Sub-inhibitory antibiotic treatment selects for enhanced metabolic efficiency.

Bacterial growth and metabolic rates are often closely related. However, under antibiotic selection, a paradox in this relationship arises: antibiotic efficacy decreases when bacteria are metabolically dormant, yet antibiotics select for resistant cells that grow fastest during treatment. That is, antibiotic selection counterintuitively favors bacteria with fast growth but slow metabolism. Despite this apparent contradiction, antibiotic resistant cells have historically been characterized primarily in the context of growth, whereas the extent of analogous changes in metabolism is comparatively unknown. Here, we observed that previously evolved antibiotic-resistant strains exhibited a unique relationship between growth and metabolism whereby nutrient utilization became more efficient, regardless of the growth rate. To better understand this unexpected phenomenon, we used a simplified model to simulate bacterial populations adapting to sub-inhibitory antibiotic selection through successive bottlenecking events. Simulations predicted that sub-inhibitory bactericidal antibiotic concentrations could select for enhanced metabolic efficiency, defined based on nutrient utilization: drug-adapted cells are able to achieve the same biomass while utilizing less substrate, even in the absence of treatment. Moreover, simulations predicted that restoring metabolic efficiency would re-sensitize resistant bacteria exhibiting metabolic-dependent resistance; we confirmed this result using adaptive laboratory evolutions of Escherichia coli under carbenicillin treatment. Overall, these results indicate that metabolic efficiency is under direct selective pressure during antibiotic treatment and that differences in evolutionary context may determine both the efficacy of different antibiotics and corresponding re-sensitization approaches.IMPORTANCEThe sustained emergence of antibiotic-resistant pathogens combined with the stalled drug discovery pipelines highlights the critical need to better understand the underlying evolution mechanisms of antibiotic resistance. To this end, bacterial growth and metabolic rates are often closely related, and resistant cells have historically been characterized exclusively in the context of growth. However, under antibiotic selection, antibiotics counterintuitively favor cells with fast growth, and slow metabolism. Through an integrated approach of mathematical modeling and experiments, this study thereby addresses the significant knowledge gap of whether antibiotic selection drives changes in metabolism that complement, and/or act independently, of antibiotic resistance phenotypes.

The economics of healthcare access: a scoping review on the economic impact of healthcare access for vulnerable urban populations in low- and middle-income countries.

BACKGROUND: The growing urban population imposes additional challenges for health systems in low- and middle-income countries (LMICs). We explored the economic burden and inequities in healthcare utilisation across slum, non-slum and levels of wealth among urban residents in LMICs. METHODS: This scoping review presents a narrative synthesis and descriptive analysis of studies conducted in urban areas of LMICs. We categorised studies as conducted only in slums, city-wide studies with measures of wealth and conducted in both slums and non-slums settlements. We estimated the mean costs of accessing healthcare, the incidence of catastrophic health expenditures (CHE) and the progressiveness and equity of health expenditures. The definitions of slums used in the studies were mapped against the 2018 UN-Habitat definition. We developed an evidence map to identify research gaps on the economics of healthcare access in LMICs. RESULTS: We identified 64 studies for inclusion, the majority of which were from South-East Asia (59%) and classified as city-wide (58%). We found severe economic burden across health conditions, wealth quintiles and study types. Compared with city-wide studies, slum studies reported higher direct costs of accessing health care for acute conditions and lower costs for chronic and unspecified health conditions. Healthcare expenditures for chronic conditions were highest amongst the richest wealth quintiles for slum studies and more equally distributed across all wealth quintiles for city-wide studies. The incidence of CHE was similar across all wealth quintiles in slum studies and concentrated among the poorest residents in city-wide studies. None of the definitions of slums used covered all characteristics proposed by UN-Habitat. The evidence map showed that city-wide studies, studies conducted in India and studies on unspecified health conditions dominated the current evidence on the economics of healthcare access. Most of the evidence was classified as poor quality. CONCLUSIONS: Our findings indicated that city-wide and slums residents have different expenditure patterns when accessing healthcare. Financial protection schemes must consider the complexity of healthcare provision in the urban context. Further research is needed to understand the causes of inequities in healthcare expenditure in rapidly expanding and evolving cities in LMICs.

Effects of social determinants on children's health in informal settlements in Bangladesh and Kenya through an intersectionality lens: a study protocol.

INTRODUCTION: Several studies have shown that residents of urban informal settlements/slums are usually excluded and marginalised from formal social systems and structures of power leading to disproportionally worse health outcomes compared to other urban dwellers. To promote health equity for slum dwellers, requires an understanding of how their lived realities shape inequities especially for young children 0-4 years old (ie, under-fives) who tend to have a higher mortality compared with non-slum children. In these proposed studies, we aim to examine how key Social Determinants of Health (SDoH) factors at child and household levels combine to affect under-five health conditions, who live in slums in Bangladesh and Kenya through an intersectionality lens. METHODS AND ANALYSIS: The protocol describes how we will analyse data from the Nairobi Cross-sectional Slum Survey (NCSS 2012) for Kenya and the Urban Health Survey (UHS 2013) for Bangladesh to explore how SDoH influence under-five health outcomes in slums within an intersectionality framework. The NCSS 2012 and UHS 2013 samples will consist of 2199 and 3173 under-fives, respectively. We will apply Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy approach. Some of SDoH characteristics to be considered will include those of children, head of household, mothers and social structure characteristics of household. The primary outcomes will be whether a child had diarrhoea, cough, fever and acute respiratory infection (ARI) 2 weeks preceding surveys. ETHICS AND DISSEMINATION: The results will be disseminated in international peer-reviewed journals and presented in events organised by the Accountability and Responsiveness in Informal Settlements for Equity consortium and international conferences. Ethical approval was not required for these studies. Access to the NCSS 2012 has been given by Africa Population and Health Center and UHS 2013 is freely available.

Economics of healthcare access in low-income and middle-income countries: a protocol for a scoping review of the economic impacts of seeking healthcare on slum-dwellers compared with other city residents.

INTRODUCTION: People living in slums face several challenges to access healthcare. Scarce and low-quality public health facilities are common problems in these communities. Costs and prevalence of catastrophic health expenditures (CHE) have also been reported as high in studies conducted in slums in developing countries and those suffering from chronic conditions and the poorest households seem to be more vulnerable to financial hardship. The COVID-19 pandemic may be aggravating the economic impact on the extremely vulnerable population living in slums due to the long-term consequences of the disease. The objective of this review is to report the economic impact of seeking healthcare on slum-dwellers in terms of costs and CHE. We will compare the economic impact on slum-dwellers with other city residents. METHODS AND ANALYSIS: This scoping review adopts the framework suggested by Arksey and O'Malley. The review is part of the accountability and responsiveness of slum-dwellers (ARISE) research consortium, which aims to enhance accountability to improve the health and well-being of marginalised populations living in slums in India, Bangladesh, Sierra Leone and Kenya. Costs of accessing healthcare will be updated to 2020 prices using the inflation rates reported by the International Monetary Fund. Costs will be presented in International Dollars by using purchase power parity. The prevalence of CHE will also be reported. ETHICS AND DISSEMINATION: Ethical approval is not required for scoping reviews. We will disseminate our results alongside the events organised by the ARISE consortium and international conferences. The final manuscript will be submitted to an open-access international journal. Registration number at the Research Registry: reviewregistry947.