Abstract
Objectives: Carbapenemase-producing organisms (CPOs) are associated with high mortality rates. The recent development of β-lactamase inhibitors (BLIs) has made it possible to control CPO infections safely and effectively with β-lactams (BLs). This study aims to explicate the quantitative relationship between BLI’s β-lactamase inhibition and CPO’s BL susceptibility restoration, thereby providing the infectious disease society practical scientific grounds for regulating the use of BL/BLI 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 β-lactamase inhibition, BL susceptibility restoration, and their correlation were followed quantitatively for each isolate by coupling FIBA (fluorescence identification of β-lactamase activity) and BL antibiotic susceptibility testing.Results: The β-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 β-lactamase inhibition, CPO’s BL susceptibility restoration is universally low across all tested carbapenemase molecular groups. However, a high degree of β-lactamase inhibition would not necessarily lead to a substantial BL susceptibility restoration in CPO probably due to the existence of non-β-lactamase BL resistance mechanisms.Conclusion: BL/BLI choice and dosing should be guided by quantitative tools that can evaluate the inhibition across the entire β-lactamase background of the CPO upon the BLI administion. Furthermore, rapid molecular diagnostics for BL/BLI resistances, especially those sensitive to β-lactamase independent BL resistance mechanisms, should be exploited to prevent ineffective BL/BLI treatment.
Highlights
Carbapenemase-producing organisms (CPOs) are multidrugresistant pathogens associated with high mortality rates (13.3– 67%; Tamma et al, 2017)
Bacterial isolates of human CPO infection were acquired from the CDC and FDA Antibiotic Resistance Isolate Bank
These isolates produce a range of carbapenemase molecular classes commonly found in clinic, including Class A carbapenemases (n = 43, Table 1), Class B carbapenemases (n = 45, Table 2), and Class D carbapenemases (n = 73, Table 3)
Summary
Carbapenemase-producing organisms (CPOs) are multidrugresistant pathogens associated with high mortality rates (13.3– 67%; Tamma et al, 2017). Recent clinical data have emerged demonstrating that treatment failures and subsequent bacterial resistance development may occur in CPO treatments with BLs and novel BLIs, necessitating further development of guidelines on rational use of BLs and BLIs for CPO infections (Shields et al, 2016; Cui et al, 2020). Whether the desired anti-CPO effect of the chosen BL/BLI agent could be achieved across diverse pathogens by a fixed BLI dosage is still of great concern for the infectious disease society (Spellberg and Bonomo, 2016) due to the large variety of CPO carbapenemase molecular structures and expression statuses. The further complicating effects of other BL resistance mechanisms unrelated to β-lactamase (e.g., efflux pump overproduction, drug target alterations and porin mutations) and their influence on CPO response to BL/BLI agents remain unclear (Karumathil et al, 2018; Nicolas-Chanoine et al, 2018; Nordmann and Poirel, 2019; Black et al, 2020)
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