Determination of minimum inhibitory concentrations using machine-learning-assisted agar dilution.

Effective policy to address the global threat of antimicrobial resistance requires robust antimicrobial susceptibility data. Traditional methods for measuring minimum inhibitory concentration (MIC) are resource intensive, subject to human error, and require considerable infrastructure. AIgarMIC streamlines and standardizes MIC measurement and is especially valuable for large-scale surveillance activities. MICs were measured using agar dilution for n = 10 antibiotics against clinical Enterobacterales isolates (n = 1,086) obtained from a large tertiary hospital microbiology laboratory. Escherichia coli (n = 827, 76%) was the most common organism. Photographs of agar plates were divided into smaller images covering one inoculation site. A labeled data set of colony images was created and used to train a convolutional neural network to classify images based on whether a bacterial colony was present (first-step model). If growth was present, a second-step model determined whether colony morphology suggested antimicrobial growth inhibition. The ability of the AI to determine MIC was then compared with standard visual determination. The first-step model classified bacterial growth as present/absent with 94.3% accuracy. The second-step model classified colonies as "inhibited" or "good growth" with 88.6% accuracy. For the determination of MIC, the rate of essential agreement was 98.9% (644/651), with a bias of -7.8%, compared with manual annotation. AIgarMIC uses artificial intelligence to automate endpoint assessments for agar dilution and potentially increases throughput without bespoke equipment. AIgarMIC reduces laboratory barriers to generating high-quality MIC data that can be used for large-scale surveillance programs. IMPORTANCE: This research uses modern artificial intelligence and machine-learning approaches to standardize and automate the interpretation of agar dilution minimum inhibitory concentration testing. Artificial intelligence is currently of significant topical interest to researchers and clinicians. In our manuscript, we demonstrate a use-case in the microbiology laboratory and present validation data for the model's performance against manual interpretation.

Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing.

SUMMARYThe World Health Organisation's 2022 AWaRe Book provides guidance for the use of 39 antibiotics to treat 35 infections in primary healthcare and hospital facilities. We review the evidence underpinning suggested dosing regimens. Few (n = 18) population pharmacokinetic studies exist for key oral AWaRe antibiotics, largely conducted in homogenous and unrepresentative populations hindering robust estimates of drug exposures. Databases of minimum inhibitory concentration distributions are limited, especially for community pathogen-antibiotic combinations. Minimum inhibitory concentration data sources are not routinely reported and lack regional diversity and community representation. Of studies defining a pharmacodynamic target for ß-lactams (n = 80), 42 (52.5%) differed from traditionally accepted 30%-50% time above minimum inhibitory concentration targets. Heterogeneity in model systems and pharmacodynamic endpoints is common, and models generally use intravenous ß-lactams. One-size-fits-all pharmacodynamic targets are used for regimen planning despite complexity in drug-pathogen-disease combinations. We present solutions to enable the development of global evidence-based antibiotic dosing guidance that provides adequate treatment in the context of the increasing prevalence of antimicrobial resistance and, moreover, minimizes the emergence of resistance.

Antimicrobial treatment imprecision: an outcome-based model to close the data-to-action loop.

Health-care systems, food supply chains, and society in general are threatened by the inexorable rise of antimicrobial resistance. This threat is driven by many factors, one of which is inappropriate antimicrobial treatment. The ability of policy makers and leaders in health care, public health, regulatory agencies, and research and development to deliver frameworks for appropriate, sustainable antimicrobial treatment is hampered by a scarcity of tangible outcome-based measures of the damage it causes. In this Personal View, a mathematically grounded, outcome-based measure of antimicrobial treatment appropriateness, called imprecision, is proposed. We outline a framework for policy makers and health-care leaders to use this metric to deliver more effective antimicrobial stewardship interventions to future patient pathways. This will be achieved using learning antimicrobial systems built on public and practitioner engagement; solid implementation science; advances in artificial intelligence; and changes to regulation, research, and development. The outcomes of this framework would be more ecologically and organisationally sustainable patterns of antimicrobial development, regulation, and prescribing. We discuss practical, ethical, and regulatory considerations involved in the delivery of novel antimicrobial drug development, and policy and patient pathways built on artificial intelligence-augmented measures of antimicrobial treatment imprecision.

Antimicrobial learning systems: an implementation blueprint for artificial intelligence to tackle antimicrobial resistance.

The proliferation of various forms of artificial intelligence (AI) brings many opportunities to improve health care. AI models can harness complex evolving data, inform and augment human actions, and learn from health outcomes such as morbidity and mortality. The global public health challenge of antimicrobial resistance (AMR) needs large-scale optimisation of antimicrobial use and wider infection care, which could be enabled by carefully constructed AI models. As AI models become increasingly useful and robust, health-care systems remain challenging places for their deployment. An implementation gap exists between the promise of AI models and their use in patient and population care. Here, we outline an adaptive implementation and maintenance framework for AI models to improve antimicrobial use and infection care as a learning system. The roles of AMR problem identification, law and regulation, organisational support, data processing, and AI development, assessment, maintenance, and scalability in the implementation of AMR-targeted AI models are considered.

A MHz X-ray diffraction set-up for dynamic compression experiments in the diamond anvil cell.

An experimental platform for dynamic diamond anvil cell (dDAC) research has been developed at the High Energy Density (HED) Instrument at the European X-ray Free Electron Laser (European XFEL). Advantage was taken of the high repetition rate of the European XFEL (up to 4.5 MHz) to collect pulse-resolved MHz X-ray diffraction data from samples as they are dynamically compressed at intermediate strain rates (≤103 s-1), where up to 352 diffraction images can be collected from a single pulse train. The set-up employs piezo-driven dDACs capable of compressing samples in ≥340 µs, compatible with the maximum length of the pulse train (550 µs). Results from rapid compression experiments on a wide range of sample systems with different X-ray scattering powers are presented. A maximum compression rate of 87 TPa s-1 was observed during the fast compression of Au, while a strain rate of ∼1100 s-1 was achieved during the rapid compression of N2 at 23 TPa s-1.

Assessment of Antifungal Pharmacodynamics.

Pharmacokinetic-pharmacodynamic (PK-PD) analysis is of central importance to the progress of an antifungal agent into clinical use. It is crucial to ensure that preclinical studies give the best possible prediction of the way drugs are likely to behave in a clinical setting. This review details the last 30 years of progress in terms of disease model design, efficacy outcome selection and translational modelling in antifungal PK-PD studies. The principles of how PK-PD parameters inform current clinical practice are also discussed, including a review of how these apply to existing and novel agents.

CON: Serum biomarker monitoring should not replace primary antifungal chemoprophylaxis in patients with acute leukaemia receiving systemic anti-cancer therapy.

Primary antifungal chemoprophylaxis (PAC) is the widespread strategy of choice for the prevention of invasive fungal disease in patients with acute leukaemia (AL). Twice-weekly monitoring of the serum biomarkers (SBM) galactomannan and 1,3-ß-d-glucan has been proposed as an alternative prevention strategy to PAC for these patients. This paper outlines the arguments for why PAC should remain as the standard of care in AL, instead of switching to twice-weekly SBM. Arguments put forward in favour of PAC are the strength of evidence for its safety, cost-effectiveness and adaptability, and its adoption by multiple international guidelines as standard of care. The potential implications of PAC for drug interactions and antifungal resistance are also discussed. The drawbacks of twice-weekly SBM are appraised, including missed or delayed diagnoses, unnecessary investigations, deferral of systemic anti-cancer therapy and increased pressure on laboratory services.

Piperacillin/tazobactam-resistant, cephalosporin-susceptible Escherichia coli bloodstream infections are driven by multiple acquisition of resistance across diverse sequence types.

Resistance to piperacillin/tazobactam (TZP) in Escherichia coli has predominantly been associated with mechanisms that confer resistance to third-generation cephalosporins. Recent reports have identified E. coli strains with phenotypic resistance to piperacillin/tazobactam but susceptibility to third-generation cephalosporins (TZP-R/3GC-S). In this study we sought to determine the genetic diversity of this phenotype in E. coli (n=58) isolated between 2014-2017 at a single tertiary hospital in Liverpool, UK, as well as the associated resistance mechanisms. We compare our findings to a UK-wide collection of invasive E. coli isolates (n=1509) with publicly available phenotypic and genotypic data. These data sets included the TZP-R/3GC-S phenotype (n=68), and piperacillin/tazobactam and third-generation cephalosporin-susceptible (TZP-S/3GC-S, n=1271) phenotypes. The TZP-R/3GC-S phenotype was displayed in a broad range of sequence types, which was mirrored in the same phenotype from the UK-wide collection, and the overall diversity of invasive E. coli isolates. The TZP-R/3GC-S isolates contained a diverse range of plasmids, indicating multiple acquisition events of TZP resistance mechanisms rather than clonal expansion of a particular plasmid or sequence type. The putative resistance mechanisms were equally diverse, including hyperproduction of TEM-1, either via strong promoters or gene amplification, carriage of inhibitor-resistant ß-lactamases, and an S133G blaCTX-M-15 mutation detected for the first time in clinical isolates. Several of these mechanisms were present at a lower abundance in the TZP-S/3GC-S isolates from the UK-wide collection, but without the associated phenotypic resistance to TZP. Eleven (19%) of the isolates had no putative mechanism identified from the genomic data. Our findings highlight the complexity of this cryptic phenotype and the need for continued phenotypic monitoring, as well as further investigation to improve detection and prediction of the TZP-R/3GC-S phenotype from genomic data.

The Effect of Tannin-Rich Witch Hazel on Growth of Probiotic Lactobacillus plantarum.

Probiotic bacteria help maintain microbiome homeostasis and promote gut health. Maintaining the competitive advantage of the probiotics over pathogenic bacteria is a challenge, as they are part of the gut microbiome that is continuously exposed to digestive and nutritional changes and various stressors. Witch hazel that is rich in hamamelitannin (WH, whISOBAXTM) is an inhibitor of growth and virulence of pathogenic bacteria. To test for its effect on probiotic bacteria, WH was tested on the growth and biofilm formation of a commercially available probiotic Lactobacillus plantarum PS128. As these bacteria are aerotolerant, the experiments were carried out aerobically and in nutritionally inadequate/poor (nutrient broth) or adequate/rich (MRS broth) conditions. Interestingly, despite its negative effect on the growth and biofilm formation of pathogenic bacteria such as Staphylococcus epidermidis, WH promotes the growth of the probiotic bacteria in a nutritionally inadequate environment while maintaining their growth under a nutritionally rich environment. In the absence of WH, no significant biofilm is formed on the surfaces tested (polystyrene and alginate), but in the presence of WH, biofilm formation was significantly enhanced. These results indicate that WH may thus be used to enhance the growth and survival of probiotics.

Piperacillin/tazobactam resistance in a clinical isolate of Escherichia coli due to IS26-mediated amplification of blaTEM-1B.

A phenotype of Escherichia coli and Klebsiella pneumoniae, resistant to piperacillin/tazobactam (TZP) but susceptible to carbapenems and 3rd generation cephalosporins, has emerged. The resistance mechanism associated with this phenotype has been identified as hyperproduction of the ß-lactamase TEM. However, the mechanism of hyperproduction due to gene amplification is not well understood. Here, we report a mechanism of gene amplification due to a translocatable unit (TU) excising from an IS26-flanked pseudo-compound transposon, PTn6762, which harbours blaTEM-1B. The TU re-inserts into the chromosome adjacent to IS26 and forms a tandem array of TUs, which increases the copy number of blaTEM-1B, leading to TEM-1B hyperproduction and TZP resistance. Despite a significant increase in blaTEM-1B copy number, the TZP-resistant isolate does not incur a fitness cost compared to the TZP-susceptible ancestor. This mechanism of amplification of blaTEM-1B is an important consideration when using genomic data to predict susceptibility to TZP.

A statewide assessment of youth sports- and recreation-related injuries using emergency department administrative records.

PURPOSE: Adequate levels of physical activity are essential for health, but participation in sports and recreational physical activities is associated with an increased risk of injury. The present study quantifies the impact of sports- and recreation-related injuries (SRIs) for middle and high school-aged Kentucky children. METHODS: The study describes unintentional injuries in 2010-2012 Kentucky emergency department (ED) administrative records for patients age 10-18 years. SRIs were identified based on external codes of injuries, according to the International Classification of Diseases, Ninth Revision, Clinical Modification. RESULTS: A total of 163,252 ED visits by 10- to 18-year olds occurred during the study period, of which 31,898 (20%) were related to participation in physical activity. Males accounted for 70% of the SRIs. The primary mechanisms for SRIs were strikings (55%), falls (26%), and overexertion (13%). Superficial contusions (25%), sprains/strains (33%), and fractures (18%) were the primary diagnoses. The total charges billed for SRIs exceeded $40 million, or 19% of the total charges billed for all unintentional injury-related ED visits in this age group. CONCLUSIONS: The present study revealed one fifth of all Kentucky ED visits, and ED charges billed for unintentional injury among youth aged 10-18 years were related to sport and recreation. In the absence of a dedicated SRI surveillance system, ED administrative records provide meaningful utility for conducting statewide assessments of adolescent SRIs.

'The letting go, the building up, [and] the gradual process of rebuilding': identity change and post-traumatic growth in myalgic encephalomyelitis/chronic fatigue syndrome.

The aim of this study was to explore the phenomenon of identity change and subsequent post-traumatic growth (PTG) in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Ten participants (average illness duration 7.4 years) were interviewed (average length, 79 minutes) via a semi-structured interview schedule and verbatim transcriptions were analysed with interpretative phenomenological analysis. The four superordinate themes revealed were 'comparisons of past to present self: "you have to be someone else, and you have to live with that''', 'the effect of social isolation on identity and subsequent insights into others' behaviours', 'contemplation of future and identity: ''where do I go from here?"', and 'PTG: "the letting go, the building up, [and] the gradual process of rebuilding"'. These themes outlined the experiences of those with ME/CFS as they underwent changes in identity due to the limitations the condition imposed on activities and roles, understanding others' behaviours after a period of isolation, the comparison of the past self with the present self and finally, the positive growth that was noted by two of the interviewees with regards to a new 'true' self. Despite the distressing and unpredictable nature of ME/CFS, it appears that individuals with this disorder can experience personal growth.

A preliminary prospective study of nutritional, psychological and combined therapies for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in a private care setting.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a condition characterised by severe and persistent fatigue, neurological disturbances, autonomic and endocrine dysfunctions and sleep difficulties that have a pronounced and significant impact on individuals' lives. Current National Institute for Health and Clinical Excellence guidelines within the UK suggest that this condition should be treated with cognitive behavioural therapy and/or graded exercise therapy, where appropriate. There is currently a lack of an evidence base concerning alternative techniques that may be beneficial to those with ME/CFS. OBJECTIVES: This study aimed to investigate whether three modalities of psychology, nutrition and combined treatment influenced symptom report measures in those with ME/CFS over a 3-month time period and whether there were significant differences in these changes between groups. DESIGN AND SETTING: This is a preliminary prospective study with one follow-up point conducted at a private secondary healthcare facility in London, UK. PARTICIPANTS: 138 individuals (110 females, 79.7%; 42 participants in psychology, 44 in nutrition and 52 in combined) participated at baseline and 72 participants completed the battery of measures at follow-up (52.17% response rate; 14, 27 and 31 participants in each group, respectively). OUTCOME MEASURES: Self-reported measures of ME/CFS symptoms, functional ability, multidimensional fatigue and perceived control. RESULTS: Baseline comparisons showed those in the combined group had higher levels of fatigue. At follow-up, all groups saw improvements in fatigue, functional ability and symptomatology; those within the psychology group also experienced a shift in perceived control over time. CONCLUSIONS: This study provides early evidence that psychological, nutritional and combined techniques for the treatment of ME/CFS may influence symptomatology, fatigue, function and perceived control. However, these results must be viewed with caution as the allocation to groups was not randomised, there was no control group and the study suffered from high drop-out rates.

Methods in public health services and systems research: a systematic review.

CONTEXT: Public Health Services and Systems Research (PHSSR) is concerned with evaluating the organization, financing, and delivery of public health services and their impact on public health. The strength of the current PHSSR evidence is somewhat dependent on the methods used to examine the field. Methods used in PHSSR articles, reports, and other documents were reviewed to assess their methodologic strengths and challenges in light of PHSSR goals. EVIDENCE ACQUISITION: A total of 364 documents from the PHSSR library met the inclusion criteria as empirical and based in the U.S. After additional exclusions, 327 of these were analyzed. EVIDENCE SYNTHESIS: A detailed codebook was used to classify articles in terms of (1) study design; (2) sampling; (3) instrumentation; (4) data collection; (5) data analysis; and (6) study validity. Inter-coder reliability was assessed for the codebook; once it was found reliable, the available empirical documents were coded. CONCLUSIONS: Although there has been a dramatic increase in the amount of published PHSSR recently, methods used remain primarily cross-sectional and descriptive. Moreover, although appropriate for exploratory and foundational work in a new field, these approaches are limiting progress toward some PHSSR goals. Recommendations are given to advance and strengthen the methods used in PHSSR to better meet the goals and challenges facing the field.

Characteristics of Kentucky local health departments that influence public health communication during times of crisis: information dissemination associated with H1N1 novel influenza.

OBJECTIVE: The purpose of this study was to investigate the association of selected characteristics of local health departments (LHDs) in Kentucky with the receipt of information by external stakeholders, specifically physicians and pharmacists, during the initial H1N1 outbreak of 2009. METHODS: This study utilized a cross-sectional survey to gather characteristic information from local health departments. In addition, cross sectional surveys of physicians and pharmacists were used to determine information receipt. All 54 LHDs in Kentucky were surveyed; however, only those physicians belonging to the Kentucky Family Physician Association or the Kentucky Ambulatory Network were surveyed. Also, pharmacists included in this survey were members of the Kentucky Pharmacist Association. Descriptive data analyses, including chi-square test of independence, were conducted, and generalized estimating equations were used to calculate odds ratios to depict associations related to information exchange in this study. RESULTS: Response rates for the study were as follows: LHDs 65% (35/54), physicians 18.5% (96/518), and pharmacists 21.1% (211/1000). Of the 35 participating LHDs the most common characteristic identified was the presence of a public information officer (PIO) and a pandemic influenza plan, 76% and 64%, respectively. Despite these factors, 72% of external stakeholders did not receive any information regarding H1N1 from the LHD. Generalized estimating equations also indicated that stakeholders in jurisdictions lacking a PIO had 6 (95% confidence interval, 1.3-26.95) greater odds of not receiving information from the LHD. External stakeholders in jurisdictions without a pandemic influenza plan had 3.38 (95% confidence interval, 0.80-1.17) increased odds of not receiving information but this association was not statistically significant. CONCLUSION: Observations from this study indicate a need to improve information exchange between LHDs and their external stakeholders, specifically physicians and pharmacists. Present results suggest the designation of a PIO may positively influence communication between LHDs and other health care providers, particularly physicians.

Communication efforts among local health departments and health care professionals during the 2009 H1N1 outbreak.

OBJECTIVES: The purpose of this study was to examine the public health response to the emergence of influenza H1N1 by evaluating the effectiveness of communication between health departments, community physicians, and pharmacists in Kentucky during the initial H1N1 outbreak. METHODS: This study used a cross-sectional survey design to gather information from health departments, physicians, and pharmacists regarding information dissemination and receipt during the early H1N1 outbreak (April to July2009). Study participants included members of practice-based research networks in public health, primary care, pharmacy, and their partners. RESULTS: Ninety-five percent of participating local health departments (LHDs) reported that health care professional notification was a risk mitigation strategy initiated in their local jurisdiction, and 81% of responding LHDs rated their capacity to disseminate information to health care providers as very good or excellent. However, only 52% of surveyed physicians and 16% of surveyed pharmacists reported receiving any information about H1N1 from an LHD. Seventy-four percent of pharmacists were not aware of their LHD's emergency plan in the event of an influenza outbreak. CONCLUSION: These findings suggest that deficiencies exist in the outreach and effectiveness of information dissemination efforts from LHDs to health care professionals during an influenza outbreak. Research that identifies improved methods for members of public health and health care systems to communicate and share information with one another is needed. An intervention focused on improving communication about infectious disease outbreaks and examining the impact of such an intervention would be useful and productive.