No proarrhythmic properties of the antibiotics Moxifloxacin or Azithromycin in anaesthetized dogs with chronic-AV block.
OBJECTIVE
The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not been shown to cause torsades de pointes arrhythmias (TdP). Azithromycin is a macrolide antibiotic that has rarely been associated, clinically, with cases of proarrhythmia. As there is a lack of clinical data available, the cardiac safety of these drugs was assessed in a TdP-susceptible animal model by evaluating their repolarization and proarrhythmia effects.


RESULTS
In transfected HEK cells, the IC(50)s for I (hERG) were 45+/-6 and 856+/-259 microg ml(-1) for moxifloxacin and azithromycin, respectively. Intravenous administration of 2 and 8 mg kg(-1) moxifloxacin (total peak-plasma concentrations 4.6+/-1.5 and 22.9+/-6.8 microg ml(-1)) prolonged the QT(c) in 6 anaesthetized dogs with chronic AV block by 7+/-3 and 21+/-19%, respectively. Similar intravenous doses of azithromycin (total peak-plasma concentrations 5.4+/-1.3 and 20.8+/-4.9 microg ml(-1)) had no electrophysiological effects in the same dogs. The reference compound, dofetilide (25 microg kg(-1) i.v.) caused QT(c) prolongation (29+/-15%) and TdP in all dogs. Beat-to-beat variability of repolarization (BVR), quantified as short-term variability of the left ventricular monophasic action potential duration, was only increased after dofetilide (1.8+/-0.7 to 3.8+/-1.5 ms; P<0.05).


CONCLUSIONS
As neither moxifloxacin nor azithromycin caused TdP or an increase in the BVR, we conclude that both drugs can be used safely in clinical situations.
Thomsen
M B
MB
Department of Medical Physiology, Heart Lung Centre Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
Beekman
J D M
JD
Attevelt
N J M
NJ
Takahara
A
A
Sugiyama
A
A
Chiba
K
K
Vos
M A
MA
D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D001372:Aza Compounds / Q000633:toxicity*; D017963:Azithromycin / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects; D004594:Electrophysiology; D024841:Fluoroquinolones; D006327:Heart Block / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D000077266:Moxifloxacin; D010627:Phenethylamines / Q000494:pharmacology; D011804:Quinolines / Q000633:toxicity*; D013449:Sulfonamides / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D010627:Phenethylamines; D011804:Quinolines; D013449:Sulfonamides; D017963:Azithromycin; C063533:dofetilide; D000077266:Moxifloxacin