Antidote for Valproic Acid Toxicity: a New Indication for Meropenem Antibiotic. A Randomized Placebo-controlled Trial

JUSTIFICATION AND SIGNIFICANCE:

Valproic acid (VPA) -a branched chain carboxylic acid- introduced by the Food and Drug Administration in 1978 for the treatment of seizure disorders(1). In the following years, VPA gained further approved indications to treat bipolar and behavioral disorders(2), migraine prophylaxis(3) as well as other psychiatric indications(4).The growing use of VPA and its availability resulted in increased prevalence of VPA overdoses(5,6). The rising incidence of acute VPA toxicity is either resulting from suicidal attempts, accidental ingestions, or following VPA dose increments to achieve the desired therapeutic effect(7). Acute VPA toxicity is an emergency condition which may commonly present with central nervous system (CNS) depression(5). In mild poisoning, associated with VPA ingestions of 200 mg/kg, sedation and lethargy commonly occur(6); while in severe VPA poisoning associated with ingestions of 400 mg/kg or more, life threatening events are likely to occur as respiratory depression, metabolic acidosis, encephalopathy, hemodynamic instability, and cerebral edema which may progress to coma and even death -if not treated promptly(5,8). Serum VPA concentration is the most functional tool in diagnosing and determining the severity of toxicity. Supportive care along with early gastric decontamination using activated charcoal (AC) (which may only be given if patient presented early after ingestion), in addition to intravenous (IV) administration of Levocarnitine (L-Carnitine) and ensuring adequate airway protection are the cornerstone of treatment, but there remains no drug listed as a specific antidote for acute VPA intoxication(5,9).

Carbapenems are a group of β-lactam antibiotics with a growing need to use in the empiric and definitive treatment, due to the emerging resistance to antibiotics(10). A multitude of case reports(11-13), retrospective observational studies(14-19) and reviews(20-22) demonstrated that combined use of VPA and carbapenem antibiotics -mainly meropenem (16)(23)- is associated with a potential drug interaction that can significantly decrease VPA serum concentration(24). One retrospective trial included 36 patients concluded that VPA mean ± SEM serum concentration dropped from 50.8 ± 4.5 µg/mL to 9.9 ± 2.1 µg/mL(P < .001) following meropenem administration with a mean decrease of 82.1% ± 2.7%(18), while a recent prospective observational trial determined that the mean drop in serum VPA level was 80% ranging from(49%-99%)(23). However, despite VPA toxicity with fatal events being reported for over 20 years, only a few case reports documented successful intentional use of meropenem as an antidote for VPA poisoning(25-27). To date, no randomized-controlled trials were conducted.

Specific aims: Determine if meropenem is effective in treating acute VPA toxicity, manifested by achieving reduced VPA plasma levels and/or enhanced mentation.

Hypothesis: Administration of meropenem combined with standard care is effective in managing VPA intoxication, affirmed by providing lower serum VPA concentrations and/or better level of consciousness; in contrast to standard care alone.