Balancing access to antibiotics with control of antibiotic resistance is a global public health priority. Currently, antibiotic stewardship is informed by a 'use it and lose it' principle, in which population antibiotic use is linearly related to resistance rates. However, theoretical and mathematical models suggest use-resistance relationships are non-linear. One explanation is that resistance genes are commonly associated with 'fitness costs', impairing pathogen replication or transmissibility. Therefore, resistant genes and pathogens may only gain a survival advantage where antibiotic selection pressures exceed critical thresholds. These thresholds may provide quantitative targets for stewardship: optimising control of resistance while avoiding over-restriction of antibiotics. We evaluated the generalisability of a nonlinear time-series analysis approach for identifying thresholds using historical prescribing and microbiological data from five populations in Europe. We identified minimum thresholds in temporal relationships between use of selected antibiotics and rates of carbapenem-resistant Acinetobacter baumannii (in Hungary), extended spectrum β-lactamase producing Escherichia coli (Spain), cefepime-resistant Escherichia coli (Spain), gentamicin-resistant Pseudomonas aeruginosa (France), and methicillin-resistant Staphylococcus aureus (Northern Ireland) in different epidemiological phases. Using routinely generated data, our approach can identify context-specific quantitative targets for rationalising population antibiotic use and controlling resistance. Prospective intervention studies restricting antibiotic consumption are needed to validate Results Identifying non-linear temporal relationships: from experiment to applicationIn a Monte Carlo experiment we compared the ability of linear and non-linear time-series analysis (Multivariate Adaptive Regression Splines, MARS) to identify pre-defined relationships between simulated explanatory and outcome time-series (Supplementary Figure 1). Non-linear time-series analysis (NL-TSA) accurately identified both truly linear and nonlinear associations. However, linear time-series analysis provided biased estimations and overall poorer data-fit if relationships were non-linear. NL-TSA models applied to retrospective time-series data from five European study populations (examples 1-5), frequently identified minimum thresholds in antibiotic useresistance relationships, (figures 1-5 and Supplementary Table 1). 'Ceiling effects', in which further increases in explanatory variables did not affect resistance rates, were found at highlevels of use of some antibiotics and hand hygiene. Non-linearities in autoregression and population interaction terms further indicated the complexity of transmission dynamics within and between clinical populations. Example 1: Carbapenem-resistant Acinetobacter baumannii (Debrecen, Hungary) We examined ecological determinants of carbapenem-resistant A. baumannii (CRAb) in a tertiary hospital population in Debrecen, Hungary (figure 1). Betwee...

Background Chagas disease (CD) is a chronic parasitic disease caused by Trypanosoma cruzi and is endemic to continental Latin America. In Spain, the main transmission route is congenital. We aimed to assess adherence to regional recommendations of universal screening for CD during pregnancy in Latin American women in the province of Alicante from 2014 to 2018. Methodology/Principal findings Retrospective quality study using two availa sources: 1) delivery records of Latin American women that gave birth in the 10 public hospitals of Alicante between January 2014 and December 2018; and 2) records of Chagas serologies carried out in those centers between May 2013 and December 2018. There were 3026 deliveries in Latin American women during the study period; 1178 (38.9%) underwent CD serology. Screening adherence ranged from 17.2% to 59.3% in the different health departments and was higher in Bolivian women (48.3%). Twenty-six deliveries (2.2%) had a positive screening; CD was confirmed in 23 (2%) deliveries of 21 women. Bolivians had the highest seroprevalence (21/112; 18.7%), followed by Colombians (1/333; 0.3%) and Ecuadorians (1/348; 0.3%). Of 21 CD-positive women (19 Bolivians, 1 Colombian, 1 Ecuadorian), infection was already known in 12 (57.1%), and 9 (42.9%) had already been treated. Only 1 of the 12 untreated women (8.3%) was treated postpartum. Follow-up started in 20 of the 23 (87.0%) neonates but was completed only in 11 (47.8%); no cases of congenital transmission were detected. Among the 1848 unscreened deliveries, we estimate 43 undiagnosed cases of CD and 1 to 2 undetected cases of congenital transmission. Conclusions/Significance Adherence to recommendations of systematic screening for CD in Latin American pregnant women in Alicante can be improved. Strategies to strengthen treatment of postpartum women and monitoring of exposed newborns are needed. Currently, there may be undetected cases of congenital transmission in our province.

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