Comparative Assessment of Prurifloxacin, Sparfloxacin, Gatifloxacin and Levofloxacin in the Rabbit Model of Proarrhythmia

Abstract

The administration of certain quinolone antibiotics has been associated with a prolongation of the QT interval on electrocardiogram, and in rare cases ventricular arrhythmias such as torsades de pointes. In this in vivo study using a rabbit arrhythmia model, we assessed the proarrhythmic effects and changes in the QT interval elicited by the administration of NM394 (UFX), an active metabolite of the new quinolone antibiotic prulifloxacin, and three representative quinolones, sparfloxacin (SPFX), gatifloxacin (GFLX) and levofloxacin (LVFX). Chloralose-anesthetized rabbits were co-administered a continuous infusion of methoxamine (15 microg/kg/min) together with NaOH (vehicle, 0.2 mol/L), SPFX (2, 3, 4 mg/kg/min), GFLX (4 mg/kg/min), LVFX (4 mg/kg/min) or UFX (4 mg/kg/min) via the ear vein, and then the effects on electrocardiogram were examined. SPFX and GFLX both prolonged the QT and QTc intervals. GFLX also induced premature ventricular contractions in all 6 rabbits that received it, and subsequently it induced torsades de pointes (TdP) in 3 of the 6 rabbits. SPFX infused at the dose of 4 mg/ kg/min induced conduction blocks without inducing TdP, whereas that infused at the lower dose of 3 mg/ kg/min induced both conduction blocks and TdP. The infusions with LVFX and UFX did not elicit remarkable prolongations in the QT interval, and none of the animals infused with the agents developed arrhythmia. These findings suggested that LVFX and UFX were less potent than SPFX and GFLX in prolonging the QT interval and inducing life-threatening arrhythmias.

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

“…As a consequence there are ongoing efforts to develop validated preclinical models that are useful to measure drug-induced prolongation and perhaps more importantly predict torsade de pointes (Friedrichs et al, 2005;Lawrence et al, 2005;Reinhart et al, 2005;Shah, 2005). There are increasing reports of QT prolongation and TdP associated with antibacterials (Frothingham, 2001;Iannini, 2002;Ray et al, 2004), and several models have been used to measure changes in cardiac repolarization and proarrhythmic liability with antibiotics such as: the Langendorff perfused rabbit heart (Milberg et al, 2002), methoxamine infused rabbit (Anderson et al, 2001;Akita et al, 2004), canine Purkinje fiber (Patmore et al, 2000), and the chronic atrioventricular-blocked dog (Chiba et al, 2004). We have recently reported results using an anesthetized guinea pig model to measure electrical alternans of monophasic action potential duration during rapid ventricular pacing with several hERG-blocking drugs (Fossa et al, 2004).…”

Prulifloxacin: a review focusing on its use beyond respiratory and urinary tract infections

“…Recent data point to a potentially decreased risk of cardiotoxicity associated with prulifloxacin in comparison with other quinolones [55][56][57][58][59]. Specifically, in a clinical trial involving healthy patients the maximum QTc prolongation during a 5-day course was 4 ms for prulifloxacin and 12 ms for moxifloxacin [55].…”

Quinolones

“…In rabbits, the potency of quinolones in prolonging the maximum QT interval was sparfloxacin > moxifloxacin = gatifloxacin = grepafloxacin, and ventricular tachycardia and torsades des pointes were only induced in sparfloxacin-treated animals [395]. In rabbits, the rank order potency of quinolones in prolonging the maximum QT interval was sparfloxacin = gatifloxacin >> levofloxacin = ulifloxacin and conduction blocks, premature ventricular contractions, and torsades des pointes were only induced in sparfloxacin-and gatifloxacintreated animals [400]. In dogs receiving 3 and 30 mg/kg iv doses of sparfloxacin, cardiac output and ventricular repolarization and refractory periods rose, and heart rate fell.…”

“…In healthy volunteers treated for 14 days with various doses of once-daily intravenous gatifloxacin (200,400, 600, 800 mg), a transient, dose-dependent reduction in fasting serum glucose concentration at the end of the infusion without corresponding changes in serum insulin/C-peptide concentrations occurred.…”