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Analysis of the use of antibiotics by AWaRe categories during the COVID-19 pandemic in hospitals across Scotland: a national population-based study ..................................................................................................................... 3 Evaluation of the stability of aciclovir in elastomeric infusion devices used for outpatient parenteral antimicrobial therapy ......................................................................................................................... 7

Toward a better understanding about real-world evidence ....................................................................................................................................... 13

Advanced therapy medicinal products ........................................................................................................ 17

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Analysis of the use of antibiotics by AWaRe categories during the COVID-19 pandemic in hospitals across Scotland: a national population- based study Euan Proud , 1,2 Tanja Mueller, 1,3 Karen Gronkowski, 1 Amanj Kurdi, 1,3,4 Niketa Platt, 1 Aidan Morrison, 1 Marion Bennie, 1,3 William Malcolm 1 Original research

ABSTRACT Objective The Access, Watch and Reserve (AWaRe) list of antibiotics was developed by the WHO to support antibiotic stewardship programmes (ASP). The Access group incorporates first-line options, while Watch antibiotics have higher resistance potential or toxicity, and Reserve drugs should be used only for complex infections. ASP implementation has been challenged during the COVID-19 pandemic. There is a knowledge gap regarding in-hospital prescribing patterns of antibiotics nationally during the COVID-19 pandemic, and on the characteristics of hospitalised patients prescribed antibiotics during this time. We aimed to evaluate quality of antibiotic use according to AWaRe classification in Scottish hospitals, including assessing the impact of COVID-19 on trends. Methods Cross-sectional study of antibiotics prescribed to hospitalised patients from 1 January 2019 to 30 June 2022 in a selection of Scottish hospitals, covering approximately 60% (3.6 million people) of the Scottish population. Data were obtained from the Hospital Electronic Prescribing and Medicines Administration system. Prescribing trends were explored over time, by age and by sex. Results Overall, a total 1 353 003 prescriptions were identified. An increase in Access antibiotics was found from 55.3% (31 901/57 708) to 62.3% (106 449/170 995) over the study period, alongside a decrease in Watch antibiotics from 42.9% (24 772/57 708) to 35.4% (60 632/170 995). Reserve antibiotic use was limited throughout, with minor changes over time. Changes in prescribing were most pronounced in the older age group (>65 years): proportions of Access antibiotics increased from 56.4% (19 353/34 337) to 65.8% (64 387/97 815, p<0.05), while Watch antibiotics decreased from 41.9% (14 376/34 337) to 32.3% (31 568/97 815, p<0.05) between Q1 2019 and Q2 2022. Differences between males and females were insignificant. Conclusions Findings showed encouraging trends in Access and Watch use among hospitalised patients, in line with Scottish national standards. There was no noteworthy effect of COVID-19 on prescribing trends despite reports indicating stewardship programmes being negatively impacted by the pandemic.

► Additional supplemental material is published online only. To view, please visit the journal online (https:// doi.org/10.1136/ejhpharm- 2023-003874). 1 Public Health Scotland Glasgow Office, Glasgow, UK 2 Pharmacy, NHS Forth Valley, Stirling, UK 3 University of Strathclyde, Glasgow, UK 4 Department of Pharmacology, Hawler Medical University, Erbil, Iraq Correspondence to Euan Proud, Public Health Scotland Glasgow Office, Glasgow G2 6QE, UK; euan. proud2@phs.scot Received 12 June 2023 Accepted 23 January 2024 EAHP Statement 4: Clinical Pharmacy Services.

INTRODUCTION Antimicrobial resistance (AMR) is one of the biggest threats to health globally, complicating the treat- ment of common infections and increasing dura- tion of illness, mortality rates and treatment costs. 1 Modifiable drivers of AMR include the overuse and misuse of antimicrobials, including unwarranted use of broader spectrum antibiotics and unneces- sarily prolonged antibiotic courses. 2 The WHO compiled a list of 180 commonly used antibiotics and categorised these into the Access, Watch and Reserve (AWaRe) classification system. 2 The Access group consists of first-choice agents for common infections, generally with narrower spec- trums of action. The Watch group contains antibiotics more commonly used as second-line treatments, or for treating resistant organisms. Finally, the Reserve group contains antibiotics considered drugs of last resort, when no other options are available, for example, in extensively drug-resistant infections. The AWaRe list requires local adaption given geographical WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒ Antimicrobial prescribing should primarily be from the WHO Access class to minimise the risk of developing resistance and preserve broader spectrum antibiotics. There is conflicting evidence around the quality of prescribing of antibiotics in hospitals during the COVID-19 pandemic. WHAT THIS STUDY ADDS ⇒ This study adds value in its duration (prepandemic, during and in the recovery phase), large sample size and patient-level data. This study showed COVID-19 did not appear to detrimentally effect the quality of prescribing with any increase in the proportion of broader spectrum antibiotics being prescribed and Reserve antibiotic use remained reassuringly low throughout the pandemic. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY ⇒ Further research could include data on the indication for antibiotics which was not available here and incorporate both primary care and hospital data together.

To cite: Proud E, Mueller T, Gronkowski K, et al . Eur J Hosp Pharm Epub ahead of print: [ please include Day Month Year]. doi:10.1136/ ejhpharm-2023-003874 © European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.

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variation in resistance patterns and local stewardship priorities (UK-adapted version, see online supplemental material 1). 3 Although the WHO named AMR a public health priority for 2020, priorities changed with the emergence of the COVID-19 pandemic. Work conducted in England indicated a negative impact on an estimated 64% of stewardship activities when stewardship leads were surveyed. 4 Furthermore, it was hypothesised that COVID-19 may have increased prescribing of common respira- tory antibiotics given the similar presentation of COVID-19 and bacterial respiratory tract infections. 5 A meta-analysis found up to 70% of patients with COVID-19 received antibiotics, while the rate of bacterial coinfection was estimated to be 8.6%. 6 Subsequent studies have suggested that this figure is even lower, with a more recent study finding the rate of bacterial coinfection in patients with COVID-19 to be 3%. 7 These figures likely indicate high levels of inappropriate prescribing of antibiotics in patients with COVID-19 admitted to hospital early in the pandemic. In the UK, the National Action Plan for AMR (2019–2024) included targets for a 10% reduction in hospital use of Reserve and Watch antibiotics using 2017 as the baseline. 8 In Scotland, to meet WHO targets, at least 60% of overall antibiotic use should be Access group antibiotics by the end of 2022. 8 Nevertheless, there are currently knowledge gaps with regard to in-hospital prescribing of antibiotics. There is a lack of up-to-date data on utilisation patterns, especially in the era of COVID-19; moreover, data on the characteristics of hospitalised patients being prescribed anti- biotics are scarce. The Hospital Electronic Prescribing and Medi- cines Administration (HEPMA) system is being rolled out across Scotland and can provide inpatient, individual-level medicines data which may fill these data gaps. This study, therefore, aimed to evaluate the utilisation pattern of antibiotics according to the UK AWaRe classification using HEPMA data, including assessing any impact of the COVID-19 pandemic.

Statistical analysis All analyses were descriptive. Categorical variables were summarised as frequencies (count, percentage). For percentages, the numerator was the number of prescriptions of interest, and the denominator was the overall number of prescriptions of any antibiotic during the study period. Relative and absolute changes as well as the average quarterly change for each class were calcu- lated using trend analysis. Simple linear regression was used to determine significance of trends over time. Analyses have been conducted using R Studio Server Pro V.3.6.1. Reporting follows the Strengthening the Reporting of Observa- tional Studies in Epidemiology (STROBE) guidelines 9 ; a STROBE checklist can be found in online supplemental material 2. RESULTS The study comprised 1353003 unique prescriptions of antibi- otics across the 4-year study period. Of those, 702318 (51.9%) were for female patients; 582059 (43.0%) prescriptions were for 16–65year-olds; and 770944 (57.0%) were for >65 year-olds. The most prescribed antibiotics every year were amoxicillin (Access, 261562 prescriptions), followed by co-amoxiclav (Watch, 196902 prescriptions) and metronidazole (Access, 147033 prescriptions). When comparing year-on-year utilisation across AWaRe cate- gories, a steady absolute increase was apparent in proportions of Access antibiotics used, growing by 7% overall; from 55.3% (31 901/57 708) in Q1 2019 to 62.3% (106 449/170 995) in Q2 2022, a relative increase of 12.7%. A corresponding absolute decrease of 7.4% was observed in the watch class of antibiotics over the same time period from 42.9% (24 772/57 708) in Q1 2019 to 35.4% (60 632/170 995) in Q2 2022, a relative decrease of 17.3%. When stratified by sex, there were only minor differences. The aforementioned increases and decreases in Access and Watch classes, respectively, were observed equally in male and female patients, across all years studied (figure 1). No notable difference was seen in the proportion of Reserve antibiotics being used, continuing to represent a small percentage of overall use, ranging from a low of 1.4% in Q1 2020 to a high of 2.1% in Q1 2021. Use of Reserve antibiotics was higher every year in men than in women; however, the differences were small (ranging from 0.1% to 0.6% difference). No considerable change was seen in Q1 and Q2 of 2020 when COVID-19 initially caused increased hospital admissions and the first national lockdown. When inspected by age, similar trends were seen with Access usage increasing in 16–65year-olds as well as over 65 year-olds (figure 2). Differences were more pronounced in the older age group with a 9.4% increase over the 4 years, compared with only 3.7% in the 16–65year-olds, increasing from 56.4% (19 353/34 337) to 65.8% (64 387/97 815) and 53.7% (12 548/23 371) to 57.4% (44 185/76 956), respectively, between Q1 2019 and Q2 2022. The decrease in the proportion of Watch antibiotics used was more pronounced in the older age group. Utilisation of Watch antibiotics in >65 year-olds decreased year on year for corre- sponding quarters, with a total fall of 9.6% from a high of 41.9% (14 376/34 337) in Q1 2019 to 32.3% (31 568/97 815) in Q2 2022. A more modest decrease from 44.5% (10 396/23 371) to 39.8% (30 616/76 956) was noted in the 16–65 year-olds, with far more variation in this age group quarter to quarter. No discernible seasonal trend was noted in any class. The trend of increasing proportions of Access antibiotic use over time was significant only in the >65age group (p<0.05). In both male (p<0.05) and female patients (p<0.05) this trend was also significant. The decreasing trend in Watch antibiotics

PATIENTS AND METHODS Study design

This study was a repeated, cross-sectional study of all antibiotics prescribed to hospitalised patients from 1 January 2019 to 30 June 2022 using HEPMA. Start dates were chosen as 2019 presented a prepandemic baseline of antibiotic use and also coincided with data becoming available from some of the largest hospitals in the country providing significant increases in patient numbers. Scot- land has 14 territorial health boards, of which six contributed data: NHS Ayrshire & Arran; NHS Dumfries & Galloway; NHS Forth Valley; NHS Greater Glasgow & Clyde; NHS Lanarkshire; and NHS Lothian, collectively covering around 60% of the Scottish population. The roll-out of HEPMA has been gradual over time with differing timescales across health boards and hospitals, there- fore, data availability differs between sites. All data for this study were obtained from HEPMA, including dates (prescribed and administered), drug names and formulations, dosages and routes of administration. HEPMA also includes patient age and sex via unique patient identifiers. Data on antibiotics were extracted using the chemical name of the drug and route of administration. Study population and outcome The study subjects comprised prescriptions for any antibiotic indi- cated for systemic use and administered to patients >16 years, admitted to hospital for any reason during the study period. The study outcome was the antibiotic utilisation pattern in terms of quarterly number of prescriptions, classified according to the UK-adapted AWaRe classification, stratified by age groups and sex. 3

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Figure 1 Percentage of antibiotic prescriptions according to the Access, Watch and Reserve (AWaRe) classification from January 2019 to June 2022, stratified by patient sex.

reassuringly low, and no noteworthy increases were seen over the study period. Recently reported UK hospital antibiotic consumption according to AWaRe classification, using aggregated data, found Access prescribing in Scotland was 62.4% in 2021, broadly agreeing with this study. 10 Although a number of studies 11–13 reported high antibiotic usage in hospitals during the COVID-19 pandemic, particularly in the Watch class, we did not see a spike in the proportion of these drugs in Scotland during Q1 and Q2 of 2020. Conversely, our results showed decreasing trends in the Watch class, including a decrease in these antibiotics prescribed

was significant in >65year-olds (p<0.05), likewise in both male (p<0.05) and female patients (p<0.05).

DISCUSSION This is the first national, patient-level antibiotic utilisation study in hospitalised patients in Scotland. Hospital antibiotic use in Scotland appeared to be at expected levels, with Access antibiotic use highest of the three classes and positive trends developing. Importantly, findings indicate hospitals were meeting the Scottish government national standard on antibiotic use of >60% of total antibiotic prescribing being from the Access class. Reserve antibiotic use was

Figure 2 Percentage of antibiotic prescriptions according to the Access, Watch and Reserve (AWaRe) classification from January 2019 to June 2022, stratified by patient age group.

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Original research in the older age group. This decrease is despite many stewardship programmes in the UK being negatively impacted due to COVID- 19, suggesting clinicians are effectively following guidelines to use Access antibiotics as first-line options. Work conducted in England indicated that the rate of patients prescribed Watch anti- biotics rose, particularly early in the pandemic. 14 In contrast, our results showed decreasing rates of Watch prescribing, indicating responsiveness from clinicians to rapidly developed guidelines. These results showing lower use of broader spectrum agents may suggest the positive impact of efforts by local and national groups such as the Scottish Antimicrobial Prescribing Group (SAPG) in Scotland continuing to promote appropriate antibiotic use during the COVID-19 pandemic, and this could be a reason for apparent differences with England and Wales. 15 This does not rule out a spike in use over shorter time periods around the first lockdown but is nonetheless reassuring. Where other studies found increased antibiotic prescribing in older age groups, 5 longer term trends here showed this age group had the largest reductions in higher risk antibiotic categories. However, over half of antibiotic prescriptions were in the older age group, therefore this remains a key patient cohort to target interventions towards. Given the increased risk of recurrent and resistant infections in this age group, who are more likely to be exposed to repeated courses of antibiotics and hospital admis- sions, 16 this is a positive trend. Despite assumptions that overlapping respiratory symptoms of COVID-19 and bacterial pneumonia may cause overprescribing and unnecessary escalation, it is reassuring that this was not borne out in our results, possibly due to effective early messaging from infection prevention and control teams, and dissemination of early research showing infrequent concomitant bacterial and COVID-19 infections. 17 Ultimately, it seems that the impact of COVID-19 on the util- isation and quality of antibiotic usage in Scotland appears to be non-detrimental. This observation can likely be attributed to the effective implementation of antimicrobial stewardship initia- tives championed by the SAPG. 18 SAPG has been proactive on a national scale, promoting practices such as antibiotic reviews, the reduction of prescription durations when appropriate and cessa- tion of antibiotic use on confirmation of COVID-19. 10 12 18 19 Furthermore, SAPG has developed specific prescribing guidelines for both primary and secondary care. In tandem with these efforts, a communication from the Scottish government addressed to all prescribers, including the chief medical officer, chief pharmacy officer and chief nursing officer, aimed to encourage judicious anti- biotic prescribing during the pandemic. The strength of this study is the currency and detail of the data available. The main limitation is incomplete geograph- ical coverage and lack of information on the indication for the prescribed antibiotics. Furthermore, results portray the picture in Scottish hospitals only. Acknowledgements We thank all lead COVID-19 and HEPMA pharmacists from NHS Health Boards in Scotland for their assistance in collecting the data presented here. Contributors Writing and literature search were conducted by EP. TM, KG and AM conducted data analysis. All authors contributed to data interpretation and approved the final manuscript. WM and MB conceived and oversaw this work. EP is the guarantor of this work. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient consent for publication Not applicable.

Ethics approval Ethics approval was not deemed necessary due to the nature of the study. This was a retrospective medication utilisation study with anonymised findings at a population level. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data can be available via Public Health Scotland’s electronic Data Research and Innovation Service, subject to reasonable request and public benefit and privacy panel evaluation. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. ORCID iD Euan Proud http://orcid.org/0000-0002-6014-9881 REFERENCES 1 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis - the lancet. Available: https://www. thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext [Accessed 5 Dec 2022]. 2 World Health Organisation. WHO antibiotics portal. Available: https://aware. essentialmeds.org/groups [Accessed 5 Dec 2022]. 3 Budd E, Cramp E, Sharland M, et al . Adaptation of the WHO essential medicines list for national antibiotic stewardship policy in England: being AWaRe. J Antimicrob Chemother 2019;74:3384–9. 4 Ashiru-Oredope D, Kerr F, Hughes S, et al . Assessing the Impact of COVID-19 on Antimicrobial Stewardship Activities/Programs in the United Kingdom. Antibiotics (Basel ) 2021;10:110. 5 Langford BJ, So M, Raybardhan S, et al . Antibiotic prescribing in patients with COVID-19: rapid review and meta-analysis. Clin Microbiol Infect 2021;27:520–31. 6 Langford BJ, So M, Raybardhan S, et al . Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect 2020;26:1622–9. 7 Hedberg P, Johansson N, Ternhag A, et al . Bacterial co-infections in community- acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus. BMC Infect Dis 2022;22:108. 8 HM Government. UK 5-year action plan for antimicrobial resistance 2019 to 2024. GOV.UK. Available: https://www.gov.uk/government/publications/uk-5-year-action- plan-for-antimicrobial-resistance-2019-to-2024 [Accessed 14 Dec 2022]. 9 Group BMJP. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 2007;335. 10 ARHAI Scotland. Scottish one health antimicrobial use and antimicrobial resistance in 2021. Scotland 2021. 2021. Available: https://www.nss.nhs.scot/publications/scottish- one-health-antimicrobial-use-and-antimicrobial-resistance-in-2021/ [Accessed 6 Dec 2022]. 11 Seaton RA, Cooper L, Gibbons CL, et al . Antibiotic prescribing for respiratory tract infection in patients with suspected and proven COVID-19: results from an antibiotic point prevalence survey in Scottish hospitals. JAC Antimicrob Resist 2021;3:dlab078. 12 Russell CD, Fairfield CJ, Drake TM, et al . Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study. Lancet Microbe 2021;2:e354–65. 13 Khan S, Hasan SS, Bond SE, et al . Antimicrobial consumption in patients with COVID-19: a systematic review and meta-analysis. Expert Rev Anti Infect Ther 2022;20:749–72. 14 Andrews A, Budd E, Hendrick A, et al . Surveillance of Antibacterial Usage during the COVID-19 Pandemic in England, 2020. Antibiotics 2020;10:841. 15 Seaton A. COVID-19 and its impact on antimicrobial stewardship. REVIVE. Available: https://revive.gardp.org/covid-19-and-its-impact-on-antimicrobial-stewardship/ [Accessed Nov 2023]. 16 Faulkner CM, Cox HL, Williamson JC. Unique aspects of antimicrobial use in older adults. Clin Infect Dis 2005;40:997–1004. 17 Alshaikh FS, Godman B, Sindi ON, et al . Prevalence of bacterial coinfection and patterns of antibiotics prescribing in patients with COVID-19: A systematic review and meta-analysis. PLOS ONE 2022;17:e0272375. 18 MacBride-Stewart S, McTaggart S, Kurdi A, et al . Initiatives and reforms across Scotland in recent years to improve prescribing; findings and global implications of drug prescriptions. Int J Clin Exp Med 2021;14:2563–86. 19 Seaton RA, Gibbons CL, Cooper L, et al . Survey of antibiotic and antifungal prescribing in patients with suspected and confirmed COVID-19 in Scottish hospitals. J Infect 2020;81:952–60.

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Evaluation of the stability of aciclovir in elastomeric infusion devices used for outpatient parenteral antimicrobial therapy Fekade Bruck Sime , 1 Steven Wallis, 1 Conor Jamieson, 2 Tim Hills, 3 Mark Gilchrist, 4 Mark Santillo, 5,6 R Andrew Seaton, 7 Felicity Drummond, 8 Jason Roberts, 1,9,10,11 on behalf of the BSAC OPAT Drug Stability Testing Programme

ABSTRACT Objectives To investigate the stability of aciclovir solutions in elastomeric devices used for outpatient parenteral antimicrobial therapy (OPAT). Methods Triplicates of two elastomeric devices, Accufuser and Easypump II, were filled with a solution of 200 mg, 2400 mg, and 4500 mg aciclovir in 240 mL 0.9% w/v saline. Devices were stored at room temperature for 14 days, followed by 24 hours storage at 32°C. Assessment using a stability indicating assay, pH and subvisible particle analysis was undertaken at 11 time points throughout the study. Results Aciclovir solution at 200 mg and 2400 mg in 240 mL was stable for 14 days at room temperature (<20°C) and 24 hours of 32°C ’in-use’ temperature exposure, remaining above the 95% limit for NHS stability protocols. The high dose was also stable for 14 days at room temperature, but when stored at 32°C there was precipitation of aciclovir within 4 hours in both devices. The precipitate was confirmed as aciclovir and precipitation was not a sign of chemical degradation. Conclusions Aciclovir concentrations above 2400 mg/240 mL are liable to precipitation and cannot be recommended for OPAT services because of heightened risks of nephrotoxicity. Aciclovir solution can be given as a continuous 24-hour infusion for OPAT services at a concentration range of 200–2400 mg in 240 mL in Accufuser and Easypump II elastomeric devices following 14 days storage at room temperature, protected from light. INTRODUCTION Aciclovir is an antiviral drug introduced in 1982 as a topical agent and later in 1983 for intravenous (IV) treatment of herpes virus infections. 1 It can be used to treat infections caused by herpes simplex virus (HSV), varicella-zoster virus and Epstein- Barr virus. 2 3 Structurally, it is a guanine nucleoside analogue and therefore serves as a false substrate in the synthesis of viral DNA, effectively blocking the synthesis of viral DNA and the proliferation of the virus. 4 Aciclovir is available in various dosage forms including topical preparation, oral formulations and IV solution or powder for injection. Oral aciclovir has a limited use and efficacy due to poor bioavail- ability. 5 Currently, IV aciclovir remains the gold standard for the treatment of HSV encephalitis,

For numbered affiliations see end of article.

where treatment duration is at least 2 weeks, 6 and for congenital HSV infections in neonates. 7 Outpatient parenteral antimicrobial therapy (OPAT) programmes are designed to support early hospital discharge for patients requiring parenteral therapy, which extends beyond the patient’s need to otherwise remain in hospital. As such, OPAT has been used to effectively complete IV aciclovir therapy in clinically improving patients with HSV encephalitis. 8 9 However, there are limited data on aciclovir stability in the OPAT setting. Despite this, continuous infusion of IV aciclovir is currently being used in OPAT. 8 Data from non-OPAT condition stability studies suggest aciclovir is stable without any significant loss of potency when reconstituted in 5% dextrose or 0.9% sodium chloride solution at a concen- tration of 5 mg/mL at 5°C and 25°C for up to 37 days. 10 However, an icy white precipitation of aciclovir was observed at 5°C which re-dissolved when the temperature was brought to 25°C. A later study 11 tested aciclovir stability at low (1 mg/ mL), intermediate (7 mg/mL) and high (10 mg/mL) concentrations using 5% dextrose or 0.9% sodium WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒ There are limited data on aciclovir stability in the outpatient parenteral antimicrobial therapy (OPAT) setting. Despite this, continuous infusion of IV aciclovir is currently being used in OPAT. WHAT THIS STUDY ADDS ⇒ Aciclovir solution at 200 mg and 2400 mg in 240 mL was stable for 14 days at room temperature (<20°C) and 24 hours of 32°C ‘in- use’ temperature exposure. ⇒ High concentration of aciclovir (4500 mg/240 mL) massively precipitates when exposed to OPAT ‘in-use’ temperature of 32°C. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY ⇒ In the concentration range of 200 mg/240 mL to 2400 mg/240 mL, aciclovir solution in saline is stable, allowing the use of continuous aciclovir infusion in OPAT services. ⇒ Precipitation of aciclovir at the highest concentration tested (4500 mg/240 mL) at 32°C would preclude its use in any clinical setting.

Correspondence to Dr Fekade Bruck Sime, The University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia; f.sime@uq.edu.au Received 29 March 2023 Accepted 7 November 2023 EAHP Statement 3: Production and

Compounding. EAHP Statement 4: Clinical Pharmacy Services.

To cite: Sime FB, Wallis S, Jamieson C, et al . Eur J Hosp Pharm Epub ahead of print: [ please include Day Month Year]. doi:10.1136/ ejhpharm-2023-003784 © European Association of Hospital Pharmacists 2023. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.

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Original research chloride at 4°C and 23°C. No precipitate was noted for the low concentration when stored at 4°C; however, at the intermediate and higher concentrations tested, precipitation was noted and as previously reported. Similarly, in another study aciclovir 5 mg/ mL solution in 0.9% sodium chloride did not precipitate when stored at 4°C with stability demonstrated for at least 21 days of refrigeration. 12 A recent study with similar conditions reported an extended fridge stability at 5 mg/mL concentrations of >63 days. 13 Continuous infusions of antimicrobial agents, traditionally given in multiple daily doses, are convenient for OPAT services and patients where appropriate stability allows. Elastomeric devices delivering a continuous infusion of antimicrobials are often prefilled, stored in a fridge for up to 14 days for conve- nience, then attached to the patient for 24-hour infusion. Previous studies have shown that the temperature of the anti- microbial solution in OPAT infusion pumps exceeds the usual ambient room temperature of 25°C. Generally, 32°C is consid- ered the maximum in-use temperature reached in most parts of the world although, in some hot climate zones, this may reach up to 34°C. 14 Unfortunately, no stability data exist for aciclovir at these in-use temperature conditions and including the range of doses of clinical interest, as required by the UK National Health Service (NHS) protocol for the assessment of the stability of small molecules, the Yellow Cover Document (YCD). 15 The lack of regulatory-compliant stability data has limited the usage of aciclovir in OPAT despite the high clinical interest. The aim of this study was to investigate the suitability of continuous infusion of aciclovir in the OPAT setting by evaluating its stability in two elastomeric infusion devices. Stability was assessed in line with the requirements of the UK NHS YCD, with the excep- tion of the room temperature storage condition which was not compliant with the requirement of 25±2°C. Acetonitrile HPLC Lichrosolv (Merck, Darmstadt, Germany) was HPLC grade. Disodium hydrogen phosphate was AR grade from Merck (Darmstadt, Germany). Aciclovir for calibrators and quality control samples (QCs) was DBL aciclovir IV infusion (Batch: H161213AA, Hospira Australia, Mulgrave, Australia), the same batch used to generate the test samples. Guanine (used for degradation identification) was sourced from Sigma-Aldrich (St Louis, USA). Water used was Milli-Q. Two infusion devices, Easypump II LT 270–27-S (lot no 19E29GE221; B Braun Ltd, Sheffield, UK) and Accufuser VAWC0100L (lot no 1BBC170; Vygon UK Ltd, Swindon, UK) were used. Normal saline (0.9% w/v NaCl) was obtained from Baxter Healthcare Pty Ltd, New South Wales, Australia. MATERIALS AND METHODS Materials Assay method Calibrators were prepared by dilution of the aciclovir pharma- ceutical product with water to concentrations of 0.4, 0.6, 0.7, 0.8, 0.9 and 1 mg/mL. QCs were prepared by dilution of the aciclovir pharmaceutical product with water to concentrations of 0.833, 10 and 18.75 mg/mL. Calibrators were stored in sepa- rate aliquots at −80°C until required. The chromatography was adapted from the stability-indicating method of Malabagal et al , 16 using an Acquity UPLC BEH C18 (1.8 µ m) 2.1×30 mm analytical column (Waters, Milford, USA) as the stationary phase. The mobile phase was 97% 25mM phosphate buffer at pH 3.0 with 3% acetonitrile delivered isoc- ratically at 0.4 mL/min with a 3 min run time. Aciclovir and

guanine were detected at wavelengths of 252 nm and 247 nm, respectively. Calibrators, QCs and test samples were thawed at room temperature then vortex mixed. Calibrators and low concentra- tion (0.833 mg/mL) QCs and samples were centrifuged and then directly injected. Samples and QCs at the intermediate and high concentrations were centrifuged and then diluted with a dilution factor of 12.5 (50 µ L of sample combined with 575 µ L water) and 22.5 (40 µ L of sample combined with 860 µ L water), respec- tively, prior to injection. Assay performance Calibrators from 0.4 to 1 mg/mL (n=7 levels) were used to create the calibration curve, covering a range of 48–125% of the nominal test concentration. Linearity of the method was established from three separate calibration lines: slopes were 4434, 4504 and 4468; intercepts were −95178 to –4504 and −90900; correlation coefficients (r 2 ) were 0.99992, 0.99881 and 0.99934, with all calibrators being within 0.3%, 1.6% and 1.3% of nominal, respectively. Precision (%RSD) of the assay, demonstrated by replicate analysis (n=9) of QCs, was 1.2% at 0.833 mg/mL and 1.2% at 18.75 mg/mL. Accuracy (% bias) from the same QCs was −0.2% (0.833 mg/mL) and −1.1% (18.75mg/mL). With regard to specificity, aciclovir gave a peak at retention time 1.33 min. Guanine eluted with baseline separation prior to aciclovir at 0.47 min. Huidobro et al 17 reported that impurities were all more strongly retained than aciclovir, so a secondary chromatographic method that included a gradient of acetonitrile from 3% to 20% was used to search for the impurities during validation, but none were found. The mean peak purity index for chromatograms of the samples was 1.000. Preparation of aciclovir-filled infuser devices The required volume of aciclovir solution for IV infusion was transferred into a sterile measuring cylinder in a Class II biosafety cabinet and subsequently diluted to volume with normal saline to make a centralised stock solution at the desired concentration. Three concentrations of aciclovir were tested. These concentra- tions were selected to cover the clinical range of doses (concen- trations) corresponding to low dose (200 mg/240 mL=0.833 mg/ mL), intermediate dose (2400mg/240mL=10mg/mL) and high dose (4500mg/240mL=18.75mg/mL) when the devices are filled to the volume of 240 mL. The nominal reservoir fill volume of 240 mL was transferred from the central stock solu- tion to each device using a 60 mL syringe; devices were prepared in triplicate at each concentration. Flow restrictors and in-line filters were removed from all devices to enable sampling and the outlet line was clamped. Aciclovir-filled devices were stored at room temperature (reported as <20°C). Each device was wrapped with aluminium foil to completely cover its surfaces and prevent exposure to light during storage and sampling. Following the 14 days of room temperature storage, the devices were stored within an incubator at the maximum expected in-use temperature of 32°C for 24 hours. Duplicate samples were collected from each indi- vidual device for the two device types that were tested at three concentrations in triplicate devices at 11 different time points which included 0, 12, 24, 48, 96, 168, 240 and 336 hours at room temperature and 344, 348 and 360 hours at 32°C in-use temperature (running phase). A total of 396 samples were collected and an aliquot of 0.5 mL of each sample was immedi- ately stored in a −80°C freezer for concentration measurement.

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remained clear, colourless and no visible precipitation was noted. However, a massive white precipitation was noted for the high concentration (4500 mg/240 mL). A sample of the recovered precipitant paste (0.11 g) was dissolved in 3 mL of 0.1 M NaOH. Injection of the solution revealed a massive (off-scale) aciclovir peak. For comparison, a solution of guanine in 0.1 M NaOH was injected producing a peak at its expected earlier retention time. This confirmed the precipitate to be aciclovir. Sub-visible liquid particles All samples scanned for sub-visible liquid particle analysis were within the USP <788> sub-visible particle testing require- ments. 18 However, no samples of the high concentration at in-use temperature were scanned for sub-visible particle analysis due to the significant visible precipitation. pH Changes Changes in the pH of the aciclovir solution from base- line in the two elastomeric devices are summarised in tables 1 and 2. Overall, the pH gradually decreased during storage at room temperature and substantially during exposure to in-use temperature of 32°C. The highest reduction was observed at the low concentration, which was the most diluted in terms of NaOH content (each vial of aciclovir IV infusion formulation contained 92.9mg NaOH in 20mL). Aciclovir concentration Figures 1 and 2 show the percentage of aciclovir remaining within the infusers during room temperature storage and expo- sure to 32°C, respectively. The mean (SD) percentage of aciclovir remaining at each time point for the Accufuser and Easypump devices is shown in tables 3 and 4, respectively. Aciclovir solu- tion demonstrated high stability at room temperature with >98% remaining unchanged for 14 days. At 32°C aciclovir remained stable at the low (200 mg/240 mL) and intermediate (2400 mg/240 mL) dose with >95%active pharmaceutical ingredient remaining after 24 hours. However, at the high dose (4500 mg/240 mL) there was a rapid decline in aciclovir concen- tration with ≥20% loss within 4 hours of exposure to 32°C. This decline in concentration parallels the massive white precipitation observed during this temperature. Following forced degradation, only strong acidic conditions (1M HCl) stored at 60°C for 24 hours resulted in conversion

Samples were collected from each device for visual analysis of colour, clarity and any precipitation at similar time points of sampling for concentration measurement. The pH of these samples was measured using an Orion double junction semi- micro pH electrode with Eutech pH700 pH metre (Eutech Instru- ments, Singapore). The study was run in two batches: low and high dose initially, followed by the intermediate dose. Sub-visible particles assessment was performed using Zetasizer Nano serious (Malvern Instruments, Worcestershire, UK) in the initial phase of the study. In the second phase, sub-visible particle counts were performed at 0 hours (just after reconstitution) and at 24 hours, 168 hours, 336 hours and 360 hours using a Beckman Coulter HIAC 9703+ Series precision liquid particle sampler. The HIAC analysis of each sample was performed in triplicate for each of the three replicate devices at each time point. Forced degradation Forced degradation of aciclovir was investigated under the following conditions: (1) water, kept at room temperature (RT); (2) water, kept in the oven (initially 60°C but changed to 38°C after 20 hours); (3) 0.1 M HCl, kept at RT; (4) 1 M HCl, kept at RT; (5) 0.1 M NaOH, kept at RT; (6) 1 M NaOH, kept at RT; (7) 3% H 2 O 2 , kept at RT; (8) 0.1 M HCl, kept in the oven (initially 60°C but changed to 38°C after 20 hours); (9) 1 M HCl, kept in the oven (initially 60°C but changed to 38°C after 20 hours); (10) 0.1 M NaOH, kept in the oven (initially 60°C but changed to 38°C after 20 hours); and (11) 1 M NaOH, kept in the oven (initially 60°C but changed to 38°C after 20 hours) The room temperature on sampling days was determined to be 19.0±0.5°C. During 14 days of room temperature storage, aciclovir solution in both the Easypump II LT 270–27-S and Accufuser VAWC0100L elastomeric infusion pumps was clear and colourless with no visible precipitation in samples collected or within the body of the infusers. However, from day 7 onwards, small crystals were noted at the tip of the sampling tube for the intermediate and high concentration while the body of the infuser was clear. During the subsequent exposure to in-use temperature of 32°C, at the low concentration (200 mg/240 mL) and intermediate concentration (2400 mg/240 mL) the solution RESULTS Colour, clarity and precipitation

Table 1 Observed change in pH of aciclovir solution in the Accufuser VAWC0100L elastomeric infusion device during storage at room temperature and subsequent exposure to in-use temperature of 32°C

Observed mean±SD pH and change in mean pH from baseline by concentration Low concentration Intermediate concentration

High concentration

Temperature condition

Time (hours)

Observed pH

Δ pH

Observed pH

Δ pH Observed pH

Δ pH

Room temperature (<20°C)

10.24±0.01 10.30±0.01 10.27±0.03 10.17±0.03 10.02±0.06 9.85±0.07 9.67±0.09 9.47±0.11 9.26±0.15 7.43±0.24 6.91±0.02 6.86±0.04

0.00 0.05 0.03

11.20±0.00 11.16±0.04 11.08±0.01 11.06±0.00 10.93±0.02 10.95±0.03 10.70±0.04 10.58±0.03 10.44±0.03 10.45±0.04 10.45±0.04 10.37±0.03

0.00

11.25±0.01 11.25±0.01 11.27±0.01 11.22±0.02 11.25±0.05 11.15±0.04 11.04±0.08 10.94±0.11 10.88±0.13 10.44±0.05 10.28±0.09 10.06±0.21

0.00 0.00 0.01

12 24 48 96

−0.04 −0.12 −0.14 −0.27 −0.25 −0.50 −0.62 −0.76 −0.75 −0.75 −0.83

−0.07 −0.23 −0.39 −0.57 −0.77 −0.99 −2.81 −3.33 −3.38

−0.03 −0.01 −0.11 −0.21 −0.31 −0.37 −0.82 −0.98 −1.20

120 168 240 336 344 348 360

In-use temperature (32°C)

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Table 2 Observed change in pH of aciclovir solution in the Easypump II LT 270–27-S elastomeric infusion device during storage at room temperature and subsequent exposure to in-use temperature of 32°C

Observed mean±SD pH and change in mean pH from baseline by concentration Low concentration Intermediate concentration

High concentration

Temperature condition Time (hours)

Observed pH

Δ pH

Observed pH

Δ pH

Observed pH

Δ pH

Room temperature (<20°C)

10.11±0.01 10.23±0.04 10.22±0.02 10.08±0.04 9.88±0.02 9.71±0.02 9.50±0.04 9.26±0.06 9.00±0.04 7.28±0.4 6.82±0.02 6.85±0.05

0.00 0.12 0.11

11.03±0.00 11.07±0.01 11.05±0.01 11.04±0.01 10.92±0.04 10.96±0.00 10.75±0.04 10.61±0.04 10.53±0.06 10.56±0.05 10.53±0.06 10.45±0.05

0.00 0.04 0.02 0.01

11.13±0.01 11.26±0.02 11.27±0.01 11.22±0.01 11.22±0.01 11.06±0.02 10.92±0.02 10.82±0.02 10.74±0.01 10.35±0.02 10.18±0.04 9.82±0.08

0.00 0.13 0.14 0.09 0.09

12 24 48 96

−0.03 −0.23 −0.40 −0.61 −0.85 −1.11 −2.83 −3.29 −3.26

−0.11 −0.07 −0.28 −0.42 −0.50 −0.47 −0.50 −0.58

120 168 240 336 344 348 360

−0.07 −0.22 −0.32 −0.39 −0.78 −0.95 −1.31

In-use temperature (32°C)

concentration. For 14 days storage at room temperature aciclovir remained stable in solution (figure 1) with no sign of precipita- tion within the body of the infusers at any of the concentrations tested. At the in-use temperature of 32°C, the low and interme- diate doses retained stability above the 95% cut-off, but there was significant precipitation and consequent loss of stability in the high-dose devices. Due to the lack of degradation of any of the concentrations of aciclovir stored at room temperature, we were unable to calculate a degradation rate which could have been applied to a storage period at 25°C. The mid-range concentration (2400 mg/240 mL) showed no degradation in the 24 hours at 32°C while the low concentration results indicated a low level of degradation (2%) at this temperature for 24 hours. Translating this into clinical practice, continuous IV infusion of aciclovir in the OPAT setting is possible at the usual dose used for HSV encephalitis of 30 mg/kg/24 hours. The concentration range we tested would allow for dosing at a weight range of between 6.7 kg and 80 kg, so incorporating a proportion of the paediatric population as well as adult patients. Significant precipitation (rather than degradation) of aciclovir (figure 2) was observed and confirmed by HPLC analysis during

of aciclovir to guanine. Aciclovir under all other conditions was stable (≥95% remaining) for at least 24 hours.

DISCUSSION Treatment courses with IV aciclovir for severe HSV infection can be prolonged, even when the patient is clinically improved, due to lack of suitable oral treatment options. Typical dosing of IV aciclovir with infusions 8-hourly will usually preclude its use in an OPAT setting. Once-daily continuous infusion would be desirable and could allow OPAT use if aciclovir stability was maintained over the 24-hour infusion. In this study, for the first time, the stability of aciclovir in two elastomeric infusion pumps was tested during 14 days of room temperature storage followed by 24 hours exposure to in-use temperature of 32°C at a low, intermediate and high concentration in accordance with most of the UK NHS YCD requirements. Storage at room tempera- ture was interpreted in line with the European Pharmacopoeia rather than the UK NHS stability testing protocol, which spec- ifies room temperature as 25±2°C. As such, our data are not fully compliant with the UK NHS stability protocol. However, our results importantly show that the suitability of aciclovir delivered via OPAT as a continuous infusion is dependent on the

Figure 2 Percentage of aciclovir remaining during exposure to in-use temperature of 32°C following 14 days (336 hours) storage at room temperature by device and dose (low dose=200 mg/240 mL; intermediate dose=2400 mg/240 mL; high dose=4500 mg/240 mL). The grey band shows 95% CI.

Figure 1 Percentage of aciclovir remaining during room temperature (15–25°C) storage for 14 days (336 hours) by device and dose (low dose=200 mg/240 mL; intermediate dose=2400 mg/240 mL; high dose=4500 mg/240 mL). The grey band shows 95% CI.

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Table 3 Percentage of aciclovir remaining in the Accufuser VAWC0100L elastomeric infusion device during storage at room temperature and subsequent exposure to in-use temperature of 32°C

Mean and SD of percent remaining by initial concentration 200 mg/240 mL 2400 mg/240 mL

4500 mg/240 mL

Temperature condition

Time (hours)

Mean

Room temperature (<20°C)

100.00 100.25

0.00 0.86 1.32 0.93 0.72 0.66 0.90 0.90 0.71 4.19 3.46 1.31

100.00 100.10 100.05 100.77 101.01 100.97 101.29 101.87 101.17 101.07 100.96 101.01

0.00 0.49 0.32 0.33 0.31 0.40 0.51 0.87 0.42 0.60 0.62 0.58

100.00 100.03 100.31 100.20 101.04 101.16 100.78 100.59

0.00 0.51 1.28 1.50 0.75 0.54 1.02 0.84 1.37 4.07 2.96 2.92

12 24 48 96

99.92

100.44 100.55 101.09 100.60

120 168 240 336 344 348 360

99.92

100.49

99.31 69.62 56.17 21.46

In-use temperature (32°C)

97.48 97.57 98.11

fluid balance in outpatient settings may not be practical. Thus, hydration advice and education should be an important part of the OPAT assessment for clinically improving patients to be discharged on aciclovir. Similarly, monitoring of renal function should be undertaken in the OPAT setting as is advised in the inpatient setting in accordance with the product data sheet for IV aciclovir. 23 The pH of the aciclovir solution in the devices was high due to the composition of the clinical formulation used for reconstitu- tion. Each vial of the IV solution for injection contained 92.9 mg NaOH in 20mL designed to keep the pH at approximately 11 for sustained stability of the solution during storage. Further reconsti- tution with saline in the devices did not lower the pH much for the intermediate and high concentrations (tables 1 and 2). The relatively lower pH observed at the low concentration (although >9) is most likely related to the low concentration of NaOH when the clinical formulation was diluted to the low aciclovir concen- tration. Overall, given the high pH of the aciclovir saline solution, infusion via a peripherally inserted central catheter (PICC) line may be necessary to ensure better haemodilution to avoid local irritancy with peripheral infusion. PICC lines are usually recom- mended at the extremes of pH (<5 or >9) to minimise irritation. 24

in-use temperature at very high dosing concentrations (equiv- alent to 45 mg/kg/24 hours for a 100 kg non-obese adult). Such doses are not commonplace in clinical practice but were included in this study in case of emergent evidence for efficacy in severe infection in the future. The observation of precipitation at high concentration is in agreement with others. 11 Precipita- tion of aciclovir is not an in vitro problem only; it can occur in vivo in renal tubules if the maximum solubility of free aciclovir (2500 mg/L at 37°C in water) is exceeded. In one case report, a cloudy white precipitate of needle-shaped crystals was observed at the base of the urinary catheter of a patient following IV aciclovir administration. 19 IV infusion of a high concentration may risk acute kidney injury due to tubular damage and, as such, adequate hydration is an essential co-therapy. 20 21 Indeed, the most common mechanism of aciclovir-induced acute kidney injury is due to crystal obstruction. 22 Any off-label use of higher concentrations (dose) of aciclovir in the OPAT setting requires a careful safety consideration. Although the slow continuous infusion in OPAT is advanta- geous in minimising the risk of precipitation when compared with the traditional 1–2 hours of infusion for inpatient inter- mittent treatment with aciclovir, maintaining and monitoring a

Table 4 Percentage of aciclovir remaining in the Easypump II LT 270–27-S elastomeric infusion device during storage at room temperature and subsequent exposure to in-use temperature of 32°C

Mean and SD of percent remaining by initial concentration 200 mg/240 mL 2400 mg/240 mL

4500 mg/240 mL

Temperature condition

Time (hours)

Mean

Room temperature (<20°C)

100.00

0.00 1.23 1.03 0.36 0.65 1.02 0.99 0.61 0.66 1.26 1.70 2.79

100.00

0.00 0.11 0.29 0.31 0.35 0.34 0.18 0.46 0.75 1.37 1.14 1.63

100.00 100.38 101.54 100.55 100.18 100.94 100.74 100.51 100.13

0.00 0.61 0.75 1.02 1.46 0.65 0.32 0.31 0.52 9.31

12 24 48 96

99.49 99.73

99.77 99.67

100.13 100.03

100.35 100.46 100.56 100.66 100.66 100.27 100.16

120 168 240 336 344 348 360

99.89

100.01

99.71 99.80

In-use temperature (32°C)

100.11

82.12 69.75 39.86

99.88 98.18

99.99

13.80 20.30

100.26

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