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Cefixime

A Review of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Potential

Summary

Synopsis

Cefixime, previously designated FK027, FR17027 and CL284635, is an orally active cephalosporin with a broad spectrum of antibacterial activity in vitro. It is particularly active against many Enterobacteriaceae, Haemophilus influenzae, Streptococcus pyogenes, Streptococcus pneumoniae and Branhamella catarrhalis, and is resistant to hydrolysis by many β-lactamases. Cefixime has little activity against Staphylococcus aureus and is inactive against Pseudomonas aeruginosa.

Cefixime is distinguished by its 3- hour elimination half-life which permits twice daily, or in many instances once daily, administration. Comparative trials, though few, indicate that the clinical and bacteriological efficacy of cefixime 200 to 400mg daily, administered as a single dose or in 2 divided doses, is comparable with that of multiple daily doses of co-trimoxazole (trimethoprim + sulphamethoxazole) or amoxycillin in acute uncomplicated urinary tract infection, with that of amoxycillin, amoxycillin/clavulanic acid and cefaclor in acute lower respiratory tract infections, and with that of amoxycillin and cefroxidine in adult patients with acute tonsillitis or pharyngitis. Several comparative trials in children with acute otitis media demonstrate the similar effectiveness of cefixime 8 mg/ kg daily (in 2 divided doses, or as a single daily dose), cefaclor 20 to 40 mg/kg daily and amoxycillin 40 mg/kg daily in 3 divided doses.

The most frequently reported adverse effects, diarrhoea and stool changes, are usually mild to moderate in severity, transient, and mostly occur in the first few days of treatment with cefixime.

Thus, cefixime is an effective orally active cephalosporin with a relatively long elimination half life permitting a simplified treatment regimen. It is a suitable alternative to cefaclor or amoxycillin in acute otitis media and acute upper and lower respiratory tract infections, and to amoxycillin or co-trimoxazole in acute uncomplicated urinary tract infections.

Antibacterial Activity

Most tested strains of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Proteus vulgaris, Citrobacter diversus and Providencia rettgeri were inhibited in vitro by cefixime 1 mg/L or less. Haemophilus influenzae, Branhamella catarrhalis and Neisseria gonorrhoeae were also inhibited by low concentrations of cefixime. A study of large numbers of Enterobacteriaceae conducted in the USA noted that the MIC50 was below 1 mg/L for most clinical isolates of all species other than Citrobacter freundii, Enterobacter cloacae, Hafnia alvei and Morganella morganii. Cefixime is more potent (MIC90 lower by 2 or more dilutions) in vitro than cefaclor and cephalexin against Enterobacteriaceae, but less potent than ciprofloxacin.

Cefixime is active against Streptococcus pyogenes, S. pneumoniae, S. agalactiae and most strains of streptococci belonging to Lancefield group C, but Lancefield groups F and G are only moderately sensitive and Staphylococcus aureus, S. epidermidis and Enterococcus faecal is are generally resistant. Pseudomonas aeruginosa is resistant to cefixime, as are most strains of the Bacteroides species, and many strains of Peptostreptococcus species and Flavobacterium species.

In common with other cephalosporins such as cefotaxime and β-lactam antibacterial drugs such as latamoxef, cefixime is stable to hydrolysis by a wide range of β-lactamases. Its β-lactamase stability is greater than that of cephalexin, cephradine and cefadroxil and comparable to the profile of ceftizoxime.

Cefixime has high affinity for penicillin-binding proteins 3, la and lb, and its affinity for the latter explains the rapid lytic activity of cefixime relative to that of the other orally active cephalosporins cefaclor and cephalexin.

Pharmacokinetic Properties

Following oral administration peak plasma concentrations of cefixime are generally attained in 3 or 4 hours and are about 2.0 to 2.6 mg/L (mean) after a single 200mg dose. Other than a delay to peak plasma concentrations the pharmacokinetics of cefixime are not influenced by food. There is no evidence of drug accumulation following administration of 200mg twice daily or 400mg once daily for 15 days. In children, the pharmacokinetics of cefixime 8 mg/kg were similar to those observed in adults given a 400mg capsule dose. The calculated absolute bioavailability of cefixime was 40% for 400mg capsules, 48% for 200mg capsules and 52% for an oral solution.

Apparent volume of distribution was 6.7L after a single intravenous dose. At steady-state volume of distribution was about 17L. Three to 5 hours following single 100mg doses, drug concentrations in palatine tonsil and maxillary sinus mucosa were 0.2 to 0.8 mg/kg and 0.5 to 1.05 mg/L, respectively, while 0.04 to 0.06 mg/L were found in sputum 6 to 8 hours after a 100mg dose. Concentrations of 0.09 to 1.46 mg/L were observed in middle ear discharge after single or repeated 100mg doses of cefixime. High concentrations are attained in bile. Concentrations of cefixime in umbilical cord serum were about 15 to 30% those in maternal plasma 0.5 to 5 hours after a 100mg dose. Cefixime is about 70% protein bound in healthy subjects.

No biologically active metabolites of cefixime have been identified in plasma or urine and an average of about 12 to 20% of a 200mg dose is recovered unchanged in the urine over 24 hours, although somewhat higher recovery has been reported in some Japanese studies. Mean maximum urinary concentrations of 73, 107 and 164 mg/L were reported 4 to 6 hours after single doses of cefixime 100, 200 and 400mg, respectively. After intravenous administration total systemic clearance was about 4.4 L/h (73 ml/min), with renal clearance accounting for nearly 40% of this. Oral clearance was 9.7 and 11.4 L/h (150 and 190 ml/min) after a 200 or 400mg dose, respectively. The elimination half-life during the terminal phase was generally about 3 hours in healthy volunteers and is prolonged in patients with impaired renal function, though significantly so only in patients whose creatinine clearance is below 20 ml/min in whom dosage adjustment becomes necessary. Although an increase in maximum plasma concentration and area under the plasma concentration-time curve was reported in elderly compared with young subjects after 5 consecutive days’ administration of cefixime 400mg once daily, adjustment of dosage in the elderly should generally riot be required. Similarly, dosage adjustment is unnecessary in patients with mild to moderate renal dysfunction, becoming necessary only when creatinine clearance is below 20 ml/min. Although urinary concentrations of cefixime are decreased in patients with moderate or severe renal dysfunction, they remain above the MIC for common urinary pathogens for at least 12 hours after a single 400mg dose.

Therapeutic Trials

Cefixime has been studied by numerous groups of investigators in Japan prior to marketing, each of whom prescribed the drug for small numbers of patients with uncomplicated or complicated urinary tract infections, acute pharyngitis or tonsillitis or acute lower respiratory tract infections. To date there have been only a few controlled therapeutic trials comparing the clinical and bacteriological efficacy of cefixime with that of other orally active antibacterial drugs in adults, although several studies have compared cefixime with amoxycillin or cefaclor in children with acute otitis media with effusion.

Pooled data from non-comparative clinical studies of cefixime in uncomplicated urinary tract infection conducted in Japan, all of which utilised standard criteria devised by the Urinary Tract Committee in Japan, revealed overall therapeutic efficacy to be excellent in 67%, moderate in 30%, and poor in 3% of patients treated with the usual dose of cefixime 100mg daily (generally in 2 divided doses) for 3 to 7 days. Infecting pathogens, most often E. coli, were eradicated at the end of treatment in 97% of patients.

Complicated urinary tract infections were treated by Japanese investigators with cefixime 200mg daily in divided doses in most instances and with 400mg daily occasionally. Overall results were excellent in 40.5%, good in 28.5%, and poor in 31% of patients. Urinary pathogens, which were mostly Enterobacteriaceae, were eradicated in 69.5% of instances.

A multicentre comparison of cefixime 400mg once daily and amoxycillin 250mg 3 times daily reported clinical cure in 90% of patients with uncomplicated urinary tract infection treated with cefixime and 83% given amoxycillin, with eradication of isolated pathogens in 92% and 84% of patients, respectively.

Cefixime 200 or 400mg daily (as 1 or 2 divided doses) was comparable with cotrimoxazole (trimethoprim 160mg + sulphamethoxazole 800mg) twice daily in uncomplicated urinary tract infections. In the treatment of complicated infections cefixime 400mg once daily appeared less effective than ciprofloxacin 500mg twice daily while cefixime 200mg twice daily was of similar efficacy as norfloxacin 400mg twice daily. However, further appropriately designed studies are needed to clearly determine the efficacy of cefixime relative to that of other orally active antibacterial drugs in the treatment of complicated urinary tract infections.

Cefixime 200mg daily, or 200mg on the first day and 100mg daily thereafter, for 7 to 14 days was effective in eliminating TV. gonorrhoeae from the urethra of males as was a single 400mg dose, in a preliminary study.

In lower respiratory tract infections, pooled results of non-comparative Japanese studies, each of which assessed small numbers of patients, reveal an excellent or good clinical response in 80% of patients with acute pneumonia and 78% of patients with acute bronchitis following administration of cefixime 200 to 400mg daily, usually in 2 divided doses. As might be expected, ‘excellent’ and ‘good’ clinical responses occurred in a lower proportion (about 60%) of patients with chronic bronchitis or bronchiectasis. Cefixime treatment was effective in eradicating H. influenzae and S. pneumoniae in 85 and 78% of instances, respectively, but as expected from in vitro results it seldom eradicated P. aeruginosa. Cefixime 200mg twice daily and amoxycillin 500mg 3 or 4 times daily or amoxycillin/clavulanic acid 500/125mg 3 times daily were of similar efficacy in acute pneumonia or bronchitis, as were cefixime 100mg twice daily and cefaclor 2 50mg 3 times daily, cefixime 400mg once daily and cephalexin 250mg 6-hourly, in patients with acute or chronic bronchitis. Cefixime 200mg twice daily and cefaclor 500mg 3 times daily were of similar efficacy in patients with acute exacerbation of chronic obstructive lung disease.

Resolution of signs and symptoms of pharyngitis was achieved in nearly all children treated with cefixime 5 to 12 mg/kg daily. Excellent to good results were also obtained in most adults with pharyngitis (81%) or tonsillitis (85%) and in children with tonsillitis (81%) or scarlet fever (100%).

Comparative trials in children with acute otitis media with effusion have shown cefixime in a usual total daily dosage of 8 mg/kg daily (in divided doses, or as a single daily dose) to be similarly effective as cefaclor 20 to 40 mg/kg daily and amoxycillin 40mg daily, both in divided doses. Cefixime 200mg twice daily and amoxycillin 250mg 3 times daily were similarly effective in the treatment of adult pharyngitis and tonsillitis, while cefroxidine 250mg 3 times daily appeared clinically superior to cefixime 100mg twice daily in a study comparing these drugs in adult tonsillitis.

Adverse Effects

Clinical adverse experiences reported by investigators in patients treated with cefixime have usually been mild to moderate in severity, and transient. Diarrhoea and stool changes (as distinct from diarrhoea) have been the most commonly reported adverse effects, occurring in 13.8 and 13.5% of patients, respectively. Diarrhoea tended to be more frequent following once daily (15.3%) than twice daily (10.3%) administration in adults, but this trend was not apparent in children. In about two-thirds of instances diarrhoea and stool changes were evident within 4 days of beginning treatment, which is contrary to the pattern usually encountered with changes in bowel flora. Comparative trials conducted in the USA revealed a greater frequency of diarrhoea and stool changes with cefixime than with amoxycillin, while other gastrointestinal complaints occurred with similar frequency with both drugs.

Dosage and Administration

The usual adult dosage is 400mg daily administered as a single dose or in 2 equally divided doses. A lower dosage of 200mg daily has been used in uncomplicated urinary tract infections. In children, cefixime 8 mg/kg/day once daily or in 2 divided doses has been the most widely used dosage for treating acute otitis media, acute tonsillitis and acute pharyngitis. In patients with severe renal dysfunction (creatinine clearance <20 ml/min) half the standard dose of cefixime should be administered once daily.

Japanese dosage recommendations are generally lower (100 to 200 mg/day for adults and 3 to 6 mg/kg/day for children; administered orally in 2 divided doses) although in severe infections and non-responders higher dosages are recommended (400 mg/day for adults and 12 mg/kg/day for children; again administered orally in 2 divided doses).

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Various sections of the manuscript reviewed by: A.L. Barry, Clinical Microbiology Institute, Tualatin, Oregon, USA; C.D. Bluestone, Department of Pediatric Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; A. W. Chow, Division of Infectious Diseases, University of British Columbia and Vancouver General Hospital, Vancouver, Canada; D. Greenwood, University Hospital Queen’s Medical Centre, Nottingham, England; T.J.J. Inglis, Department of Microbiology, The University of Leeds, Leeds, England; A. Iravani, Department of Pediatric Nephrology, College of Medicine, University of Florida, Gainsville, Florida, USA; R. Janknegt, Klinische Farmacie, Sittard, The Netherlands; N.E. Møller, Ronnebaervej, Holte, Denmark; S.R. Norrby, Department of Infectious Diseases, University of Lund, Lund, Sweden; D. Pastel, Department of Pharmacy Services, Cedars-Sinai Medical Center, Los Angeles, California, USA; D.J. Winston, Chalon Rd, Los Angeles, California, USA; R. Wise, Department of Medical Microbiology, Dudley Road Hospital, Birmingham, England.

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Brogden, R.N., Campoli-Richards, D.M. Cefixime. Drugs 38, 524–550 (1989). https://doi.org/10.2165/00003495-198938040-00004

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Keywords

  • Urinary Tract Infection
  • Acute Otitis Medium
  • Divided Dose
  • Lower Respiratory Tract Infection
  • Pharyngitis