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      Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-, Cefiderocol-Resistant ST-512 Klebsiella pneumoniae–Producing KPC-31, a D179Y Variant of KPC-3

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          Abstract

          A 68-year-old man had recurrent bacteremia by Klebsiella pneumoniae carbapenemase (KPC)–producing K. pneumoniae resistant to ceftazidime-avibactam and cefiderocol. The sequencing of a target region showed that it harbored a KPC-3 variant enzyme (D179Y; KPC-31), which confers resistance to ceftazidime-avibactam and restores meropenem susceptibility. The patient was successfully treated with meropenem-vaborbactam.

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          Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections.

          Ryan K. Shields, Brian Potoski, Ghady Haidar … (2016)
          Thirty-seven carbapenem-resistant Enterobacteriaceae (CRE)-infected patients were treated with ceftazidime-avibactam. Clinical success and survival rates at 30 days were 59% (22/37) and 76% (28/37), respectively. In 23% (5/22) of clinical successes, CRE infections recurred within 90 days. Microbiologic failure rate was 27% (10/37). Ceftazidime-avibactam resistance was detected in 30% (3/10) of microbiologic failures.
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            New β-Lactam–β-Lactamase Inhibitor Combinations

            Dafna Yahav, Christian G Giske, Alise Grāmatniece … (2020)
            The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa . Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa . Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales . Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa . Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii . Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales , with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).
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              In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against Carbapenem-Nonsusceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014 to 2016

              Meredith Hackel, Masakatsu Tsuji, Yoshinori Yamano … (2018)
              ABSTRACT The in vitro activity of the investigational siderophore cephalosporin, cefiderocol (formerly S-649266), was determined against a 2014–2016, 52-country, worldwide collection of clinical isolates of carbapenem-nonsusceptible Enterobacteriaceae (n = 1,022), multidrug-resistant (MDR) Acinetobacter baumannii (n = 368), MDR Pseudomonas aeruginosa (n = 262), Stenotrophomonas maltophilia (n = 217), and Burkholderia cepacia (n = 4) using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB), prepared according to a recently approved (2017), but not yet published, CLSI protocol, was used to test cefiderocol; all other antimicrobial agents were tested using CAMHB. The concentration of cefiderocol inhibiting 90% (MIC90) of isolates of carbapenem-nonsusceptible Enterobacteriaceae was 4 μg/ml; cefiderocol MICs ranged from 0.004 to 32 μg/ml, and 97.0% (991/1,022) of isolates demonstrated cefiderocol MICs of ≤4 μg/ml. The MIC90s for cefiderocol for MDR A. baumannii, MDR P. aeruginosa, and S. maltophilia were 8, 1, and 0.25 μg/ml, respectively, with 89.7% (330/368), 99.2% (260/262), and 100% (217/217) of isolates demonstrating cefiderocol MICs of ≤4 μg/ml. Cefiderocol MICs for B. cepacia ranged from 0.004 to 8 μg/ml. We conclude that cefiderocol demonstrated potent in vitro activity against a 2014–2016, worldwide collection of clinical isolates of carbapenem-nonsusceptible Enterobacteriaceae, MDR A. baumannii, MDR P. aeruginosa, S. maltophilia, and B. cepacia isolates as 96.2% of all (1,801/1,873) isolates tested had cefiderocol MICs of ≤4 μg/ml.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Open Forum Infect Dis
                Journal ID (iso-abbrev): Open Forum Infect Dis
                Journal ID (publisher-id): ofid
                Title: Open Forum Infectious Diseases
                Publisher: Oxford University Press (US )
                ISSN (Electronic): 2328-8957
                Publication date Collection: June 2021
                Publication date (Electronic): 20 March 2021
                Publication date PMC-release: 20 March 2021
                Volume: 8
                Issue: 6
                Electronic Location Identifier: ofab141
                Affiliations
                [1 ]Infectious Diseases Clinic, Department of Clinical and Experimental Medicine, Azienda Universitaria Ospedaliera Pisana , University of Pisa, Pisa, Italy
                [2 ]Microbiology Unit, Azienda Universitaria Ospedaliera Pisana , Pisa, Italy
                [3 ]Department of Molecular Medicine, “Sapienza” University of Rome , Rome, Italy
                Author notes
                Correspondence: Marco Falcone, MD, Infectious Diseases Unit, Azienda Ospedaliera Universitaria Pisana, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy ( marco.falcone@ 123456unipi.it ).
                Article
                Publisher ID: ofab141
                DOI: 10.1093/ofid/ofab141
                PMC ID: 8233566
                PubMed ID: 34189161
                SO-VID: 69215891-781e-449c-9111-136119e8d213
                Copyright © © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Date received : 02 February 2021
                Date: 17 March 2021
                Date accepted : 18 March 2021
                Date: 26 June 2021
                Page count
                Pages: 4
                Categories
                Subject: ID Teaching Cases
                Subject: AcademicSubjects/MED00290

                Keywords: ceftazidime-avibactam resistant,klebsiella pneumoniae,kpc,kpc-3,meropenem-vaborbactam
                Data availability:
                Keywords: ceftazidime-avibactam resistant, klebsiella pneumoniae, kpc, kpc-3, meropenem-vaborbactam

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