Often-Misused Fluoroquinolone Antibiotics Pose Serious Risks

One of the biggest-selling and most overprescribed classes of antibiotics in the United States is the family called fluoroquinolones.[1],[2] These antibiotics can be used to treat bacterial infections in many parts of the body in appropriately selected patients. For example, for certain infections, a fluoroquinolone may be a reasonable treatment option for individuals who are allergic to, or whose infections are resistant to, safer antibiotics.

However, fluoroquinolones — like many other antibiotics — are commonly misprescribed for viral infections, such as colds and most sore throats, which do not respond to antibiotics.[3],[4],[5] In addition, the drugs often are used to treat bacterial infections, such as bladder infections and community-acquired (as opposed to hospital-acquired) pneumonia, when other, safer, antibiotics would be the first choice.[6],[7]

Such misuse of fluoroquinolones exposes patients to the risk of a variety of potentially serious, avoidable adverse effects.

Two of five: Do Not Use

Five fluoroquinolones currently are available in either oral or intravenous form in the U.S. (see table, this page). (Additional fluoroquinolones are available only as eyedrops or ear drops and are not discussed here.) Each has been approved by the Food and Drug Administration (FDA) for treating several types of infections caused by specific types of susceptible bacteria. These antibiotics are easily recognized as members of the fluoroquinolone family because their generic names all end with "floxacin."

Fluoroquinolones Available in the U.S.For Oral or Intravenous (IV) Use

*Do Not Use.
**Limited Use.

Public Citizen's Health Research Group has designated two of the five as Do Not Use. The first is gemifloxacin (FACTIVE), which was approved by the FDA in 2003. During the FDA's preapproval review of gemifloxacin, significant questions arose regarding the drug's safety.[13] Major concerns involved the relationship between gemifloxacin and a higher-than-expected rate of rash reported in patients receiving the drug, the possibility that the frequent occurrence of rash may foreshadow a risk for more serious skin reactions, and the potential for inducing allergies to other fluoroquinolone antibiotics. Also, there were unresolved questions regarding liver safety and concern that the drug may cause QT prolongation in some patients. QT prolongation, a change in the electrical activity of the heart, can lead to a fatal heart rhythm disturbance called torsades de pointes, resulting in sudden death.

The second fluoroquinolone designated as Do Not Use is moxifloxacin (AVELOX), which was approved by the FDA in 1999.[14] The drug is no more effective than other fluoroquinolones, and it also can cause QT prolongation.[15]

We have designated the other fluoroquinolones — ciprofloxacin (CIPRO, CIPRO XR), levofloxacin (LEVAQUIN) and ofloxacin (available only in generic form) — as Limited Use drugs. For many infections for which these drugs are FDA-approved, there are other, safer antibiotics that are likely to be as or more effective than one of these fluoroquinolones.

For example, for many women with uncomplicated acute bladder infection, the antibiotic combination trimethoprim-sulfamethoxazole (BACTRIM, SEPTRA, SULFATRIM PEDIATRIC) is an appropriate first-choice antibiotic. This can be used unless the bacteria causing the infection are resistant to this drug or the patient is allergic to the medication.[16]

Likewise, for previously healthy adults who develop community-acquired pneumonia, azithromycin (ZITHROMAX, ZMAX) and clarithromycin (BIAXIN) are the preferred, first-line antibiotics.[17]

Key safety warnings

Tendon injury[18]

In 2006, Public Citizen's Health Research Group petitioned, and later successfully sued, the FDA to add a black-box warning to all fluoroquinolone labeling about the risk of tendinitis, including the possibility of complete tendon rupture.[19] Our petition also asked the FDA to require pharmacists to distribute FDA-approved Medication Guides informing consumers about this risk and what steps to take if unexplained tendon pain should develop while taking one of these antibiotics. The FDA granted our petition in 2008.

This adverse reaction most frequently involves the Achilles tendon, the tendon that runs from the back of the heel to the calf. Rupture of the Achilles tendon may require surgical repair. Damage to tendons in the rota­tor cuff (the shoulder), hand, biceps and thumb also has been seen with fluoroquinolone use.

Tendon injury appears to be more common in those taking steroid drugs, older patients and organ transplant recipients, but cases have occurred in people without any of these risk factors. The onset of symptoms is sudden and may occur as soon as 24 hours after starting treatment with a fluoroquinolone. Most people recover completely after one to two months.

Antibiotic-associated diarrhea[20]

Antibiotic-associated diarrhea (AAD) is a common adverse effect of antibiotic treatment. Many different types of antibiotics, including fluoroquinolones, can cause AAD. One potentially life-threatening form of AAD is caused by C. difficile — short for Clostridium difficile bacteria — which can infect the colon following antibiotic treatment. (See the August 2015 issue of Worst Pills, Best Pills News for a detailed discussion of this disease.[21])

Muscle disorder

The product labeling for all fluoroquinolones includes a black-box warning indicating that the drugs can cause worsening muscle weakness in patients with a known history of myasthenia gravis.[22] Myasthenia gravis is a rare disease caused by antibodies produced by the body's own immune system that block nerve impulses to muscles.[23] The main symptom of the disease is muscle weakness, particularly during periods of activity.[24] Muscles that control eye and eyelid movement, facial expression, and swallowing are most frequently affected.[25]

Nerve damage[26]

Fluoroquinolones have been associated with rare cases of peripheral neuropathy (damage to the nerves in the arms, hands, legs or feet). Symptoms may include numbness; tingling, burning or other abnormal sensations; and weakness.

Abnormal heart rhythm

The labels for all fluoroquinolones now warn about the risk of QT prolongation and life-threatening abnormal heart rhythms.[27],[28],[29],[30],[31] The risk of this adverse event appears to be lowest with ciprofloxacin, levofloxacin, and ofloxacin and highest with moxifloxacin.[32] All fluoroquinolones should be avoided in patients who already have some degree of QT prolongation, have hypokalemia (low blood potassium levels) or are taking other drugs that cause QT prolongation.

Fetal damage

Fluoroquinolones caused fetal harm in animal studies, including decreased body weight and malformed bones, as well as an increased risk of death.[33]

What You Can Do

Whenever your doctor prescribes you a fluoroquinolone, you should ask whether your illness requires any antibiotic and, if so, whether an alternative antibiotic would likely be as or more effective.

If you are pregnant, do not use these drugs: There is potential for serious adverse effects to the fetus.

If you develop tendon pain or symptoms of nerve injury while taking a fluoroquinolone, you should immediately contact the prescribing doctor or your primary health care provider so that you can be switched to a different antibiotic in order to decrease your risk of progression to a tendon rupture or permanent nerve injury.

Call your doctor immediately if you experience any of the symptoms listed in the box on this page, as these may indicate other serious adverse drug reactions.

You should not discontinue the use of any medication without first consulting your doctor.

References

[1] Werner NL, Hecker MT, Sethi AK, Donskey CJ. Unnecessary use of fluoroquinolone antibiotics in hospitalized patients. BMC Infect Dis. 2011;11:187. doi: 10.1186/1471-2334-11-187.

[2] Linder JA, Huang ES, Steinman MA, et al. Fluoroquinolone prescribing in the United States: 1995-2000. Am J Med. 2005;118(3):259-268.

[3] Werner NL, Hecker MT, Sethi AK, Donskey CJ. Unnecessary use of fluoroquinolone antibiotics in hospitalized patients. BMC Infect Dis. 2011;11:187. doi: 10.1186/1471-2334-11-187.

[4] Linder JA, Huang ES, Steinman MA, et al. Fluoroquinolone prescribing in the United States: 1995-2000. Am J Med. 2005, 118(3):259-268.

[5] Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. JAMA Intern Med. 2014;174(1):138-140.

[6] Werner NL, Hecker MT, Sethi AK, Donskey CJ. Unnecessary use of fluoroquinolone antibiotics in hospitalized patients. BMC Infect Dis. 2011;11:187. doi: 10.1186/1471-2334-11-187.

[7] Lautenbach E, Larosa LA, Kasbekar N, et al. Fluoroquinolone utilization in the emergency departments of academic medical centers: Prevalence of, and risk factors for, inappropriate use. Arch Intern Med. 2003;163(5):601-605.

[8] Bayer HealthCare Pharmaceuticals. Drug label for CIPRO. Revised February 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019537s083,020780s041lbl.pdf. Accessed July 27, 2015.

[9] Merus Labs International. Drug label for FACTIVE. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021158s022lbl.pdf. Accessed July 27, 2015.

[10] Janssen Pharmaceuticals. Drug label for LEVAQUIN. http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=a1f01e8e-97e9-11de-b91d-553856d89593&type=pdf&name=a1f01e8e-97e9-11de-b91d-553856d89593. Accessed July 27, 2015.

[11] Bayer HealthCare Pharmaceuticals. Drug label for AVELOX. Revised May 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021085s060,021277s056lbl.pdf. Accessed July 27, 2015.

[12] Teva Pharmaceuticals USA. Drug label for OFLOXACIN. http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=95b9fc17-9c94-4762-910c-df0bb0b2aa85&type=pdf&name=95b9fc17-9c94-4762-910c-df0bb0b2aa85. Accessed July 27, 2015.

[13] WorstPills.org. Drug profile for gemifloxacin. Last reviewed April 30, 2015. /monographs/view/263. Accessed July 27, 2015.

[14] Food and Drug Administration. Letter to Bayer Corporation approving the new drug application for Avelox, NDA 21-085. December 10, 1999. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1999/21085ltr.pdf. Accessed July 27, 2015.

[15] WorstPills.org. Drug profile for gatifloxacin, moxifloxacin, and sparfloxacin. Last reviewed April 30, 2015. /monographs/view/256. Accessed July 27, 2015.

[16] Hooton TM, Gupta K. Acute uncomplicated cystitis and pyelonephritis in women. UpToDate. Updated August 4, 2014.

[17] File TM. Treatment of community-acquired pneumonia in adults in the outpatient setting. UpToDate. Last updated June 18, 2015.

[18] WorstPills.org. Drug profile for ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin. Last reviewed April 30, 2015. /monographs/view/258. Accessed July 27, 2015.

[19] Public Citizen. Petition for a black box warning on fluoroquinolone antibiotics. August 29, 2006. http://www.citizen.org/Page.aspx?pid=693. Accessed August 6, 2015.

[20] WorstPills.org. Drug profile for ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin. Last reviewed April 30, 2015. /monographs/view/258. Accessed July 27, 2015.

[21] Antibiotics, common heartburn drugs and spread of potentially fatal intestinal infection. Worst Pills, Best Pills News. August 2015. /newsletters/view/978. Accessed August 5, 2015.

[22] WorstPills.org. Drug profile for ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin. Last reviewed April 30, 2015. /monographs/view/258. Accessed July 27, 2015.

[23] National Institute of Neurological Disorders and Stroke. Myasthenia gravis fact sheet. Last updated July 27, 2015. http://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm. Accessed July 28, 2015.

[24] Ibid.

[25] Ibid.

[26] WorstPills.org. Drug profile for ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin. Last reviewed April 30, 2015. /monographs/view/258. Accessed July 27, 2015.

[27] Bayer HealthCare Pharmaceuticals. Drug label for CIPRO. Revised February 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019537s083,020780s041lbl.pdf. Accessed July 27, 2015.

[28] Merus Labs International. Drug label for FACTIVE. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021158s022lbl.pdf . Accessed July 27, 2015.

[29] Janssen Pharmaceuticals. Drug label for LEVAQUIN. http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=a1f01e8e-97e9-11de-b91d-553856d89593&type=pdf&name=a1f01e8e-97e9-11de-b91d-553856d89593. Accessed July 27, 2015.

[30] Bayer HealthCare Pharmaceuticals. Drug label for AVELOX. Revised May 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021085s060,021277s056lbl.pdf. Accessed July 27, 2015.

[31] Teva Pharmaceuticals USA. Drug label for OFLOXACIN. http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=95b9fc17-9c94-4762-910c-df0bb0b2aa85&type=pdf&name=95b9fc17-9c94-4762-910c-df0bb0b2aa85. Accessed July 27, 2015.

[32] Hooper DC. Fluoroquinolones. UpToDate. Updated July 21, 2015. http://www.uptodate.com/contents/fluoroquinolones?source=search_result&search=fluoroquinolones&selectedTitle=1~150. Accessed July 28, 2015.

[33] WorstPills.org. Drug profile for ciprofloxacin, levofloxacin, lomefloxacin and ofloxacin. Last reviewed April 30, 2015. /monographs/view/258. Accessed July 27, 2015.