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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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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In vitro activity of #cefepime-#enmetazobactam against #Gramnegative isolates collected from #USA & #European #hospitals during 2014-2015 (Antimicrob Agents Chemother., abstract)

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

In vitro activity of cefepime-enmetazobactam against Gram-negative isolates collected from United States and European hospitals during 2014-2015

Ian Morrissey, Sophie Magnet, Stephen Hawser, Stuart Shapiro, Philipp Knechtle

DOI: 10.1128/AAC.00514-19

 

ABSTRACT

Enmetazobactam, formerly AAI101, is a novel penicillanic acid sulfone extended-spectrum β-lactamase inhibitor. The combination of enmetazobactam with cefepime has entered clinical trials to assess safety and efficacy in patients with complicated urinary tract infections. Here, the in vitro activity of cefepime-enmetazobactam was determined for 1,993 clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa collected in the US and Europe during 2014 and 2015. Enmetazobactam at a fixed concentration of 8 μg/ml lowered the cefepime MIC90from 16 to 0.12 μg/ml for Escherichia coli, >64 to 0.5 μg/ml for Klebsiella pneumoniae, 16 to 1 μg/ml for Enterobacter cloacae, and 0.5 to 0.25 μg/ml for Enterobacter aerogenes. Enmetazobactam did not enhance the potency of cefepime against P. aeruginosa. Applying the CLSI ‘susceptible-dose dependent’ (SDD) breakpoint of 8 μg/ml to cefepime-enmetazobactam for comparative purposes resulted in cumulative inhibitions of 99.9% for E. coli, 96.4% for K. pneumoniae, 97.0% for E. cloacae, 100% for E. aerogenes, 98.1% for all Enterobacteriaceae surveilled, and 82.8% for P. aeruginosa. Comparator susceptibilities for all Enterobacteriaceae were 99.7% for ceftazidime-avibactam, 96.2% for meropenem, 90.7% for ceftolozane-tazobactam, 87% for cefepime (SDD breakpoint), 85.7% for piperacillin-tazobactam, and 81.2% for ceftazidime. For the subset of ESBL-producing K. pneumoniae isolates, addition of 8 μg/ml enmetazobactam to cefepime lowered the MIC90 from >64 to 1 μg/ml, whereas the shift for 8 μg/ml tazobactam was from >64 to 8 μg/ml. Cefepime-enmetazobactam may represent a novel carbapenem-sparing option for empiric treatment of serious Gram-negative infections in settings where ESBL-producing Enterobacteriaceae are expected.

Copyright © 2019 Morrissey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Cefepime; Enmetazobactam.

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Efficacy of #Ceftriaxone, Cefepime, #Doxycycline, #Ciprofloxacin, and Combination #Therapy for #Vibrio vulnificus #Foodborne #Septicemia (AAC, abstract)

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

Efficacy of Ceftriaxone, Cefepime, Doxycycline, Ciprofloxacin, and Combination Therapy for Vibrio vulnificus Foodborne Septicemia

Sonya A. Trinh a, Hannah E. Gavin b and Karla J. F. Satchell b*

Author Affiliations: a Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Infectious Diseases, 645 North Michigan Avenue, Suite 900, Chicago, Illinois, 60611, USA; b Northwestern University Feinberg School of Medicine, Department of Microbiology-Immunology, 303 East Chicago Avenue, Ward 6-225, Chicago, Illinois, 60611, USA

 

ABSTRACT

Vibrio vulnificus foodborne infections have higher rates of sepsis and mortality compared to wound infections; however, antibiotic efficacy studies have not been performed in foodborne infection models. The efficacy of ceftriaxone, cefepime, doxycycline, ciprofloxacin, and combination therapy was assessed in a V. vulnificus intestinal infection in mice to model foodborne infections. Consistent with prior studies of cefotaxime, cefepime was synergistic with doxycycline and ciprofloxacin in vitro; combination therapy significantly decreased bacterial growth by ≥2log10 compared to antibiotic monotherapy (p<0.01). In vivo, survival in the ceftriaxone (50%), doxycycline (79%), and ciprofloxacin (80%) groups were significantly higher than the control group (0%) (p<0.0001). Survival with ceftriaxone-doxycycline (91%) and ceftriaxone-ciprofloxacin (100%) therapy was significantly higher than with ceftriaxone (50%) (p≤0.05). Survival with cefepime-doxycycline (96%) and cefepime-ciprofloxacin (90%) therapy was significantly higher than with cefepime (20%) (p<0.001). There was no difference in survival between the combination therapy groups. Thus, we conclude that combination therapy was the most effective treatment for V. vulnificus foodborne septicemia. In a septic patient with a recent ingestion of raw seafood, cefepime in combination with doxycycline or ciprofloxacin should be initiated for coverage of resistant Gram-negative organisms and V. vulnificus while awaiting a microbiological diagnosis. Once a diagnosis of V. vulnificus foodborne septicemia is established, treatment can be safely transitioned to ceftriaxone in combination with doxycycline or ciprofloxacin.

 

FOOTNOTES

*Corresponding Author: Karla J. F. Satchell, Northwestern University Feinberg School of Medicine, Department of Microbiology-Immunology, 303 East Chicago Avenue, Ward 6-205, Chicago, Illinois, 60611, USA, k-satchell@northwestern.edu

Copyright © 2017 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Vibrio Vulnificus; Ceftriaxone; Ciprofloxacin; Cefepime; Doxycycline.

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