MPA | Pharmacy News

by Kara Buck, Pharm.D., Pharmacy Resident, St. Joseph Mercy Hospital, Ann Arbor, MSHP member

Fluoroquinolones (FQ) are widely used in both inpatient and outpatient settings to treat pneumonia, urinary tract infections, intra-abdominal infections and others. In 2011, approximately 23 million patients filled outpatient prescriptions for fluoroquinolones and 3.8 million inpatients billed for fluoroquinolones.1 However, given the notable toxicities and development of resistance, there has been a recent effort to restrict their use.

Fluoroquinolone labeling currently contains warnings regarding tendonitis, tendon rupture, central nervous system effects, peripheral neuropathy, myasthenia gravis exacerbation, hepatotoxicity, QT prolongation, Torsades de Pointes, phototoxicity and hypersensitivity amongst other precautions.2 In 2013, the FDA required stricter warning labeling for FQs that highlights the risk of peripheral neuropathy which can last months or be permanent.1 Additionally, some FDA committee members suggested adding the risk of prolonged neuropathy to the Boxed Warning.

Fluoroquinolone related-toxicities garnered so much provider and public attention that a term, fluoroquinolies-associated disability (FQAD), was coined to describe the constellation of symptoms resulting in disability lasting 30 days after the end of treatment. Notably, FQAD cases reported in the FDA Adverse Events Reporting System (FAERS) were not associated more frequently with any one of the three major FQs: moxifloxacin, levofloxacin or ciprofloxacin. Typically FAERS reports are generated by healthcare professionals; however a disproportionate 84% of FQAD cases were reported to the system by the public.3

In addition to heightened awareness of toxicities, poor evidence exists for many indications for which FQs are used. Two FDA Advisory Committees, Antimicrobial Drugs and Drug Safety and Risk Management, overwhelmingly agreed in November 2015 that evidence is lacking for use of FQs as first line therapy in acute bacterial sinusitis, COPD exacerbations and uncomplicated UTI.4 Prescribing practices, however, lag behind the evidence. The question still remains, though, as to what clinicians should be relying on.

Inappropriate use and overuse of antibiotics is a factor in the continued spread of antibiotic-resistant microbes. In order to improve quality of care and lower healthcare costs, antimicrobial stewardship has become a priority. By taking a closer look at FQ pitfalls, we can generate a list of supportive evidence for recommending discontinuation or switching to therapy as appropriate.

Uncomplicated UTI COPD exacerbations Acute bacterial sinusitis
  • Nitrofurantoin: previously discouraged in renal insufficiency, now generally regarded as effective and safe with CrCl ≥ 30 mL/min
  • Trimethoprim/sulfamethoxazole
  • Cephalosporins: if organism is susceptible
  • Amoxicillin/clavulanate
  • Azithromycin
  • Doxycycline
  • Ceftriaxone or cefepime
  • Limit antibiotics to patients with severe exacerbations having at least 2 of 3 cardinal symptoms: increase in sputum purulence, volume or dyspnea
  • Amoxicillin/clavulanate
  • Doxycycline: in PCN allergic patients
  • Over 90% of cases are viral. Consider antibiotics only for patients with ≥ 10 days without improvement or severe symptoms such as fever ≥ 102 °F


  • Quinolone Interactions
    Chelation Other Interactions
    Interactions
    1. Metals: iron, zinc, calcium, magnesium, aluminum
    2. Medications: antacids, sucralfate, phosphate binders
    3. Food: dairy products
    Avoid concomitant use with other agents that prolong QT intervals
    Ciprofloxacin: take interacting chelators at least two hours before or six hours after ciprofloxacin Warfarin: increased risk of bleeding
    1. Requires increased INR monitoring
    Levofloxacin: take interacting chelators at least two hours before or two hours after levofloxacin Antidiabetic agents: hypo- or hyperglycemia reported
    1. Increase blood glucose monitoring
    Ciprofloxacin inhibits CYP1A2 which can increase the serum concentration of substrates including:
    1. Tizanidine: contraindicated with ciprofloxacin
    2. Duloxetine: avoid use with ciprofloxacin
    3. Methylxanthines, caffeine, ropinerole, clozapine, olanzapine (Use with caution with ciprofloxacin)


    Quinolone Side Effects
    Peripheral neuropathy and paresthesias5 (0.1% - 1%) 1. Nerve damage can persist for months or indefinitely
    2. Discontinue FQ if patient develops symptoms
    Clostridium difficile 1. Fluoroquinolones are the leading antibiotic class causing Clostridium difficile associated diarrhea6
    2. Development of C. difficile increases hospital length of stay and healthcare expenditures 7
    Tendinitis and tendon rupture8 Risk factors: age > 60, male > female (2:1), concurrent corticosteroids (46 x greater risk), renal dysfunction, DM, musculoskeletal disease
    2. Compared to other antibiotic classes, FQ's have four fold greater risk for Achilles tendinitis or rupture (90-95% of cases involve the Achilles; median onset is six days; risk persists after discontinuation of FQ)
    QT prolongation Increased risk for Torsades de Pointes
    Delirium (rare) Increased risk with elderly and concomitant use of NSAIDs
    Hypo- or hyperglycemia in diabetic patients
    Photosensitivity
    Retinal detachment (controversial)9
    Pancytopenia (rare)


    Knowing the risks that accompany FQ use is important. The public grows increasingly more aware and wary of FQ-related toxicities. Not only are FQs making their way into national news, but social media is also impacting public opinion with the emergence of a multitude of support groups for affected patients (who often refer to themselves as "Floxies"). Being well-versed in the appropriate indications and the relative risks and benefits of FQs will help us best assist patients and providers in making informed, and individualized therapy decisions.

    References
    1. FDA U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or injection. Updated 8/15/2013. http://www.fda.gov/Drugs/DrugSafety/ucm365050.htm
    2. Cipro® [package insert]. Ciprofloxacin package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.
    3. Smith, M. Evidence Lacking for Some Fluoroquinolone Use. Medpage Today. Updated 11/06/2015. Accessed 2/01/16. http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/54528?xid=nl_mpt_guptaguide_2015-11-06&eun=g8286033d10r
    4. FDA Briefing Document. 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). 11/05/2015. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM467383.pdf
    5. Kuehn BM. FDA warning and study highlight fluoroquinolone risks. JAMA. 2013;310(10):1014.
    6. McCusker ME, Harris AD, Perencevich E, Roghmann MC. Fluoroquinolone Use and Clostridium difficile–Associated Diarrhea. Emerging Infectious Diseases. 2003;9(6):730-733.
    7. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to clostridium difficile. Clin Infect Dis. 2002;34(3):346-353.
    8. Kim GK, Del Rosso JQ. The risk of fluoroquinolone induced tendinopathy and tendon rupture: what does the clinician need to know? Clinical and Aesthetic Dermatology. 2010;3(41):49-54.
    9. Etminan M, Forooghian F, Brophy J, Bird ST, Maberley D. Oral fluoroquinolones and the risk of retinal detachment. JAMA. 2012;307(13):1414-1419.

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