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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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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In vitro activity of #imipenem/relebactam against Gram-negative #ESKAPE #pathogens isolated in 17 European countries: 2015 SMART surveillance programme (J Antimicrob Chemother., abstract)

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

In vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens isolated in 17 European countries: 2015 SMART surveillance programme

James A Karlowsky, Sibylle H Lob, Krystyna M Kazmierczak, Stephen P Hawser, Sophie Magnet, Katherine Young, Mary R Motyl, Daniel F Sahm

Journal of Antimicrobial Chemotherapy, dky107, https://doi.org/10.1093/jac/dky107

Published: 11 April 2018

 

Abstract

Objectives

Relebactam is an inhibitor of class A β-lactamases, including KPC β-lactamases, and class C β-lactamases, and is currently under clinical development in combination with imipenem. The objective of the current study was to evaluate the in vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) submitted by clinical laboratories in 17 European countries to the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance programme in 2015.

Methods

MICs were determined using the CLSI standard broth microdilution method and interpreted using EUCAST clinical breakpoints. Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. Imipenem/relebactam MICs were interpreted using breakpoints for imipenem.

Results

Rates of susceptibility to imipenem and imipenem/relebactam for isolates of P. aeruginosa (n = 1705), K. pneumoniae (n = 1591) and Enterobacter spp. (n = 772) were 72.0/94.7%, 88.7/94.8% and 95.6/96.8%, respectively. Relebactam restored imipenem susceptibility to 81.1%, 54.2% and 26.5% of imipenem-non-susceptible isolates of P. aeruginosa (n = 477), K. pneumoniae (n = 179) and Enterobacter spp. (n = 34). Most imipenem/relebactam-non-susceptible isolates carried MBLs, OXA-48 or GES carbapenemases. Relebactam did not increase the number of isolates of A. baumannii (n = 486) susceptible to imipenem.

Conclusions

Relebactam restored susceptibility to imipenem for the majority of imipenem-non-susceptible isolates of P. aeruginosa and K. pneumoniae tested as well as some isolates of imipenem-non-susceptible Enterobacter spp. Based on our results, imipenem/relebactam appears to be a promising therapeutic option for treating patients with infections caused by antimicrobial-resistant Gram-negative bacilli.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Klebsiella Pneumoniae; Pseudomonas Aeruginosa; Acinetobacter Baumannii; Imipenem; Relebactam.

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