Navigating the Current Treatment Landscape of Metallo-β-Lactamase-Producing Gram-Negative Infections: What are the Limitations?

Abstract

The spread of carbapenemase-producing gram-negative pathogens, especially those producing metallo-β-lactamases (MBLs), has become a major health concern. MBLs are molecularly the most diverse carbapenemases, produced by a wide spectrum of gram-negative organisms, including the Enterobacterales, Pseudomonas spp., Acinetobacter baumannii, and Stenotrophomonas maltophilia, and can hydrolyze most β-lactams using metal ion cofactors in their active sites. Over the years, the prevalence of MBL-carrying isolates has increased globally, particularly in Asia. MBL infections are associated with adverse clinical outcomes including longer length of hospital stay, ICU admission, and increased mortality across the globe. The optimal treatment for MBL infections not only depends on the pathogen but also on the underlying resistance mechanisms. Currently, there are only few drugs or drug combinations that can efficiently offset MBL-mediated resistance, which makes the treatment of MBL infections challenging. The rising concern of MBLs along with the limited treatment options has led to the need and development of drugs that are specifically targeted towards MBLs. This review discusses the prevalence of MBLs, their clinical impact, and the current treatment options for MBL infections and their limitations. Furthermore, this review will discuss agents currently in the pipeline for treatment of MBL infections.

Keywords: Avibactam; Aztreonam; Carbapenem resistant; Cefiderocol; Metallo-β-lactamase.

Fig. 1

Distribution of MBL-positive Enterobacterales isolates among the carbapenem-nonsusceptible isolates collected globally and in each region between 2012 and 2017 compared to those collected between 2018 and 2019 [21, 22]. APAC Asia–Pacific, AfME Africa/Middle East, LATAM Latin America, MBL metallo-β-lactamases. The number of carbapenem-nonsusceptible (C-NS) and MBL-positive isolates collected in each region were Global, MBL/C-NS, 2012–2017, 547/2666 and 2018–2019, 818/2228; AfME, 2012–2017, 62/140 and 2018–2019, 94/192; APAC, 2012–2017, 162/294 and 2018–2019, 300/505; Europe, 2012–2017, 268/1441 and 2018–2019, 284/1020; LATAM, 2012–2017, 50/689 and 2018–2019, 123/401; North America, 2012–2017, 5/102 and 2018–2019, 17/110