A Personalized Approach Could Help To Tackle the Global AMR Crisis

Many of us are alive today thanks to modern medicine and the infections and illnesses that once would have claimed many lives are fought back with therapeutic agents. Having the tools to nip infections in the bud has also helped to reduce transmission to others, reducing disease burden on the population. However, humanity is facing a serious problem.

Antimicrobial resistance (AMR) is threatening the effective treatment and prevention of a wide range of infections, with serious potential consequences for health and the economy. According to the World Health Organization (WHO), AMR was associated with the deaths of nearly 5 million people globally in 2019 and they predict if no action is taken, it could cost the world’s economy $ 100 trillion USD by 2050. Factors such as poor antimicrobial stewardship, a lack of understanding when it comes to taking prescribed medication and a “one size fits all approach” are helping to drive the spread of AMR genes through microbial populations, perpetuating the problem. It’s clear that something needs to change.

We spoke to Dr. Alaa Riezk, research associate at the Centre for Antimicrobial Optimisation (CAMO), Imperial College London, about the problem of usage and dosage of antimicrobials and AMR and how he and the team are working to address it.

Karen Steward (KS): Can you please explain why it is critical that we aim to optimize the usage and dosage of antimicrobials?

Alaa Riezk (AR): AMR is an escalating global threat that poses a risk to modern medicine. Effectively addressing the challenge of AMR requires a multifaceted approach focused on optimizing existing antimicrobials. This optimization aims to achieve several critical goals, including maximizing therapeutic efficacy, minimizing the risk of drug-related toxicity and reducing the emergence of antimicrobial resistance.

Typically, antimicrobial treatment is based on a "one dose fits all" approach. However, this does not account for significant variations in how individuals metabolize drugs. Factors such as obesity, characteristics of the infecting organisms and concurrent medication usage can greatly impact the pharmacokinetics of antimicrobials. Therefore, it is essential to develop personalized approaches to treatment. This shift towards tailored treatment regimens is vital for ensuring that antimicrobial therapy is not only effective but also safe for each patient.

KS: Why is antimicrobial optimization so challenging?

AR: The "one dose fits all" approach, where antimicrobial prescriptions do not account for pharmacokinetic (drug exposure) and pharmacodynamic (individual treatment response) variabilities, has been a longstanding issue. Typically, antimicrobial dosing regimens are selected based on data from the general population, neglecting the unique characteristics of individual patients and organisms.

Current therapeutic drug monitoring (TDM) practices involve collecting patient samples and sending them to laboratories. Subsequently, these samples go through a series of steps, including sample check-in, centrifugation, analysis, reporting, review by a prescriber and dose adjustment. This process is not only time-consuming but also financially burdensome, making it an impractical choice. It's no surprise that TDM is not widely implemented in clinical practice.

To address this challenge, the Center for Antimicrobial Optimisation (CAMO) is committed to developing point-of-care devices for the detection and monitoring of antimicrobials. These innovative devices aim to revolutionize the way antimicrobial therapy is administered, by providing rapid and cost-effective solutions that enable personalized dosing based on individual patient needs. This approach has the potential to enhance the efficacy and safety of antimicrobial treatment greatly while reducing the burden on healthcare resources.

KS: How has access to the AMS helped to facilitate and expedite your work?

AR: At the heart of CAMO, our primary objective is to advance state-of-the-art technologies through collaborations with multidisciplinary experts, patients and healthcare workers to facilitate personalized therapy. One of our pioneering initiatives involves the development of point-of-care devices tailored to various classes of antibiotics, with our initial focus being on penicillin.

Within CAMO, our dedicated team has crafted a remarkable, wearable microneedle sensor. These microneedles are ingeniously coated with antibiotic resistance enzymes designed to break down the beta-lactam ring, releasing protons in the process. The subsequent change in pH can be discerned as a voltage shift on these diminutive microneedles. This breakthrough enables us to continuously monitor penicillin concentrations without the need for invasive blood sampling, and importantly, it is entirely painless, as the microneedles only penetrate the epidermis.^1,2 

CAMO recently conducted its inaugural clinical study involving human participants to assess and evaluate the efficacy of these microneedle sensors. Healthy volunteers were administered penicillin, and on the study day, we conducted a comprehensive pharmacokinetic analysis, employing both blood samples and microdialysis samples. The analysis of penicillin concentration in these samples was performed using the gold standard liquid chromatography-mass spectrometry (LC-MS) method. Subsequently, we compared this data with the information obtained from the microneedle sensors.

To execute this task, I utilized the triple quadrupole LC-MS system, conveniently located in the Agilent Measurement Suite (AMS) within Imperial's White City campus. The utilization of the AMS played a pivotal role in our equipment selection process when establishing our in-house LC-MS laboratory at CAMO. CAMO provides state-of-the-art laboratories and data science suites to support innovative research and the development of emerging technologies.

I aimed to develop and validate a method for the analysis of three types of penicillin (benzylpenicillin, phenoxymethylpenicillin and amoxicillin) in minute volumes of human serum and interstitial fluid samples. The primary goal was to achieve a superior limit of detection (LOD) and limit of quantification (LOQ) compared to existing assays.³ This optimized method was subsequently employed for the analysis of our blood and interstitial fluid samples, thereby supporting the clinical study involving the microneedles.

The results have been promising, as the sensor responses closely tracked the trends observed in both dialysate and serum samples. In a proof-of-concept trial with healthy volunteers, we have successfully demonstrated the potential of these biosensors to provide real-time tracking of penicillin concentrations in vivo.

KS: Can you tell us about some of the key findings and outputs from your studies so far? How are you hoping to expand on this work?

AR: CAMO is based at Imperial College and was funded by a £4 M infrastructure grant from the Department of Health and Social Care (DHSC). The grant was set up to support research with a focus on developing emerging, novel approaches to optimize antimicrobial use. Its primary goal is to sustain the effectiveness of these drugs, especially in light of the increasing challenge of AMR and the absence of new treatments. This funding and subsequent funding from Wellcome for the creation of CAMO-Net has allowed us to develop research on antimicrobial optimization, including the development of emerging diagnostic methods, data sciences and AI approaches to support infection management.

We are developing a pipeline of biosensors for several antimicrobial drugs and diagnostic biomarkers.

Besides the microneedle platform mentioned before, a novel method for direct electrochemical detection of cefiderocol was published in Electrochemistry Communications and the sensor is currently undergoing clinical validation.^4,5 Cefiderocol, an innovative antibiotic, has exhibited remarkable efficacy in combating multi-drug-resistant infections. Its approval for use in multiple countries highlights its potential in the fight against AMR. As a result, the need for a new antibiotic TDM method has become increasingly imperative to ensure the responsible use of this novel drug.^5,6 Another example is our ongoing research into the development of biosensors for lactate. This research is particularly significant due to the growing interest in utilizing lactate as a diagnostic marker for conditions such as sepsis, septic shock and trauma.^6,7

This point-of-care sensor represents a significant advancement in antibiotic monitoring, filling a critical gap in our ability to effectively manage and utilize this essential antibiotic in the battle against drug-resistant infections.

Dr. Alaa Riezk was speaking to Dr. Karen Steward, Senior Scientific Specialist for Technology Networks.

About the interviewee 

Alaa Riezk joined Imperial College as a Postdoctoral Researcher in the Centre for Antimicrobial Optimisation (CAMO) where he has been involved in several antimicrobial optimization projects, including the establishment of in-house testing of various selected antimicrobial agents to support the development of novel biosensors for antimicrobial optimization. Alaa is currently working on the development and clinical testing of the microneedle biosensor project, incorporating closed-loop control of penicillin delivery.