FDA stresses new warnings for Fluoroquinolone antibiotics

levofloxacin moleculeciprofloxacin molecule
The US Federal Drug Agency (FDA) Antimicrobial Drugs Advisory and the Drug Safety and Risk Management Advisory Committees met in early november (1, 2) to discuss the effectiveness and safety of systemic fluoroquinolones (FQs) antibiotics for the currently approved indications of acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis in patients who have chronic obstructive pulmonary disease (ABECB-COPD), and uncomplicated urinary tract infections (uUTIs). The meeting saw presentations from both the FDA and the pharmaceutical industry (and also heard from patients who were prescribed FQs) whereafter panel members voted on questions concerning whether the indications are supported by clinical evidence in light of new post-marketing surveillance data.


This review comes after the FDA required (Black) Boxed Warnings in FQ monographs for tendinitis and tendon rupture in 2008, and also for an association of peripheral neuropathy in 2013. The new safety issues  –  a constellation of symptoms termed fluoroquinolone-associated disability (FQAD)  –  are an example of the importance of post-marketing surveillance when very rare side-effects, which may or may not have been apparent in a relatively small sample of patients in pre-market clinical trials, are magnified after being approved for sale in the general population. In this case, the committees were presented data showing there still may be a problem of over-prescribing FQs for the following illness-specific reasons:

  • randomized trials in ABS and mild cases of ABECB-COPD show a large proportion of patients in placebo group recovered similarly to the respiratory FQ treatment arm and as such can be considered self-limiting illnesses in many cases (2)
  • recent international guidelines of uUTIs favor using potentially safer alternatives such as nitrofurantoin and sulfamethoxazole-trimethoprim (see Fig.1).


Figure 1 - uUTI Internation Guidelines (2)

Figure 1: Treatment algorithm for uUTIs, from the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases (3)


The committees also made recommendations aimed at manufacturers and other stakeholders such as:

  • Manufacturers: product labeling with more specific language indicating use as second line therapy ; incorporation of treatment guidelines put forth by professional societies; including language that describes the constellation of adverse effects identified as Fluoroquinolone-Associated Disability (FQAD); removing language identifying susceptible microorganisms and adding language stating that a positive culture should be obtained prior to initiating treatment with a fluoroquinolone (for ABECB-COPD)
  • Prescribers and Patients: adding a REMS program to the fluoroquinolones ranging from a Medication Guide to required education for prescribers and patients
  • Regulators, Industry and Academia: further study of FQAD, peripheral neuropathy, and psychiatric adverse effects
  • Professional Societies: change of drug labeling such as requiring urine cultures may be an important consideration for future guidelines in treating adult patients (uUTIs)
Figure 2 - bronchitis in COPD

Figure 2: Treatment algorithm for ABECB-COPD by Canadian Thoracic Society and the Canadian (5)


Given the limited benefits and the new potential safety risks reported as FQAD, the joint committees voted that fluoroquinolones are not supported for the currently labeled indications for the treatment of ABS, (mild) ABECB-COPD, or uUTI. The FDA has mentioned important caveats: first, there is robust evidence of effectiveness for moderate to severe ABECB-COPD and is often warranted in hospitalised patients (5, fig.2). Also, using FQs of uUTIs are effective for microbiological eradication of bacteria and resolution of symptoms, but ibuprofen-controlled trials showed similar proportions of symptom resolution. With regards to ABS, clinical guidelines still recommend using FQs in certain cases where first-line treatments are contraindicated or have failed (4, fig.3). It is also worth noting that these new safety issues are based mostly on temporal associations from analysis of surveillance data which cannot conclusively determine causality – this is why further study of FQAD is warranted. The medications affected by these recommendations include: ciprofloxacin (Cipro™), gemifloxacin (Factive™), levofloxacin (Levaquin™), moxifloxacin (Avelox™) and ofloxacin (Floxin™) and norfloxacin (generic only) in Canada.

Figure 3 - acute bacterial sinusitis

Figure 3: Treatment regimens for acute bacterial sinusitis in adults from the Infectious Disease Society of America (4)


By: Nicolas Basque, BscPharm, RPh




  1. Food and Drug Administration Center for Drug Evaluation and Research, Summary Minutes of the Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Risk and Safety Management Advisory Committee November 5, 2015 : http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm475246.pdf
  2. The Benefits and Risks of Systemic Fluoroquinolone Antibacterial Drugs for the Treatment of Acute Bacterial Sinusitis (ABS), Acute Bacterial Exacerbation of Chronic Bronchitis in Patients Who Have Chronic Obstructive Pulmonary Disease (ABECB-COPD), and Uncomplicated Urinary Tract Infections (uUTI), FDA Briefing Document Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee November 5, 2015 : http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM467383.pdf
  3. Gupta K 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-e120.doi: 10.1093/cid/ciq257 : http://cid.oxfordjournals.org/content/52/5/e103.full
  4. Chow AW et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults,  Clin Infect Dis. 2012 Apr;54(8):e72-e112. doi: 10.1093/cid/cir1043. Epub 2012 Mar 20.
  5. Balter SM et al., Canadian Guidelines for the management of acute exacerbations of chronic bronchitis: Executive Summary,Canadian Thoracic Society and the Canadian Infectious Disease Society, Can Respir J. Vol 10, No.5 July/August 2003

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