Delaying cefiderocol resistance development in NDM-producingEnterobacter cloacaecomplex by combining cefiderocol with aztreonamin vitro

Abstract

Background: The rapid development of cefiderocol resistance poses a significant concern, particularly in Enterobacterales that produce New Delhi metallo-beta-lactamase (NDM). This study aims to explore the potential of inhibiting in vitro cefiderocol resistance development by combining cefiderocol with aztreonam. Methods: A resistance induction experiment using 20 clinical isolates was performed to assess the impact of cefiderocol-aztreonam on preventing cefiderocol resistance development at 4x and 10x cefiderocol MIC, with and without aztreonam (2, 4, 8 μg/ml). Additionally, serial passaging with doubling cefiderocol concentrations was performed with and without aztreonam. Whole genome sequencing (WGS) was performed to identify potential bacterial factors associated with resistance development. Results: Among the 20 E. cloacae complex isolates, 40% (8/20) exhibited a significant reduction in cefiderocol MIC (≥ 4-fold MIC reduction) in the presence of 4 μg/ml aztreonam. Combining cefiderocol with a fixed concentration of 4 μg/ml aztreonam effectively inhibited cefiderocol resistance development in these eight isolates at an inoculum of 107 cfu/ml. Additional resistance induction experiments through serial passaging indicated a delayed emergence of cefiderocol-resistant clones when cefiderocol was combined with aztreonam. WGS analysis revealed a significant positive association between blaCTX-M-15, blaOXA-1, and other co-localized genes with a substantial MIC reduction for cefiderocol-aztreonam compared to cefiderocol alone. Conclusion: Our study suggested that cefiderocol resistance development in NDM-producing E. cloacae complex can be delayed or inhibited by combining cefiderocol with aztreonam, even in the presence of multiple beta-lactamase genes. A MIC reduction of at least 4-fold emerges as the most reliable predictor for the inhibition of resistance development.