Ceftriaxone

Nervous system

Pseudotumor cerebri has been attributed to ceftriaxone [ ].

Metabolism

Although possible interference with the metabolism of carnitine by pivaloylmethyl-esterified beta-lactams is a matter of concern [ ], new similar prodrug derivatives of cephalosporins continue to be marketed, as do reports that they can be given to healthy volunteers without concern [ ].

However, taking a closer look at the data, it is evident that healthy volunteers lost around 10% of their body stores of carnitine within 2 weeks of being given antibiotics containing pivalic acid [ ]. The authors emphasized that prolonged used of such drugs might result in profound carnitine depletion and that this depletion might be associated with clinical sequelae.

Valproate also causes urinary loss of carnitine, most probably by a different mechanism than pivalic acid [ ]. However, the combination can rapidly cause serious adverse effects [ ].

• A 72-year-old woman taking valproate as monotherapy for her epilepsy developed a urinary tract infection and was given pivmecillinam 600 mg/day. During the next few days she became stuporose; her serum ammonia concentration was high (113 mmol/l) but liver function was normal. Pivmecillinam and valproate were withdrawn and she recovered rapidly.

The authors recommended caution when treating patients taking valproate with pivmecillinam because of the risk of hyperammonemic encephalopathy. It seems reasonable to assume that this caution should include all beta-lactams that incorporate pivalic acid.

However, there may be another mechanism by which cephalosporins can interfere with carnitine metabolism. Cephalosporins with a quaternary nitrogen (cefepime, cefluprenam, cefoselide, and cefaloridine) compete with carnitine for renal reabsorption due to OCNT2, a major member of the family of organic cationic transporters [ ]. Mutations in the OCNT2 gene are responsible for the genetic disorder primary systemic carnitine deficiency [ , ]. Since carnitine and the cephalosporins mentioned above compete for the same substrate-binding site on OCTN2, it is likely that such mutations will interfere with the pharmacokinetics of these drugs. Consequently these cephalosporins should not be given to patients with such mutations.