Kavanagh, Kimberley and Pan, Jiafeng and Marwick, Charis and Davey, Peter and Wiuff, Camilla and Bryson, Scott and Robertson, Chris and Bennie, Marion (2016) Cumulative and temporal associations between antimicrobial prescribing and community-associated Clostridium difficile infection : population-b

20 Background. Community-associated (CA) Clostridium difficile infection (CDI) is a major public health 21 problem. This study estimates the magnitude of the association between temporal and cumulative 22 prescription of antimicrobials in primary care and CA-CDI. CA-CDI is defined as cases without prior 23 hospitalisation in the previous 12 weeks who were either tested outside of hospital or tested within 2 24 days of admission to hospital. 25 Methods. Three National patient level datasets にcovering CDI cases, community prescriptions and 26 hospitalisations were linked by the NHS Scotland unique patient identifier, the community health 27 index, CHI. All validated cases of CDI from August 2010 to July 2013 were extracted and up to six 28 population-based controls were matched to each case from the CHI register for Scotland. Statistical 29 analysis used conditional logistic regression. 30 Results. 1446 unique cases of CA-CDI were linked with 7964 age, sex and location matched controls. 31 Cumulative exposure to any antimicrobial in the previous 6 months has a monotonic dose-response 32 association with CA-CDI. Individuals with excess of 28 defined daily doses (DDD) to any antimicrobial 33 (19.9% of cases) had an odds ratio (OR)=4.4 (95% CI:3.4-5.6) compared to those unexposed. 34 Individuals exposed to 29+ DDD of high risk antimicrobials (cephalosporins, clindamycin co-amoxiclav, 35 or fluoroquinolones) had an OR=17.9 (95% CI:7.6-42.2). Elevated CA-CDI risk following high risk 36 antimicrobial exposure was greatest in the first month (OR=12.5 (8.9-17.4)) but was still present 4-6 37 months later (OR=2.6 (1.7-3.9)). Cases exposed to 29+DDD had prescription patterns more consistent 38 with repeated therapeutic courses, using different antimicrobials, than long term prophylactic use. 39 Conclusions. This analysis demonstrated temporal and dose-response associations between CA-CDI 40 risk and antimicrobials with an impact of exposure to high risk antimicrobials remaining 4-6 months 41 later. 42