Impact case study database

Figure 1. Summary of impact on A) monitoring of toxic antibiotics streptomycin and colistin and B) safe drug development. Processes are shown before and after McCalley’s research.

**Improving patient safety through laboratory tests to monitor toxic antibiotics (2013-2020; figure 1A)**Multi-drug resistant (MDR) bacterial infection is a growing issue in Europe and the UK as the region is seeing the highest rate of incidence of MDR-tuberculosis ( S1, S2). Outbreaks can lead to thousands of MDR infections across the UK annually ( S1). There are few, highly toxic, drug options for the treatment of MDR infections. Drug testing, developed by McCalley ( R6) and conducted at the Antimicrobial Reference Laboratory (ARL) allows clinicians to monitor levels of toxic drugs in samples of patient blood, optimising efficacy against the pathogens and minimising the toxicity risk ( S1).

McCalley and his team worked with ARL to develop tests for the drugs streptomycin and colistin ( S3). Streptomycin treats tuberculosis but has a narrow therapeutic window – too little is ineffective while too much causes permanent hearing and balance loss (figure 1A); and it can only be used safely if monitored ( S1). Before McCalley’s work with ARL, streptomycin could only be tested at a US laboratory, making turnaround times impractical for UK and EU patients and preventing safe use of this important drug ( S3). Drawing on his research into the mechanisms underlying HPLC separation ( R1), McCalley developed the sole commercial test for streptomycin in Europe now used by ARL. The lead Consultant in Infection and Professor of Antimicrobial Therapeutics at North Bristol NHS Trust, said ‘ without this new assay [test], we would struggle to use streptomycin safely’ ( S1). As the only European-based lab with these capabilities, ARL ‘ has seen a significant year-on-year growth in use of the service’ ( S3).

Previously, tests for colistin, which is used to treat sepsis, could not differentiate between the active and non-active form of the drug (figure 1A), leading to over-estimations of the active form and under-dosing of patients ( S1). Under-dosing with colistin in the first days of hospitalisation leads to poor efficacy, while over-dosing can permanently damage renal function ( S3). The new liquid chromatography mass spectrometry (LC-MS) test developed by UWE ‘ far out-performed the bioassay [test] used previously due to improved specificity for the active form’ said the then Head of the ARL ( S3). It is comparable to tests used internationally, allowing ‘ clinical staff to optimise patient prescribing in the context of published evidence” said the Consultant in Infection and Professor of Antimicrobial Therapeutics ( S1). The Consultant added:

‘ with this improved LC-MS test, we can now use colistin more effectively and more safely in last resort situations’ and ‘ in my opinion monitoring of colistin by LC-MS is essential to its use, and is leading to better outcomes for sepsis patients suffering multi-drug resistant infection’ ( S1).

This is particularly significant given that rates of colistin use are rising in acute care (66% increase since 2016-2017) ( S4).

The laboratory tests McCalley developed provide the basis for a monitoring service helping clinicians and improving patient care throughout Europe by administering safely toxic (streptomycin and colistin) and last-resort (colistin) antibiotics targeted at MDR infections. ARL is the largest provider of antimicrobial Therapeutic Drug Monitoring in the UK and over 240 laboratories using this service across the UK and Europe. ARL tests 10-15 colistin and 5-10 streptomycin samples per week at GBP120 per sample ( S3), resulting in revenue of approximately GBP125,000 per year.

**Safe drug development at GlaxoSmithKline (GSK): reducing cost and improving speed (2013-2020; figure 1B)**Approval and launch of a new medicine from drug discovery takes on average 9.5-15 years ( S5). Drug discovery starts with screening of between 5,000-10,000 compounds out of which typically only 5 make it to Phase 1 clinical trials. GSK Pharmaceutical core annual R&D investment was GBP2,500,000,000 in 2014, 29% of this spent on early-stage research (drug discovery). The strategic aim of GSK was to improve the proportion of high-quality early drug candidates that progress to clinical development, and to reduce the time and cost involved ( S5).

Collaboration with McCalley enabled GSK to apply HILIC as one of the HPLC procedures used to solve pharmaceutical separation problems in early stage research in identifying impurities in the active pharmaceutical ingredient as well as the preparative separation of pure product from cruder mixtures (figure 1B). McCalley’s work showed that HILIC could be used as an analytical process, and also scaled up to allow larger quantities of material to be purified ( S6, R2- 6). With a shorter, more effective screening process, and simpler scale-up for purification than previously, GSK have reduced their turnaround times and the number of screening rounds required to find optimum analysis conditions. The Head of UK Purification at GSK said their use of McCalley’s methods have led to:

‘approximately a 50% reduction in the running costs of finding suitable separations for scale-up’ and that they ‘speed up the processes required to discover new active chemical entities’ ( S6, R3, R4).

McCalley also demonstrated that HPLC CAD could replace GSK’s previous method for assessing the solubility of new molecules ( R2). GSK adopted the CAD system as the universal detector for drug solubility measurements, which now produces data for hundreds of compounds per week. The Head of UK Purification describes the performance as ‘ an order of magnitude increase on our previous capacity’. In contrast to its predecessor, the CAD system is ‘ robust and easy to operate, allowing quantification of structurally diverse compounds, most importantly in a high throughput fashion’ ( S6, R2). The data from the CAD system allows GSK chemists to rank candidate drugs and identify issues at early stages of development, described as ‘ reducing attrition rates and speeding up the process toward candidate [drug] selection with obvious attendant cost savings’ ( S6).