Investigational drugs for the treatment of infections caused by multidrug-resistant Gram-negative bacteria

ABSTRACT

Introduction: Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are associated with significant mortality and costs. New drugs in development to combat these difficult-to-treat infections primarily target carbapenem-resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii.

Areas covered: The authors summarize in vitro and in vivo efficacy studies, as well as available clinical trial findings, for new agents in development for treatment of infection caused by MDR-GNB. Information regarding dosage regimens utilized in clinical trials and key pharmacokinetic and pharmacodynamic considerations are provided if available. A summary of recently approved agents, delafloxacin and meropenem/vaborbactam, is also included.

Expert opinion: The development of multiple novel agents to fight MDR-GNB is promising to help save the lives of patients who acquire infection, and judicious use of these agents is imperative once they come to market to prevent the development of resistance. The other component paramount to this field of research is implementation of effective infection control policies and carbapenem-resistant Enterobacteriaceae (CRE) carrier screening protocols to mitigate the worldwide spread of MDR-GNB. Further investigation of anti-infective synergistic combinations will also be important, as well as support for economic research to reveal the true cost-benefit of utilization of the new agents discussed herein.

KEYWORDS:

• Drug development
• multidrug resistant
• carbapenem-resistant Enterobacteriaceae

Article highlights

• Several new anti-infective combinations with a β-lactamase inhibitor (BLI) are in early stages of clinical development: cefepime/zidebactam, cefepime/tazobactam, cefepime/AAI101, VNRX-5133 (BLI only), meropenem/nacubactam, aztreonam/avibactam, and ceftaroline/avibactam.

• Non-β-lactam anti-infectives moving on to Phase 2 clinical trials include the pathogen-specific antipseudomonal agent, murepavadin, and new fluoroquinolone, finafloxacin.

• Five agents are in the late stages of clinical development: cefiderocol, eravacycline, imipenem-cilastatin/relebactam, omadacycline, and plazomicin.

• Delafloxacin (Baxdela™) and meropenem/vaborbactam (Vabomere™) are newly approved agents that have activity against Gram-negative bacteria (GNB) that produce extended-spectrum β-lactamases; Vabomere™ also provides coverage against carbapenem-resistant Enterobacteriaceae (CRE).

• It will be important to ensure appropriate use of new antibiotics that come to market, and it is equally important to maintain quality infection control practices to prevent patient-to-patient transmission of resistant pathogens.

This box summarizes key points contained in the article.

Declaration of interest

DP Nicolau has been a consultant and speaker for and received research grants from Achaogen, Bayer, Cepheid, Merck, The Medicines Company, Pfizer, and Shionogi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is not funded.