In vitro potency of xeruborbactam in combination with multiple β-lactam antibiotics in comparison with other β-lactam/β-lactamase inhibitor (BLI) combinations against carbapenem-resistant and extended-spectrum β-lactamase-producing Enterobacterales

Recently, several beta-lactam (BL)/beta-lactamase inhibitor (BLI) combinations have entered clinical testing or have been marketed for use, but limited direct comparative studies of their in vitro activity exist. Xeruborbactam (XER, also known as QPX7728), which is undergoing clinical development, is a cyclic boronate BLI with potent inhibitory activity against serine (serine beta-lactamase) and metallo-beta-lactamases (MBLs). The objectives of this study were (i) to compare the potency and spectrum of beta-lactamase inhibition by various BLIs in biochemical assays using purified beta-lactamases and in microbiological assays using the panel of laboratory strains expressing diverse serine and metallo-beta-lactamases and (ii) to compare the in vitro potency of XER in combination with multiple beta-lactam antibiotics to that of other BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant Enterobacterales (CRE). Minimal inhibitory concentrations (MICs) of XER combinations were tested with XER at fixed 4 or 8 mu g/mL, and MIC testing was conducted in a blinded fashion using Clinical and Laboratory Standards Institute reference methods. Xeruborbactam and taniborbactam (TAN) were the only BLIs that inhibited clinically important MBLs. The spectrum of activity of xeruborbactam included several MBLs identified in Enterobacterales, e.g., and various IMP enzymes and NDM-9 that were not inhibited by taniborbactam. Xeruborbactam potency against the majority of purified beta-lactamases was the highest in comparison with other BLIs. Meropenem-xeruborbactam (MEM-XER, fixed 8 mu g/mL) was the most potent combination against MBL-negative CRE with MIC90 values of 0.125 mu g/mL. MEM-XER and cefepime-taniborbactam (FEP-TAN) were the only BL/BLIs with activity against MBL-producing CREs; with MEM-XER (MIC90 of 1 mu g/mL) being at least 16-fold more potent than FEP-TAN (MIC90 of 16 mu g/mL). MEM-XER MIC values were <= 8 mu g/mL for >90% of CRE, including both MBL-negative and MBL-positive isolates, with FEP-TAN MIC of >8 mu g/mL. Xeruborbactam also significantly enhanced potency of other beta-lactam antibiotics, including cefepime, ceftolozane, ceftriaxone, aztreonam, piperacillin, and ertapenem, against clinical isolates of Enterobacterales that carried various class A, class C, and class D extended-spectrum beta-lactamases and carbapenem-resistant Enterobacterales, including metallo-beta-lactamase-producing isolates. These results strongly support further clinical development of xeruborbactam combinations.

Automated summary

Recently, there has been a lack of comparative studies on the in vitro activity of beta-lactamase/beta-lactamase inhibitor (BL/BLI) combinations. This study compared the potency and spectrum of beta-lactamase inhibition by various BLIs and the in vitro potency of Xeruborbactam (XER) combined with beta-lactam antibiotics against carbapenem-resistant Enterobacterales (CRE). XER showed the highest potency against purified beta-lactamases and significantly enhanced the potency of other beta-lactam antibiotics. These results suggest the importance of further clinical development of XER combinations.