Activity of #cefepime / #zidebactam (WCK 5222) against #Enterobacteriaceae, #Pseudomonas aeruginosa and #Acinetobacter baumannii endemic to #NYC #medical centres (J Antimicrob Chemother., abstract)

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

Activity of cefepime/zidebactam (WCK 5222) against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii endemic to New York City medical centres

Zeb Khan, Alejandro Iregui, David Landman, John Quale

Journal of Antimicrobial Chemotherapy, dkz294, https://doi.org/10.1093/jac/dkz294

Published: 11 July 2019

 

Abstract

Background

The combination of cefepime and zidebactam (WCK5222), a novel β-lactam enhancer, has demonstrated activity against a wide variety of Gram-negative pathogens and is currently under clinical evaluation.

Objectives

To examine the activity of cefepime/zidebactam against: (i) a contemporary collection of Gram-negative isolates from New York City; (ii) a collection of carbapenem-resistant clinical isolates; and (iii) a collection of isolates with characterized resistance mechanisms.

Methods

Susceptibility tests were performed using broth microdilution for cefepime, zidebactam and cefepime/zidebactam (1:1).

Results

More than 99% of a contemporary collection of Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. had cefepime/zidebactam MICs ≤2 mg/L, the susceptibility breakpoint for cefepime. For K. pneumoniae, the acquisition of blaKPC resulted in increased MICs, although MICs remained ≤2 mg/L for 90% of KPC-possessing isolates. Overall for Pseudomonas aeruginosa, 98% of isolates had MICs ≤8 mg/L and MICs were affected by increased expression of ampC. For carbapenem-resistant P. aeruginosa, 78% of isolates had cefepime/zidebactam MICs ≤8 mg/L. The activity of cefepime/zidebactam against Acinetobacter baumannii was lower, with 85% of all isolates and 34% of carbapenem-resistant isolates with MICs ≤8 mg/L (cefepime interpretative criteria).

Conclusions

Cefepime/zidebactam demonstrated excellent activity against Enterobacteriaceae and P. aeruginosa, although activity was reduced in carbapenem-non-susceptible isolates. The activity against A. baumannii was reduced and studies examining the therapeutic efficacy in strains with high cefepime/zidebactam MICs are warranted.

Topic:  pseudomonas aeruginosa – cefepime – enterobacter – enterobacteriaceae – new york city – acinetobacter baumannii – bacterial carbapenemase resistance blakpc gene – malnutrition-inflammation-cachexia syndrome – carbapenem resistance

Issue Section: ORIGINAL RESEARCH

© 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.

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; Enterobacteriaceae; Pseudomonas aeruginosa; Acinetobacter baumannii; Cefepine; Zidebactam; USA; NYC.

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Susceptibility of #carbapenemase-producing #Enterobacterales (CPE) to #nitroxoline (J Antimicrob Chemother., abstract)

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

Susceptibility of carbapenemase-producing Enterobacterales (CPE) to nitroxoline

Frieder Fuchs, Axel Hamprecht

Journal of Antimicrobial Chemotherapy, dkz275, https://doi.org/10.1093/jac/dkz275

Published: 10 July 2019

 

Abstract

Background

Infections caused by carbapenemase-producing Enterobacterales (CPE) constitute a major global health concern and are associated with increased morbidity and mortality. Nitroxoline is an old antibiotic, which has recently been re-launched for the treatment of uncomplicated urinary tract infection. Because of low resistance rates it could be an interesting option for treatment of MDR isolates, yet data on CPE susceptibility are scarce.

Objectives

To analyse the in vitro activity of nitroxoline against CPE.

Methods

MICs of nitroxoline were determined by agar dilution for a collection of well-characterized carbapenemase producers (n = 105), producing OXA-48-like (n = 36), VIM (n = 21), IMI (n = 9), IMP (n = 6), NDM (n = 22), KPC (n = 11), OXA-58 (n = 2) and GES (n = 2). For comparison, MICs of ertapenem, imipenem and meropenem were determined by agar gradient diffusion.

Results

For all 105 isolates, the MIC50/90 of nitroxoline was 8/16 mg/L. All Escherichia coli isolates (30/30, 100%) showed low MICs of 2–8 mg/L and were susceptible to nitroxoline. MICs of 32 mg/L were recorded for five isolates of VIM- and IMI-producing Enterobacter cloacae (n = 3) and OXA- and VIM-producing Klebsiella pneumoniae (n = 2).

Conclusions

Nitroxoline exhibited excellent in vitro activity against most isolates producing common and rare carbapenemases. If the current EUCAST susceptibility breakpoint of ≤16 mg/L for E. coli in uncomplicated urinary tract infections was applied, 95.2% (100/105) of isolates would be classified as susceptible. Nitroxoline could therefore be an alternative oral option for treatment of uncomplicated urinary tract infections caused by CPE.

Topic: antibiotics – urinary tract infections – diffusion – agar – enterobacter cloacae – imipenem – klebsiella pneumoniae – world health – infection – morbidity – mortality – meropenem – ertapenem – escherichia coli – dilution technique – dilute (action) – malnutrition-inflammation-cachexia syndrome

Issue Section: ORIGINAL RESEARCH

© 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.

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; UTI; Enterobacteriaceae; Nitroxoline.

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#Antibiotics with activity against #intestinal #anaerobes and the #hazard of acquired #colonization with #ceftriaxone-resistant Gram-negative pathogens in #ICU patients: a propensity score-based analysis (J Antimicrob Chemother., abstract)

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

Antibiotics with activity against intestinal anaerobes and the hazard of acquired colonization with ceftriaxone-resistant Gram-negative pathogens in ICU patients: a propensity score-based analysis

Maxime Boutrot, Khalid Azougagh, Jérôme Guinard, Thierry Boulain, François Barbier

Journal of Antimicrobial Chemotherapy, dkz279, https://doi.org/10.1093/jac/dkz279

Published: 09 July 2019

 

Abstract

Background

Intestinal colonization resistance is mainly exerted by commensal anaerobes.

Objectives

To assess whether exposure to non-carbapenem antibiotics with activity against intestinal anaerobes (namely, piperacillin/tazobactam, amoxicillin/clavulanate and metronidazole) may promote the acquisition of gut colonization with ceftriaxone-resistant Gram-negative bacteria (CFR-GNB) in ICU patients.

Patients and methods

All patients with a first stay >3 days in a single surgical ICU over a 30 month period were retrospectively included. Rectal carriage of CFR-GNB (i.e. ESBL-producing Enterobacteriaceae, AmpC-hyperproducing Enterobacteriaceae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia and CFR Acinetobacter baumannii) was routinely screened for at admission then weekly. The impact of anti-anaerobe antibiotics was investigated in propensity score (PS)-matched cohorts of patients exposed and not exposed to these drugs and through PS-based inverse probability of treatment weighting on the whole study cohort, treating in-ICU death or discharge as competing risks for CFR-GNB acquisition.

Results

Among the 352 included patients [median ICU stay 16 (9–30) days, in-ICU mortality 12.2%], 120 (34.1%) acquired one or more CFR-GNB, mostly AmpC-hyperproducing Enterobacteriaceae (17.6%) and P. aeruginosa (14.8%). Exposure to anti-anaerobe antibiotics was the main predictor of CFR-GNB acquisition in both the PS-matched cohorts [adjusted HR (aHR) 3.92, 95% CI 1.12–13.7, P = 0.03] and the whole study cohort (aHR 4.30, 95% CI 1.46–12.63, P = 0.01). Exposure to other antimicrobials—especially ceftriaxone and imipenem/meropenem—exerted no independent impact on the likelihood of CFR-GNB acquisition.

Conclusions

Exposure to non-carbapenem antibiotics with activity against intestinal anaerobes may predispose to CFR-GNB acquisition in ICU patients. Restricting the use of these drugs appears to be an antibiotic stewardship opportunity.

Topic: antibiotics – ceftriaxone – exertion – carbapenem – amoxicillin-potassium clavulanate combination – anaerobic bacteria – disease transmission – imipenem – intensive care unit – intestines – metronidazole – aryl hydrocarbon receptor – meropenem – piperacillin/tazobactam – pathogenic organism – antimicrobials – microbial colonization

Issue Section: ORIGINAL RESEARCH

© 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.

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; Ceftriaxone; Enterobacteriaceae; ICU.

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Optical #DNA #Mapping Combined with #Cas9-Targeted #Resistance #Gene #Identification for Rapid #Tracking of Resistance #Plasmids in a #NICU #Outbreak (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

Optical DNA Mapping Combined with Cas9-Targeted Resistance Gene Identification for Rapid Tracking of Resistance Plasmids in a Neonatal Intensive Care Unit Outbreak

Santosh K. Bikkarolla, Viveka Nordberg, Fredrika Rajer, Vilhelm Müller, Muhammad Humaun Kabir, Sriram KK, Albertas Dvirnas, Tobias Ambjörnsson, Christian G. Giske, Lars Navér,Linus Sandegren, Fredrik Westerlund

Spyros Pournaras, Invited Editor, Karen Bush, Editor

DOI: 10.1128/mBio.00347-19

 

ABSTRACT

The global spread of antibiotic resistance among Enterobacteriaceae is largely due to multidrug resistance plasmids that can transfer between different bacterial strains and species. Horizontal gene transfer of resistance plasmids can complicate hospital outbreaks and cause problems in epidemiological tracing, since tracing is usually based on bacterial clonality. We have developed a method, based on optical DNA mapping combined with Cas9-assisted identification of resistance genes, which is used here to characterize plasmids during an extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae outbreak at a Swedish neonatal intensive care unit. The outbreak included 17 neonates initially colonized with ESBL-producing Klebsiella pneumoniae (ESBL-KP), some of which were found to carry additional ESBL-producing Escherichia coli (ESBL-EC) in follow-up samples. We demonstrate that all ESBL-KP isolates contained two plasmids with the blaCTX-M-15 gene located on the smaller one (~80 kbp). The same ESBL-KP clone was present in follow-up samples for up to 2 years in some patients, and the plasmid carrying the blaCTX-M-15 gene was stable throughout this time period. However, extensive genetic rearrangements within the second plasmid were observed in the optical DNA maps for several of the ESBL-KP isolates. Optical mapping also demonstrated that even though other bacterial clones and species carrying blaCTX-M group 1 genes were found in some neonates, no transfer of resistance plasmids had occurred. The data instead pointed toward unrelated acquisition of ESBL-producing Enterobacteriaceae (EPE). In addition to revealing important information about the specific outbreak, the method presented is a promising tool for surveillance and infection control in clinical settings.

IMPORTANCE

This study presents how a novel method, based on visualizing single plasmids using sequence-specific fluorescent labeling, could be used to analyze the genetic dynamics of an outbreak of resistant bacteria in a neonatal intensive care unit at a Swedish hospital. Plasmids are a central reason for the rapid global spread of bacterial resistance to antibiotics. In a single experimental procedure, this method replaces many traditional plasmid analysis techniques that together provide limited details and are slow to perform. The method is much faster than long-read whole-genome sequencing and offers direct genetic comparison of patient samples. We could conclude that no transfer of resistance plasmids had occurred between different bacteria during the outbreak and that secondary cases of ESBL-producing Enterobacteriaceae carriage were instead likely due to influx of new strains. We believe that the method offers potential in improving surveillance and infection control of resistant bacteria in hospitals.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Beta-lactams; Nosocomial Outbreaks; Diagnostic tests.

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#Carbapenemase-producing #Enterobacteriaceae and #Aeromonas spp. present in #wastewater treatment #plant effluent and nearby surface waters in the #US (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Carbapenemase-producing Enterobacteriaceae and Aeromonas spp. present in wastewater treatment plant effluent and nearby surface waters in the US

Dimitria A. Mathys, Dixie F. Mollenkopf, Sydnee M. Feicht, Rachael J. Adams, Amy L. Albers, David M. Stuever, Susan V. Grooters, Gregory A. Ballash, Joshua B. Daniels, Thomas E. Wittum

Published: June 26, 2019 / DOI: https://doi.org/10.1371/journal.pone.0218650

 

Abstract

Carbapenemase-producing bacteria (CPB) are rare, multidrug resistant organisms most commonly associated with hospitalized patients. Metropolitan wastewater treatment plants (WWTP) treat wastewater from large geographic areas which include hospitals and may serve as epidemiologic reservoirs for the maintenance or expansion of CPB that originate from hospitals and are ultimately discharged in treated effluent. However, little is known about the potential impact of these WWTP CPB on the local surface water and their risk to the public health. In addition, CPB that are present in surface water may ultimately disseminate to intensively-managed animal agriculture facilities where there is potential for amplification by extended-spectrum cephalosporins. To better understand the role of WWTPs in the dissemination of CPB in surface waters, we obtained samples of treated effluent, and both upstream and downstream nearby surface water from 50 WWTPs throughout the US. A total of 30 CPB with clinically-relevant genotypes were recovered from 15 WWTPs (30%) of which 13 (50%) serviced large metropolitan areas and 2 (8.3%) represented small rural populations (P < 0.05). Recovery of CPB was lowest among WWTPs that utilized ultraviolet radiation for primary disinfection (12%), and higher (P = 0.11) for WWTPs that used chlorination (42%) or that did not utilize disinfection (50%). We did not detect a difference in CPB recovery by sampling site, although fewer CPB were detected in upstream (8%) compared to effluent (20%) and downstream (18%) samples. Our results indicate that WWTP effluent and nearby surface waters in the US are routinely contaminated with CPB with clinically important genotypes including those producing Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-beta-lactamase (NDM). This is a concern for both public health and animal agriculture because introduction of CPB into intensively managed livestock populations could lead to their amplification and foodborne dissemination.

___

Citation: Mathys DA, Mollenkopf DF, Feicht SM, Adams RJ, Albers AL, Stuever DM, et al. (2019) Carbapenemase-producing Enterobacteriaceae and Aeromonas spp. present in wastewater treatment plant effluent and nearby surface waters in the US. PLoS ONE 14(6): e0218650. https://doi.org/10.1371/journal.pone.0218650

Editor: Zhi Zhou, Purdue University, UNITED STATES

Received: September 22, 2018; Accepted: June 6, 2019; Published: June 26, 2019

Copyright: © 2019 Mathys et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The data have been deposited with links to BioProject accession number PRJNA472583 in the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/).

Funding: Funding for this project was provided by the USDA NIFA award no. 2014-67005-21709 (TEW, JBD).

Competing interests: The authors have declared that no competing interests exist.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; Environmental pollution; USA:

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#Structural bases for F #plasmid #conjugation and F pilus #biogenesis in #Escherichia coli (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Structural bases for F plasmid conjugation and F pilus biogenesis in Escherichia coli

Bo Hu, Pratick Khara, and Peter J. Christie

PNAS first published June 25, 2019 / DOI: https://doi.org/10.1073/pnas.1904428116

Edited by Scott J. Hultgren, Washington University School of Medicine, St. Louis, MO, and approved June 5, 2019 (received for review March 14, 2019)

 

Significance

Bacterial “sex,” or conjugation, is a central mechanism underlying the proliferation of antibiotic resistance. Despite the discovery of conjugation by F plasmids in Escherichia coliover seven decades ago, we have only now visualized the F-encoded transfer channel and F pilus-associated platforms in the E. coli cell envelope by cryoelectron tomography. The channel supports plasmid transfer or assembly of F pili, which remarkably upon synthesis are deposited onto alternative basal structures around the cell surface. The F plasmid transfer system is a paradigm for the bacterial type IV secretion system (T4SS) superfamily. Consequently, the F-encoded structures are broadly informative of mechanisms underlying the biogenesis and function of type IV secretion machines and associated conjugative pili.

 

Abstract

Bacterial conjugation systems are members of the large type IV secretion system (T4SS) superfamily. Conjugative transfer of F plasmids residing in the Enterobacteriaceae was first reported in the 1940s, yet the architecture of F plasmid-encoded transfer channel and its physical relationship with the F pilus remain unknown. We visualized F-encoded structures in the native bacterial cell envelope by in situ cryoelectron tomography (CryoET). Remarkably, F plasmids encode four distinct structures, not just the translocation channel or channel-pilus complex predicted by prevailing models. The F1 structure is composed of distinct outer and inner membrane complexes and a connecting cylinder that together house the envelope-spanning translocation channel. The F2 structure is essentially the F1 complex with the F pilus attached at the outer membrane (OM). Remarkably, the F3 structure consists of the F pilus attached to a thin, cell envelope-spanning stalk, whereas the F4 structure consists of the pilus docked to the OM without an associated periplasmic density. The traffic ATPase TraC is configured as a hexamer of dimers at the cytoplasmic faces of the F1 and F2 structures, where it respectively regulates substrate transfer and F pilus biogenesis. Together, our findings present architectural renderings of the DNA conjugation or “mating” channel, the channel–pilus connection, and unprecedented pilus basal structures. These structural snapshots support a model for biogenesis of the F transfer system and allow for detailed comparisons with other structurally characterized T4SSs.

cryoelectron tomography – DNA conjugation – type IV secretion – pilus – protein transport

 

Footnotes

1 To whom correspondence may be addressed. Email: bo.hu@uth.tmc.edu or peter.j.christie@uth.tmc.edu.

Author contributions: B.H. and P.J.C. designed research; B.H. and P.K. performed research; B.H., P.K., and P.J.C. analyzed data; and P.J.C. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: Density maps and coordinate data that support the F-encoded channel structures determined by cryoelectron tomography have been deposited in The Electron Microscopy Data Bank (EMDB), https://www.ebi.ac.uk/pdbe/emdb (entry nos. EMD-9344 and EMD-9347).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1904428116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Enterobacteriaceae; Plasmids.

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#Carbapenem and #Cephalosporin #Resistance among #Enterobacteriaceae in #Healthcare-Associated #Infections, #California, #USA (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 7—July 2019 / Dispatch

Carbapenem and Cephalosporin Resistance among Enterobacteriaceae in Healthcare-Associated Infections, California, USA1

Kyle Rizzo  , Sam Horwich-Scholefield, and Erin Epson

Author affiliations: California Department of Public Health, Richmond, California, USA

 

Abstract

We analyzed antimicrobial susceptibility test results reported in healthcare-associated infections by California hospitals during 2014–2017. Approximately 3.2% of Enterobacteriaceae reported in healthcare-associated infections were resistant to carbapenems and 26.9% were resistant to cephalosporins. The proportion of cephalosporin-resistant Escherichia coli increased 7% (risk ratio 1.07, 95% CI 1.04–1.11) per year during 2014–2017.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Cephalosporins; Nosocomial Outbreraks; California; USA.

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