Cardiac events after macrolides or fluoroquinolones in patients hospitalized for community-acquired pneumonia: post-hoc analysis of a cluster-randomized trial

Abstract

Background: Guidelines recommend macrolides and fluoroquinolones in patients hospitalized with community-acquired pneumonia (CAP), but their use has been associated with cardiac events. We quantified associations between macrolide and fluoroquinolone use and cardiac events in patients hospitalized with CAP in non-ICU wards.

Methods: This was a post-hoc analysis of a cluster-randomized trial as a cohort study; including patients with a working diagnosis of CAP admitted to non-ICU wards without a cardiac event on admission. We calculated cause-specific hazard ratio's (HR's) for effects of time-dependent macrolide and fluoroquinolone exposure as compared to beta-lactam monotherapy on cardiac events, defined as new or worsening heart failure, arrhythmia, or myocardial ischemia during hospitalization.

Results: Cardiac events occurred in 146 (6.9%) of 2107 patients, including heart failure (n = 101, 4.8%), arrhythmia (n = 53, 2.5%), and myocardial ischemia (n = 14, 0.7%). These occurred in 11 of 207 (5.3%), 18 of 250 (7.2%), and 31 of 277 (11.2%) patients exposed to azithromycin, clarithromycin, and erythromycin for at least one day, and in 9 of 234 (3.8%), 5 of 194 (2.6%), and 23 of 566 (4.1%) exposed to ciprofloxacin, levofloxacin, and moxifloxacin, respectively. HR's for erythromycin, compared to beta-lactam monotherapy, on any cardiac event and heart failure were 1.60 (95% CI 1.09;2.36) and 1.89 (95% CI 1.22;2.91), respectively. HR's for levofloxacin and moxifloxacin, compared to beta-lactam monotherapy, on any cardiac event were 0.40 (95% CI 0.18;0.87)and 0.56 (95% CI 0.36;0.87), respectively. Findings remained consistent after adjustment for confounders and/or in a sensitivity analysis of radiologically confirmed CAP (n = 1604, 76.1%).

Conclusions: Among patients with CAP hospitalized to non-ICU wards, erythromycin use was associated with a 68% increased risk of hospital-acquired cardiac events, mainly heart failure. Levofloxacin and moxifloxacin were associated with a lower risk of heart failure. Although our study does not fully exclude confounding bias, findings remained largely unchanged in crude, adjusted, and sensitivity analyses. These findings may caution the use of erythromycin as empirical therapy in these patients.

Trial registration: The original trial was retrospectively registered under ClinicalTrials.gov Identifier NCT01660204 on August 8th, 2012.

Keywords: Antibiotics; Cardiac events; Community-acquired pneumonia; Complications; Fluoroquinolones; Macrolides.

Conflict of interest statement

Ethics approval and consent to participate

Data collection for the current analysis was approved by the ethics review board of the University Medical Center Utrecht with a waiver for additional informed consent.

Consent for publication

Not applicable

Competing interests

CHvW reports consultation fees, presentation fees, and thesis print support from Pfizer. MJMB reports research grants and an educations grant from Pfizer, paid to institution. Other authors have nothing to disclose.

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Figures

Fig. 1

Inclusion of patients and cardiac event rates per population. n/w new or worsening; BL beta-lactam; BLM beta-lactam combination with macrolide; FQL fluoroquinolone. The population for the primary analysis consisted of patients with a working diagnosis of CAP; the population for the sensitivity analysis consisted of the patients that developed radiological evidence of CAP during the first 48 h of admission. Crude new or worsening cardiac event rates are presented from the original trial arms for patients only receiving the cluster-randomized antibiotic strategy (per protocol) or who were non-adherent to the strategy

Fig. 2

Timing of events in macrolide users with cardiac events. Figure depicts timing of events through admission for each patient which used a macrolide and experienced a cardiac event. Individual patients are on the y-axis and time in days of admission is on the x-axis. Cardiac events occurring before prescription of a macrolide were not attributed to the antibiotic in statistical models as antibiotics were modelled time-dependently