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InFocus

Rethinking the Use of Fluoroquinolones

Roberts, James R. MD

doi: 10.1097/01.EEM.0000503374.23445.6d
InFocus

Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, CEN, athttp://emn.online/ProceduralPauseEMN, and read his past columns athttp://emn.online/InFocusEMN.

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Fluoroquinolones are a popular class of antibiotics for a variety of infections; six different ones are currently available to clinicians. These antibiotics have a rather broad spectrum of activity for mainly gram-negative bacteria but also for some gram-positive organisms. Hardly a day goes by that we emergency physicians do not write a prescription for a fluoroquinolone, and he rarely gives it a second thought.

We do not see patients in long-term follow-up, and do not know or frequently encounter many of the adverse side effects, but multiple toxicities are associated with fluoroquinolone antibiotics. In fact, a number of fluoroquinolones, such as grepafloxacin, sparfloxacin, trovafloxacin, gatifloxacin, and norfloxacin have been withdrawn in the United States because of adverse side effects. Fluoroquinolones are antibacterial agents that have a rather unique mechanism of action. They inhibit bacterial enzymes that have a distinct role in DNA replication and block the enzyme system in bacteria, leading to cell death.

Bacterial resistance to fluoroquinolones has occurred rather frequently, but their use remains widespread. As with most antibiotics, resistance is thought to be related to intensity and duration of therapy. In fact, it may take only a few days for bacteria to become resistant to a given fluoroquinolone. Fluoroquinolone resistance has now been found in a number of strains of Klebsiella, Escherichia coli, and Enterobacter. Resistance mechanisms are rather complex, but fluoroquinolone resistance has been most frequent in methicillin-resistant strains of Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Fluoroquinolones were once the mainstay of therapy for gonorrhea, but they are no longer recommended for treating this sexually transmitted disease in the United States. Resistance has also been creeping up in Campylobacter and Streptococcus pneumoniae.

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Fluoroquinolones have their greatest clinical activity against aerobic gram-negative bacilli, and ciprofloxacin remains one of the most potent antibiotics against gram-negative bacteria. Other bacteria inhibited by fluoroquinolones include Legionella, Mycoplasma, and Chlamydia organisms. Fluoroquinolones are also quite active against common respiratory pathogens such as Haemophilus influenzae, Moraxella catarrhalis, and S. pneumoniae, which is why the fluoroquinolone levofloxacin is recommended as single empiric therapy for community-acquired pneumonia.

Fluoroquinolones are generally well tolerated, but common adverse effects include gastrointestinal and central nervous system toxicities, rashes, tendinitis and tendon rupture, QT prolongation, hyper- and hypoglycemia, and hematologic toxicity. The FDA Safety and Information Adverse Event Reporting Program issued a drug safety communication in July entitled, “Fluoroquinolone Antibacterial Drugs for Systemic Use: Drug Safety Communication-Warnings Updated Due to Disabling Side Effects.” (http://bit.ly/2aWhprE.) The fluoroquinolones involved were moxifloxacin (Avelox), ciprofloxacin (Cipro), gemifloxacin (Factive), ofloxacin, and levofloxacin (Levaquin).

Comment: The FDA in May restricted the use of fluoroquinolones for certain common uncomplicated infections. Serious side effects are associated with fluoroquinolones that generally outweigh the benefits, and the FDA advised against using fluoroquinolones for patients with sinusitis, bronchitis, or uncomplicated urinary tract infections when other options exist. Fluoroquinolones, particularly ciprofloxacin, used to be a mainstay for treating run-of-the-mill cystitis, but that drug was taken off the preferred antibiotic list by infectious disease society recommendations a number of years ago. Many clinicians still prescribe it.

Sinusitis and bronchitis are usually viral and don't require antibiotics anyway, but it is common for clinicians to prescribe fluoroquinolones for these infections. The FDA stated that fluoroquinolones are associated with disabling and potentially permanent serious neurologic side effects, an important caution. These side effects could involve muscles, joints, peripheral nerves, and the central nervous system, and the FDA required drug label and medication guide changes for all fluoroquinolones to reflect the updated safety information.

The FDA added a black box warning back in July 2008 that fluoroquinolones could cause tendonitis and tendon rupture, particularly in patients over 60 and especially for those with kidney, heart, and lung transplants who were using concomitant steroid therapy. It was further advised that physicians should stop fluoroquinolone use at the first sign of tendon pain, swelling, or inflammation. Clinicians should also advise patients to avoid exercise in the affected areas. I would add that immobilization also be used to limit Achilles tendon use.

The FDA also issued fluoroquinolone advisory in August 2013, saying fluoroquinolones could cause peripheral neuropathy soon after the drugs were taken, and it could be prolonged or even permanent. I have not seen the FDA become so involved in commenting on and warning about potential side effects of antibiotics as it has with fluoroquinolones. Side effects associated with these antibiotics range from rashes to QT prolongation.

Gastrointestinal: GI side effects occur in five to 15 percent of patients taking fluoroquinolones. These include anorexia, nausea, vomiting, and abdominal discomfort, which are usually mild. Diarrhea is less frequent. Fluoroquinolones have been associated institutional outbreaks of Clostridium difficile-associated diarrhea. Patients would likely associate such GI side effects with antibiotic use, but these side effects should prompt change in antibiotics.

Nervous System: Up to about 10 percent of patients taking fluoroquinolones will have CNS side effects. Symptoms include mild headache, dizziness, insomnia, and alterations in mood. Most emergency clinicians would unlikely be notified of these side effects, but they can be rather striking and could present to the ED for evaluation, where it would be important to have the history. Hallucinations, delirium, and even acute psychosis and seizures have been reported, but they are rare. I once saw a seizure in a patient after two doses of oral ciprofloxacin.

Peripheral neuropathy is an important but often unappreciated potential toxicity of fluoroquinolones. These are worrisome adverse reactions. The clinical scenario might be vague, but will include neurologic symptoms in the arm or leg such as burning, tingling, numbness, weakness, and change in sensation and temperature sense. This annoying side effect can last for months to years, and has also been reported to be permanent. The onset is rather rapid, occurring within a few days. Peripheral neuropathy is a rather unusual and potentially serious side effect that has no known specific risk factors, and is likely simply bad luck for the patient who develops them. Again, patients and clinicians would not likely associate these symptoms with antibiotic use immediately, and could continue the offending medication.

Skin Rashes: Unspecified skin rashes have developed in about two percent of patients taking fluoroquinolones.

Tendinopathy and Tendon Rupture: Tendinopathy and tendon rupture have been reported in adults given fluoroquinolones, most often involving the Achilles tendon. Other tendons involved include the rotator cuff, biceps, and thumb. It would be unusual for a patient, even a physician, to associate pain in the heel, arm, or the shoulder with an antibiotic previously given for a urinary tract infection or sinusitis. This side effect, however, garnered a specific black box warning for all fluoroquinolones. The drug should be stopped when these side effects occur, but there is no known other intervention that is curative. Achilles tendon rupture can occur in elderly patients with minor trauma and absent fluoroquinolone use. Complications secondary to using the drugs for many months have also been suggested, so patients don't have to be currently taking the antibiotics.

QT Prolongation and Arrhythmia: QTc prolongation and development of serious arrhythmias are rarely linked to fluoroquinolone use. The drug most commonly involved was gatifloxacin. It is unclear whether ciprofloxacin or levofloxacin are associated with this cardiovascular side effect. It has not been suggested that an ECG be done prior to fluoroquinolone use, but use caution when these antibiotics are administered to patients who are also treated with other drugs that prolong the QTc interval. The list of medications and conditions that prolong the QTc interval is enormous, and would include most of the antipsychotic medications and tricyclic antidepressants, a variety of antiarrhythmic drugs including amiodarone, and hypokalemia and hypomagnesemia drugs.

In short, physicians should have great respect for fluoroquinolone side effects and should not prescribe them routinely for sinusitis, bronchitis, or uncomplicated urinary tract infections. It would now be prudent for clinicians to warn patients of fluoroquinolone-related adverse effects, but it's not clear exactly what to tell them. Often stopping the drugs does not alter some of the adverse effects. Importantly, there appears to be no way to predict who will develop adverse effects. Many patients would not take the drugs if all of the fluoroquinolone side effects were stressed, so one must temper warnings with clinical use.

Psychosis, seizures, bizarre dreams, and hallucinations would not likely be attributed to an antibiotic by most patients or clinicians, but they are clearly associated with fluoroquinolones. It is best to provide a written list of potential complications at discharge, and this is best done with a computer-based program. Pharmacies now provide such written information with all prescriptions. Whether patients remember multiple warnings or appropriately react to such cautions is uncertain. One might consider a fluoroquinolone side effect in a patient who comes to the ED with a number of unusual musculoskeletal complaints, dizziness, numbness and tingling, or syncope that may have been produced by QT prolongation arrhythmias. To make it more complicated, the drugs may have been prescribed in the past and not be on the current medication list.

Finally, a perusal of Google yields some really bad press for these antibiotics, and the medicolegal side has tweaked plaintiff lawyers. Reading some of the horror stories in chat rooms will inflame and convince many that fluoroquinolones have produced their multiple unexplained conditions, but the exact correlation of fluoroquinolone use with many bizarre and prolonged complaints is suspect. I posit that the best approach is to limit the use of these antibiotics, and when prescribed, carefully document that you cautioned patients about the side effects. In the long run, however, it is impossible to predict who will develop a specific adverse effect because they often occur with minimal use. The only way to avoid side effects is to eschew the fluoroquinolones prescription.

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International Clinical Practice Guidelines for 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

Optimal Treatment for Acute Uncomplicated Cystitis

  • Nitrofurantoin (100 mg twice daily for five days) is an appropriate choice for therapy because of minimal resistance and propensity for collateral damage.
  • Trimethoprim-sulfamethoxazole (one double-strength tablet twice-daily for three days) is an appropriate choice for therapy.
  • Fosfomycin trometamol (3 g in a single dose) where available is a good choice because of minimal resistance and propensity for collateral damage, but it appears to have inferior efficacy compared with standard short-course regimens.
  • Ofloxacin, ciprofloxacin, and levofloxacin are highly efficacious in three-day regimens, but have a propensity for collateral damage and should be reserved for important uses other than acute cystitis and thus should be considered alternative antimicrobials for acute cystitis.

Source: Clin Infect Dis 2011;52(5):e103.

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FDA Fluoroquinolone Alerts

May 26, 2016: The FDA is advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options.

Aug. 15, 2013: The FDA has required the drug labels and medication guides for all fluoroquinolone antibacterial drugs to be updated to better describe the serious side effect of peripheral neuropathy. This serious nerve damage potentially caused by fluoroquinolones may occur soon after these drugs are taken and may be permanent.

If a patient develops symptoms of peripheral neuropathy, the fluoroquinolone should be stopped, and the patient should be switched to another non-fluoroquinolone antibacterial drug unless the benefit of continued treatment with a fluoroquinolone outweighs the risk. Peripheral neuropathy is a nerve disorder occurring in the arms or legs. Symptoms include pain, burning, tingling, numbness, weakness, or a change in sensation to light touch, pain, or temperature, or the sense of body position. It can occur at any time during treatment with fluoroquinolones and can be permanent or last for months to years after the drug is stopped.

July 8, 2008: The FDA is notifying the makers of fluoroquinolone antimicrobial drugs for systemic use of the need to add a boxed warning to the prescribing information about the increased risk of developing tendinitis and tendon rupture in patients taking fluoroquinolones and to develop a medication guide for patients. The addition of a boxed warning and a medication guide would strengthen the existing warning information already included in the prescribing information for fluoroquinolone drugs.

Fluoroquinolones are associated with an increased risk of tendinitis and tendon rupture. Physicians should advise patients at the first sign of tendon pain, swelling, or inflammation to stop taking the fluoroquinolone, to avoid exercise and use of the affected area, and to promptly contact their doctor about changing to a non-fluoroquinolone antimicrobial drug.

Selection of a fluoroquinolone for the treatment or prevention of an infection should be limited to those conditions that are proven or strongly suspected to be caused by bacteria.

Reader Feedback: Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to emn@lww.com.

Dr. Roberts: Thank you for your article on the diagnosis of ureteral stones in the ED. (“Treating the Pain of Renal Colic,” EMN 2006;28[5]:24; http://bit.ly/2b1K5e4.) I am a general surgeon seeing a complicated older patient with lower left quadrant pain, flank pain, vomiting, a 104°F temperature, and severe dehydration. He appeared to have pyelonephritis, but the urinalysis was negative. A small distal left ureteral stone was found on CT, but it was negative for general surgical pathology.

I searched for 40 minutes online to find a good article on ureteral stones, pyelonephritis, etc., with negative urinalysis — nothing. Then I found your incredibly clear, informative, and comprehensive article, and it answered all of my questions. I learned important information, including looking for an alternative pathology given my patient's age. I just wanted you to know that you are helping doctors (and patients) beyond your targeted audience.

Keep up the good work. We in the field are fortunate to have academic authorities like you. — Erik Borncamp, MD

Dr. Roberts responds: Thanks so much for your accolades and kind words. I never thought a surgeon would read Emergency Medicine News. Your comments are much appreciated.

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