Carnitine and derivatives

Bupivacaine

Isovaleric acidemia (an autosomal recessive disorder of leucine metabolism causing episodes of acidosis during catabolic stress) and carnitine deficiency have been associated with a lowered threshold for bupivacaine-induced dysrhythmias [ ].

Parenteral nutrition

Deficiency of carnitine has been described in all of a series of surgical neonates receiving parenteral nutrition [ ]; carnitine intake was far below the recommended minimal requirement of 11 mmol/kg/day. Although only three of the infants had symptoms suggestive of carnitine deficiency, the authors recommended carnitine supplementation for all neonates who receive parenteral nutrition for more than 2 weeks.

Pivaloyl-containing compounds

Pivaloyl-containing compounds (such as baccefuconam, cefetamet pivoxil, cefteram pivoxil, pivampicillin, pivmecillinam, and tebipenem pivoxil) can significantly increase urinary carnitine excretion [ ]. These compounds are esterified prodrugs, which become effective only after release of pivalic acid, which in turn is esterified with carnitine. Carnitine loss induced by pivaloyl-containing beta-lactams was first described in children and can produce symptoms similar to other types of carnitine deficiency, for example secondary to organic acidurias [ ].

• A 1-year old-boy who had received different pivoxil-containing cephalosporins developed a tremor in his hands and feet, followed by a generalized convulsion; his blood carnitine concentration was about 1/10 normal [ ].

The administration of pivaloyl-conjugated beta-lactam antibiotics to healthy volunteers for 54 days reduced mean serum carnitine 10-fold and muscle carnitine, as measured per non-collagen protein, more than two-fold [ ]. Treatment of children for 12–37 months to prevent urinary tract infection resulted in serum carnitine concentrations of 0.9–3.6 μmol/l (reference range 23–60 μmol/l). In four cases muscle carnitine was 0.6–1.4 μmol/g non-collagen protein (reference range 7.1–19) [ ]. In another study, 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.

Some prodrug derivatives of cephalosporins reportedly can be given to healthy volunteers without concern [ ].

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

• A 72-year-old woman taking valproate monotherapy 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 giving pivmecillinam to patients taking valproate because of the risk of hyperammonemic encephalopathy. It seems reasonable to assume that this caution should include all beta-lactams that incorporate pivalic acid.

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.

Although oral carnitine aided the elimination of the pivaloyl moiety, its simultaneous use did not fully compensate for the adverse metabolic effects of pivaloyl-containing beta-lactams [ , ].

The consequences of pivaloyl-induced carnitine loss seem to be generally reversible. But as long as the risk of pivaloyl-induced urinary loss of carnitine and particular risk factors are not better defined, it is prudent to use pivaloyl-containing prodrugs only in short-term treatment.