Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Abstract

Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á -go-go-related gene (hERG) with IC 20 concentrations of 31 M (moxifloxacin), 21 M (erythromycin), and 11 M (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 M). Erythromycin also increased MAPD at its highest free drug concentration (58 M), but alternans occurred at a relatively lower therapeutic multiple (13.9 M), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 M). The relative risk at therapeutic concentrations is erythromycin Ͼ moxifloxacin Ͼ telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.

Comparison of the Effect of Azithromycin Versus Erythromycin on Antroduodenal Pressure Profiles of Patients with Chronic Functional Gastrointestinal Pain and Gastroparesis

“…First, several reports of arrhythmias associated with use of either oral or intravenous (IV) EES have been reported [17][18][19]. Second, in 2004, a large cohort study of Tennessee Medicaid patients from 1988 to 1993 showed a possible association between EES with a risk of sudden cardiac death through its extensive metabolism by the cytochrome P-450 3A isoenzymes [17].…”

Erythromycin, QTc interval prolongation, and torsade de pointes: Case reports, major risk factors and illness severity

“…In monophasic AP recordings from anesthetized guinea-pigs, erythromycin has been observed to increase both AP duration and alternans [Wisialowski et al 2006]. The drug has also been shown to increase AP duration in a concentration dependent fashion in rabbit Purkinje fibers and to prolong both QT interval and T peak T end in a concentration-dependent fashion in an arterial perfused rabbit left ventricular wedge preparation [Lu et al 2007].…”

“…Volberg and colleagues reported I hERG inhibition in a mammalian cell expression system by erythromycin with a half maximal inhibitory concentration (IC 50 ) of 72.2 mM, whilst in the same study its metabolite desmethyl-erythromycin also produced weaker I hERG inhibition (IC 50 of 147.1 mM). Some subsequent studies have reported lower I hERG block IC 50 values for erythromycin of 38.9 mM [Stanat et al 2003], 59.3 mM [Duncan et al 2006], and 21 mM [Wisialowski et al 2006].…”

Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives

“…There have been reports of erythromycin being associated with serious cardiac arrhythmias and prolonged QTc [38][39][40] . Erythromycin should not be used concurrently with medications metabolized by cytochrome P450 3A4 (CYP3A4) such as cisapride, terfenadine, pimozide, or astemizole as it is a CYP3A4 inhibitor.…”