Association Between Third-Generation Fluoroquinolones and Achilles Tendon Rupture: A Self-Controlled Case Series Analysis

INTRODUCTION

Fluoroquinolone-induced tendon injury is a rare event. Nevertheless, a systematic review found that exposure to fluoroquinolones was associated with an increased occurrence of Achilles tendon rupture.¹ In a population-based cohort study, 5 patients experienced Achilles tendon rupture among 28,262 fluoroquinolone users (standardized incidence rate ratio [IRR] = 3.1; 95% CI, 1.0-7.3).² A case-crossover study found that the odds of rupture were doubled with fluoroquinolone exposure relative to nonexposure (odds ratio = 2.0; 95% CI, 1.2-3.3).³ In a case-control study that adjusted for potential confounders, risk was more than quadrupled (adjusted odds ratio = 4.3; 95% CI, 2.4-7.8).⁴ Several studies, however, have indicated that the risk of Achilles tendon rupture varies depending on the type of fluoroquinolone.^1,4

Newer, third-generation fluoroquinolones such as garenoxacin and sitafloxacin developed in 2006 and 2008, respectively, have been widely used in recent years.^5,6 Previous studies have investigated the associations between first- and second-generation fluoroquinolones and Achilles tendon rupture^6,7; however, the association for third-generation fluoroquinolones remains unclear. Several studies were unable to successfully control for interindividual confounding factors, including age, sex, renal failure, and corticosteroids use.^1,3 Self-controlled case series analysis can address this shortcoming by eliminating time-invariant intra-individual confounders, and comparing incidence of an outcome during an exposure period relative to a nonexposure period.^8,9

The aim of the present study was to investigate the association between fluoroquinolones and Achilles tendon rupture, particularly focusing on third-generation fluoroquinolones, by self-controlled case series analysis.

METHODS

Periods

The observation period for a given patient was defined as the period from the first month to the last month of his or her insurance coverage (Figure 1). We divided the observation period into antibiotic exposure and nonexposure periods.

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Figure 1.

Schematic diagram of the observation period for a hypothetical patient according to the self-controlled case series design.

Note: The observation period for each Achilles tendon rupture case (outcome 0, no event; outcome 1, Achilles tendon rupture) was divided into baseline and exposure periods for each antibiotic (exposure 0, baseline period; exposure 1, first- and second-generation fluoroquinolones risk period; exposure 2, third-generation fluoroquinolones risk period; exposure 3, nonfluoroquinolones risk period). The risk period was set at 30 days from antibiotic prescription according to a previous study. If the risk periods for different antibiotics overlapped, the stacked risks for Achilles tendon rupture in the overlapping risk periods were combined.

The exposure period (risk period) was defined as the 30-day period starting on the date of an intravenous or oral antibiotic prescription (Figure 1), based on a previous case-crossover study.³ In Japan, intravenous and oral antibiotics can be prescribed in both hospitals and clinics, and we therefore extracted all antibiotic prescriptions from the database. Eye drops and ointments were not included in antibiotic exposure. We categorized antibiotics into fluoroquinolones and nonfluoroquinolones, and then further classified the fluoroquinolones into 3 generations, as shown in Table 1.^5-7 If there were overlapping exposure periods for different types of antibiotics, we combined the stacked risks of Achilles tendon rupture in the overlapping exposure periods.¹⁴

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Table 1.

Classification of Fluoroquinolones Available in Japan

The nonexposure period (baseline period) was the period in which the patient was not prescribed any intravenous or oral antibiotics (Figure 1). We did not define a washout period between exposure and nonexposure periods.

RESULTS

We extracted data for 533 patients who experienced Achilles tendon rupture during the 5-year study period. The median observation period was 4.1 years (interquartile range = 3.7-4.9 years).

A total of 29 patients did not receive antibiotics during their observation period and were therefore excluded, leaving 504 patients for analyses. Their baseline characteristics are shown in Table 2.

None of the patients experienced more than 1 Achilles tendon rupture. The population incidence rate was 16.0 cases per 100,000 person-years. The total exposure periods during the observation period and the numbers of Achilles tendon ruptures occurring during these exposure periods are shown in Table 3.

The risks of Achilles tendon rupture for the various types of antibiotics are shown in Table 4. Risk was not significantly elevated during exposure to third-generation fluoroquinolones (IRR = 1.05; 95% CI, 0.33-3.37) and nonfluoroquinolones (IRR = 1.08; 95% CI, 0.80-1.47). In contrast, risk was significantly elevated during exposure to first- and second-generation fluoroquinolones (IRR = 2.94; 95% CI, 1.90-4.54).

The results of subgroup analyses are shown in Table 5. Findings for men and women and for patients with and without recent corticosteroid use were similar to those of the main analysis.

DISCUSSION

This study shows that risk of Achilles tendon rupture differs among the various generations of fluoroquinolones, and that third-generation fluoroquinolones are not associated with an increase in risk. Our results for first- and second-generation fluoroquinolones are similar to those of previous studies.^1-3 The majority of the fluoroquinolones evaluated in previous studies were first and second generation.^5,6 Our study is the first to investigate the risk of Achilles tendon rupture associated with third-generation fluoroquinolones by self-controlled case series analysis and using a large administrative claims database.

A systematic review suggested that a structure within fluoroquinolones can affect tendon injury risk.¹⁸ Findings of a preclinical study showed that risk of tendon injury was higher with a methylpiperazinyl substituent than with a piperazinyl substituent.¹⁹ Only a few third-generation fluoroquinolones, such as gatifloxacin and prulifloxacin, have a methylpiperazinyl substituent, whereas most first- and second-generation fluoroquinolones do. This difference may explain why the third-generation fluoroquinolones were not associated with Achilles tendon rupture in our study.

Some researchers have argued that use of fluoroquinolones should be avoided for athletes if alternative antibiotics are available.²⁰ Taking the results of the present study and previous studies into account, we believe that third-generation fluoroquinolones may be a safer option with respect to risk of Achilles tendon rupture when patients need a fluoroquinolone. Fluoroquinolones are necessary for patients with allergy to β-lactam antibiotics or with Legionella pneumophila infection.

Our study has some limitations. First, we used an administrative claims database, in which the accuracy of diagnoses was not validated,^10,21 and data for patients enrolled in other health insurance systems were not included. In a previous validation study of the Japanese administrative database, however, specificities of 17 diagnoses exceeded 96%.²¹ We therefore assumed that the diagnosis of Achilles tendon rupture was highly specific. Second, the sample size may have been insufficient to estimate the risk for individual fluoroquinolones. Third, the claims data did not include information on whether the prescribed drugs were actually dispensed. Fourth, the doses used for several fluoroquinolones in Japan are lower than those used in western countries.²² For example, the daily dose of oral ciprofloxacin is 0.2 to 0.6 g in Japan, compared with 0.5 to 1.5 g in western countries.²² Fifth, whether repeated exposures to fluoroquinolones incrementally increase the incidence of Achilles tendon rupture remains unknown. Finally, we investigated only Achilles tendon rupture as an outcome and used data from only a single prefecture. Further studies are required to determine whether third-generation fluoroquinolones affect risks of other rare adverse events, such as aortic aneurysm and dissection,²³ and to perform self-controlled case series analyses using data for the entire Japanese population.

In conclusion, using administrative claims data for a single prefecture in Japan, we found that third-generation fluoroquinolones were not associated with a significant increase in Achilles tendon rupture, whereas first- and second-generation fluoroquinolones were. This information may be useful in personalizing antibiotic therapy for individual patients.