Ceftibuten

Absorption

Rapidly absorbed following oral administration.

Toxicity

Overdosage of cephalosporins can cause cerebral irritation leading to convulsions.

Description

Ceftibuten is a new, once daily, orally active cephalosporin introduced as a treatment of Gram-negative bacteria-related urinarylrespiratory tract and gynecological infections. In vitro studies of 359 strains of Gram-negative bacteria demonstrated that ceftibuten was superior to cefaclor and as active or slightly more active than cefixime and cefteram.

Originator

Shionogi (Japan)

The Uses of Ceftibuten

anorexic, antidepressant, inhibitor of 5HT, norepinephrine & dopamine uptake

Background

Ceftibuten is a third-generation cephalosporin antibiotic that is orally-administered. It is typically used to treat acute bacterial exacerbations of chronic bronchitis (ABECB), acute bacterial otitis media, pharyngitis, and tonsilitis.

Indications

Indicated for the treatment of acute bacterial exacerbations of chronic bronchitis (ABECB), acute bacterial otitis media, pharyngitis, and tonsilitis.

Definition

ChEBI: A third-generation cephalosporin antibiotic with a [(2Z)-2-(2-amino-1,3-thiazol-4-yl)-4-carboxybut-2-enoyl]amino substituent at the 7 position of the cephem skeleton. An orally-administered agent, ceftibuten is used as the dihydrate to tre t urinary-tract and respiratory-tract infections.

Manufacturing Process

The 1st method of synthesis
The 8-oxo-7-phenylacetylamino-5-thia-1-aza-bicyclo[4.2.0]oct-1-ene-2- carboxylic acid benzhydryl ester is reacted with phosphorus pentachloride/pyridine reagent in methylene dichloride, and the reaction mixture is thereafter cooled to -35°C and treated with methanol to produce hydrochloride of 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid benzhydryl ester. This hydrochloride is reacted with 4-(3- aminothiophen-2-yl)-5-oxohex-3-enoic acid 3-methylbut-2-enyl ester. Then 7- [2-(2-benzoylamino-thiazol-5-yl)(3-tert-butyl-4,4-dimethylpent-2- enoxycarbonyl)-pent-2-enoylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylic acid synthesized is reacted with aluminum chloride in anisole and diluted hydrochloric acid and then with dimethylmalonate to give 5-thia- 1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-2-(2-amino-4- thiazolyl)-4-carboxy-1-oxo-2-butenyl)amino)-8-oxo-, (6R,7R)- (Ceftibuten).
The 2st method of synthesis
Formulation of the diphenylmethyl thiazoleacetate with ethyl formate leads to 2-(2-aminothiazol-5-yl)-3-hydroxyacrylic acid benzhydryl ester. Condensation of 2-(2-aminothiazol-5-yl)-3-hydroxyacrylic acid benzhydryl ester with the phosphorane from benzyl 2-triphenylphosphonium acetate leads to the 2-(2- aminothiazol-5-ylmethylene)succinic acid 1-benzhydryl ester 4-benzyl ester. Exposure of this ester to trifluoroacetic acid selectively cleaves the diphenylmethyl group over the benzyl ester to give 2-(2-aminothiazol-5- ylmethylene)succinic acid 4-benzyl ester. Condensation of the acid with free amino group in the desmethyl cephalosporin affords the amide of 7-[3-(2- aminothiazol-5-yl)-2-benzoylcarbonylmethylacryloylamino)-8-oxo-5-thia-1- azabicyclo[4.2.1]oct-2-ene-2-carboxylic acid benzyl ester. The remaining benzyl ester protecting groups are removed by means of aluminum chloride to afford 7-[3-(2-aminothiazol-5-yl)-2-benzoylcarbonylmethylacryloylamino)-8- oxo-5-thia-1-azabicyclo[4.2.1]oct-2-ene-2-carboxylic acid or ceftibuten

brand name

Cedax (Schering);Seftem.

Therapeutic Function

Antibiotic

Antimicrobial activity

A semisynthetic cephalosporin formulated as the dihydrate for oral administration.
It exhibits good activity against many Gram-negative bacilli, but its activity against Gram-positive cocci is very poor. It is stable to hydrolysis by the common plasmid-mediated β-lactamases, but not derepressed chromosomal enzymes .
It is rapidly and almost completely absorbed by mouth and is excreted in the urine with a half-life of 1.5–3 h. An oral dose of 400 mg achieves a peak plasma concentration of around 15 mg/L. Binding to plasma proteins is 65–77%.
Side effects mostly consist of mild gastrointestinal symptoms and mild liver function test changes. Clinical trials have mainly been conducted in urinary tract and respiratory tract infections which, despite the poor in-vitro activity against Str. pneumoniae, have shown ceftibuten to be as efficacious as comparator agents.

General Description

Chemical structure: ?-lactam

Biochem/physiol Actions

Ceftibuten is a third generation cephalosporin antibiotic

Pharmacokinetics

Ceftibuten is an antibiotic with bactericidal actions.

Pharmacokinetics

Ceftibuten is highly (75–90%) absorbed on oral administration, but this is decreased significantly by food. Being lipophilic and acidic, it is significantly (65%) serum protein bound. Some isomerization of the geometry of the olefinic linkage appears to take place in vivo before excretion.

Clinical Use

Ceftibuten (Cedax) is a recently introduced, chemicallynovel analog of the oximino cephalosporins in which anolefinic methylene group (C＝CHCH_2-) with Z stereochemistryhas replaced the syn oximino (CBNO-) group.
This isosteric replacement yields a compound that retainsresistance to hydrolysis catalyzed by many β-lactamases,has enhanced chemical stability, and is orally active. Oralabsorption is rapid and nearly complete. It has the highestoral bioavailability of the third-generation cephalosporins.Ceftibuten is excreted largely unchanged in the urine andhas a half-life of about 2.5 hours. Plasma protein binding ofthis cephalosporin is estimated to be 63%.
Ceftibuten possesses excellent potency against mostmembers of the Enterobacteriaceae family, H. influenzae,Neisseria spp., and M. catarrhalis. It is not active against S.aureus or P. aeruginosa and exhibits modest antistreptococcal activity. Ceftibuten is recommended in the managementof community-acquired respiratory tract, urinary tract, andgynecological infections.

Metabolism

A study with radiolabeled ceftibuten administered to 6 healthy adult male volunteers demonstrated that cis-ceftibuten is the predominant component in both plasma and urine. About 10% of ceftibuten is converted to the trans-isomer is approximately 1/8 as antimicrobially potent as the cis-isomer.