Activity of meropenem/vaborbactam and comparators against non-carbapenemase-producing carbapenem-resistant Enterobacterales isolates from Europe

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Abstract

Background

Carbapenem-resistant Enterobacterales (CRE) isolates have disseminated worldwide. CREs usually produce a carbapenemase; however, some isolates are negative for known carbapenemases. In this study, we evaluated the activity of meropenem/vaborbactam and comparators against CREs without a carbapenemase (nonCP CREs) collected from European hospitals from 2016 to 2019.

Materials and methods

23 043 Enterobacterales clinical isolates were collected in 41 hospitals located in 20 countries. Susceptibility (S) testing was performed using the broth microdilution method. CLSI/EUCAST (2021) interpretive criteria were used. 978 CREs were identified with MICs >2 mg/L to meropenem or imipenem. Whole-genome sequencing was performed on each CRE isolate. 125 isolates were negative for carbapenemase genes, including bla _KPC, bla _NDM, bla _IMP, bla _VIM and bla _OXA-48-like. NonCP CRE isolates were analysed for the presence of other β-lactamases, multilocus sequence types (ST) and mutations in outer membrane protein (OMP) sequences.

Results

Most nonCP CRE were Klebsiella pneumoniae (KPN; n = 97/125). 84.0% of nonCP CRE ( n = 105) were from Poland, including 88 KPN. The most common β-lactamase was bla _CTX-M-15 in 92/125 isolates. OMP disruptions or alterations were noted among 76 KPN. Among KPN isolates that had MLST typing, 30 belonged to ST11, 18 to ST152 and 17 to ST147, while 13 other STs were observed. Susceptibility to meropenem/vaborbactam was 96.0/97.6% (CLSI/EUCAST) while meropenem was 2.4/8.0%S.

Conclusions

Meropenem/vaborbactam had potent in vitro activity against CRE isolates that lacked known carbapenemases. Resistance mechanisms observed among nonCP CREs included acquired β-lactamases and OMP alterations. These results indicate that meropenem/vaborbactam may be a useful treatment for infections caused by nonCP CREs.

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Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis

(2022)

Summary Background Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen–drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date. Methods We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23 pathogens and 88 pathogen–drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the global and regional level. Findings On the basis of our predictive statistical models, there were an estimated 4·95 million (3·62–6·57) deaths associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911–1·71) deaths attributable to bacterial AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27·3 deaths per 100 000 (20·9–35·3), and lowest in Australasia, at 6·5 deaths (4·3–9·4) per 100 000. Lower respiratory infections accounted for more than 1·5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000–1 270 000) deaths attributable to AMR and 3·57 million (2·62–4·78) deaths associated with AMR in 2019. One pathogen–drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000–100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistant E coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae. Interpretation To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen–drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programmes, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasising the need to expand microbiology laboratory capacity and data collection systems to improve our understanding of this important human health threat. Funding Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.

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Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study.

Hajo Grundmann, Corinna Glasner, Barbara Albiger … (2017)

Gaps in the diagnostic capacity and heterogeneity of national surveillance and reporting standards in Europe make it difficult to contain carbapenemase-producing Enterobacteriaceae. We report the development of a consistent sampling framework and the results of the first structured survey on the occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in European hospitals.

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Epidemiology and Diagnostics of Carbapenem Resistance in Gram-negative Bacteria

Patrice Nordmann, Laurent Poirel (2019)

Abstract Carbapenem resistance in gram-negative bacteria has caused a global epidemic that continues to grow. Although carbapenemase-producing Enterobacteriaceae have received the most attention because resistance was first reported in these pathogens in the early 1990s, there is increased awareness of the impact of carbapenem-resistant nonfermenting gram-negative bacteria, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Moreover, evaluating the problem of carbapenem resistance requires the consideration of both carbapenemase-producing bacteria as well as bacteria with other carbapenem resistance mechanisms. Advances in rapid diagnostic tests to improve the detection of carbapenem resistance and the use of large, population-based datasets to capture a greater proportion of carbapenem-resistant organisms can help us gain a better understanding of this urgent threat and enable physicians to select the most appropriate antibiotics.

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Author and article information

Contributors

Dee Shortridge:

ORCID: https://orcid.org/0000-0002-1215-5216

Lalitagauri M Deshpande:

ORCID: https://orcid.org/0000-0003-1709-1132

Jennifer M Streit:

ORCID: https://orcid.org/0000-0002-8419-6308

Mariana Castanheira:

ORCID: https://orcid.org/0000-0003-0126-1782

Journal

Journal ID (nlm-ta): JAC Antimicrob Resist

Journal ID (iso-abbrev): JAC Antimicrob Resist

Journal ID (publisher-id): jacamr

Title: JAC-Antimicrobial Resistance

Publisher: Oxford University Press (US )

ISSN (Electronic): 2632-1823

Publication date Collection: October 2022

Publication date (Electronic): 30 September 2022

Publication date PMC-release: 30 September 2022

Volume: 4

Issue: 5

Electronic Location Identifier: dlac097

Affiliations

JMI Laboratories , North Liberty, IA, USA

Author notes

Corresponding author. JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, E-mail: dee-shortridge@ 123456jmilabs.com @jmilabs

Author information

Dee Shortridge https://orcid.org/0000-0002-1215-5216

Lalitagauri M Deshpande https://orcid.org/0000-0003-1709-1132

Jennifer M Streit https://orcid.org/0000-0002-8419-6308

Mariana Castanheira https://orcid.org/0000-0003-0126-1782

Article

Publisher ID: dlac097

DOI: 10.1093/jacamr/dlac097

PMC ID: 9524562

PubMed ID: 36196439

SO-VID: 6562474a-5831-4495-b39a-1b7a0356d114

License:

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

Date received : 08 June 2022

Date accepted : 20 August 2022

Page count

Pages: 8

Funding

Funded by: Meropenem/vaborbactam had potent in vitro activity against CRE isolates that lacked known carbapenemases. Resistance mechanisms observed among nonCP CREs included acquired β-lactamases and OMP alterations.;

Funded by: A. Menarini Industrie Farmaceutiche Riunite SRL, doi 10.13039/501100014337;

Activity of meropenem/vaborbactam and comparators against non-carbapenemase-producing carbapenem-resistant Enterobacterales isolates from Europe

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Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis

Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study.

Epidemiology and Diagnostics of Carbapenem Resistance in Gram-negative Bacteria

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