13th October 2020, Dr Chee L Khoo
Aortic aneurysm (AA) and aortic dissection (AD) are potentially fatal conditions. Without treatment, ruptured AA/AD carries a mortality rate of up to 90%. Population-based studies estimated the annual incidence to be 2.4 to 14.8 per 100 000 persons for AA (1-4) and 3.8 to 8.8 per 100 000 persons for AD (3,5-7). Although the incidence varied across countries, the number has universally increased over time (1-5,7). Epidemiological studies report more than 2-fold increased risk of AA/AD when oral fluoroquinolones (FQ) are used. The US Food and Drug Administration (8) and the European Medicines Agency (9) issued safety warnings about fluoroquinolones in patients with AA/AD. Have those studies adequately adjusted for all the confounders though?
FQs directly inhibit bacterial deoxyribonucleic acid synthesis by binding two bacterial enzymes: DNA gyrase and topoisomerase IV. FQs possess favourable pharmacokinetics properties, particularly good tissue penetration that is reflected by their high volume of distribution. First-generation FQs are especially active against Gram-negative organisms, while the “new generation” FQs possess improved activity against Gram-positive and anerobic bacteria. Their favourable pharmacokinetics characteristics and broad-spectrum activity make this class of antibiotics one of the most used antibiotics.
FQs include the narrower-spectrum drugs such as ciprofloxacin, ofloxacin, norfloxacin and lomefloxacin and the broader-spectrum drugs such as levofloxacin, trovafloxacin, gatifloxacin, grepafloxacin, and moxifloxacin.
How does FQ affect the Achilles tendon and aorta?
Achilles tendinopathy or rupture is among the most serious side effects associated with FQ use, with reports markedly increasing, especially with the use of ciprofloxacin. The histopathologic findings include degenerative lesions, fissures, interstitial oedema without cellular infiltration, necrosis and neovascularisation. There are possible molecular mechanisms accounting for FQ-associated tendinopathy. It is thought that ciprofloxacin up-regulates the expressions of MMP-2 in tendon cells and thus degraded type I collagen.
Collagen is abundant in the aortic wall, and the substantiated deleterious effects of FQs on collagen raise the concern for a contributory role in aortic aneurysm or dissection. An association between the progression of thoracic aortic aneurysm and FQ consumption has recently been proposed as well as an increased risk of acute aortic dissection (AAD). This association is based on a number of studies:
Daneman (2015) – Treatment versus nontreatment periods:
This Canadian study followed 657,950 older adults (>65 years) who received at least one FQ prescription. FQs were associated with an increased hazard risk during treatment periods of 3.13 for tendon rupture, 1.28 for retinal detachment, and 2.72 for aortic aneurysm (10).
Lee (2015) – Case-control analysis:
This Taiwanese study compared 1,477 patients who experienced aortic aneurysm or dissection to 147,000 controls. They found an increased RR of 2.43 (11).
Pasternak (2018) – Fluoroquinolone treatment compared with amoxicillin treatment:
This Swedish database study compared propensity score for aortic aneurysm or dissection among 360,088 fluroquinolone treatment episodes to the same number of amoxicillin treatment episodes. The hazard ratio was 1.66 and the increase in aortic events was 66%. The increased incidence was most pronounced within the first 10 days from start of FQ treatment (12).
Lee (2018)15 (Treatment versus nontreatment periods.):
In this study from Taiwan, the odds ratio (OR) for an aortic event was 2.71 time higher for the 60 days after FQ prescription than for an equivalent non-FQ period. The OR was higher (2.83) for prolonged FQ exposure (>14 days) than for shorter exposure (2.41) (13)
However, these studies might not have adequately adjusted for the effect of coexisting infections. Patients treated with fluoroquinolones may have different infection types or severity vs those not treated with fluoroquinolones. Patients on FQ may have severe infections which may increase the risk of infection related AA/AD. Further, patients may also have infections followed by the onset of AA and fluoroquinolone use within a short period, and the diagnosis of AA was confirmed only after clinical workup.
In a recent nested control study, patients on FQ for indicated infections were compared with matched controlled patients on other antibiotics for similar indicated infections to reduce confounding bias (14). Fluoroquinolone use was NOT associated with a greater risk of AA/AD vs comparison antibiotics in this study. The authors concluded that “These results highlight the importance of accounting for coexisting infections while examining the safety of antibiotics using real-world data; the concern about aortic aneurysm or aortic dissection should not deter fluoroquinolone use for patients with indicated infections.”
This is one of many studies looking into the association (or lack of) between FQ and AA/AD. The jury is still out.
We all have patients with “small” aortic aneurysm that we watch and monitor over time. Surgery is not indicated in these patients but some of these patients may have significant infections like chest infections, bowel infections, urinary tract infections or wound infections that necessitate ciprofloxacin or norfloxacin. It would be easy to forget and not consider whether a FQ may contribute to a rupture.
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8. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. Published December 20, 2018.
9. European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of PRAC meeting on 10-13 May 2016. Published June 9, 2016.
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13. Lee CC, LeeMG, Hsieh R, et al. Oral fluoroquinolone and the risk of aortic dissection. J Am Coll Cardiol 2018;72(12):1369–1378
14. Tsai WC, Hsu CC, Chen CP, Chang HN, Wong AM, Lin MS, Pang JH. Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen. J Orthop Res. 2011 Jan;29(1):67-73. doi: 10.1002/jor.21196. PMID: 20602464.