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

© 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; Colistin; MCR1; Enterobacteriaceae; Imipenem; Relebactam.

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#Therapeutic efficacy of LN-1-255 in combination with #imipenem in severe #infection caused by #carbapenem-resistant #Acinetobacter baumannii (Antimicrob Agents Chemother., abstract)

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

Therapeutic efficacy of LN-1-255 in combination with imipenem in severe infection caused by carbapenem-resistant Acinetobacter baumannii

Juan Carlos Vázquez-Ucha, Marta Martínez-Guitián, María Maneiro, Kelly Conde-Pérez, Laura Álvarez-Fraga, Gabriel Torrens, Antonio Oliver, John D. Buynak, Robert A. Bonomo,Germán Bou, Concepción González-Bello, Margarita Poza, Alejandro Beceiro

DOI: 10.1128/AAC.01092-19

 

ABSTRACT

OBJETIVES:

The Carbapenem-Hydrolyzing Class D β-Lactamases (CHDLs) are the main mechanism of carbapenem resistance in A. baumannii. CHDLs are not effectively inactivated by clinically available β-lactam-type inhibitors. We have previously described the in vitroefficacy of the inhibitor LN-1-255 in combination with carbapenems. The aim of this study was to compare the efficacy of LN-1-255 with that of imipenem in murine pneumonia using A. baumannii strains carrying their most extended carbapenemases: OXA-23 and OXA-24/40.

METHODS:

The blaOXA-23 and blaOXA-24/40 genes were cloned into carbapenem-susceptible A. baumannii ATCC 17978 strain. Clinical isolates AB1 and JC12/04, producing the enzymes OXA-23 and OXA-24/40, respectively, were used in the study. Pharmacokinetic parameters were determined. An experimental pneumonia model was used to evaluate the efficacy of the combined imipenem/LN-1-255 therapy.

RESULTS:

MICs of imipenem decreased between 32 and 128-fold in presence of LN-1-255. Intramuscular treatment with imipenem/LN-1-255 (30/50 mg/Kg) decreased the bacterial burden i) 4 and 1.7 log10 CFU/g lung in the infection with the ATCC 17978-OXA-23 and the AB1 strains, respectively and ii) 2.5 and 4.5 log10 CFU/g lung the infection produced by the ATCC 17978-OXA-24/40 and the JC12/04 strains, respectively. In all assays combined therapy offered higher protection against pneumonia than those treated with monoteraphy. No toxicity was observed in treated mice.

CONCLUSIONS:

Imipenem treatment combined with LN-1-255 reduced significantly the severity of infection by carbapenem-resistant A. baumannii strains carrying CHDLs. Preclinical assays demonstrated the potential of the therapy of LN-1-255 and imipenem as new antibacterial treatment.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Imipenem; Acinetobacter baumannii; Animal models.

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Emergence of #ceftazidime / #avibactam #resistance in #KPC-3-producing #Klebsiella pneumoniae in vivo (J Antimicrob Chemother., abstract)

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

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

Stephan Göttig, Denia Frank, Eleonora Mungo, Anika Nolte, Michael Hogardt, Silke Besier,Thomas A Wichelhaus

Journal of Antimicrobial Chemotherapy, dkz330, https://doi.org/10.1093/jac/dkz330

Published: 31 July 2019

 

Abstract

Objectives

The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro.

Methods

Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination.

Results

The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival.

Conclusions

Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivoinfection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

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; Ceftazidime; Avibactam; Imipenem; Klebsiella pneumoniae.

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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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Activity of # imipenem / #relebactam against #MDR #Pseudomonas aeruginosa in #Europe: SMART 2015–17 (J Antimicrob Chemother., abstract)

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

Activity of imipenem/relebactam against MDR Pseudomonas aeruginosa in Europe: SMART 2015–17

Sibylle H Lob, James A Karlowsky, Katherine Young, Mary R Motyl, Stephen Hawser, Nimmi D Kothari, Melinda E Gueny, Daniel F Sahm

Journal of Antimicrobial Chemotherapy, dkz191, https://doi.org/10.1093/jac/dkz191

Published: 13 May 2019

 

Abstract

Objectives

Relebactam is a diazabicyclooctane non-β-lactam inhibitor of Ambler class A and C β-lactamases that is in clinical development in combination with imipenem/cilastatin. The current study evaluated the in vitro activity of imipenem/relebactam against 5447 isolates of Pseudomonas aeruginosasubmitted to the SMART global surveillance programme in 2015–17 by 67 clinical laboratories in 22 European countries.

Methods

MICs were determined using the CLSI broth microdilution reference method (Eleventh Edition: M07, 2018). Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. MICs were interpreted using EUCAST clinical breakpoints (version 8.1); imipenem breakpoints were applied to imipenem/relebactam.

Results

Rates of susceptibility to imipenem and imipenem/relebactam (MIC ≤4 mg/L) were 69.4% and 92.4%, respectively, for all isolates of P. aeruginosa. Over one-third of all isolates (34.9%, 1902/5447) were MDR; lower respiratory tract isolates (38.3%, 1327/3461) were more frequently MDR than were intraabdominal (28.5%, 355/1245) or urinary tract (29.7%, 212/714) isolates. Of all MDR isolates, 78.2% were susceptible to imipenem/relebactam, a rate that was 50–77 percentage points higher than the rate of susceptibility to imipenem or any other β-lactam tested; rates of susceptibility to imipenem/relebactam were similar for MDR isolates from lower respiratory tract (77.8% susceptible), intraabdominal (80.3%) and urinary tract (76.4%) infections. Overall, relebactam restored imipenem susceptibility to 75.2% (1254/1668) of imipenem-non-susceptible isolates of P. aeruginosa and to 69.6% (947/1361) of imipenem-non-susceptible isolates with an MDR phenotype.

Conclusions

Relebactam restored in vitro susceptibility to imipenem for most imipenem-non-susceptible and MDR clinical isolates of P. aeruginosa from European patients.

Topic: phenotype – pseudomonas aeruginosa – imipenem – lactams – respiratory system – urinary tract – infection

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Relebactam; Imipenem; European Region.

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Potentiation of #imipenem by #relebactam for #Pseudomonas aeruginosa from #bacteraemia and respiratory infections (J Antimicrob Chemother., abstract)

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

Potentiation of imipenem by relebactam for Pseudomonas aeruginosa from bacteraemia and respiratory infections

Carolyne Horner, Shazad Mushtaq, David M Livermore, BSAC Resistance Surveillance Standing Committee

Journal of Antimicrobial Chemotherapy, dkz133, https://doi.org/10.1093/jac/dkz133

Published: 29 April 2019

 

Abstract

Background

Imipenem resistance in Pseudomonas aeruginosa most often entails loss of the ‘carbapenem-specific’ porin OprD; more rarely it reflects acquired carbapenemases. Loss of OprD only confers resistance to imipenem if AmpC β-lactamase is expressed, and we investigated whether this mechanism was overcome by relebactam, a developmental diazabicyclooctane β-lactamase inhibitor.

Methods

Consecutive P. aeruginosa isolates causing bacteraemia or hospital-onset lower respiratory tract infections were collected between 2014 and 2016 under the aegis of the BSAC Resistance Surveillance Programme. Imipenem MICs were determined centrally by BSAC agar dilution, with relebactam at a fixed concentration (4 mg/L).

Results

For most imipenem-susceptible P. aeruginosa (726/759, 95.7%), the MICs of imipenem alone were 0.5–2 mg/L and were decreased 3- to 4-fold by addition of relebactam, as based on geometric means or modes. For most imipenem-resistant P. aeruginosa (82/92, 89%), imipenem MICs were 8–16 mg/L, and were reduced to 1–2 mg/L by relebactam. These patterns applied regardless of whether the isolates were susceptible to penicillins and cephalosporins or had phenotypes suggesting derepressed AmpC or up-regulated efflux. Imipenem MICs for five P. aeruginosa with MBLs remained high (≥16 mg/L) regardless of relebactam.

Conclusions

Potentiation of imipenem by relebactam was almost universal, in accordance with the view that endogenous pseudomonal AmpC ordinarily protects against this carbapenem to a small degree. Imipenem MICs were reduced to the current breakpoint, or lower, except for MBL producers. Potentiation was not compromised by derepression of AmpC or up-regulation of efflux.

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Imipenem; Relebactam.

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The first #isolation of #Clostridium difficile RT078/ST11 from #pigs in #China (PLoS One, abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

The first isolation of Clostridium difficile RT078/ST11 from pigs in China

Li-Juan Zhang, Ling Yang, Xi-Xi Gu, Pin-Xian Chen, Jia-Li Fu, Hong-Xia Jiang

Published: February 26, 2019 / DOI: https://doi.org/10.1371/journal.pone.0212965

 

Abstract

We investigated the molecular characteristics and antimicrobial susceptibility of Clostridium difficile isolated from animals in China. We obtained 538 rectal swabs from pigs, chickens and ducks in 5 provinces during 2015 and 2016. C. difficile isolates were characterized by detection of toxin genes, multilocus sequence typing and ribotyping. And antimicrobial susceptibility testing was performed using the agar dilution method. Out of 538 samples, 44 (8.2%) were C. difficile positive with high prevalence in pigs (n = 31). Among these, 39 (88.6%) were toxigenic including 14 (31.8%) that were A+B+CDT+ and 13 (29.5%) A+B+. The remaining 12 (27.3%) were A-B+. We identified 7 ST types and 6 PCR ribotypes. The most predominant type was ST11/RT078 with toxin profile A+B+CDT+ and all were isolated from piglets with diarrhea. ST109 isolates possessed two different toxigenic profiles (A-B-CDT- and A-B+CDT-) and although it was not the most prevalent sequence type, but it was widely distributed between chickens, ducks and pigs in the 5 provinces. All C. difficile isolates were fully susceptible to vancomycin, metronidazole, fidaxomicin, amoxicillin/clavulanate and meropenem but retained resistance to 4 or 5 of the remaining antibiotics, especially cefotaxime, tetracycline, ciprofloxacin, cefoxitin. The RT078/ST11 isolates were simultaneously resistant to cefotaxime, tetracycline, cefoxitin, ciprofloxacin and imipenem. This is the first report of the molecular epidemiology of C. difficile isolated from food animals in China. We identified the epidemic strain RT078/ST11 as the predominate isolate among the animals we screened in our study.

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Citation: Zhang L-J, Yang L, Gu X-X, Chen P-X, Fu J-L, Jiang H-X (2019) The first isolation of Clostridium difficile RT078/ST11 from pigs in China. PLoS ONE 14(2): e0212965. https://doi.org/10.1371/journal.pone.0212965

Editor: Pradeep Dudeja, University of Illinois at Chicago, UNITED STATES

Received: November 2, 2018; Accepted: February 12, 2019; Published: February 26, 2019

Copyright: © 2019 Zhang 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: All relevant data are within the paper.

Funding: This work was supported by the National Natural Science Foundation of China (31272602) (H-XJ) and Graduate Student Oversea Study Program of South China Agriculture University (2017LHPY029) (LY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

Keywords: Antibiotics; Drugs Resistance; Clostridium difficile; Pigs; China.

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