Infectious Disease

You Can't Spell Fluoroquinolones without N-O

Once routinely prescribed for a variety of infections, fluoroquinolones have been shown to increase the likelihood of a host of negative effects and are now used sparingly. Do you know the 3 conditions for which they're still first-line treatment?

Fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin, among others) are an important class of antibiotics used in a variety of settings. Until fairly recently, ciprofloxacin was a primary treatment option for cystitis. It has been used routinely for inpatient treatment of pneumonia, and many still consider it part of the first-line treatment for diverticulitis. However, in the past few years its role has come into question as concerns abound regarding its safety profile. The quinolone class of antibiotics is associated with tendinitis and Achilles tendon rupture, and potentially significant adverse effects don't stop there: other deleterious muscle and connective tissue effects may be seen.

In 2008, the FDA added its first black box warning to fluoroquinolones, indicating the risk for tendon injuries. Despite this, in 2010, levofloxacin was the best-selling antibiotic in the U.S., with sales exceeding $1.5 billion. By 2012, it was the subject of more than 3,000 lawsuits following severe reactions.

The first successful lawsuit involved an 82-year-old male who was prescribed levofloxacin and a corticosteroid for an upper respiratory infection. He suffered bilateral Achilles tendon ruptures and was ultimately awarded $1.8 million. In a large population-based case control analysis, patients treated with fluoroquinolones had a 4.1-fold increase in risk of Achilles tendon rupture and a 46 times greater risk if there was concomitant use of corticosteroids.1

Risk factors include:

  • Elderly males (over the age of 60)
  • Patients with chronic renal disease
  • Patients taking corticosteroids

Symptoms of tendinopathy typically begin about 6 days after the onset of treatment, but the risk of tendon rupture persists for up to 90 days. More than 50% of patients experience symptoms that began after their treatment was completed.2

Oral fluoroquinolones have been shown to interfere with collagen synthesis. They also have a relatively high volume of distribution and bioavailability: this makes for a dangerous combination. A 2012 case-control study published in JAMA concluded that oral fluoroquinolones were associated with an increased risk of developing retinal detachment. Current users of oral fluoroquinolones were nearly 5 times more likely to be diagnosed with retinal detachment than non-users, although the risk did not translate to patients who had already completed treatment.3

Another case-control study attempted to quantify the risk of acute kidney injury. Researchers found a two-fold increase in the risk of acute kidney injury in patients currently taking fluoroquinolones.4

A study in JAMA Surgery found that patients who received fluoroquinolones had a higher risk for aneurysms, ruptures, or dissections than those who did not receive the antibiotics. The study showed that normal, unstressed mice who took the antibiotic did not show significant negative effects on the aorta. Mice with moderately stressed aortas who were given fluoroquinolones developed aortic aneurysm and dissection 79% of the time, compared to 45% of those moderately stressed mice who did not receive the antibiotic.5 This led the FDA to issue the following statement in December 2018:

"A U.S. Food and Drug Administration (FDA) review found that fluoroquinolone antibiotics can increase the occurrence of rare but serious events of ruptures or tears in the main artery of the body, called the aorta....Fluoroquinolones should not be used in patients at increased risk unless there are no other treatment options available. People at increased risk include those with...high blood pressure, certain genetic disorders that involve blood vessel changes, and the elderly..."

The manufacturer is reportedly facing an $800 million lawsuit, alleging that the company hid vital information about side effects of levofloxacin. The lawsuit argues, among other things, that in 2015 at an Advisory Committee meeting, the manufacturers were made aware of and chose to ignore a potential link between levofloxacin and "Fluoroquinolone- Associated Disability" (FQAD). Long-term FQAD may manifest as chronic fatigue, neuropathies, and memory and concentration problems.

There are 3 conditions for which fluoroquinolones are still considered first-line treatment:

  1. Prostatitis
  2. Anthrax
  3. Plague

In the absence of any of these conditions, strongly consider an alternate class of antibiotic.

For instance, for years, the goto outpatient treatment for patients diagnosed with diverticulitis has been 10 days of ciprofloxacin and metronidazole. An acceptable alternative is amoxicillinclavulanate 875 mg every 8 hours (or 1 g every 12 hours). Trimethoprimsulfamethoxazole (1 double-strength tablet every 12 hours) can also replace ciprofloxacin and be used in concert with metronidazole. A 2017 study questioned the use of antibiotics altogether in a first episode of CT-proven uncomplicated acute diverticulitis. Approximately 260 patients were randomized to observation and 260 to antibiotics; there were no significant differences between the groups for complications, ongoing diverticulitis, recurrence, sigmoid resection, readmission, or mortality.6 Antibiotics remain the standard of care and should be prescribed, but this study does provide food for thought.

When prescribing fluoroquinolones, consider any reasonable alternative. If there is none, explain the potential risks and benefits to your patient. Document this conversation to minimize risk in the event of a bad outcome.


References
1. Giovanni C et al. Evidence of tendinitis provoked by fluoroquinolone treatment. Drug Saf. 2006;29(10):889–896.
2. Royer RJ et al. Features of tendon disorders with fluoroquinolones. Therapie. 49(1):75-6.
3. Etminan M et al. Oral fluoroquinolones and the risk of retinal detachment. JAMA. 2012;307(13):1414-1419.
4. Bert S et al. Risk of acute kidney injury associated with the use of fluoroquinolones. CMAJ. 2013 Jul 9; 185(10): E475–E482.
5. LeMaire S et al. Effect of Ciprofloxacin on susceptibility to aortic dissection and rupture in mice. JAMA Surg. 2018;153(9).
6. Daniels L et al. Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis. Br J Surg. 2017 Jan;104(1):52-61.
7. Kabbani S et al. Opportunities to improve fluoroquinolone prescribing in the United States for adult ambulatory care visits. Clinical Infectious Diseases. 2018 Jun;67(1):134–136.

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