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      Activity of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected in central and northern Europe (Belgium, Norway, Sweden, Switzerland)—SMART 2017–21

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          Abstract

          Objectives

          To evaluate the in vitro activities of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Gram-negative bacilli collected in four central and northern European countries (Belgium, Norway, Sweden, Switzerland) during 2017–21.

          Methods

          Participating clinical laboratories each collected up to 250 consecutive Gram-negative isolates per year from patients with bloodstream, intraabdominal, lower respiratory tract or urinary tract infections. MICs were determined by CLSI broth microdilution and interpreted using 2022 EUCAST breakpoints. β-Lactamase genes were identified in select β-lactam-non-susceptible isolate subsets.

          Results

          Ninety-five percent of all Enterobacterales ( n = 4158), 95% of ESBL-positive non-carbapenem-resistant Enterobacterales (non-CRE) phenotype Escherichia coli and 85% of ESBL-positive non-CRE phenotype Klebsiella pneumoniae were ceftolozane/tazobactam susceptible. By country, 88% (Belgium), 91% (Sweden, Switzerland) and 96% (Norway) of ESBL-positive non-CRE phenotype Enterobacterales were ceftolozane/tazobactam susceptible. Greater than ninety-nine percent of non-Morganellaceae Enterobacterales and all ESBL-positive non-CRE phenotype Enterobacterales were imipenem/relebactam susceptible. Ceftolozane/tazobactam (96%) and imipenem/relebactam (95%) inhibited most Pseudomonas aeruginosa ( n = 823). Both agents retained activity against ≥75% of cefepime-resistant, ceftazidime-resistant and piperacillin/tazobactam-resistant isolates; 56% and 43% of meropenem-resistant isolates were ceftolozane/tazobactam susceptible and imipenem/relebactam susceptible, respectively. By country, 94% (Belgium), 95% (Sweden) and 100% (Norway, Switzerland) of P. aeruginosa were ceftolozane/tazobactam susceptible and 93% (Sweden) to 98% (Norway, Switzerland) were imipenem/relebactam susceptible. Carbapenemase gene carriage among Enterobacterales and P. aeruginosa isolates was generally low (<1%) or completely absent with one exception: an estimated 2.7% of P. aeruginosa isolates from Belgium carried an MBL.

          Conclusions

          Recent clinical isolates of Enterobacterales and P. aeruginosa collected in four central and northern European countries were highly susceptible (≥95%) to ceftolozane/tazobactam and imipenem/relebactam.

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          Most cited references16

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          ResFinder 4.0 for predictions of phenotypes from genotypes

          Abstract Objectives WGS-based antimicrobial susceptibility testing (AST) is as reliable as phenotypic AST for several antimicrobial/bacterial species combinations. However, routine use of WGS-based AST is hindered by the need for bioinformatics skills and knowledge of antimicrobial resistance (AMR) determinants to operate the vast majority of tools developed to date. By leveraging on ResFinder and PointFinder, two freely accessible tools that can also assist users without bioinformatics skills, we aimed at increasing their speed and providing an easily interpretable antibiogram as output. Methods The ResFinder code was re-written to process raw reads and use Kmer-based alignment. The existing ResFinder and PointFinder databases were revised and expanded. Additional databases were developed including a genotype-to-phenotype key associating each AMR determinant with a phenotype at the antimicrobial compound level, and species-specific panels for in silico antibiograms. ResFinder 4.0 was validated using Escherichia coli (n = 584), Salmonella spp. (n = 1081), Campylobacter jejuni (n = 239), Enterococcus faecium (n = 106), Enterococcus faecalis (n = 50) and Staphylococcus aureus (n = 163) exhibiting different AST profiles, and from different human and animal sources and geographical origins. Results Genotype–phenotype concordance was ≥95% for 46/51 and 25/32 of the antimicrobial/species combinations evaluated for Gram-negative and Gram-positive bacteria, respectively. When genotype–phenotype concordance was <95%, discrepancies were mainly linked to criteria for interpretation of phenotypic tests and suboptimal sequence quality, and not to ResFinder 4.0 performance. Conclusions WGS-based AST using ResFinder 4.0 provides in silico antibiograms as reliable as those obtained by phenotypic AST at least for the bacterial species/antimicrobial agents of major public health relevance considered.
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            In Vitro Susceptibility of Global Surveillance Isolates of Pseudomonas aeruginosa to Ceftazidime-Avibactam (INFORM 2012 to 2014).

            Broth microdilution antimicrobial susceptibility testing was performed for ceftazidime-avibactam and comparator agents against 7,062 clinical isolates of Pseudomonas aeruginosa collected from 2012 to 2014 in four geographic regions (Europe, Asia/South Pacific, Latin America, Middle East/Africa) as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. The majority of isolates were susceptible to ceftazidime-avibactam, with the proportions susceptible differing marginally across the four regions (MIC90, 8 to 16 μg/ml; 88.7 to 93.2% susceptible), in contrast to lower susceptibilities to the following comparator β-lactam agents: ceftazidime (MIC90, 32 to 64 μg/ml; 71.5 to 80.8% susceptible), meropenem (MIC90, >8 μg/ml; 64.9 to 77.4% susceptible), and piperacillin-tazobactam (MIC90, >128 μg/ml; 62.3 to 71.3% susceptible). Compared to the overall population, susceptibility to ceftazidime-avibactam of isolates that were nonsusceptible to ceftazidime (n = 1,627) was reduced to between 56.8% (Middle East/Africa; MIC90, 64 μg/ml) and 68.9% (Asia/South Pacific; MIC90, 128 μg/ml), but these percentages were higher than susceptibilities to other β-lactam agents (0 to 44% susceptible, depending on region and agent; meropenem MIC90, >8 μg/ml; 26.5 to 43.9% susceptible). For this subset of isolates, susceptibilities to amikacin (MIC90, >32 μg/ml; 53.2 to 80.0% susceptible) and colistin (MIC90, 1 μg/ml; 98.5 to 99.5% susceptible) were comparable to or higher than that of ceftazidime-avibactam. A similar observation was made with isolates that were nonsusceptible to meropenem (n = 1,926), with susceptibility to ceftazidime-avibactam between 67.8% (Middle East/Africa; MIC90, 64 μg/ml) and 74.2% (Europe; MIC90, 32 μg/ml) but again with reduced susceptibility to comparators except for amikacin (MIC90, >32 μg/ml; 56.8 to 78.7% susceptible) and colistin (MIC90, 1 μg/ml; 98.9 to 99.3% susceptible). Of the 8% of isolates not susceptible to ceftazidime-avibactam, the nonsusceptibility of half could be explained by their possession of genes encoding metallo-β-lactamases. The data reported here are consistent with results from other country-specific and regional surveillance studies and show that ceftazidime-avibactam demonstrates in vitro activity against globally collected clinical isolates of P. aeruginosa, including isolates that are resistant to ceftazidime and meropenem.
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              Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa.

              MK-7655 is a novel inhibitor of class A and C β-lactamases. We investigated its potential to protect imipenem. Chequerboard MICs were determined by CLSI agar dilution: (i) for Enterobacteriaceae with carbapenemases; (ii) for Enterobacteriaceae with carbapenem resistance contingent on combinations of impermeability together with an extended-spectrum β-lactamase or AmpC enzyme; and (iii) for Pseudomonas aeruginosa and other non-fermenters. At a concentration of 4 mg/L, MK-7655 reduced imipenem MICs for Enterobacteriaceae with KPC carbapenemases from 16-64 mg/L to 0.12-1 mg/L. Synergy also was seen for Enterobacteriaceae with impermeability-mediated carbapenem resistance, with weaker synergy seen for isolates with the OXA-48 enzyme. On the other hand, MK-7655 failed to potentiate imipenem against Enterobacteriaceae with metallo-carbapenemases. In the case of P. aeruginosa, where endogenous AmpC confers slight protection versus imipenem, 4 mg/L MK-7655 reduced the MIC of imipenem for all isolates, except those with metallo-carbapenemases: the MICs of imipenem fell from 1-2 mg/L to 0.25-0.5 mg/L for imipenem-susceptible P. aeruginosa and from 16-64 mg/L to 1-4 mg/L for OprD-deficient strains. No potentiation was seen for chryseobacteria or for Stenotrophomonas maltophilia. MK-7655 potentiated imipenem against Enterobacteriaceae with KPC carbapenemases or combinations of β-lactamase and impermeability, but not those with metallo-carbapenemases. It augmented the activity of imipenem against P. aeruginosa in general and OprD mutants in particular.

                Author and article information

                Contributors
                Journal
                JAC Antimicrob Resist
                JAC Antimicrob Resist
                jacamr
                JAC-Antimicrobial Resistance
                Oxford University Press (US )
                2632-1823
                August 2023
                11 August 2023
                11 August 2023
                : 5
                : 4
                : dlad098
                Affiliations
                IHMA , Schaumburg, IL 60173, USA
                Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba, Canada
                IHMA , Schaumburg, IL 60173, USA
                IHMA , Monthey, Switzerland
                IHMA , Monthey, Switzerland
                Merck & Co., Inc. , Rahway, NJ, USA
                MSD , Dubai, United Arab Emirates
                Merck & Co., Inc. , Rahway, NJ, USA
                Merck & Co., Inc. , Rahway, NJ, USA
                Merck & Co., Inc. , Rahway, NJ, USA
                IHMA , Schaumburg, IL 60173, USA
                Author notes
                Corresponding author. E-mail: jkarlowsky@ 123456sharedhealthmb.ca
                Article
                dlad098
                10.1093/jacamr/dlad098
                10416811
                37577157
                78155d70-32db-446c-9feb-43e528817214
                © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 25 May 2023
                : 02 August 2023
                Page count
                Pages: 6
                Funding
                Funded by: Merck Sharp & Dohme LLC, DOI 10.13039/100009947;
                Categories
                Original Article
                AcademicSubjects/MED00740
                AcademicSubjects/SCI01150

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