When Acute Chest Pain Just Might Be a Drug Reaction

Douglas S. Paauw, MD

Disclosures

December 28, 2015

The Adverse Effects of Fluoroquinolones

Aortic disease. A study[1] published in November 2015 examined the association between fluoroquinolones, including ciprofloxacin, and aortic disease. This nested case/control study examined 1477 patients hospitalized with aortic dissection or aneurysm and 147,700 controls identified from Taiwan's National Health Insurance Research Database. Exposure to current or past fluoroquinolone used was evaluated. After propensity-score adjustment, current use of fluoroquinolones was found to be associated with increased risk for aortic aneurysm or dissection (relative risk [RR], 2.43; 95% confidence interval [CI], 1.83-3.22). Past use was also associated with risk, though on a smaller scale (RR, 1.48; 95% CI, 1.18-1.86).

Retinal detachment. This newly identified risk adds to concerns about other important, previously identified side effects with these agents, although the evidence for some of these adverse effects is not complete. One concern is the possibility that fluoroquinolones increase the risk for retinal detachment, an potential association first raised in a study[2] published in 2012 that received much attention in the lay media. The study, also a nested case/control design, examined a cohort of patients visiting an ophthalmologist in British Columbia between 2000 and 2007. Patients with retinal detachment were identified and matched with 10 controls. The entire cohort comprised almost 1 million patients, and 4384 cases of retinal detachment were identified and matched with 43,840 controls. Current use of fluoroquinolones was associated with a risk for retinal detachment (adjusted rate ratio, 4.50; 95% CI, 3.56-5.70, with an average time from use to detachment of 4.5 days.

Subsequent studies have looked at this same question, and although some have documented a positive association between fluoroquinolones and retinal detachment, there have also been negative studies that have not found such an association. Recently, a meta-analysis[3] tried to help answer this question. The meta-analysis included seven observational studies; three case-control/self-control series and four cohort studies were narratively reviewed. Three of the four cohort studies found no significant association between fluoroquinolones use and the development of retinal detachment. The pooled absolute risk for retinal detachment while on current oral fluoroquinolone treatment was estimated to be 4.85 per 100,000 prescriptions.

The conclusion of this meta-analysis was that there was no association between oral fluoroquinolone use and the development of retinal detachment. Given the low absolute risks, if there was an association, such an event would be rare.

Tendon disorders. Another risk with use of fluoroquinolones that has been recognized for quite some time has been the risk for tendon rupture. A case-crossover study[4] published in 2012 attempted to identify factors that might predispose an individual using these drugs to a risk for Achilles tendinitis or rupture.

Using data from over 6 million patients collected in a large healthcare database, the researchers identified almost 29,000 patients with Achilles tendonitis and 7600 cases of Achilles tendon rupture. Charts were reviewed for antibiotic use in the preview 30 days and compared with the control patients. Risk factors for tendinitis evaluated were steroid use, body mass index (BMI), presence of diabetes, and renal failure.

Quinolone antibiotics were associated with an odds ratio (OR) of 4.3 for Achilles tendonitis and an OR of 2.04 for Achilles rupture. Risk for Achilles tendonitis was 48 per 100,000 new prescriptions; for Achilles tendon rupture, the risk was 6 per 100,000. Risk for Achilles tendonitis was higher in patients older than 60 years (OR, 8.3 vs 1.6 for patients < 60 years of age). Patients with a BMI < 30 kg/m2 had an OR of 7.7, whereas the OR in patients with a BMI > 30 kg/m2 was 2.4. Glucocorticoid use was associated with a stunning increase in risk, with an OR of 9.1 for Achilles tendonitis in patients taking steroids at the time they were prescribed quinolones vs an OR of 3.2 in patients not taking concomitant steroids.

A systematic literature search with best-evidence synthesis[5] published in 2014 examined risk factors for primary Achilles tendon rupture. Thirty-one studies were included, of which 6.5% were considered to be high-quality. Moderate evidence was found for an increased risk for Achilles tendon rupture in patients with decreased fiber size of the Achilles tendon. Also, limited evidence was found that increased body weight and concurrent oral corticosteroid use were risk factors. The authors that suggested further research was needed.

It should be emphasized that there have also been reports of tendon disorders in the shoulder and hand, although Achilles tendon involvement is more common. This adverse effect can occur anytime during the course of treatment and even after treatment; the risk is highest in older patients and those using corticosteroids.

Arrhythmia. The last side effect of fluoroquinolones I would like to touch on is the risk for arrhythmia with fluoroquinolones. A retrospective review of a database from a large prescription drug plan in Canada identified over 600,000 patients treated for respiratory conditions from 1990 to 2005. A total of 1838 cases of serious arrhythmia were identified—an incidence rate of 4.7 per 10,000 person-years. A nested case/control analysis was performed, and these patients were matched with up to 20 controls. Concurrent fluoroquinolone use was associated with an elevated risk for serious arrhythmia (RR, 1.76; 95% CI, 1.19-2.59); the RR rose to 2.23 (95% CI, 1.31-3.80) with new current use. Risk varied for individual drugs in this class (Table).

Table 1. Risk for Serious Arrhythmia With New Current Use of Individual Fluoroquinolones

Drug Relative Risk 95% Confidence Interval
Gatifloxacin 7.38 2.30-23.70
Moxifloxacin 3.30 1.47-7.37
Ciprofloxacin 2.15 1.34-3.46

I think this study is a helpful one, because it gives us solid numbers to think about and can help rank the fluoroquinolone in terms of risk for this very rare but serious side effect. Several fluoroquinolones have been taken off the market in the past because of increased arrhythmia risk.

In November, a joint meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee was held to make recommendations to the US Food and Drug Administration on the risk/benefit tradeoffs of fluoroquinolone use for different infections. The joint committee recommended against the use of fluoroquinolones for uncomplicated urinary tract infections, acute bacterial sinusitis, and acute bacterial exacerbations of chronic bronchitis in patients who have chronic obstructive pulmonary disease.

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