Quantitative Insights Into beta-Lactamase Inhibitor's Contribution in the Treatment of Carbapenemase-Producing Organisms With beta-Lactams

Objectives: Carbapenemase-producing organisms (CPO0s) are associated with high mortality rates. The recent development of beta-lactamase inhibitors (BLIs) has made it possible to control CPO infections safely and effectively with beta-lactams (BLs). This study aims to explicate the quantitative relationship between BLI's beta-lactamase inhibition and CPO's BL susceptibility restoration, thereby providing the infectious disease society practical scientific grounds for regulating the use of BUBLI in CPO infection treatment. Methods: A diverse collection of human CPO infection isolates was challenged by three structurally representative BLIs available in the clinic. The resultant beta-lactamase inhibition, BL susceptibility restoration, and their correlation were followed quantitatively for each isolate by coupling FIBA (fluorescence identification of beta-lactamase activity) and BL antibiotic susceptibility testing. Results:The beta-lactamase inhibition and BL susceptibility restoration are positively correlated among CPOs under the treatment of BLIs. Both of them are dependent on the target CPO's carbapenemase molecular identity. Of note, without sufficient beta-lactamase inhibition, CPO's BL susceptibility restoration is universally low across all tested carbapenemase molecular groups. However, a high degree of beta-lactamase inhibition would not necessarily lead to a substantial BL susceptibility restoration in CPO probably due to the existence of non-beta-lactamase BL resistance mechanisms. Conclusion: BL/BLI choice and dosing should be guided by quantitative tools that can evaluate the inhibition across the entire beta-lactamase background of the CPO upon the BLI administion. Furthermore, rapid molecular diagnostics for BL/BLI resistances, especially those sensitive to beta-lactamase independent BL resistance mechanisms, should be exploited to prevent ineffective BL/BLI treatment.