Precision medicine for the diagnosis and treatment of carbapenem-resistant Enterobacterales: time to think from a different perspective

ABSTRACT

Introduction

Carbapenem-resistant Enterobacterales (CRE) represent a global public health problem. Precision medicine (PM) is a multicomponent medical approach that should be used to individualize the management of patients infected with CRE.

Areas covered

Here, we differentiate carbapenem-producing CRE (CP-CRE) from non-CP-CRE and the importance of this distinction in clinical practice. The current phenotypic CRE-case definition and its implications are also discussed. Additionally, we summarize data regarding phenotypic and molecular diagnostic tools and available antibiotics. In order to review the most relevant data, a comprehensive literature search of peer-reviewed articles in PubMed and abstracts presented at high-impact conferences was performed.

Expert opinion

PM in CRE infections entails a multi-step process that includes applying the current phenotypic definition, utilization of the right phenotypic or molecular testing methods, and thorough evaluation of risk factors, source of infection, and comorbidities. A powerful armamentarium is available to treat CRE infections, including recently approved agents. Randomized controlled trials targeting specific pathogens instead of site of infections may be appropriate to fill in the current gaps. In light of the diverse enzymology behind CP-CRE, PM should be employed to provide the best therapy based on the underlying resistance mechanism.

KEYWORDS:

• Carbapenem-resistant Enterobacterales
• carbapenemase
• gram-negative bacteria
• multidrug resistant
• precision medicine

Article highlights

• Carbapenem-resistance Enterobacterales (CRE) designation is based on a phenotypic profile (i.e. antimicrobial susceptibility testing) that can be divided into two categories: carbapenem-producing CRE (CP-CRE) and non-CP-CRE.

• Understanding of the mechanism of resistance causing carbapenem resistance (CP-CRE vs. non-CPCRE) has important clinical implications and results in different prevention measurements and individualized antibiotic therapy.

• The current phenotypic CRE-case definition implemented and validated by the Centers for Disease and Prevention (CDC) should be used in all clinical laboratories (i.e. resistance to any carbapenem based on CLSI breakpoints). This definition has high sensitivity and therefore detects more CP-CRE cases that would be missed with the previous definition but also detects more non-CP-CRE (false positives).

• Only three phenotypic methods for carbapenemase detection in Enterobacterales isolates should be used (i.e. Carba NP, mCIM, and eCIM) based on CLSI recommendations. Laboratories should decide which one is more suitable considering their advantages and disadvantages.

• Molecular diagnostic tools remain the gold-standard for carbapenemase detection, but their use is mainly limited by their high costs, unavailability in most of the clinical laboratories, and new enzymes not detected by commercially available panels.

• Although a robust armamentarium of new drugs for the treatment of CRE infections have come to market in the last 5 years (including the most recently approved imipenem-relebactam and cefiderocol), there is not a ‘perfect’ antibiotic, and therapy should be addressed following a PM approach.

• The ‘zone of hope’ is a simple phenotypic tool to help choose the right therapy in CP-CRE expressing multiple carbapenemases such as NDM and OXA-48.

Declaration of interest

DP Nicolau has been a consultant, participated in the speaker bureau, and/or received research grants from Achaogen, Cepheid, Melinta, Merck, Pfizer, Shionogi, and Tetraphase. S Reyes has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The paper is not funded.