Episode 194: Interaction between valproic acid and carbapenem antibiotics – should it be considered contraindicated in ICU patients?

In this episode, I’ll discuss the interaction between valproic acid and carbapenem antibiotics.

Since the late 1990s, it has been known that carbapenem antibiotics lower plasma concentrations of valproic acid.

The level of significance for this interaction varies between different references. Most drug interaction references list the combination of carbapenems and valproic acid as a serious interaction where an alternative should be used. Some references list the combination as a less severe interaction where monitoring is acceptable.

Numerous case reports describe the interaction as occurring within the first 1 to 7 days of concomitant use. Valproic acid levels may not return to normal until days to weeks after the combination is stopped. The mechanism by which valproic acid plasma concentrations are lowered by carbapenems is not completely understood. The rapid onset of the interaction suggests that enzyme induction by carbapenems is not likely to be part of the interaction. Various mechanisms have been proposed:

1. Increased distribution of valproic acid into red blood cells
2. Decreased intestinal absorption of valproic acid
3. Inhibition of the hydrolysis of glucuronidated valproic acid back into the active form

Simply increasing the valproic acid dose or giving valproic acid intravenously does not raise levels back into the normal range. This suggests that inhibition of hydrolysis by carbapenems is the likely cause. Here is how it works:

1. Valproic acid is rapidly glucuronidated in an inactive metabolite called valproic acid glucuronide.
2. The enzyme beta-glucuronidase then hydrolyzes the metabolite back into valproic acid.
3. Carbapenems likely irreversibly inhibit beta-glucuronidase. This explains why the interaction can take weeks to recover from as new beta-glucuronidase must be synthesized.

The consequences of this interaction can be severe in critically ill patients.

If valproic acid is being used as a mood stabilizer, the patient may become agitated when the valproic acid levels drop. This means the patient will need to receive other medications to control the agitation, placing the patient at risk for respiratory failure, delirium, hemodynamic instability, or cardiac arrhythmias depending on which alternative agents need to be used. Uncontrolled agitation or side effects from additional medications can lead to a prolonged length of stay in the ICU.

If the valproic acid is being used to prevent seizures, the patient may develop seizures when the valproic acid levels drop. Because levels will not rise by increasing the valproic acid dose, other medications will be needed to control the seizures. The patient will again be placed at significant risk of adverse reactions or increased length of stay in the ICU.

Carbapenems share a spectrum of action with many other antibiotics, and an alternative antibiotic may be easy to find. You can see alternatives to carbapenems in my free, updated visual critical care antibiotic guide by clicking here.

In most ICU patients, I consider the combination of valproic acid and carbapenems to be relatively contraindicated. If the valproic acid dose could be raised to manage the interaction I would be less concerned. The severe potential consequences of reduced valproic acid levels and the ease of finding an alternative to carbapenems make this an interaction that should be avoided at all costs.

Let me know what you think about this interaction in the comments below.

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