Abstract
Currently, assays for rapid therapeutic drug monitoring (TDM) of β-lactam antibiotics in blood, which might be of benefit in optimizing doses for treatment of critically ill patients, remain challenging. Previously, we developed an assay for determining the penicillin-class antibiotics in blood using a thermometric penicillinase biosensor. The assay eliminates sample pretreatment, which makes it possible to perform semicontinuous penicillin determinations in blood. However, penicillinase has a narrow substrate specificity, which makes it unsuitable for detecting other classes of β-lactam antibiotics, such as cephalosporins and carbapenems. In order to assay these classes of clinically useful antibiotics, a novel biosensor was developed using New Delhi metallo-β-lactamase-1 (NDM-1) as the biological recognition layer. NDM-1 has a broad specificity range and is capable of hydrolyzing all classes of β-lactam antibiotics in high efficacy with the exception of monobactams. In this study, we demonstrated that the NDM-1 biosensor was able to quantify multiple classes of β-lactam antibiotics in blood plasma at concentrations ranging from 6.25 mg/L or 12.5 mg/L to 200 mg/L, which covered the therapeutic concentration windows of the tested antibiotics used to treat critically ill patients. The detection of ceftazidime and meropenem was not affected by the presence of the β-lactamase inhibitors avibactam and vaborbactam, respectively. Furthermore, both free and protein-bound β-lactams present in the antibiotic-spiked plasma samples were detected by the NDM-1 biosensor. These results indicated that the NDM-1 biosensor is a promising technique for rapid TDM of total β-lactam antibiotics present in the blood of critically ill patients.
Highlights
The optimization of antibiotic dosing regimens for patients with antimicrobial-resistant (AMR) infections has the potential to dramatically improve therapeutic outcomes while reducing the development of antibiotic resistance
Performance in the activity measurement of two cephalosporins and two carbapenems was assessed and compared using the antibiotics spiked in HEPES buffer while using penicillin G and aztreonam as two references
The results indicated that the New Delhi metallo-β-lactamase-1 (NDM-1) biosensor bears a broader analytical capacity than the penicillinase biosensor in the detection of the cephalosporin and carbapenem β-lactam antibiotics
Summary
The optimization of antibiotic dosing regimens for patients with antimicrobial-resistant (AMR) infections has the potential to dramatically improve therapeutic outcomes while reducing the development of antibiotic resistance. This is especially important when treating critically ill patients where administration of standard antibiotic dosages sometimes results in subtherapeutic antibiotic blood concentration levels that adversely affect treatment outcomes [1,2]. Optimization of blood drug levels using TDM has been successfully used to improve patient outcomes for a variety of illnesses [8,9] This strategy has been shown to improve outcomes for critically ill patients undergoing antibiotic treatment [10]
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