Cipro and the aorta Fluoroquinolone attack? Bulat A. Ziganshin, MD, PhD and John A. Elefteriades, MD, PhD (hon)

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1 Cipro and the aorta Fluoroquinolone attack? Bulat A. Ziganshin, MD, PhD and John A. Elefteriades, MD, PhD (hon) Aortic Institute at Yale-New Haven, Yale University School of Medicine New Haven, Connecticut, USA

2 Disclosures I do not have any potential conflicts of interest to disclose relevant to this presentation. 2

3 Fluoroquinolone Usage in the US: The most commonly prescribed antibiotic class 22 million prescriptions are written per year 24% of all antibiotic prescriptions written are for fluoroquinolones Most commonly Ciprofloxacin and Levofloxacin Have been administered to 10% of adults Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS. Fluoroquinoloneprescribing in the United States: 1995 to Am J Med. 2005;118: Mamdani M, McNeely D, Evans G, et al. Impact of a fluoroquinolone restriction policy in an elderly population. Am J Med. 2007;120:

4 Properties of Fluoroquinolones Directly inhibit bacterial DNA synthesis Possess favorable pharmacokinetics properties, particularly good tissue penetration First generation FQs active against gram-negative organisms New generation of FQs improved activity against gram-positive and anaerobic bacteria FQs most commonly used for treatment of genitourinary infections and hospital-acquired infections associated with urinary catheters Zhanel GG, Ennis K, Vercaigne L, et al. A critical review of the fluoroquinolones: focus on respiratory infections. Drugs. 2002;62:13-59.

5 Side effects of Fluoroquinolones Generally well tolerated drugs Common non-specific side effects: gastrointestinal tract (nausea and diarrhea) central nervous system (headache and dizziness) Some FQs are associated with prolongation of the QT interval Most worrisome adverse effects of FQs is atraumatic rupture of the Achilles tendon

6 Achilles Tendon Rupture Association with FQ use suspected since 1983 Estimated incidence in FQ treated patients = 3.2 cases per 1000 patient years Image source Mayo Clinic:

7 Achilles Tendon Structure Composed primarily of Collagen Types I and III Collagen production and degradation regulated by MMPs and TIMPs MMP-2 and -9 are most active in tendons Image source OrthoPod: Increase in MMP activity Molecular mechanism of FQassociated collagen toxicity

8 MMP-2 MMP-9

9 New Fluoroquinolone Side Effect has been Discovered Type A Type B Aortic Aneurysm Aortic Dissection

10 JAMA Intern Med 2015: Canadian population 2015: Taiwan population

11 Evidence Implicating Fluoroquinolones Lee CC, Lee MT, Chen YS, et al. Risk of Aortic Dissection and Aortic Aneurysm in Patients Taking Oral Fluoroquinolone. JAMA internal medicine. 2015;175: Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015;5:e

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15 How does dissection pick one point in time to occur? Fluoroquinolones Fluoroquinolones Exertion or emotion MMPs Blood Pressure Genetic Predisposition Aortic Dilatation Elefteriades JA, ed. Acute Aortic Disease. Vol 61. New York: Informa Healthcare; 2007 Acute Aortic Dissection 15

16 Conclusions There is credible evidence to implicate fluroquinolone use with aortic aneurysm and aortic dissection Ultrastructural similarity of tendon and aortic wall, together with FQ induced MMP over-activity, might explain the emerging association In August 2016 the FDA enhanced its warning regarding the collagen-damaging effects of fluoroquinolones Cardiologists and cardiac surgeons increase their vigilance in looking for a connection of acute aortic events with fluoroquinolones