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THReshold EStimation Helping Optimise Local Decisions in antibiotic Stewardship

Project Summary


Antibiotics are a cornerstone of modern medicine but indiscriminate use means that antibiotic resistance is an emerging threat to global public health. The challenge for antibiotic stewardship is to balance appropriate clinical use with containment of resistance. Theoretical and mathematical models have suggested that resistance is only sustained in populations where antibiotic selection pressure exceeds total use thresholds. However, to date ecological analyses have assumed linear associations between population antibiotic use and resistance.


To demonstrate applications of non-linear time-series analysis in identifying associations between population antibiotic use and antibiotic resistant infections and informing antibiotic stewardship strategies in various clinical populations in Europe.


Multi-centre ecological study and non-linear time-series analysis.


Hospital and community populations from 5 European countries (France, Hungary, Northern Ireland, Scotland, Switzerland, Spain)


Primary outcomes will be incidence of selected antibiotic resistant or C.difficile infections (CDI) measured as cases per 1000 occupied bed days (OBDs) in hospital, or cases per 1000 inhabitant-days (IDs) in community populations.


From each centre we will collate retrospective time-series data (minimum 80 monthly intervals) on antibiotic resistant infections, population antibiotic consumption, and (where relevant) infection control measures. Non-linear time-series analysis will be used to explore temporal associations between resistance and dynamic ecological exposures. Multivariate Adaptive Regression Spline (MARS) models will be built incorporating candidate explanatory variables (and lags) identified from visual inspections of output from a General Additive Model (GAM) procedure. From MARS models we will forecast impacts of real-life antibiotic stewardship interventions, and validate predictions against observed data.


Data collection and analysis is expected to take 4-months (June to September 2015), with report completed by December 2015.

Related papers

Lawes T, López-Lozano J-M, Nebot CA, et al. Effects of national antibiotic stewardship and infection control strategies on hospital-associated and community-associated meticillin-resistant Staphylococcus aureus infections across a region of Scotland: a non-linear time-series study. Lancet Infect Dis 2015; published online Sept 25.

Lawes T, López-Lozano JM, Nebot C, Macartney G, Subbarao-Sharma R, Dare CR, Edwards GF, Gould IM. Turning the tide or riding the waves? Impacts of antibiotic stewardship and infection control on MRSA strain dynamics in a Scottish region over 16 years: non-linear time series analysis. BMJ Open. 2015 Mar 26;5(3)

Antimicrobial resistance: The Lancet Infectious Diseases, Sept 25, 2015

Discussion of the effects of national antibiotic stewardship and infection prevention and control programmes on MRSA prevalence in Scotland.

(mp3, 24:53 mins, 22.7Mb)

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