The metabolism and clinical safety of the
pivalic acid-containing
antibiotic S-1108, an orally active
pro-drug cephalosporin, were investigated to assess the clinical effects, with special emphasis on the influence of
carnitine consumption in 15 patients with various
infectious diseases receiving
S-1108 three times a day at
a 300- or 600-mg total daily dose for 3 to 7 days. The free
carnitine concentrations in plasma were greatly reduced to approximately 65% of pretreatment levels, and the plasma
pivaloylcarnitine (the main metabolite of pivaloyloxymethyl
ester) concentrations were increased during the 200-mg (three times a day) regimens but returned to the pretreatment levels within 3 to 5 days after the
cessation of treatment. In three elderly patients with declining renal function (
creatinine clearance rate, 31 to 50 ml/min), the
acylcarnitine/free
carnitine ratio increased from 0.1 to 0.4 up to 0.7 to 1.5 at day 5 during the 7-day treatment, showed a tendency to decrease, and then returned to the pretreatment ratio 4 days after discontinuation of the drug. The degree of free
carnitine reduction and increase of the
acylcarnitine/free
carnitine ratio depended mostly on the dose and the duration of
S-1108 treatment. The increased
acylcarnitine/free
carnitine ratio in elderly patients was due to reduction of the free
carnitine concentration in plasma and mainly to the retardation of nontoxic
pivaloylcarnitine excretion. This study indicated that there was a decrease in free
carnitine levels in plasma, but there were no clinical symptoms or adverse effects associated with
carnitine reduction in patients during the 7-day multiple administration of
S-1108.