Patient Factors and Pathological Mechanisms Influencing the Effects of Fluoroquinolones Among Patients With Aortic Aneurysm and Dissection

Fluoroquinolones are broad-spectrum antibacterial agents active against various aerobic gram-positive and -negative organisms. They have been widely used as a treatment for respiratory and urinary tract infections etc. Hence, they are one of the most prescribed antibiotics worldwide.

Article p ????

However, recently adverse effects of fluoroquinolone use have been reported. In response to these reports, the US Food and Drug Administration (FDA) issued a Boxed Warning about fluoroquinolones in 2008, citing an increased risk of tendinitis and tendon rupture. Since then, the FDA has released warnings on the use of fluoroquinolone and its effects on neuropathy and mental health,¹ and in 2015 Lee et al reported an association between the use of fluoroquinolones and aortic disease, citing an approximately two-fold increase in the risk of aortic aneurysm and dissection (AAD) based on the results of their analysis of Taiwan’s National Health Insurance Research Database.² Additionally, several other studies have shown an increased risk of AAD with the use of fluoroquinolones.^3–5 Subsequently, in December 2018, the FDA issued a warning about an increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients.^6,7

As the mechanism, the effect of fluoroquinolones on the activity of matrix metalloproteases (MMPs), of which MMP-2 and MMP-9 are gelatinases with collagenolytic activity, has often been reported. Ciprofloxacin reportedly upregulates the expression of MMP-2 in tendon cells with concomitant degradation of type I collagen, and the use of fluoroquinolone antibiotics may induce proteolytic degradation of the collagen structure by promoting MMP activity in the aortic wall.^8,9 Recently, LeMaire et al’s study in mice showed that ciprofloxacin possibly inhibits the expression and activity of lysyl oxidase, leading to increased MMP levels and activity, cell injury, and fiber elastic fragmentation.¹⁰ Inada et al have shown in their mouse study that moxifloxacin may induce the development of AAD and aortic tunica media weakening by increasing the expressions of osteopontin and MMP-2 and decreasing the expression of smooth muscle proteins.¹¹ In an in vitro microphysiological study, Xiang et al reported that ciprofloxacin induced mitochondrial dysfunction in human aortic smooth muscle cells and further increased apoptosis by activating the extracellular signal-regulated kinase 1/2 and P38 mitogen-activated protein kinase pathways, and that extracellular matrix degradation and apoptosis were aggravated after ciprofloxacin exposure in the aortic walls of thoracic aortic aneurysm-induced mice.¹²

In this issue of the Journal, Chen et al¹³ examine whether fluoroquinolone use also increases the risk of AAD in patients with congenital aortic disease, including Marfan syndrome, who are deemed at high risk for AAD, using a Taiwanese nationwide database. They were prompted to conduct their study by the aforementioned FDA warning in 2018 “to avoid prescribing fluoroquinolone antibiotics to patients who have an aortic aneurysm or are at risk for an aortic aneurysm, such as patients with certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome.” However, they found no association between fluoroquinolone use and an increased risk of AAD in patients with congenital aortic disease, including Marfan syndrome.

Regarding these results, they consider that the patients’ ages affected the study’s outcomes. Many of the previous observational studies on the relationship between fluoroquinolone use and AAD have been limited to adults or elderly patients. In comparison, the mean age of the patients with congenital aortic disease in this study was 37 years. Indeed, Lee et al’s study also showed that the increased risk of AAD development in any prior year of fluoroquinolone use was greater in patients aged >70 than in patients aged ≤70 years, indicating that the elderly are at a higher risk of AAD.² Recently, Al-Neklawy et al, who examined the effects of fluoroquinolone administration on adult and senile rats, demonstrated that ciprofloxacin treatment led to thinning out, fragmentation, and increased spacing between the elastic laminae of the aortic tunica media; they also reported interesting results that the oral administration of ciprofloxacin caused deleterious structural changes in the thoracic aorta of the senile rats compared with adult male rats.¹⁴ Taken together, the reports suggest that the aorta in the elderly may be more susceptible to the adverse effects of fluoroquinolone use because of age-related degeneration of the aorta itself, including decreased density of elastic fibers in the aortic wall and fragmentation and thinning of the elastic laminae. A recent study of Marfan mice demonstrated that ciprofloxacin accelerated aortic root enlargement and increased the incidence of aortic dissection and rupture; however, few other studies have investigated the genetic predisposition and increased risk of AAD among patients using fluoroquinolones.¹⁵

In the future, accumulating further experimental and clinical data will be necessary to clarify the factors and mechanisms affecting the occurrence of aortic events with the use of fluoroquinolones. In any case, because experimental and observational studies to date suggest that the use of fluoroquinolones is associated with the occurrence of AAD and other adverse events, it is important to ensure the proper use of fluoroquinolones not only in patients with congenital aortic disease but also in all patients, with careful consideration of their necessity and adverse effects.

Disclosure

The authors declare that there are no conflicts of interest.

References

• 1.   Bridget M, Kuehn MSJ. FDA warning and study highlight fluoroquinolone risks. JAMA 2013; 310: 1014.
• 2.   Lee CC, Lee MT, Chen YS, Lee SH, Chen YS, Chen SC, et al. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Intern Med 2015; 175: 1839–1847, doi:10.1001/jamainternmed.2015.5389.
• 3.   Pasternak B, Inghammar M, Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: Nationwide cohort study. BMJ 2018; 360: k678, doi:10.1136/bmj.k678.
• 4.   Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: A longitudinal cohort study. BMJ Open 2015; 5: e010077, doi:10.1136/bmjopen-2015-010077.
• 5.   Howard DP, Banerjee A, Fairhead JF, Handa A, Silver LE, Rothwell PM, et al. Age-specific incidence, risk factors and outcome of acute abdominal aortic aneurysms in a defined population. Br J Surg 2015; 102: 907–915, doi:10.1002/bjs.9838.
• 6.   FDA Drug Safety Communication. FDA warns about increased risk of ruptures or tears in the aortal blood vessel with FQs antibiotics in certain patients (2018). https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-updates-warnings-oral-and-injectable-fluoroquinolone-antibiotics (accessed March 2023).
• 7.   Bennett AC, Bennett CL, Witherspoon BJ, Knopf KB. An evaluation of reports of ciprofloxacin, levofloxacin, and moxifloxacin-association neuropsychiatric toxicities, long-term disability, and aortic aneurysms/dissections disseminated by the Food and Drug Administration and the European Medicines Agency. Expert Opin Drug Saf 2019; 18: 1055–1063, doi:10.1080/14740338.2019.1665022.
• 8.   Tsai WC, Hsu CC, Chen CP, Chang HN, Wong AM, Lin MS, et al. Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen. J Orthop Res 2011; 29: 67–73, doi:10.1002/jor.21196.
• 9.   Wang D, Jahangir A, Tajik JK. Ciprofloxacin enhances matrix metalloproteinases activity in human ASMCs. J Patient Centered Res Rev 2014; 1: 58–59, doi:10.1002/art.10617.
• 10.   LeMaire SA, Zhang L, Luo W, Ren P, Azares AR, Wang Y, et al. Effect of ciprofloxacin on susceptibility to aortic dissection and rupture in mice. JAMA Surg 2018; 153: e181804, doi:10.1001/jamasurg.2018.1804.
• 11.   Inada K, Koga M, Yamada A, Dohgu S, Yamauchi A. Moxifloxacin induces aortic aneurysm and dissection by increasing osteopontin in mice. Biochem Biophys Res Commun 2022; 629: 1–5, doi:10.1016/j.bbrc.2022.08.080.
• 12.   Xiang B, Abudupataer M, Liu G, Zhou X, Liu D, Zhu S, et al. Ciprofloxacin exacerbates dysfunction of smooth muscle cells in a microphysiological model of thoracic aortic aneurysm. JCI Insight 2023; 8: e161729, doi:10.1172/jci.insight.161729.
• 13.   Chen SW, Lin CP, Chan YH, Wu VCC, Cheng YT, Tung YC, et al. Fluoroquinolones and risk of aortic aneurysm or dissection in patients with congenital aortic disease and Marfan syndrome. Circ J 2023, doi:10.1253/circj.CJ-22-0682.
• 14.   Al-Neklawy AF, El-Nefiawy NE, Rady HY. Does oral ciprofloxacin affect the structure of thoracic aorta in adult and senile male albino rats?: A clue to fluoroquinolones-induced risk of aortic dissection. Anat Cell Biol 2022; 55: 79–91, doi:10.5115/acb.21.170.
• 15.   LeMaire SA, Zhang L, Zhang NS, Luo W, Barrish JP, Zhang Q, et al. Ciprofloxacin accelerates aortic enlargement and promotes dissection and rupture in Marfan mice. J Thorac Cardiovasc Surg 2022; 163: e215–e226, doi:10.1016/j.jtcvs.2020.09.069.