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1 Supplementary Online Content Raguideau F, Lemaitre M, Dray-Spira R, Zureik M. Association between oral fluoroquinolone use and retinal. JAMA Ophthalmol. Published online March 10, doi: /jamaophthalmol etable 1. Summary of Other Epidemiological Studies etable 2. Variables Used to Identify Concomitant Medical Conditions etable 3. Surgical Procedure Codes Used for Retinal Detachment Identification etable 4. of the Population With Rhegmatogenous Retinal Detachment etable 5. Crude and Adjusted Odds Ratios of Rhegmatogenous Retinal Detachment According to Patient etable 6. Crude and Adjusted Odds Ratios of Retinal Detachment for Current Use According to Patient emethods. Comparison of Distribution of Fluoroquinolone Before and After the Retinal Detachment This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Summary of other epidemiological studies Reference Year Etminan et al Pasternak et al Country Canada (British Columbia) Study period 1/ /2007 Study population Study design Endpoint ascertainment British Columbia linked health database Cohort of ophthalmology patients Denmark Health Care and administrative registries Cohort of episodes of oral fluoroquinolone use and nonuse Nested-case control study Cohort study Procedure codes for retinal after documented physician service code Diagnosis code with code for surgical procedure for retinal within 14 days following diagnosis Number of included patients, Demographics 4,384 cases, 43,840 controls cases (controls): Age 61.1 ± 16.6 (61.1 ± 16.6), Female 41.8% (56.5%); Cataract surgery 46.2% (33.9%), Myopia 3.7% (3.1%), Diabetes 15.4% (13.1%) 5,164,479 persons included : FQ (No FQ) Age: 57.7 ± 19.9 (59.0 ± 19.1) Cataract surgery 7% (7%), Diabetes 7% (5%) Adjustment Matching on age and month and year of cohort entry. Covariables: Sex, previous history of cataract surgery, myopia, diabetes, number of visits to ophthalmologist, number of prescribed drugs. Propensity score (21 variables) see text for all, among them: severe eye trauma, retinal disorders, cataract surgery, major eye surgery, diabetes Outcomes/ RD cases/ incidence in background population 145 cases with current use vs 275 controls, 12 cases with 7 day FQ exposure vs 93; 288 cases with 365 day FQ exposure vs 2685 FQ non use: 494/2,602,472 PY, Incidence: 19.0 per 100,000 PY FQ use current: 5/19,797, recent 7/37,015, past 14/52,207 Exclusion criteria Prior retinal, procedure code for endophthalmitis, intravitreal antibiotic injection, vitreous biopsy Prior retinal Prior FQ exposure History of endophthalmitis Intravitreal injection, Choroidal, retial or vitreal biopsy, Patients with cataract surgery, other major eye surgery or severe eye trauma within the last 30 days Risk estimate Current FQ use 4.50 ( ), 7 days FQ use 0.92 ( ), 365 days FQ use 1.03 ( ) 10 days FQ use RR 1.29 ( ); 30 days FQ use 0.97 ( ); 60 days FQ use 1.37 ( ) Kapoor et al U.S.A (Olmsted, Minnesota) 01/ /2011 Medical record linkage system Rochester Epidemiology Project (REP) Cohorts of patients prescribed fluoroquinolones, macrolides or beta-lactams Cohort study Procedural codes for rhegmatogenous retinal or retinal breaks, Specialist chart review for exclusion FQ: n= 38,046; Age: 50.6 ± 19.6; Female: 61% Macrolide: n=48,074; Age: 43.1 ± 17.7; Female: 61% Beta-lactam: n=69,079; Age: 42.8 ± 18.6; Female: 57% Unknown, ageand sexstandardized incidence rate calculated FQ: 7: 0/38, /38,046, 90 3/38,046, /38,046 Controls: Macrolides: 7: 1/48, /48,074, 90 2/48,074, 365 8/48,074 Beta-lactams: 7: 0/69, /69,079, 90 5/69,079, /69,079 tractional retinal, previous retinal repair, endophthalmitis, necrotizing retinitis patients with intraocular surgery or severe head/eye trauma 90 days serous/exudative retinal diabetic retinopathyrelated tractional Unadjusted estimates calculated from crude rates: RR 7 days: n.a. RR 30 days vs BL 1.82 ( ) RR 90 days vs BL 1.08 (95% CI )

3 Reference Year Country Study period Study population Study design Endpoint ascertainment Number of included patients, Demographics Adjustment Outcomes/ RD cases/ incidence in background population Background Incidence: 28.8 per 100,000 per year (11 events per patientyears) Exclusion criteria Risk estimate Eftekhari et al United Kingdom 06/ /2012 THIN Database Cohort of patients prescribed fluoroquinolones or beta-lactams Cohort study Procedural codes for rhegmatogenous retinal or retinal tears FQ: n=247,073 Age: 55.1 (1-109) Female: 54% Diabetics: 10% BL: n=3,303,641 Age: 40.0 (1-111) Female: 56% Diabetic: 6% Age, index year, gender, diabetes FQ: FQ: 7: 0/247, /247,073, 90 5/247,073, /247,073 Incidence: 8.63 per 100,000 patient years BL: 7: 7/3,303, /3,303,641, 90 87/3,303,641, /3,303,641 Prior retinal break Patients receiving both antibiotics Intraocular surgery or a diagnosis of endophthalmitis within 90 days prior to the antibiotic prescription. HR 30 days: 0.56 (95% CI ) HR 90 days: 0.87 (95% CI ) (age adjusted) Incidence: 6.38 per 100,000 patient years Fife et al. 2014a U.S.A 01/ /2012 Healthcare databases MarketScan Commercial Claims and Encouters database (CCAE) Cohort of ophthalmology patients Case-control study Procedural codes. Analysis 1: as in Etminan (Analysis 2: excluding serous and tractional RD Analysis 3: with patients without a prior ophthalmologist visit ) Analysis 1: 7,844 cases 77,654 Controls Cases (controls): Age: ± 9.22 (55.23 ± 9.24) Female: 40% (59%) Cataract Surgery: 16.8% (1.76%) Myopia 1.92% (0.59%), Diabetes 21.7% (13.41%) Analysis 1: Sex, Cataract surgery, myopia,, No of visits to ophthalmologist, No of prescriptions 1,344 cases with any FQ use versus 6,500 cases with nonuse, Cases with current use: 66, cases with recent use: 39, cases with past use: 1,239 Analysis 1: prior retinal current or prior (10 days) hospitalisation prior endophtalmitis OR current FQ use vs non-use: 1.33 ( ) OR 7 days vs. nonuse: 1.19 ( )

4 Reference Year Fife et al. 2014b Country Study period U.S.A 09/ /2012 Study population Study design Endpoint ascertainment Optum ClinFormatics database Cohort of ophthalmology patients Case-control study Procedural codes. Analysis 1: as in Etminan (Analysis 2: excluding serous and tractional RD Analysis 3: with patients without a prior ophthalmologist visit) Number of included patients, Demographics Analysis 1: 7,844 cases 77,654 Control Cases (Controls): Age: ±11.7 (58.10 ± Female: 40% (57%) Cataract Surgery: 19.35% (2.1%) Myopia 4.97% (1.94%), Diabetes 19.12% (10.83%)) Adjustment Analysis 1: Sex, Cataract surgery, myopia,, No of visits to ophthalmologist, No of prescriptions Outcomes/ RD cases/ incidence in background population 559 cases with any FQ use versus 2,500 without FQ use; Cases with current use: 13, cases with recent us: 9; cases with past use: 537 Exclusion criteria See above Risk estimate OR current FQ use 0.93 ( ) OR 7 days vs. non-use 0.74( ) Fife et al. 2014c U.S.A 01/ /2012 MarketScan Commercial Claims and Encouters database (CCAE) Self controlled case series Procedural codes. excluding serous and tractional RD Cases from Fife a n.a. 19,191 cases See Fife a IRR 1.13 ( ) (risk period of 30 days) Fife et al. 2014d U.S.A 01/ /2012 Optum ClinFormatics (Optum) database Self controlled case series Procedural codes. excluding serous and tractional RD Cases from Fife b n.a. 6,896 cases See Fife b IRR 0.85 ( ) (risk period of 30 days) Kuo et al Taiwan 1/ /2010 Taiwan National Health Insurance Database Cohort of patients prescribed fluoroquinolones or amoxicillins Cohort study Record of diagnosis code from ophthalmologist for rhegmatogenous retinal 178,179 prescriptions for FQ or AM FQ cohort (AM) Age 47.2 ± 18.3 (47.3±18.2), Female 59.2% (59.2%), Diabetes: 17.9% (17.9%), Underlying ophthalmic conditions 12.6% (12.6%) Matching on year of prescription, age, sex, diabetes and ophthalmic conditions (amongst other: endophthalmitis, retinitis, eye trauma, high myopia, proliferative diabetic retinopathy, cataract surgery), respiratory infections and propensity score FQ cohort: 96 cases in 43,935 PY, incidence: per 100,000 PY; Amoxicillin cohort: 46 cases in 43,935 PY, incidence: per 100,000 PY Treatment with FQ or amoxicillin in the previous 90 days Previous diagnosis or procedure for RD, blind patients, patients with procedures for enucleation HR 90 days 2.07 ( )

5 Reference Year Chui et al Country Hong Kong Taiwan Study period 1/ /2012 1/ /2010 Study population Study design Endpoint ascertainment CDARS database Taiwan National Health Insurance Database Self-controlled case series ICD-9 code for procedure for retinal Number of included patients, Demographics Hong Kong: 469 exposed cases Age 54.7 ± 13.7; Female: 41.8% Taiwan: 947 exposed cases Age 48.5 ± 15.7; Female: 53.0% Adjustment Variables: Age, history of diabetes, cataract surgery Outcomes/ RD cases/ incidence in background population 1.3 cases per 200,000 fluoroquinolone prescriptions Risk period was not defined Exclusion criteria Previous RD events,2 year prior inclusion, with diagnosis of endophthalmitis or history of head or eye trauma 30 days before first event. Risk estimate Hong Kong IRR: 0,.82 ( ) Taiwan: IRR: 1.45 ( ) Combined IRR: 1.26 ( ) 9 events during the risk period

6 etable 2. Variables Used to Identify Concomitant Medical Conditions Variables Data sources Codes Comments Age SNIIRAM at the index date Gender SNIIRAM Chorioretinitis/choroidal disorder ICD-10: H30,H31,H32 Retinopathy and other retinal diseases ICD-10: H35, H36 Retinal vascular occlusion ICD-10: H34 Vitreous disease or degeneration (including degenerative myopia) ICD-10: H43, H44, H45 Disorders of the orbit ICD-10: H05 Severe ocular trauma + burning eye Cataract surgery (including congenital cataract) Diabetes Cardiovascular disease SNIIRAM ICD-10: S050- S059,S021,S023,S028, T262, T267 ICD-10: Q120, H25, H26, H28, H590 Code ATC : A10A, A10B LTD diabetes ICD-10: I00-09, I20-99, G45-56 (excluding hypertensive disease) 2 prescriptions of insulin or oral antidiabetic drugs in the year before the RD and/or LTD Renal disease ICD-10: I12, I13, N00-08, N17,N18,N19,N25,Z49,Z940,Z992 Reimbursement of glasses or contact lenses SNIIRAM , , , , , , , , , , , in the study period Glaucoma (including congenital glaucoma) ICD-10: Q150, H40, H42 Congenital malformation of the eye ICD-10: Q10-Q14, Q158, Q159 Ophthalmologist visit SNIIRAM the year before the RD Ophthalmic antibiotic treatment SNIIRAM ATC:S01AA, S01AB, S01CA, S01 AX11,S01 AX11, S01 AX12, S01 AX13,S01 AX17, S01 AX19, S01 at the index date AX21, S01 AX22 Other oral antibiotic treatments SNIIRAM ATC J01 at the index date Corticosteroids SNIIRAM ATC:H02AB at the index date SNIIRAM: Health insurance database ; : Hospital discharge Database ; RD: Retinal Detachment ; LTD: Long Term Disease

7 etable 3. Surgical Procedure Codes Used for Retinal Detachment Identification CCAM Code Surgical procedure BGBA001 Internal tamponade of the posterior segment of the eye by the optic disc pit or macular hole, for retinal BGDA008 Retinopexy by coagulation, cryotherapy or extraocular laser without scleral bucking, with internal gas tamponade BGDA004 Retinopexy by coagulation, cryotherapy or extraocular laser with scleral buckling limited to one quadrant, without tamponade BGDA003 Retinopexy by coagulation, cryotherapy or extraocular laser with scleral buckling limited to one quadrant, with internal gas tamponade BGDA002 Retinopexy by coagulation, cryotherapy or extraocular laser with scleral buckling on more than one quadrant, without tamponade BGDA001 Retinopexy by coagulation, cryotherapy or extraocular laser with scleral buckling on more than one quadrant, with internal gas tamponade BGDA005 Retinopexy by coagulation, cryotherapy or extraocular laser with scleral buckling over 360 [cerclage], without tamponade BGDA006 Retinopexy by coagulation, cryotherapy or extraocular laser with scleral buckling over 360 [cerclage], with internal gas tamponade BGDA007 Balloon scleral buckling BGMA003 Modification of a scleral buckle for persistent retinal BGFA001 Vitrectomy by posterior sclerotomy without retinal coagulation BGFA009 Vitrectomy by posterior sclerotomy with retinal laser endocoagulation or by diathermy without tamponade BGFA006 Vitrectomy by posterior sclerotomy with scleral retinal coagulation without tamponade BGFA010 Vitrectomy by posterior sclerotomy with retinal coagulation and temporary internal tamponade BGFA011 Vitrectomy by posterior sclerotomy with extraction of the crystalline lens BGFA005 Vitrectomy by posterior sclerotomy with dissection of the vitreous cortex [peeling] and internal gas tamponade BGFA003 Vitrectomy with membrane dissection, coagulation and intraocular tamponade or scleral buckling for retinopathy of prematurity BGFA012 Excision of a scleral lesion BGCA002 Suture of a scleral wound BGSA002 Closure of a scleral fistula BGMA900 Posterior scleral reinforcement of the eye by tissue autograft BGMA901 Posterior scleral reinforcement of the eye with synthetic material BGPA002 Dissection of epiretinal membrane and/or vitreal membrane [hyaloid] BGPA003 Section or release of adhesions, membranes and/or postoperative vitreoretinal adhesions BGPP002 Laser vitreosection Retinovitreal surgery involving at least four of the following: coagulation, vitrectomy, BGMA002 laser endocoagulation, retinotomy, internal tamponade, fluid-air exchange, dissection of adhesions, retinectomy Retinovitreal surgery involving scleral buckling and at least four of the following: BGMA001 coagulation, vitrectomy, laser endocoagulation, retinotomy, internal tamponade, fluid-air exchange, dissection of adhesions, CCAM: Common Classification of Medical procedures

8 etable 4. of the Population With Rhegmatogenous Retinal Detachment No. (%) Retinal Detachment n=18629 Age, mean (SD), y <60 years 60 years Men Type of surgery procedures 1 Retinovitreal surgery 2 Retinopexy Vitrectomy 3 Other procedures 3 Ophthalmologic history 4 Cataract Other retinal and choroidal disorder (including retinopathy) Vitreous disease or degeneration (including degenerative myopia) Glaucoma Other ocular diseases 5 Other medical history Diabetes Cardiovascular diseases 4 Renal diseases 4 Use of antibiotic eyedrops at the index date Use of other oral antibiotics at the index date Use of oral corticosteroid at the index date Reimbursement of glasses or contact lenses Any ophthalmologist visit during the year before retinal Retinal Detachment and fluoroquinolone use n=435 61,0 (13.4) 63.4 (12.7) (41.8) 154 (35.4) (58.2) 281 (64.6) (58.3) 198 (45.5) (58.8) 259 (59.6) (31.6) 136 (31.3) (9.4) 40 (9.2) 47 (0.3) 0 (0.0) 23 (5.5) 656 (3.5) 20 (4.6) 293 (1.6) 10 (2.3) 108 (0.6) 0 (0.0) (9.6) 41 (9.4) (11.7) 69 (15.9) 176 (0.9) 6 (1.4) (11.9) 54 (12.4) 377 (2.0) 12 (2.8) 315 (1.7) 12 (2.8) (77.9) 363 (83.5) (41.4) 200 (46.0) 1 One hospital stay may be associated with several procedures, these data report only a single procedure per patient. 2 Vitreous surgery involving at least 4 of the following: coagulation, vitrectomy, laser endocoagulation, retinotomy, internal tamponade, fluid-air exchange, dissection of adhesions and retinectomy or buckling and at least 3 of the previous procedures 3 in combination with a specific RD procedure (24.9) 128 (29.4) 760 (4.1) 4 As the persons hospitalised during the 6 were excluded, these data refer to the four years prior to the 6 months before DR. 5 Including orbital disorders, ocular trauma, and congenital malformation

9 etable 5. Crude and Adjusted Odds Ratios of Rhegmatogenous Retinal Detachment According to Patient No. Fluoroquinolone use n=435 Crude OR Ajusted OR 1 Sex Men (1.10-2,57) 1,56(1,02-2,40) Women (0, ) 1.25 ( ) Age <60 years ( ) 1.46 ( ) 60 years ( ) 1.36 ( ) History of cataract Yes (0.90-2,57) 1.46 ( ) No ( ) 1.36 ( ) History of diabetes Yes ( ) 1.54 ( ) No ( ) 1.37 ( ) Any ophthalmologist visit in the 12 months prior to retinal Yes ( ) 1.88 ( ) No ( ) 1.01 ( ) 1 age, ophthalmologic history, diabetes, cardiovascular disease, renal disease, glaucoma, corticosteroid use, reimbursement of eyeglasses or contact lenses

10 etable 6. Crude and Adjusted Odds Ratios of Retinal Detachment for Current Use According to Patient No. Fluoroquinolone use n=663 Crude OR Ajusted OR 1 p-value 2 Sex Men (1.46-2,81) 1,75 (1,23-2,49) Women (0, ) 1.24 ( ) Age Under 60 years ( ) 1.60 ( ) Over 60 years ( ) 1.40 ( ) History of cataract Yes (1.14-2,64) 1.63 ( ) No ( ) 1.40 ( ) History of diabetes Yes ( ) 3.03 ( ) No ( ) 1.31 ( ) Any ophthalmologist visit in the 12 months prior to retinal Yes ( ) 1.95 ( ) No ( ) 1.09 ( ) 1 age, ophthalmologic history, diabetes, cardiovascular disease, renal disease, glaucoma, corticosteroid use, reimbursement of eyeglasses or contact lenses 2 multivariate model

11 emethods. Comparison of Distribution of Fluoroquinolone Before and After the Retinal Detachment We performed an additional analysis to compare distribution of fluoroquinolone before the retinal (between D-180 and D-60 before the RD) and after the RD (between D+60 and D+180 after the RD). We intentionally choose 2 symmetric periods to the retinal with a delay of 60 days framing the RD to be outside of the potential prophylactic use of fluoroquinolone (see figure below). The number of dispensings of fluoroquinolones during each period and by delay of 10 days are reported in the table 1 below. The distribution of fluoroquinolone exposure between both periods is no statistically significantly different (p=0.09). Table 1: Number of dispensings of fluoroquinolones during each periods Number of dispensings Total Before RD D 180 to D 60 After RD D+60 to D+180 Frequency Row Pct Frequency Row Pct Total Frequency

Progressive Symptomatic Retinal Detachment Complicating Retinoschisis. Initial Reporting Questionnaire

Progressive Symptomatic Retinal Detachment Complicating Retinoschisis In association with the British Ophthalmological Surveillance Unit Ethics ref: 13/NW/0037 Initial Reporting Questionnaire Case Definition: