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

Douwe F Postma,Cristian Spitoni,Leontine J R Van Elden,Cornelis H Van Werkhoven,Jan Jelrik Oosterheert,Marc J M Bonten

doi:10.1186/s12879-018-3630-7

Douwe F Postma, Cristian Spitoni + Show 4 more

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https://doi.org/10.1186/s12879-018-3630-7

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Abstract

BackgroundGuidelines 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.MethodsThis 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.ResultsCardiac 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%).ConclusionsAmong 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 registrationThe original trial was retrospectively registered under ClinicalTrials.gov Identifier NCT01660204 on August 8th, 2012.

Highlights

Guidelines recommend macrolides and fluoroquinolones in patients hospitalized with communityacquired pneumonia (CAP), but their use has been associated with cardiac events
A recent Swiss randomized clinical trial showed a non-significant increase in 30-day mortality of 1.4% (p = 0.42) for beta-lactam monotherapy compared to combination therapy with a macrolide in hospitalized CAP patients; clinical stability criteria were met earlier in the combination group (4.5 days) vs beta-lactam monotherapy (5 days) [13]. This is in line with our own cluster-randomized trial, in which we demonstrated that a strategy of beta-lactam monotherapy was non-inferior to beta-lactams combined with a macrolide or fluoroquinolone monotherapy in terms of all-cause mortality for CAP patients admitted to non- intensive care unit medical wards [14]
Patients We included 2107 patients who were admitted to non-Intensive Care Unit (ICU) wards with a working diagnosis of CAP and without a cardiac event on admission (Fig. 1)

Summary

Introduction

Guidelines recommend macrolides and fluoroquinolones in patients hospitalized with communityacquired 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. The use of beta-lactam, macrolide, and fluoroquinolone antibiotics, either alone or in combination, is recommended in international guidelines for empirical treatment of patients hospitalized with community-acquired pneumonia (CAP) [1,2,3]. The evidence-base for the addition of atypical coverage, especially macrolides, to beta-lactam antibiotics in patients with CAP admitted to non-ICU wards has been questioned [4, 5]

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