Development of a Minimally Invasive Microneedle-Based Sensor for Continuous Monitoring of β-Lactam Antibiotic Concentrations in Vivo

Abstract

Antimicrobial resistance poses a global threat to patient health. Improving the use and effectiveness of antimicrobials is critical in addressing this issue. This includes optimising the dose of antibiotic delivered to each individual. New sensing approaches that track antimicrobial concentration for each patient in real time could allow individualised drug dosing. This work presents a potentiometric microneedlebased biosensor to detect levels of β-lactam antibiotics in vivo in a healthy human volunteer. The biosensor is coated with a pH-sensitive iridium oxide layer, which detects changes in local pH as a result of β-lactam hydrolysis by β-lactamase immobilised on the electrode surface. Development and optimisation of the biosensor coatings are presented, giving a limit of detection of 6.8 µM in 10 mM PBS solution. Biosensors were found to be stable for up to two weeks at-20°C and to withstand sterilisation. Sensitivity was retained after application for 6 hours in vivo. Proofof-concept results are presented showing that penicillin concentrations measured using the microneedle-based biosensor track those measured using both discrete blood and microdialysis sampling in vivo. These preliminary results show the potential of this microneedle-based biosensor to provide a minimally-invasive means to measure real-time β-lactam concentrations in vivo, representing an important first step towards a closed-loop therapeutic drug monitoring system.

Diagnostic and medical needs for therapeutic drug monitoring of antibiotics

“…In the latter study, elegant microneedle-based biosensors were used for betalactam detection. Recent publications revealed the successful use of microfluidic devices for monitoring aminoglycoside or beta-lactam concentrations in whole blood with a wide dynamic range [55,56]. The development of such miniaturized and potentially automatable methods can better position TDM in routine microbiology laboratories, particularly if they are shown to be cost-effective.…”

Microchip capillary electrophoresis dairy device using fluorescence spectroscopy for detection of ciprofloxacin in milk samples

“…To reduce the manual error associated with manual devices (as discussed above), laboratory device tests may be employed to detect the presence of antibiotics in milk. These laboratory device tests include mass spectrometry 9 , liquid chromatography 10 , immunoassay 11 , potentiometric 12 , and surface plasmon resonance 13 devices. However, these laboratory devices are slow because they require cumbersome processes including transportation off-site from the dairy farm, sample preparation, and extensive incubation periods 9 , 12 .…”

Dermal Microdialysis in Pharmacokinetics

“…The mean age of participants was 42 years (SD 14) and seven (70%) of ten participants were men. Participants mean height was 174 cm (11), weight 74 kg (15), and BMI 24 kg/m² (3). Mean creatinine clearance was 114 mL/min (29).…”

“…Potential for disruption of local tissues, inflammation, and bleeding during insertion 18 Practicality for use in clinical practice Easy application, no needles or skin puncture required Requires training and puncture of the skin In-vivo measurement Direct detection in vivo Not applicable (diasylate collected and analysed ex vivo) Quantification Direct quantification of drug concentration 15,[24][25][26] Estimation of drug concentration calculated often using an internal standard method [18][19][20] Resolution of sampling…”