#1863 Antibiotic Prescribing Before and After an FDA Boxed Warning on Fluoroquinolones in 2016 Zach Willis,1 Stacie Dusetzina,2 Deverick Anderson,3 Nick Pajewski,4 Alan Kinlaw1 1University of North Carolina School of Medicine, 2Vanderbilt University School of Medicine, 3Duke University School of Medicine, 4Wake Forest University School of Medicine Background Results • Overuse of Fluoroquinolones (FQ) contributes to Clostridium difficile infection All Diagnoses Sinusitis Only (n = 6,384) (Dingle 2017) and rapid development of resistance. • CDC: 5% of FQ prescriptions are for conditions not requiring antibiotics; 20% are non-first-line (Kabbani 2018) • Post-marketing surveillance has identified severe toxicities (Etminan 2014, Wise 2012, van der Linden 2002, van der Linden 2013). • FDA has released a series of safety communications about the FQ class, including a July 2016 boxed (“black-box”) warning specifically warning against use for urinary tract infection (UTI), acute bacterial sinusitis (ABS), and acute bacterial exacerbation of chronic bronchitis. • The impact of FDA warnings on antibiotic class utilization is unknown. • Concerns about antimicrobial resistance, C. difficile infection, and drug toxicity are aligned in the case of current FQ prescribing patterns. • This study uses electronic health record (EHR) data to assess the impact of the FDA’s July 2016 warning on utilization of FQ in a large academic health care system.

Objectives ALL DIAGNOSES Pre-Warning Trend Post-Warning Change in trend SINUSITIS Pre-Warning Trend Post-Warning Change in trend (Orders per 1000 Trend (95% CI) (Orders per 1000 Trend (95% CI) Drug Class encounters per year) Drug Class encounters per year) 1. Examine changes in fluoroquinolone prescribing before and after the FDA’s Fluoroquinolones -0.6 -2.5 -1.9 (-2.6 to -1.1)* Fluoroquinolones +4.9 -17.5 -22.4 (-48.3 to +3.5) boxed warning in July 2016 Beta-lactams +0.4 -2.8 -3.1 (-5.8 to -0.5)* Amox ± Clav +56.4 -6.6 -63.0 (-211.5 to +85.5) • Did gross FQ prescribing change in response to the boxed warning? Azithromycin +0.2 -1.0 -1.2 (-2.5 to +0.1) Azithromycin +10.0 +21.1 +11.1 (-25.8 to +47.9) 2. Evaluate heterogeneity in FQ prescribing time trends across patient Negative Control -0.1 -0.3 -0.2 (-0.5 to +0.2) subgroups. • Did patients with less severe presentations, including outpatients and Urinary Tract Infection Only (n = 186,859) Discussion patients with UTI, sinusitis, and acute bacterial exacerbation of chronic bronchitis, see a greater decrease in FQ use? The July 2016 FDA warning on FQ was associated with a small deceleration in 3. Assess FQ replacement by antibiotics with similar antibacterial specimen. FQ prescribing. In aggregate, there was no clear evidence of replacement by antibiotics with similar indications. There was no change in utilization of our • Did prescriptions of beta-lactams, macrolides, etc. increase to replace FQ? control medication class (inhaled corticosteroids). The 2016 warning specifically warned that risks of FQ outweigh benefits for certain common diagnoses, including acute bacterial sinusitis (ABS) and urinary Methods tract infection (UTI). We specifically analyzed the use of FQ for these common diagnoses: UTI and sinusitis. For UTI, we did detect an apparent shift from FQ to Study Design: Interrupted time series analysis cephalosporins and, to a lesser extent, nitrofurantoin and trimethoprim- Setting: University of North Carolina Health Care System, currently with 12 hospitals sulfamethoxazole. For sinusitis, use was uncommon at baseline and there was a and a large network of primary-care and subspecialty clinics nonsignificant trend downward, with some replacement by azithromycin. Timing: April 2014-August 2017 Limitations: Patients: All patients 2 years of age or greater at the time of encounter • Data come from a single center Outcome measure: Systemic fluoroquinolone orders (ciprofloxacin, levofloxacin, • We cannot rule out other factors at a similar time, such as antimicrobial moxifloxacin) per 1,000 patient encounters stewardship interventions or shifts in antimicrobial susceptibility, that may Comparator (negative control): Inhaled corticosteroids used for lung diseases UTI Pre-Warning Trend Post-Warning Change in trend have influenced antibiotic prescribing. (Orders per 1000 Trend (95% CI) Assessed potential replacement antibiotics: Amoxicillin, amoxicillin-clavulanate, Drug Class encounters per year) We tentatively conclude that the 2016 FDA warning may have encouraged a shift away from FQ, especially in UTI, where several viable alternatives exist. FDA cephalosporins, azithromycin, nitrofurantoin, trimethoprim-sulfamethoxazole Fluoroquinolones -0.6 -11.1 -10.5 (-23.1 to +2.1) safety warnings may have the ability to impact utilization of an antibiotic class. Analysis: Segmented linear regression of interrupted time series data before and Cephalosporins +0.7 +55.7 +55.0 (+40.6 to +69.4)* after July 2016. Models accounted for seasonality and autocorrelated errors. Future research will include further subgroup and antibiotic class analysis (e.g., Nitrofurantoin -1.9 +25.5 +27.3 (+21.7 to +33.0)* Subanalysis: In addition to overall trend analysis, we assessed antibiotic prescribing inpatient vs outpatient) and expanding our analysis to include two additional large TMP-SMX 0.0 +11.5 +11.5 (+5.3 to +17.7)* for urinary tract infection and sinusitis separately. healthcare systems.