time by our center in 2016. The present study aimed to describe the prevalence of mcr-1 positive col-R strains in E. coli-related bloodstream infection among patients hospitalized in Fondazione IRCCS Policlinico San Matteo in Pavia, Italy, from 2012 to 2018, including the three cases already published.

METHODS:

All col-R E. coli strains isolated from blood cultures collected during the study period were analyzed. The minimal inhibitory concentration of colistin was determined using broth microdilution and detection of mcr-1 and mcr-2 genes was performed by PCR. The sequence type of E. coli mcr-1 positive was determined according to Multilocus sequence typing.

RESULTS:

Out of 1557 samples, 14 strains (0.90%) were col-R. and positive for the presence of the mcr-1 gene, with no mcr-2 detected. The most common ST was ST10 (n = 3), followed by ST410 (n = 2). The remaining strains exhibited different MLST profiles, indicating that they were genetically unrelated.

CONCLUSIONS:

Proper reporting of the presence of mcr-1 genes is an essential component to anticipate the spread of colistin resistance. This public health issue is particularly alarming in Italy due to the consistent circulation of MDR bacteria.

KEYWORDS: Blood stream infection; Colistin resistance; Drug resistance; Escherichia coli; mcr-1 gene

PMID: 31758437 DOI: 10.1007/s15010-019-01377-4

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Keywords: Antibiotics; Drugs Resistance; Colistin; MCR1; E. Coli; Italy.

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#Colistin #resistance-mediated #bacterial surface #modification sensitizes #phage infection (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Colistin-resistance-mediated bacterial surface modification sensitizes phage infection

Guijuan Hao, Annie I. Chen, Ming Liu, Haijian Zhou, Marisa Egan, Xiaoman Yang, Biao Kan, Hui Wang, Mark Goulian, Jun Zhu

DOI: 10.1128/AAC.01609-19

ABSTRACT

Colistin is a drug of last resort for the treatment of many multidrug resistant Gram-negative bacteria, including Klebsiella pneumoniae. However, bacteria readily acquire resistance to this antibiotic via lipopolysaccharide modifications caused by spontaneous mutations or from enzymes acquired by lateral gene transfer. The fitness cost associated with these modifications remains poorly understood. In this study, we show that colistin-resistant K. pneumoniae are more susceptible to killing by a newly isolated lytic phage than the colistin sensitive parent strain. We observe this behavior for colistin-resistance conferred by a horizontally transferred mcr-1 containing plasmid and also from the inactivation of the chromosomal gene mgrB. By measuring zeta potentials, we found that the phage particles were negatively charged at neutral pH and that colistin-resistant bacteria had less negative zeta potentials than did wildtype. These results suggest that the decreased negative surface charge of colistin-resistant cells lowers the electrostatic repulsion between the phage and bacteria, thereby promoting phage adherence and subsequent infection. To further explore this, we tested the effect of phage treatment on K. pneumoniae growing in several different environments. We found that colistin-resistant cells were more susceptible to phage than were the wildtype cells when growing in biofilms or infected moth larvae and when colonizing the mammalian gut. A better understanding of these fitness costs may lead to new treatment approaches that minimize the emergence and spread of colistin-resistant pathogens in human and environmental reservoirs.

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Keywords: Antibiotics; Drugs Resistance; Colistin; MCR1; Klebsiella pneumoniae; Bacteriophages.

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A novel #plasmid-mediated #polymyxin #resistance determinant (#mcr-1.8) in #Escherichia coli recovered from broiler #chickens in #Brunei Darussalam (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

A novel plasmid-mediated polymyxin resistance determinant (mcr-1.8) in Escherichia coli recovered from broiler chickens in Brunei Darussalam

Muhd Haziq F Abdul Momin, Apostolos Liakopoulos, David C Bean, Lynette M Phee,David W Wareham

Journal of Antimicrobial Chemotherapy, dkz352, https://doi.org/10.1093/jac/dkz352

Published: 23 August 2019

Issue Section: Research letter

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Sir,

MDR Gram-negative bacteria are identified as critical pathogens and their effective treatment increasingly relies on the polymyxins (polymyxin B, colistin), either alone or as part of unorthodox combination therapies.1 The rapid emergence of polymyxin resistance due to mutations/insertions in genes involved in LPS modifications (lpxCAD, pmrA/B, mgrB, phoP/Q, ccrAB) has been reported among individuals exposed to or treated with polymyxins.1 Of greater concern are increasing reports of resistance due to the acquisition of phosphoethanolamine (PEtN) transferases, enzymes that catalyse the addition of phosphoethanolamine to lipid A, resulting in lower binding affinity of polymyxins.1

(…)

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© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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Keywords: Antibiotics; Drugs Resistance; MCR1; Polymyxins; Poultry; Brunei.

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Activity of #imipenem / #relebactam against #carbapenemase-producing #Enterobacteriaceae with high #colistin resistance (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Activity of imipenem/relebactam against carbapenemase-producing Enterobacteriaceae with high colistin resistance

Jessica Carpenter, Nick Neidig, Alex Campbell, Tanner Thornsberry, Taylor Truex,Tiffany Fortney, Yunliang Zhang, Karen Bush

Journal of Antimicrobial Chemotherapy, dkz354, https://doi.org/10.1093/jac/dkz354

Published: 20 August 2019

Abstract

Objectives

Imipenem/relebactam, an investigational β-lactam/β-lactamase inhibitor combination for treatment of Gram-negative infections, and comparators including ceftazidime/avibactam, piperacillin/tazobactam and colistin were tested for activity against representative carbapenemase-producing Enterobacteriaceae (CPE) isolates.

Methods

MICs of the antimicrobial agents were determined using standard broth microdilution methodology for CPE isolates collected from Indiana patients, primarily during the time frame of 2013–17 (n = 199 of a total of 200 isolates). Inhibitors were tested at 4 mg/L in all combinations.

Results

Of the CPE in the study, 199 produced plasmid-encoded KPC class A carbapenemases; 1 Serratia marcescens isolate produced the SME-1 chromosomal class A carbapenemase. MIC50/MIC90 values of imipenem/relebactam were ≤0.25/0.5 mg/L, whereas MIC50/MIC90 values of ceftazidime/avibactam were 1/2 mg/L. Resistance to colistin was observed in 54% (n = 97) of 180 non-Serratia isolates tested (MIC50 of 4 mg/L). Colistin resistance mechanisms included production of a plasmid-encoded mcr-1-like gene (n = 2) or an inactivated mgrB gene.

Conclusions

Imipenem/relebactam was the most potent agent tested against CPE in this study and may be a useful addition to the antimicrobial armamentarium to treat infections caused by these pathogens.

Issue Section: ORIGINAL RESEARCH

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Keywords: Antibiotics; Drugs Resistance; Carbapenem; Colistin; MCR1; Enterobacteriaceae; Imipenem; Relebactam.

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#Polymyxin #resistance in #Klebsiella pneumoniae: multifaceted mechanisms utilized in the presence and absence of the #plasmid-encoded phosphoethanolamine transferase gene #mcr-1 (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Polymyxin resistance in Klebsiella pneumoniae: multifaceted mechanisms utilized in the presence and absence of the plasmid-encoded phosphoethanolamine transferase gene mcr-1

Sue C Nang, Mei-Ling Han, Heidi H Yu, Jiping Wang, Von Vergel L Torres, Chongshan Dai,Tony Velkov, Marina Harper, Jian Li

Journal of Antimicrobial Chemotherapy, dkz314, https://doi.org/10.1093/jac/dkz314

Published: 31 July 2019

Abstract

Objectives

Until plasmid-mediated mcr-1 was discovered, it was believed that polymyxin resistance in Gram-negative bacteria was mainly mediated by the chromosomally-encoded EptA and ArnT, which modify lipid A with phosphoethanolamine (pEtN) and 4-amino-4-deoxy-L-arabinose (L-Ara4N), respectively. This study aimed to construct a markerless mcr-1 deletion mutant in Klebsiella pneumoniae, validate a reliable reference gene for reverse transcription quantitative PCR (RT–qPCR) and investigate the interactions among mcr-1, arnT and eptA, in response to polymyxin treatments using pharmacokinetics/pharmacodynamics (PK/PD).

Methods

An isogenic markerless mcr-1 deletion mutant (II-503Δmcr-1) was generated from a clinical K. pneumoniae II-503 isolate. The efficacy of different polymyxin B dosage regimens was examined using an in vitro one-compartment PK/PD model and polymyxin resistance was assessed using population analysis profiles. The expression of mcr-1, eptA and arnT was examined using RT–qPCR with a reference gene pepQ, and lipid A was profiled using LC-MS. In vivo polymyxin B efficacy was investigated in a mouse thigh infection model.

Results

In K. pneumoniae II-503, mcr-1 was constitutively expressed, irrespective of polymyxin exposure. Against II-503Δmcr-1, an initial bactericidal effect was observed within 4 h with polymyxin B at average steady-state concentrations of 1 and 3 mg/L, mimicking patient PK. However, substantial regrowth and concomitantly increased expression of eptA and arnT were detected. Predominant L-Ara4N-modified lipid A species were detected in II-503Δmcr-1 following polymyxin B treatment.

Conclusions

This is the first study demonstrating a unique markerless deletion of mcr-1 in a clinical polymyxin-resistant K. pneumoniae. The current polymyxin B dosage regimens are suboptimal against K. pneumoniae, regardless of mcr, and can lead to the emergence of resistance.

Issue Section: ORIGINAL RESEARCH

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Keywords: Antibiotics; Drugs Resistance; Klebsiella pneumoniae; MCR1; Plasmids; Polymyxin B.

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Emergence of a hybrid #plasmid derived from IncN1-F33:A−:B− and #mcr-1-bearing plasmids mediated by IS26 (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Emergence of a hybrid plasmid derived from IncN1-F33:A−:B− and mcr-1-bearing plasmids mediated by IS26

Dandan He, Yingying Zhu, Ruichao Li, Yushan Pan, Jianhua Liu, Li Yuan,Gongzheng Hu

Journal of Antimicrobial Chemotherapy, dkz327, https://doi.org/10.1093/jac/dkz327

Published: 30 July 2019

Abstract

Objectives

To characterize the complete sequences of four plasmids in MCR-1-producing clinical Escherichia coli strain D72, and to depict the formation mechanism and characteristics of the cointegrate plasmid derived from the pD72-mcr1 and pD72-F33 plasmids.

Methods

The genetic profiles of plasmids in strain D72 and its transconjugant were determined by conjugation, S1-PFGE, Southern hybridization, WGS analysis and PCR. Plasmid sequences were analysed with bioinformatic tools. The traits of the fusion plasmid were characterized by cointegration, stability and conjugation assays.

Results

Strain D72, belonging to ST1114, contained four plasmids, including mcr-1-carrying pD72-mcr1, blaCTX-M-55-carrying pD72-F33, blaTEM-238-bearing pD72-IncP and pD72-IncX1 carrying aph(3′)-Ia, qnrS2 and floR. A single plasmid, pD72C, in the transconjugant was found to be larger than any plasmid in the original strain D72. Sequence analysis showed that pD72C was the fusion product of pD72-mcr1 and pD72-F33, and the recombinant event involved an intermolecular replicative mechanism. Plasmid fusion occurred at a frequency of 1.75 × 10−4 cointegrates per transconjugant. The fusion plasmid presented a high stability and conjugation frequency of 8.00 × 10−3.

Conclusions

To our knowledge, this is the first report of the IS26-mediated fusion of an IncN1-F33:A−:B− plasmid and an mcr-1-carrying phage-like plasmid, providing evidence for the important role of IS26 in the recombination of plasmids. The biological advantages of the fusion plasmid indicated that the fusion event presumably plays a potential role in the dissemination of mcr-1.

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Keywords: Antibiotics; Drugs Resistance; Colistin; E. Coli; MCR1; Plasmids.

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