Abstract
ABSTRACTThe global dissemination of metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) is a serious public health concern. Specifically, NDM (New Delhi MBL) has been a major cause of carbapenem therapy failures in recent years, particularly as effective treatments for serine-β-lactamase (SBL)-producing Enterobacterales are now commercially available. Since the NDM gene is carried on promiscuous plasmids encoding multiple additional resistance determinants, a large proportion of NDM-CREs are also resistant to many commonly used antibiotics, resulting in limited and suboptimal treatment options. ANT2681 is a specific, competitive inhibitor of MBLs with potent activity against NDM enzymes, progressing to clinical development in combination with meropenem (MEM). Susceptibility studies have been performed with MEM-ANT2681 against 1,687 MBL-positive Enterobacterales, including 1,108 NDM-CRE. The addition of ANT2681 at 8 μg/ml reduced the MEM MIC50/MIC90 from >32/>32 μg/ml to 0.25/8 μg/ml. Moreover, the combination of 8 μg/ml of both MEM and ANT2681 inhibited 74.9% of the Verona integron-encoded MBL (VIM)-positive and 85.7% of the imipenem hydrolyzing β-lactamase (IMP)-positive Enterobacterales tested. The antibacterial activity of MEM-ANT2681 against NDM-CRE compared very favorably to that of cefiderocol (FDC) and cefepime (FEP)-taniborbactam, which displayed MIC90 values of 8 μg/ml and 32 μg/ml, respectively, whereas aztreonam-avibactam (ATM-AVI) had a MIC90 of 0.5 μg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive Escherichia coli (MIC90 1 μg/ml), in contrast to ATM-AVI (MIC90 4 μg/ml), FDC (MIC90 >32 μg/ml), and FEP-taniborbactam (MIC90 >32 μg/ml), which were less effective due to the high incidence of resistant PBP3-insertion mutants. MEM-ANT2681 offers a potential new therapeutic option to treat serious infections caused by NDM-CRE.
Highlights
The global dissemination of metallo-b-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) is a serious public health concern
Marketing of third-generation cephalosporins and aztreonam in the 1980s was followed by the appearance of extended-spectrum b-lactamases (ESBLs) [2, 3], which made carbapenems the treatment of choice for serious infections caused by ESBL-positive organisms [4]
New Delhi metallo-b-lactamase (NDM) was only reported for the first time in 2008, it already accounted for 10% of the carbapenemase genes among carbapenem-resistant Enterobacterales (CRE) collected in 2014 to 2016 as part of the SENTRY antimicrobial surveillance program, concomitant with a decrease in the two other major MBLs, namely, VIM (Verona integron-encoded MBL), from 2.4% to 1.9%, and imipenem hydrolyzing b-lactamase (IMP), from 1.9% to 0.4%, during the same time period [5]
Summary
The global dissemination of metallo-b-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) is a serious public health concern. NDM (New Delhi MBL) has been a major cause of carbapenem therapy failures in recent years, as effective treatments for serine-b-lactamase (SBL)-producing Enterobacterales are commercially available. An alternative to the development of novel b-lactam antibiotics refractory to these newer enzymes is the use of b-lactamase inhibitors to restore the activity of those agents which are already available This approach has yielded excellent ESBL and SBL inhibitors, such as avibactam, vaborbactam, and relebactam, but there are no specific metallo-b-lactamase (MBL) inhibitors in the market at the time of writing (recently reviewed in references 1, 8–11). NDM has been detected in all continents but is most prevalent in the Indian subcontinent, the Balkan states, Nigeria, and Kenya [12]
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