Ceftibuten (original) (raw)

Abstract

Synopsis

Ceftibuten is an orally active third generation cephalosporin which has a broad spectrum of in vitro antibacterial activity, encompassing the majority of Gram-negative pathogens and streptococci, and which shows greater stability than several other cephalosporins against bacteria producing extended-spectrum β-lactamases.

In clinical studies, ceftibuten (generally 400 mg/day in adults or 9 mg/kg/day in children, administered once daily) was effective in the treatment of acute uncomplicated or complicated urinary tract infections, demonstrating an efficacy similar to that of cefaclor (1500 mg/day), and similar or superior to that of cotrimoxazole (trimethoprim/sulfamethoxazole; 8/40 mg/kg/day) in children. The majority of patients with acute or chronic lower respiratory tract infections responded to treatment with ceftibuten, and response rates were similar to those achieved with cefaclor (750 or 1500 mg/day). Ceftibuten 9 mg/kg/day was at least as effective as cefaclor and as effective as amoxicillin/clavulanic acid (both 40 mg/kg/day) in children with acute otitis media, and was superior to phenoxymethylpenicillin (penicillin V; 25 mg/kg/day) in children and adolescents with streptococcal pharyngitis or scarlet fever caused by Group A β-haemolytic streptococci.

Ceftibuten was well tolerated in most patients, with adverse events (mostly mild to moderate gastrointestinal disturbances) generally occurring in 5 to 10% of patients.

Thus, ceftibuten, with a once- or twice-daily oral dosage regimen, good tolerability profile and activity against a wide range of bacterial organisms, offers a promising alternative to other agents (including cefaclor, cotrimoxazole, amoxicillin/clavulanic acid, bacampicillin and phenoxymethylpenicillin) for the treatment of patients with urogenital and respiratory tract infections. Its place in therapy will be more clearly defined following further large comparative trials, in which it is likely to prove most useful in patients with infections caused by β-lactamase-producing pathogens.

Antibacterial Activity

In this review, bacterial organisms were considered susceptible to ceftibuten if the minimum concentration required to inhibit 90% of tested strains in vitro was ≤ 8 mg/L.

Most strains of Enterobacteriaceae were susceptible to ceftibuten, including Citrobacter diversus, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus mirabilis, P. vulgaris, Providencia rettgeri, P. stuartii, Salmonella spp., Shigella spp. and Yersinia enterolitica. Morganella morganii and Serratia marcescens were moderately susceptible, whereas the majority of strains of C. freundii, Enterobacter aerogenes and E. cloacae were resistant. The activity of ceftibuten was generally greater than that of cefaclor and cefuroxime and comparable with that of cefixime, against tested strains of Enterobacteriaceae.

Other Gram-negative pathogens, including β-lactamase positive and negative strains of Haemophilus influenzae and Moraxella catarrhalis (formerly Branhamella catarrhalis), Neisseria gonorrhoea and N. meningitidis, were all susceptible to ceftibuten; however, Pseudomonas, Acinetobacter and Bordetella spp. were resistant.

b-Haemolytic streptococci groups A (Streptococci pyogenes), C, F and G were highly susceptible to ceftibuten, whereas Group B (S. agalactiae) were generally resistant. Ceftibuten inhibited penicillin-susceptible strains of S. pneumoniae but was inactive against penicillin-resistant strains, and was also inactive against staphylococci, enterococci and Listeria spp. Anaerobic organisms including Bacteroides spp., Clostridium spp. and Peptostreptococcus magnus were generally resistant to ceftibuten, although some strains of Helicobacter pylori and Campylobacter jejuni were moderately susceptible.

Ceftibuten was stable to hydrolysis by the majority of extended-spectrum β-lactamases produced by E. coli and K. pneumoniae. Its stability was generally greater than that of cefaclor, cefoxitin, cefpodoxime, ceftazidime, cefuroxime and cefalexin, and similar to that of cefixime and cefotaxime. Ceftibuten and other cephalosporins tested were not stable to hydrolysis by β-lactamases produced by Pseudomonas aeruginosa and Enterobacter spp., or the plasmidmediated CHO and MIR-1 enzymes produced by isolates of K. pneumoniae.

Ceftibuten showed high affinity for penicillin binding protein (PBP) 3 of E. coli and PBPs 2, 4 and 5 of H. influenzae. Minimum bactericidal concentrations of ceftibuten against most susceptible bacteria were generally similar to, or within 4-fold, of minimum inhibitory concentrations (MIC), and ceftibuten showed a postantibiotic effect ranging from 1 to > 10 hours against the respiratory pathogens S. pneumoniae, S. pyogenes, H. influenzae and M. catarrhalis. Increasing the inoculum size (by approximately 102 to 103 colony forming units/ml) increased MIC values for ceftibuten against selected organisms, whereas increasing the medium pH (from 5.5 to 8) reduced MIC values.

Ceftibuten had a moderate effect on the intestinal microflora in healthy volunteers, causing an overgrowth of enterococci and decreasing numbers of E. coli and anaerobic cocci.

Pharmacokinetic Properties

The bioavailability of ceftibuten following oral administration is between 75 and 90%. In healthy Western volunteers, peak plasma concentrations (Cmax) ranging from 9.9 to 23.3 mg/L were reached approximately 1.7 to 2.6 hours after administration of ceftibuten 200 to 800mg. Cmax values of between 1.9 and 11.6 mg/L were reached within 2 to 3 hours in Japanese volunteers administered ceftibuten 25 to 200mg. No significant drug accumulation was evident during administration of multiple doses of up to 300mg twice daily. The rate and/or extent of absorption of ceftibuten was decreased when administered in doses > 400mg, and when administered with food.

The apparent volume of distribution in healthy volunteers was about 0.2 to 0.25 L/kg and approximately 60 to 64% was bound to plasma proteins. The drug penetrated well into blister fluid and middle ear fluid, achieving concentrations similar to those in plasma within about 4 hours. Ceftibuten penetrates into lung tissue and nasal, tracheal and bronchial secretions, but has shown little penetration into sputum.

About 60 to 70% of an administered dose of ceftibuten was recovered unchanged in the urine of healthy volunteers over 24 hours, and an additional 10 to 20% as the trans isomer, which has about 8-fold less antibacterial activity than the active cis form. Renal clearance ranged from about 3.5 to 4.4 L/h and from 2.7 to 3.1 L/h in Japanese and Western volunteers, respectively, and the mean elimination half-life (t1/2β) of ceftibuten ranged from 1.5 to 2.2 hours and 2.0 to 2.8 hours, respectively.

In elderly individuals (> 65 years), Cmax and the area under the plasma concentration-time curve (AUC) were slightly increased compared with those in younger persons, renal clearance was lower (about 1.65 L/h) and the time to reach peak plasma concentrations (tmax) was slightly delayed (3.2 hours). The pharmacokinetic properties of ceftibuten in healthy children and adolescents (6 months to 17 years) were similar to those seen in adults.

Total serum and renal clearance were reduced in patients with renal impairment and t1/2β was was prolonged, from 2.7 hours in healthy persons [creatinine clearance (CLcr) > 4.8 L/h] to 13.4 hours in patients with severe renal impairment (CLcr < 1.8 L/h). Haemodialysis removed about 39% of the drug from the body within 3 hours at a rate of 4.6 L/h. The pharmacokinetic properties of ceftibuten were unchanged in patients with chronic liver disease.

Clinical Efficacy

Ceftibuten has shown clinical and bacteriological efficacy in adults and children with urogenital or respiratory tract infections following once- or twice-daily oral administration.

In noncomparative studies ceftibuten 100 or 200mg twice daily or 400mg once daily achieved clinical responses (cure or improvement, or ‘good’ or ‘excellent’ responses) in 93 to 100% of adult patients with acute uncomplicated urinary tract infections, and in 65 to 83% of patients with complicated or recurrent infections. Bacteriological eradication of causative pathogens, which included E. coli, Proteus spp., Klebsiella spp. and Enterobacter spp., was generally achieved in 60 to 90% of patients with acute or complicated infections. The efficacy of ceftibuten 200mg twice daily was similar to that of cefaclor 500mg 3 times daily in patients with complicated urinary tract infections. Clinical cure was achieved in 90% of infants and children with complicated or recurrent urinary tract infections following treatment with ceftibuten 9 mg/kg/day for 10 days, which was similar to the response rate achieved with cotrimoxazole 8/40 mg/kg/day. However, ceftibuten eradicated pathogens from significantly more patients than cotrimoxazole (98 vs 88%).

Ceftibuten 400mg once daily or 200mg twice daily demonstrated therapeutic efficacy in patients with acute or chronic lower respiratory tract infections, similar to that of cefaclor 500mg 3 times daily. Clinical responses were achieved in all patients with acute bronchitis in one study, and in 69 to 79% of patients with chronic infections (bronchitis, or infected bronchiectasis) in noncomparative studies. Bacteriological eradication occurred in 77 to 91% of ceftibuten recipients vs 65 to 89% in cefaclor recipients.

In 2 studies in children with acute otitis media, ceftibuten 9 mg/kg/day for 10 days showed clinical and bacteriological efficacy which was similar to that of cefaclor or amoxicillin/clavulanic acid 40 mg/kg/day (clinical and bacteriological response rates approximately 90%). Ceftibuten 9 mg/kg/day was significantly more effective than phenoxymethylpenicillin (penicillin V) 25 mg/kg/day administered in 3 divided doses in children and adolescents with Group A β-haemolytic streptococcal pharyngitis or scarlet fever, achieving clinical response and bacteriological eradication in 97 vs 89% and 91 vs 80% of patients, respectively. Clinical responses occurred in all patients with bacterial sinusitis (clinical cure in 68%) treated with ceftibuten 400mg once daily, which was similar to the response rate in patients treated with amoxicillin/clavulanic acid 500mg 3 times daily.

Satisfactory clinical responses were achieved in 80 to 100% of patients with obstetric or gynaecological infections, and bacteriological eradication rates ranged from 50 to 73% following administration of ceftibuten 100 or 200mg 2 or 3 times daily. Ceftibuten showed efficacy similar to that of bacampicillin 250mg 4 times daily in this indication.

In other preliminary studies, ceftibuten showed variable clinical efficacy in patients with bacterial prostatitis (30 or 70% response rate), and was effective in the treatment of patients with cotrimoxazole-resistant bacillary dysentery caused by either Shigella spp. or enteroinvasive E. coli.

Tolerability

Ceftibuten was well tolerated in both adult and paediatric patients in clinical trials. Adverse events were generally reported in about 5 to 10% of patients, and mostly consisted of mild to moderate gastrointestinal disturbances. Diarrhoea was the most common event, but was only severe in a small number of patients, and rarely necessitated discontinuation of therapy. In children, diarrhoea and vomiting each occurred in 3% of patients. Nausea, dyspepsia, abdominal pain and loose stools have also been reported in adults and children, but relatively infrequently (< 2%). Dizziness and rash were reported in 2% of patients, and headache, fungal infection and rhinitis were reported rarely (< 1%).

Laboratory abnormalities (increased levels of eosinophils, liver enzymes and blood urea nitrogen, and decreased levels of haemoglobin and platelets, and decreased white blood cell count), observed in a small proportion of patients (≤ 5%), were generally mild and transient, and ceftibuten did not affect platelet aggregation or vitamin K-dependent blood coagulation parameters.

The tolerability of ceftibuten was generally similar to that of cefaclor, bacampicillin, cotrimoxazole, and phenoxymethylpenicillin and better than that of amoxicillin/clavulanic acid in comparative studies.

Dosage and Administration

The recommended dosage of ceftibuten in adults with acute or complicated urinary tract infections is 400mg administered orally once daily for 5 to 10 days. The same dosage, given for 5 to 14 days, is recommended in patients with acute exacerbations of chronic bronchitis, whereas a dosage of 200mg twice daily for 5 to 14 days is recommended in patients with community-acquired pneumonia. Ceftibuten should be administered in a once-daily dosage of 9 mg/kg/day for 10 days to children with recurrent or complicated urinary tract infections, acute otitis media or pharyngitis.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand
    Lynda R. Wiseman & Julia A. Balfour

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  1. Lynda R. Wiseman
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  2. Julia A. Balfour
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Additional information

Various sections of the manuscript reviewed by: A. Banfi, Pediatric Department, Luis Calvo Mackenna Hospital, Santiago, Chile; A. Bauernfeind, Max von Pettenkofer-Institut, Ludwig-Maximilians-Universität, München, Germany; P.C. Braga, Centro di Farmacologia Respiratoria, Università Degli Studi di Milano, Milano, Italy; C.A. De Abate, Medical Research Center, Metairie, Louisiana, USA; E. Debbia, Istituto di Microbiologia, Università Degli Studi di Genova, Genova, Italy; K. Dornbusch, Department of Clinical Microbiology, Karolinska Hospital, Stockholm, Sweden; R.N. Jones, Department of Pathology, The University of Iowa, Iowa City, Iowa, USA; H. Lode, Pneumologie I, Lungenklinik Heckshorn, Berlin, Germany; T. Mazzulli, Department of Microbiology, Mount Sinai Hospital, Toronto, Ontario, Canada; M.E. Pichichero, Division of Infectious Diseases, The Strong Children’s Medical Center, Rochester, New York, USA.

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Wiseman, L.R., Balfour, J.A. Ceftibuten.Drugs 47, 784–808 (1994). https://doi.org/10.2165/00003495-199447050-00006

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