Diverse #vectors and mechanisms #spread #NDM beta-lactamases among #carbapenem resistant #Enterobacteriaceae in the Greater #Boston area (Antimicrob Agents Chemother., abstract)

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

Diverse vectors and mechanisms spread NDM beta-lactamases among carbapenem resistant Enterobacteriaceae in the Greater Boston area

Nicole Pecora, Xiaomin Zhao, Kathleen Nudel, Maria Hoffmann, Ning Li, Andrew B. Onderdonk, Deborah Yokoe, Eric Brown, Marc Allard, Lynn Bry

DOI: 10.1128/AAC.02040-18

 

ABSTRACT

New Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized. A prospective genomic surveillance program among Boston-area hospitals identified multiple new occurrences of NDM carrying strains of E. coli and E. cloacaecomplex in inpatient and outpatient settings, representing the first occurrences of NDM-mediated resistance since initiating genomic surveillance in 2011. Cases included domestic patients with no international exposures. PacBio sequencing of isolates identified strain characteristics, resistance genes, and the complement of mobile vectors mediating spread. Analyses revealed a common 3114-bp region containing the blaNDM gene, with carriage of this conserved region among unique strains by diverse transposon and plasmid backbones. Functional studies revealed broad capacity for blaNDM transmission by conjugation, transposition, and complex inter-plasmid recombination events. NDMs represent a rapidly spreading form of drug resistance that can occur in inpatient and outpatient settings and in patients without international exposures. In contrast to Tn4401-based spread of Klebsiella pneumoniae carbapenemases (KPCs), diverse transposable elements mobilize NDM enzymes, commonly with other resistance genes, enabling naïve strains to acquire multi- and extensively-drug resistance profiles with single transposition or plasmid conjugation events. Genomic surveillance provides effective means to rapidly identify these gene-level drivers of resistance and mobilization, to inform clinical decisions to prevent further spread.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; NDM1; USA; Enterobacteriaceae.

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#Spreading #patterns of #NDM-producing #Enterobacteriaceae in clinical and #environmental settings in #Yangon, #Myanmar (Antimicrob Agents Chemother., abstract)

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

Spreading patterns of NDM-producing Enterobacteriaceae in clinical and environmental settings in Yangon, Myanmar

Yo Sugawara, Yukihiro Akeda, Hideharu Hagiya, Noriko Sakamoto, Dan Takeuchi, Rathina Kumar Shanmugakani, Daisuke Motooka, Isao Nishi, Khwar Nyo Zin, Mya Mya Aye, Thuzar Myint,Kazunori Tomono, Shigeyuki Hamada

DOI: 10.1128/AAC.01924-18

 

ABSTRACT

The spread of carbapenemase-producing Enterobacteriaceae (CPE) has become a global concern, contributing to widespread carbapenem resistance. However, the specific dissemination patterns of carbapenemase genes have not been intensively investigated in developing countries, including Myanmar, where NDM-type carbapenemases are spreading in clinical settings. In the present study, we phenotypically and genetically characterized 91 CPE isolates obtained from clinical (n = 77) and environmental (n = 14) samples in Yangon, Myanmar. We determined the dissemination of plasmids harboring genes encoding NDM-1 and its variants using whole-genome sequencing and plasmid analysis. IncFII plasmids harboring blaNDM-5 and IncX3 plasmids harboring blaNDM-4 or blaNDM-7 were the most prevalent plasmid types identified among the isolates. The IncFII plasmids were predominantly carried by clinical isolates of Escherichia coli, and their clonal expansion was observed within the same ward of a hospital. By contrast, the IncX3 plasmids were found in phylogenetically divergent isolates from clinical and environmental samples classified into nine species, suggesting the widespread dissemination of plasmids via horizontal transfer. Half of the environmental isolates were found to possess IncX3 plasmids, and this type of plasmid was confirmed to transfer more effectively to recipient organisms at a relatively low temperature (25°C) compared to the IncFII plasmid. Moreover, various other plasmid types were identified harboring blaNDM-1, including IncFIB, IncFII, IncL/M, and IncA/C2, among clinical isolates of Klebsiella pneumoniae or Enterobacter cloacae complex. Overall, our results highlight three distinct patterns of the dissemination of blaNDM-harboring plasmids among CPE isolates in Myanmar, contributing to gaining a better understanding of their molecular epidemiology and dissemination in an endemic setting.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Myanmar; Enterobacteriaceae.

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#Cefiderocol versus #imipenem-cilastatin for the #treatment of complicated #UTIs caused by Gram-negative #uropathogens: a phase 2, randomised, double-blind, non-inferiority trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial

Simon Portsmouth, MD,  David van Veenhuyzen, MBChB, Roger Echols, MD, Mitsuaki Machida, MS, Juan Camilo Arjona Ferreira, MD, Mari Ariyasu, BPharm, Prof Peter Tenke, MD, Tsutae Den Nagata, MD

Published: October 25, 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30554-1

 

Summary

Background

Carbapenem-resistant Gram-negative bacteria represent the highest priority for addressing global antibiotic resistance. Cefiderocol (S-649266), a new siderophore cephalosporin, has broad activity against Enterobacteriaceae and non-fermenting bacteria, such asPseudomonas aeruginosa and Acinetobacter baumannii, including carbapenem-resistant strains. We assessed the efficacy and safety of cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-negative infections.

Methods

We did a phase 2, multicentre, double-blind, parallel-group non-inferiority trial at 67 hospitals in 15 countries. Adults (≥18 years) admitted to hospital with a clinical diagnosis of complicated urinary tract infection with or without pyelonephritis or those with acute uncomplicated pyelonephritis were randomly assigned (2:1) by an interactive web or voice response system to receive 1 h intravenous infusions of cefiderocol (2 g) or imipenem-cilastatin (1 g each) three times daily, every 8 h for 7–14 days. Patients were excluded if they had a baseline urine culture with more than two uropathogens, a fungal urinary tract infection, or pathogens known to be carbapenem resistant. The primary endpoint was the composite of clinical and microbiological outcomes at test of cure (ie, 7 days after treatment cessation), which was used to establish non-inferiority (15% and 20% margins) of cefiderocol versus imipenem-cilastatin. The primary efficacy analysis was done on a modified intention-to-treat population, which included all randomly assigned individuals who received at least one dose of study drug and had a qualifying Gram-negative uropathogen (≥1 × 10 5 colony-forming units [CFU]/mL). Safety was assessed in all randomly assigned individuals who received at least one dose of study drug, according to the treatment they received. This study is registered withClinicalTrials.gov, number NCT02321800.

Findings

Between Feb 5, 2015, and Aug 16, 2016, 452 patients were randomly assigned to cefiderocol (n=303) or imipenem-cilastatin (n=149), of whom 448 patients (n=300 in the cefiderocol group; n=148 in the imipenem-cilastatin group) received treatment. 371 patients (n=252 patients in the cefiderocol group; n=119 patients in the imipenem-cilastatin group) had qualifying Gram-negative uropathogen (≥1 × 105 CFU/mL) and were included in the primary efficacy analysis. At test of cure, the primary efficacy endpoint was achieved by 183 (73%) of 252 patients in the cefiderocol group and 65 (55%) of 119 patients in the imipenem-cilastatin group, with an adjusted treatment difference of 18·58% (95% CI 8·23–28·92; p=0·0004), establishing the non-inferiority of cefiderocol. Cefiderocol was well tolerated. Adverse events occurred in 122 (41%) of 300 patients in the cefiderocol group and 76 (51%) of 148 patients in the imipenem-cilastatin group, with gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) the most common adverse events for both treatment groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group).

Interpretation

Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing.

Funding

Shionogi & Co Ltd, Shionogi Inc.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Imipenem-Cilastatin; Cefiderocol.

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Impact of Combination #Therapy vs Monotherapy on #Mortality from #Carbapenem-Resistant #Enterobacteriaceae #Bacteremia: A Retrospective Observational Study from a Chinese Network (Antimicrob Agents Chemother., abstract)

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

Impact of Combination Therapy vs Monotherapy on Mortality from Carbapenem-Resistant Enterobacteriaceae Bacteremia: A Retrospective Observational Study from a Chinese Network

Xiaojuan Wang, Qi Wang, Bin Cao, Shijun Sun, Yawei Zhang, Bing Gu, Binbin Li, Kang Liao, Feng Zhao, Liang Jin, Chunmei Jin, Chunxia Yang, Fengyan Pei, Zhijie Zhang, Hui Wang

DOI: 10.1128/AAC.01511-18

 

ABSTRACT

A total of 164 bloodstream infection cases due to carbapenem-resistant Enterobacteriaceae (CRE) in 2013-2017 were retrospectively collected from 36 tertiary hospitals in 19 provinces in China to evaluate outcomes and risk factors for mortality by univariable and multivariable analysis. The most frequent infected species was Klebsiella pneumoniae (69.5%, 114/164). The overall in-hospital and 14-day mortality were 32.9% (54/164) and 31.1% (42/135), respectively. Multivariable analysis revealed that septic shock (adjusted odds ratio [aOR] 6.339, 95% confidence interval [CI] 1.586-25.332, P = 0.009), Pitt bacteremia score (aOR 1.300, 95% CI 1.009-1.676, P = 0.042), and Charlson comorbidity index (aOR 1.392, 95% CI 1.104-1.755, P = 0.005) were independently associated with hazard effect on mortality. Combination therapy, especially tigecycline-based combination therapy had the lowest in-hospital mortality and rates of bacterial clearance. Survival analysis revealed that appropriate therapy was associated with lower 14-day mortality than inappropriate therapy (including non-active therapy, P = 0.022); combination therapy was superior to monotherapy (P = 0.036); metallo-β-lactamase producers resulted in lower 14-day mortality than strains without carbapenemases or KPC-2 producers (P= 0.009); strains with minimum inhibitory concentrations (MICs) > 8 mg/L for meropenem were associated with higher 14-day mortality than that with MICs ≤ 8 mg/L (P = 0.037). Collectively, severity of illness, meropenem MICs > 8 mg/L, carbapenemase-producing types are associated with clinical outcome. Early detection of carbapenemase type and initiating appropriate combination therapy within 96 h might be helpful for improving survival.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Tigecycline; Enterobacteriaceae; China.

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CG258 #Klebsiella pneumoniae isolates without β-lactam #resistance at the onset of the #carbapenem-resistant #Enterobacteriaceae #epidemic in #NYC (J Antimicrob Chemother., abstract)

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

CG258 Klebsiella pneumoniae isolates without β-lactam resistance at the onset of the carbapenem-resistant Enterobacteriaceae epidemic in New York City

Brandon Eilertson, Liang Chen, Audrey Li, Kalyan D Chavda, Bhakti Chavda, Barry N Kreiswirth

Journal of Antimicrobial Chemotherapy, dky394, https://doi.org/10.1093/jac/dky394

Published: 01 October 2018

 

Abstract

Objectives

To examine the epidemiology of β-lactam resistance in ‘clonal group 258’ (CG258), a successful KPC clonal group, over 14 years.

Methods

Isolates were collected from 1999 to 2013 for a study of antibiotic resistance in Enterobacteriaceae in New York City; 515 bloodstream isolates had antibiotic susceptibility data available and 436 were available for a CG258 PCR assay. The 56 resulting CG258 isolates were characterized by MLST, capsular type and ESBL and KPC carriage. KPC-positive isolates were assessed for common KPC plasmid types, KPC subtype and Tn4401 isoform.

Results

RT–PCR revealed 56 isolates were CG258. Seventeen of the 56 CG258 isolates were phenotypically susceptible to all carbapenems (all KPC negative). Five out of 17 susceptible isolates were of the cps-2 (wzi154) capsule type; none was cps-1 (wzi29). Nineteen out of 28 KPC-2 isolates were cps-1 (wzi29) and 8/10 KPC-3 isolates carried cps-2 (wzi154); however, cps-2 (wzi154) predominated among KPC-2-positive isolates in 2003 and 2004. KPC-2 was first detected in 2003 and KPC-3 was first detected in 2006. KPC-harbouring plasmids pKpQIL (all Tn4401a) and pBK30683 (all Tn4401d) were detected in 16/38 and 6/38 carbapenem-resistant isolates, respectively.

Discussion

CG258-lineage Klebsiella pneumoniae isolates were completely absent in 1999, but common in 2003. Twenty-one percent of CG258 isolates were susceptible to carbapenems in addition to lacking both common ESBL and blaKPC-mediated resistance. The cps-2 (wzi154) capsule type was common in both these susceptible isolates and in early KPC-2-harbouring isolates, suggesting it was the initial capsule type in CG258. Carbapenem-resistant isolates carried common KPC-harbouring plasmids with the same KPC and Tn4401 isoforms, suggesting frequent clonal spread.

Topic: polymerase chain reaction – plasmids – antibiotic resistance, bacterial – carbapenem – epidemiology – disease transmission – enterobacteriaceae – klebsiella pneumoniae – lactams – new york city – protein isoforms – reverse transcriptase  polymerase chain reaction – epidemics – antimicrobial susceptibility – multi-antibiotic resistance – extended-spectrum beta lactamases – bacterial carbapenemase resistance blakpc gene – carbapenem resistance – carbapenem-resistant enterobacteriaceae

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2018. 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.

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)

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Beta-lactams; Enterobacteriaceae; NYC; USA; Klebsiella pneumoniae.

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A large, #refractory #nosocomial #outbreak of #KPC-producing #Ecoli demonstrates carbapenemase gene #outbreaks involving #sink sites require novel approaches to infection control (AAC, abstract)

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

A large, refractory nosocomial outbreak of Klebsiella pneumoniaecarbapenemase (KPC)-producing Escherichia coli demonstrates carbapenemase gene outbreaks involving sink sites require novel approaches to infection control

V Decraene, H. T. T. Phan, R George, D. H. Wyllie, O Akinremi, Z Aiken, P Cleary, A Dodgson, L Pankhurst, D. W. Crook, C Lenney, A. S. Walker, N Woodford, R Sebra, F Fath-Ordoubadi,A. J. Mathers, A. C. Seale, M Guiver, A McEwan, V Watts, W Welfare, N Stoesser, J Cawthorne, the TRACE Investigators’ Group

DOI: 10.1128/AAC.01689-18

 

ABSTRACT

Carbapenem-resistant Enterobacteriaceae (CRE) are a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly highlighted as important potential reservoirs. We investigated a large Klebsiella pneumoniae carbapenemase (KPC)-producing E. coli (KPC-EC) outbreak and wider CRE incidence trends over eight years in the Central Manchester Foundation NHS Trust (CMFT), UK, to determine the impact of Infection Prevention and Control measures.

Bacteriology and patient administration data (2009 to 2017) were linked; a subset of CMFT/regional KPC-EC isolates (n=268) was sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (n=184,539 screens), environmental sampling, enhanced cleaning, and ward closure/plumbing replacement. Segmented regression of time trends of CRE detections was used to evaluate the impact of interventions on CRE incidence.

Genomic analysis (n=268 isolates) identified spread of a KPC-EC outbreak clone (ST216, strain-A; n=125) amongst patients and the environment, particularly on two cardiac wards (W3/W4), despite control measures. ST216 strain-A had caused an antecedent outbreak, and shared its KPC plasmids with other E. coli lineages and Enterobacteriaceae. CRE acquisition incidence declined after W3/W4 closure and plumbing replacement, suggesting an environmental contribution. However, W3/W4 wastewater sites were rapidly re-colonised with CRE and patient CRE acquisitions recurred, albeit at lower rates.

Patient relocation and plumbing replacement were associated with control of a clonal KPC-EC outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and persistence of blaKPC in E. coli, including pathogenic lineages, is a concern.

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Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; UK; England; E. Coli; Carbapenem; Nosocomial Outbreaks.

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Averting the #postantibiotic era: successful use of #meropenem/vaborbactam for #carbapenem-resistant #Serratia marcescens and #Enterobacter aerogenes bacteraemia in a haemodialysis patient (J Antimicrob Chemother., abstract)

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

Averting the post-antibiotic era: successful use of meropenem/vaborbactam for carbapenem-resistant Serratia marcescens and Enterobacter aerogenes bacteraemia in a haemodialysis patient

Sarah C J Jorgensen, Philip McDonald, Ryan P Mynatt, Jason M Pogue, Stephen A Lerner, Sorabh Dhar, Hossein Salimnia, Michael J Rybak

Journal of Antimicrobial Chemotherapy, dky346, https://doi.org/10.1093/jac/dky346

Published: 04 September 2018

Sir,

The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) has increased dramatically over the past two decades, fuelling speculation that we are nearing the ‘post-antibiotic era’ and attesting to the critical need for novel antibiotics with activity against MDR pathogens.1 In 2015 the US FDA approved ceftazidime/avibactam for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections caused by MDR Gram-negative bacteria.2 The introduction of ceftazidime/avibactam represented significant progress in the treatment of CRE, with accumulating real‐world data demonstrating improved efficacy and safety compared with older, more toxic antibiotics.3–5However, treatment failure rates as high as 30%–50% have been…

(…)

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Issue Section: Research letter

© The Author(s) 2018. 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.

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)

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Serratia marcescens; Enterobacter aerogenes; Bacteremia; Meropenem; Vaborbactam.

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