Linezolid (LZD)-resistant. However, seven different variants were identified by spa typing. According to the Escherichia coli numbering system, seven LRSA isolates contained a G2576T mutation (G2603T, S. aureus numbering) in one to four of the five copies of domain V of the 23S rRNA genes. One strain also contained a mutation (C2461T, E. coli numbering) not previously reported. Two strains, including one without domain V mutations, possessed single amino acid substitutions (Gly152Asp or Gly139Arg) in the ribosomal protein L3 of the peptidyltransferase center, substitutions not previously reported in clinical isolates. Emergence of LRSA is a serious concern for CF patients who undergo prolonged courses of LZD therapy.

Fomepizole, 4-methylpyrazole (4-MP), is a competitive antagonist of alcohol dehydrogenase with a binding affinity >8000 times that of ethanol. The drug is currently labeled by the United States Food and Drug Administration for the treatment of adult patients with known or suspected ethylene glycol or methanol poisoning. Fomepizole's wide therapeutic dose range and safety profile confer several advantages over standard ethanol therapy for the treatment of toxic alcohol exposures, including the lack of ethanol-associated side effects. Published data and data obtained from the drug's manufacturer implies that the dose escalation after 48 hours is to compensate for fomepizole-induced increased body clearance resulting from autoinduction of the cytochrome P450 (CYP) drug metabolizing enzyme CYP2E1. However, we were unable to identify any evidence of fomepizole's metabolism occurring via CYP2E1 in humans while the data most frequently cited as evidence for induction do not appear to support this claim. Based on this data along with the apparent zero-order kinetics, the current dose increase recommendations may be unnecessary and considering the safety margin described for fomepizole, an extremely conservative constant higher dose administered every 12 hours would appear to assure efficacy and tolerability. Despite the evidence, dose changes should only be implemented after careful clinical trials.

A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperchloremic acidosis, serum VPA concentration of 86 mg/L, and urine drug screen result that was positive for marijuana. She was admitted to the pediatric intensive care unit for persistent symptoms, prolonged QTc, and medical history. Blood ammonia concentrations were obtained because of her persistent altered mental status, initially 94 µmol/L and a peak of 252 µmol/L. A serum carnitine profile was obtained at the time of hyperammonemia and was found to be normal (results were available postdischarge). VPA and TPM were discontinued on day 1 and day 2, respectively, as the patient's blood ammonia concentration remained elevated. On day 3, her mental status had returned to baseline, and blood ammonia concentrations trended downward; by day 4 her blood ammonia concentration was 23 µmol/L. VPA has been associated with numerous side effects including hyperammonemia and encephalopathy. Recently, drug interactions with TPM and VPA have been reported; however, serum carnitine concentrations have not been available. We discuss the possible mechanisms that VPA and TPM may affect serum ammonia and carnitine concentrations and the use of levocarnitine for patients or treating toxicity.INDEX TERMS: hyperammonemia, levocarnitine, serum carnitine, topiramate, valproic acid J Pediatr Pharmacol Ther 2013;18(2):128-136

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