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10/15/2001

Oral Prodrug Enters Cephalosporin Market

Cheryl A. Thompson

Cefditoren pivoxil (Spectracef, TAP), a cephalosporin prodrug for oral administration, has been approved for marketing by FDA.

The antibiotic is indicated for the treatment of the following mild to moderate infections:

  • Acute exacerbation of chronic bronchitis caused by Haemophilus influenzae, including beta-lactamase-producing strains; H. parainfluenzae, including beta-lactamase-producing strains; penicillin-susceptible strains of Streptococcus pneumoniae; or Moraxella catarrhalis, including beta-lactamase-producing strains;
  • Pharyngitis or tonsillitis caused by Strep. pyogenes; and
  • Uncomplicated skin and skin-structure infections caused by Staphylococcus aureus, including beta-lactamase-producing strains, or Strep. pyogenes.

Although cefditoren pivoxil can eradicate Strep. pyogenes from the oropharynx, the antibiotic has not been studied as an agent to prevent the subsequent development of rheumatic fever.

After oral ingestion, cefditoren pivoxil undergoes hydrolysis by esterases during absorption to produce the active cephalosporin and pivalate. The peak plasma concentration of cefditoren occurs 1.5–3 hours after ingestion of a 200-mg dose by a fasting person; under that condition, the absolute bioavailability of the prodrug is 14%. Ingestion of the drug after a high-fat meal doubles the peak plasma concentration, compared with the fasted state, and increases the patient's total exposure to cefditoren by 70%. On average, 88% of cefditoren is bound to plasma proteins.

The elimination half-life of cefditoren averages 1.6 hours in young healthy adults and 1.8–2 hours in people age 65 or older. Renal elimination of cefditoren occurs by tubular secretion and glomerular filtration; this occurs 13% slower in females, compared with males. Little of an absorbed dose undergoes metabolism.

At least 70% of the pivalate created during hydrolysis of the prodrug is absorbed. Nearly all of the absorbed pivalate is renally excreted as pivaloylcarnitine. This process greatly decreases the plasma concentration of carnitine during continuous therapy with cefditoren pivoxil and for several days thereafter.

Prolonged treatment with the prodrug is not recommended because of the potential for clinical signs of carnitine deficiency to develop. For short-term treatment, the product’s labeling does not recommend routinely measuring a patient's serum carnitine concentration or administering a carnitine supplement.

During the clinical trials of cefditoren 200 or 400 mg twice daily, the most commonly reported adverse events were diarrhea, nausea, and vaginal moniliasis. Some 2–3% of study participants had hematuria or an increased white-blood-cell count in the urine.

The drug is contraindicated in patients with carnitine deficiency, an inborn error in metabolism that may produce clinically important carnitine deficiency, or a known allergy to a cephalosporin.

Cefditoren pivoxil should not be taken with an antacid or a histamine H2-receptor antagonist and, perhaps, by women who are breast-feeding. The labeling suggests that the routine monitoring of elderly patients' renal function during cefditoren therapy may be useful.

The recommended cefditoren dosage for adults and children 12 years or older is 400 mg twice daily for pharyngitis, tonsillitis, or acute exacerbation of chronic bronchitis and 200 mg twice daily for uncomplicated skin and skin-structure infections. Both dosages should be taken with meals for 10 days. For patients with renal impairment, the maximum cefditoren dosage is 200 mg twice daily if the calculated creatinine clearance (CLcr) is 30–49 mL/min/1.73m2 and 200 mg daily if the CLcr is <30 mL/min/1.73m2.

Each white film-coated Spectracef tablet contains 200 mg of cefditoren. The product is available in 20-tablet bottles, sufficient for a 10-day regimen of 200 mg twice daily, and 60-tablet bottles, for a 14-day regimen of 400 mg twice daily. Among the tablets' nontherapeutic ingredients is sodium caseinate, a milk protein to which some patients may be hypersensitive.