Previous studies have drawn causal associations between fluoroquinolone use and collagen pathologies including tendon rupture and retinopathy. This meta-analysisattempted to assess the association between fluoroquinolone use and the risk of aortic dissection or aortic aneurysm. A systematic search was performed on Medline, EMBASE, and the Cochrane library. 9 studies were included in final analysis. Primary random-effects meta-analysis of 7 studies, excluding 2 pharmacovigilance studies demonstrated statistically increased odds of aortic dissection (OR, 2.38; 95% CI, 1.71-3.32) aortic aneurysm (OR, 1.98; 95% CI, 1.59-2.48), and aortic aneurysm or dissection (OR, 1.47; 95% CI, 1.13-1.89; I = 72%) with current use of fluoroquinolones compared to their nonuser counterparts. Based on the "number needed-to-harm" analysis, 7246 (95%

Ci: 4329 to 14,085) patients would need to be treated with fluoroquinolones for a duration of at least three days in order for one additional patient to be harmed, assuming a population baseline incidence of aortic dissection and aneurysm rupture to be 10 per 100,000 patient-years. With strong statistical association, these findings suggest a causal relationship, warranting future research to elucidate the pathophysiological and mechanistic plausibility of this association. These findings however, should not cease prescription of fluoroquinolones, especially when clinically indicated.

Objective: To investigate whether oral fluoroquinolone use is associated with an increased risk of aortic aneurysm or dissection.

Design: Nationwide historical cohort study using linked register data on patient characteristics, filled prescriptions, and cases of aortic aneurysm or dissection.

Setting: Sweden, July 2006 to December 2013.

Participants: 360 088 treatment episodes of fluoroquinolone use (78%ciprofloxacin) and propensity score matched comparator episodes of amoxicillin use (n=360 088).

Main Outcome Measures: Cox regression was used to estimate hazard ratios for a first diagnosis of aortic aneurysm or dissection, defined as admission to hospital or emergency department for, or death due to, aortic aneurysm or dissection, within 60 days from start of treatment.

Results: Within the 60 day risk period, the rate of aortic aneurysm or dissection was 1.2 cases per 1000 person years among fluoroquinolone users and 0.7 cases per 1000 person years among amoxicillin users. Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection (hazard ratio 1.66 (95% confidence interval 1.12 to 2.46)), with an estimated absolute difference of 82 (95% confidence interval 15 to 181) cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes. In a secondary analysis, the hazard ratio for the association with fluoroquinolone use was 1.90 (1.22 to 2.96) for aortic aneurysm and 0.93 (0.38 to 2.29) for aortic dissection.

Conclusions: In a propensity score matched cohort, fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection. This association appeared to be largely driven by aortic aneurysm.

Background: Our objective was to evaluate the association between fluoroquinolone use and aortic dissection or aortic aneurysm in a systematic review and meta-analysis.

Methods: We searched Medline, Embase, and Scopus from inception to February 15, 2017. We selected controlled studies for inclusion if they reported data on aortic dissection and aortic aneurysm associated with fluoroquinolones exposure versus no exposure. Data were extracted by 2 independent reviewers, with disagreements resolved through further discussion. We assessed the quality of studies using the Newcastle-Ottawa Scale for observational studies and the strength of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. The odds ratios (ORs) from observational studies were pooled using the fixed-effect inverse variance method, and statistical heterogeneity was assessed using the I2 statistic.

Results: After a review of 714 citations, we included 2 observational studies in the meta-analysis. Current use of fluoroquinolones was associated with a statistically significantly increased risk of aortic dissection (OR, 2.79; 95% confidence interval [CI], 2.31-3.37; I2 = 0%) and aortic aneurysm (OR, 2.25; 95% CI, 2.03-2.49; I2 = 0%) in a fixed-effects meta-analysis. The unadjusted OR estimates and sensitivity analysis using a random-effects model showed similar results. We rated the strength of evidence to be of moderate quality. The number needed to treat to harm for aortic aneurysm for elderly patients aged more than 65 years who were current users of fluoroquinolones was estimated to be 618 (95% CI, 518-749).

Conclusions: Evidence from a small number of studies suggests that exposure to fluoroquinolones is consistently associated with a small but significantly increased risk of aortic dissection and aortic aneurysm.

Several observational studies reported an elevated risk of AA/AD with oral fluoroquinolone use. Daneman et al found that fluoroquinolone use (vs nonuse) was associated with an increased AA risk in a cohort study of elderly Canadian patients (hazard ratio, 2.24; 95% CI, 2.02-2.49). Lee et al analyzed a random sample of 1 million individuals from the same database used in the current study using various designs and observed an elevated risk of AA/AD for fluoroquinolone use vs nonuse; the OR was 2.28 (95% CI, 1.67-3.13) in the nested case-control design, 2.71 (95% CI, 1.14-6.46) in the case-crossover design, and 3.61 (95% CI, 3.56-3.63) in the case-time-control design. In a Swedish cohort study with an active comparator design, Pasternak et al reported a greater risk of AA/AD when comparing fluoroquinolones with amoxicillin (hazard ratio, 1.66; 95% CI, 1.22-2.46). These studies might not have adequately adjusted for the effect of coexisting infections. The nonuser comparison approach is susceptible to confounding by indication because patients treated with fluoroquinolones may have different infection types or severity vs those not treated with fluoroquinolones.

The present study analyzed a nationwide database and meticulously controlled for infections and infection severity. In the model that simultaneously included infections and concomitant antibiotic use, we also observed an increased risk of AA/AD with fluoroquinolone use (vs nonuse) as in the prior studies. However, the observed association was probably biased, as in those studies. Specifically, we observed an elevated risk of AA/AD with indicated infections and multiple other antibiotics in the model. All these antibiotics may have been associated with a greater risk of AA/AD, but a more plausible explanation would be that the associations were biased owing to residual confounding.

Question Is fluoroquinolone use associated with increased risk of aortic aneurysm or aortic dissection?

Findings In this cohort study of patients with pneumonia (n = 279 554) or urinary tract infection (n = 948 364), those receiving fluoroquinolones for pneumonia had an increased rate of aortic aneurysm or aortic dissection vs those receiving azithromycin (0.03% vs 0.01%). In a comparison of fluoroquinolones vs combined trimethoprim and sulfamethoxazole for urinary tract infection, no increased rate was noted (<0.01% in both groups).

Meaning The findings of this study suggest that, given the low rates of aortic aneurysm or aortic dissection across cohorts (ie, <0.1%), the benefits of choosing fluoroquinolones, when appropriate, may outweigh a small potential increased risk of aortic aneurysms or dissections.

Fluoroquinolones are one of the most commonly prescribed antibiotic classes in the world. The 2 most common clinical indications for these agents are urinary tract infection (UTI) and respiratory tract infection (eg, community-acquired pneumonia), although fluoroquinolones are also prescribed for gastrointestinal infections and skin and soft tissue infections. Fluoroquinolones exhibit excellent bioavailability and broad coverage for both common (eg, Streptococcus pneumoniae and Escherichia coli ) and uncommon (eg, Pseudomonas aeruginosa and extended-spectrum β-lactamase E coli ) bacteria. Although they are generally well tolerated, fluoroquinolones are thought to cause Clostridium difficile infection, tendon rupture, and QT interval prolongation.

Observational studies suggest that fluoroquinolones might also be associated with an increased risk of aortic aneurysm or aortic dissection (AA/AD). Pasternak et al observed a 66% higher rate of AA/AD with fluoroquinolones vs amoxicillin in a cohort study, while other studies observed relative risks in excess of 2. Based on these results, the US Food and Drug Administration and European Medicines Agency released drug safety communications warning about this potential risk. The observed increased risk in the studies generally occurred within days after starting the medication. Although AAs generally develop slowly over years rather than days, in vitro and in vivo studies have reported that fluoroquinolones can stimulate metalloproteinases resulting in collagen breakdown. As the aortic wall is primarily composed of collagen, it is theoretically possible that fluoroquinolones could increase the risk of AA/AD within a shorter time or worsen an existing, undetected aneurysm.

However, the observed associations may also be explained, at least in part, by residual confounding or differences in detection of preexisting AA/AD owing to a greater frequency of imaging among patients receiving fluoroquinolones. In earlier studies, the comparator group was typically adults who did not receive an antibiotic (nonusers) or received amoxicillin.

Importance 
Fluoroquinolones have been associated with collagen degradation, raising safety concerns related to more serious collagen disorders with use of these antibiotics, including aortic aneurysm and dissection.
Objective 
To examine the relationship between fluoroquinolone therapy and the risk of developing aortic aneurysm and dissection.
Design, Setting, and Participants 
We conducted a nested case-control analysis of 1477 case patients and 147 700 matched control cases from Taiwan’s National Health Insurance Research Database (NHIRD) from among 1 million individuals longitudinally observed from January 2000 through December 2011. Cases patients were defined as those hospitalized for aortic aneurysm or dissection. One hundred control patients were matched for each case based on age and sex.
Exposures 
Current, past, or any prior-year use of fluoroquinolone. Current use was defined as a filled fluoroquinolone prescription within 60 days of the aortic aneurysm or dissection; past use refers to a filled fluoroquinolone prescription between 61 and 365 days prior to the aortic aneurysm; and any prior-year use refers to having a fluoroquinolone prescription filled for 3 or more days any time during the 1-year period before the aortic aneurysm or dissection.
Main Outcomes and Measures 
Risk of developing aortic aneurysm or dissection.
Results 
A total of 1477 individuals who experienced aortic aneurysm or dissection were matched to 147 700 controls. After propensity score adjustment, current use of fluoroquinolones was found to be associated with increased risk for aortic aneurysm or dissection (rate ratio [RR], 2.43; 95% CI, 1.83-3.22), as was past use, although this risk was attenuated (RR, 1.48; 95% CI, 1.18-1.86). Sensitivity analysis focusing on aortic aneurysm and dissection requiring surgery also demonstrated an increased risk associated with current fluoroquinolone use, but the increase was not statistically significant (propensity score–adjusted RR, 2.15; 95% CI, 0.97-4.60).
Conclusions and Relevance 
Use of fluoroquinolones was associated with an increased risk of aortic aneurysm and dissection. While these were rare events, physicians should be aware of this possible drug safety risk associated with fluoroquinolone therapy.

As summarized in Table 2, all 3 types of fluoroquinolone users (current, past, or any prior-year use) had increased risk of aortic aneurysm or dissection. Current use of fluoroquinolone was associated with the highest risk of aortic aneurysm or dissection (RR, 2.93; 95% CI, 2.17-3.97) in our crude analysis. The increase in risk of aortic aneurysm or dissection remained after adjusting for individual confounders (RR, 2.28; 95% CI, 1.67-3.13), adjustment by propensity score (RR, 2.43; 95% CI, 1.83-3.22), and propensity score matching (RR, 1.75; 95% CI, 1.11-2.74). The crude (RR, 1.82; 95% CI, 1.44-2.29) and propensity score–matched effect estimates (RR, 1.19; 95% CI, 0.85-1.66) for past use of fluoroquinolone were all attenuated compared with current use. The crude (RR, 2.11; 95% CI, 1.75-2.55) and propensity score–matched effect estimates (RR, 1.37; 95% CI, 1.04-1.79) for any prior-year use of fluoroquinolone fell between those of current and past use.

Table 2:
Caption: Rate Ratios Associated With Aortic Aneurysm or Dissection, and Different Types of Fluoroquinolone Use

To further assess the robustness of our results, we stratified the study population based on age and sex. We found that the risk increase of aortic aneurysm or dissection in any prior-year use of fluoroquinolone was more substantial in patients older than 70 years (RR, 1.72; 95% CI, 1.37-2.16) than in patients 70 years or younger (RR, 1.46; 95% CI, 0.98-2.18). The risk increase for aortic aneurysm or dissection was also more substantial in female patients (RR, 1.83; 95% CI, 1.27-2.64) than in male patients (RR, 1.61; 95% CI, 1.28-2.03).

We also investigated the duration-response relationship between duration of fluoroquinolone therapy and risk of aortic aneurysm and dissection (Table 4). It was found that as the duration of fluoroquinolone therapy increased from 3 to 14 days to greater than 14 days, there was an increasing risk of aortic aneurysm and dissection in both the crude incidence (2.60% vs 2.92%) and the propensity score–adjusted effect estimate (RR, 1.60; 95% CI, 1.10-2.52 vs RR, 1.81; 95% CI, 0.91-3.17).

Table 4:
Caption: Risk of Aortic Aneurysm or Aortic Dissection Associated With Increasing Duration of Fluoroquinolone Use

Background: Fluoroquinolone antibiotics have a high potential for serious adverse drug reactions, but real-world evidence in European patient cohorts is lacking. Therefore, we aim to examine the association between fluoroquinolone exposure and potentially life-threatening adverse events stratified by age and gender in Germany.

Methods: We conducted an administrative cohort study using the active comparator new user design with a risk window up to 365 days between January 2013 and December 2019. Population-based longitudinal data from one of the largest German statutory health insurances were used. Episodes of newly dispensed fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, norfloxacin, and enoxacin) were compared to other antibiotics (amoxicillin, amoxicillin clavulanic acid, azithromycin, cefuroxime, cephalexin, clindamycin, sulfamethoxazole-trimethoprim, and doxycycline). Endpoints were defined by incident diagnoses of aortic aneurysm/dissection, cardiac arrhythmia, hepatotoxicity, and all-cause mortality. Adjusted hazard ratios were estimated from piece-wise exponential additive mixed models with smooth non-linear effects for person-time and age and adjusted for comorbidities, year and quarter at index.

Results: The cohorts comprised 15,139,840; 11,760,159; 11,027,175; and 15,305,757 antibiotic episodes. Patients during fluoroquinolone episodes were older (59 versus 51 years) and more often female (58% versus 54%). We counted 46,502; 446,727; 19,125; and 474,411 incident endpoints. Relative risk for all-cause mortality and hepatotoxicity was high for < 40-year- and 40-69-year-old females (aHR = 1.77, 95% CI 1.55-2.03 and aHR = 1.42, 95% CI 1.32-1.53), respectively. For aortic aneurysm/dissection a nominally increased relative risk for < 40-year-old females was found (aHR = 1.42, 95% CI 0.96-2.11), although 95% CI indicates that a small relative risk reduction is also supported by the data. Relative risk for cardiac arrhythmia was increased for men aged < 40 years (aHR = 1.14, 95% CI 1.08-1.20). High relative risks for each endpoint were also identified depending on choice of active comparator, and risks increased with higher defined daily doses and shorter follow-up.

Conclusions: This study contributes real-world evidence to endpoint-specific differences of risks in patient subgroups which need to be considered to improve fluoroquinolone drug safety.