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...

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Early HbA1c predicted future glycaemic control across childhood. Trajectories were further modified by biological factors, exposures to psychosocial adversity, and healthcare use.

ObjectivesTo explore temporal associations between planned antibiotic stewardship and infection control interventions and the molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA).DesignRetrospective ecological study and time-series analysis integrating typing data from the Scottish MRSA reference laboratory.SettingRegional hospital and primary care in a Scottish Health Board.ParticipantsGeneral adult (N=1 051 993) or intensive care (18 235) admissions and primary care registrations (460 000 inhabitants) between January 1997 and December 2012.InterventionsHand-hygiene campaign; MRSA admission screening; antibiotic stewardship limiting use of macrolides and ‘4Cs’ (cephalosporins, coamoxiclav, clindamycin and fluoroquinolones).Outcome measuresPrevalence density of MRSA clonal complexes CC22, CC30 and CC5/Other in hospital (isolates/1000 occupied bed days, OBDs) and community (isolates/10 000 inhabitant-days).Results67% of all clinical MRSA isolates (10 707/15 947) were typed. Regional MRSA population structure was dominated by hospital epidemic strains CC30, CC22 and CC45. Following declines in overall MRSA prevalence density, CC5 and other strains of community origin became increasingly important. Reductions in use of ‘4Cs’ and macrolides anticipated declines in sublineages with higher levels of associated resistances. In multivariate time-series models (R2=0.63–0.94) introduction of the hand-hygiene campaign, reductions in mean length of stay (when >4 days) and bed occupancy (when >74 to 78%) predicted declines in CC22 and CC30, but not CC5/other strains. Lower importation pressures, expanded MRSA admission screening, and reductions in macrolide and third generation cephalosporin use (thresholds for association: 135–141, and 48–81 defined daily doses/1000 OBDs, respectively) were followed by declines in all clonal complexes. Strain-specific associations with fluoroquinolones and clindamycin reflected resistance phenotypes of clonal complexes.ConclusionsInfection control measures and changes in population antibiotic use were important predictors of MRSA strain dynamics in our region. Strategies to control MRSA should consider thresholds for effects and strain-specific impacts.

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BackgroundLate diagnosis is an important cause of HIV-related morbidity, mortality and healthcare costs in the UK and undiagnosed infection limits efforts to reduce transmission. National guidelines provide recommendations to increase HIV testing in all healthcare settings. We evaluated progress towards these recommendations by comparing missed opportunities for HIV testing and late diagnosis in two six year cohorts from North East Scotland.MethodsWe reviewed diagnostic pathways of all patients newly diagnosed with HIV referred to infectious diseases and genito-urinary medicine services between 1995 and 2000 (n = 48) and 2004 to 2009 (n = 117). Missed presentations (failure to diagnose ≤ 1 month of a clinical or non-clinical indicator for testing), late diagnosis (CD4 < 350 cells/mm3), and time to diagnosis (months from first presentation to diagnosis) were compared between cohorts using χ2 and log-rank tests. Determinants of missed presentation were explored by multivariate logistic regression. Breslow-Day tests assessed change in diagnostic performance by patient subgroup.ResultsThere were significant decreases in missed presentations (33% to 17%; P = 0.02) and time to diagnosis (mean 17 months to 4 months; P = 0.005) but not in late diagnosis (56% vs. 60%; P = 0.57) between earlier and later cohorts. In the later cohort patients were significantly more likely to have acquired HIV abroad and presented with early HIV disease, and testing was more likely to be indicated by transmission risk or contact with GUM services than by clinical presentation. Missed presentation remained significantly less likely in the later cohort (OR = 0.28, 95% CI 0.11 to 0.72; P = 0.008) after adjustment for age, transmission risks and number of clinical indicators. Reductions in missed presentation were greater in patients < 40 years, of non-UK origin, living in least deprived neighbourhoods and with early disease at presentation (P < 0.05). 27% of missed presentations occurred in primary care and 46% in general secondary care.ConclusionsWhile early diagnosis has improved in epidemiological risk groups, clinical indications for HIV testing continue to be missed, particularly in patients who are older, of UK origin and from more deprived communities. Increasing testing in non-specialist services is a priority.

ObjectivesTo describe secular trends in Staphylococcus aureus bacteraemia (SAB) and to assess the impacts of infection control practices, including universal methicillin-resistant Staphylococcus aureus (MRSA) admission screening on associated clinical burdens.DesignRetrospective cohort study and multivariate time-series analysis linking microbiology, patient management and health intelligence databases.SettingTeaching hospital in North East Scotland.ParticipantsAll patients admitted to Aberdeen Royal Infirmary between 1 January 2006 and 31 December 2010: n=420 452 admissions and 1 430 052 acute occupied bed days (AOBDs).InterventionUniversal admission screening programme for MRSA (August 2008) incorporating isolation and decolonisation.Primary and secondary measuresHospital-wide prevalence density, hospital-associated incidence density and death within 30 days of MRSA or methicillin-sensitive Staphylococcus aureus (MSSA) bacteraemia.ResultsBetween 2006 and 2010, prevalence density of all SAB declined by 41%, from 0.73 to 0.50 cases/1000 AOBDs (p=0.002 for trend), and 30-day mortality from 26% to 14% (p=0.013). Significant reductions were observed in MRSA bacteraemia only. Overnight admissions screened for MRSA rose from 43% during selective screening to >90% within 4 months of universal screening. In multivariate time-series analysis (R2 0.45 to 0.68), universal screening was associated with a 19% reduction in prevalence density of MRSA bacteraemia (−0.035, 95% CI −0.049 to −0.021/1000 AOBDs; p<0.001), a 29% fall in hospital-associated incidence density (−0.029, 95% CI −0.035 to −0.023/1000 AOBDs; p<0.001) and a 46% reduction in 30-day mortality (−15.6, 95% CI −24.1% to −7.1%; p<0.001). Positive associations with fluoroquinolone and cephalosporin use suggested that antibiotic stewardship reduced prevalence density of MRSA bacteraemia by 0.027 (95% CI 0.015 to 0.039)/1000 AOBDs. Rates of MSSA bacteraemia were not significantly affected by screening or antibiotic use.ConclusionsDeclining clinical burdens from SAB were attributable to reductions in MRSA infections. Universal admission screening and antibiotic stewardship were associated with decreases in MRSA bacteraemia and associated early mortality. Control of MSSA bacteraemia remains a priority.