Epileptogenic Potential of Carbapenem Agents

Mechanism of Action, Seizure Rates, and Clinical Considerations

April D. Miller, Pharm.D.; Amanda M. Ball, Pharm.D.; P. Brandon Bookstaver, Pharm.D.; Emily K. Dornblaser, Pharm.D.; Charles L. Bennett, M.D., Ph.D.

Disclosures

Pharmacotherapy. 2011;31(4):408-423. 

In This Article

Drug Interactions

There are few clinically relevant drug interactions with the carbapenem class of antibiotics, as they are not substrates of the cytochrome P450 system, nor do they greatly affect this system or P-glycoprotein–mediated clearance of other drugs.[124] Concurrent use with probenecid has been shown to increase carbapenem exposure by 30–50% through inhibition of renal tubular excretion.[124] Although in many patients this lacks clinical relevance, in those with diminished renal function or at high risk for seizures, this interaction could exaggerate an otherwise small risk of seizure. Theoretically, additive interactions with other drugs known to lower seizure threshold or enhance proseizure activity may exist. In several case reports of carbapenem-induced seizures, concurrent drugs with a risk of seizures were administered (e.g., fluoroquinolones, anesthetics).[69,87,107] However, no direct link of additive toxicity with concurrent drugs has been established.

A significant interaction with valproic acid has been described with several members of the carbapenem class.[123,125] Numerous case reports and case series in both adults and children treated with imipenem-cilastatin, doripenem, meropenem, panipenem, and ertapenem have documented significant reductions in valproic acid serum concentrations.[123] Coadministration of these agents results in reductions in valproic acid serum concentrations from 60–120 mg/L to subtherapeutic concentrations of 0–40 mg/L in as little as 24 hours. Often, these reductions in serum concentrations have resulted in seizure activity.[123,125] Valproic acid undergoes conjugation and glucuronidation by uridine diphosphate glucuronosyltransferase in the liver and is renally eliminated as the glucuronide compound. Carbapenems have been shown to induce metabolic conversion of valproic acid to valproic acid–glucuronide and subsequently increase renal elimination of the glucuronide conjugate.[126] Another report suggests suppression of the hydrolytic enzyme responsible for valproic acid-glucuronide to valproic acid conversion in the liver.[127] Enzymatic changes cannot fully explain the rapid and pronounced decline in valproic acid concentrations. Absorption of valproic acid in the intestines is inhibited by carbapenem antibiotics contributing to decreased serum concentrations. In addition, intestinal transporters of valproic acid are inhibited; however, how this contributes to decreased serum concentrations is not completely understood. Carbapenems also interact on valproic acid already present in the serum through shifts of valproic acid from the plasma into erythrocytes. This shift reduces the amount of free, active drug but may also influence distribution of valproic acid encased in erythrocytes throughout the body.[126] Given the profound reduction in valproic acid levels and reported seizure activity in patients receiving concomitant carbapenem therapy, the combination should be avoided whenever possible.

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