Abstract
Carbapenems are considered as last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. With the increasing use of carbapenems in clinical practice, the emergence of carbapenem-resistant pathogens now poses a great threat to human health. Currently, antibiotic options for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) are very limited, with polymyxins, tigecycline, fosfomycin, and aminoglycosides as the mainstays of therapy. The need for new and effective anti-CRE therapies is urgent. Here, we describe the current understanding of issues related to CRE and review combination therapeutic strategies for CRE infections, including high-dose tigecycline, high-dose prolonged-infusion of carbapenem, and double carbapenem therapy. We also review the newly available antibiotics which have potential in the future treatment of CRE infections: ceftazidime/avibactam, which is active against KPC and OXA-48 producers; meropenem/vaborbactam, which is active against KPC producers; plazomicin, which is a next-generation aminoglycoside with in vitro activity against CRE; and eravacycline, which is a tetracycline class antibacterial with in vitro activity against CRE. Although direct evidence for CRE treatment is still lacking and the development of resistance is a concern, these new antibiotics provide additional therapeutic options for CRE infections. Finally, we review other potential anti-CRE antibiotics in development: imipenem/relebactam and cefiderocol. Currently, high-dose and combination strategies that may include the new β-lactam/β-lactamase inhibitors should be considered in severe CRE infections to maximize treatment success. In the future, when more treatment options are available, therapy for CRE infections should be individualized and based on molecular phenotypes of resistance, susceptibility profiles, disease severity, and patient characteristics. More high-quality studies are needed to guide effective treatment for infections caused by CRE.
Highlights
The increasing prevalence of bacterial resistance to antibiotics is a critical public health problem
Along with carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Enterobacteriaceae (CRE) are among the top tier of the WHO list of antibiotic-resistant “priority pathogens” that pose the greatest threat to human health (Willyard, 2017)
Carbapenems still play a role in the treatment of CRE infections, when used in the treatment of CRE with lower minimum inhibitory concentrations (MICs), either in higher doses, in combination with other active anti-CRE agents, or through double-carbapenem therapy (DCT)
Summary
The increasing prevalence of bacterial resistance to antibiotics is a critical public health problem. The three major classes of carbapenemases are Ambler Class A Klebsiella pneumoniae carbapenemase (KPC); Class B metallo-β-lactamases (MBLs) such as New Delhi MBL (NDM), Verona integrin-encoded MBL (VIM), and imipenemase (IMP); and Class D oxacillinases (OXA)-type enzymes such as OXA48-like carbapenemases These carbapenemases exhibit variable levels of carbapenem resistance through their carbapenemhydrolyzing activity. Carbapenems still play a role in the treatment of CRE infections, when used in the treatment of CRE with lower MICs, either in higher doses, in combination with other active anti-CRE agents, or through double-carbapenem therapy (DCT) Older antibiotics such as minocycline, doxycycline, trimethoprim/sulfamethoxazole, and chloramphenicol may be effective for some CRE isolates (Falagas et al, 2011; Livermore et al, 2011). Among the studies that found combination therapy to contribute to lower mortality rates than monotherapy
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