Antibiotic Consumption During the Coronavirus Disease 2019 Pandemic and Emergence of Carbapenemase-Producing Klebsiella pneumoniae Lineages Among Inpatients in a Chilean Hospital: A Time-Series Study and Phylogenomic Analysis.

BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) on antimicrobial use (AU) and resistance has not been well evaluated in South America. These data are critical to inform national policies and clinical care. METHODS: At a tertiary hospital in Santiago, Chile, between 2018 and 2022, subdivided into pre- (3/2018-2/2020) and post-COVID-19 onset (3/2020-2/2022), we evaluated intravenous AU and frequency of carbapenem-resistant Enterobacterales (CRE). We grouped monthly AU (defined daily doses [DDD]/1000 patient-days) into broad-spectrum ß-lactams, carbapenems, and colistin and used interrupted time-series analysis to compare AU during pre- and post-pandemic onset. We studied the frequency of carbapenemase-producing (CP) CRE and performed whole-genome sequencing analyses of all carbapenem-resistant (CR) Klebsiella pneumoniae (CRKpn) isolates collected during the study period. RESULTS: Compared with pre-pandemic, AU (DDD/1000 patient-days) significantly increased after the pandemic onset, from 78.1 to 142.5 (P < .001), 50.9 to 110.1 (P < .001), and 4.1 to 13.3 (P < .001) for broad-spectrum ß-lactams, carbapenems, and colistin, respectively. The frequency of CP-CRE increased from 12.8% pre-COVID-19 to 51.9% after pandemic onset (P < .001). The most frequent CRE species in both periods was CRKpn (79.5% and 76.5%, respectively). The expansion of CP-CRE harboring blaNDM was particularly noticeable, increasing from 40% (n = 4/10) before to 73.6% (n = 39/53) after pandemic onset (P < .001). Our phylogenomic analyses revealed the emergence of two distinct genomic lineages of CP-CRKpn: ST45, harboring blaNDM, and ST1161, which carried blaKPC. CONCLUSIONS: AU and the frequency of CP-CRE increased after COVID-19 onset. The increase in CP-CRKpn was driven by the emergence of novel genomic lineages. Our observations highlight the need to strengthen infection prevention and control and antimicrobial stewardship efforts.

The impact of inpatient bloodstream infections caused by antibiotic-resistant bacteria in low- and middle-income countries: A systematic review and meta-analysis.

BACKGROUND: Bloodstream infections (BSIs) produced by antibiotic-resistant bacteria (ARB) cause a substantial disease burden worldwide. However, most estimates come from high-income settings and thus are not globally representative. This study quantifies the excess mortality, length of hospital stay (LOS), intensive care unit (ICU) admission, and economic costs associated with ARB BSIs, compared to antibiotic-sensitive bacteria (ASB), among adult inpatients in low- and middle-income countries (LMICs). METHODS AND FINDINGS: We conducted a systematic review by searching 4 medical databases (PubMed, SCIELO, Scopus, and WHO's Global Index Medicus; initial search n = 13,012 from their inception to August 1, 2022). We only included quantitative studies. Our final sample consisted of n = 109 articles, excluding studies from high-income countries, without our outcomes of interest, or without a clear source of bloodstream infection. Crude mortality, ICU admission, and LOS were meta-analysed using the inverse variance heterogeneity model for the general and subgroup analyses including bacterial Gram type, family, and resistance type. For economic costs, direct medical costs per bed-day were sourced from WHO-CHOICE. Mortality costs were estimated based on productivity loss from years of potential life lost due to premature mortality. All costs were in 2020 USD. We assessed studies' quality and risk of publication bias using the MASTER framework. Multivariable meta-regressions were employed for the mortality and ICU admission outcomes only. Most included studies showed a significant increase in crude mortality (odds ratio (OR) 1.58, 95% CI [1.35 to 1.80], p < 0.001), total LOS (standardised mean difference "SMD" 0.49, 95% CI [0.20 to 0.78], p < 0.001), and ICU admission (OR 1.96, 95% CI [1.56 to 2.47], p < 0.001) for ARB versus ASB BSIs. Studies analysing Enterobacteriaceae, Acinetobacter baumanii, and Staphylococcus aureus in upper-middle-income countries from the African and Western Pacific regions showed the highest excess mortality, LOS, and ICU admission for ARB versus ASB BSIs per patient. Multivariable meta-regressions indicated that patients with resistant Acinetobacter baumanii BSIs had higher mortality odds when comparing ARB versus ASB BSI patients (OR 1.67, 95% CI [1.18 to 2.36], p 0.004). Excess direct medical costs were estimated at $12,442 (95% CI [$6,693 to $18,191]) for ARB versus ASB BSI per patient, with an average cost of $41,103 (95% CI [$30,931 to $51,274]) due to premature mortality. Limitations included the poor quality of some of the reviewed studies regarding the high risk of selective sampling or failure to adequately account for relevant confounders. CONCLUSIONS: We provide an overview of the impact ARB BSIs in limited resource settings derived from the existing literature. Drug resistance was associated with a substantial disease and economic burden in LMICs. Although, our results show wide heterogeneity between WHO regions, income groups, and pathogen-drug combinations. Overall, there is a paucity of BSI data from LMICs, which hinders implementation of country-specific policies and tracking of health progress.

ß-Lactam-Resistant Streptococcus pneumoniae Dynamics Following Treatment: A Dose-Response Meta-analysis.

BACKGROUND: Patient exposure to antibiotics promotes the emergence of drug-resistant pathogens. The aim of this study was to identify whether the temporal dynamics of resistance emergence at the individual-patient level were predictable for specific pathogen-drug classes. METHODS: Following a systematic review, a novel robust error meta-regression method for dose-response meta-analysis was used to estimate the odds ratio (OR) for carrying resistant bacteria during and following treatment compared to baseline. Probability density functions fitted to the resulting dose-response curves were then used to optimize the period during and/or after treatment when resistant pathogens were most likely to be identified. RESULTS: Studies of Streptococcus pneumoniae treatment with ß-lactam antibiotics demonstrated a peak in resistance prevalence among patients 4 days after completing treatment with a 3.32-fold increase in odds (95% confidence interval [CI], 1.71-6.46). Resistance waned more gradually than it emerged, returning to preexposure levels 1 month after treatment (OR, 0.98 [95% CI, .55-1.75]). Patient isolation during the peak dose-response period would be expected to reduce the risk that a transmitted pathogen is resistant equivalently to a 50% longer isolation window timed from the first day of treatment. CONCLUSIONS: Predictable temporal dynamics of resistance levels have implications both for surveillance and control.

The gap in life expectancy and lifespan inequality between Iran and neighbour countries: the contributions of avoidable causes of death.

BACKGROUND: Healthcare system and intersectoral public health policies play a crucial role in improving population health and reducing health inequalities. This study aimed to quantify their impact, operationalized as avoidable deaths, on the gap in life expectancy (LE) and lifespan inequality (LI) between Iran and three neighbour countries viz., Turkey, Qatar, and Kuwait in 2015-2016. METHODS: Annual data on population and causes of deaths by age and sex for Iran and three neighbour countries were obtained from the World Health Organization mortality database for the period 2015-2016. A recently developed list by the OECD/Eurostat was used to identify avoidable causes of death (with an upper age limit of 75). The cross-country gaps in LE and LI (measured by standard deviation) were decomposed by age and cause of death using a continuous-change model. RESULTS: Iranian males and females had the second lowest and lowest LE, respectively, compared with their counterparts in the neighbour countries. On the other hand, the highest LIs in both sexes (by 2.3 to 4.5 years in males and 1.1 to 3.3 years in females) were observed in Iran. Avoidable causes contributed substantially to the LE and LI gap in both sexes with injuries and maternal/infant mortality represented the greatest contributions to the disadvantages in Iranian males and females, respectively. CONCLUSIONS: Higher mortality rates in young Iranians led to a double burden of inequality -shorter LE and greater uncertainty at timing of death. Strengthening intersectoral public health policies and healthcare quality targeted at averting premature deaths, especially from injuries among younger people, can mitigate this double burden.

The contributions of public health policies and healthcare quality to gender gap and country differences in life expectancy in the UK.

BACKGROUND: In many high-income countries, life expectancy (LE) has increased, with women outliving men. This gender gap in LE (GGLE) has been explained with biological factors, healthy behaviours, health status, and sociodemographic characteristics, but little attention has been paid to the role of public health policies that include/affect these factors. This study aimed to assess the contributions of avoidable causes of death, as a measure of public health policies and healthcare quality impacts, to the GGLE and its temporal changes in the UK. We also estimated the contributions of avoidable causes of death into the gap in LE between countries in the UK. METHODS: We obtained annual data on underlying causes of death by age and sex from the World Health Organization mortality database for the periods 2001-2003 and 2014-2016. We calculated LE at birth using abridged life tables. We applied Arriaga's decomposition method to compute the age- and cause-specific contributions into the GGLE in each period and its changes between two periods as well as the cross-country gap in LE in the 2014-2016 period. RESULTS: Avoidable causes had greater contributions than non-avoidable causes to the GGLE in both periods (62% in 2001-2003 and 54% in 2014-2016) in the UK. Among avoidable causes, ischaemic heart disease (IHD) followed by injuries had the greatest contributions to the GGLE in both periods. On average, the GGLE across the UK narrowed by about 1.0 year between 2001-2003 and 2014-2016 and three avoidable causes of IHD, lung cancer, and injuries accounted for about 0.8 years of this reduction. England & Wales had the greatest LE for both sexes in 2014-2016. Among avoidable causes, injuries in men and lung cancer in women had the largest contributions to the LE advantage in England & Wales compared to Northern Ireland, while drug-related deaths compared to Scotland in both sexes. CONCLUSION: With avoidable causes, particularly preventable deaths, substantially contributing to the gender and cross-country gaps in LE, our results suggest the need for behavioural changes by implementing targeted public health programmes, particularly targeting younger men from Scotland and Northern Ireland.

[Impact of COVID-19 pandemic on the mental health of healthcare workers]. / El impacto de la pandemia de COVID-19 en la salud mental de los trabajadores de la salud en Chile: datos iniciales de The Health Care Workers Study.

BACKGROUND: Healthcare workers' mental health was affected by SARS-CoV-2 pandemic. AIM: To evaluate healthcare workers' mental health and its associated factors during the pandemic in Chile. MATERIAL AND METHODS: An online self-reported questionnaire was designed including the Goldberg Health Questionnaire, the Patient Health Questionnaire, (PHQ-9), and the Columbia-Suicide Severity Rating Scale among other questions. It was sent to 28,038 healthcare workers. RESULTS: The questionnaire was answered by 1,934 participants, with a median age of 38 years (74% women). Seventy five percent were professionals, and 48% worked at a hospital. Fifty nine percent of respondents had a risk of having a mental health disorder, and 73% had depressive symptoms. Significant associations were found with sex, workplace, and some of the relevant experiences during the pandemic. Fifty one percent reported the need for mental health support, and 38% of them received it. CONCLUSIONS: There is a high percentage of health workers with symptoms of psychological distress, depression, and suicidal ideas. The gender approach is essential to understand the important differences found. Many health workers who required mental health care did not seek or received it.

Socioeconomic factors associated with antimicrobial resistance of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli in Chilean hospitals (2008-2017).

OBJECTIVE: To identify socioeconomic factors associated with antimicrobial resistance of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli in Chilean hospitals (2008-2017). METHODS: We reviewed the scientific literature on socioeconomic factors associated with the emergence and dissemination of antimicrobial resistance. Using multivariate regression, we tested findings from the literature drawing from a longitudinal dataset on antimicrobial resistance from 41 major private and public hospitals and a nationally representative household survey in Chile (2008-2017). We estimated resistance rates for three priority antibiotic-bacterium pairs, as defined by the Organisation for Economic Co-operation and Development; i.e., imipenem and meropenem resistant P. aeruginosa, cloxacillin resistant S. aureus, and cefotaxime and ciprofloxacin resistant E. coli. RESULTS: Evidence from the literature review suggests poverty and material deprivation are important risk factors for the emergence and transmission of antimicrobial resistance. Most studies found that worse socioeconomic indicators were associated with higher rates of antimicrobial resistance. Our analysis showed an overall antimicrobial resistance rate of 32.5%, with the highest rates for S. aureus (40.6%) and the lowest for E. coli (25.7%). We found a small but consistent negative association between socioeconomic factors (income, education, and occupation) and overall antimicrobial resistance in univariate (p < 0.01) and multivariate analyses (p < 0.01), driven by resistant P. aeruginosa and S. aureus. CONCLUSION: Socioeconomic factors beyond health care and hospital settings may affect the emergence and dissemination of antimicrobial resistance. Preventing and controlling antimicrobial resistance requires efforts above and beyond reducing antibiotic consumption.

Causes of death among international travellers in Peru, 2017 to 2021.

BACKGROUND: The wellbeing and safety of international tourists is a paramount concern for governments and stakeholders. Mortality among travellers and the causes of death serve as a significant metric of destination safety. We describe the epidemiology and causes of death among international travellers in Peru. METHODS: Data retrieved from the Peruvian government's deaths certificates registry included all non-residents who died between January 2017 and December 2021. We analysed the national incidence and causes of death among international travellers in Peru. Causes of death were classified into non-communicable diseases (NCD), communicable diseases and injuries. We classified fatalities according to the existence of preventive measures that could be provided during the travel medicine consultation to decrease the risk. RESULTS: We obtained records from 1514 deaths among international travellers (973 males, 64%). The incidence increased from 0.2 deaths per 10 000 travellers in 2017 to 9.9 in 2021. NCDs were the most common causes of death (n = 560, 37%), followed by communicable diseases (n = 487, 32%), and injuries (n = 321, 21%). Causes of death were unknown in 9.7% of the records. The leading causes of death in these categories were cancer, cardiovascular disease, COVID-19 and trauma. We found similar sex distribution of NCDs in travellers aged >50 years and higher rates of communicable diseases among males across all ages. Injury-associated deaths were significantly higher among males aged 18-29 years (P < 0.001) compared with other sex-age groups. We estimated that for 57.7% of deaths risk could have been decreased through pre-travel advice. CONCLUSION: Rates of deaths among travellers to Peru increased over time. Most deaths were due to NCDs, followed by communicable diseases and injuries. Pre-travel medical optimization and effective advice focused on age-sex and destination specific risks could reduce risk among travellers. Increased awareness among travel medicine practitioners and improvement of emergency medical response systems in Peru could decrease mortality.

Access to general health care among people with disabilities in Latin America and the Caribbean: a systematic review of quantitative research.

In Latin America and the Caribbean (LAC), there are 85 million people with disabilities (PwD). They often experience barriers accessing healthcare and die, on average, 10-20 years earlier than those without disabilities. This study aimed to systematically review the quantitative literature on access to general healthcare among PwD, compared to those without disabilities, in LAC. A systematic review and narrative synthesis was conducted. We searched in EMBASE, MEDLINE, LILACS, MedCarib, PsycINFO, SciELO, CINAHL, and Web of Science. Eligible articles were peer-reviewed, published between January 2000 and April 2023, and compared healthcare access (utilization, coverage, quality, affordability) between PwD and without disabilities in LAC. The search retrieved 16,538 records and 30 studies were included, most of which had a medium or high risk of bias (n = 23; 76%). Overall, the studies indicated that PwD use healthcare services more than those without disabilities. Some evidence indicated that women with disabilities were less likely to have received cancer screening. Limited evidence showed that health services affordability and quality were lower among PwD. In LAC, PwD appear to experience health inequities, although large gaps exist in the current evidence. Harmonization of disability and health access data collection is urgently needed to address this issue.

Opportunities and challenges in antimicrobial resistance policy including animal production systems and humans across stakeholders in Argentina: a context and qualitative analysis.

INTRODUCTION: Gaps in antimicrobial resistance (AMR) surveillance and control, including implementation of national action plans (NAPs), are evident internationally. Countries' capacity to translate political commitment into action is crucial to cope with AMR at the human-animal-environment interface. METHODS: We employed a two-stage process to understand opportunities and challenges related to AMR surveillance and control at the human-animal interface in Argentina. First, we compiled the central AMR policies locally and mapped vital stakeholders around the NAP and the national commission against bacterial resistance. Second, we conducted qualitative interviews using a semistructured questionnaire covering stakeholders' understanding and progress towards AMR and NAP. We employed a mixed deductive-inductive approach and used the constant comparative analysis method. We created categories and themes to cluster subthemes and determined crucial relationships among thematic groups. RESULTS: Crucial AMR policy developments have been made since 1969, including gradually banning colistin in food-producing animals. In 2023, a new government decree prioritised AMR following the 2015 NAP launch. Our qualitative analyses identified seven major themes for tackling AMR: (I) Cultural factors and sociopolitical country context hampering AMR progress, (II) Fragmented governance, (III) Antibiotic access and use, (IV) AMR knowledge and awareness throughout stakeholders, (V) AMR surveillance, (VI) NAP efforts and (VII) External drivers. We identified a fragmented structure of the food production chain, poor cross-coordination between stakeholders, limited surveillance and regulation among food-producing animals and geographical disparities over access, diagnosis and treatment. The country is moving to integrate animal and food production into its surveillance system, with most hospitals experienced in monitoring AMR through antimicrobial stewardship programmes. CONCLUSION: AMR accountability should involve underpinning collaboration at different NAP implementation levels and providing adequate resources to safeguard long-term sustainability. Incorporating a multisectoral context-specific approach relying on different One Health domains is crucial to strengthening local AMR surveillance.

Extended-Spectrum ß-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae: Risk Factors and Economic Burden Among Patients with Bloodstream Infections.

Introduction: Although Extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK) significantly contribute to bloodstream infections, their economic repercussions remain largely unquantified. Data Source and Methods: We performed a retrospective analysis of inpatients diagnosed with Escherichia coli or Klebsiella pneumoniae bacteremia in a tertiary hospital from January 2020 to December 2022 in Guangzhou, China. We employed the chi-square test to examine ESBL risk factors and utilized propensity score matching (PSM) to negate baseline confounding factors, assessing economic burden through disability-adjusted life years (DALYs), hospital costs and productivity losses. We employed mediation analysis to eliminate confounding factors and better identify ESBL sources of burden related. Results: We found 166 ESBL-EC/KP BSI patients (52.2% of the total examined 318 patients). Post-PSM analysis revealed that ESBL-producing EC/KP will reduce the effectiveness of empirical medication by 19.8%, extend the total length of hospitalization by an average of 3 days, and increase the patient's financial burden by US$2047. No significant disparity was found in overall mortality and mean DALYs between the groups. Mediation analysis showed that the link between ESBL and hospital costs is predominantly, if not entirely, influenced by the appropriateness of empirical antibiotic treatment and length of hospital stay. Conclusion: Patients with BSI due to ESBL-producing ESBL-EK incur higher costs compared to those with non-ESBL-EK BSI. This cost disparity is rooted in varying rates of effective empirical antimicrobial therapy and differences in hospital stay durations. A nuanced approach, incorporating a thorough understanding of regional epidemiological trends and judicious antibiotic use, is crucial for mitigating the financial impact on patients.

Costs-effectiveness and cost components of pharmaceutical and non-pharmaceutical interventions affecting antibiotic resistance outcomes in hospital patients: a systematic literature review.

INTRODUCTION: Limited information on costs and the cost-effectiveness of hospital interventions to reduce antibiotic resistance (ABR) hinder efficient resource allocation. METHODS: We conducted a systematic literature review for studies evaluating the costs and cost-effectiveness of pharmaceutical and non-pharmaceutical interventions aimed at reducing, monitoring and controlling ABR in patients. Articles published until 12 December 2023 were explored using EconLit, EMBASE and PubMed. We focused on critical or high-priority bacteria, as defined by the WHO, and intervention costs and incremental cost-effectiveness ratio (ICER). Following Preferred Reporting Items for Systematic review and Meta-Analysis guidelines, we extracted unit costs, ICERs and essential study information including country, intervention, bacteria-drug combination, discount rates, type of model and outcomes. Costs were reported in 2022 US dollars ($), adopting the healthcare system perspective. Country willingness-to-pay (WTP) thresholds from Woods et al 2016 guided cost-effectiveness assessments. We assessed the studies reporting checklist using Drummond's method. RESULTS: Among 20 958 articles, 59 (32 pharmaceutical and 27 non-pharmaceutical interventions) met the inclusion criteria. Non-pharmaceutical interventions, such as hygiene measures, had unit costs as low as $1 per patient, contrasting with generally higher pharmaceutical intervention costs. Several studies found that linezolid-based treatments for methicillin-resistant Staphylococcus aureus were cost-effective compared with vancomycin (ICER up to $21 488 per treatment success, all 16 studies' ICERs

Fatal journeys: causes of death in international travellers in South America.

BACKGROUND: Understanding mortality among travellers is essential for mitigating risks and enhancing travel safety. However, limited evidence exists on severe illnesses and injuries leading to death among travellers, particularly in low- and middle-income countries and remote regions. METHODS: We conducted a retrospective census study using country-level observational data from death certificates of travellers of seven South American countries (Argentina, Brazil, Chile, Colombia, Ecuador, Peru, and Uruguay) from 2017 to 2021. Causes of death were evaluated using ICD-10 codes, categorised into non-communicable diseases (NCDs), communicable diseases, and injuries. We quantified causes of death by demographic characteristics (e.g. age, sex), and geographical variables. Chi-square tests were used to assess differences between categories. We calculated crude mortality rates and incidence rate ratios (IRRs) per country's subregions. RESULTS: A total of 17 245 deaths were reported. NCDs (55%) were the most common cause of death, followed by communicable diseases (23.4%) and injuries (18.1%). NCD-associated deaths increased after age 55 years and were highest among ≥85 years. Communicable diseases were more common at younger age (<20 years). Injury-associated deaths were more common in men (79.9%) and 25-29-year-olds (17.1%). Most deaths (68.2%) could have been avoided by prevention or treatment. Mortality risk was higher among travellers in bordering regions between countries. In Roraima [Brazil] and Norte de Santander [Colombia], locations bordering Venezuela, the death incidence rate ratio was 863 and 60, respectively. These countries' reference mortality rates in those regions were much lower. More than 80% of the deaths in these border regions of Brazil and Colombia involved Venezuelan citizens. Conclusion: The study identified risk factors and high-risk locations for deaths among travellers in seven countries of South America. Our findings underscore the need for specific health interventions tailored to traveller demographics and destination to optimise prevention of avoidable deaths in South America.

A country-wide health policy in Chile for deaf adults using cochlear implants: Analysis of health determinants and social impacts.

BACKGROUND: Post-lingual deafness represents a critical challenge for adults' well-being with substantial public health burdens. One treatment of choice has been cochlear implants (CI) for people with severe to profound hearing loss (HL). Since 2018, Chile has implemented a high-cost policy to cover CI treatment, the "Ley Ricarte Soto" (LRS) health policy. However, wide variability exists in the use of this device. To date, no related study has been published on policy evaluation in Chile or other Latin American countries. OBJECTIVES: This study aimed to evaluate the impact of the LRS policy on the treatment success and labour market inclusion among deaf or hard of hearing (DHH) adults using CI. We examined and characterised outcomes based on self-reports about treatment success and occupation status between 2018 and 2020. DESIGN: We performed a prospective study using hospital clinical records and an online questionnaire with 76 DHH adults aged >15 who had received CIs since the introduction of the LRS policy in 2018. Using univariate and multivariate regression models, we investigated the relationship between demographic, audiological, and social determinants of health and outcomes, including treatment success for social inclusion (International Outcome inventory for Hearing Aids and CIs assessment: IOI-HA) and occupation status for labour market inclusion. RESULTS: Our study showed elevated levels of treatment success in most of the seven sub-scores of the IOI-HA assessment. Similarly, around 70% of participants maintained or improved their occupations after receiving their CI. We found a significant positive association between treatment success and market inclusion. Participants diagnosed at younger ages had better results than older participants in both outcomes. Regarding social determinants of health, findings suggested participants with high social health insurance and a shorter commute time to the clinic had better results in treatment success. For labour market inclusion, participants with high education levels and better pre- CI occupation had better post-CI occupation status. CONCLUSIONS: In evaluating the LRS policy for providing CIs for DHH adults in Chile, we found positive effects relating to treatment success and occupation status. Our study supports the importance of age at diagnosis and social determinants of health, which should be assessed by integrating public services and bringing them geographically closer to each beneficiary. Although evidence-based guidelines for candidate selection given by the LRS policy might contribute to good results, these guidelines could limit the policy access to people who do not meet the requirements of the guidelines due to social inequalities.

What and how can we learn from complex global problems for antimicrobial resistance policy? A comparative study combining historical and foresight approaches.

OBJECTIVES: To (i) develop a methodology for using historical and comparative perspectives to inform policy and (ii) provide evidence for antimicrobial-resistance (AMR) policymaking by drawing on lessons from climate change and tobacco control. METHODS: Using a qualitative design, we systematically examined two other complex, large-scale policy issues-climate change and tobacco control-to identify what relevance to AMR can be learned from how these issues have evolved over time. During 2018-2020, we employed a five-stage approach to conducting an exploratory study involving a review of secondary historical analysis, identification of drivers of change, prioritisation of the identified drivers, scenario generation and elicitation of possible policy responses. We sought to disrupt more 'traditional' policy and research spaces to create an alternative where, stimulated by historical analysis, academics (including historians) and policymakers could come together to challenge norms and practices and think creatively about AMR policy design. RESULTS: An iterative process of analysis and engagement resulted in lessons for AMR policy concerning persistent evidence gaps and uncertainty, the need for cross-sector involvement and a collective effort through global governance, the demand for new interventions through more investment in research and innovation, and recognising the dynamic relationship between social change and policy to change people's attitudes and behaviours are crucial towards tackling AMR. CONCLUSION: We draw on new methodological lessons around the pragmatism of future- and policy-oriented approaches incorporating robust historical and comparative analysis. The study demonstrates proof of concept and offers a reproducible method to advance further methodology, including transferrable policies that could tackle health problems, such as AMR.

Global antimicrobial-resistance drivers: an ecological country-level study at the human-animal interface.

BACKGROUND: Antimicrobial resistance (AMR) is a pressing, holistic, and multisectoral challenge facing contemporary global health. In this study we assessed the associations between socioeconomic, anthropogenic, and environmental indicators and country-level rates of AMR in humans and food-producing animals. METHODS: In this modelling study, we obtained data on Carbapenem-resistant Acinetobacter baumanii and Pseudomonas aeruginosa, third generation cephalosporins-resistant Escherichia coli and Klebsiella pneumoniae, oxacillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium AMR in humans and food-producing animals from publicly available sources, including WHO, World Bank, and Center for Disease Dynamics Economics and Policy. AMR in food-producing animals presented a combined prevalence of AMR exposure in cattle, pigs, and chickens. We used multivariable ß regression models to determine the adjusted association between human and food-producing animal AMR rates and an array of ecological country-level indicators. Human AMR rates were classified according to the WHO priority pathogens list and antibiotic-bacterium pairs. FINDINGS: Significant associations were identified between animal antimicrobial consumption and AMR in food-producing animals (OR 1·05 [95% CI 1·01-1·10]; p=0·013), and between human antimicrobial consumption and AMR specifically in WHO critical priority (1·06 [1·00-1·12]; p=0·035) and high priority (1·22 [1·09-1·37]; p<0·0001) pathogens. Bidirectional associations were also found: animal antibiotic consumption was positively linked with resistance in critical priority human pathogens (1·07 [1·01-1·13]; p=0·020) and human antibiotic consumption was positively linked with animal AMR (1·05 [1·01-1·09]; p=0·010). Carbapenem-resistant Acinetobacter baumanii, third generation cephalosporins-resistant Escherichia coli, and oxacillin-resistant Staphylococcus aureus all had significant associations with animal antibiotic consumption. Analyses also suggested significant roles of socioeconomics, including governance on AMR rates in humans and animals. INTERPRETATION: Reduced rates of antibiotic consumption alone will not be sufficient to combat the rising worldwide prevalence of AMR. Control methods should focus on poverty reduction and aim to prevent AMR transmission across different One Health domains while accounting for domain-specific risk factors. The levelling up of livestock surveillance systems to better match those reporting on human AMR, and, strengthening all surveillance efforts, particularly in low-income and middle-income countries, are pressing priorities. FUNDING: None.

Trends and socioeconomic, demographic, and environmental factors associated with antimicrobial resistance: a longitudinal analysis in 39 hospitals in Chile 2008-2017.

Background: Antimicrobial resistance (AMR) is among the most critical global health threats of the 21st century. AMR is primarily driven by the use and misuse of antibiotics but can be affected by socioeconomic and environmental factors. Reliable and comparable estimates of AMR over time are essential to making public health decisions, defining research priorities, and evaluating interventions. However, estimates for developing regions are scant. We describe the evolution of AMR for critical priority antibiotic-bacterium pairs in Chile and examine their association with hospital and community-level characteristics using multivariate rate-adjusted regressions. Methods: Drawing on multiple data sources, we assembled a longitudinal national dataset to analyse AMR levels for critical priority antibiotic-bacterium combinations in 39 private and public hospitals (2008-2017) throughout the country and characterize the population at the municipality level. We first described trends of AMR in Chile. Second, we used multivariate regressions to examine the association of AMR with hospital characteristics and community-level socioeconomic, demographic, and environmental factors. Last, we estimated the expected distribution of AMR by region in Chile. Findings: Our results show that AMR for priority antibiotic-bacterium pairs steadily increased between 2008 and 2017 in Chile, driven primarily by Klebsiella pneumoniae resistant to third-generation cephalosporins and carbapenems, and vancomycin-resistant Enterococcus faecium. Higher hospital complexity, a proxy for antibiotic use, and poorer local community infrastructure were significantly associated with greater AMR. Interpretation: Consistent with research in other countries in the region, our results show a worrisome increase in clinically relevant AMR in Chile and suggest that hospital complexity and living conditions in the community may affect the emergence and spread of AMR. Our results highlight the importance of understanding AMR in hospitals and their interaction with the community and the environment to curtail this ongoing public health crisis. Funding: This research was supported by the Agencia Nacional de Investigación y Desarrollo (ANID), Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT, The Canadian Institute for Advanced Research (CIFAR), and Centro UC de Políticas Públicas, Pontificia Universidad Católica de Chile.

Economic evaluation of novel Mycobacterium tuberculosis specific antigen-based skin tests for detection of TB infection: A modelling study.

Evidence on the economic impact of novel skin tests for tuberculosis infection (TBST) is scarce and limited by study quality. We used estimates on the cost-effectiveness of the use of TBST compared to current tuberculosis infection (TBI) tests to assess whether TBST are affordable and feasible to implement under different country contexts. A Markov model parametrised to Brazil, South Africa and the UK was developed to compare the cost-effectiveness of three TBI testing strategies: (1) Diaskintest (DST), (2) TST test, and (3) IGRA QFT test. Univariate and probabilistic sensitivity analyses over unit costs and main parameters were performed. Our modelling results show that Diaskintest saves $5.60 and gains 0.024 QALYs per patient and $8.40, and 0.01 QALYs per patient in Brazil, compared to TST and IGRA respectively. In South Africa, Diaskintest is also cost-saving at $4.39, with 0.015 QALYs per patient gained, compared to TST, and $64.41, and 0.007 QALYs per patient, compared to IGRA. In the UK, Diaskintest saves $73.33, and gaines 0.0351 QALYs per patient, compared to TST. However, Diaskintest, compared to IGRA, showed an incremental cost of $521.45 (95% CI (500.94-545.07)) per QALY, below the willingness-to-pay threshold of $20.223 per QALY. Diaskintest potentially saves costs and results in greater health gains than the TST and IGRA tests in Brazil and South Africa. In the UK Diaskintest would gain health but also be more costly. Our results have potential external validity because TBST remained cost-effective despite extensive sensitivity analyses.

A decision support tool for risk-benefit analysis of Japanese encephalitis vaccine in travellers.

BACKGROUND: During pre-travel consultations, clinicians and travellers face the challenge of weighing the risks verus benefits of Japanese encephalitis (JE) vaccination due to the high cost of the vaccine, low incidence in travellers (~1 in 1 million), but potentially severe consequences (~30% case-fatality rate). Personalised JE risk assessment based on the travellers' demographics and travel itinerary is challenging using standard risk matrices. We developed an interactive digital tool to estimate risks of JE infection and severe health outcomes under different scenarios to facilitate shared decision-making between clinicians and travellers. METHODS: A Bayesian network (conditional probability) model risk-benefit analysis of JE vaccine in travellers was developed. The model considers travellers' characteristics (age, sex, co-morbidities), itinerary (destination, departure date, duration, setting of planned activities) and vaccination status to estimate the risks of JE infection, the development of symptomatic disease (meningitis, encephalitis), clinical outcomes (hospital admission, chronic neurological complications, death) and adverse events following immunization. RESULTS: In low-risk travellers (e.g. to urban areas for <1 month), the risk of developing JE and dying is low (<1 per million) irrespective of the destination; thus, the potential impact of JE vaccination in reducing the risk of clinical outcomes is limited. In high-risk travellers (e.g. to rural areas in high JE incidence destinations for >2 months), the risk of developing symptomatic disease and mortality is estimated at 9.5 and 1.4 per million, respectively. JE vaccination in this group would significantly reduce the risk of symptomatic disease and mortality (by ~80%) to 1.9 and 0.3 per million, respectively. CONCLUSION: The JE tool may assist decision-making by travellers and clinicians and could increase JE vaccine uptake. The tool will be updated as additional evidence becomes available. Future work needs to evaluate the usability of the tool. The interactive, scenario-based, personalised JE vaccine risk-benefit tool is freely available on www.VaxiCal.com.

Global Pain and Aging: A Cross-Sectional Study on Age Differences in the Intensity of Chronic Pain Among Middle-Aged and Older Adults in 20 Countries.

OBJECTIVES: This study aims to examine age differences in the intensity of chronic pain among middle-aged and older adults, where intensity is measured on a scale differentiating between chronic pain that is often troubling and likely requires intervention versus more endurable sensations. We aim to explore whether individual health and national gross domestic product (GDP) explain these differences as well. METHODS: Cross-nationally harmonized data from 20 countries on self-reported intensity of chronic pain (0 = no, 1 = mild, 2 = moderate, 3 = severe) in 104,826 individuals aged 50+ observed in 2012-2013. Two-level hierarchical ordinal linear models with individuals nested within countries were used to isolate estimations from heterogeneity explained by methodological differences across single-country studies. RESULTS: Overall, mean participant age was 66.9 (SD = 9.9), 56.1% were women, and 41.9% of respondents reported any chronic pain. Chronic pain intensity rose sharply with age in some countries (e.g., Korea and Slovenia), but this association waned or reversed in other countries (e.g., the United States and Denmark). Cross-country variation and age differences in chronic pain were partly explained (85.5% and 35.8%, respectively) by individual-level health (especially arthritis), country-level wealth (as indicated by GDP per capita), and demographics. DISCUSSION: Chronic pain intensity is not an inevitable consequence of chronological age, but the consequence of potential selection effects and lower activity levels combined with individual-level health and country-level wealth. Our findings suggest further investigation of health conditions and country affluence settings as potential targets of medical and policy interventions aiming to prevent, reduce, or manage chronic pain among older patients and aging populations.