A low-volume LC/MS method for highly sensitive monitoring of phenoxymethylpenicillin, benzylpenicillin, and probenecid in human serum.

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.

Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 across a London regional network. METHODS: We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE positive patients. Genomes of IMP-encoding CPE isolates were overlayed with patient contacts to imply potential transmission events. RESULTS: Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, E. coli); 86% (72/84) harboured an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68/72). Phylogenetic analysis of IncHI2 plasmids identified three lineages showing significant association with patient contacts and movements between four hospital sites and across medical specialities, which was missed on initial investigations. CONCLUSIONS: Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multi-modal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks.

A Multi-Site, Multi-Wavelength PPG Platform for Continuous Non-Invasive Health Monitoring in Hospital Settings.

This article presents a novel PPG acquisition platform capable of synchronous multi-wavelength signal acquisition from two measurement locations with up to 4 independent wavelengths from each in parallel. The platform is fully configurable and operates at 1ksps, accommodating a wide variety of transmitters and detectors to serve as both a research tool for experimentation and a clinical tool for disease monitoring. The sensing probes presented in this work acquire 4 PPG channels from the wrist and 4 PPG channels from the fingertip, with wavelengths such that surrogates for pulse wave velocity and haematocrit can be extracted. For conventional PPG sensing, we have achieved the mean error of 4.08 ± 3.72 bpm for heart-rate and a mean error of 1.54 ± 1.04% for SpO 2 measurement, with the latter lying within the FDA limits for commercial pulse oximeters. We have further evaluated over 700 individual peak-to-peak time differences between wrist and fingertip signals, achieving a normalized weighted average PWV of 5.80 ± 1.58 m/s, matching with values of PWV found for this age group in literature. Lastly, we introduced and computed a haematocrit ratio ( Rhct) between the deep IR and deep red wavelength from the fingertip sensor, finding a significant difference between male and female values (median of 1.9 and 2.93 respectively) pointing to devices sensitivity to Hct.

Towards optimizing carbapenem selection in stewardship strategies: a prospective propensity score-matched study of ertapenem versus class 2 carbapenems for empirical treatment of third-generation cephalosporin-resistant Enterobacterales bacteraemia.

BACKGROUND: Third-generation cephalosporin-resistant Enterobacterales (3GCRE) are increasing in prevalence, leading to greater carbapenem consumption. Selecting ertapenem has been proposed as a strategy to reduce carbapenem resistance development. However, there are limited data for the efficacy of empirical ertapenem for 3GCRE bacteraemia. OBJECTIVES: To compare the efficacy of empirical ertapenem and class 2 carbapenems for the treatment of 3GCRE bacteraemia. METHODS: A prospective non-inferiority observational cohort study was performed from May 2019 to December 2021. Adult patients with monomicrobial 3GCRE bacteraemia receiving carbapenems within 24 h were included at two hospitals in Thailand. Propensity scores were used to control for confounding, and sensitivity analyses were performed in several subgroups. The primary outcome was 30 day mortality. This study is registered with clinicaltrials.gov (NCT03925402). RESULTS: Empirical carbapenems were prescribed in 427/1032 (41%) patients with 3GCRE bacteraemia, of whom 221 received ertapenem and 206 received class 2 carbapenems. One-to-one propensity score matching resulted in 94 pairs. Escherichia coli was identified in 151 (80%) of cases. All patients had underlying comorbidities. Septic shock and respiratory failure were the presenting syndromes in 46 (24%) and 33 (18%) patients, respectively. The overall 30 day mortality rate was 26/188 (13.8%). Ertapenem was non-inferior to class 2 carbapenems in 30 day mortality (12.8% versus 14.9%; mean difference -0.02; 95% CI: -0.12 to 0.08). Sensitivity analyses were consistent regardless of aetiological pathogens, septic shock, source of infection, nosocomial acquisition, lactate levels or albumin levels. CONCLUSIONS: Ertapenem may be of comparable efficacy to class 2 carbapenems in the empirical treatment of 3GCRE bacteraemia.

Can precision antibiotic prescribing help prevent the spread of carbapenem-resistant organisms in the hospital setting?

The emergence of carbapenem-resistant organisms (CROs) is a significant global threat. Reduction of carbapenem consumption can decrease CROs. In the global endemic era of ESBL-producing bacteria, carbapenems are considered the treatment of choice, leading to challenge in limiting carbapenem use. This review describes the role of precision prescribing for prevention of CROs. This involves improving antibiotic selection, dosing and shortening duration. The effect of different antibiotics, dosing and duration on CRO development are explored. Available options for precision prescribing, gaps in the scientific evidence, and areas for future research are also presented.

Learning meaningful latent space representations for patient risk stratification: Model development and validation for dengue and other acute febrile illness.

Background: Increased data availability has prompted the creation of clinical decision support systems. These systems utilise clinical information to enhance health care provision, both to predict the likelihood of specific clinical outcomes or evaluate the risk of further complications. However, their adoption remains low due to concerns regarding the quality of recommendations, and a lack of clarity on how results are best obtained and presented. Methods: We used autoencoders capable of reducing the dimensionality of complex datasets in order to produce a 2D representation denoted as latent space to support understanding of complex clinical data. In this output, meaningful representations of individual patient profiles are spatially mapped in an unsupervised manner according to their input clinical parameters. This technique was then applied to a large real-world clinical dataset of over 12,000 patients with an illness compatible with dengue infection in Ho Chi Minh City, Vietnam between 1999 and 2021. Dengue is a systemic viral disease which exerts significant health and economic burden worldwide, and up to 5% of hospitalised patients develop life-threatening complications. Results: The latent space produced by the selected autoencoder aligns with established clinical characteristics exhibited by patients with dengue infection, as well as features of disease progression. Similar clinical phenotypes are represented close to each other in the latent space and clustered according to outcomes broadly described by the World Health Organisation dengue guidelines. Balancing distance metrics and density metrics produced results covering most of the latent space, and improved visualisation whilst preserving utility, with similar patients grouped closer together. In this case, this balance is achieved by using the sigmoid activation function and one hidden layer with three neurons, in addition to the latent dimension layer, which produces the output (Pearson, 0.840; Spearman, 0.830; Procrustes, 0.301; GMM 0.321). Conclusion: This study demonstrates that when adequately configured, autoencoders can produce two-dimensional representations of a complex dataset that conserve the distance relationship between points. The output visualisation groups patients with clinically relevant features closely together and inherently supports user interpretability. Work is underway to incorporate these findings into an electronic clinical decision support system to guide individual patient management.

Continuous Measurement of Lactate Concentration in Human Subjects through Direct Electron Transfer from Enzymes to Microneedle Electrodes.

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.

A rapid, simple, high-performance liquid chromatography method for the clinical measurement of beta-lactam antibiotics in serum and interstitial fluid.

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.

An analysis of existing national action plans for antimicrobial resistance-gaps and opportunities in strategies optimising antibiotic use in human populations.

At the 2015 World Health Assembly, UN member states adopted a resolution that committed to the development of national action plans (NAPs) for antimicrobial resistance (AMR). The political determination to commit to NAPs and the availability of robust governance structures to assure sustainable translation of the identified NAP objectives from policy to practice remain major barriers to progress. Inter-country variability in economic and political resilience and resource constraints could be fundamental barriers to progressing AMR NAPs. Although there have been regional and global analyses of NAPs from a One Health and policy perspective, a global assessment of the NAP objectives targeting antimicrobial use in human populations is needed. In this Health Policy, we report a systematic evidence synthesis of existing NAPs that are aimed at tackling AMR in human populations. We find marked gaps and variability in maturity of NAP development and operationalisation across the domains of: (1) policy and strategic planning; (2) medicines management and prescribing systems; (3) technology for optimised antimicrobial prescribing; (4) context, culture, and behaviours; (5) operational delivery and monitoring; and (6) patient and public engagement and involvement. The gaps identified in these domains highlight opportunities to facilitate sustainable delivery and operationalisation of NAPs. The findings from this analysis can be used at country, regional, and global levels to identify AMR-related priorities that are relevant to infrastructure needs and contexts.

Triple quadrupole LC/MS method for the simultaneous quantitative measurement of cefiderocol and meropenem in serum.

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.

Machine learning and synthetic outcome estimation for individualised antimicrobial cessation.

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.

Addition of probenecid to oral ß-lactam antibiotics: a systematic review and meta-analysis.

OBJECTIVES: To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral ß-lactams. METHODS: Medline and EMBASE were searched from inception to December 2021 for all English language studies comparing the addition of probenecid (intervention) with an oral ß-lactam [flucloxacillin, penicillin V, amoxicillin (±â€Šclavulanate), cefalexin, cefuroxime axetil] alone (comparator). ROBINS-I and ROB-2 tools were used. 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%) screened abstracts were included. Populations, methodology and outcome data were heterogeneous. Common populations included healthy volunteers (9/18; 50%) and those with gonococcal infection (6/18; 33%). Most studies were crossover trials (11/18; 61%) or parallel-arm randomized trials (4/18; 22%). Where pharmacokinetic analyses were performed, addition of probenecid to oral ß-lactams increased total AUC (7/7; 100%), Cmax (5/8; 63%) and serum t½ (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. CONCLUSIONS: Probenecid-boosted ß-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid-boosted oral ß-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy studies are required.

The Diagnosis of Dengue in Patients Presenting With Acute Febrile Illness Using Supervised Machine Learning and Impact of Seasonality.

Background: Symptomatic dengue infection can result in a life-threatening shock syndrome and timely diagnosis is essential. Point-of-care tests for non-structural protein 1 and IgM are used widely but performance can be limited. We developed a supervised machine learning model to predict whether patients with acute febrile illnesses had a diagnosis of dengue or other febrile illnesses (OFI). The impact of seasonality on model performance over time was examined. Methods: We analysed data from a prospective observational clinical study in Vietnam. Enrolled patients presented with an acute febrile illness of <72 h duration. A gradient boosting model (XGBoost) was used to predict final diagnosis using age, sex, haematocrit, platelet, white cell, and lymphocyte count collected on enrolment. Data was randomly split 80/20% into a training and hold-out set, respectively, with the latter not used in model development. Cross-validation and hold out set testing was used, with performance over time evaluated through a rolling window approach. Results: We included 8,100 patients recruited between 16th October 2010 and 10th December 2014. In total 2,240 (27.7%) patients were diagnosed with dengue infection. The optimised model from training data had an overall median area under the receiver operator curve (AUROC) of 0.86 (interquartile range 0.84-0.86), specificity of 0.92, sensitivity of 0.56, positive predictive value of 0.73, negative predictive value (NPV) of 0.84, and Brier score of 0.13 in predicting the final diagnosis, with similar performances in hold-out set testing (AUROC of 0.86). Model performances varied significantly over time as a function of seasonality and other factors. Incorporation of a dynamic threshold which continuously learns from recent cases resulted in a more consistent performance throughout the year (NPV >90%). Conclusion: Supervised machine learning models are able to discriminate between dengue and OFI diagnoses in patients presenting with an early undifferentiated febrile illness. These models could be of clinical utility in supporting healthcare decision-making and provide passive surveillance across dengue endemic regions. Effects of seasonality and changing disease prevalence must however be taken into account-this is of significant importance given unpredictable effects of human-induced climate change and the impact on health.

Applied machine learning for the risk-stratification and clinical decision support of hospitalised patients with dengue in Vietnam.

BACKGROUND: Identifying patients at risk of dengue shock syndrome (DSS) is vital for effective healthcare delivery. This can be challenging in endemic settings because of high caseloads and limited resources. Machine learning models trained using clinical data could support decision-making in this context. METHODS: We developed supervised machine learning prediction models using pooled data from adult and paediatric patients hospitalised with dengue. Individuals from 5 prospective clinical studies in Ho Chi Minh City, Vietnam conducted between 12th April 2001 and 30th January 2018 were included. The outcome was onset of dengue shock syndrome during hospitalisation. Data underwent random stratified splitting at 80:20 ratio with the former used only for model development. Ten-fold cross-validation was used for hyperparameter optimisation and confidence intervals derived from percentile bootstrapping. Optimised models were evaluated against the hold-out set. FINDINGS: The final dataset included 4,131 patients (477 adults and 3,654 children). DSS was experienced by 222 (5.4%) of individuals. Predictors were age, sex, weight, day of illness at hospitalisation, indices of haematocrit and platelets over first 48 hours of admission and before the onset of DSS. An artificial neural network model (ANN) model had best performance with an area under receiver operator curve (AUROC) of 0.83 (95% confidence interval [CI], 0.76-0.85) in predicting DSS. When evaluated against the independent hold-out set this calibrated model exhibited an AUROC of 0.82, specificity of 0.84, sensitivity of 0.66, positive predictive value of 0.18 and negative predictive value of 0.98. INTERPRETATION: The study demonstrates additional insights can be obtained from basic healthcare data, when applied through a machine learning framework. The high negative predictive value could support interventions such as early discharge or ambulatory patient management in this population. Work is underway to incorporate these findings into an electronic clinical decision support system to guide individual patient management.

Exploring the Pharmacokinetics of Phenoxymethylpenicillin (Penicillin-V) in Adults: A Healthy Volunteer Study.

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 concentrations were determined, and a base population PK model was fitted to the data.

Resistance Trend Estimation Using Regression Analysis to Enhance Antimicrobial Surveillance: A Multi-Centre Study in London 2009-2016.

In the last years, there has been an increase of antimicrobial resistance rates around the world with the misuse and overuse of antimicrobials as one of the main leading drivers. In response to this threat, a variety of initiatives have arisen to promote the efficient use of antimicrobials. These initiatives rely on antimicrobial surveillance systems to promote appropriate prescription practices and are provided by national or global health care institutions with limited consideration of the variations within hospitals. As a consequence, physicians' adherence to these generic guidelines is still limited. To fill this gap, this work presents an automated approach to performing local antimicrobial surveillance from microbiology data. Moreover, in addition to the commonly reported resistance rates, this work estimates secular resistance trends through regression analysis to provide a single value that effectively communicates the resistance trend to a wider audience. The methods considered for trend estimation were ordinary least squares regression, weighted least squares regression with weights inversely proportional to the number of microbiology records available and autoregressive integrated moving average. Among these, weighted least squares regression was found to be the most robust against changes in the granularity of the time series and presented the best performance. To validate the results, three case studies have been thoroughly compared with the existing literature: (i) Escherichia coli in urine cultures; (ii) Escherichia coli in blood cultures; and (iii) Staphylococcus aureus in wound cultures. The benefits of providing local rather than general antimicrobial surveillance data of a higher quality is two fold. Firstly, it has the potential to stimulate engagement among physicians to strengthen their knowledge and awareness on antimicrobial resistance which might encourage prescribers to change their prescription habits more willingly. Moreover, it provides fundamental knowledge to the wide range of stakeholders to revise and potentially tailor existing guidelines to the specific needs of each hospital.

Informing antimicrobial management in the context of COVID-19: understanding the longitudinal dynamics of C-reactive protein and procalcitonin.

BACKGROUND: To characterise the longitudinal dynamics of C-reactive protein (CRP) and Procalcitonin (PCT) in a cohort of hospitalised patients with COVID-19 and support antimicrobial decision-making. METHODS: Longitudinal CRP and PCT concentrations and trajectories of 237 hospitalised patients with COVID-19 were modelled. The dataset comprised of 2,021 data points for CRP and 284 points for PCT. Pairwise comparisons were performed between: (i) those with or without significant bacterial growth from cultures, and (ii) those who survived or died in hospital. RESULTS: CRP concentrations were higher over time in COVID-19 patients with positive microbiology (day 9: 236 vs 123 mg/L, p < 0.0001) and in those who died (day 8: 226 vs 152 mg/L, p < 0.0001) but only after day 7 of COVID-related symptom onset. Failure for CRP to reduce in the first week of hospital admission was associated with significantly higher odds of death. PCT concentrations were higher in patients with COVID-19 and positive microbiology or in those who died, although these differences were not statistically significant. CONCLUSIONS: Both the absolute CRP concentration and the trajectory during the first week of hospital admission are important factors predicting microbiology culture positivity and outcome in patients hospitalised with COVID-19. Further work is needed to describe the role of PCT for co-infection. Understanding relationships of these biomarkers can support development of risk models and inform optimal antimicrobial strategies.

Optimising antimicrobial use in humans - review of current evidence and an interdisciplinary consensus on key priorities for research.

Addressing the silent pandemic of antimicrobial resistance (AMR) is a focus of the 2021 G7 meeting. A major driver of AMR and poor clinical outcomes is suboptimal antimicrobial use. Current research in AMR is inequitably focused on new drug development. To achieve antimicrobial security we need to balance AMR research efforts between development of new agents and strategies to preserve the efficacy and maximise effectiveness of existing agents. Combining a review of current evidence and multistage engagement with diverse international stakeholders (including those in healthcare, public health, research, patient advocacy and policy) we identified research priorities for optimising antimicrobial use in humans across four broad themes: policy and strategic planning; medicines management and prescribing systems; technology to optimise prescribing; and context, culture and behaviours. Sustainable progress depends on: developing economic and contextually appropriate interventions; facilitating better use of data and prescribing systems across healthcare settings; supporting appropriate and scalable technological innovation. Implementing this strategy for AMR research on the optimisation of antimicrobial use in humans could contribute to equitable global health security.