Aortopathy: a concerning side-effect of fluoroquinolones

Fluoroquinolones make up one of the most prescribed classes of antibacterial medications. They have a wide antimicrobial spectrum of action and an excellent degree of oral bioavailability, which is why they are so widely used in treating infections. They are used to treat all sorts of infections, ranging from those that affect bone tissue to those that affect soft tissues in the lungs, digestive tract and genitourinary organs. It is well-known that antibacterial drugs must be prescribed rationally in order to prevent the occurrence of superinfections and antimicrobial resistance. However, medical practitioners should also always consider if a certain medication carries more risks than benefits before prescribing it to patients.

Unexpected side-effects of fluoroquinolones

The effect of fluoroquinolones on the dysregulation of the extracellular matrix was discovered in 2008. The United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) then issued a warning linking fluoroquinolones to tendon disorders, such as tendonitis and ruptures, due to this unexpected side-effect. Studies suggest that this side-effect’s underlying mechanism might be connected to the increase in the amount of matrix metalloproteinases (MMPs), which results in increased collagen degradation.

The effect of fluoroquinolones on the aorta

Just like tendons, the aorta is rich in collagen as well. The regulation of collagen production and degradation is essential for the normal functioning of the aorta – the largest blood vessel. The dysregulation of these two processes leads to aortic aneurysms and dissections. Given that fluoroquinolones directly affect the extracellular matrix, different studies have been conducted to investigate the link between fluoroquinolone usage and aortic disease.

A Canadian study from 2015 [2] showed that tendon rupture occurred in 2,1% of patients above the age of 65 who took fluoroquinolones, whilst 1,1% of patients from the same experimental group developed an aortic aneurysm, a “new” symptom, in under 30 days since the beginning of treatment. Additional studies confirmed that patients who took fluoroquinolones had a 66% greater risk of developing an aortic dissection or aneurysm during a period of 60 days since the beginning of treatment than those who were prescribed penicillins. [4] This led to great concern and increased interest in the mechanism of these side-effects and the ways of dealing with them.

Aortopathy

Aortopathy is an unpredictable and life-threatening medical condition. It is defined as a disorder of the aorta characterized by the abnormal remodelling of the aortic wall which ultimately leads to progressive weakening and dilatation of an aneurysm, aortic dissections or a catastrophic aortic rupture. Population studies estimate annual incidences to be as following: 2,4 – 14,8 cases per 100 000 people for aortic aneurysms and 3,8 – 8,8 cases per 100 000 people for aortic dissections. Despite their relative rarity in the overall population, aortic aneurysms and dissections are one of the most debilitating collagen-related medical conditions because they tend to have devastating outcomes. Known risk factors for the onset of aortopathy include congenital connective tissue disorders, hypertension, atherosclerosis, old age and smoking. Men are also more commonly affected than women. [6] [7]

Figure 1. The aortic wall consists of three separate layers: the intima, media and adventitia. An aortic aneurysm forms when the aorta dilates as a result of its wall’s progressive weakening. Most patients with an aneurysm do not present with any symptoms until complications occur, i. e. until the aorta ruptures. If it is not immediately treated, an aortic rupture leads to massive internal haemorrhaging, ultimately increasing mortality rates up to 90%. An aortic dissection occurs when a tear forms inside of the aortic wall, causing the blood to flow between the laminar layers of the media, forcing them apart and creating a false lumen.

The underlying mechanism of aortopathy

Experiments have been conducted on an in vitro model of myofibroblasts isolated from the tissue of an aorta with an aneurysm. After treating them with clinically relevant doses of fluoroquinolones, scientists discovered that fluoroquinolone exposure reduces the expression of type I collagen depending on the exact dose. In addition to this, an imbalance is caused between MMPs and their tissue inhibitors (TIMPs), therefore facilitating the degradation of the extracellular matrix. [3]

Figure 2. Fluoroquinolone-induced dysregulation of the extracellular matrix (ECM). Myofibroblasts make up a large portion of cells in the adventitia. They are responsible for the structural modelling of the extracellular matrix. MMP stands for matrix metalloproteinase, while TIMP stands for tissue inhibitor of metalloproteinase.

It is also believed that fluoroquinolones are responsible for the reduction in the total amount of synthesised collagen due to their ability to form strong chelates with metal ions. Metal ions are important for the proper functioning of enzymes involved in post-translational modifications of collagen (e. g. prolyl-hydroxylase and lysyl-hydroxylase). These post-translational modifications are, in turn, important for the reticulation and structural rigidity of collagen fibres. [8]

Is there a solution?

Studies have shown that this side-effect is largely dose dependent and more frequent in older patients with pre-existing aortopathy. Therefore, guidelines state that fluoroquinolones should not be prescribed to such patients for uncomplicated infections where alternative drugs exist. If prescribing fluoroquinolones to an aortopathic patient is indispensable, they should be given out in smaller doses and with great caution.

What studies on fluoroquinolones taught us in the end

The first fluoroquinolones have been used medicinally since the 1980s. However, it took scientists more than 30 years to discover these “new” potentially life-threatening side-effects. That is precisely why monitoring and reporting new side-effects is important even after a drug becomes commercially available. Besides, it is an example of why continuous education is important in the biomedical field. The case of fluoroquinolone-induced aortopathy is indeed a serious one, serving as a reminder to all medical practitioners to follow the newest guidelines and discoveries while prescribing medication to patients.