, Volume 79, Issue 7, pp 705–714 | Cite as

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

  • Shio-Shin Jean
  • Ian M. Gould
  • Wen-Sen Lee
  • Po-Ren HsuehEmail author
  • International Society of Antimicrobial Chemotherapy (ISAC)
Current Opinion


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.



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).

Compliance with Ethical Standards


No specific grant from any funding agency in the public, commercial, or not-for-profit sector was obtained for this article.

Conflict of interest

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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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Shio-Shin Jean
    • 1
    • 2
  • Ian M. Gould
    • 3
  • Wen-Sen Lee
    • 4
    • 5
  • Po-Ren Hsueh
    • 6
    • 7
    Email author
  • International Society of Antimicrobial Chemotherapy (ISAC)
  1. 1.Department of Emergency, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  2. 2.Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Wan Fang HospitalTaipei Medicine UniversityTaipeiTaiwan
  3. 3.Aberdeen Royal InfirmaryAberdeenScotland, UK
  4. 4.Division of Infectious Diseases, Department of Internal Medicine, Wan Fang HospitalTaipei Medical UniversityTaipeiTaiwan
  5. 5.Department of Internal Medicine, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  6. 6.Department of Laboratory MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
  7. 7.Department of Internal MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan

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