Antibiotics for Treating Severe Valproic Acid Overdose?

Figure 1: Apparent autoinduction of valproate β-oxidation in humans. Reproduced with permission of John Wiley & Sons Ltd from McLaughlin et al.3I know that, to some, this idea might at first seem counterintuitive, or even crazy. But hear me out. There's emerging medical literature suggesting that one or two doses of a drug such as meropenem may be beneficial in managing the sickest of these patients. A fascinating recent paper by Dr David Juurlink from the University of Toronto and the Ontario Poison Centre gives an excellent summary of the (admittedly limited) evidence we have to date supporting this novel therapy.1 Dr Juurlink points out that valproic acid (VPA) was first synthesized in 1882. As a fatty acid that mixed poorly with water but readily dissolved organic compounds, VPA was used for decades as a solvent in laboratory experiments. In the 1960s, scientists investigating a number of different chemicals for anticonvulsant activity found that all the chemicals seemed to have antiseizure effects. Eventually, they realized that such effects were caused not by the individual chemicals themselves, but by the solvent they were using. That solvent was VPA. By 1978, VPA was approved by the US Food and Drug Administration for treating petit mal (absence) seizures. In 1983, that approval was extended to include managing complex partial seizures. Today, VPA is also used to treat bipolar disorder and to prevent (but not treat) migraine episodes. Although the pharmacology of VPA is still not understood completely, the drug seems to enhance activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), impair activity of the excitatory neurotransmitter glutamate, and block sodium channels. Traditional treatment of VPA overdose includes use of oral activated charcoal (if not contraindicated), L-carnitine to lower serum ammonia levels, hemodialysis in more severe cases, and, of course, good supportive care. What benefits might the administration of a carbapenem add to this mix? In a 1997 letter, Nagai et al reported three cases of children on VPA for epilepsy whose serum levels decreased dramatically after they were given a carbapenem to treat pneumonia or pleural empyema.2 Two of the children exhibited increased seizure activity as their VPA levels went down. Multiple additional reports later confirmed that carbapenems do indeed lower VPA levels, sometimes by as much as 90%. To understand why this occurs, we need to look at how VPA is metabolized and eliminated (Figure 1).3 At therapeutic doses, about 40-50% of the drug undergoes hepatic β- or ω-oxidation into active metabolites. The other 50-60% is attached to glucuronide to form the inactive conjugate VPA–glucuronide (VPA-GLUC), which is then eliminated in bile and urine. But here's the key thing. Glucuronidation of VPA is reversible. The hepatic enzyme acylpeptide hydrolase (APEH) facilitates conversion of VPA–GLUC back to VPA, markedly impairing the drug's elimination and prolonging its half-life. Carbapenems, especially meropenem and ertapenem, inhibit the action of APEH, allowing more VPA to remain as the inactive, readily eliminated conjugate. This rapidly and significantly lowers VPA levels. And that's not all. Adverse effects of VPA overdose, lethargy, coma, and respiratory depression, are caused not only by the drug itself but also by active metabolites formed via β- and ω-oxidation. The carbapenem-induced inhibition of APEH causes more VPA to be metabolized by glucuronidation, decreasing the amount of active metabolites formed. Carbapenems thus provide a double benefit, lowering levels of both the parent drug and active metabolites. There is, of course, a danger that carbapenems might go on to be considered an “antidote” to VPA poisoning, with some clinicians tempted to overuse it in routine cases. (I've described my distaste for the entire concept of “antidotes” in a previous column, arguing that the term leads to muddy thinking and failure to weigh critically whether or not a specific intervention is indicated in individual cases.4) Dr Juurlink is careful to point out that the vast majority of VPA overdose cases will not need a carbapenem because most patients improve with routine treatment. He envisions two situations where use of a carbapenem might be considered: Patients with manifestations of severe VPA poisoning. Markers of severity might include symptoms such as significant CNS depression, elevated serum drug levels, and metabolic acidosis. Dr Juurlink suggests that any patient who meets the EXtracorporeal TReatments In Poisoning (ExTRIP) criteria for hemodialysis might be a candidate.5 In fact, it's possible that use of a carbapenem would obviate the need for dialysis in some patients or serve as a bridge in patients who meet the ExTRIP criteria but experience delay in starting dialysis because of factors such as need to transfer to another facility. Patients expected to develop severe VPA poisoning. Although the paper does not outline specific criteria for identifying patients who might deteriorate significantly, some combination of dose ingested, time of ingestion, specific form of VPA involved (long-acting preparations pose an increased risk of continued delayed absorption), serum VPA level on presentation, and symptoms should be considered. There is still much uncertainty about the optimal way to use carbapenems in these cases because, at this point, the medical literature contains only case reports and mechanistic studies. As always, your regional poison center is available 24/7 for consultation and up-to-date information about managing these cases. Just don't be surprised if their suggestions include the use of a carbapenem antibiotic.

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