Effects of Macrolide Antibiotics on Rat Embryonic Heart Function In Vitro

Abstract

The Swedish Medical Product Agency (MPA) has listed erythromycin as a suggested human teratogen, causing cardiovascular malformations. It is further suggested that this may be a class effect of macrolide antibiotics. The proposed teratogenic mechanism is blockade of the human ether-á-go-go-related (hERG)/IKr current in the embryonic heart causing bradycardia and arrhythmia resulting in altered cardiac blood flow and/or embryonic hypoxia. To test this hypothesis, we examined the effect of three macrolide antibiotics on the function of the rat embryonic heart. Gestational day 13 rat embryos in vitro were exposed to erythromycin (25-500 μM), clarithromycin (25-500 μM), or azithromycin (100 μM to 1 mM) for 3 hr. The effect on the embryonic heart was monitored every hour. The results showed that erythromycin and clarithromycin caused a concentration-dependent bradycardia. Twenty-five micromolar was a no-effect concentration for erythromycin and was close to a no-effect concentration for clarithromycin. Azithromycin only caused significant bradycardia at 1 mM. Additional studies were performed with the embryos cultured at 40°C instead of 38°C, to mimic fever. The increased temperature increased the number of arrhythmias but did not worsen the drug-induced bradycardia. The results support the concept that erythromycin and clarithromycin can adversely affect the embryonic heart but only at concentrations well outside expected embryonic exposure in the human.

Early Gestational Hypoxia and Adverse Developmental Outcomes

“…Hypokalemia, hyperthermia, or metabolic acidosis could all potentiate the effect of hypoxia. In a recent systematic review, there was strong evidence that hypokalemia was a risk factor for QT‐prolongation (Vandael et al, ), while hyperthermia has been shown to increase the number of arrhythmias in whole rat embryo culture (Nilsson and Webster, ). In other in vitro models, decreased intracellular pH exacerbated the HR response to hypoxia (Zhou et al, ).…”

“…This was based on its known risk of TdP and two studies from Hungary (Czeizel et al, ) and Sweden (Kallen et al, ) identifying a doubling in incidence of cardiac defects, especially VSDs. Preclinical in vivo animal studies have been negative for erythromycin (Karlsson et al, ), although in vitro embryo culture studies did identify the IKr blocking potential, but only at high concentrations unlikely to occur with oral dosing in humans (Nilsson and Webster, ). A follow‐up Swedish study confirmed the association with cardiac defects (Källén and Danielsson, ), but others have been largely negative (Cooper et al, ; Crider et al, ; Romoren et al, ; Lin et al, ).…”

Bruk av antibiotika i svangerskapet

“…Det ble heller ikke inkludert en kontrollgruppe der andre antibiotika var brukt, slik at en mulig effekt av den underliggende infeksjonen ikke kan utelukkes. Forfatterne av den svenske studien har tidligere foreslått at evnen makrolider har til å blokkere en spesiell kaliumkanal i hjertet (hERG-kanaler) kunne vaere en plausibel teratogen meksmisme (35), noe andre har trukket i tvil (36). På bakgrunn av hovedvekten av data, inkludert norske, og fordi den biologiske plausibiliteten er diskuterbar, mener vi makrolider bør kunne vaere annenhåndsvalg, altså i de tilfellene førstehåndsvalget ikke kan brukes på grunn av allergi eller andre kontraindikasjoner.…”

Long-term programming effects on blood pressure following gestational exposure to the I Kr blocker Dofetilide

“…Fetal bradycardia may manifest as a result of congenital channelopathies, maternal autoantibodies, or following exposure to cardioactive drugs (Strasburger and Wakai ; Nilsson et al. ; Nilsson and Webster ).…”