Professor Jiun-Ling Wang
Medical Doctor and Associate Professor
Department of Internal Medicine
National Cheng Kung University Hospital
Taiwan

Observational studies^1-4 have shown more than two-fold increased risk of aortic aneurysm or aortic dissection (AA/AD) with the use of fluoroquinolones in treating lower respiratory tract infections (LRTIs) and genitourinary tract infections (GUTIs).⁵ These findings have prompted the US Food and Drug Administration (FDA)⁶ and the European Medicines Agency (EMA)⁷ to issue safety warnings about the potential risks associated with the use of fluoroquinolones.

Professor Jiun-Ling Wang – medical doctor and associate professor at the National Cheng Kung University Hospital in Taiwan – shares insights into the association between fluoroquinolones and the risk of AA/AD.

Q1. In a recent publication that you authored, it was found that the underlying infection – rather than the antibiotic choice – was the cause of increased risk for AA/AD.⁸ How are infections associated with risk of AA/AD?

The association between infections and risk of AA/AD may be explained as follows:

1. Some cases of AA/AD were initially misdiagnosed as infections. For example, abdominal aortic aneurysm (AAA) may be diagnosed as pyelonephritis whereas thoracic aorta disease may be diagnosed as pneumonia.
2. Fever or infection may be related to stress or hypertension, which may in turn lead to AD or aneurysm rupture. Furthermore, some bacterial infections e.g., Salmonella or staphylococcal infections are associated with infective AA. Septic emboli, bacteraemic seeding into the arterial wall, and infections from adjacent surroundings of the aorta may lead to inflammation of the aorta tissue. Bacteria may produce proteases, including matrix metalloproteinases (MMPs).

Chlamydia pneumoniae may lead to AAA progression. Bacterial DNA of Porphyromonas gingivalis and Streptococcus mutans have recently been identified in AAA tissue.⁹ Bacteria can interact directly with activated platelets and make the intraluminal thrombus an ideal site for bacterial adhesion.

Q2. Do these findings rule out causal association between fluoroquinolones and AA/AD as reported in earlier studies^1-4?

Previous studies did not include good control groups and did not take the role of infections into consideration. Using non-antibiotic users or first-line antibiotics such as amoxicillin as comparator may lead to an unfair outcome. In a similar manner to the cardiovascular safety issue of azithromycin, the decreased risk of AA/AD with an active comparator suggests significant confounding by indication.¹⁰

Q3. How has the issuance of safety warnings by FDA and EMA affected the recommendations and guidelines for the use of fluoroquinolones in Taiwan? What about in clinical practice – how has the selection of antibiotic changed?

In my opinion, the use of fluoroquinolones in hospitals in Taiwan are regulated by antibiotic stewardship programmes. As such, if healthcare workers are concerned about the FDA warning, they may avoid using fluoroquinolones. However, they may face other challenges in managing patients with potential underlying AA or at high-risk of Marfan syndrome. In relation to the FDA warning of the risk of aortic tear, physicians should evaluate the patient’s condition to determine whether to avoid using fluoroquinolones. For instance, in patients with common atherosclerotic risks such as hypertension and smoking, it is not necessary to avoid the use of fluoroquinolone.

Q4. What precautions should clinicians take when prescribing fluoroquinolones for patients with AA/AD or those who are at risk for these conditions according to your study?

This study emphasises the importance of considering coexisting infections and the safety of antibiotics using real-world data.  Confounding by indication and choosing an adequate comparator of antibiotic is important in the evaluation of antibiotic safety. In patients with infection who potentially require fluoroquinolone treatment, aorta tears should not be a contraindication before further evidence is available.

Q5. What is your advice to clinicians on the use of fluoroquinolones?

In cases of moderate/severe community-acquired pneumonia (CAP), especially when Legionella infection is a concern, respiratory fluoroquinolones may be a good treatment option. In other deep Gram-negative bacterial infections without fluoroquinolones resistance, fluoroquinolones may have better penetration than beta-lactam antibiotics. In areas of endemic non-typhoid Salmonella bacterial infection, the use of fluoroquinolones and other antibiotics classes should be balanced. There is inadequate evidence of causal relationship between fluoroquinolones and AA/AD. In cases of Salmonella mycotic aneurysm or deep infection, fluoroquinolones should still be the antimicrobial of choice – particularly in cases with cephalosporin treatment failure.

References

1. Daneman N, et al. BMJ Open 2015;5:ee010077.
2. Lee CC, et al. JAMA Intern Med 2015;175:1839-1847.
3. Lee CC, et al. J Am Coll Cardiol 2018;72:1369-1378.
4. Pasternak B, et al. BMJ 2018;360:k678.
5. Emmerson AM, Jones AM. J Antimicrob Chemother 2003;51(Suppl 1):13-20.
6. US Food and Drug Administration. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics. Accessed 30 October 2020.
7. European Medicines Agency. Pharmacovigilance Risk Assessment Commettee (PRAC): Minutes of PRAC meeting on 10–13 May 2016. Available at: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-10-13-may-2016_en.pdf. Accessed 30 October 2020.
8. Dong YH, et al. JAMA Intern Med 2020 Sep 8;e204192. doi: 10.1001/jamainternmed.2020.4192. Online ahead of print.
9. Michel JB, et al. Cardiovasc Res 2011;90:18-27.
10. Trifirò G, et al. CMAJ 2017;189:E560-E568.