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Protecting healthcare and patient pathways from infection and antimicrobial resistance. Innovative whole system approaches to integrate research and novel technologies within patient pathways are needed to target antibiotic use, minimise healthcare associated infections, and adapt to novel pathogens, write Derek Cocker and colleagues

In the SARS-CoV-2 pandemic, high levels of covid-19 infection in staff and hospital inpatients showed the key role that healthcare has in disease transmission and led to considerable disruption in the delivery of healthcare.4 5 Similarly, common preventable infections (for example, influenza, norovirus) and antimicrobial resistance can be easily acquired in hospital and reduce the capacity for healthcare to function safely and effectively. All patients in healthcare are at risk of acquiring infections, with the most serious outcomes in vulnerable groups. Deaths from covid-19 occurred disproportionately among elderly, immunosuppressed, and socioeconomically deprived people.6 Healthcare acquired infections and antimicrobial resistance affect these populations similarly, with higher rates of disease and colonisation with drug resistant organisms and drug resistant infections.7 Adoption of preventive measures and system-wide approaches to limit healthcare acquired infections and antimicrobial resistance across a range of people exposed to healthcare is important to prevent infections, protect at-risk groups, and safeguard elective and emergency healthcare.

isms and drug resistant infections.7 Adoption of preventive measures and system-wide approaches to limit healthcare acquired infections and antimicrobial resistance across a range of people exposed to healthcare is important to prevent infections, protect at-risk groups, and safeguard elective and emergency healthcare. Key risks for acquisition and transmission of healthcare acquired infections and antimicrobial resistance include hygiene factors, alongside direct and indirect exposures to contaminated environments with a high prevalence of environmental or human resistant microbial strains (that is, healthcare settings or nursing homes), poor staff to patient ratios, and selection pressures imparted by antibiotic exposure, whether appropriate or inappropriate.8 Recognition of key infection and antimicrobial resistance risks is essential to target care accordingly, particularly in acute healthcare and linked pathways (for example, outpatient care and dialysis units). Part of this will be to reconsider and adapt current patient pathways in the UK, which often put patients at risk along the pathway from pre-admission to post-discharge.

risks is essential to target care accordingly, particularly in acute healthcare and linked pathways (for example, outpatient care and dialysis units). Part of this will be to reconsider and adapt current patient pathways in the UK, which often put patients at risk along the pathway from pre-admission to post-discharge. Here, the focus needs to be on the concept of pathways, not buildings.9 The strict divide between primary or secondary care and community or hospital settings is unhelpful, and a whole health economy approach to prevention of healthcare acquired infections and antibiotic stewardship should be developed that spans health sector boundaries.9 Often, the health sector works in silos, and structural barriers and disparate information technology lead to fragmentation of care and inefficient allocation of resources. This results in suboptimal patient outcomes and increased costs to an already overstretched healthcare system .10 Many national and international organisations have called for a shift to patient centred care, with seamless integration between healthcare settings and better data sharing.10 Widening the scope of the patient journey and intervening at multiple points will be necessary to interrupt escalating rates of healthcare acquired infections and antimicrobial resistance. Additionally, the notion of distinct outpatient versus inpatient care should be re-evaluated. Instead, these should be considered part of a care continuum that poses risks and opportunities for action from the perspective of healthcare acquired infections and antimicrobial resistance.

ions and antimicrobial resistance. Additionally, the notion of distinct outpatient versus inpatient care should be re-evaluated. Instead, these should be considered part of a care continuum that poses risks and opportunities for action from the perspective of healthcare acquired infections and antimicrobial resistance. For example, renal, haematology, and oncology patients often have higher rates of attendance for dialysis, chemotherapy, and clinic appointments—alongside increased immunosuppression—leading to higher rates of infection (either healthcare associated or community acquired) and subsequent antibiotic exposure.11 12 Antibiotic use, in turn, results in a higher prevalence of drug resistant colonisation and infection, leading to a cycle of exposure-risk. Breaking this cycle with pre-emptive measures along the patient journey will benefit both the patient and healthcare itself.

Infection prevention and the effect on the wider patient population are rarely considered adequately by researchers and policy makers, largely because of the absence of connected data and a lack of contextual understanding. To create an effective system that limits healthcare acquired infections and the spread of antimicrobial resistance in healthcare requires rapid expansion of the evidence base for putative interventions along patient pathways. Current interventional trials have many pitfalls to achieving this goal, and an overhaul of clinical trial design and associated regulation is needed to optimise future research. A disconnect often exists between participants in infection trial designs and those who would receive the intervention in practice. Despite increasing multimorbidity and polypharmacy in the population,13 trial designs often prefer safer participants who are younger and have less comorbidity.14 Additionally, many multisite or international trials undertake research in populations where intervention uptake is precluded by cost or access, leading to unequal opportunity, particularly in resource limited settings.

lation,13 trial designs often prefer safer participants who are younger and have less comorbidity.14 Additionally, many multisite or international trials undertake research in populations where intervention uptake is precluded by cost or access, leading to unequal opportunity, particularly in resource limited settings. Infection trials should consider measuring multiple endpoints to evaluate impact more broadly. Given the difficulty in assessing the burden of healthcare acquired infection and antimicrobial resistance, trials need a comprehensive range of antimicrobial resistance proxies and outcomes of interest, including the effects on the individual (eg, mortality and colonisation status), the population (eg, antimicrobial use and prevalence of antimicrobial resistance), and the health system (eg, ward closures, antibiotic costs, surgical delays, isolation requirements, length of stay, and economic impact).15 Ideally, this should account for colonisation status in the community as well as infection rates within healthcare, alongside pathogen and antimicrobial resistance exposure, including those linked to global travel.

sures, antibiotic costs, surgical delays, isolation requirements, length of stay, and economic impact).15 Ideally, this should account for colonisation status in the community as well as infection rates within healthcare, alongside pathogen and antimicrobial resistance exposure, including those linked to global travel. Future trials assessing mortality should take an intervention based causal approach using suitably matched cohorts to evaluate the harm from drug resistant infections and drug sensitive infections, alongside where infections have been prevented. Such methods reduce systematic biases and give better estimates of the true burden of antimicrobial resistance.15 Although mortality is often the main trial outcome, colonisation with both resistant and sensitive organisms should be evaluated, given the propensity for horizontal gene transfer between sensitive and resistant organisms16 and because colonisation with drug resistant organisms such as carbapenemase producing Enterobacteriaceae provides a substantial ongoing risk for future infections.17

both resistant and sensitive organisms should be evaluated, given the propensity for horizontal gene transfer between sensitive and resistant organisms16 and because colonisation with drug resistant organisms such as carbapenemase producing Enterobacteriaceae provides a substantial ongoing risk for future infections.17 Gaining regulatory approval for infection trials is time consuming. In the UK, changes have been proposed for clinical trial regulation to make approvals faster and easier18; however, several regulatory and administrative challenges remain that may prevent these benefits being fully realised and applied to protect people in healthcare and the maintenance of safe healthcare. Regulatory support, for example, through the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) innovative licensing and access pathway, is welcomed but it could offer a greater focus on healthcare acquired infections or antimicrobial resistance treatments and prevention. Off-the-shelf predefined and agreed trial designs that can be rapidly implemented in the UK and internationally are also needed to tackle emerging health threats. Where possible, trials should be expanded to include sites across multiple countries with varying resource infrastructure, to reduce global health inequities, enable generalisability of the results, and provide a better understanding of outcomes in populations that often have the greatest disease burden.19

Novel statistical analysis and trial designs exist that evaluate better the effects of interventions in complex systems, interrogate the available data more effectively, and can adapt and respond to evolving health threats.20 21 Analytical approaches should be applied to trials that focus on infection prevention and the design and management of patient pathways to expedite the testing and prioritisation of interventions in these complex systems to mitigate present and future health threats. To help prioritise the research agenda, previous modelling studies can be used to estimate the effect of putative antimicrobial stewardship or infection prevention interventions.22 Wherever possible, more advanced clinical trial designs, such as platform trials, used successfully in early phase evaluation of novel or re-purposed antivirals in the covid-19 pandemic, should be implemented.21 These generate innovative trial endpoints and statistics to deliver smaller, but no less rigorous, clinical trials, in shorter time frames.23

clinical trial designs, such as platform trials, used successfully in early phase evaluation of novel or re-purposed antivirals in the covid-19 pandemic, should be implemented.21 These generate innovative trial endpoints and statistics to deliver smaller, but no less rigorous, clinical trials, in shorter time frames.23 Multi-agent or multi-arm infection trials that use data obtained during the trial to refine interventions for subsequent recruits based on more effective treatments, whether alone or in combination, can rapidly expand the evidence base.20 24 25 The flexibility of multi-agent or multi-arm studies provides additional benefit beyond testing the intended outcome and can be repurposed for evolving infection threats or in outbreak settings. For example, the Remap-Cap trial (Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia) was initiated to generate evidence for best practice in the treatment of patients with severe community acquired pneumonia in intensive care units, but it was adapted in 2020 to rapidly evaluate treatments in the covid-19 pandemic.20 Given the propensity for novel healthcare acquired infections and antimicrobial resistance outbreaks, the adaptability of these designs is valuable for both research into the protection of healthcare and pandemic preparedness.

units, but it was adapted in 2020 to rapidly evaluate treatments in the covid-19 pandemic.20 Given the propensity for novel healthcare acquired infections and antimicrobial resistance outbreaks, the adaptability of these designs is valuable for both research into the protection of healthcare and pandemic preparedness. The analysis underpinning infection and antimicrobial resistance trials is also evolving rapidly, particularly in relation to the assessment of antimicrobial selection, antibiotic duration, and the collateral effects of antibiotic use.26 27 28 These novel analytical approaches can combine multiple clinical outcomes into a single score and rank multiple treatments against each other in a pragmatic way, gaining insights into the best options for care. The correct application of these methodologies in infection prevention trials will enable testing of several interventions, dose durations, and outcomes and provide practical solutions to optimise the design of patient pathways, promoting safer delivery of healthcare.

Trials need to be developed that enable testing of innovative screening, targeted prophylaxis, and preventative interventions (that is, vaccination and immunotherapies) aimed at protecting patients who come into contact with healthcare, patient pathways, and the delivery of state healthcare.

Trials need to be developed that enable testing of innovative screening, targeted prophylaxis, and preventative interventions (that is, vaccination and immunotherapies) aimed at protecting patients who come into contact with healthcare, patient pathways, and the delivery of state healthcare. Vaccines and immunotherapies could be used to protect populations from unnecessary infections and resulting use of antibiotics. For example, vaccinations against SARS-CoV-2, influenza, and respiratory syncytial virus reduce hospital admissions, limit transmission in hospital, and avert disease associated with inappropriate antibiotic use, preventing healthcare acquired infections, antimicrobial resistance colonisation, and subsequent antimicrobial resistance transmission in the community.29 30 Vaccination of healthcare staff is equally important to prevent infections, reduce ongoing transmission in healthcare and community settings, and limit staff absences.31 32 33 Protecting healthcare staff in turn protects patients and the safe delivery of healthcare. Preventive therapies should be considered for specific groups, such as patients having elective surgery, chemotherapy, or renal replacement, or those admitted to neonatal units or intensive care units.34 35 These can include screening methods at the point of care to identify patients colonised with resistant bacteria, integrated with vaccination and decolonisation regimens. Implementing such therapies can reduce the burden of sensitive or resistant infections, limit antimicrobial use, reduce length of stay, minimise costs, and enhance healthcare resilience.34

the point of care to identify patients colonised with resistant bacteria, integrated with vaccination and decolonisation regimens. Implementing such therapies can reduce the burden of sensitive or resistant infections, limit antimicrobial use, reduce length of stay, minimise costs, and enhance healthcare resilience.34 Trials should be embedded into pathways that include data on antimicrobial use, antimicrobial resistance, screening, and surveillance systems for healthcare acquired infections to allow holistic health system analysis and ongoing patient involvement, including access to patient pathway mapping and genomic relatedness to infer transmission dynamics.36 This can be enhanced by using systems dynamic modelling and simulation scenario testing methods to capture structural and behavioural influences in decision making around proposed interventions.37 Pathway and policy decisions about antibiotic optimisation can lead to unintended consequences, and public awareness campaigns and surveillance should be developed in parallel with proposed interventions to ensure shared decision making and monitoring.38

al influences in decision making around proposed interventions.37 Pathway and policy decisions about antibiotic optimisation can lead to unintended consequences, and public awareness campaigns and surveillance should be developed in parallel with proposed interventions to ensure shared decision making and monitoring.38 The UK is well placed to develop optimal healthcare pathways given integrated care systems, a unique patient identifier, and a regulatory framework governing antibiotic prescription. However, this is complicated by a growing use of the independent sector, with variations in care delivery and lack of comprehensive surveillance. Artificial intelligence (AI) could be used to aid pathway development and clinical decision making, targeting prevention of healthcare acquired infections and antimicrobial resistance.39 AI presents vast opportunities, but it needs to be practical, streamlined, and cost effective and depends on data collection systems, staffing, and infrastructure, which are often lacking.40

In the UK, as elsewhere, information technology systems and infrastructure limit use of the extensive data available.19 39 40 Investment in real time surveillance, information and data linkage systems, alongside provision and training of staff are required to integrate metadata (from community, hospital, and national surveillance sources) and evaluate system-wide approaches that protect individuals, pathways, and healthcare from healthcare acquired infections and antimicrobial resistance.6 39 Better data linkage systems would further permit the integration of healthcare acquired infection and antimicrobial resistance datasets with national surveillance networks to enable real time open source analysis and reporting mechanisms that promote dissemination of findings to policy makers for inclusion in national policy.41 Opportunities to identify patterns in complex linked metadata will benefit from a change in approach, from traditional analyses to machine learning or AI technology.39 The feasibility of these technologies is as yet unclear, but UK health and care digital strategies, include their ongoing development and operationalisation of such systems, would have far reaching benefits beyond healthcare acquired infections and antimicrobial resistance.40 Community and other stakeholder engagement will be vital in developing these information systems to maximise their efficiency and maintain public support.6

r ongoing development and operationalisation of such systems, would have far reaching benefits beyond healthcare acquired infections and antimicrobial resistance.40 Community and other stakeholder engagement will be vital in developing these information systems to maximise their efficiency and maintain public support.6 Given finite NHS budgets, trials and pathway developments should be dovetailed with cost-benefit analysis to delineate the impact of interventions on preventing healthcare acquired infections and antimicrobial resistance across community and healthcare settings,9 to develop those with the greatest impact for investment.34 Flexibility and use of datasets from other diseases (that is, cross surveillance platforms) should be maximised wherever possible, to leverage information, reduce costs, and promote timely decision making. Finally, research outputs should align with stated gaps in knowledge and practice identified in the UK national action plans (for example, on antimicrobial resistance and tuberculosis), ideally with clearly identified policy goals with either broad applicability or specifically targeted to groups with high disease burden.42

ly, research outputs should align with stated gaps in knowledge and practice identified in the UK national action plans (for example, on antimicrobial resistance and tuberculosis), ideally with clearly identified policy goals with either broad applicability or specifically targeted to groups with high disease burden.42 In the face of an ongoing antimicrobial resistance pandemic and associated public health crisis, society needs to protect healthcare itself. Current pathways can facilitate healthcare acquired infections and antimicrobial resistance, contributing to increasing global trends of infection and antimicrobial resistance, posing substantial risks to the safe delivery of healthcare. Trialling preventive interventions is imperative, as are tailored care pathways that can adapt to the needs of individuals and the system to mitigate future health shocks. Future trial designs should enable the flexibility of testing multiple interventions and outcomes that consider the protection of staff and patients from healthcare acquired infections and antimicrobial resistance, which in turn will enhance the resilience of the health system.