AHHME: A model for estimating the holistic cost-effectiveness of antimicrobial resistance interventions in food animal production.

Antimicrobial resistance (AMR) is considered a global priority for human health, and reducing antimicrobial use in food animals has been suggested as a key area for interventions aiming to reduce resistant infections in humans. In addition to the effect on human health, such interventions may have effects across food animal productivity, healthcare sector costs, and the broader macroeconomy, but these effects are rarely captured in the AMR health economic literature. Without being able to estimate these effects, it is difficult to understand the true cost-effectiveness of antimicrobial stewardship interventions in food animal production, or to correctly design and prioritise such interventions. We explore and demonstrate the potential use of a novel compartment-based mathematical model to estimate the holistic cost-effectiveness of AMR-related interventions in food animal production from a One Health perspective. The Agriculture Human Health Micro-Economic model (AHHME) uses Markov state transition models to model the movement of humans and food animals between health states. It assigns values to these health states utilising empiric approaches, from the perspectives of human health, food animal productivity, labour productivity and healthcare sector costs. Providing AHHME open-source code and interactive online modelling tools allow for capacity building in AMR intervention modelling. This model represents a useful framework for capturing the cost-effectiveness of AMR-related interventions in food animal production in a more holistic way: it can allow us to capture the often-overlooked benefits of such interventions in like terms while considering distributional concerns. It also demonstrates that methodological assumptions such as willingness-to-pay thresholds and discount rates can be just as important to health decision models as epidemiological parameters, and allows these assumptions to be altered. We provide example outputs, and encourage researchers and policymakers to use and adapt our code to explore, design, and prioritise AMR-related interventions in their own country contexts.

Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis.

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission.

Quantitatively evaluating the cross-sectoral and One Health impact of interventions: A scoping review and case study of antimicrobial resistance.

BACKGROUND: Current frameworks evaluating One Health (OH) interventions focus on intervention-design and -implementation. Cross-sectoral impact evaluations are needed to more effectively tackle OH-issues, such as antimicrobial resistance (AMR). We aimed to describe quantitative evaluation methods for interventions related to OH and cross-sectoral issues, to propose an explicit approach for evaluating such interventions, and to apply this approach to AMR. METHODS: A scoping review was performed using WebofScience, EconLit, PubMed and gray literature. Quantitative evaluations of interventions that had an impact across two or more of the human, animal and environment sectors were included. Information on the interventions, methods and outcome measures found was narratively summarised. The information from this review informed the construction of a new approach to OH-related intervention evaluation, which then was applied to the field of AMR. RESULTS: The review included 90 studies: 73 individual evaluations (from 72 papers) and 18 reviews, with a range of statistical modelling (n = 13 studies), mathematical modelling (n = 53) and index-creation/preference-ranking (n = 14) methods discussed. The literature highlighted the need to (I) establish stakeholder objectives, (II) establish quantifiable outcomes that feed into those objectives, (III) establish agents and compartments that affect these outcomes and (IV) select appropriate methods (described in this review) accordingly. Based on this, an evaluation model for AMR was conceptualised; a decision-tree of intervention options, a compartmental-microeconomic model across sectors and a general-equilibrium (macroeconomic) model are linked. The outcomes of this multi-level model (including cost-utility and Gross Domestic Product impact) can then feed into multi-criteria-decision analyses that weigh respective impact estimates alongside other chosen outcome estimates (for example equity or uncertainty). CONCLUSION: In conclusion, stakeholder objectives are key in establishing which evaluation methods (and associated outcome measures) should be used for OH-related interventions. The stated multi-level approach also allows for sub-systems to be modelled in succession, where resources are constrained.

COVID-19 length of hospital stay: a systematic review and data synthesis.

BACKGROUND: The COVID-19 pandemic has placed an unprecedented strain on health systems, with rapidly increasing demand for healthcare in hospitals and intensive care units (ICUs) worldwide. As the pandemic escalates, determining the resulting needs for healthcare resources (beds, staff, equipment) has become a key priority for many countries. Projecting future demand requires estimates of how long patients with COVID-19 need different levels of hospital care. METHODS: We performed a systematic review of early evidence on length of stay (LoS) of patients with COVID-19 in hospital and in ICU. We subsequently developed a method to generate LoS distributions which combines summary statistics reported in multiple studies, accounting for differences in sample sizes. Applying this approach, we provide distributions for total hospital and ICU LoS from studies in China and elsewhere, for use by the community. RESULTS: We identified 52 studies, the majority from China (46/52). Median hospital LoS ranged from 4 to 53 days within China, and 4 to 21 days outside of China, across 45 studies. ICU LoS was reported by eight studies-four each within and outside China-with median values ranging from 6 to 12 and 4 to 19 days, respectively. Our summary distributions have a median hospital LoS of 14 (IQR 10-19) days for China, compared with 5 (IQR 3-9) days outside of China. For ICU, the summary distributions are more similar (median (IQR) of 8 (5-13) days for China and 7 (4-11) days outside of China). There was a visible difference by discharge status, with patients who were discharged alive having longer LoS than those who died during their admission, but no trend associated with study date. CONCLUSION: Patients with COVID-19 in China appeared to remain in hospital for longer than elsewhere. This may be explained by differences in criteria for admission and discharge between countries, and different timing within the pandemic. In the absence of local data, the combined summary LoS distributions provided here can be used to model bed demands for contingency planning and then updated, with the novel method presented here, as more studies with aggregated statistics emerge outside China.

The health and cost burden of antibiotic resistant and susceptible Escherichia coli bacteraemia in the English hospital setting: A national retrospective cohort study.

INTRODUCTION: Antibiotic resistance poses a threat to public health and healthcare systems. Escherichia coli causes more bacteraemia episodes in England than any other bacterial species. This study aimed to estimate the burden of E. coli bacteraemia and associated antibiotic resistance in the secondary care setting. MATERIALS AND METHODS: This was a retrospective cohort study, with E. coli bacteraemia as the main exposure of interest. Adult hospital in-patients, admitted to acute NHS hospitals between July 2011 and June 2012 were included. English national surveillance and administrative datasets were utilised. Cox proportional hazard, subdistribution hazard and multistate models were constructed to estimate rate of discharge, rate of in-hospital death and excess length of stay, with a unit bed day cost applied to the latter to estimate cost burden from the healthcare system perspective. RESULTS: 14,042 E. coli bacteraemia and 8,919,284 non-infected inpatient observations were included. E. coli bacteraemia was associated with an increased rate of in-hospital death across all models, with an adjusted subdistribution hazard ratio of 5.88 (95% CI: 5.62-6.15). Resistance was not found to be associated with in-hospital mortality once adjusting for patient and hospital covariates. However, resistance was found to be associated with an increased excess length of stay. This was especially true for third generation cephalosporin (1.58 days excess length of stay, 95% CI: 0.84-2.31) and piperacillin/tazobactam resistance (1.23 days (95% CI: 0.50-1.95)). The annual cost of E. coli bacteraemia was estimated to be £14,346,400 (2012 £), with third-generation cephalosporin resistance associated with excess costs per infection of £420 (95% CI: 220-630). CONCLUSIONS: E. coli bacteraemia places a statistically significant burden on patient health and the hospital sector in England. Resistance to front-line antibiotics increases length of stay; increasing the cost burden of such infections in the secondary care setting.

Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.

BACKGROUND: To end the global tuberculosis epidemic, latent tuberculosis infection needs to be addressed. All standard treatments for latent tuberculosis contain drugs to which multidrug-resistant (MDR) Mycobacterium tuberculosis is resistant. We aimed to estimate the global burden of multidrug-resistant latent tuberculosis infection to inform tuberculosis elimination policy. METHODS: By fitting a flexible statistical model to tuberculosis drug resistance surveillance and survey data collated by WHO, we estimated national trends in the proportion of new tuberculosis cases that were caused by MDR strains. We used these data as a proxy for the proportion of new infections caused by MDR M tuberculosis and multiplied trends in annual risk of infection from previous estimates of the burden of latent tuberculosis to generate trends in the annual risk of infection with MDR M tuberculosis. These estimates were used in a cohort model to estimate changes in the global and national prevalence of latent infection with MDR M tuberculosis. We also estimated recent infection levels (ie, in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis in 2035 and 2050. FINDINGS: 19·1 million (95% uncertainty interval [UI] 16·4 million-21·7 million) people were latently infected with MDR tuberculosis in 2014-a global prevalence of 0·3% (95% UI 0·2-0·3). MDR strains accounted for 1·2% (95% UI 1·0-1·4) of the total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6-3·1) of the burden among children younger than 15 years (risk ratio for those younger than 15 years vs those aged 15 years or older 2·65 [95% UI 2·11-3·25]). Recent latent infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million-2·3 million) people globally were at high risk of active MDR tuberculosis in 2015. INTERPRETATION: We estimate that three in every 1000 people globally carry latent MDR tuberculosis infection, and prevalence is around ten times higher among those younger than 15 years. If current trends continue, the proportion of latent tuberculosis caused by MDR strains will increase, which will pose serious challenges for management of latent tuberculosis-a cornerstone of tuberculosis elimination strategies. FUNDING: UK Medical Research Council, Bill & Melinda Gates Foundation, and European Research Council.

Fast and expensive (PCR) or cheap and slow (culture)? A mathematical modelling study to explore screening for carbapenem resistance in UK hospitals.

BACKGROUND: Enterobacteriaceae are a common cause of hospital infections. Carbapenems are a clinically effective treatment of such infections. However, resistance is on the rise. In particular, carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) are increasingly common. In order to limit spread in clinical settings, screening and isolation is being recommended, but many different screening methods are available. We aimed to compare the impact and costs of three algorithms for detecting CP-CRE carriage. METHODS: We developed an individual-based simulation model to compare three screening algorithms using data from a UK National Health Service (NHS) trust. The first algorithm, "Direct PCR", was highly sensitive/specific and quick (half a day), but expensive. The second, "Culture + PCR", was relatively sensitive/specific but slower, requiring 2.5 days. A third algorithm, "PHE", repeated the "Culture + PCR" three times with an additional PCR. Scenario analysis was used to compare several levels of CP-CRE prevalence and coverage of screening, different specialities as well as isolation strategies. Our outcomes were (1) days that a patient with CP-CRE was not detected and hence not isolated ("days at risk"), (2) isolation bed days, (3) total costs and (4) mean cost per CP-CRE risk day averted per year. We also explored limited isolation bed day capacity. RESULTS: We found that although a Direct PCR algorithm would reduce the number of CP-CRE days at risk, the mean cost per CP-CRE risk day averted per year was substantially higher than for a Culture + PCR algorithm. For example, in our model of an intensive care unit, during a year with a 1.6% CP-CRE prevalence and 63% screening coverage, there were 508 (standard deviation 15), 642 (14) and 655 (14) days at risk under screening algorithms Direct PCR, Culture + PCR and PHE respectively, with mean costs per risk day averted of £192, £61 and £79. These results were robust to sensitivity analyses. CONCLUSIONS: Our results indicate that a Culture + PCR algorithm provides the optimal balance of cost and risk days averted, at varying isolation, prevalence and screening coverage scenarios. Findings from this study will help clinical organisations determine the optimal screening approach for CP-CRE, balancing risk and resources.

Estimating the burden of antimicrobial resistance: a systematic literature review.

Background: Accurate estimates of the burden of antimicrobial resistance (AMR) are needed to establish the magnitude of this global threat in terms of both health and cost, and to paramaterise cost-effectiveness evaluations of interventions aiming to tackle the problem. This review aimed to establish the alternative methodologies used in estimating AMR burden in order to appraise the current evidence base. Methods: MEDLINE, EMBASE, Scopus, EconLit, PubMed and grey literature were searched. English language studies evaluating the impact of AMR (from any microbe) on patient, payer/provider and economic burden published between January 2013 and December 2015 were included. Independent screening of title/abstracts followed by full texts was performed using pre-specified criteria. A study quality score (from zero to one) was derived using Newcastle-Ottawa and Philips checklists. Extracted study data were used to compare study method and resulting burden estimate, according to perspective. Monetary costs were converted into 2013 USD. Results: Out of 5187 unique retrievals, 214 studies were included. One hundred eighty-seven studies estimated patient health, 75 studies estimated payer/provider and 11 studies estimated economic burden. 64% of included studies were single centre. The majority of studies estimating patient or provider/payer burden used regression techniques. 48% of studies estimating mortality burden found a significant impact from resistance, excess healthcare system costs ranged from non-significance to $1 billion per year, whilst economic burden ranged from $21,832 per case to over $3 trillion in GDP loss. Median quality scores (interquartile range) for patient, payer/provider and economic burden studies were 0.67 (0.56-0.67), 0.56 (0.46-0.67) and 0.53 (0.44-0.60) respectively. Conclusions: This study highlights what methodological assumptions and biases can occur dependent on chosen outcome and perspective. Currently, there is considerable variability in burden estimates, which can lead in-turn to inaccurate intervention evaluations and poor policy/investment decisions. Future research should utilise the recommendations presented in this review. Trial registration: This systematic review is registered with PROSPERO (PROSPERO CRD42016037510).

Methods for estimating the burden of antimicrobial resistance: a systematic literature review protocol.

BACKGROUND: Estimates of the burden of antimicrobial resistance (AMR) are needed to ascertain AMR impact, to evaluate interventions, and to allocate resources efficiently. Recent studies have estimated health, cost, and economic burden relating to AMR, with outcomes of interest ranging from drug-bug resistance impact on mortality in a hospital setting to total economic impact of AMR on the global economy. However, recent collation of this information has been largely informal, with no formal quality assessment of the current evidence base (e.g. with predefined checklists). This review therefore aims to establish what perspectives and resulting methodologies have been used in establishing the burden of AMR, whilst also ascertaining the quality of these studies. METHODS: The literature review will identify relevant literature using a systematic review methodology. MEDLINE, EMBASE, Scopus and EconLit will be searched utilising a predefined search string. Grey literature will be identified by searching within a predefined list of organisational websites. Independent screening of retrievals will be performed in a two-stage process (abstracts and full texts), utilising a pre-defined inclusion and exclusion criteria. Data will be extracted into a data extraction table and descriptive examination will be performed. Study quality will be assessed using the Newcastle-Ottawa scales and the Philips checklists where appropriate. A narrative synthesis of the results will be presented. DISCUSSION: This review will provide an overview of previous health, cost and economic definitions of burden and the resultant impact of these different definitions on the burden of AMR estimated. The review will also explore the methods that have been used to calculate this burden and discuss resulting study quality. This review can therefore act as a guide to methods for future research in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037510.

Systematic review of mathematical models exploring the epidemiological impact of future TB vaccines.

Mathematical models are useful for assessing the potential epidemiological impact of future tuberculosis (TB) vaccines. We conducted a systematic review of mathematical models estimating the epidemiological impact of future human TB vaccines. PubMed, Embase and WHO Global Health Library were searched, 3-stage manual sifted, and citation- and reference-tracked, identifying 23 papers. An adapted quality assessment tool was developed, with a resulting median study quality score of 20/28. The literature remains divided as to whether vaccines effective pre- or post-infection would provide greatest epidemiological impact. However, all-age or adolescent/adult targeted prevention of disease vaccines achieve greater and more rapid impact than neonatal vaccines. Mass campaigns alongside routine neonatal vaccination can have profound additional impact. Economic evaluations found TB vaccines overwhelmingly cost-effective, particularly when targeted to adolescents/adults. The variability of impact by setting, age group and vaccine characteristics must be accounted for in the development and delivery of future TB vaccines.

The Impact and Cost-Effectiveness of a Four-Month Regimen for First-Line Treatment of Active Tuberculosis in South Africa.

BACKGROUND: A 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa. METHOD: An individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015-2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds. RESULTS: It was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618). CONCLUSION: The introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa.

The Distribution of Fitness Costs of Resistance-Conferring Mutations Is a Key Determinant for the Future Burden of Drug-Resistant Tuberculosis: A Model-Based Analysis.

BACKGROUND: Drug resistance poses a serious challenge for the control of tuberculosis in many settings. It is well established that the expected future trend in resistance depends on the reproductive fitness of drug-resistant Mycobacterium tuberculosis. However, the variability in fitness between strains with different resistance-conferring mutations has been largely ignored when making these predictions. METHODS: We developed a novel approach for incorporating the variable fitness costs of drug resistance-conferring mutations and for tracking this distribution of fitness costs over time within a transmission model. We used this approach to describe the effects of realistic fitness cost distributions on the future prevalence of drug-resistant tuberculosis. RESULTS: The shape of the distribution of fitness costs was a strong predictor of the long-term prevalence of resistance. While, as expected, lower average fitness costs of drug resistance-conferring mutations were associated with more severe epidemics of drug-resistant tuberculosis, fitness distributions with greater variance also led to higher levels of drug resistance. For example, compared to simulations in which the fitness cost of resistance was fixed, introducing a realistic amount of variance resulted in a 40% increase in prevalence of drug-resistant tuberculosis after 20 years. CONCLUSIONS: The differences in the fitness costs associated with drug resistance-conferring mutations are a key determinant of the future burden of drug-resistant tuberculosis. Future studies that can better establish the range of fitness costs associated with drug resistance-conferring mutations will improve projections and thus facilitate better public health planning efforts.

Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries.

To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost-effectiveness of potential TB vaccines in low- and middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, to prevent active TB in all individuals, to have a 5-y to lifetime duration of protection, to have 40-80% efficacy, and to be targeted at "infants" or "adolescents/adults." Vaccine prices were tiered by income group (US $1.50-$10 per dose), and cost-effectiveness was assessed using incremental cost per disability adjusted life year (DALY) averted compared against gross national income per capita. Our results suggest that over 2024-2050, a vaccine targeted to adolescents/adults could have a greater impact than one targeted at infants. In low-income countries, a vaccine with a 10-y duration and 60% efficacy targeted at adolescents/adults could prevent 17 (95% range: 11-24) million TB cases by 2050 and could be considered cost-effective at $149 (cost saving to $387) per DALY averted. If targeted at infants, 0.89 (0.42-1.58) million TB cases could be prevented at $1,692 ($634-$4,603) per DALY averted. This profile targeted at adolescents/adults could be cost-effective at $4, $9, and $20 per dose in low-, lower-middle-, and upper-middle-income countries, respectively. Increased investments in adult-targeted TB vaccines may be warranted, even if only short duration and low efficacy vaccines are likely to be feasible, and trials among adults should be powered to detect low efficacies.