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New Drugs for Multidrug-Resistant Gram-Negative Organisms: Time for Stewardship

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Abstract

A gradual rise in drug-resistant trends among Gram-negative organisms, especially carbapenem-resistant (CR) Enterobacteriaceae (CRE), CR-Pseudomonas aeruginosa, and extensively-drug-resistant (XDR) Acinetobacter baumannii, poses an enormous threat to healthcare systems worldwide. In the last decade, many pharmaceutical companies have devoted enormous resources to the development of new potent antibiotics against XDR Gram-negative pathogens, particularly CRE. Some of these novel antibiotics against CRE strains are β-lactam/β-lactamase-inhibitor combination agents, while others belong to the non-β-lactam class. Most of these antibiotics display good in vitro activity against the producers of Ambler class A, C, and D β-lactamase, although avibactam and vaborbactam are not active in vitro against metallo-β-lactamase (MβL) enzymes. Nevertheless, in vitro efficacy against the producers of some or all class B enzymes (New Delhi MβL, Verona integron-encoded MβL, etc) has been shown with cefepime-zidebactam, aztreonam-avibactam, VNRX-5133, cefiderocol, plazomicin, and eravacycline. As of Feburary 2019, drugs approved for treatment of some CRE-related infections by the US Food and Drug Administration included ceftazidime-avibactam, meropenem-vaborbactam, plazomicin, and eravacycline. Although active against extended-spectrum and AmpC β-lactamase-producing Enterobacteriaceae, delafloxacin does not show in vitro activity against CRE. Murepavadin is shown to be specifically active against CR- and colistin-resistant P. aeruginosa strains. Despite successful development of novel antibiotics, strict implementation of an antibiotic stewardship policy in combination with the use of well-established phenotypic tests and novel multiplex PCR methods for detection of the most commonly encountered β-lactamases/carbapenemases in hospitals is important for prescribing effective antibiotics against CRE and decreasing the resistance burden due to CRE.

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Acknowledgements

The content of this manuscript is partly based on content presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Madrid, Spain in April 2018 during the session ‘Therapy of MDR/XDR Gram-Negative Bacteria: Dealing with the Devil’ (SY026).

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Authors and Affiliations

  1. Department of Emergency, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Shio-Shin Jean

  2. Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Wan Fang Hospital, Taipei Medicine University, Taipei, Taiwan

    Shio-Shin Jean

  3. Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland, UK

    Ian M. Gould

  4. Division of Infectious Diseases, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Wen-Sen Lee

  5. Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Wen-Sen Lee

  6. Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Po-Ren Hsueh

  7. Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Po-Ren Hsueh

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Authors SSJ, IMG, WSL, and PRH have no conflicts of interest to declare. Author IMG has served as a speaker on antibiotic resistance and stewardship for Merck, Bayer, Norma Hellas, Pfizer, Basilea, Xelia, and Sanofi and has received consulting honoraria from Merck, Bayer, Basilea, Pfizer, Achaogen, and AstraZeneca.

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Jean, SS., Gould, I.M., Lee, WS. et al. New Drugs for Multidrug-Resistant Gram-Negative Organisms: Time for Stewardship. Drugs 79, 705–714 (2019). https://doi.org/10.1007/s40265-019-01112-1

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