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

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) [1‐3]. However, 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].

Results from observational studies have suggested that the use of macrolides (azithromycin, clarithromycin, and erythromycin) is associated with the occurrence of cardiovascular events, especially in patients with increased cardiovascular risk [6‐10]. In a Danish study the relative risk for cardiac events after receiving azithromycin was not increased in the general population [11]. In US patients hospitalized with CAP, azithromycin was associated with a lower risk of all-cause mortality and any cardiac event, although the risk for myocardial infarction up to day 90 after admission did increase (5.1% vs 4.4%; odds ratio 1.17 95% confidence interval (CI) 1.08 to 1.25) with azithromycin use [7]. In another study, clarithromycin use during admission had an increased hazard ratio for cardiovascular events of 1.68 (95% CI 1.18 to 2.38) after one year follow-up among patients hospitalized with CAP [8]. Fluoroquinolones have been associated with an increased risk of arrhythmia in the general population, thus potentially increasing cardiovascular risk when treating CAP patients [10, 12].

Naturally, residual confounding cannot be excluded in these observational studies. However, the possibility of harm caused by macrolides or fluoroquinolones is likely to change the risk-benefit evaluation for atypical coverage in the empirical antibiotic treatment of CAP patients; particularly for macrolides in the context of limited evidence of benefit.

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 (non-ICU) medical wards [14]. Here we present the results of a post-hoc analysis of these data on the association between specific macrolides and fluoroquinolones and the occurrence of cardiac events during hospitalization.

In this study of 2107 patients hospitalized with CAP to non-ICU wards, of which 146 (6.9%) developed a cardiac event during admission, erythromycin use was associated with a 68% higher hazard of cardiac events during hospital admission. This effect almost completely resulted from episodes of new or worsening heart failure. In contrast, levofloxacin and moxifloxacin were associated with a lower risk of cardiac events, mainly because of a lower risk of heart failure during admission.

This was a post-hoc analysis of a cluster-randomized cross-over study evaluating three antibiotic treatment strategies for patients hospitalized with CAP [14]. Baseline differences between patients who did or did not receive macrolides or fluoroquinolones during admission were small. Disease severity scores (i.e. PSI and CURB-65) at baseline were slightly lower in patient who received macrolides at any time during admission, although these differences do not seem clinically significant. If anything, classical cardiovascular risk factors were less prevalent in patients that received macrolides such as erythromycin. Hence, it is possible that physicians considered these antibiotics as potential risks for cardiac events in CAP patients, which may have attenuated the crude effect estimates in this analysis [20]. Consequently, the effect estimate between macrolides and cardiac events increased after adjustment for potential confounders. The findings were largely unchanged in patients with radiologically confirmed CAP. As associations between erythromycin use and competing outcomes such as in-hospital death or hospital discharge could change the interpretation of effect estimates, we performed a competing risk analysis which did not change our results [17]. Assessing associations with the original trial arms would have diluted effect sizes too much due to protocol non-adherence, while using subgroups (per-protocol and non-adherent populations) would have led to the same loss of randomization, but with smaller groups, as our current observational cohort study approach. We have tried to optimally correct for indication bias by using time-varying effects for antibiotic exposure and adjustment for confounders.

Several biological mechanisms could explain the observed associations between erythromycin, levofloxacin, and moxifloxacin use and cardiac events, which could be attributed almost completely to occurrences of heart failure. The proposed explanation for this is the volume and sodium load associated with intravenous administration of erythromycin, compared to regimens including either other macrolides (which are only orally available) or monotherapy with levofloxacin or moxifloxacin. The latter fluoroquinolones are also frequently given as oral treatment as the bioavailability of these antibiotics is known to be high [21]. When looking at the different beta-lactams co-administered with the three types of macrolides, erythromycin was most frequently prescribed together with penicillin. Still, we assume that different beta-lactams are not cardiotoxic and that the sodium and volume load does not differ too much between beta-lactams (Table 4). Unfortunately, we did not have data on fluid balances (intravenous fluid administration) for our patients to further strengthen this hypothesis. In addition, erythromycin is a pro-arrhythmic drug, metabolized through CYP3A4 thus frequently interacting with other drugs, which can prolong the QT-interval [22, 23]. Such effects would most likely occur shortly after start of treatment, and can lead to anything from self-limiting episodes of arrhythmia to severe arrhythmia or Torsade des Pointes, and consequently to demand ischemia and/or decompensated heart failure. Yet, the current analysis might have been underpowered to identify associations between use of any macrolide and occurrence of arrhythmias, as compared to previous analyses in out-patient populations [6, 9, 10, 12]. Finally, erythromycin might have a weaker anti-inflammatory effect than other macrolides, thus leading to more heart failure if this was predominantly driven by pro-inflammatory cytokines [24, 25].

Our findings do not support previous findings of increased risks for cardiac events when using azithromycin or clarithromycin in hospitalized CAP patients [7, 8]. In these studies all hospitalized patients with CAP, including those needing ICU-admission, were included with considerable longer follow-up periods for cardiac events, ranging from 90 days after discharge to one year after admission. In both studies, cardiac events mainly involved myocardial ischemia, which was a relatively infrequent event during hospitalization in our study. Moreover, fluoroquinolones have been associated with an increased risk for arrhythmia in the general population, [10, 12] as mentioned before, our study was probably underpowered to properly assess this association.

Our post-hoc analysis has limitations. The occurrence of cardiac events during the course of the study was based on medical chart review in an open-label trial. This methodology has a risk for misclassification and observational bias. Random misclassification might have led to general underreporting of cardiac events, which would affect the precision of the effect estimates. More importantly, observational bias might have occurred if treating physicians would be more alert to report cardiac events in medical charts of erythromycin users, which would have biased the results from null. As this could also apply to registration of cardiac events by researchers, we used pre-specified criteria for recording cardiac events to reduce this bias. Unfortunately, we were not able to systematically gather information on the etiology of heart failure, e.g. true left-ventricular heart failure as compared to sepsis-induced episodes, which would have helped in identifying causal mechanisms. Another limitation could be residual confounding by indication. Although patient groups were comparable in terms of disease severity at baseline (Table 1), clinical stability during the first two to four days of admission is an important prognostic factor for adverse outcomes in CAP [26, 27]. Therefore, clinical deterioration during the first days of admission might have stimulated treating physicians to add macrolides or fluoroquinolones, creating confounding by indication. Since changes in disease severity during these first days of admission were not determined, this could not be accounted for. Still, the majority of erythromycin users with a cardiac event (n = 25, 80.6%) started with erythromycin on the day of admission. (Fig. 2) Lastly, we did not have data on concomitant use of drugs interacting with macrolides or fluoroquinolones, nor did we determine specific causes of death. The latter could have increased the efficacy of end-point detection, and might have allowed discrimination between sudden cardiac death, cardiovascular death, and death due to other causes, although cause-of-death statements are not always interpreted unequivocally [28].

In this post-hoc analysis, intravenous erythromycin use, but not oral azithromycin or clarithromycin use, increases the risk for cardiac events, especially heart failure, in patients hospitalized with CAP to non-ICU wards. Volume overload associated with intravenous administration of erythromycin in elderly could be one of the mechanisms for heart failure. Inversely, this might explain why levofloxacin and moxifloxacin were associated with a lower risk of cardiac events, mainly heart failure, during admission. Although our study does not fully exclude confounding bias, findings remained largely unchanged in crude, adjusted, and sensitivity analyses. Together with the absence of survival benefit these findings may caution the use of intravenous erythromycin for empirical treatment of CAP patients admitted to non-ICU wards.