Treatment options for infections caused by carbapenem-resistantEnterobacteriaceae: can we apply “precision medicine” to antimicrobial chemotherapy?

Abstract

Introduction 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. Areas covered 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 clinical experience treating CRE infections with antibiotic combination therapy. Finally, we review ceftazidime/avibactam and imipenem/relebactam, 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. Expert Opinion It is essential to define the molecular mechanisms of resistance and to apply insights about pharmacodynamic and pharmacokinetic properties of antibiotics, in order to maximize the impact of old and new therapeutic approaches against 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.

Clinical and laboratory considerations for the rapid detection of carbapenem-resistant Enterobacteriaceae

“…However, this drug does not have activity against the class B metallo-b-lactamases (such as NDM), 72 and resistance in at least one KPC-producing K. pneumoniae has been described. 73 A few publications propose potential algorithms for treatment of CRE infection based on molecular detection of specific carbapenemases 74 and carbapenem MIC. 75,76 Infection control implications of rapid detection of CP-CRE Timely identification of individuals who are infected or colonized with CP-CRE would enable prompt implementation of infection control interventions, including patient cohorting and isolation, precautions during invasive procedures and patient transport, and appropriate environmental disinfection.…”

Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae

“…n addition to other classes of antimicrobial agents, Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae isolates are resistant to carbapenems, one of the main classes of antibiotics used against ␤-lactamase-producing microorganisms (1). The bacterium's high dissemination rate is a major public health problem worldwide, and the limited options of antimicrobial agents further complicate the management of infections caused by this difficult-to-treat pathogen, resulting in high morbidity and mortality rates (2,3).…”

What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

“…Furthermore, given its excellent activity against P. aeruginosa, TOL/TAZ is the preferred agent against serious infections by this pathogen, especially when MDRs are suspected or involved [21]. Therefore, information about the exact epidemiology of CRE in a given context is mandatory to ensure optimal empiric therapy [36]. Implementation of molecular microbiologic platforms able to detect particular forms of resistance (e.g.…”

“…Implementation of molecular microbiologic platforms able to detect particular forms of resistance (e.g. production of MBLs) can guide treatment in an ideal 'precision medicine' scenario [36].…”