Case report: Use of therapeutic drug monitoring and pharmacogenetic testing as opportunities to individualize care in a case of flecainide toxicity after fetal supraventricular tachycardia.

Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs. There remains a paucity of standard guidelines and data to inform the timing and frequency of the aforementioned test in pregnancy and timing of flecainide discontinuation prior to childbirth. Flecainide primarily undergoes metabolism via cytochrome P450 (CYP). Given the variance of CYP-mediated metabolism at the level of the individual patient, pharmacogenomics can be considered in patients who present with flecainide toxicity to determine the maternal vs. fetal factors as an etiology for the event. Finally, pharmacogenetic testing can be utilized as an adjunct to guide flecainide dosing decisions, but must be done with caution in neonates <2 weeks of age. This case report highlights utilization of pharmacogenomic testing and therapeutic drug monitoring as adjuncts to guide therapy for a newborn with refractory supraventricular tachycardia, who experienced flecainide toxicity immediately post-partum and was trialed unsuccessfully on multiple alternative antiarrhythmics without rhythm control.

The expression of the Acinetobacter calcoaceticus recA gene increases in response to DNA damage independently of RecA and of development of competence for natural transformation.

Using the lacZ operon fusion technique, the transcriptional control of the Acinetobacter calcoaceticus recA gene was studied. A low (approximately twofold) inductive capacity was observed for compounds that damage DNA and/or inhibit DNA replication, e.g. methyl methanesulfonate, mitomycin C, UV light and nalidixic acid. Induction of the recA gene by DNA damage was independent of functional RecA. The presence of the recA promoter region on a multicopy plasmid had the same effect on recA transcription as the presence of DNA-damaging agents. Thus, recA expression in A. calcoaceticus appears to be regulated in a novel fashion, possibly involving a non-LexA-like repressor. Regulation of the recA gene in A. calcoaceticus appears not to be part of a regulon responsible for competence for natural transformation: in cells exhibiting extremely low transformation frequencies, the level of transcription of the recA gene was found to be comparable to the level found in cells in the state of maximal competence.