Did the 2016 Fluoroquinolone Boxed Warning Change Outpatient Treatment of Uncomplicated UTIs?


Evaluating the impact of the 2016 FDA boxed warning on fluoroquinolone prescribing rates for uncomplicated urinary tract infections.

Highlighted Study:

Cowart K, Worley M, El Rouby N, Sando K. Evaluation of FDA Boxed Warning on Prescribing Patterns of Fluoroquinolones for Uncomplicated Urinary Tract Infections. Ann Pharmacother. 2019; 53(12):1192-1199. doi:10.1177/1060028019865224.

The treatment of urinary tract infections in the outpatient setting represents an area with an opportunity for antimicrobial stewardship efforts. According to the 2010 Infectious Diseases Society of America (IDSA) guidelines, nitrofurantoin, trimethoprim-sulfamethoxazole, and Fosfomycin are recommended first-line antibiotic treatment options for acute uncomplicated cystitis. Although fluoroquinolones are efficacious against common urinary pathogens, they are associated with a “propensity for collateral damage” and consequently should be reserved for patients who are unable to receive treatment with the first-line agents.1

On May 12, 2016, the US Food and Drug Administration (FDA) issued a safety announcement reinforcing the recommendation to avoid fluoroquinolones in uncomplicated urinary tract infections (uUTI), as well as in acute sinusitis and acute bronchitis. Other treatment options are often available for these uncomplicated infections to avoid the “disabling and potentially permanent serious side effects” of fluoroquinolones on the tendons, muscles, joints, nerves, and central nervous system.2 On July 26, 2016, this statement was formally added to the boxed warning on fluoroquinolone drug labelling.3

Cowart and colleagues conducted a retrospective cohort study at 6 family medicine clinics within the University of Florida Academic Health Center in order to evaluate the impact of the 2016 FDA boxed warning on fluoroquinolone prescribing rates for uUTIs.4 Antibiotic prescribing was assessed pre-FDA boxed warning (January 1, 2016 through July 26, 2016) and post-FDA boxed warning (July 27, 2016 through December 31, 2016). The analysis included women aged 18-65 years who had a clinic visit that listed uUTI as the primary or secondary billable diagnosis code and generated an antibiotic in the electronic medical record during the visit. Patients with complicated UTI, immunosuppressive disease, diabetes mellitus, recent antibiotic prescriptions, or recent hospitalization were excluded.

A total of 436 patients were included in the analysis with 274 patients in the pre-FDA boxed warning group and 162 patients in the post-FDA boxed warning group. Baseline characteristics were similar between groups and nitrofurantoin was the most commonly prescribed treatment during both time periods. Of note, only 60% of patients in both groups presented with urinary symptoms.

For the primary outcome, fluoroquinolones were prescribed in 38% of patients pre-FDA boxed warning and in 30% of patients post-FDA boxed warning (8% reduction; P = 0.08). A step-wise logistic regression was performed to identify predictors of fluoroquinolone prescribing in a subgroup of 371 patients with renal function data available. Age ≥ 58 years and chronic kidney disease, defined as a glomerular filtration rate <60 mL/min/1.73m2 were both associated with a statistically significant increase in fluoroquinolone prescribing. Although the FDA boxed warning was associated with a 33% decrease in fluoroquinolone prescribing, this finding did not meet statistical significance (Table).

Secondary outcomes of the study included concordance of antibiotic prescribing with clinical practice guidelines and treatment failure. The overall concordance of antibiotic dose, frequency and duration of therapy with the IDSA recommendations was 26%, and ranged from 15% to 47% between the clinic sites. Treatment failure, defined as a second prescribed antibiotic, emergency department visit, or hospitalization for UTI, occurred in 45 patients (10%).

The authors of this study concluded that the 2016 FDA boxed warning did not significantly decrease the rate of fluoroquinolone prescribing for uUTIs in their family medicine practice clinics. Although this study had limitations, including its single-center, retrospective design, the shorter, 5-month time period after July 2016, and the lack of antibiotic cost analysis, the findings were corroborated by a similar study at the University of North Carolina Health Care System from April 2014 to August 2017.5

These results highlight the need for antimicrobial stewardship initiatives in inpatient, outpatient, and emergency department settings to optimize the treatment of uUTIs in regard to antibiotic selection, dosing, and duration of treatment. Furthermore, 40% of the patients in this study received antibiotic prescriptions for asymptomatic bacteriuria, supporting other published literature on the need for education regarding the appropriate use of antibiotics in this context.

Notably, patients aged ≥ 58 years were 3-times more likely to be prescribed a fluoroquinolone for uUTIs in this study. Given the increased risk of severe fluoroquinolone-induced adverse effects and increased difficulty of symptomatic UTI diagnosis with older age, this may represent a valuable patient population for targeted antimicrobial stewardship. 6-8 Strategies such as decision algorithms, prescriber education, peer comparison, and computer-based order sets have been shown to effectively decrease inappropriate antibiotic use.9,10 Specifically at primary care practice sites, peer comparison was found to have a sustained benefit even 12 months after the intervention was stopped, confirming the importance of establishing impactful methods of antimicrobial stewardship. 10 Interventions such as these will be even more important in the future, with the pending Joint Commission requirement of antimicrobial stewardship in ambulatory care centers.

Catherine Li, PharmD, is currently a PGY-2 infectious diseases pharmacy resident at Beth Israel Deaconess Medical Center in Boston, MA. Her clinical interests include antimicrobial stewardship, antimicrobial resistance, and transitions of care.


  1. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the infectious diseases society of America and the European society for microbiology and infectious diseases. Clin Infect Dis. 2011;52(5): e103-120. doi:10.1093/cid/ciq257.
  2. US Food and Drug Administration. FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. https://www.fda.gov/media/97602/download. Published May 12, 2016. Accessed September 22, 2019.
  3. US Food and Drug Administration. FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. https://www.fda.gov/media/99425/download. Published July 26, 2016. Accessed September 22, 2019.
  4. Cowart K, Worley M, El Rouby N, Sando K. Evaluation of FDA Boxed Warning on Prescribing Patterns of Fluoroquinolones for Uncomplicated Urinary Tract Infections. Ann Pharmacother. 2019; 53(12):1192-1199. doi:10.1177/1060028019865224.
  5. Willis Z, Dusetzina S, Anderson DJ, Paiewski N, Kinlaw A. Antibiotic prescribing before and after an FDA boxed warning on fluoroquinolones in 2016. Open Forum Infect Dis. 2018;5 (suppl 1):S532. doi:10.1093/ofid/ofy210.1519.
  6. Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly: an update. Drugs Aging. 2010; 27(3):193-209. doi:10.2165/11531490-000000000-00000.
  7. Mayne S, Bowden A, Sundvall PD, Gunnarsson R. The scientific evidence for a potential link between confusion and urinary tract infection in the elderly is still confusing - a systematic literature review. BMC Geriatrics. 2019; 19(1): 32. doi:10.1186/s12877-019-1049-7.
  8. Gbinigie OA, Ordonez-Mena JM, Fanshawe, Plüddemann A, Heneghan C. Diagnostic value of symptoms and signs for identifying urinary tract infection in older adult outpatients: Systematic review and meta-analysis. J Infect. 2018; 77(5):379-390. doi:10.1016/j.jinf.2018.06.012
  9. Trautner BW, Grigoryan L, Petersen NJ, et al. Effectiveness of an antimicrobial stewardship approach for urinary catheter-associated asymptomatic bacteriuria. JAMA Intern Med. 2015; 175(7):1120-1127. doi: 10.1001/jamainternmed.2015.1878.
  10. Linder JA, Meeker D, Fox CR, et al. Effects of behavioral interventions on inappropriate antibiotic prescribing in primary care 12 months after stopping interventions. JAMA. 2017; 318(14):1391-92. doi:10.1001/jama.2017.11152.
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