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Ceftibuten

Ceftibuten is a semisynthetic, third generation cephalosporin antibiotic.

Uses

Ceftibuten is used orally for the treatment of mild to moderate respiratory tract infections (i.e., acute exacerbations of chronic bronchitis) caused by susceptible bacteria. The drug also is used orally for the treatment of acute otitis media caused by susceptible bacteria and pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A b-hemolytic streptococci).

Oral ceftibuten also has been used for the treatment of urinary tract infections caused by susceptible bacteria.

Respiratory Tract Infections

Acute Exacerbations of Chronic Bronchitis

Oral ceftibuten is used for the treatment of acute exacerbations of chronic bronchitis caused by susceptible Streptococcus pneumoniae (penicillin-susceptible strains only), Haemophilus influenzae (including b-lactamase-producing strains), or Moraxella (formerly Branhamella) catarrhalis (including b-lactamase-producing strains. Results of randomized clinical studies in adults with acute exacerbations of chronic bronchitis indicate that oral ceftibuten is at least as effective as oral amoxicillin and clavulanate potassium, oral cefaclor, oral clarithromycin, or oral ciprofloxacin for the empiric treatment of these infections.

The overall clinical success rates reported in these studies were 79.3-84, 79, or 83.7% in those who received ceftibuten, amoxicillin and clavulanate potassium, or ciprofloxacin, respectively. When results were stratified according to the causative organism, the microbiologic eradication rate in patients receiving ceftibuten was 66-100% in those with infections caused by S. pneumoniae, 72-100% in those with infections caused by M. catarrhalis, and 73-95.2% in those with infections caused by H. influenzae or H. parainfluenzae. The manufacturer cautions that, while ceftibuten has been clinically equivalent to comparator drugs in clinical studies, ceftibuten was associated with a lower bacteriologic eradication rate than the comparator in some studies when used for the treatment of acute bacterial exacerbations of chronic bronchitis when M. catarrhalis was isolated from infected sputum at baseline.

Acute Sinusitis

Oral ceftibuten has been effective when used in adults for the treatment of acute maxillary sinusitis caused by susceptible S. pneumoniae, H. influenzae, or M. catarrhalis.

Otitis Media

Acute Otitis Media

Oral ceftibuten is used for the treatment of acute otitis media caused by H. influenzae (including b-lactamase-producing strains), M. catarrhalis (including b-lactamase-producing strains), or S. pyogenes.

Results of controlled clinical studies in children 6 months to 11 years of age with clinically and/or microbiologically confirmed acute otitis media indicate that a 10-day regimen of oral ceftibuten generally is as effective as a 10-day regimen of oral cefaclor, oral amoxicillin and clavulanate potassium, or oral cefprozil. In published studies, the overall clinical response rate to a 10-day regimen of oral ceftibuten in pediatric patients with acute otitis media has been 83.3-93%. In one study when results were stratified according to causative organism, the clinical response rate to ceftibuten in pediatric patients with acute otitis media caused by Haemophilus (including H. influenzae), M. catarrhalis, or S. pyogenes was 92-100% and the response rate in those with otitis media caused by S. pneumoniae was 80%.

Since there is some evidence that ceftibuten may be less effective than some other b-lactam antibiotics for the treatment of otitis media caused by S. pneumoniae, the manufacturer cautions that ceftibuten should be used for the empiric treatment of acute bacterial otitis media only when adequate antimicrobial coverage against S. pneumoniae has been previously administered. For additional information regarding treatment of acute otitis media, see Acute Otitis Media under Uses: Otitis Media, in the Cephalosporins General Statement 8:12.06.

Otitis Media with Effusion

Results of a randomized study in children 7 months to 12 years of age with otitis media with effusion indicate that 14 days of treatment with oral ceftibuten (9 mg/kg once daily) or oral amoxicillin (40 mg/kg daily in 3 divided doses) is equally effective for the short-term resolution of otitis media with effusion and that the rate of recurrence is similar with both drugs. At completion of the 14-day regimen, middle ear effusion had resolved (based on otoscopy) in 29.% of those who received ceftibuten and 27.% of those who received amoxicillin; acute otitis media developed during treatment in 7 and 2.8% of patients, respectively.

Of those who were effusion-free at completion of therapy, there was recurrence of effusion within 2 weeks in 36% of those who received ceftibuten and 48.% of those who received amoxicillin; at 16-week follow-up, there was recurrence of effusion in 60% of those who received ceftibuten and 67% of those who received amoxicillin.

Optimum strategies for the management of otitis media with effusion (residual or persistent middle ear effusion without signs or symptoms of infection; also referred to as noninfected or nonsuppurative otitis media, secretory otitis media, serous otitis media, middle ear effusion, glue ear) have not been identified, and use of anti-infective agent therapy in such patients remains controversial. For additional information regarding treatment of otitis media with effusion, see Otitis Media with Effusion under Uses: Otitis Media, in the Cephalosporins General Statement 8:12.06.

Ceftibuten

Pharyngitis and Tonsillitis

Oral ceftibuten is used for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A b-hemolytic streptococci).

Although ceftibuten usually is effective in eradicating S. pyogenes from the nasopharynx, efficacy of the drug in the subsequent prevention of rheumatic fever remains to be established. Results of a randomized, multicenter study in children 3-18 years of age with S. pyogenes pharyngitis or tonsillitis indicate that 10 days of therapy with oral ceftibuten (9 mg/kg once daily) is more effective than 10 days of therapy with oral penicillin V (25 mg/kg daily given in 3 divided doses). At early follow-up (i.e., 5-7 days after completion of therapy), 97% of those who received ceftibuten and 89% of those who received penicillin V had clinical cure or improvement and the bacteriologic elimination rate in these groups was 91 and 80%, respectively.

At late follow-up (i.e., 2-3 weeks after completion of therapy), the bacteriologic elimination rate was 89% in those who received ceftibuten and 79% in those who received penicillin V and the relapse rate was 4 and 6%, respectively. Selection of an anti-infective agent regimen for the treatment of S. pyogenes pharyngitis and tonsillitis should be based on the drug’s spectrum of activity as well as the regimen’s bacteriologic and clinical efficacy, potential adverse effects, ease of administration and patient compliance, and cost. No regimen has been found to date that effectively eradicates group A b-hemolytic streptococci in 100% of patients.

Because penicillin has a narrow spectrum of activity, is inexpensive, and generally is effective, the US Centers for Disease Control and Prevention (CDC), American Academy of Pediatrics (AAP), American Academy of Family Physicians (AAFP), Infectious Diseases Society of America (IDSA), American Heart Association (AHA), American College of Physicians-American Society of Internal Medicine (ACP-ASIM), and others consider natural penicillins (i.e., 10 days of oral penicillin V or a single IM dose of penicillin G benzathine) the treatment of choice for streptococcal pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever, although oral amoxicillin often is used instead of penicillin V in small children because of a more acceptable taste.

Other anti-infectives (e.g., oral cephalosporins, oral macrolides) generally are considered alternatives. There is some evidence that bacteriologic and clinical cure rates reported with 10-day regimens of certain oral cephalosporins (e.g., cefaclor, cefadroxil, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, cefuroxime axetil, ceftibuten, cephalexin) are slightly higher than those reported with the 10-day oral penicillin V regimen. In addition, there is some evidence that a shorter duration of therapy with certain oral cephalosporins (e.g., a 5-day regimen of cefadroxil, cefdinir, cefixime, or cefpodoxime proxetil or a 4- or 5-day regimen of cefuroxime axetil) achieves bacteriologic and clinical cure rates equal to or greater than those achieved with the traditional 10-day oral penicillin V regimen.

Based on these results, some clinicians suggest that oral cephalosporins be included as agents of choice for the treatment of S. pyogenes pharyngitis and tonsillitis. However, the IDSA states that first generation cephalosporins can be used for the treatment of pharyngitis in patients hypersensitive to penicillins (except those with immediate-type hypersensitivity to b-lactam anti-infectives) but that cephalosporins appear to offer no advantage over penicillins since they have a broader spectrum of activity and generally are more expensive. In addition, because of limited data to date, the IDSA states that use of cephalosporin regimens administered for 5 days or less for the treatment of S. pyogenes pharyngitis cannot be recommended at this time.

Urinary Tract Infections

Oral ceftibuten has been used effectively for the treatment of acute uncomplicated urinary tract infections or the treatment of complicated or recurrent urinary tract infections caused by susceptible Escherichia coli, Klebsiella, Proteus mirabilis, Enterobacter, or staphylococci. In one study in adult women with acute uncomplicated urinary tract infections who received a 7-day regimen of oral ceftibuten (400 mg once daily), the clinical cure and bacteriologic eradication rate 5-9 days after completion of therapy was 93%.

In pediatric patients 6 months to 12 years of age with complicated, recurrent urinary tract infections randomized to receive a 10-day regimen of oral ceftibuten or oral co-trimoxazole, the clinical response rate (cure plus improvement) was 98% in those who received ceftibuten and 96% in those who received co-trimoxazole; however, the bacteriologic elimination rate was 99 and 88%, respectively.

The most appropriate agent for the treatment of urinary tract infections should be selected based on the severity of the infection and results of culture and in vitro susceptibility testing.

Some clinicians suggest that certain oral third generation cephalosporins (cefdinir, cefixime, cefpodoxime proxetil, ceftibuten) are one of several alternatives that can be used for the outpatient treatment of recurrent urinary tract infections or urinary tract infections acquired in hospitals or nursing homes since these infections are likely to be caused by multidrug-resistant gram-negative bacilli; however, these oral cephalosporins are not appropriate for the treatment of more severely ill patients hospitalized with urinary tract infections.

Dosage and Administration

Reconstitution and Administration

Ceftibuten dihydrate is administered orally. Ceftibuten dihydrate capsules may be administered without regard to meals; however, since bioavailability of ceftibuten from the oral suspension is decreased when administered with food (see Pharmacokinetics: Absorption), ceftibuten dihydrate oral suspension should be administered at least 2 hours before or 1 hour after meals. Ceftibuten dihydrate powder for oral suspension should be reconstituted at the time of dispensing by adding the amount of water specified on the container to provide a suspension containing 90 or 180 mg of ceftibuten per 5 mL.

The water should be added in 2 equal portions and the bottle shaken after each addition.

Dosage

Dosage of ceftibuten, which is commercially available for oral use as ceftibuten dihydrate, is expressed in terms of anhydrous ceftibuten.

Adult Dosage For the treatment of acute exacerbations of chronic bronchitis, pharyngitis and tonsillitis, or acute otitis media in adults and children 12 years of age and older, the usual dosage of ceftibuten is 400 mg once daily for 10 days. Pediatric Dosage Children 12 years of age or older may receive the usual adult dosage of ceftibuten.

The usual dosage of ceftibuten for the treatment of pharyngitis and tonsillitis or acute otitis media in children 6 months of age or older is 9 mg/kg (up to 400 mg) once daily for 10 days. When the oral suspension is used, pediatric patients weighing 10, 20, or 40 kg should receive once-daily doses of 90, 180, or 360 mg respectively. Pediatric patients weighing more than 45 kg should receive the maximum dosage of 400 mg daily.

Ceftibuten

Dosage in Renal and Hepatic Impairment

Patients with creatinine clearances of 50 mL/minute or greater may receive the usual dosage of ceftibuten. The manufacturer recommends that patients with creatinine clearances of 30-49 mL/minute receive a ceftibuten dosage of 4.5 mg/kg or 200 mg every 24 hours.

Patients with creatinine clearances of 5-29 mL/minute should receive a ceftibuten dosage of 2.25 mg/kg or 100 mg every 24 hours. Since ceftibuten is partially removed by hemodialysis, patients undergoing hemodialysis 2 or 3 times weekly may receive a single dose of 400 mg (given as a capsule) or 9 mg/kg (up to 400 mg; given as the oral suspension) at the end of each dialysis period.

Limited data suggest that chronic hepatic impairment does not affect the pharmacokinetics of ceftibuten, and the manufacturer makes no specific recommendations for modification of dosage in patients with hepatic impairment.

Cautions

Adverse Effects

Adverse effects reported with ceftibuten are similar to those reported with other oral cephalosporins. (See Cautions in the Cephalosporins General Statement 8:12.06.) Ceftibuten generally is well tolerated.

Most adverse effects are transient and mild to moderate in severity, but have been severe enough to require discontinuance of the drug in up to 2% of patients. GI effects, including nausea, diarrhea, melena, dyspepsia, vomiting, and abdominal pain, are the most frequent adverse reactions reported with ceftibuten and these effects generally have been reported in 1-4% of patients receiving the drug.

Precautions and Contraindications

Ceftibuten shares the toxic potentials of other cephalosporins, and the usual cautions, precautions, and contraindications associated with cephalosporin therapy should be observed. Prior to initiation of ceftibuten therapy, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among cephalosporins and other b-lactam antibiotics, including penicillins and cephamycins.

Ceftibuten is contraindicated in patients who are hypersensitive to the drug or other cephalosporins and should be used with caution in patients with a history of hypersensitivity to penicillins. Use of cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins.

If a hypersensitivity reaction occurs during ceftibuten therapy, the drug should be discontinued and the patient treated with appropriate therapy (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen) as indicated. Individuals with diabetes mellitus should be informed that reconstituted ceftibuten oral suspension contains 1 g of sucrose per 5 mL.

For a more complete discussion of these and other precautions associated with the use of ceftibuten, see Cautions: Precautions and Contraindications in the Cephalosporins General Statement 8:12.06.

Pediatric Precautions

Safety and efficacy of ceftibuten in children younger than 6 months of age have not been established. Adverse effects reported in pediatric patients receiving oral ceftibuten are similar to those reported in adults receiving the drug and include GI effects (diarrhea, vomiting, abdominal pain) and rash. The manufacturer states that diarrhea has been reported more frequently in younger children than in older children and has been reported in 8% of those who were 2 years of age or younger and in 2% of those older than 2 years of age.

Geriatric Precautions

Although pharmacokinetic studies indicate that peak plasma concentrations and half-life of the drug may be higher in geriatric patients than in younger adults, the clinical importance of these effects is not clear since it is not known whether these geriatric individuals had renal impairment. The manufacturer states that adjustments in ceftibuten dosage may be necessary in geriatric patients based on the degree of renal impairment. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

In vivo and in vitro studies evaluating ceftibuten have not shown evidence of mutagenicity. Long-term animal studies have not been performed to date to evaluate the carcinogenic potential of the drug.

Pregnancy, Fertitlity and Lactation

Reproduction studies in rats or rabbits using oral ceftibuten dosages up to 400 mg/kg daily (approximately 8.6 times the usual human dosage on a mg/m2 basis) or 40 mg/kg daily (approximately 1.5 times the usual human dosage on a mg/m2 basis), respectively, have not revealed evidence of teratogenicity or harm to the fetus.

There are no adequate and controlled studies using ceftibuten in pregnant women or during labor and delivery, and the drug should be used during pregnancy only when clearly needed.

Studies in rats using oral ceftibuten in dosages up to 2 g/kg daily (approximately 43 times the usual human dosage based on a mg/m2 basis) have not revealed evidence of impaired fertility. Since it is not known whether ceftibuten is distributed into milk, the drug should be used with caution in nursing women.

Spectrum Based on its spectrum of activity, ceftibuten is classified as a third generation cephalosporin. For information on the classification of cephalosporins and closely related b-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06. Ceftibuten is stable in the presence of a variety of b-lactamases produced by gram-positive and gram-negative bacteria.

Like other currently available oral third generation cephalosporins (e.g., cefixime, cefpodoxime proxetil, cefdinir), ceftibuten has an expanded spectrum of activity against aerobic gram-negative bacteria compared with first and second generation cephalosporins, but is inactive against most strains of Enterobacter and Pseudomonas aeruginosa. In vitro on a weight basis, ceftibuten is more active than other currently available oral third generation cephalosporins against Enterobacteriaceae that produce plasmid-mediated b-lactamases. Ceftibuten generally is inactive against enterococci (e.g., Enterococcus faecalis [formerly Streptococcus faecalis]), methicillin-resistant staphylococci, and anaerobic bacteria.

In Vitro Susceptibility Testing

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to ceftibuten, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated.

If results indicate that a clinical isolate has intermediate susceptibility to ceftibuten, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue drug concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated (e.g., urine) or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.

If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to ceftibuten, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical trials. Strains of staphylococci resistant to penicillinase-resistant penicillins should be considered resistant to ceftibuten, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to ceftibuten, a disk containing 30 mcg of ceftibuten should be used. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Enterobacteriaceae (urinary isolates only) with growth inhibition zones of 21 mm or greater are susceptible to ceftibuten, those with zones of 18-20 mm have intermediate susceptibility, and those with zones of 17 mm or less are resistant to the drug.

When disk-diffusion susceptibility testing for Haemophilus is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), isolates with growth inhibition zones of 28 mm or greater are considered susceptible to ceftibuten. Because of limited data on resistant strains of these organisms, NCCLS recommends that any Haemophilus isolate that appears to be nonsusceptible to ceftibuten be submitted to a reference laboratory for further testing. Interpretive criteria are not available to determine susceptibility of Streptococcus pneumoniae to ceftibuten using the ceftibuten disk; however, NCCLS states that S. pneumoniae found to be susceptible to penicillin using the NCCLS standardized disk-diffusion procedure and a 1-mcg oxacillin disk can be considered susceptible to ceftibuten. In addition, S. pyogenes (group A streptococci) found to be susceptible to penicillin using a penicillin or ampicillin disk can be considered susceptible to ceftibuten.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Enterobacteriaceae (urinary isolates only) with MICs of 8 mcg/mL or less are susceptible to ceftibuten, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug.

When dilution susceptibility testing of Haemophilus is performed according to NCCLS standardized procedures using HTM, isolates with MICs of 2 mcg/mL or less are considered susceptible to ceftibuten. Because of limited data on resistant strains of these organisms, NCCLS recommends that any Haemophilus that appears to be nonsusceptible to ceftibuten be submitted to a reference laboratory for further testing. Interpretive criteria are not available to determine susceptibility of S. pneumoniae to ceftibuten using the dilution procedure; however, NCCLS states that S. pneumoniae found to be susceptible to penicillin using the NCCLS standardized procedure can be considered susceptible to ceftibuten.

Testing of ceftibuten against penicillin-intermediate or -resistant isolates is not recommended since reliable interpretive criteria are not available. In addition, S. pyogenes (group A b-hemolytic streptococci) found to be susceptible to penicillin using the dilution procedure can be considered susceptible to ceftibuten.

Pharmacokinetics

Ceftibuten exhibits linear dose-dependent pharmacokinetics over the dosage range of 200-400 mg, but exhibits nonlinear pharmacokinetics at higher dosages. In healthy adult males with normal renal function, peak plasma concentrations of ceftibuten at steady state are approximately 20% higher than those after a single oral dose of the drug. Peak plasma concentrations of ceftibuten are slightly higher and the plasma half-life of the drug is more prolonged in geriatric adults than in younger adults; however, these differences appear to be related to changes in renal function rather than age. Studies in adults with impaired renal function indicate that the pharmacokinetics of ceftibuten are affected by the degree of renal impairment and that plasma half-life and total body clearance of the drug decrease in proportion to increases in renal impairment. Limited data suggest that chronic hepatic impairment does not affect the pharmacokinetics of ceftibuten.

Absorption

Ceftibuten is rapidly and almost completely absorbed following oral administration as capsules or oral suspension, and oral bioavailability of the drug ranges from 75-90%. Results of crossover studies in healthy adult males indicate that a 400-mg oral dose of ceftibuten given as the oral suspension is bioequivalent to a 400-mg oral dose of the drug given as 400- or 200-mg capsules.

Food decreases the rate and extent of absorption of oral ceftibuten; however, food has a greater effect on the bioavailability of ceftibuten when the drug is administered as the oral suspension than when it is administered as capsules. Compared with administration in the fasting state, administration of a 400-mg oral dose of ceftibuten as capsules to healthy adult males immediately after a standardized meal (53. g fat, 31. g protein; 841 calories) delays the time to peak plasma concentrations by 1.75 hours and decreases the peak plasma concentration and area under the plasma concentration-time curve (AUC) by 18 and 8%, respectively.

Results of a crossover study in healthy adult males indicate that administration of a single 400-mg oral dose of ceftibuten as the oral suspension with a high-fat, 850-calorie meal decreases the peak plasma concentration and AUC by 26 or 17%, respectively, compared with administration in the fasting state; administration of the same dose with a nonfat, 400-calorie meal decreased the peak plasma concentration and AUC by 17 and 12%, respectively. In healthy adults who receive a single 400- or 800-mg oral dose of ceftibuten as capsules, peak plasma concentrations of the drug are attained within 2-2. hours and average 15-17. or 23. mcg/mL, respectively.

Following oral administration of a single 400-mg dose of ceftibuten as capsules in healthy adult males, plasma concentrations average 6.1, 11…2, and 1.1 mcg/mL at 1, 2, 4, 8, and 12 hours, respectively, after the dose. In a study in healthy adults receiving oral ceftibuten in a dosage of 400 mg twice daily, peak plasma concentrations after the first dose averaged 17. mcg/mL and steady-state peak plasma concentrations averaged 20. mcg/mL. In children 6 months to 16 years of age who receive a single 9- or 13.-mg/kg oral dose of ceftibuten as the oral suspension, peak plasma concentrations are attained within 1.9-2. hours and average 13.-16. or 23. mcg/mL, respectively. In children 6 months to 12 years of age who receive a single 9-mg/kg oral dose of ceftibuten as the oral suspension, plasma concentrations of the drug average 9.3, 11..6, 1.6, and 0.5 mcg/mL at 1, 2, 4, 8, and 12 hours, respectively, after the dose.

Distribution

The volume of distribution of ceftibuten averages 0.21 L/kg in healthy adults and 0.5 L/kg in pediatric patients.

Following oral administration, ceftibuten is distributed into blister fluid, bronchial secretions, nasal secretions, sputum, middle ear fluid, tracheal secretions, and tonsillar tissue. In adults with acute exacerbations of chronic bronchitis who received a single 400-mg oral dose of ceftibuten, peak concentrations of the drug in bronchial secretions were attained 4 hours after the dose and averaged 9.2 mcg/mL; concentrations in bronchial secretions 24 hours after the dose averaged 0.4 mcg/mL.

Concentrations of ceftibuten in epithelial lining fluid or bronchial mucosa generally are 15 or 37%, respectively, of concurrent plasma concentrations. Concentrations of ceftibuten in sputum are approximately 7% of concurrent plasma concentrations. In a study in adults who received oral ceftibuten in a dosage of 200 mg twice daily or 400 mg once daily, peak concentrations were attained in sputum 2 hours after a dose and averaged 1.5 mcg/mL.

In pediatric patients 7 months to 4 years of age with acute otitis media who received oral ceftibuten in a dosage of 9 mg/kg once daily, concentrations of the drug in middle ear fluid on the third day of therapy averaged 4.4, 14., 0.8, and 0.9 mcg/mL at 2, 4, 6, and 12 hours, respectively, after a dose; concurrent serum concentrations of the drug were 14..72, and 0.28 mcg/mL, respectively. Information on distribution of ceftibuten into CSF is not available. It is not known whether ceftibuten crosses the placenta or is distributed into human milk. Ceftibuten is approximately 65% bound to plasma proteins; binding is independent of plasma concentrations of the drug.

Elimination

The plasma half-life of ceftibuten averages 2-2. hours in healthy adults with normal renal function and 1.9-2. hours in children 6 months to 16 years of age. In a study in pediatric patients, plasma half-life averaged 1.9-2 hours in those 6 months to 10 years of age and 2.2 hours in those older than 10 years of age. BR> Ceftibuten is present in plasma and urine principally as cis-ceftibuten; however, about 10% of a dose is converted in vivo to trans-ceftibuten. The trans-isomer has some antibacterial activity, but only about 12% of that of the cis-isomer.

Plasma half-life of ceftibuten is prolonged in patients with renal impairment. In one study, plasma half-life of the drug averaged 7.1, 13., or 22. hours in patients with creatinine clearances of 30-49, 5-29, or less than 5 mL/minute, respectively.

The cis- and trans-isomers of ceftibuten are eliminated principally in urine. Following oral administration of a single 400-mg oral dose of ceftibuten as capsules in healthy men, approximately 57-70% of the dose is eliminated in urine as unchanged ceftibuten and approximately 7-20% is eliminated in urine as cis-ceftibuten. Following oral administration of radiolabeled ceftibuten, approximately 56% of the radioactivity is eliminated in urine and 39% is eliminated in feces within 24 hours.

Ceftibuten is removed by hemodialysis; it is not known whether the drug is removed by peritoneal dialysis. The amount of ceftibuten removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow-rate); however, a 2- to 4-hour period of hemodialysis reportedly removes 39-65% of the drug from the body.

Chemistry and Stability

Chemistry

Ceftibuten is a semisynthetic cephalosporin antibiotic.

The drug is an oral aminothiazolyl cephalosporin. Ceftibuten is structurally similar to other oral (cefdinir, cefixime, cefpodoxime proxetil) and parenteral (cefepime, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone) cephalosporins that contain an aminothiazolyl side chain at position 7 of the cephalosporin nucleus. The aminothiazolyl group enhances antibacterial activity, particularly against Enterobacteriaceae, and generally results in enhanced stability against b-lactamases.

However, ceftibuten contains a carboxyethylidine group in the side chain rather than the methoxyimino group contained in many aminothiazolyl cephalosporins. The carboxyethylidine group may contribute to oral bioavailability and increased stability against b-lactamases. Ceftibuten is administered orally as the cis-isomer of the drug and is commercially available as ceftibuten dihydrate; potency is expressed on the anhydrous basis.

Ceftibuten dihydrate occurs as a white to off-white powder and has a solubility of less than 0.1 mg/mL in water and a solubility of 0.13 mg/mL in alcohol at 20°C. The drug has pKas of 2.17, 3.67, and 4.07. Commercially available ceftibuten dihydrate powder for oral suspension occurs as a light yellow to buff, cherry-flavored powder. Following reconstitution, the oral suspension contains 90 or 180 mg of ceftibuten per 5 mL1 and has a pH of 3.5-5.5.

Stability

Ceftibuten capsules and powder for oral suspension should be stored at 2-25°C. Following reconstitution, ceftibuten oral suspension should be stored in a tight container and is stable for 14 days when refrigerated at 2-8°C; any unused suspension should be discarded after this period. For further information on chemistry, mechanism of action, spectrum, resistance, uses, cautions, acute toxicity, drug interactions, or laboratory test interferences of ceftibuten, see the Cephalosporins General Statement 8:12.06.

Preparations

Ceftibuten Dihydrate Oral Capsules 400 mg (of anhydrous Cedax®, ceftibuten) Biovail For suspension 90 mg (of anhydrous Cedax®, ceftibuten) per 5 mL Biovail

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