Towards A Minimally Invasive Device For Continuous Monitoring Of Beta-Lactam Antibiotics

Background: There is a need to develop novel mechanisms for monitoring and subsequently improving the precision of how we use antibiotics across care settings. We report the development of a microneedle array for the continuous monitoring of beta-lactam antibiotics. Methods & Materials: A surface modified microneedle array was developed for monitoring beta-lactam antibiotic concentrations in human interstitial fluid (ISF). The sensor was fabricated by anodically electrodepositing iridium oxide (AEIROF) onto a platinum surface on the microneedle followed by fixation of beta-lactamase enzyme within a hydrogel. Calibration of the sensor was performed to penicillin-G in buffer solution (PBS) and artificial ISF. Further calibration was undertaken using amoxicillin, ceftriaxone, and amoxicillin-clavulinate. Open-circuit potentials were recorded and data analysed using the Hill equation and log(concentration [M]) plots. Sensor performance during continuous monitoring in human tissue was modelled by development of a physiologically inspired calibration rig mimicking antimicrobial perfusion through tissue. The test rig was used to determine the diffusion (D) and partition coefficients (K) of penicillin-G within the test rig set at an initial flow rate of 10 μLmin−1. Results: The microneedle sensor demonstrated high reproducibility between penicillin-G runs in PBS with mean Km (± 1SD) = 4.4 ± 1.3 mM and mean slope function of log(concentration) plots 29 ± 1.80 mV/decade (r2 = 0.933). Response was reproducible after 28 days storage at 4 °C. In artificial ISF, the sensors response was Km (±1SD) = 7.7 ± 18.7 mM and a slope function of 34 ± 1.85 mv/decade (r2 = 0.995). Similar response was observed to amoxicillin. Ceftriaxone demonstrated a reduced but acceptable response. Addition of beta-lactamase inhibitor (clavulanic acid) inhibited response of the antimicrobial sensor to increasing concentrations of amoxicillin. Finally, the microneedle sensor was able to accurately respond to increasing and decreasing penicillin-G concentrations over a period of 2.5 hours on the test rig. Conclusion: Our results suggest that microneedle array based beta-lactam sensing may be a future application of this AEIROF based enzymatic sensor facilitating advanced control of antimicrobial delivery. Further work is now underway to evaluate the performance of microneedle sensing in humans receiving beta-lactam antibiotics and develop closed-loop-control systems for optimisation of dosing.