title: Treatment options for infections caused by carbapenem-resistant Enterobacteriaceae: can we apply "precision medicine" to antimicrobial chemotherapy?
abstract: BACKGROUND
  For the past three decades, carbapenems played a central role in our antibiotic armamentarium, trusted to effectively treat infections caused by drug-resistant bacteria. The utility of this class of antibiotics has been compromised by the emergence of resistance especially among Enterobacteriaceae.
  
  
  METHODS
  We review the current mainstays of pharmacotherapy against infections caused by carbapenem-resistant Enterobacteriaceae (CRE) including tigecycline, aminoglycosides, and rediscovered 'old' antibiotics such as fosfomycin and polymyxins, and discuss their efficacy and potential toxicity. We also summarize the contemporary clinical experience treating CRE infections with antibiotic combination therapy. Finally, we discuss ceftazidime/avibactam and imipenem/relebactam, containing a new generation of beta-lactamase inhibitors, which may offer alternatives to treat CRE infections. We critically evaluate the published literature, identify relevant clinical trials and review documents submitted to the United States Food and Drug Administration.
  
  
  CONCLUSIONS
  Defining the molecular mechanisms of resistance and applying insights about pharmacodynamic and pharmacokinetic properties of antibiotics, in order to maximize the impact of old and new therapeutic approaches should be the new paradigm in treating infections caused by CRE. A concerted effort is needed to carry out high-quality clinical trials that: i) establish the superiority of combination therapy vs. monotherapy; ii) confirm the role of novel beta-lactam/beta-lactamase inhibitor combinations as therapy against KPC- and OXA-48 producing Enterobacteriaceae; and, iii) evaluate new antibiotics active against CRE as they are introduced into the clinic.
authors.affiliation: a Medical Service , Louis Stokes Cleveland Department of Veterans Affairs Medical Center , Cleveland , OH , USA.|b Research Services , Louis Stokes Cleveland Department of Veterans Affairs Medical Center , Cleveland , OH , USA.|c Department of Medicine , University Hospitals Case Medical Center , Cleveland , OH , USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Perez
authors.affiliation: c Department of Medicine , University Hospitals Case Medical Center , Cleveland , OH , USA.
authors.forename: Nadim G
authors.initials: NG
authors.lastname: El Chakhtoura
authors.affiliation: b Research Services , Louis Stokes Cleveland Department of Veterans Affairs Medical Center , Cleveland , OH , USA.|c Department of Medicine , University Hospitals Case Medical Center , Cleveland , OH , USA.|d Departments of Pharmacology , Case Western Reserve University School of Medicine , Cleveland , OH , USA.
authors.forename: Krisztina M
authors.initials: KM
authors.lastname: Papp-Wallace
authors.affiliation: e VISN-10 Geriatrics Research, Education and Clinical Center , Cleveland , OH , USA.
authors.forename: Brigid M
authors.initials: BM
authors.lastname: Wilson
authors.affiliation: a Medical Service , Louis Stokes Cleveland Department of Veterans Affairs Medical Center , Cleveland , OH , USA.|b Research Services , Louis Stokes Cleveland Department of Veterans Affairs Medical Center , Cleveland , OH , USA.|c Department of Medicine , University Hospitals Case Medical Center , Cleveland , OH , USA.|d Departments of Pharmacology , Case Western Reserve University School of Medicine , Cleveland , OH , USA.|e VISN-10 Geriatrics Research, Education and Clinical Center , Cleveland , OH , USA.|f Department of Molecular Biology and Microbiology , Case Western Reserve University School of Medicine , Cleveland , OH , USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D015780:Carbapenems / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D004755:Enterobacteriaceae / Q000187:drug effects*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy*; D006801:Humans; D057285:Precision Medicine; D065093:beta-Lactamase Inhibitors / Q000627:therapeutic use*; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
keywords: Enterobacteriaceae; beta-lactamase inhibitors; carbapenems; drug combinations; drug resistance; multiple