Treatment options for infections caused by carbapenem-resistant Enterobacteriaceae: 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 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.

Expert opinion: 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.

Keywords: Enterobacteriaceae; beta-lactamase inhibitors; carbapenems; drug combinations; drug resistance; multiple.

Figure 1

Structure of commercially available carbapenems.

Figure 2

Structure of polymyxin.

Figure 3

Structure of fosfomycin and tigecycline.

Figure 4

Comparison of risk ratio of mortality of patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae treated with combination antibiotic therapy (with and without a carbapanem) versus monotherapy, determined and pooled from four retrospective observational studies (Daikos et al. [122], Qureshi et al. [104], Tumbarello et al. [105], Zarkotou et al. [18]). The size of each square indicates the relative size of each study; horizontal lines denote 95% confidence intervals. Results less than 1 indicate lower mortality with combination therapy. Pooled numbers are Mantel-Haenszel risk ratio estimates.

Figure 5

Concentration of meropenem (in µg/ml) over time (in hours) when administered as an intermittent (triangle), extended (square), or continuous (circle) infusion (derived from Nicolau [166], Dandekar et al. [167] and Krueger et al.[168]. Continuous line represents MIC = 4 µg/ml, and dotted line MIC = 16 µg/ml. Note that only an extended infusion may result in sufficiently elevated serum meropenem concentrations when isolates approach MIC of 16 µg/ml. Antibiotics that permeabilize the bacterial cell membrane (e.g. polymyxins), interfere with cell wall synthesis (e.g. fosfomycin), or inhibit protein synthesis (e.g. aminoglycosides or tigecycline) may decrease the MIC sufficiently so that it is exceeded when a carbapenem is co-admininstered as a prolonged (continuous or extended) infusion, thereby achieving satisfactory microbiological and clinical outcomes.

Figure 6

Structure of avibactam and relebactam (diazabicyclooctane beta-lactamase inhibitors) and of RPX7009 (oxaboronate beta-lactamase inhibitor).

Figure 7

Guide for the empiric treatment of infections where carbapenem-resistant Enterobacteriaceae is suspected, based on the local prevalence of metallo-beta-lactamases and results of rapid molecular diagnostics.