Drug Criteria & Outcomes: Third-generation oral cephalosporin formulary evaluation

By Jacqueline Ragusa, PharmD candidate
Harrison School of Pharmacy
Auburn (AL) University

Drugs

  • Cefditoren pivoxil (Spectracef)
  • Cefpodoxime proxetil (Vantin)
  • Cefdinir (Omnicef)

Mechanism of action

The third-generation cephalosporins work to inhibit mucopeptide synthesis in the bacterial cell wall by binding to penicillin-binding proteins. It is this interference that produces a defective cell wall and leads to cell death.

Chemistry

Cefditoren is structurally similar to cefpodoxime and cefdinir; however, cefditoren contains a methylthiazolyl group off the C-3 position. This structure resembles first-generation cephalosporins and is thought to contribute to cefditoren’s activity against gram-positive organisms. Cefditoren and cefpodoxime are formulated as prodrugs to facilitate oral use.

Pharmacokinetics

Similar to cefpodoxime proxetil, cefditoren pivoxil cannot reach maximal activity until hydrolyzed by esterases found in the intestinal lumen.

Cefditoren, cefpodoxime, and cefdinir all penetrate blister fluid, tonsil tissue, sinus tissue, and middle ear fluid. The distribution of cefdinir and cefpodoxime extends further to bronchial mucosa and epithelial lining fluid. In addition, cefpodoxime distributes to interstitial fluid, pleural fluid, lung tissue, myometrium, seminal fluid, prostatic adenoma tissue, and bile. Penetration into human cerebrospinal fluid for these agents is not known.

Cefditoren is eliminated primarily by excretion into the urine, similar to cefpodoxime and cefdinir. As shown in Table 1, cefditoren generally shares similar pharmacokinetic parameters as cefpodoxime and cefdinir.

Indications and antibacterial activity

Cefditoren exhibits broad-spectrum activity against most respiratory organisms. A comparison of the antibacterial activity for cefditoren, cefpodoxime, and cefdinir are listed in Table 2. Cefpodoxime offers a broader spectrum of activity against gram-negative organisms such as Peptostreptococcus sp., Acinetobacter sp., Citrobacter sp., and Neisseria meningitidis.

The minimum inhibitory concentrations (MICs) for all of these agents are listed in Table 3. Overall, cefditoren exhibits lower MICs against gram-positive organisms than cefpodoxime and cefdinir. However, all have demonstrated activity against all of these organisms listed.

Cefditoren has not been approved for use in patients less than 12 years of age. Cefpodoxime and cefdinir are both approved for use in pediatric patients. Those as young as six months old may receive cefdinir, while those more than two months old may receive cefpodoxime.

Clinical trials

  • Acute exacerbation of chronic bronchitis (AECB): In a double-blind multicenter study of 903 patients 12 years of age or older with AECB, patients were randomized to cefditoren 200-400 mg BID or clarithromycin 500 mg BID for 10 days. Clinical cure rates for cefditoren 200 mg BID, cefditoren 400 mg BID, and clarithromycin 500 mg BID post-therapy were 81%, 78%, and 83%, respectively. The overall eradication rates were 79% for cefditoren 200 mg BID, 78% for cefditoren 400 mg BID, and 83% for clarithromycin. The incidence of adverse events for cefditoren 200 mg, cefditoren 400 mg, and clarithromycin were 26%, 30%, and 36%, respectively. No statistically significant differences were observed in safety or efficacy issues. The investigators concluded that cefditoren is safe and effective in treating AECB.
  • Pharyngitis/tonsillitis: Cefditoren was compared with penicillin for the treatment of pharyngitis/tonsillitis. A double-blind multicenter trial was conducted involving 1,001 patients with a diagnosis of pharyngitis or tonsillitis caused by S. pyogenes. The patients were randomized to cefditoren 200 mg BID x 10 days or penicillin VK 250 mg QID x 10 days. Clinical cure rates occurred in 89% of the cefditoren patients and 86% of the penicillin patients. A higher eradication rate occurred with cefditoren both at short-term follow-up (90% vs. 83%) and long-term follow-up (85% vs. 77%). This difference in efficacy could have been due to compliance, because patients were receiving penicillin VK four times a day. S. pyogenes is more common among pediatric patients; however, cefditoren is not approved for use in pediatrics, nor is a suspension available with this agent.
  • Uncomplicated skin and skin structure infections: A double-blind trial compared the use of cefditoren 200 mg BID, cefditoren 400 mg BID, and cefuroxime 250 mg BID in uncomplicated skin and skin structure infections. Clinical cure rates post-therapy were 84% for both doses of cefditoren and 88% for cefuroxime. Eradication rates for cefditoren 200 mg, cefditoren 400 mg, and cefuroxime were 81%, 85%, and 85%, respectively.

Another double-blind trial involving 828 patients evaluated the use of cefditoren vs. cefadroxil. Patients were randomized to receive cefditoren 200 mg BID, cefditoren 400 mg BID, or cefadroxil 500 mg BID. Overall eradication rates for causative skin pathogens S. aureus and S. pyogenes were 87% for cefditoren 200 mg, 82% for cefditoren 400 mg, and 77% for cefadroxil. Clinical cure rates for cefditoren 200 mg, cefditoren 400 mg, and cefadroxil were 85%, 81%, and 85%, respectively.

A limit to both of the above studies is that only the abstracts are available, making it difficult to evaluate the information.

All of the trials listed above contained a large sample size and involved many centers in the United States. There are no clinical trials to date comparing cefditoren to cefdinir or cefpodoxime, but the trials listed above demonstrate cefditoren’s similar efficacy and safety profiles to the other cephalosporins.

Contraindications/precautions

As with cefpodoxime and cefdinir, patients with a known allergy to cephalosporins should avoid cefditoren. Caution should be used in patients with a previous hypersensitivity to other cephalosporins or penicillins.

An additional contraindication with cefditoren is carnitine deficiency. The hydrolysis of cefditoren pivoxil results in the formation of pivalate. After multiple dosing, pivalate is absorbed and excreted as pivaloylcarnitine. This may cause a further decrease in plasma carnitine concentrations. Cefditoren is not recommended when prolonged therapy is warranted. It is likely that cefditoren will cause clinical manifestations of carnitine deficiency.

Cefditoren, cefpodoxime, and cefdinir are pregnancy category B. These antibiotics are not recommended for use in pregnant mothers unless there is a strong need. Caution should be used when these agents are administered to nursing mothers.

Drug interactions

In general, cephalosporins are associated with fewer drug interactions, because they undergo little hepatic metabolism. There are several interactions that inhibit cephalosporin absorption, particularly with cefpodoxime and cefditoren. Absorption of these two agents is dependent on pH, whereas the absorption of cefdinir is not affected by pH. Antacids and H2 antagonists should be administered at least two hours before or after cefpodoxime and cefditoren. Similar to beta-lactam antibiotics, a drug interaction may occur with probenecid. Coadministration of cefditoren and probenecid results in higher plasma concentrations of cefditoren. Iron supplements should be separated by two hours from cefdinir administration, because these agents may reduce absorption.

Adverse effects

The adverse effects associated with cefditoren are mild and commonly present as gastrointestinal (GI) disturbances. The rates of diarrhea, nausea, and abdominal pain are similar with cefpodoxime and cefditoren. Diarrhea with cefdinir has been reported in up to 15%-19% of patients. In one study, cefditoren demonstrated a higher GI side effect incidence than cefaclor.

Dosage/administration

Cefditoren pivoxil, cefpodoxime proxetil, and cefdinir are all administered orally. The absorption of cefditoren and cefpodoxime is increased when given with a high-fat meal. In contrast, a high-fat meal will decrease the rate and extent of absorption if given with cefdinir. These reductions, however, are not likely to be clinically significant, allowing for cefdinir to be taken without regard to food.

Like most cephalosporins, clearance is reduced in patients with renal dysfunction. Therefore, patients with moderate or severe renal impairment require a dosage adjustment. It is recommended that no more than 200 mg BID be administered to patients with moderate renal impairment (ClCr 30-49 mL/min/1.73m2) and no greater than 200 mg QD be administered to patients with severe renal impairment (ClCr <30 mL/min/1.73m2).

No dose adjustments are necessary for elderly patients with normal renal function or gender.

Following hemodialysis, 30% of cefditoren is removed. The appropriate dose for end-stage renal disease has not yet been determined.

Dose adjustments are not necessary in patients with hepatic impairment.

The usage of all three drugs is relatively low with patients at Huntsville (AL) Hospital.

Current automatic interchange regimen

Presently, cefditoren is not listed in the formulary. Cefpodoxime is the current interchange regimen for cefdinir based on the dosages below:

• Cefpodoxime 200 mg q12hr for:

— Cefdinir 300 mg q12hr

— Cefdinir 600 mg q24hr

Recommendations

Continue with cefpodoxime as the primary third-generation oral cephalosporin. Cefpodoxime is available in suspensions for pediatrics and has more approved indications when compared with cefditoren. It also offers a broader spectrum of activity against gram-negative organisms.

In consideration of a third-generation cephalosporin agent, one must consider various factors, including populations for use and other factors discussed in this evaluation. Although less expensive, the coverage cefditoren provides for many organisms is not as good as that provided by the other two drugs. Also, cefditoren is not approved for pediatric use. This newer drug has not been studied as extensively as the other two drugs, nor does it have FDA approval for the variety of indications for which the other drugs have approval. For broad-use purposes, it currently does not meet the variety of clinical needs met by cefpodoxime and cefdinir and probably would not be adequate as a single formulary representative of this drug group.

Although cefdinir is somewhat less expensive than cefpodoxime, its rate of GI side effects has been reported to be higher (from noncomparative clinical trials). Cefpodoxime is perhaps the strongest candidate for a single formulary representative of this group. Although cefditoren has lower MIC values of specific gram-positive organisms, cefpodoxime still offers good coverage here. Cefpodoxime, with more approved indications, offers the broadest coverage overall and has served as a valuable drug in programs focusing on early conversion of intravenous second- and third-generation cephalosporins to the oral root. Based on institutional needs, cefpodoxime or cefdinir could serve as a single formulary representative for this drug group. (See tables 4, 5, 6 and 7)

Reference

• Cefdinir. In: McEvoy GK, ed. AHFS 2002: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2002:150-152.

• Cefdinir. In: Patient Package Insert. Chicago: Abbott Laboratories; 2000.

• Cefditoren. In: Patient Package Insert. Lake Forest, IL: TAP Pharmaceuticals; 2001.

• Cefpodoxime. In: McEvoy GK, ed. AHFS 2002: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2002:180-184.

• Cephalosporins. In: McEvoy GK, ed. AHFS 2002: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2002:129-141.

• Gilbert DN, ed. The Sanford Guide to Antimicrobial Therapy 2001. Hyde Park, VT: Antimicrobial Therapy; 2001:52-3.

• Henry DC, et al. A double-blind, randomized study of cefditoren vs. cefuroxime for AECB. J Respir Dis 2001; 22:S69-S74.

• Jones RN, et al. Defining microbiologic characteristics of a new oral cephalosporin. J Respir Dis 2001; 22:S26-S31.

• Kaplan EL, et al. A multicenter comparison of cefditoren pivoxil and penicillin VK. J Respir Dis 2001; 22:S60-S64.

• Kuti JL. Cefditoren pivoxil: A novel broad-spectrum oral cephalosporin. Formulary 2001; 36:265-275.

• Nightingale CH. Old and new cephalosporins: Clinical utility and benefits. J Respir Dis 2001; 22:S8-S17.

• Sawchuk RJ et al. Pharmacokinetics of a new cephalosporin. J Respir Dis 2001; 22:S43-S51.

• Hendrickson JR. North DS. Pharmacoeconomic benefits of antibiotic step-down therapy; converting patients from intravenous ceftriaxone to oral cefpodoxime proxetil. Ann Pharmaco Ther 1995; 29:561-565.