Key Points
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.
Abstract
Importance
Previous observational studies have suggested that fluoroquinolones are associated with aortic aneurysm or dissection, but these studies may be subject to confounding by indication or surveillance bias.
Objective
To assess the association of fluoroquinolones with risk of aortic aneurysm or aortic dissection (AA/AD) while accounting for potential confounding by fluoroquinolone indication and bias owing to differential surveillance.
Design, Setting, and Participants
In an observational cohort study using a US commercial claims database, 2 pairwise 1:1 propensity score–matched cohorts were identified: patients aged 50 years or older with a diagnosis of pneumonia 3 days or less before initiating treatment with a fluoroquinolone or azithromycin and patients aged 50 years or older with a urinary tract infection (UTI) diagnosis 3 days or less before initiating a fluoroquinolone or combined trimethoprim and sulfamethoxazole. Hazard ratios (HRs) and 95% CIs were estimated controlling for 85 baseline confounders. In a secondary analysis, patients receiving fluoroquinolones were compared with those receiving amoxicillin, both with and without considering baseline aortic imaging, to address differences in detection of AA/AD before antibiotic use. Data on patients within the database from January 1, 2003, through September 30, 2015, were analyzed. Data analysis was conducted from July 23, 2019, to July 6, 2020.
Main Outcomes and Measures
Hospitalization for AA/AD occurring within 60 days following treatment initiation.
Results
After propensity score matching, patient characteristics were well balanced, with 279 554 patients (mean [SD] age, 63.66 [10.93] years; 149 976 women [53.6%]) in the pneumonia cohort and 948 364 patients (mean [SD] age, 62.06 [10.33] years; 823 667 women [86.9%]) in the UTI cohort. Initiators of fluoroquinolones (n = 139 772 pairs in the pneumonia cohort and n = 474 182 pairs in the UTI cohort) had an increased rate of AA/AD compared with initiators of azithromycin (HR, 2.57; 95% CI, 1.36-4.86; incidence, 0.03% for fluoroquinolones vs 0.01% for azithromycin) but no increased rate compared with initiators of combined trimethoprim and sulfamethoxazole (HR, 0.99; 95% CI, 0.62-1.57; incidence, <0.01% in both UTI groups). Secondary analysis using amoxicillin as a comparator (n = 3 976 162 pairs) produced results consistent with those from earlier studies (HR, 1.54; 95% CI, 1.33-1.79; incidence, <0.01% in both groups). Requiring baseline imaging in this cohort (n = 542 649 pairs) to address surveillance bias attenuated the increased rate (HR, 1.13; 95% CI, 0.96-1.33; incidence, 0.06% for fluoroquinolones vs 0.05% for amoxicillin).
Conclusions and Relevance
The findings of this nationwide cohort study of adults with pneumonia or UTI suggest an increased relative rate of AA/AD associated with fluoroquinolones within the pneumonia cohort but not within the UTI cohort. In both cohorts, the absolute rate of AA/AD appeared to be low (<0.1%). The increased relative rate observed in the pneumonia cohort may be due to residual confounding or surveillance bias.
This cohort study examines the risk for aortic aneurysm or aortic dissection in patients receiving fluoroquinolones for treatment of pneumonia or urinary tract infection.
Introduction
Fluoroquinolones are one of the most commonly prescribed antibiotic classes in the world.1,2 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.1,3 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.1,4 Although they are generally well tolerated, fluoroquinolones are thought to cause Clostridium difficile infection, tendon rupture, and QT interval prolongation.1
Observational studies suggest that fluoroquinolones might also be associated with an increased risk of aortic aneurysm or aortic dissection (AA/AD).5,6,7,8 Pasternak et al7 observed a 66% higher rate of AA/AD with fluoroquinolones vs amoxicillin in a cohort study, while other studies5,6,8 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.9 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,10 in vitro and in vivo studies have reported that fluoroquinolones can stimulate metalloproteinases resulting in collagen breakdown.11,12,13,14 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.5,6,7,8 Nonusers tend to be healthier than patients who receive a medication,15 and amoxicillin is a narrow-spectrum antibiotic typically used to treat mild infections in adults who are otherwise healthy. Moreover, none of the studies considered the specific indication for which fluoroquinolones were prescribed. While fluoroquinolones are effective against mild infections, their broad spectrum of activity and excellent oral bioavailability results in their preferential use to treat adults with more severe illness and/or comorbid conditions.4 Furthermore, because the diagnosis of AA/AD requires imaging, surveillance bias may also be implicated. Adults who receive a fluoroquinolone may be more likely than those who receive amoxicillin or no antibiotic to undergo thoracic or abdominal imaging because of either their clinical presentation (eg, severe abdominal or back pain) and/or severity of illness necessitating advanced imaging (eg, abdominal imaging for suspected pyelonephritis), which may have led to greater detection of AAs or ADs. The objective of our study was to assess the association of fluoroquinolones with risk of AA/AD in specific indications (pneumonia and UTI) with clinically appropriate comparators and account for potential differences in surveillance.
Methods
Data Source
This study was conducted using a large, commercial US health insurance claims database (IBM MarketScan) that also includes patients with Medicare Advantage plans, employer-sponsored coverage of older individuals, and Medicare supplemental insurance (ie, policies sold by private companies that help pay some health care costs not covered by Medicare). This database contains demographic information; enrollment status; longitudinal records of reimbursed medical services, including inpatient and outpatient diagnoses that have been coded using International Classification of Diseases, Ninth Revision, Clinical Modification codes and procedure codes (ie, Current Procedural Terminology) for imaging procedures; and prescription claims data.
All individual data were deidentified, the study was approved by the Brigham and Women’s Hospital Institutional Review Board, and signed data license agreements were in place. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.
Study Population
Using data from January 1, 2003, through September 30, 2015, we identified 2 cohorts of patients who initiated an oral fluoroquinolone or a comparator medication: patients aged 50 years or older with a diagnosis of pneumonia 3 days or less before initiating a fluoroquinolone or azithromycin and patients aged 50 years or older with a UTI diagnosis 3 days or less before initiating a fluoroquinolone or combined trimethoprim and sulfamethoxazole. Definitions of pneumonia and UTI are presented in eTable 2 in the Supplement. The cohort entry date was defined as the day of the first filled prescription of a fluoroquinolone or a comparator among patients with 6 months or more of continuous enrollment before drug initiation. In a secondary analysis, we mimicked a prior study by comparing initiators of fluoroquinolones with initiators of amoxicillin, excluding the indication for treatment.7 To address potential surveillance bias, we analyzed this comparison both with and without restricting analysis to patients with baseline imaging (defined as ultrasonographic, computed tomographic, or magnetic resonance imaging of the thorax, abdomen, or pelvis (eTable 2 in the Supplement) in the 6 months before and including the cohort entry date), which could have detected an aneurysm. In all of the cohorts, we excluded patients who had a diagnosis of AA/AD at baseline, alcohol or drug use disorder, hospitalizations in the 6 months before and including the day of cohort entry, and those who received antibiotics other than the study drugs (fluoroquinolones or a comparator of interest) on the cohort entry date to enhance the comparability of the exposure groups and reduce confounding by indication.
Follow-up began the day after cohort entry and continued for 60 days until the occurrence of the outcome, dispensing of the other study drug in the comparison, nursing home admission, death, plan disenrollment, or end of the study period (September 30, 2015), whichever came first.
Study Outcomes
The primary outcome was hospitalization with a primary discharge diagnosis of AA/AD (eTable 1 in the Supplement provides outcome definitions for International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes) occurring in the 60 days following treatment initiation. Outcomes were also assessed separately for AAs and ADs, site of aneurysm, and whether the aneurysm ruptured. These codes were used in previous studies assessing the association between fluoroquinolones and AA/AD and had a positive predictive value of 92% in a study from Taiwan.6 The AD codes were found to have positive predictive values greater than 85% in a US database.16 To assess the robustness of our results, we also compared the rates of heart failure hospitalization and rates of acute myocardial infarction as negative control outcomes, as there is no known association between fluoroquinolones and these outcomes. We conducted analyses stratified by baseline comorbidity score17 for the primary outcomes and, in sensitivity analyses, the outcome definition was expanded to include hospitalizations with a diagnosis code in any position.
Statistical Analysis
We used 1:1 propensity score matching to control for 85 potential confounders, which were measured during the 6 months before and including the cohort entry date (day of treatment initiation) and included demographics, calendar time, comorbidities, medication use, indicators of health care use as proxies for overall disease state, care intensity, and surveillance, as well as a validated, claims-based frailty index (eTable 3 in the Supplement). Nearest-neighbor matching without replacement was performed using a caliper of 0.05 on the propensity score scale. In sensitivity analyses, we fit high-dimensional propensity scores, which have been shown to further reduce confounding through the inclusion of an additional 200 empirically identified proxies for confounders.18
Covariate balance within the matched cohorts was assessed using standardized differences, with a standardized difference less than 0.1 indicating adequate balance between groups.19 Hazard ratios (HRs) and 95% CIs were estimated in each propensity score–matched cohort using Cox proportional hazards regression models. In sensitivity analyses, we used stratified Cox proportional hazards regression models using the matched sets as strata to account for the matching. All significance tests were 2-sided, and results were deemed statistically significant if the 95% CI did not overlap 1. Data analysis was conducted from July 23, 2019, to July 6, 2020, and all analyses were performed using Aetion, platform version 3.11 with R, version 3.4.2 (The R Foundation for Statistical Computing).20
Results
The final study population after 1:1 propensity score matching included 279 554 patients (mean [SD] age, 63.66 [10.93] years; 149 976 women [53.6%] and 129 578 men [46.4%]) in the pneumonia cohort (Figure 1) and 948 364 patients (mean age, 62.06 [10.33] years; 823 667 women [86.9%] and 124 697 men [13.1%]) in the UTI cohort (Figure 2). In the pneumonia cohort, fluoroquinolone vs azithromycin initiators before propensity score matching were older (mean [SD], 64.60 [11.22] vs 63.31 [10.84] years), had a greater burden of comorbidities (0.41 [1.29] vs 0.28 [1.12]), had a higher prevalence of characteristics suggestive of frailty (0.14 [0.05] vs 0.13 [0.04]), and were prescribed more medications at baseline (7.79 [4.63] vs 6.99 [4.32]), although most variables at baseline had standardized differences less than 0.1 (Table 1). In the UTI cohort, fluoroquinolone vs combined trimethoprim and sulfamethoxazole users were more likely to be men (249 178 [19.9%] vs 62 187 [13.0%]) before propensity score matching but otherwise had similar baseline characteristics (Table 2). In both the pneumonia and UTI cohorts, the rates of baseline imaging were well balanced before propensity score matching (eTable 5 in the Supplement). In contrast to the primary cohorts, the cohort comparing fluoroquinolones with amoxicillin and ignoring the indication for treatment showed imbalances in baseline patient characteristics before propensity score matching. Fluoroquinolone users were older (62.15 [10.29] vs 60.02 [8.99] years); had a higher prevalence of characteristics suggestive of frailty; were more likely to have a history of pneumonia, chronic obstructive pulmonary disease, asthma, UTI, and cancer; were prescribed more medications; and had more office visits and higher rates of baseline imaging. After propensity score matching, exposure groups in all 3 cohorts achieved adequate balance on measured covariates (Tables 1 and 2; eTable 6 in the Supplement); however, the rates of baseline imaging, which were not included in the propensity score, remained imbalanced between fluoroquinolone and amoxicillin users (eTable 5 in the Supplement). The type of fluoroquinolones used varied across cohorts. In the pneumonia cohort, most patients received a respiratory fluoroquinolone (levofloxacin, 173 856 [73%]), whereas ciprofloxacin was the most frequently used agent in the UTI cohort (1 059 453 [85%]), the amoxicillin cohort (3 352 966 [49%]), and the amoxicillin cohort restricted to baseline imaging (741 462 [55%]) (eTable 4 in the Supplement).
Figure 1. Pneumonia Cohort Formation.
Figure 2. Urinary Tract Infection Cohort Formation.
Table 1. Baseline Characteristics Before and After Propensity Score Matching in the Pneumonia Cohort.
| Variable | Before matching | Standardized difference | After matching | Standardized difference | ||
|---|---|---|---|---|---|---|
| Fluoroquinolones | Azithromycin | Fluoroquinolones | Azithromycin | |||
| No. of patients | 239 664 | 148 595 | 139 772 | 139 772 | ||
| Demographic characteristic | ||||||
| Age, mean (SD), y | 64.60 (11.22) | 63.31 (10.84) | 0.12 | 63.68 (10.93) | 63.63 (10.92) | 0.01 |
| Age categories, No. (%), y | ||||||
| 50-54 | 47 287 (19.7) | 34 447 (23.2) | 0.11 | 31 036 (22.2) | 30 898 (22.1) | 0.01 |
| 55-64 | 99 689 (41.6) | 63 847 (43.0) | 59 364 (42.5) | 59 834 (42.8) | ||
| 65-74 | 41 304 (17.2) | 23 395 (15.7) | 22 665 (16.2) | 22 665 (16.2) | ||
| ≥75 | 51 384 (21.4) | 26 906 (18.1) | 26 707 (19.1) | 26 375 (18.9) | ||
| Men, No. (%) | 116 476 (48.6) | 67 594 (45.5) | 0.06 | 64 815 (46.4) | 64 753 (46.3) | 0 |
| Combined comorbidity index, mean (SD) | 0.41 (1.29) | 0.28 (1.12) | 0.10 | 0.31 (1.17) | 0.30 (1.14) | 0.01 |
| Frailty index, mean (SD) | 0.14 (0.05) | 0.13 (0.04) | 0.14 | 0.13 (0.04) | 0.13 (0.04) | 0.01 |
| Comorbidities | ||||||
| COPD | 25 754 (10.7) | 10 800 (7.3) | 0.12 | 10 901 (7.8) | 10 702 (7.7) | 0.01 |
| Asthma | 16 577 (6.9) | 10 773 (7.2) | 0.01 | 10 011 (7.2) | 9893 (7.1) | 0 |
| Urinary tract infection | 10 771 (4.5) | 4625 (3.1) | 0.07 | 5802 (4.2) | 4474 (3.2) | 0.05 |
| Acute coronary syndrome | 1022 (0.4) | 467 (0.3) | 0.02 | 461 (0.3) | 460 (0.3) | 0 |
| Ischemic heart disease | 25 370 (10.6) | 12 694 (8.5) | 0.07 | 12 666 (9.1) | 12 436 (8.9) | 0.01 |
| Congestive heart failure | 9811 (4.1) | 4401 (3.0) | 0.06 | 4530 (3.2) | 4330 (3.1) | 0.01 |
| Ischemic stroke | 7193 (3.0) | 3318 (2.2) | 0.05 | 3383 (2.4) | 3277 (2.3) | 0.01 |
| CABG, PTCA, or stent | 1992 (0.8) | 1025 (0.7) | 0.02 | 1013 (0.7) | 1010 (0.7) | 0 |
| Valve disorder | 2174 (0.9) | 1157 (0.8) | 0.01 | 1136 (0.8) | 1130 (0.8) | 0 |
| Atrial fibrillation | 11 206 (4.7) | 6075 (4.1) | 0.03 | 6039 (4.3) | 5876 (4.2) | 0.01 |
| Kidney dysfunction | 11 008 (4.6) | 5697 (3.8) | 0.04 | 5650 (4.0) | 5517 (3.9) | 0.01 |
| Liver disease | 4897 (2.0) | 2703 (1.8) | 0.02 | 2649 (1.9) | 2604 (1.9) | 0 |
| Depression | 13 156 (5.5) | 8887 (6.0) | 0.02 | 8213 (5.9) | 8076 (5.8) | 0 |
| Cancer | 30 271 (12.6) | 16 110 (10.8) | 0.06 | 15 664 (11.2) | 15 569 (11.1) | 0 |
| Medication use | ||||||
| Nonstudy antibiotic | 76 626 (32.0) | 37 711 (25.4) | 0.15 | 37 393 (26.8) | 37 045 (26.5) | 0.01 |
| COPD/asthma medication | 66 294 (27.7) | 34 741 (23.4) | 0.10 | 33 727 (24.1) | 33 591 (24.0) | 0 |
| ACE inhibitor or ARB | 86 918 (36.3) | 49 617 (33.4) | 0.06 | 47 579 (34.0) | 47 547 (34.0) | 0 |
| Loop diuretic | 23 830 (9.9) | 10 967 (7.4) | 0.09 | 11 165 (8.0) | 10 794 (7.7) | 0.01 |
| Other diuretic | 3875 (1.6) | 1978 (1.3) | 0.02 | 1966 (1.4) | 1919 (1.4) | 0 |
| β-Blocker | 58 765 (24.5) | 32 774 (22.1) | 0.06 | 31 729 (22.7) | 31 655 (22.6) | 0 |
| Digoxin | 5874 (2.5) | 2523 (1.7) | 0.05 | 2586 (1.9) | 2498 (1.8) | 0.01 |
| Nitrate | 9871 (4.1) | 4840 (3.3) | 0.05 | 4805 (3.4) | 4754 (3.4) | 0 |
| Platelet inhibitor | 18 997 (7.9) | 9174 (6.2) | 0.07 | 9160 (6.6) | 9009 (6.4) | 0 |
| Anticoagulant | 12 158 (5.1) | 6565 (4.4) | 0.03 | 6496 (4.6) | 6374 (4.6) | 0 |
| Statin | 85 461 (35.7) | 49 715 (33.5) | 0.05 | 47 602 (34.1) | 47 628 (34.1) | 0 |
| Noninsulin diabetes medication | 38 561 (16.1) | 20 531 (13.8) | 0.06 | 19 987 (14.3) | 19 875 (14.2) | 0 |
| Insulin | 10 479 (4.4) | 5433 (3.7) | 0.04 | 5201 (3.7) | 5276 (3.8) | 0 |
| NSAID | 32 062 (13.4) | 19 767 (13.3) | 0.00 | 18 718 (13.4) | 18 503 (13.2) | 0.01 |
| Oral glucocorticoid | 62 120 (25.9) | 33 898 (22.8) | 0.07 | 32 683 (23.4) | 32 678 (23.4) | 0 |
| Opioid | 75 499 (31.5) | 39 560 (26.6) | 0.11 | 38 478 (27.5) | 38 307 (27.4) | 0 |
| Antidepressant | 54 737 (22.8) | 31 331 (21.1) | 0.04 | 29 802 (21.3) | 29 715 (21.3) | 0 |
| Antipsychotic | 5455 (2.3) | 2534 (1.7) | 0.04 | 2515 (1.8) | 2462 (1.8) | 0 |
| Benzodiazepine | 30 512 (12.7) | 17 054 (11.5) | 0.04 | 16 569 (11.9) | 16 229 (11.6) | 0.01 |
| Sedative/hypnotic | 17 693 (7.4) | 9739 (6.6) | 0.03 | 9410 (6.7) | 9214 (6.6) | 0.01 |
| Health care use, mean (SD) | ||||||
| No. of office visits | 4.35 (3.82) | 4.07 (3.63) | 0.08 | 4.14 (3.70) | 4.12 (3.65) | 0.01 |
| No. of medications | 7.79 (4.63) | 6.99 (4.32) | 0.18 | 7.15 (4.34) | 7.11 (4.35) | 0.01 |
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; NSAID, nonsteroidal anti-inflammatory drug; PTCA, percutaneous transluminal coronary angioplasty.
Table 2. Baseline Characteristics Before and After Propensity Score Matching in the Urinary Tract Infection Cohort.
| Variable | Before matching | Standardized difference | After matching | Standardized difference | ||
|---|---|---|---|---|---|---|
| Fluoroquinolones | Trimethoprim and sulfamethoxazole | Fluoroquinolones | Trimethoprim and sulfamethoxazole | |||
| No. of patients | 1 249 037 | 477 327 | 474 182 | 474 182 | ||
| Demographic characteristic | ||||||
| Age, mean (SD), y | 62.59 (10.53) | 62.04 (10.30) | 0.05 | 62.07 (10.36) | 62.04 (10.30) | 0 |
| Age categories, No. (%), y | ||||||
| 50-54 | 314 297 (25.2) | 128 495 (26.9) | 0.05 | 127 639 (26.9) | 127 705 (26.9) | 0 |
| 55-64 | 548 349 (43.9) | 209 669 (43.9) | 207 755 (43.8) | 208 245 (43.9) | ||
| 65-74 | 184 499 (14.8) | 68 130 (14.3) | 67 571 (14.3) | 67 665 (14.3) | ||
| ≥75 | 201 892 (16.2) | 71 033 (14.9) | 71 217 (15.0) | 70 567 (14.9) | ||
| Men, No. (%) | 249 178 (19.9) | 62 187 (13.0) | 0.19 | 63 026 (13.3) | 61 786 (13.0) | 0.01 |
| Combined comorbidity index, mean (SD) | 0.15 (1.04) | 0.10 (0.97) | 0.04 | 0.11 (0.97) | 0.10 (0.97) | 0.01 |
| Frailty index, mean (SD) | 0.13 (0.04) | 0.13 (0.04) | 0.06 | 0.13 (0.04) | 0.13 (0.04) | 0 |
| Comorbidities, No. (%) | ||||||
| COPD | 38 384 (3.1) | 13 532 (2.8) | 0.01 | 13 467 (2.8) | 13 439 (2.8) | 0 |
| Asthma | 43 358 (3.5) | 15 536 (3.3) | 0.01 | 15 377 (3.2) | 15 417 (3.3) | 0 |
| Pneumonia | 11 267 (0.9) | 3112 (0.7) | 0.03 | 3938 (0.8) | 3086 (0.7) | 0.02 |
| Acute coronary syndrome | 3411 (0.3) | 1185 (0.2) | 0.01 | 1225 (0.3) | 1179 (0.2) | 0 |
| Ischemic heart disease | 82 829 (6.6) | 26 442 (5.5) | 0.05 | 26 927 (5.7) | 26 254 (5.5) | 0.01 |
| Congestive heart failure | 21 151 (1.7) | 6975 (1.5) | 0.02 | 7175 (1.5) | 6919 (1.5) | 0 |
| Ischemic stroke | 28 656 (2.3) | 9313 (2.0) | 0.02 | 9295 (2.0) | 9252 (2.0) | 0 |
| CABG, PTCA, or stent | 5844 (0.5) | 1850 (0.4) | 0.01 | 1891 (0.4) | 1833 (0.4) | 0 |
| Valve disorder | 8318 (0.7) | 2804 (0.6) | 0.01 | 2789 (0.6) | 2789 (0.6) | 0 |
| Atrial fibrillation | 34 528 (2.8) | 12 130 (2.5) | 0.01 | 12 370 (2.6) | 12 049 (2.5) | 0 |
| Kidney dysfunction | 53 640 (4.3) | 14 758 (3.1) | 0.06 | 15 171 (3.2) | 14 642 (3.1) | 0.01 |
| Liver disease | 27 273 (2.2) | 8548 (1.8) | 0.03 | 8581 (1.8) | 8471 (1.8) | 0 |
| Depression | 85 105 (6.8) | 33 053 (6.9) | 0 | 32 736 (6.9) | 32 823 (6.9) | 0 |
| Cancer | 149 675 (12.0) | 50 980 (10.7) | 0.04 | 50 977 (10.8) | 50 630 (10.7) | 0 |
| Medication use | ||||||
| Nonstudy antibiotic | 447 131 (35.8) | 160 402 (33.6) | 0.05 | 158 888 (33.5) | 159 301 (33.6) | 0 |
| COPD/asthma medication | 189 943 (15.2) | 69 064 (14.5) | 0.02 | 68 436 (14.4) | 68 588 (14.5) | 0 |
| ACE inhibitor or ARB | 412 618 (33.0) | 147 079 (30.8) | 0.05 | 146 515 (30.9) | 146 116 (30.8) | 0 |
| Loop diuretic | 71 194 (5.7) | 24 991 (5.2) | 0.02 | 25 186 (5.3) | 24 833 (5.2) | 0 |
| Other diuretic | 16 094 (1.3) | 5309 (1.1) | 0.02 | 5434 (1.1) | 5280 (1.1) | 0 |
| β-Blocker | 260 331 (20.8) | 93 177 (19.5) | 0.03 | 93 096 (19.6) | 92 545 (19.5) | 0 |
| Digoxin | 16 734 (1.3) | 5886 (1.2) | 0.01 | 6031 (1.3) | 5856 (1.2) | 0 |
| Nitrate | 31 249 (2.5) | 10 741 (2.3) | 0.02 | 10 942 (2.3%) | 10 666 (2.2) | 0 |
| Platelet inhibitor | 71 098 (5.7) | 23 258 (4.9) | 0.04 | 23 458 (4.9) | 23 120 (4.9) | 0 |
| Anticoagulant | 37 841 (3.0) | 13 020 (2.7) | 0.02 | 13 079 (2.8) | 12 933 (2.7) | 0 |
| Statin | 398 202 (31.9) | 142 005 (29.8) | 0.05 | 141 097 (29.8) | 141 089 (29.8) | 0 |
| Noninsulin diabetes medication | 175 095 (14.0) | 62 064 (13.0) | 0.03 | 62 013 (13.1) | 61 702 (13.0) | 0 |
| Insulin | 41 961 (3.4) | 14 317 (3.0) | 0.02 | 14 433 (3.0) | 14 215 (3.0) | 0 |
| NSAID | 189 908 (15.2) | 72 072 (15.1) | 0 | 71 496 (15.1) | 71 600 (15.1) | 0 |
| Oral glucocorticoid | 182 156 (14.6) | 65 523 (13.7) | 0.03 | 65 554 (13.8) | 65 063 (13.7) | 0 |
| Opioid | 323 956 (25.9) | 113 239 (23.7) | 0.05 | 112 353 (23.7) | 112 477 (23.7) | 0 |
| Antidepressant | 304 708 (24.4) | 117 915 (24.7) | 0.01 | 117 136 (24.7) | 117 163 (24.7) | 0 |
| Antipsychotic | 23 569 (1.9) | 8944 (1.9) | 0 | 9068 (1.9) | 8890 (1.9) | 0 |
| Benzodiazepine | 180 041 (14.4) | 67 285 (14.1) | 0.01 | 66 602 (14.0) | 66 788 (14.1) | 0 |
| Sedative/hypnotic | 104 394 (8.4) | 37 281 (7.8) | 0.02 | 36 867 (7.8) | 37 011 (7.8) | 0 |
| Health care use, mean (SD) | ||||||
| No. of office visits | 4.47 (3.70) | 4.23 (3.49) | 0.07 | 4.24 (3.51) | 4.23 (3.49) | 0 |
| No. of medications | 7.04 (4.40) | 6.71 (4.28) | 0.08 | 6.72 (4.25) | 6.71 (4.28) | 0 |
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; NSAID, nonsteroidal anti-inflammatory drug; PTCA, percutaneous transluminal coronary angioplasty.
After propensity score matching, fluoroquinolone initiators in the pneumonia cohort had a higher rate of AA/AD compared with azithromycin initiators (HR, 2.57; 95% CI, 1.36-4.86; incidence, 0.03% for fluoroquinolones vs 0.01% for azithromycin). The high-dimensional propensity score–matched analysis produced consistent results (HR, 2.50; 95% CI, 1.32-4.73) (eTable 9 in the Supplement). In the UTI cohort, the incidence was lower (<0.01% in both UTI groups), with fluoroquinolone initiators having similar rates of AA/AD compared with initiators of combined trimethoprim and sulfamethoxazole (HR, 0.99; 95% CI, 0.62-1.57) (Table 3).
Table 3. Risk of Aortic Aneurysm or Dissection Before and After Propensity Score Matching.
| Analyses | Before matching | After matching | ||
|---|---|---|---|---|
| Pneumonia cohort | ||||
| Antibiotic | Fluoroquinolone | Azithromycin | Fluoroquinolone | Azithromycin |
| No. of patients | 239 664 | 148 595 | 139 772 | 139 772 |
| Primary outcomes | ||||
| Aortic aneurysm/aortic dissection events (IR/1000 person-years) | 71 (2.0) | 13 (0.6) | 35 (1.7) | 13 (0.6) |
| Hazard ratio (95% CI) | 3.24 (1.80-5.86) | 1 [Reference] | 2.57 (1.36-4.86) | 1 [Reference] |
| Aortic aneurysm events (IR/1000 person-years) | 58 (1.6) | 10 (0.5) | 29 (1.4) | 10 (0.5) |
| Hazard ratio (95% CI) | 3.44 (1.76-6.73) | 1 [Reference] | 2.77 (1.35-5.68) | 1 [Reference] |
| Aortic dissection events (IR/1000 person-years) | 14 (0.4) | 3 (0.1) | 6 (0.3) | 3 (0.2) |
| Hazard ratio (95% CI) | 2.79 (0.80-9.69) | 1 [Reference] | 1.92 (0.48-7.68) | 1 [Reference] |
| Negative control outcomes | ||||
| Congestive heart failure events (IR/1000 person-years) | 1047 (29.0) | 511 (23.9) | 535 (25.3) | 502 (24.9) |
| Hazard ratio (95% CI) | 1.23 (1.10-1.36) | 1 [Reference] | 1.03 (0.91-1.16) | 1 [Reference] |
| Acute myocardial infarction events (IR/1000 person-years) | 385 (10.7) | 181 (8.5) | 207 (9.8) | 180 (8.9) |
| Hazard ratio (95% CI) | 1.27 (1.07-1.52) | 1.11 (0.91-1.36) | ||
| Urinary tract infection cohort | ||||
| Antibiotic | Fluoroquinolone | Trimethoprim/sulfamethoxazole | Fluoroquinolone | Trimethoprim/sulfamethoxazole |
| No. of patients | 1 249 037 | 477 327 | 474 182 | 474 182 |
| Primary outcomes | ||||
| Aortic aneurysm/aortic dissection events (IR/1000 person-years) | 130 (0.7) | 35 (0.5) | 37 (0.5) | 35 (0.5) |
| Hazard ratio (95% CI) | 1.33 (0.91-1.93) | 1 [Reference] | 0.99 (0.62-1.57) | 1 [Reference] |
| Aortic aneurysm events (IR/1000 person-years) | 117 (0.6) | 32 (0.5) | 33 (0.5) | 32 (0.5) |
| Hazard ratio (95% CI) | 1.30 (0.88-1.93) | 1 [Reference] | 0.97 (0.59-1.57) | 1 [Reference] |
| Aortic dissection events (IR/1000 person-years) | 13 (0.07) | 3 (0.04) | 4 (0.05) | 3 (0.04) |
| Hazard ratio (95% CI) | 1.56 (0.45-5.49) | 1 [Reference] | 1.25 (0.28-5.60) | 1 [Reference] |
| Negative control outcomes | ||||
| Congestive heart failure events (IR/1000 person-years) | 964 (5.0) | 318 (4.7) | 314 (4.3) | 318 (4.7) |
| Hazard ratio (95% CI) | 1.08 (0.95-1.22) | 1 [Reference] | 0.92 (0.79-1.08) | 1 [Reference] |
| Acute myocardial infarction events (IR/1000 person-years) | 736 (0.6) | 254 (0.5) | 268 (3.6) | 254 (3.7) |
| Hazard ratio (95% CI) | 1.03 (0.89-1.19) | 1 [Reference] | 0.99 (0.83-1.17) | 1 [Reference] |
| Fluoroquinolone vs amoxicillin cohort | ||||
| Antibiotic | Fluoroquinolone | Amoxicillin | Fluoroquinolone | Amoxicillin |
| No. of patients | 6 850 968 | 4 623 222 | 3 976 162 | 3 976 162 |
| Primary outcomes | ||||
| Aortic aneurysm/aortic dissection events (IR/1000 person-years) | 895 (0.8) | 314 (0.4) | 445 (0.7) | 284 (0.5) |
| Hazard ratio (95% CI) | 1.90 (1.67-2.16) | 1 [Reference] | 1.54 (1.33-1.79) | 1 [Reference] |
| Aortic aneurysm events (IR/1000 person-years) | 805 (0.7) | 271 (0.4) | 401 (0.6) | 249 (0.4) |
| Hazard ratio (95% CI) | 1.97 (1.72-2.27) | 1 [Reference] | 1.59 (1.35-1.86) | 1 [Reference] |
| Aortic dissection events (IR/1000 person-years) | 91 (0.08) | 44 (0.06) | 44 (0.07) | 36 (0.06) |
| Hazard ratio (95% CI) | 1.38 (0.96-1.97) | 1 [Reference] | 1.20 (0.78-1.87) | 1 [Reference] |
| Negative control outcomes | ||||
| Congestive heart failure events (IR/1000 person-years) | 7582 (7.0) | 2383 (3.3) | 3166 (5.0) | 2230 (3.6) |
| Hazard ratio (95% CI) | 2.12 (2.02-2.22) | 1 [Reference] | 1.40 (1.33-1.48) | 1 [Reference] |
| Acute myocardial infarction events (IR/1000 person-years) | 5074 (4.7) | 2286 (3.2) | 2489 (4.0) | 2054 (3.3) |
| Hazard ratio (95% CI) | 1.48 (1.41-1.55) | 1 [Reference] | 1.19 (1.13-1.27) | 1 [Reference] |
| Fluoroquinolones vs amoxicillin cohort restricted to patients with baseline imaging | ||||
| Antibiotic | Fluoroquinolone | Amoxicillin | Fluoroquinolone | Amoxicillin |
| No. of patients | 1 359 586 | 544 804 | 542 649 | 542 649 |
| Primary outcomes | ||||
| Aortic aneurysm/aortic dissection events (IR/1000 person-years) | 679 (3.2) | 276 (3.3) | 312 (3.7) | 271 (3.3) |
| Hazard ratio (95% CI) | 0.97 (0.84-1.11) | 1 [Reference] | 1.13 (0.96-1.33) | 1 [Reference] |
| Aortic aneurysm events (IR/1000 person-years) | 635 (3.0) | 262 (3.1) | 293 (3.4) | 258 (3.1) |
| Hazard ratio (95% CI) | 0.95 (0.82-1.10) | 1 [Reference] | 1.11 (0.94-1.32) | 1 [Reference] |
| Aortic dissection events (IR/1000 person-years) | 44 (0.2) | 14 (0.2) | 19 (0.2) | 13 (0.2) |
| Hazard ratio (95% CI) | 1.24 (0.68-2.26) | 1 [Reference] | 1.43 (0.71-2.90) | 1 [Reference] |
| Negative control outcomes | ||||
| Congestive heart failure events (IR/1000 person-years) | 2205 (10.3) | 538 (6.4) | 830 (9.7) | 530 (6.4) |
| Hazard ratio (95% CI) | 1.61 (1.46-1.77) | 1 [Reference] | 1.53 (1.38-1.71) | 1 [Reference] |
| Acute myocardial infarction events (IR/1000 person-years) | 1209 (5.7) | 371 (4.4) | 429 (5.0) | 370 (4.4) |
| Hazard ratio (95% CI) | 1.28 (1.14-1.44) | 1 [Reference] | 1.14 (0.99-1.30) | 1 [Reference] |
Abbreviation: IR, incidence rate.
The secondary analysis using amoxicillin as a comparator without including a specific indication for treatment produced results consistent with those from earlier studies (HR, 1.54; 95% CI, 1.33-1.79; incidence, <0.01% in both groups).7,8Requiring baseline imaging to address surveillance bias attenuated the association (HR, 1.13; 95% CI, 0.96-1.33; incidence, 0.06% for fluoroquinolones vs 0.05% for amoxicillin).
The increased rates observed for fluoroquinolones compared with azithromycin in the pneumonia cohort and compared with amoxicillin in the secondary analyses were largely associated with AAs (fluoroquinolone vs azithromycin: HR, 2.77; 95% CI, 1.35-5.68, and fluoroquinolone vs amoxicillin: HR, 1.59; 95% CI, 1.35-1.86), which accounted for most of the events (pneumonia: 82% and amoxicillin: 90%).
In evaluating heart failure hospitalization and acute myocardial infarction as negative control outcomes, we observed no significant differences in the rates for fluoroquinolones compared with azithromycin (heart failure hospitalization: HR, 1.03; 95% CI, 0.91-1.16 and acute myocardial infarction: HR, 1.11; 95% CI, 0.91-1.36) or combined trimethoprim and sulfamethoxazole (heart failure hospitalization: HR, 0.92; 95% CI, 0.79-1.08 and acute myocardial infarction: HR, 0.99; 95% CI, 0.83-1.17). In secondary analyses, we observed an increased rate of heart failure hospitalizations and acute myocardial infarction compared with amoxicillin (heart failure hospitalization: HR, 1.40; 95% CI, 1.33-1.48 and acute myocardial infarction: HR, 1.19; 95% CI, 1.13-1.27), which persisted in patients with baseline imaging (heart failure hospitalization: HR, 1.53; 95% CI, 1.38-1.71 and acute myocardial infarction: HR, 1.14; 95% CI, 0.99-1.30). Other sensitivity and subgroup analyses were consistent with the primary findings (eTables 10-13 in the Supplement).
Discussion
In this large, nationwide cohort study, we observed an increase in the rate of AA/AD in patients with pneumonia treated with fluoroquinolones vs azithromycin but found no evidence of an increased rate when fluoroquinolones were compared with combined trimethoprim and sulfamethoxazole in patients with a UTI. In secondary analyses, we also observed an increased rate of AA/AD with fluoroquinolones when amoxicillin was used as the comparator group; however, this association was attenuated after accounting for recent imaging that could have detected existing AAs or ADs. Using heart failure hospitalizations and hospitalization for acute myocardial infarction as negative control outcomes suggested that the primary analyses in the pneumonia and UTI cohorts were robust; however, the secondary analyses in the amoxicillin cohort may have been affected by residual confounding even when requiring baseline imaging. Taken together, our results suggest that fluoroquinolones may increase a person’s risk of AA/AD, although unmeasured confounding or differential surveillance cannot be ruled out since we observed too few events to implement the imaging restriction in the pneumonia cohort. The absolute rates of AA/AD were low across all cohorts (ie, <0.1%); thus, given a clear indication for antibiotic use, the benefits of choosing an appropriate antibiotic in terms of coverage may outweigh a small potential increased risk for AA/AD.
Among the previous investigations, 2 were cohort studies,7,8 1 was a case-control study,6 and 1 study included both a case-crossover and case-control design.5 In the case-control studies, fluoroquinolone use was compared with no fluoroquinolone use, which could have included use of other antibiotics or no antibiotics. Nonuser comparisons in observational studies of medications often lead to bias, as individuals who do not receive an antibiotic are less likely to have a bacterial infection and are more likely to be healthy, making them inherently different from those who receive antibiotic treatment.
Pasternak et al7 conducted a new-user, active comparator cohort study by comparing adults receiving a newly prescribed fluoroquinolone with those receiving newly prescribed amoxicillin. While this design helps to reduce various biases,21 it does not prevent surveillance bias that can occur when the clinical indication for an antibiotic is not considered. For example, a patient who received amoxicillin for a skin infection may have been compared with a patient receiving treatment for community-acquired pneumonia or pyelonephritis. The treatment of a skin infection does not typically require imaging. However, the diagnosis of community-acquired pneumonia requires thoracic imaging (eg, chest radiograph or computed tomographic scan), and patients with pyelonephritis typically receive abdominal imaging (eg, abdominal ultrasonographic or computed tomographic imaging of the abdomen). Patients who received a fluoroquinolone may have also been more likely to undergo imaging because of higher severity of illness or symptoms (eg, back pain and abdominal pain) that was initially misattributed to an infection. For example, up to 90% of patients with pyelonephritis present with back pain.22 Regardless of the reason, an imbalance in the rate of thoracic or abdominal imaging could result in surveillance bias via differential detection of preexisting AA/AD. In addition, community-acquired pneumonia and pyelonephritis are more common among adults with comorbid conditions (eg, diabetes or chronic renal failure),22,23 which may further contribute to bias if fluoroquinolone users also have a higher prevalence of preexisting AA/AD.
To account for potential surveillance bias, we analyzed a cohort of adults diagnosed with a UTI and a separate cohort of adults diagnosed with community-acquired pneumonia. By requiring a specific indication and analyzing results separately for each condition, we decreased the likelihood of surveillance bias. However, surveillance bias could still occur if adults who received a fluoroquinolone had a greater burden of comorbid illness or more severe infection. To further decrease the likelihood of bias, we selected combined trimethoprim and sulfamethoxazole as the comparator antibiotic for the UTI cohort. Combined trimethoprim and sulfamethoxazole is an appropriate comparator with fluoroquinolones because it also has excellent oral bioavailability and provides similar coverage as fluoroquinolones for bacteria that are responsible for over 90% of all UTIs (eg, E coli and Klebsiella pneumoniae).22 In contrast, amoxicillin is ineffective against K pneumoniae, and approximately 50% of E coli bacteria are resistant to amoxicillin.22,24,25
For the pneumonia cohort, we selected azithromycin as the comparator antibiotic because the Infectious Diseases Society of America guidelines previously equally recommended azithromycin or fluoroquinolones for the treatment of outpatient community-acquired pneumonia.26 However, it is possible that practice patterns evolved over the course of the study period, and azithromycin may have been preferentially given to patients with a milder form of pneumonia or those at lower risk of S pneumoniae resistance. For example, resistance of S pneumoniae to azithromycin has increased in recent years to up to approximately 30% vs less than 1% for respiratory fluoroquinolones.27 While we observed good balance of baseline characteristics and similar rates of baseline imaging even before propensity score matching when using azithromycin, this balance does not guarantee that unmeasured characteristics were well balanced.
Limitations
There are several limitations to our study. First, the patients were relatively young, had few comorbid conditions, and rates of AA/AD were generally low, which led to few events in the pneumonia and UTI cohorts; thus, the estimated treatment effects were imprecise. Second, we lacked data on other risk factors for AA/AD, such as family history or genetic predisposition. We also lacked accurate data on important risk factors, such as tobacco use or body mass index. However, we do not anticipate these factors to be differential between users of fluoroquinolones and the comparator antibiotic. Third, in the primary analyses, we restricted our cohorts to adults diagnosed with pneumonia or UTI, both of which are treated with a relatively short course of antibiotics (ie, typically <7 days), and thus our results may not apply to adults who receive fluoroquinolones over a longer time period. Fourth, we focused on oral fluoroquinolones; thus, our results may not apply to intravenous fluoroquinolones. However, since oral fluoroquinolones have nearly 100% bioavailability, we do not anticipate different results with intravenous formulations. Fifth, we used International Classification of Diseases, Ninth Revision, Clinical Modification codes for the diagnosis of AA or AD, which is less accurate than clinical adjudication. Although these codes have been validated and were found to have high positive predictive values in other studies, they have not, to our knowledge, been validated in the current data source. In addition, since we observed too few events to implement the imaging restriction in the pneumonia cohort, the observed findings could be affected by residual confounding or surveillance bias.
Conclusions
In this nationwide cohort study, we did not identify an increased rate of AA/AD in patients treated with fluoroquinolones compared with patients treated with combined trimethoprim and sulfamethoxazole. However, we observed an increased rate of AA/AD when azithromycin and amoxicillin were used as comparators. This increased rate raises the possibility that fluoroquinolones may increase the risk of AA/AD, but residual confounding and surveillance bias cannot be ruled out. The rates of AA/AD were low across cohorts (ie, <0.1%), and the benefits of choosing fluoroquinolones for treatment, when appropriate, may outweigh a small potential increased risk of AA/AD.
eTable 1. Outcome Definition
eTable 2. Definition of Inclusion Criteria for Pneumonia, UTI, and Baseline Imaging
eTable 3. Covariate Definitions
eTable 4. Distribution of Fluoroquinolones Used Across the Different Cohorts
eTable 5. Prevalence of Imaging for Aortic Aneurysm or Dissection at Baseline
eTable 6. Baseline Characteristics Before and After PS-Matching of Fluoroquinolone Users Compared to Amoxicillin Users
eTable 7. Baseline Characteristics Before and After PS-Matching of Fluoroquinolone Users Compared to Amoxicillin Users—Restricted to Baseline Imaging
eTable 8. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm—By Site and With or Without Rupture
eTable 9. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection After hdPS Matching
eTable 10. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection Stratified by Baseline Comorbidity Score
eTable 11. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection Excluding Aneurysms/Dissection at Any Time Point and Requiring Minimum 2 Years of Enrollment Prior to Cohort Entry
eTable 12. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection Using Any Inpatient Diagnosis Code for the Outcome Definition
eTable 13. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection Using Stratified Cox Regression
eFigure. Kaplan-Meier Curves for Aortic Aneurysm/Dissection—Primary Analysis
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Outcome Definition
eTable 2. Definition of Inclusion Criteria for Pneumonia, UTI, and Baseline Imaging
eTable 3. Covariate Definitions
eTable 4. Distribution of Fluoroquinolones Used Across the Different Cohorts
eTable 5. Prevalence of Imaging for Aortic Aneurysm or Dissection at Baseline
eTable 6. Baseline Characteristics Before and After PS-Matching of Fluoroquinolone Users Compared to Amoxicillin Users
eTable 7. Baseline Characteristics Before and After PS-Matching of Fluoroquinolone Users Compared to Amoxicillin Users—Restricted to Baseline Imaging
eTable 8. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm—By Site and With or Without Rupture
eTable 9. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection After hdPS Matching
eTable 10. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection Stratified by Baseline Comorbidity Score
eTable 11. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection Excluding Aneurysms/Dissection at Any Time Point and Requiring Minimum 2 Years of Enrollment Prior to Cohort Entry
eTable 12. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection Using Any Inpatient Diagnosis Code for the Outcome Definition
eTable 13. Incidence Rates and Hazard Ratios for Risk of Aortic Aneurysm/Dissection Using Stratified Cox Regression
eFigure. Kaplan-Meier Curves for Aortic Aneurysm/Dissection—Primary Analysis