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If you have any questions on BMJ Open’s open peer review process please email [email protected] BMJ Open Trends of prescribing antimicrobial drugs for urinary tract infections in primary care in the Netherlands Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-027221 review only Article Type: Research Date Submitted by the 12-Oct-2018 Author: Complete List of Authors: Mulder, Marlies; Erasmus MC, Epidemiology Baan, Esme; Erasmus MC, Verbon, Annelies ; Erasmus MC, Microbiology and Infectious diseases Stricker, Bruno; Ersamus MC, Drug Safety Unit Verhamme, Katia; Erasmus Medical Center Keywords: Urinary tract infections < UROLOGY, EPIDEMIOLOGY, PRIMARY CARE For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 28 BMJ Open 1 2 3 1 Trends of prescribing antimicrobial drugs for urinary tract infections in primary care in the 4 5 2 Netherlands 6 7 3 Running title: Prescribing of antimicrobial drugs for UTIs by GPs in the Netherlands 8 1,2 3 5 1,2,5 3,6 9 4 M. Mulder , E.J. Baan , A. Verbon , B.H.C. Stricker , K.M.C. Verhamme 10 11 5 1. Department of Epidemiology, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The 12 6 Netherlands 13 14 7 2. Health and Youth Care Inspectorate, Postbus 2518, 6401 DA Heerlen, The Netherlands 15 16 8 3. Department of MedicalFor Informatics, peer Erasmus review Medical Centre, PO only Box 2040, 3000 CA Rotterdam, The 17 9 Netherlands 18 19 20 10 4. Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Centre, PO Box 2040, 21 11 3000 CA Rotterdam, The Netherlands 22 23 12 5. Department of Internal Medicine, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The 24 13 Netherlands 25 26 14 6. Department of Bioanalysis, Faculty of Pharmaceutical Sciences, University of Ghent, Belgium 27 28 29 15 30 31 16 Keywords: antibiotic stewardship, antimicrobial drug prescribing, urinary tract infections, primary care. 32 33 17 34 35 18 Address for Correspondence: 36 19 Professor Bruno H.Ch. Stricker 37 20 Department of Epidemiology 38 21 Erasmus MC - University Medical Center Rotterdam 39 22 P.O. Box 2040 40 23 3000 CA Rotterdam 41 42 24 The Netherlands 43 25 [email protected] 44 26 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 28 1 2 3 27 Abstract 4 5 6 28 Objective: Urinary tract infections (UTIs) are an important reason to consult a General Practitioner (GP) 7 8 9 29 in the Netherlands. In this study, we describe antimicrobial drug prescribing patterns for UTIs and 10 11 30 investigate adherence of prescribers to Dutch primary care guidelines. 12 13 14 31 Methods: We conducted a population-based cohort study in IPCI, a Dutch GP database encompassing 15 16 32 approximately 2.5 millionFor patients. peer All antimicrobial review drug prescriptions only to patients ≥12 years in 1996- 17 18 33 2014 were extracted. The number of prescriptions and choice of drug type were investigated over 19 20 21 34 calendar time and in different age categories. The choice of antimicrobial drugs classes for UTIs and the 22 23 35 duration of nitrofurantoin use in women were compared to the Dutch primary care guidelines. 24 25 26 36 Results: The source population comprised 1,755,085 patients who received 2,019,335 antimicrobial 27 28 37 drug prescriptions; 401,655 (35.1%) prescriptions were for UTIs (45.2% in women; 12.6% in men). The 29 30 38 proportion of prescriptions for UTI within all prescriptions with an indication code increased from 5.2% 31 32 33 39 in 1996 to 14% in 2014 in men and from 28% in 1996 to 50% in 2014 for women. In men, UTIs were 34 35 40 most frequently treated with fluoroquinolones during the entire study period, whereas use of 36 37 41 fluoroquinolones was only advised as a first-choice in the latest guideline of 2013. In women, UTIs were 38 39 42 increasingly (p<0.05) treated with nitrofuran derivatives with a significant effect of the guideline of 2005 40 41 42 43 (p<0.05). Adherence to the advised duration of nitrofurantoin prescriptions in women has increased 43 44 44 since the guideline of 2005. 45 46 47 45 Conclusions: The antimicrobial drug prescribing for UTIs seem to have increased over time. Adherence 48 49 46 to the UTI guidelines increased with regard to choice and duration of antimicrobial drugs. We showed 50 51 47 that databases like IPCI in which prescription and indication are monitored, can be valuable antibiotic 52 53 54 48 stewardship tools. 55 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 28 BMJ Open 1 2 3 49 Strengths and limitations of this study 4 5 6 50 This study was conducted in a large database, including a substantial part (~15%) of the Dutch 7 8 51 population implying that the external validity of our study is high. 9 10 52 In the Netherlands, every person is assigned to a specific GP which limits selection bias. 11 12 53 Improvement of coding over calendar time might bias conclusions on total prescribing of 13 54 antimicrobial drugs. Therefore, we also studied the prescription data for other infections to be 14 15 55 able to study prescriptions of antimicrobial drugs for UTIs in comparison with prescriptions of 16 For peer review only 17 56 antimicrobial drugs for other infections 18 57 We analyzed the adherence of GPs to the Dutch guidelines on treatment of urinary tract 19 20 58 infections and show that database studies can be used as a tool for good antimicrobial 21 22 59 stewardship. 23 24 60 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 28 1 2 3 61 Introduction 4 5 6 62 Urinary tract infections (UTIs) are among the most common infections in humans. UTIs cause a 7 8 1 2 9 63 substantial burden of disease with major economic consequences. In women, UTIs are the most 10 11 64 common reason to consult a general practitioner (GP) in the Netherlands with 232 contacts per 1,000 12 13 65 women in 2014. In men, this number was substantially lower: 37 contacts per 1,000 men.3 14 15 16 66 In most cases UTIs areFor treated withpeer antimicrobial review drugs. The choice only of antimicrobial drug depends on the 17 18 67 antimicrobial sensitivity of pathogens in urinary cultures (if taken), severity of the symptoms and 19 20 21 68 potential co-morbidities of the individual. Based on the resistance patterns of E. coli in the Netherlands, 22 23 69 Dutch guidelines on the treatment of UTIs have changed several times in the last few decades. The latest 24 25 70 Dutch guideline for the treatment of UTIs in primary care was released in 2013 and recommends 26 27 71 nitrofurantoin as first-choice in all patients with cystitis, including men. In case of signs of tissue 28 29 4 30 72 invasion, ciprofloxacin is recommended as first-choice. Additionally, the recommended duration of 31 32 73 treatment has changed. The recommended duration of treatment with nitrofurantoin for cystitis in 33 34 74 women was 3 days in the guidelines of 1989 and 1999, whereas it has been extended to 5 days in the 35 36 75 guidelines of 2005 and 2013 (Table 1).4-7 37 38 39 76 Previous research shows that the use of antimicrobial drugs in the Netherlands in general has increased 40 41 42 77 since 2005 until approximately 2012, most prominently in elderly patients, but has decreased again 43 44 78 since then.8 9 Since UTIs are a major reason to consult a GP, use of antimicrobial drugs for UTIs 45 46 79 contribute significantly to total antimicrobial consumption. Therefore, antibiotic stewardship focusing 47 48 80 on (inappropriate) antimicrobial drug prescribing for UTIs is an important target in the fight against 49 50 51 81 antimicrobial resistance (AMR). This study aims to use a large GP database to investigate the adherence 52 53 82 of GPs to the Dutch UTI guidelines, by studying choice of antimicrobial drug and duration of 54 55 83 nitrofurantoin use over time.