Reduced #ceftazidime and #ertapenem susceptibility due to production of #OXA-2 in #Klebsiella pneumoniae ST258 (J Antimicrob Chemother., abstract)

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

Reduced ceftazidime and ertapenem susceptibility due to production of OXA-2 in Klebsiella pneumoniaeST258

Alina Iovleva, Roberta T Mettus, Christi L McElheny, Mustapha M Mustapha, Daria Van Tyne, Ryan K Shields, A William Pasculle, Vaughn S Cooper, Yohei Doi

Journal of Antimicrobial Chemotherapy, dkz183, https://doi.org/10.1093/jac/dkz183

Published: 24 May 2019

 

Abstract

Background

OXA-2 is a class D β-lactamase that confers resistance to penicillins, as well as narrow-spectrum cephalosporins. OXA-2 was recently reported to also possess carbapenem-hydrolysing activity. Here, we describe a KPC-2-encoding Klebsiella pneumoniae isolate that demonstrated reduced susceptibility to ceftazidime and ertapenem due to production of OXA-2.

Objectives

To elucidate the role of OXA-2 production in reduced ceftazidime and ertapenem susceptibility in a K. pneumoniae ST258 clinical isolate.

Methods

MICs were determined by the agar dilution method. WGS was conducted to identify and compare resistance genes between isolates. Expression of KPC-2 was quantified by quantitative RT–PCR and immunoblotting. OXA-2 was expressed in Escherichia coli TOP10, as well as in K. pneumoniae ATCC 13883, to define the relative contribution of OXA-2 in β-lactam resistance. Kinetic studies were conducted using purified OXA-2 enzyme.

Results

K. pneumoniae 1761 belonged to ST258 and carried both blaKPC-2 and blaOXA-2. However, expression of blaKPC-2 was substantially reduced due to an IS1294insertion in the promoter region. K. pneumoniae 1761, K. pneumoniae ATCC 13883 and E. coli TOP10 carrying blaOXA-2-harbouring plasmids showed reduced susceptibility to ertapenem and ceftazidime, but meropenem, imipenem and cefepime were unaffected. blaOXA-2 was carried on a 2910 bp partial class 1 integron containing aacA4-blaOXA-2-qacEΔ1-sul1 on an IncA/C2plasmid, which was not present in the earlier ST258 isolates possessing blaKPC-2 with intact promoters. Hydrolysis of ertapenem by OXA-2 was confirmed using purified enzyme.

Conclusions

Production of OXA-2 was associated with reduced ceftazidime and ertapenem susceptibility in a K. pneumoniae ST258 isolate.

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; Beta-lactams; Carbapenem; Ceftazidime; Ertapenem; Meropenem; Imipenem; Cefepime.

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Non-lytic #antibiotic #treatment in community-acquired #pneumococcal #pneumonia does not attenuate inflammation: the #PRISTINE trial (J Antimicrob Chemother., abstract)

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

Non-lytic antibiotic treatment in community-acquired pneumococcal pneumonia does not attenuate inflammation: the PRISTINE trial

Geert H Groeneveld, Tanny J van der Reyden, Simone A Joosten, Hester J Bootsma, Christa M Cobbaert Jutte, J C de Vries, Ed J Kuijper, Jaap T van Dissel

Journal of Antimicrobial Chemotherapy, dkz207, https://doi.org/10.1093/jac/dkz207

Published: 18 May 2019

 

Abstract

Background

The inflammatory response in pneumococcal infection is primarily driven by immunoreactive bacterial cell wall components [lipoteichoic acid (LTA)]. An acute release of these components occurs when pneumococcal infection is treated with β-lactam antibiotics.

Objectives

We hypothesized that non-lytic rifampicin compared with lytic β-lactam antibiotic treatment would attenuate the inflammatory response in patients with pneumococcal pneumonia.

Methods

In the PRISTINE (Pneumonia treated with RIfampicin aTtenuates INflammation) trial, a randomized, therapeutic controlled, exploratory study in patients with community-acquired pneumococcal pneumonia, we looked at LTA release and inflammatory and clinical response during treatment with both rifampicin and β-lactam compared with treatment with β-lactam antibiotics only. The trial is registered in the Dutch trial registry, number NTR3751 (European Clinical Trials Database number 2012-003067-22).

Results

Forty-one patients with community-acquired pneumonia were included; 17 of them had pneumococcal pneumonia. LTA release, LTA-mediated inflammatory responses, clinical outcomes, inflammatory biomarkers and transcription profiles were not different between treatment groups.

Conclusions

The PRISTINE study demonstrated the feasibility of adding rifampicin to β-lactam antibiotics in the treatment of community-acquired pneumococcal pneumonia, but, despite solid in vitro and experimental animal research evidence, failed to demonstrate a difference in plasma LTA concentrations and subsequent inflammatory and clinical responses. Most likely, an inhibitory effect of human plasma contributes to the low immune response in these patients. In addition, LTA plasma concentration could be too low to mount a response via Toll-like receptor 2 in vitro, but may nonetheless have an effect in vivo.

Topic: antibiotics – rifampin – inflammation – immune response – community acquired  pneumonia – biological markers – cell wall – lactams – plasma – pneumococcal infections – pneumonia, pneumococcal – treatment outcome – inflammatory response – community – toll-like receptor 2 – attenuation

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; S. pneumoniae; Pneumonia; Beta-lactams; Rifampin.

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Detection of the phenicol–oxazolidinone– #tetracycline #resistance gene poxtA in #Enterococcus faecium and Enterococcus faecalis of #food-producing #animal origin in #China (J Antimicrob Chemother., abstract)

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

Detection of the phenicol–oxazolidinone–tetracycline resistance gene poxtA in Enterococcus faecium and Enterococcus faecalis of food-producing animal origin in China

Chang-Wei Lei, Zhuang-Zhuang Kang, Shun-Kang Wu, Yan-Peng Chen, Ling-Han Kong, Hong-Ning Wang

Journal of Antimicrobial Chemotherapy, dkz198, https://doi.org/10.1093/jac/dkz198

Published: 18 May 2019

Issue Section: Research letter

___

Sir,

Oxazolidinones, including linezolid and tedizolid, are effective antimicrobial agents for treating infections caused by MDR Gram-positive bacteria, including VRE.1,2Linezolid is the first commercially available oxazolidinone that can inhibit protein synthesis by binding to the peptidyltransferase centre of the bacterial 23S rRNA. After introduction of linezolid, the resistance mechanism that emerged rapidly was related to mutations in genes coding for the 23S rRNA. The transferable oxazolidinone resistance determinants, cfr and optrA, have been reported in enterococci in several regions worldwide.3–6 Very recently, another transferable oxazolidinone resistance gene, poxtA, was reported in an MRSA of clinical origin…

(…)

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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.

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; Linezolid; Enterococcus spp.; Food Safety; China.

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#Social #norm #feedback reduces primary care #antibiotic #prescribing in a regression discontinuity study (J Antimicrob Chemother., abstract)

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

Social norm feedback reduces primary care antibiotic prescribing in a regression discontinuity study

Declan T Bradley, Sarah E Allen, Helen Quinn, Brenda Bradley, Matthew Dolan

Journal of Antimicrobial Chemotherapy, dkz222, https://doi.org/10.1093/jac/dkz222

Published: 20 May 2019

 

Abstract

Background

Reducing antibiotic prescribing is a priority for health authorities responsible for preventing antimicrobial resistance. Northern Ireland has high rates of antimicrobial use. We implemented a social norm feedback intervention and evaluated its impact.

Objectives

To estimate the size and duration of the effect of a social norm feedback letter to GPs who worked in the 20% of practices with the highest antimicrobial prescribing.

Methods

The letter was sent in October 2017 to 221 GPs in 67 practices. To assess the effect of the intervention, we used a sharp non-parametric regression discontinuity (RD) design, with prescribing rates in the four calendar quarters following the intervention as the outcome variables.

Results

In the quarter following the intervention (October to December 2017) there was a change of −25.7 (95% CI = −42.5 to −8.8, P = 0.0028) antibiotic items per 1000 Specific Therapeutic group Age-sex Related Prescribing Units (STAR-PU). At 1 year, the coefficient was −58.7 (95% CI = −116.7 to −0.7, P = 0.047) antibiotic items per 1000 STAR-PU. The greatest change occurred soon after the intervention. Approximately 18 900 fewer antibiotic items were prescribed than if the intervention had not been made (1% of Northern Ireland’s annual primary care antibiotic prescribing).

Conclusions

A social norm feedback intervention reduced antibiotic prescribing in the intervention practices. The diminishing effect over time suggests the need for more frequent feedback. The RD method allowed measurement of the effectiveness of an intervention that was delivered as part of normal business, without a randomized trial.

Topic:  antibiotics – feedback – northern ireland – primary health care – prescribing behavior – social norms

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; UK.

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#Ceftazidime – #Avibactam in Combination With #Fosfomycin: A Novel #Therapeutic Strategy Against #MDR #Pseudomonas aeruginosa (J Infect Dis., abstract)

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

Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa

Krisztina M Papp-Wallace, Elise T Zeiser, Scott A Becka, Steven Park, Brigid M Wilson, Marisa L Winkler, Roshan D’Souza, Indresh Singh, Granger Sutton, Derrick E Fouts, Liang Chen, Barry N Kreiswirth, Evelyn J Ellis-Grosse, George L Drusano, David S Perlin, Robert A Bonomo

The Journal of Infectious Diseases, jiz149, https://doi.org/10.1093/infdis/jiz149

Published: 17 May 2019

 

Abstract

Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to β-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a “mechanism-based approach” to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-β-lactamases.

Pseudomonas aeruginosa, β-lactams, fosfomycin, combination therapy

Topic:  pseudomonas aeruginosa – ceftazidime – fosfomycin – lactams – infection – mice – avibactam – avibactam/ceftazidime

Issue Section: Major Article

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Avibactam; Ceftazidime; Fosfomycin.

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#Trends and correlates of #antimicrobial use in #broiler and turkey #farms: a #poultry company registry-based study in #Italy (J Antimicrob Chemother., abstract)

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

Trends and correlates of antimicrobial use in broiler and turkey farms: a poultry company registry-based study in Italy

Claudia Caucci, Guido Di Martino, Alessandro Dalla Costa, Manuel Santagiuliana, Monica Lorenzetto, Katia Capello, Lapo Mughini-Gras, Luigi Gavazzi, Lebana Bonfanti

Journal of Antimicrobial Chemotherapy, dkz212, https://doi.org/10.1093/jac/dkz212

Published: 18 May 2019

 

Abstract

Background

Antimicrobial usage (AMU) in livestock plays a key role in the emergence and spread of antimicrobial resistance. Analysis of AMU data in livestock is therefore relevant for both animal and public health.

Objectives

To assess AMU in 470 broiler and 252 turkey farms of one of Italy’s largest poultry companies, accounting for around 30% of national poultry production, to identify trends and risk factors for AMU.

Methods

Antimicrobial treatments administered to 5827 broiler and 1264 turkey grow-out cycles in 2015–17 were expressed as DDDs for animals per population correction unit (DDDvet/PCU). A retrospective analysis was conducted to examine the effect of geographical area, season and prescribing veterinarian on AMU. Management and structural interventions implemented by the company were also assessed.

Results

AMU showed a 71% reduction in broilers (from 14 to 4 DDDvet/PCU) and a 56% reduction in turkeys (from 41 to 18 DDDvet/PCU) during the study period. Quinolones, macrolides and polymyxins decreased from 33% to 6% of total AMU in broilers, and from 56% to 32% in turkeys. Broiler cycles during spring and winter showed significantly higher AMU, as well as those in densely populated poultry areas. Different antimicrobial prescribing behaviour was identified among veterinarians.

Conclusions

This study evidenced a decreasing trend in AMU and identified several correlates of AMU in broilers and turkeys. These factors will inform the design of interventions to further reduce AMU and therefore counteract antimicrobial resistance in these poultry sectors.

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; Poultry; Food Safety; Italy.

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Presence of #NDM in non-E. coli #Enterobacteriaceae in the #poultry #production #environment (J Antimicrob Chemother., abstract)

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

Presence of NDM in non-E. coli Enterobacteriaceae in the poultry production environment

Rongmin Zhang, Jiyun Li, Yang Wang, Jianzhong Shen, Zhangqi Shen, Shaolin Wang

Journal of Antimicrobial Chemotherapy, dkz193, https://doi.org/10.1093/jac/dkz193

Published: 18 May 2019

 

Abstract

Objectives

Characterization of non-Escherichia coli NDM-carrying Enterobacteriaceae in the poultry production environment.

Methods

A total of 36 NDM-positive Enterobacteriaceae (22 Klebsiella pneumoniae, 13 Enterobacter cloacae and 1 Salmonella enterica) were isolated from a chicken farm and WGS was conducted using Illumina Hiseq2500. The genomic characterization of the isolates acquired through WGS analysis included the genomic context-flanking blaNDM genes, MLST, the antibiotic resistance genes (ARGs) and replicon types of plasmids. WGS information for another 73 K. pneumoniae isolates from different sources was retrieved from GenBank and then combined with isolates in this study for comparative genomic and phylogenetic analysis.

Results

Three types of genetic environment carrying blaNDM were identified in 36 non-E. coli Enterobacteriaceae isolates. Sequence comparison analysis indicated these genetic environments were completely identical to our previous findings. WGS further revealed three major types of plasmids (IncFIB, IncX3 and IncFII) from these isolates and the phylogenetic analysis suggested several K. pneumoniae isolates with ST11, ST37 and ST147 from the commercial chicken farm that were closely related to isolates of human origin.

Conclusions

The blaNDM-harbouring genetic contexts were identified not only in E. coli, but also in K. pneumoniae, E. cloacae and S. enterica, which may indicate that blaNDM has been widely disseminated to non-E. coli Enterobacteriaceae species in animal farms. The close relationship of K. pneumoniae isolates from different origins suggests they could serve as a key vehicle for the transfer of ARGs between humans and food animal production environments.

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; Enterobacteriaceae; NDM; Poultry; Food Safety.

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