Drug Therapy

Indian Pediatrics 1999;36: 901-904

Ceftibuten

From the Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi 110 001, India.
Reprint requests: Dr. Jagdish Chandra, Professor of Pediatrics, Flat No. 1, Lecturer's Flats, L.H.M.C. Campus, Bangla Sahib Marg, New Delhi 110 001, India.

Ceftibuten (CFT) is a new extended spectrum, cephem antimicrobial agent formulated for oral administration. Besides having excellent antimicrobial spectrum and its stability in presence of most betalactamases including the new extended spectrum enzymes, it has got a favorable side effects profile(1-6). CFT promises to be a potent reserve oral drug especially for infection of urinary tract and respiratory tract where the betalactamase resistance is expected.

Mechanism of Action

CFT acts by inhibiting mucopeptide synthesis in the bacterial cell wall making it defective and osmotically unstable(4,7). It is most effective against rapidly growing cell wall forming bacteria. The drug is usually bactericidal depending on the organism susceptibility, dose, tissue concentration and the rate at which the organisms are multiplying. The drug actively binds to the penicillin binding sites which are different from other penicillins and cephalosporins, therefore cross resistance is minimum(7).

Antimicrobial Spectrum

CFT has wide spectrum of activity which is better for Gram negative bacteria than the Gram positive bacteria(1,8). The susceptible organisms include enterobacteriaceae (in-cluding E. coli, Klebsiella spp., Proteus spp., Citrobacter diversus, Yersinia enterocolitica), H. influenzae, H. parainfluenzae, Moraxella catarrhalis, some Pneumococci, most beta hemolytic Streptococci (A, C, F and G) and pathologic Neisseria sp(1,2,5,8). A comparative antimicrobial spectrum of oral cephalosporin is given in Table I. Besides the above mentioned organisms, activity against Salmonella spp. and Shigella spp. is noteworthy(1,4). The role of CFT in enteric fever is not still established. The activity of CFT for Salmonella and Shigella is comparable to Ceftriaxone and Ciprofloxacin and exceeds that of Ampicillin and Trimetho-prim-Sulphamethoxazole combination(2). It possesses bactericidal activity against H. pylori alone or in combination with omepra-zole(4,9,10). It displays 16 fold more activity against Enterobacteriacae as compared to Cephaclor, Cephalexin, Amoxycillin clavulanic acid and Cefuroxime axetil(11). Its activity may be comparable or superior to Cefixime in H. influenzae and Brahmnella infection(11). The drug however is ineffective against Staph. aureus, group B Streptococci, Pseudomonas, Acinetobacter, Bordetella and Mycobacteria(1,4,10,12).

Table I^__Comparison of Antimicrobial Spectrum of Various Oral Cephalosporins.

+++ excellent activity compared to other cephalosporins. ++ good activity. + poor activity. 0 no activity. ** drug not available in India. * Absorption better with food.

Pharmacokinetics

CFT is derived from basic cephalosporin nucleus and has a unique carboxy ethylidine side chain at position-7 which protects it from lactamase hydrolysis(1,7,13). Following oral administration (suspension or capsule) CFT is rapidly absorbed (75% to 90%) from brush border of small intestine. A proton dependent pathway mediates this active absorption. This drug is protein bound to the extent of 60-65%. The peak concentration achieved is at 1.7 to 2.0 hours and maximum plasma concentration achieved is 17 micro gram/ml after single dose of 400 mg. Food delays its absorption but it does not necessitate dose scheduling(12). CFT has elimination half life of 2-3 hours which is less than Cefixime and Cefpodoxime(8). The drug is widely distributed in the body; its penetration ranges between 30-50% in nasal, tracheal and bronchial secretions; 70% in middle ear fluid and 70-100% in inflammatory fluids and blister fluids(4,8,14). The CFT undergoes minimal metabolism and is largely eliminated as an intact molecule through kidneys.

Formulations

CFT is available as 400 mg capsule and dried powder in a special bottle provided with a spoon. Each bottle yields 30 ml suspension containing Ceftibuten 18 mg/ml. The suspension can be kept up to 14 days at 2-8°C. In India it is available as capsule and suspension.

Therapeutic Uses

The drug is indicated in following infections:

(i) Upper respiratory tract infection: CFT can be used in pharyngitis, tonsilitis, scarlet fever, acute sinusitis and otitis media. The role in acute

otitis media in children is well established and CFT is considered in situation where lactamase resistance is expected(4,9,10,15). It is usually preferred as second line drug.

(ii) Lower respiratory tract infections: The drug is found useful in acute bronchitis, chronic bronchitis and acute bronchopneumonia as it achieves higher concentration in secretions(10,15-18).

(iii) Urinary tract infection: Both complicated and uncomplicated infections may be treated with CFT as it is excreted unchanged in urine and achieves high concentration.

(iv) Enteritis and Gastroenteritis: Shigella and Salmonella enteritis can be treated with CFT(1,4). However role of CFT in enteric fever needs some controlled trials.

Doses

The recommended dose of CFT in children is 9 mg/kg/day given as single or twice daily dose. The adult dose is 400 mg twice daily. A duration of 5-10 days is recommended depending on type of infection.

Adverse Reactions

CFT is safe and well tolerated cephalosporin. Gastrointestinal side effects range between 2-4%(1,19). Other adverse effects are reported only in less than 1% of cases. Rarely reported adverse effects include dyspepsia, gastritis, vomiting, abdominal pain, dizziness and serum sickness like disorders(1,7,19). Convulsion and C1.difficile diarrhea have also been reported occasionally(7). Laboratory abnormalities include anemia, leukopenia, eosinophilia and thrombocytosis(1). There is transient elevation of AST, ALT and LDH. All adverse effects and laboratory derangements revert back to normal upon discontinuation of drug. Anaphylaxis, allergic reactions, Steven_Johnson syndrome and epidermal necrolysis are theoretically possible but have not been reported so far(7,18).

No drug interactions are reported till date(1).

Place of Ceftibuten in Therapy

With availability of third generation cephalosporins and their demonstrable benefits in infections caused by Streptococcus penumo-niae, M. catarrhalis, H. influenzae and other Gram negative bacteria including lactamase producing species, CFT will find a place in treating infections like bronchitis, broncho-pneumonia, sinusitis, enteritis, dysentery and urinary tract infections where resistance is suspected or on failure of first line drugs. In fact owing to its stability against extended spectrum beta lactamase producing organisms of Enterobacteriaceae and H. influenzae, it is one of the oral cephalosporins most effective in treating UTI and respiratory tract infections of such resistant organisms. It may be used as follow up or weaning drug for patients on intravenous antibiotics. The patients can be discharged safely on oral CFT after initial response with parenteral antibiotics. Although the drug has similar spectrum as cefixime, once daily dosage, high bioavailability and lower side effects especially diarrhea are advantages. The higher cost of the drug may be one of the constraints in its regular use but considering the cost effectiveness, the drug is worth attention.

References

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6. Kitzis MD, Liassine N, Ferre B, Gutman I, Acar JF, Golstein F. In vitro activities of 15 oral beta lactams against Klebsiella pneumoniae harbouring new extended beta lactamases. Antimicrob Agents Chemother 1990; 34: 1783-1786.

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9. Westblom TU, Gudipati S, Midkiff BR. In vitro susceptibility of Helicobacter pylori to the new oral cephalosporins cefpodoxime, ceftibuten and cefixime. J Clin Microbiol Infect Dis 1990; 9: 691-693.

10. Alarcon T, Domingo D, Sanchez T, Diaz de Rojas F, Lopez-Brea M. In vitro activity of omeprazole in combination with several antimicrobial agents against clinical isolates of Helicobacter pylori. Eur J Clin Mirobiol Infect Dis 1996; 15: 937-940.

11. Wise R, Andrew JM, Asby JP, Thorner D. Ceftibuten a new orally absorbed cephalosporin: In vitro activity against strains from the United Kingdom - Diag Microbiol Infect Dis 1991; 14: 45-52.

12. Chin NX, Gu JW, Neu HC. Antimicrobial effects of the combination of ceftibuten and orally absorbed penem SCH 29482. Diag Microbiol Infect Dis 1991; 14: 79-83.

13. Insel PA. Antimicrobial agents, penicillins, cephalosporins and other beta lactam antibiotis. In: Goodman and Gilmans: The Pharmacological Basis of Therapeutics, 9th edn. Eds Hardman JG, Limbird LE, New York, McGrawhill, 1996; pp 1089-1098.

14. Barr WH, Lin CC. Rodwonski E, Lim J Symcorizc S, Affrime M, et al. The pharmacokinetics of ceftibuten in children. Diag Microbiol Infect Dis 1991; 14: 93-100.

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16. De Abate CA, Perrota RJ, Dennington ML, Ziering RM. The efficacy and safety of once daily ceftibuten compared with coamoxiclav in the treatment of acute bacterial sinusitis. J Chemother 1992; 4: 358-363.

17. Stekers O. Efficacy and tolerability of ceftibuten versus amoxycillin/clavulanate in the treatment of sinusitis. Chemotherapy 1997; 43: 352-357.

18. Aubier M A. Comparison of ceftibuten versus amoxycillin/clavulanate in the treatment of acute exacerbation of chronic bronchitis. Chemotherapy 1997; 43: 297-302.

19. Kuchers A. Ceftibuten. In: The use of Antibiotics. A Clinical Review of Antibacterial. Antifungals and Antiviral Drugs, 5th edn.Eds. Kuchers A, Crowe, S, Grayson ML, Oxford, Butterworth Hienemann; 1997: pp 419-421.