Effects of Fluoroquinolones on Aortic Aneurysm or Dissection Processes: A Systematic Review and Meta-Analysis

Abstract

Background:

This systematic review/meta-analysis investigated the risks of fluoroquinolones (FQs) for aortic aneurysms (thoracic/abdominal) and Stanford A/B dissections.

Methods:

We searched EMBASE, Ovid, PubMed, Web of Science, and Scopus databases in February 2024. Eligible observational studies were those that presented adjusted risk estimates for aortic aneurysm or dissection (AAD) incidence, aortic-specific mortality, or all-cause mortality in FQ-treated versus untreated unexposed populations.

Results:

A total of 13 studies were included (36,224,419 participants), eight of which were cohort studies, two were nested case-control studies, and three were case-crossover designs. FQ exposure was associated with significantly elevated de novo AAD risk within 30 days (relative risk (RR) = 3.40, 95% confidence interval (CI) = [2.72, 4.24]; heterogeneity: I² = 41.5%, p = 0.11) and 60 days (RR = 3.53, 95% CI = [2.78, 4.49]; heterogeneity: I² = 87.0%, p < 0.0001). The analysis also revealed a higher all-cause mortality risk for FQs versus non-exposed controls (odds ratio (OR) = 1.44, 95% CI = [1.08, 1.93]; heterogeneity: I² = 0%, p = 0.80). Subgroup analysis demonstrated comparable aortic dissection (AD) and aortic aneurysm (AA) risks, except for a significantly increased de novo AA risk at 30 days (RR = 9.13, 95% CI = [6.05, 13.78]; heterogeneity: I² = 68.7%, p = 0.07) and 60 days (OR = 1.69, 95% CI = [1.27, 2.26]; heterogeneity: I² = 52%, p = 0.10).

Conclusion:

This meta-analysis found a significant association between FQ use and short-term AAD risk. These results suggest that clinicians should weigh the risks of AAD before prescribing FQs, especially in patients with aortic vulnerability or pre-existing aortic pathology, considering alternative treatments when feasible.

The PROSPERO Registration:

CRD42024509853 (https://www.crd.york.ac.uk/PROSPERO/view/CRD42024509853).

Graphical abstract

Keywords

aortic aneurysm / fluoroquinolones / antibiotics / adverse reactions / meta-analysis

1. Introduction

Fluoroquinolones (FQs) (e.g., ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin) rank among the most prescribed antibiotics worldwide and are used to treat a broad spectrum of infections [1, 2]. Thus, owing to the known broad-spectrum antimicrobial activity and favorable pharmacokinetic properties, FQs have experienced a surge in global prescriptions. Despite widespread use, FQs have been linked to collagen- associated adverse events, including tendinopathy and Achilles tendon rupture [3, 4]. This potential for excessive collagen degradation has raised concerns about arterial wall damage and related adverse events. Aortic aneurysm (AA) and dissection (AAD), among the most lethal cardiovascular conditions, show strong epidemiological associations with male sex, advanced age, hypertension, and a positive family history [5, 6]. Recent studies using large-scale administrative data have demonstrated a significant association between exposure to FQs and an elevated risk of AAD [7, 8, 9, 10, 11, 12, 13, 14, 15]. Given the life-threatening nature of AAD and the increasing utilization of FQ, we conducted this systematic review and meta-analysis to evaluate FQ-associated AAD incidence and clinical outcomes.

2. Materials and Methods

2.1 Study Design

We had registered the analysis protocol in the International Prospective Register of Systematic Reviews. This work has been reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [16] and the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) guidelines [17]. Our primary objective was to evaluate the impact of FQ exposure on the prognosis of de novo AAD. Using the PICO (Population, Intervention, Comparison, Outcome) framework, we selected studies that met the following criteria: Population: Cohort participants without pre-existing AAD at baseline; Intervention: systemic FQ antibiotics; Comparison: versus placebo or non-FQ antibiotics; Outcomes: incidence of AAD, aortic rupture, or all-cause mortality [18].

2.2 Search Strategy

We systematically searched five databases (EMBASE, Ovid, PubMed, Web of Science, and Scopus) from inception to February 2024. Our search strategy combined two concept clusters: (1) FQs (including besifloxacin, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, and pefloxacin); (2) AAD (aortic aneurysm or dissection). The search used the following Boolean structure: (FQs OR [individual FQ agents]) AND (aortic aneurysm OR aortic dissection). Additionally, we manually screened reference lists from included studies and related meta-analyses to identify potentially relevant publications.

2.3 Inclusion and Exclusion Criteria

The inclusion criteria for studies included those that (1) enrolled 10 participants per exposure group; (2) performed imaging at baseline (immediately before or concurrent with first exposure to the study drug), with follow-up commencing from this time point; (3) possessed an intervention group that received \ge1 FQ prescription or reimbursement; (4) compared AAD incidence and aortic-specific/all-cause mortality between FQ-treated patients vs. controls (non-FQ antibiotics or no antibiotics). The exclusion criteria comprised: (1) case reports, case series, reviews, editorials, non-original research, or conference abstracts without full data; (2) studies with >75% missing data for predefined variables; (3) duplicate patient populations (only the most recent study retained unless outcomes were complementary).

2.4 Literature Screening and Data Extraction

After removing any duplicate citations, two independent reviewers screened the remaining titles/abstracts. Studies deemed potentially eligible underwent a full-text review, with discrepancies resolved by consensus or third-reviewer adjudication (Fig. 1). A structured extraction form was employed to systematically record study details (e.g., lead author, publication date, and methodology), demographic information, treatment protocols, duration of follow-up, and clinical endpoints (aortic-related deaths, overall mortality, and aneurysm rupture). The co-investigators independently validated all extracted data to ensure accuracy.

2.5 Risk of Bias Assessment

Methodological quality was assessed using standardized tools: the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Newcastle–Ottawa scale (NOS) for non-randomized studies, evaluating the selection of exposed/unexposed cohorts, comparability of confounding adjustment, and reliability of outcome assessment.

2.6 Data Synthesis and Statistical Analysis

Our analysis incorporated both narrative synthesis and quantitative meta-analytical approaches. For quantitative synthesis, we set a minimum threshold of three comparable studies for meta-analysis. Before pooling data, we evaluated clinical homogeneity across studies by systematically examining key parameters, including: (1) baseline demographic characteristics, (2) intervention protocols, (3) comparator groups, and (4) outcome measures. Statistical heterogeneity was quantified using the I² statistic, with interpretation thresholds set as follows: low heterogeneity (I² 50%) prompted the use of a fixed-effect model, whereas moderate-to-high heterogeneity (I² \ge50%) warranted the use of a random-effects model for the meta-analysis.

The \chi² test was used for categorical variables. Random-effects modeling was employed for the pooled analyses to account for potential between-study variability. Between-group differences were considered statistically significant when the 95% confidence intervals (CIs) of the proportions being compared did not overlap. All statistical analyses were conducted in R (version 4.1.0, R Foundation for Statistical Computing, Vienna, Austria) using specialized meta-analysis packages (meta and metafor) to ensure robustness.

3. Result

3.1 Literature Screening

Of the 1262 initially identified records, 33 articles underwent full-text assessment, and 13 studies met the inclusion criteria regarding evaluating the effects of FQs on AAD outcomes (Table 1 (Ref. [7, 8, 9, 10, 11, 12, 13, 14, 15, 19, 20, 21, 22])). The studies comprised 36,224,419 participants; 8 were cohort studies, 2 were nested case–control studies, and 3 were case–crossover studies. A total of 4 studies were conducted in China [11, 14, 19, 20], 4 in the United States [7, 9, 12, 21], 2 in Korea [8, 22], and the remainder were performed in Sweden [13], Denmark [10], and Canada [15]. Six studies [7, 9, 13, 15, 20, 21] reported associations between the use of FQs and de novo AA; five [7, 9, 13, 20, 21] reported associations with aortic dissection (AD);12 [7, 8, 9, 10, 11, 12, 13, 14, 19, 20, 21, 22] reported associations with composite AAD outcomes. A total of 8 studies compared FQs with different antibiotic classes, including 6 with \beta-lactam antibiotics [9, 11, 12, 13, 19, 22], 4 with macrolides [7, 9, 12, 21], 1 with lincomycin [9], 2 with sulfonamides [9, 12], and 1 with tetracycline [12]. In addition, 4 studies used no-FQs as controls [8, 10, 15, 20]. Table 2 summarizes the key methodological characteristics and exposure profiles of the included studies.

3.2 Literature Quality Assessment

Methodological quality assessment was performed using the NOS and demonstrated consistently high scores across all included non-randomized studies (Table 3, Ref. [7, 8, 9, 10, 11, 12, 13, 14, 15, 19, 20, 21, 22]). All articles received high scores in the Selection and Compatibility sections, except for Aspinall et al. [12], which scored only 2 points due to the potential bias introduced by the study population consisting of veterans. Additionally, most articles did not adequately report follow-up results; only Aspinall et al. [12], Lawaetz Kristensen et al. [10], and Lee et al. [14], avoided this bias owing to the experimental designs employed.

3.3 Meta-Analysis Results

The meta-analysis demonstrated significantly elevated de novo risk following the administration of FQs: at 30 days (relative risk (RR) = 3.40, 95% CI = [2.72, 4.24]; heterogeneity: I² = 41.5%, p = 0.11) and 60 days (RR = 3.53, 95% CI = [2.78, 4.49]; heterogeneity: I² = 87.0%, p 0.0001) (Figs. 2,3). However, the difference at 1 year following FQs exposure did not reach statistical significance when compared with controls (OR = 1.10, 95% CI = [0.85, 1.42]; heterogeneity: I² = 0%, p = 0.87) following FQs exposure when compared with controls (Fig. 4). Two studies [12, 19] evaluated the mortality risk associated with FQs in patients with AAD. The findings of Aspinall et al. [12] reported significantly higher mortality risk scores with FQs than with all other antibiotics assessed. This aligns with our meta-analysis that demonstrates increased all-cause mortality risk following FQ exposure (OR = 1.44, 95% CI = [1.08, 1.93]; heterogeneity: I² = 0%, p = 0.80) (Fig. 5). Meanwhile, subgroup analysis revealed no association between FQ use and the incidence of AD within 1 year of medication (Supplementary Figs. 1,2). Additionally, an increased incidence of AA was observed at the follow-up after 30 days (RR = 9.13, 95% CI = [6.05, 13.78]; heterogeneity: I² = 68.7%, p = 0.07) and 60 days (OR = 1.69, 95% CI = [1.27, 2.26]; heterogeneity: I² = 52%, p = 0.10) following the use of FQs (Supplementary Figs. 3,4); however, no significant correlation was found at the 1-year follow-up (Supplementary Fig. 5).

3.4 Publication Bias

Publication bias was assessed for the outcomes at 60 days and 1 year, with 8 studies included for each time point (Fig. 6). The funnel plots indicated that all points lay within the confidence limits and displayed approximate symmetry, suggesting an absence of significant publication bias.

4. Discussion

For many years, clinicians have been seeking interventions to slow the progression of AAD and have evaluated several drugs, including metformin, statins, and antiplatelet drugs. Most drugs did not demonstrate clinically significant efficacy, except for statins and metformin [23, 24]. Meanwhile, the use of antibiotics to slow the progression of AAD was based on the infectious agents identified in plaques; however, most relevant studies have not yielded consistent results [7, 25, 26]. The association of FQs with collagen-disrupting complications (e.g., tendon rupture, retinal detachment) underpins ongoing safety debates regarding the use of FQs in aortic pathologies [27, 28]. Triggered by reported correlations between FQs and aortic pathology [7, 8, 9, 10, 11, 12, 13, 14, 15], the current European Society for Vascular Surgery (ESVS) recommendations have adopted a cautionary stance: FQs remain permissible for small abdominal AAs, but heightened clinical vigilance is required [29].

This meta-analysis synthesizes current evidence demonstrating a significantly elevated AAD risk associated with FQ administration. We demonstrate a time-dependent risk pattern: FQ administration significantly increased short-term (30-/60-day) de novo AAD incidence, whereas no statistically significant elevation persisted beyond the initial 60-day period through 1-year follow-up. These findings are consistent with previous studies [10, 13, 22]. A Danish case–-crossover analysis identified a significantly elevated risk of ruptured AA within 28 days of FQ exposure, highlighting a critical vulnerability during antibiotic courses [10]. In addition, Pasternak et al. [13] specifically identified a 60-day risk window for incident AA following FQ prescriptions. Conversely, a nationwide cohort study using the Korean National Health Database found similar 1-year AAD risks among patients prescribed oral FQs and third-generation cephalosporins [22]. These findings may relate to the serum half-lives of FQs; thus, we observe a potential bimodal distribution of aortic disease risk after exposure, with increased risk between 30 and 50 days [13, 14, 30]. A similar pattern has been reported for FQ-induced tendon rupture, with onset occurring between 2 and 31 days (median 7 days) [31]. As the half-lives of FQs tend to increase with successive generations, more rigorous studies are needed to clarify the effects of different FQ generations on AAD. Compared with other antibiotics, FQs are associated with an elevated short-term risk of AAD, likely related to the associated acute biological effects and the sudden onset of cardiovascular events. However, the lack of a significant long-term risk difference may be explained by the reversible nature of drug effects, limitations in study methodology, and underlying differences in baseline population risk. Specifically, although the absolute risk remains low, FQs should be prescribed cautiously in high-risk patients (e.g., those with known aortic disease, hypertension, or genetic disorders), and alternative antibiotics should be considered when possible.

The precise pathophysiology underlying FQ-associated aortic complications remains incompletely characterized. However, several biologically plausible mechanisms have been proposed, primarily centered on the disruption of extracellular matrix (ECM) homeostasis in aortic tissue [32]. Indeed, FQs can disrupt the ECM by promoting matrix metalloproteinase (MMP) activation and inhibiting tissue inhibitor of metalloproteinase (TIMP) expression, thereby promoting ECM degradation [32]. FQs also suppress collagen maturation by chelating iron, a cofactor for prolyl 4-hydroxylase and lysyl hydroxylase, essential for collagen cross-linking and strength [33]. Additionally, FQs can induce cell apoptosis and inhibit proliferation in various cell types, which may contribute to aortic destruction [34, 35, 36]. Meanwhile, ciprofloxacin, a common FQ, has been shown to increase MMP expression, decrease lysyl oxidase (LOX) expression, and activate the stimulator of interferon genes (STING) pathway, contributing to aortic wall degeneration [37]. In summary, FQs may increase the risk of AAD by impairing ECM integrity, disrupting collagen synthesis, and inducing cell death.

Interestingly, subgroup analyses revealed comparable effects of FQs on AAD risks, except for de novo AA risk at the 30- and 60-day follow-ups. This divergence likely reflects distinct pathogenic pathways: aortic aneurysms primarily result from atherosclerotic degeneration, whereas dissections predominantly stem from collagen defects or inflammatory dysregulation. FQs have also been reported to alter circulating cytokine levels in patients with abdominal aortic aneurysms [38, 39]. When circulating interleukin 6 (IL-6) levels were increased by a 4-week IL-6 infusion in healthy wild-type mice, both macrophage accumulation and abdominal dilation were observed [40]. Meanwhile, collagen degradation depends critically on the enzymatic equilibrium between the lytic activity of the MMPs and the tissue inhibitors of the MMPs. Experimental studies by LeMaire et al. [37, 41] revealed that ciprofloxacin promotes aortic dissection pathogenesis in animal models through dual pathways: MMP-9 activation and decreased LOX signaling. However, few studies have examined de novo AA and AD outcomes separately, preventing a definitive assessment of differential risk profiles between these pathologies following FQ exposure.

This meta-analysis has several inherent limitations. First, the absence of RCTs restricted the evidence synthesis to observational studies. Second, although most included studies used robust matching methods to reduce confounding, unavoidable systematic biases—particularly exposure misclassification and outcome ascertainment errors—remain due to the fundamental constraints of observational designs. Third, although research on this topic has been conducted worldwide, a significant proportion of reports originates from China and the United States, which may increase the potential impact of regional and racial biases. Furthermore, the small number of studies included in the analysis may not have been sufficient to exclude potential publication bias. Lastly, the clinically oriented outcome categorization (combined AA/AD) used across studies overlooks fundamental pathophysiological distinctions between these conditions—an oversight highlighted by the differential risk patterns observed in our subgroup analyses.

5. Conclusion

This meta-analysis identified a significant association between FQs use and short-term risk of AAD. These results suggest that clinicians should carefully weigh the risks before prescribing FQs, especially in patients with aortic vulnerability or pre-existing aortic pathology, and consider alternative treatments when feasible. Further prospective studies are warranted to clarify the mechanisms underlying this association.

Availability of Data and Materials

Data extracted from included studies, data used for all analyses, analytic code, and other materials used in the systematic review are available upon request from the corresponding author.

References

[1] Hicks LA, King LM, Fleming-Dutra KE. Improving outpatient antibiotic prescribing. BMJ (Clinical Research Ed.). 2019; 364: l289. https://doi.org/10.1136/bmj.l289.

[2] Zhang Y, Steinman MA, Kaplan CM. Geographic variation in outpatient antibiotic prescribing among older adults. Archives of Internal Medicine. 2012; 172: 1465–1471. https://doi.org/10.1001/archinternmed.2012.3717.

[3] Wise BL, Peloquin C, Choi H, Lane NE, Zhang Y. Impact of age, sex, obesity, and steroid use on quinolone-associated tendon disorders. The American Journal of Medicine. 2012; 125: 1228.e23–1228.e28. https://doi.org/10.1016/j.amjmed.2012.05.027.

[4] Lewis T, Cook J. Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature. Journal of Athletic Training. 2014; 49: 422–427. https://doi.org/10.4085/1062-6050-49.2.09.

[5] Sterpetti AV, Gabriele R, Sapienza P, Marzo LD, Borrelli V. Mortality and burden related with aortic aneurysms and dissections. The importance of information and education. Current Problems in Cardiology. 2024; 49: 102384. https://doi.org/10.1016/j.cpcardiol.2024.102384.

[6] Gawinecka J, Schönrath F, von Eckardstein A. Acute aortic dissection: pathogenesis, risk factors and diagnosis. Swiss Medical Weekly. 2017; 147: w14489. https://doi.org/10.4414/smw.2017.14489.

[7] Garg M, Venugopalan V, Vouri SM, Diaby V, Iovine NM, Park H. Oral fluoroquinolones and risk of aortic aneurysm or dissection: A nationwide population-based propensity score-matched cohort study. Pharmacotherapy. 2023; 43: 883–893. https://doi.org/10.1002/phar.2841.

[8] Son N, Choi E, Chung SY, Han SY, Kim B. Risk of aortic aneurysm and aortic dissection with the use of fluoroquinolones in Korea: a nested case-control study. BMC Cardiovascular Disorders. 2022; 22: 44. https://doi.org/10.1186/s12872-022-02488-x.

[9] Newton ER, Akerman AW, Strassle PD, Kibbe MR. Association of Fluoroquinolone Use With Short-term Risk of Development of Aortic Aneurysm. JAMA Surgery. 2021; 156: 264–272. https://doi.org/10.1001/jamasurg.2020.6165.

[10] Lawaetz Kristensen K, Hallas J, Sanddal Lindholt J. Fluoroquinolones as a trigger for rupture of abdominal aortic aneurysm: A case-crossover analysis. Basic & Clinical Pharmacology & Toxicology. 2021; 129: 44–51. https://doi.org/10.1111/bcpt.13591.

[11] Dong YH, Chang CH, Wang JL, Wu LC, Lin JW, Toh S. Association of Infections and Use of Fluoroquinolones With the Risk of Aortic Aneurysm or Aortic Dissection. JAMA Internal Medicine. 2020; 180: 1587–1595. https://doi.org/10.1001/jamainternmed.2020.4192.

[12] Aspinall SL, Sylvain NP, Zhao X, Zhang R, Dong D, Echevarria K, et al. Serious cardiovascular adverse events with fluoroquinolones versus other antibiotics: A self-controlled case series analysis. Pharmacology Research & Perspectives. 2020; 8: e00664. https://doi.org/10.1002/prp2.664.

[13] Pasternak B, Inghammar M, Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ (Clinical Research Ed.). 2018; 360: k678. https://doi.org/10.1136/bmj.k678.

[14] Lee CC, Lee MTG, Hsieh R, Porta L, Lee WC, Lee SH, et al. Oral Fluoroquinolone and the Risk of Aortic Dissection. Journal of the American College of Cardiology. 2018; 72: 1369–1378. https://doi.org/10.1016/j.jacc.2018.06.067.

[15] Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015; 5: e010077. https://doi.org/10.1136/bmjopen-2015-010077.

[16] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (Clinical Research Ed.). 2021; 372: n71. https://doi.org/10.1136/bmj.n71.

[17] Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017; 358: j4008. https://doi.org/10.1136/bmj.j4008.

[18] Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to evidence-based decisions. ACP Journal Club. 1995; 123: A12–3.

[19] Chen YY, Yang SF, Yeh HW, Yeh YT, Huang JY, Tsao SL, et al. Association Between Aortic Aneurysm and Aortic Dissection With Fluoroquinolones Use in Patients With Urinary Tract Infections: A Population-Based Cohort Study. Journal of the American Heart Association. 2022; 11: e023267. https://doi.org/10.1161/JAHA.121.023267.

[20] Yu PH, Hu CF, Liu JW, Chung CH, Chen YC, Sun CA, et al. The incidence of collagen-associated adverse events in pediatric population with the use of fluoroquinolones: a nationwide cohort study in Taiwan. BMC Pediatrics. 2020; 20: 64. https://doi.org/10.1186/s12887-020-1962-0.

[21] Gopalakrishnan C, Bykov K, Fischer MA, Connolly JG, Gagne JJ, Fralick M. Association of Fluoroquinolones With the Risk of Aortic Aneurysm or Aortic Dissection. JAMA Internal Medicine. 2020; 180: 1596–1605. https://doi.org/10.1001/jamainternmed.2020.4199.

[22] Huh K, Kang M, Jung J. Lack of association between fluoroquinolone and aortic aneurysm or dissection. European Heart Journal. 2023; 44: 4476–4484. https://doi.org/10.1093/eurheartj/ehad627.

[23] Pan Z, Cui H, Wu N, Zhang H. Effect of Statin Therapy on Abdominal Aortic Aneurysm Growth Rate and Mortality: A Systematic Review and Meta-analysis. Annals of Vascular Surgery. 2020; 67: 503–510. https://doi.org/10.1016/j.avsg.2020.03.036.

[24] Niu W, Shao J, Yu B, Liu G, Wang R, Dong H, et al. Association Between Metformin and Abdominal Aortic Aneurysm: A Meta-Analysis. Frontiers in Cardiovascular Medicine. 2022; 9: 908747. https://doi.org/10.3389/fcvm.2022.908747.

[25] Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thrombosis and Haemostasis. 2011; 106: 858–867. https://doi.org/10.1160/TH11-06-0392.

[26] Baxter BT, Matsumura J, Curci JA, McBride R, Larson L, Blackwelder W, et al. Effect of Doxycycline on Aneurysm Growth Among Patients With Small Infrarenal Abdominal Aortic Aneurysms: A Randomized Clinical Trial. JAMA. 2020; 323: 2029–2038. https://doi.org/10.1001/jama.2020.5230.

[27] Stephenson AL, Wu W, Cortes D, Rochon PA. Tendon Injury and Fluoroquinolone Use: A Systematic Review. Drug Safety. 2013; 36: 709–721. https://doi.org/10.1007/s40264-013-0089-8.

[28] Chui CSL, Wong ICK, Wong LYL, Chan EW. Association between oral fluoroquinolone use and the development of retinal detachment: a systematic review and meta-analysis of observational studies. The Journal of Antimicrobial Chemotherapy. 2015; 70: 971–978. https://doi.org/10.1093/jac/dku507.

[29] Wanhainen A, Van Herzeele I, Bastos Goncalves F, Bellmunt Montoya S, Berard X, Boyle JR, et al. Editor’s Choice – European Society for Vascular Surgery (ESVS) 2024 Clinical Practice Guidelines on the Management of Abdominal Aorto-Iliac Artery Aneurysms. European Journal of Vascular and Endovascular Surgery: the Official Journal of the European Society for Vascular Surgery. 2024; 67: 192–331. https://doi.org/10.1016/j.ejvs.2023.11.002.

[30] Vouga Ribeiro N, Gouveia Melo R, Guerra NC, Nobre  Fernandes RM, Pedro LM, et al. Fluoroquinolones Are Associated With Increased Risk of Aortic Aneurysm or Dissection: Systematic Review and Meta-analysis. Seminars in Thoracic and Cardiovascular Surgery. 2021; 33: 907–918. https://doi.org/10.1053/j.semtcvs.2020.11.011.

[31] van der Linden PD, Sturkenboom MCJM, Herings RMC, Leufkens HGM, Stricker BHC. Fluoroquinolones and risk of Achilles tendon disorders: case-control study. BMJ (Clinical Research Ed.). 2002; 324: 1306–1307. https://doi.org/10.1136/bmj.324.7349.1306.

[32] Jun C, Fang B. Current progress of fluoroquinolones-increased risk of aortic aneurysm and dissection. BMC Cardiovascular Disorders. 2021; 21: 470. https://doi.org/10.1186/s12872-021-02258-1.

[33] Badal S, Her YF, Maher LJ, 3rd. Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells. The Journal of Biological Chemistry. 2015; 290: 22287–22297. https://doi.org/10.1074/jbc.M115.671222.

[34] Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, et al. cGAS produces a 2’-5’-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013; 498: 380–384. https://doi.org/10.1038/nature12306.

[35] Zhao B, Chignell CF, Rammal M, Smith F, Hamilton MG, Andley UP, et al. Detection and prevention of ocular phototoxicity of ciprofloxacin and other fluoroquinolone antibiotics. Photochemistry and Photobiology. 2010; 86: 798–805. https://doi.org/10.1111/j.1751-1097.2010.00755.x.

[36] Williams RJ, 3rd, Attia E, Wickiewicz TL, Hannafin JA. The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism. The American Journal of Sports Medicine. 2000; 28: 364–369. https://doi.org/10.1177/03635465000280031401.

[37] 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 Surgery. 2018; 153: e181804. https://doi.org/10.1001/jamasurg.2018.1804.

[38] Ogino H, Fujii M, Ono M, Maezawa K, Hori S, Kizu J. In vivo and in vitro effects of fluoroquinolones on lipopolysaccharide-induced pro-inflammatory cytokine production. Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy. 2009; 15: 168–173. https://doi.org/10.1007/s10156-009-0680-1.

[39] Dawson J, Cockerill GW, Choke E, Belli AM, Loftus I, Thompson MM. Aortic aneurysms secrete interleukin-6 into the circulation. Journal of Vascular Surgery. 2007; 45: 350–356. https://doi.org/10.1016/j.jvs.2006.09.049.

[40] Akerman AW, Stroud RE, Barrs RW, Grespin RT, McDonald LT, LaRue RAC, et al. Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation. Annals of Vascular Surgery. 2018; 46: 193–204. https://doi.org/10.1016/j.avsg.2017.10.001.

[41] 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. The Journal of Thoracic and Cardiovascular Surgery. 2022; 163: e215–e226. https://doi.org/10.1016/j.jtcvs.2020.09.069.

Funding

Fundamental Research Funds for the Central Universities, Peking Union Medical College(3332025026)

Science and Technology Projects of Xizang Autonomous Region(XZ202501ZY0115)

Beijing Natural Science Foundation(L256072)

National High Level Hospital Clinical Research Funding Project(BJ-2024-142)

National High Level Hospital Clinical Research Funding Project(BJ-2024-093)

National High Level Hospital Clinical Research Funding Project(BJ-2025-160)