Publications
22 results found
Riezk A, Wilson RC, Cass AEG, et al., 2024, A low-volume LC/MS method for highly sensitive monitoring of phenoxymethylpenicillin, benzylpenicillin, and probenecid in human serum, Analytical Methods: advancing methods and applications, Vol: 16, Pages: 558-565, ISSN: 1759-9660
Background: The optimization of antimicrobial dosing plays a crucial role in improving the likelihood of achieving therapeutic success while reducing the risks associated with toxicity and antimicrobial resistance. Probenecid has shown significant potential in enhancing the serum exposure of phenoxymethylpenicillin, thereby allowing for lower doses of phenoxymethylpenicillin to achieve similar pharmacokinetic/pharmacodynamic (PK/PD) targets. We developed a triple quadrupole liquid chromatography mass spectrometry (TQ LC/MS) analysis of, phenoxymethylpenicillin, benzylpenicillin and probenecid using benzylpenicillin-d7 and probenecid-d14 as IS in single low-volumes of human serum, with improved limit of quantification to support therapeutic drug monitoring. Methods: Sample clean-up was performed by protein precipitation using acetonitrile. Reverse phase chromatography was performed using TQ LC/MS. The mobile phase consisted of 55% methanol in water + 0.1% formic acid, with a flow rate of 0.4 mL min-1. Antibiotic stability was assessed at different temperatures. Results: Chromatographic separation was achieved within 2 minutes, allowing simultaneous measurement of phenoxymethylpenicillin, benzylpenicillin and probenecid in a single 15 μL blood sample. Validation indicated linearity over the range 0.0015-10 mg L-1, with accuracy of 96-102% and a LLOQ of 0.01 mg L-1. All drugs demonstrated good stability under different storage conditions. Conclusion: The developed method is simple, rapid, accurate and clinically applicable for the quantification of phenoxymethylpenicillin, benzylpenicillin and probenecid in tandem.
Bolton W, Wilson R, Gilchrist M, et al., 2024, Personalising intravenous to oral antibiotic switch decision making through fair interpretable machine learning, Nature Communications, Vol: 15, ISSN: 2041-1723
Antimicrobial resistance (AMR) and healthcare associated infections pose a significant threat globally. One key prevention strategy is to follow antimicrobial stewardship practices, in particular, to maximise targeted oral therapy and reduce the use of indwelling vascular devices for intravenous (IV) administration. Appreciating when an individual patient can switch from IV to oral antibiotic treatment is often non-trivial and not standardised. To tackle this problem we created a machine learning model to predict when a patient could switch based on routinely collected clinical parameters. 10,362 unique intensive care unit stays were extracted and two informative feature sets identified. Our best model achieved a mean AUROC of 0.80 (SD 0.01) on the hold-out set while not being biased to individuals protected characteristics. Interpretability methodologies were employed to create clinically useful visual explanations. In summary, our model provides individualised, fair, and interpretable predictions for when a patient could switch from IV-to-oral antibiotic treatment. Prospectively evaluation of safety and efficacy is needed before such technology can be applied clinically.
Rawson TM, Antcliffe D, Wilson R, et al., 2023, Management of bacterial and fungal infections in the ICU: diagnosis, treatment, and prevention recommendations, Infection and Drug Resistance, Vol: 16, Pages: 2709-2726, ISSN: 1178-6973
Bacterial and fungal infections are common issues for patients in the intensive care unit (ICU). Large, multinational point prevalence surveys have identified that up to 50% of ICU patients have a diagnosis of bacterial or fungal infection at any one time. Infection in the ICU is associated with its own challenges. Causative organisms often harbour intrinsic and acquired mechanisms of drug-resistance, making empiric and targeted antimicrobial selection challenging. Infection in the ICU is associated with worse clinical outcomes for patients. We review the epidemiology of bacterial and fungal infection in the ICU. We discuss risk factors for acquisition, approaches to diagnosis and management, and common strategies for the prevention of infection.
Freeman DME, Ming DK, Wilson R, et al., 2023, Continuous measurement of lactate concentration in human subjects through direct electron transfer from enzymes to microneedle electrodes, ACS Sensors, Vol: 8, Pages: 1639-1647, ISSN: 2379-3694
Microneedle lactate sensors may be used to continuously measure lactate concentration in the interstitial fluid in a minimally invasive and pain-free manner. First- and second-generation enzymatic sensors produce a redox-active product that is electrochemically sensed at the electrode surface. Direct electron transfer enzymes produce electrons directly as the product of enzymatic action; in this study, a direct electron transfer enzyme specific to lactate has been immobilized onto a microneedle surface to create lactate-sensing devices that function at low applied voltages (0.2 V). These devices have been validated in a small study of human volunteers; lactate concentrations were raised and lowered through physical exercise and subsequent rest. Lactazyme microneedle devices show good agreement with concurrently obtained and analyzed serum lactate levels.
Riezk A, Vasikasin V, Wilson RCC, et al., 2023, Triple quadrupole LC/MS method for the simultaneous quantitative measurement of cefiderocol and meropenem in serum, Analytical Methods: advancing methods and applications, Vol: 15, Pages: 746-751, ISSN: 1759-9660
Background: therapeutic drug monitoring is a crucial aspect of the management of hospitalized patients. The correct dosage of antibiotics is imperative to ensure their adequate exposure specially in critically ill patients. The aim of this study is to establish and validate a robust and fast liquid chromatography-tandem mass spectrometry (LC/MS) method for the simultaneous quantification of two important antibiotics in critically ill patients, cefiderocol and meropenem in human plasma. Methods: sample clean-up was performed by protein precipitation using acetonitrile. Reverse phase chromatography was performed using triple quadrupole LC/MS. The mobile phase was consisted of 55% methanol in water +0.1% formic acid, with flow rate of 0.4 ml min−1. Antibiotics stability was assessed at different temperatures. Serum protein binding was assessed using ultrafiltration devices. Results: chromatographic separation was achieved within 1.5 minutes for all analytes. Validation has demonstrated the method to be linear over the range 0.0025–50 mg L−1 for cefiderocol and 0.00028–50 mg L−1 for meropenem, with accuracy of 94–101% and highly sensitive, with LLOQ ≈ 0.02 mg L−1 and 0.003 mg L−1 for cefiderocol and meropenem, respectively. Both cefiderocol and meropenem showed a good stability at room temperature over 6 h, and at (4 °C) over 24 h. Cefiderocol and meropenem demonstrated a protein binding of 49–60% and 98%, respectively in human plasma. Conclusion: the developed method is simple, rapid, accurate and clinically applicable for the quantification of cefiderocol and meropenem.
Riezk A, Wilson RC, Rawson TM, et al., 2023, A rapid, simple, high-performance liquid chromatography method for the clinical measurement of beta-lactam antibiotics in serum and interstitial fluid, Analytical Methods: advancing methods and applications, Vol: 15, Pages: 829-836, ISSN: 1759-9660
Background: enhanced methods of therapeutic drug monitoring are required to support the individualisation of antibiotic dosing based on pharmacokinetics (PK) parameters. PK studies can be hampered by limited total serum volume, especially in neonates, or by sensitivity in the case of critically ill patients. We aimed to develop a liquid chromatography–mass spectrometry (LC/MS) analysis of benzylpenicillin, phenoxymethylpenicillin and amoxicillin in single low volumes of human serum and interstitial fluid (ISF) samples, with an improved limit of detection (LOD) and limit of quantification (LOQ), compared with previously published assays. Methods: sample clean-up was performed by protein precipitation using acetonitrile. Reverse phase chromatography was performed using triple quadrupole LC/MS. The mobile phase consisted of 55% methanol in water + 0.1% formic acid, with a flow rate of 0.4 mL min−1. Antibiotics stability was assessed at different temperatures. Results: chromatographic separation was achieved within 3 minutes for all analytes. Three common penicillins can now be measured in a single low-volume blood and ISF sample (15 μL) for the first time. Validation has demonstrated the method to be linear over the range 0.0015–10 mg L−1, with an accuracy of 93–104% and high sensitivity, with LOD ≈ 0.003 mg L−1 and LOQ ≈ 0.01 mg L−1 for all three analytes, which is critical for use in dose optimisation/individualisation. All evaluated penicillins indicated good stability at room temperature over 4 h, at (4 °C) over 24 h and at −80 °C for 6 months. Conclusion: the developed method is simple, rapid, accurate and clinically applicable for the quantification of three penicillin classes.
Bolton W, Rawson T, Hernandez B, et al., 2022, Machine learning and synthetic outcome estimation for individualised antimicrobial cessation, Frontiers in Digital Health, Vol: 4, Pages: 1-12, ISSN: 2673-253X
The decision on when it is appropriate to stop antimicrobial treatment in an individual patient is complex and under-researched. Ceasing too early can drive treatment failure, while excessive treatment risks adverse events. Under- and over-treatment can promote the development of antimicrobial resistance (AMR). We extracted routinely collected electronic health record data from the MIMIC-IV database for 18,988 patients (22,845 unique stays) who received intravenous antibiotic treatment during an intensive care unit (ICU) admission. A model was developed that utilises a recurrent neural network autoencoder and a synthetic control-based approach to estimate patients’ ICU length of stay (LOS) and mortality outcomes for any given day, under the alternative scenarios of if they were to stop vs. continue antibiotic treatment. Control days where our model should reproduce labels demonstrated minimal difference for both stopping and continuing scenarios indicating estimations are reliable (LOS results of 0.24 and 0.42 days mean delta, 1.93 and 3.76 root mean squared error, respectively). Meanwhile, impact days where we assess the potential effect of the unobserved scenario showed that stopping antibiotic therapy earlier had a statistically significant shorter LOS (mean reduction 2.71 days, p-value <0.01). No impact on mortality was observed. In summary, we have developed a model to reliably estimate patient outcomes under the contrasting scenarios of stopping or continuing antibiotic treatment. Retrospective results are in line with previous clinical studies that demonstrate shorter antibiotic treatment durations are often non-inferior. With additional development into a clinical decision support system, this could be used to support individualised antimicrobial cessation decision-making, reduce the excessive use of antibiotics, and address the problem of AMR.
Herrero Vinas P, Wilson R, Armiger R, et al., 2022, Closed-loop control of continuous piperacillin delivery: an in silico study, Frontiers in Bioengineering and Biotechnology, Vol: 10, ISSN: 2296-4185
Background and objective: Sub-therapeutic dosing of piperacillin-tazobactam in critically-ill patients is associated with poor clinical outcomes and may promote the emergence of drug-resistant infections. In this paper, an in silico investigation of whether closed-loop control can improve pharmacokinetic-pharmacodynamic (PK-PD) target attainment is described.Method: An in silico platform was developed using PK data from 20 critically-ill patients receiving piperacillin-tazobactam where serum and tissue interstitial fluid (ISF) PK were defined. Intra-day variability on renal clearance, ISF sensor error, and infusion constraints were taken into account. Proportional-integral-derivative (PID) control was selected for drug delivery modulation. Dose adjustment was made based on ISF sensor data with a 30-minute sampling period, targeting a serum piperacillin concentration between 32-64 mg/L. A single tuning parameter set was employed across the virtual population. The PID controller was compared to standard therapy, including bolus and continuous infusion of piperacillin-tazobactam.Results: Despite significant inter-subject and simulated intra-day PK variability and sensor error, PID demonstrated a significant improvement in target attainment compared to traditional bolus and continuous infusion approaches. Conclusion: A PID controller driven by ISF drug concentration measurements has the potential to precisely deliver piperacillin-tazobactam in critically-ill patients undergoing treatment for sepsis.
Arkell P, Wilson R, Watkins K, et al., 2022, Application of therapeutic drug monitoring to the treatment of bacterial central nervous system infection: a scoping review, Journal of Antimicrobial Chemotherapy, Vol: 77, Pages: 3408-3413, ISSN: 0305-7453
BackgroundBacterial central nervous system (CNS) infection is challenging to treat and carries high risk of recurrence, morbidity, and mortality. Low CNS penetration of antibiotics may contribute to poor clinical outcomes from bacterial CNS infections. The current application of therapeutic drug monitoring (TDM) to management of bacterial CNS infection was reviewed.MethodsStudies were included if they described adults treated for a suspected/confirmed bacterial CNS infection and had antibiotic drug concentration(s) determined that affected individual treatment.ResultsOne-hundred-and-thirty-six citations were retrieved. Seventeen manuscripts were included describing management of 68 patients. TDM for vancomycin (58/68) and the beta-lactams (29/68) was most common. Timing of clinical sampling varied widely between studies and across different antibiotics. Methods for setting individual PK-PD targets, determining parameters and making treatment changes varied widely and were sometimes unclear.DiscussionDespite increasing observational data showing low CNS penetration of various antibiotics, there are few clinical studies describing practical implementation of TDM in management of CNS infection. Lack of consensus around clinically relevant CSF PK-PD targets and protocols for dose-adjustment may contribute. Standardised investigation of TDM as a tool to improve treatment is required, especially as innovative drug concentration-sensing and PK-PD modelling technologies are emerging. Data generated at different centres offering TDM should be open access and aggregated to enrich understanding and optimize application.
Wilson R, Arkell P, Riezk A, et al., 2022, Addition of probenecid to oral beta-lactam antibiotics: a systematic review and meta-analysis, Journal of Antimicrobial Chemotherapy, Vol: 77, Pages: 2364-2372, ISSN: 0305-7453
Objective: Explore literature comparing the pharmacokinetic and clinical outcomes from addition of probenecid to oral beta-lactams.Data sources: Medline and EMBASE were searched from inception to December 2021.Study eligibility criteria: All English language studies comparing the addition of probenecid (intervention) to an oral beta-lactam (flucloxacillin, penicillin-V, amoxicillin(+/-clavulanate), cephalexin, cefuroxime-axetil) alone (comparator).Risk of bias: Risk of Bias in Non-randomised studies of interventions (ROBINS-I) and Risk of Bias for Randomised studies 2 (ROB-2) tools were used.Methods of data synthesis: Data on antibiotic therapy, infection diagnosis, primary and secondary outcomes relating to pharmacokinetics and clinical outcomes plus adverse events were extracted and reported descriptively. For a subset of studies comparing treatment failure between probenecid and control groups, meta-analysis was performed. Results: Overall, 18/295 (6%) abstracts screened were included. Populations, methodology, and outcome data were heterogenous. Common populations included healthy volunteer (9/18;50%) and gonococcal infection (6/18;33%). Most studies were cross-over trials (11/18;61%) or parallel arm randomised trial (4/18;22%). Where pharmacokinetic analyses were performed, addition of probenecid to oral beta-lactams increased total AUC (7/7;100¬%), peak observed concentration (Cmax,5/8;63%), and serum half-life (t1/2,6/8;75%). Probenecid improved PTA (2/2;100%). Meta-analysis of 3105 (2258 intervention, 847 control) patients treated for gonococcal disease demonstrated a relative risk of treatment failure in the random effects model of 0.33 (95%CI:0.20-0.55; I2=7%), favouring probenecid. Conclusion: Probenecid boosted beta-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid boosted oral beta-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy st
Rawson TM, Eigo T, Wilson R, et al., 2022, Exploring patient acceptance of research within Complex oral and IV Outpatient Parenteral Antimicrobial Therapy (COpAT) networks, JAC-Antimicrobial Resistance, Vol: 4, ISSN: 2632-1823
Ming DK, Jangam S, Gowers SAN, et al., 2022, Real-time continuous measurement of lactate through a minimally invasive microneedle patch: a phase I clinical study, BMJ Innovations, Vol: 8, Pages: 87-94, ISSN: 2055-8074
Introduction Determination of blood lactate levels supports decision-making in a range of medical conditions. Invasive blood-sampling and laboratory access are often required, and measurements provide a static profile at each instance. We conducted a phase I clinical study validating performance of a microneedle patch for minimally invasive, continuous lactate measurement in healthy volunteers.Methods Five healthy adult participants wore a solid microneedle biosensor patch on their forearms and undertook aerobic exercise for 30 min. The microneedle biosensor quantifies lactate concentrations in interstitial fluid within the dermis continuously and in real-time. Outputs were captured as sensor current and compared with lactate concentrations from venous blood and microdialysis.Results The biosensor was well-tolerated. Participants generated a median peak venous lactate of 9.25 mmol/L (IQR 6.73–10.71). Microdialysate concentrations of lactate closely correlated with blood. Microneedle biosensor current followed venous lactate concentrations and dynamics, with good agreement seen in all participants. There was an estimated lag-time of 5 min (IQR −4 to 11 min) between microneedle and blood lactate measurements.Conclusion This study provides first-in-human data on use of a minimally invasive microneedle patch for continuous lactate measurement, providing dynamic monitoring. This low-cost platform offers distinct advantages to frequent blood sampling in a wide range of clinical settings, especially where access to laboratory services is limited or blood sampling is infeasible. Implementation of this technology in healthcare settings could support personalised decision-making in a variety of hospital and community settings.
Arkell P, Wilson R, Antcliffe DB, et al., 2022, A pilot observational study of CSF vancomycin therapeutic drug monitoring during the treatment of nosocomial ventriculitis., Journal of Infection, ISSN: 0163-4453
McLeod J, Stadler E, Wilson R, et al., 2021, Electrochemical detection of cefiderocol for therapeutic drug monitoring, Electrochemistry Communications, Vol: 133, ISSN: 1388-2481
Cefiderocol is a novel siderophore-conjugated β-lactam antibiotic which has been approved for clinical use. It has demonstrated efficacy against infections caused by Gram-negative bacteria, including carbapenem-resistant strains. Novel antibiotics are rarely brought to market and, as such, are ideal candidates for therapeutic drug monitoring which enables optimised dosing across a range of clinical scenarios whilst also reducing the chances of antimicrobial resistance. Here we demonstrate direct electrochemical detection of cefiderocol by oxidation using untreated gold and glassy carbon electrodes as well as multi-walled carbon nanotube (MWCNT)-coated glassy carbon and foamed gold electrodes. Quantification of cefiderocol in the therapeutic range is demonstrated in spiked whole human blood using MWCNT-coated pyrolytic carbon screen-printed electrodes.
Rawson TM, Wilson R, Moore L, et al., 2021, Exploring the pharmacokinetics of phenoxymethylpenicillin (Penicillin-V) in adults: a healthy volunteer study, Open Forum Infectious Diseases, Vol: 8, Pages: 1-4, ISSN: 2328-8957
This healthy volunteer study aimed to explore Phenoxymethylpenicillin (Penicillin-V) pharmacokinetics (PK) to support the planning of large, dosing studies in adults. Volunteers were dosed with penicillin-V at steady state. Total and unbound penicillin-V serum concentration was determined and a base population PK model were fitted to the data.
Rawson TM, Wilson RC, O'Hare D, et al., 2021, Optimizing antimicrobial use: challenges, advances and opportunities, NATURE REVIEWS MICROBIOLOGY, Vol: 19, Pages: 747-758, ISSN: 1740-1526
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Rawson TM, Hernandez B, Moore L, et al., 2021, A real-world evaluation of a case-based reasoning algorithm to support antimicrobial prescribing decisions in acute care, Clinical Infectious Diseases, Vol: 72, Pages: 2103-2111, ISSN: 1058-4838
BackgroundA locally developed Case-Based Reasoning (CBR) algorithm, designed to augment antimicrobial prescribing in secondary care was evaluated.MethodsPrescribing recommendations made by a CBR algorithm were compared to decisions made by physicians in clinical practice. Comparisons were examined in two patient populations. Firstly, in patients with confirmed Escherichia coli blood stream infections (‘E.coli patients’), and secondly in ward-based patients presenting with a range of potential infections (‘ward patients’). Prescribing recommendations were compared against the Antimicrobial Spectrum Index (ASI) and the WHO Essential Medicine List Access, Watch, Reserve (AWaRe) classification system. Appropriateness of a prescription was defined as the spectrum of the prescription covering the known, or most-likely organism antimicrobial sensitivity profile.ResultsIn total, 224 patients (145 E.coli patients and 79 ward patients) were included. Mean (SD) age was 66 (18) years with 108/224 (48%) female gender. The CBR recommendations were appropriate in 202/224 (90%) compared to 186/224 (83%) in practice (OR: 1.24 95%CI:0.392-3.936;p=0.71). CBR recommendations had a smaller ASI compared to practice with a median (range) of 6 (0-13) compared to 8 (0-12) (p<0.01). CBR recommendations were more likely to be classified as Access class antimicrobials compared to physicians’ prescriptions at 110/224 (49%) vs. 79/224 (35%) (OR: 1.77 95%CI:1.212-2.588 p<0.01). Results were similar for E.coli and ward patients on subgroup analysis.ConclusionsA CBR-driven decision support system provided appropriate recommendations within a narrower spectrum compared to current clinical practice. Future work must investigate the impact of this intervention on prescribing behaviours more broadly and patient outcomes.
Arkell P, Mahboobani S, Wilson R, et al., 2021, Bronchoalveolar lavage fluid IMMY Sona <i>Aspergillus</i> lateral-flow assay for the diagnosis of invasive pulmonary aspergillosis: a prospective, real life evaluation, MEDICAL MYCOLOGY, Vol: 59, Pages: 404-408, ISSN: 1369-3786
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Rawson TM, Hernandez B, Wilson R, et al., 2021, Supervised machine learning to support the diagnosis of bacterial infection in the context of COVID-19, JAC-Antimicrobial Resistance, Vol: 3, Pages: 1-4, ISSN: 2632-1823
Background: Bacterial infection has been challenging to diagnose in patients with COVID-19. We developed and evaluated supervised machine learning algorithms to support the diagnosis of secondary bacterial infection in hospitalized patients during COVID-19.Methods: Inpatient data at three London hospitals for the first COVD-19 wave in March and April 2020 were extracted. Demographic, blood test, and microbiology data for individuals with and without SARS-CoV-2 positive PCR were obtained. A Gaussian-Naïve Bayes (GNB), Support Vector Machine (SVM), and Artificial Neuronal Network (ANN) were trained and compared using the area under the receiver operating characteristic curve (AUCROC). The best performing algorithm (SVM with 21 blood test variables) was prospectively piloted in July 2020. AUCROC was calculated for the prediction of a positive microbiological sample within 48 hours of admission. Results: A total of 15,599 daily blood profiles for 1,186 individual patients were identified to train the algorithms. 771/1186 (65%) individuals were SARS-CoV-2 PCR positive. Clinically significant microbiology results were present for 166/1186 (14%) patients during admission. A SVM algorithm trained with 21 routine blood test variables and over 8000 individual profiles had the best performance. AUCROC was 0.913, sensitivity 0.801, and specificity 0.890. Prospective testing on 54 patients on admission (28/54, 52% SARS-CoV-2 PCR positive) demonstrated an AUCROC of 0.960 (0.90-1.00). Conclusion: A SVM using 21 routine blood test variables had excellent performance at inferring the likelihood of positive microbiology. Further prospective evaluation of the algorithms ability to support decision making for the diagnosis of bacterial infection in COVID-19 cohorts is underway.
Rawson TM, Wilson R, Holmes A, 2020, Understanding the role of bacterial and fungal infection in COVID-19, Clinical Microbiology and Infection, ISSN: 1198-743X
Rawson TM, Gowers SAN, Freeman DME, et al., 2019, Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers, The Lancet Digital Health, Vol: 1, Pages: e335-e343, ISSN: 2589-7500
Background: Enhanced methods of drug monitoring are required to support the individualisation of antibiotic dosing. We report the first-in-human evaluation of real-time phenoxymethylpenicillin monitoring using a minimally invasive microneedle-based β-lactam biosensor in healthy volunteers.Methods: This first-in-human, proof-of-concept study was done at the National Institute of Health Research/Wellcome Trust Imperial Clinical Research Facility (Imperial College London, London, UK). The study was approved by London-Harrow Regional Ethics Committee. Volunteers were identified through emails sent to a healthy volunteer database from the Imperial College Clinical Research Facility. Volunteers, who had to be older than 18 years, were excluded if they had evidence of active infection, allergies to penicillin, were at high risk of skin infection, or presented with anaemia during screening. Participants wore a solid microneedle β-lactam biosensor for up to 6 h while being dosed at steady state with oral phenoxymethylpenicillin (five 500 mg doses every 6 h). On arrival at the study centre, two microneedle sensors were applied to the participant's forearm. Blood samples (via cannula, at −30, 0, 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) and extracellular fluid (ECF; via microdialysis, every 15 min) pharmacokinetic (PK) samples were taken during one dosing interval. Phenoxymethylpenicillin concentration data obtained from the microneedles were calibrated using locally estimated scatter plot smoothing and compared with free-blood and microdialysis (gold standard) data. Phenoxymethylpenicillin PK for each method was evaluated using non-compartmental analysis. Area under the concentration–time curve (AUC), maximum concentration, and time to maximum concentration were compared. Bias and limits of agreement were investigated with Bland–Altman plots. Microneedle biosensor limits of detection were estimated. The study was registered with Clinical
Gowers SAN, Freeman DME, Rawson TM, et al., 2019, Development of a minimally invasive microneedle-based sensor for continuous monitoring of β-lactam antibiotic concentrations in vivo, ACS sensors, Vol: 4, Pages: 1072-1080, ISSN: 2379-3694
Antimicrobial resistance poses a global threat to patient health. Improving the use and effectiveness of antimicrobials is critical in addressing this issue. This includes optimizing the dose of antibiotic delivered to each individual. New sensing approaches that track antimicrobial concentration for each patient in real time could allow individualized drug dosing. This work presents a potentiometric microneedle-based 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 immobilized on the electrode surface. Development and optimization 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 2 weeks at -20 °C and to withstand sterilization. Sensitivity was retained after application for 6 h in vivo. Proof-of-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 toward a closed-loop therapeutic drug monitoring system.
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