Cefradine

Description

Cefradine is an orally bioavailable β-lactam cephalosporin antibiotic. It is active against S. pyogenes, E. coli, K. pneumoniae, and E. cloacae (MICs = 0.04, 9.4, 9.4, and 6.3 μg/ml, respectively). Cefradine is also active against clinical isolates of S. aureus (MICs = 0.8-6 μg/ml) and S. pyogenes (MICs = 0.1-0.4 μg/ml), as well as H. influenzae, E. coli, and K. pneumoniae (MICs = 6.2-12.5 μg/ml). It increases survival in mouse models of systemic lethal infection by S. pyogenes, E. coli, K. pneumoniae, or E. cloacae (ED₅₀s = 5, 37, 122, and 50 mg/kg, respectively), as well as by penicillin-susceptible or -resistant strains of S. aureus (ED₅₀s = 18 and 91 mg/kg, respectively). Formulations containing cefradine have previously been used in the treatment of respiratory and urinary tract infections, skin infections, and otitis media.

Description

In cephradine, an interesting drug design device has been used. The aromatic ring in the ampicillin side chain has been partially hydrogenated by a Birch reduction such that the resulting molecule is still planar and π-electron excessive but has no conjugated olefinic linkages. It is comparatively acid stable and, therefore, is rapidly and nearly completely absorbed from the GI tract. Cephradine has the useful characteristic that it can be used both orally and IM so that parenteral therapy can be started in an institutional setting and then the patient can be sent home with the oral form, thus avoiding the risk of having to establish a different antibiotic. This is consistent with the present economics requiring sending patients home earlier than some physicians prefer. Unfortunately, however, for other reasons the IM and intravenous (IV) versions of cephradine are no longer available in the United States.

Description

This drug is very similar to cephalexin in its antimicrobial activity and in most other respects (Moellering and Swartz, 1976). Unlike cephalexin, for which a parenteral preparation is not generally available, cephradine is marketed in some countries (for example, Portugal) for both oral and parenteral use.

Chemical properties

Solid

Originator

Sefril,Squibb,Switz.

The Uses of Cefradine

Cephalosporin antibacterial.

The Uses of Cefradine

A semi-synthetic cephalosporin antibiotic that is used to study the effect of expression, binding, and inhibition of PBP3 and other penicillin-binding proteins (PBPs) on bacterial cell wall mucopeptide synthesis

The Uses of Cefradine

Cephradine is a first generation cephalosporin antibiotic. Cephradine has broad spectrum of bactericidal activity against infections caused by Streptococcus, Staphylococcus, Diplococcus pneumoniae, Es cherichia, Klebsiella, Salmonella, and indole-negative Proteus.

Definition

ChEBI: A cephalosporin with a methyl substituent at position 3, and a (2R)-2-amino-2-cyclohexa-1,4-dien-1-ylacetamido substituent at position 7, of the cephem skeleton.

What are the applications of Application

Cephradine is a cephalosporin β-lactam antibiotic

Background

A semi-synthetic cephalosporin antibiotic.

What are the applications of Application

Cephradine was synthesized by the Squibb Institute of Medical Research in 1971. It shows almost the same antibacterial activity and pharmacokinetic properties as cephalexin. Cephradine has been used for therapy of urinary and respiratory tract infections caused by Staphylococcus, Streptococcus, Escherichia coli, Klebsiella, and Proteus mirabilis.

Manufacturing Process

In a first step, D-2-amino-2-(1,4-cyclohexadienyl)acetic acid is obtained as follows. A solution of 11.0 g (72.7 mmol) of D-phenylglycine in 900 ml distilled ammonia (which has been treated with 45 mg lithium after distillation to destroy traces of moisture) is slowly diluted with 370 ml dry ten-butyl alcohol.
Over a period of hours, 1.65 g lithium (3.27 eq) is added in small portions until a permanent blue color is obtained. The blue reaction mixture is then treated with 38 g of triethylamine hydrochloride. The ammonia is allowed to evaporate at room temperature overnight and the residual solvent is evaporated at reduced pressure. The white residue is taken up in a small amount of methanol-water and added to 4 liters of cold 1:1 chloroform-acetone to precipitate the crude product. After 20 minutes stirring the suspension is filtered and the white filter cake dried in vacuo; the filter cake is then pulverized and submitted once more to the precipitation process from 1:1 chloroform-acetone.
The white, crystalline product, 11.8 g, MP 297°C (dec), [α]D -89.7 (2 N NaOH) is quantitatively obtained but is slightly contaminated with lithium chloride, 0.6% ionic chlorine being found by analysis.
The product of a second step is the methyl acetoacetic ester enamine of N-2- amino-2-(1,4-cyclohexadienyl)acetic acid sodium salt. 306 mg D-2-amino-2- (1,4-cyclohexadienyl)acetic acid (2.00 mmol) are dissolved by warming in a solution of 108 mg of NaOCH3 (2.00 mmol) in 4.3 ml reagent grade MeOH. 255 mg (0.24 ml, 2.20 mmol) methyl acetoacetate are added and the mixture refluxed for 45 minutes. The MeOH is almost totally stripped off in vacuo. Five milliliters benzene are added and distilled off to a small residual volume. The addition and distillation of benzene is repeated to insure complete removal of the MeOH and water. The product crystallizes out overnight from a small residual volume of benzene. It is filtered off, washed with benzene, and dried in vacuo. Yield 463 mg.
Then 3-deacetoxy-7-aminocephalosporanic acid is condensed with the above described sodium salt in the presence of triethylamine to give cephradine.

brand name

Anspor (GlaxoSmith- Kline); Velosef (Bristol-Myers Squibb).

Therapeutic Function

Antibiotic

Antimicrobial activity

Cephradine. A semisynthetic cephalosporin available in both oral and injectable forms. The antibacterial spectrum and susceptibility to β-lactamases are almost identical to those of cefalexin .
It is almost completely absorbed when given by mouth. A 500 mg oral dose achieves a concentration of about 18–20 mg/L after 1 h. The peak is delayed and reduced by food, but the half-life is not altered. Intramuscular administration of 1 g results a plasma concentration of 10–12 mg/L within 2 h. The plasma half-life is around 1 h and protein binding low.
Concentrations of up to 40% of those simultaneously found in the serum have been demonstrated in lung tissue. Penetration into the CSF is poor. Levels in sputum were about 20% of those simultaneously present in the plasma following a 1 g oral dose and similar levels have been found in bone. Breast milk concentrations approaching 1 mg/L have been found after 500 mg orally every 6 h and similar concentrations have been found in amniotic fluid. Cord blood concentration is said to be similar to that in the maternal blood.
It is excreted unchanged in the urine mostly in the first 6 h, achieving concentrations exceeding 1 g/L. Probenecid markedly increases the plasma concentration and delays the peak.
There is some biliary excretion. The parenteral forms may give rise to local pain or thrombophlebitis. Other side effects common to cephalosporins have been described. In some patients Candida vaginitis has been troublesome.
Clinical use is similar to that of cefalexin, but it has been largely superseded by later cephalosporins.

Clinical Use

Cephradine (Anspor, Velosef) is the only cephalosporinderivative available in both oral and parenteral dosageforms. It closely resembles cephalexin chemically (it maybe regarded as a partially hydrogenated derivative ofcephalexin) and has very similar antibacterial and pharmacokineticproperties.
It occurs as a crystalline hydrate that is readily soluble inwater. Cephradine is stable to acid and absorbed almostcompletely after oral administration. It is minimally proteinbound and excreted almost exclusively through the kidneys.It is recommended for the treatment of uncomplicated urinarytract and upper respiratory tract infections caused bysusceptible organisms. Cephradine is available in both oraland parenteral dosage forms.

Synthesis

Cefradin, [6R-[6|á,7|?(R)]]-3-methyl-8-oxo-7-[(amino-1,4-cyclohexadien-1- ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.13), is a close analog of cephalexin and differs in that the phenyl group in phenylglycine is partially hydrated to a 1,4-cyclohexadienyl moiety.
It is synthesized from phenylglycine, which is partially reduced by lithium in liquid ammonia, which forms 1,4-cyclohexadienylglycine (32.1.2.11), and the amino group in this compound is protected by reacting it with methyl acetoacetate in the presence of sodium methoxide. The resulting salt (32.1.2.12) is transformed into a mixed anhydride by a reaction with ethyl chloroformate in triethylamine, and reacted with deacetoxylated 7-aminocephalosporanic acid, which gives cefradin (32.1.2.13).

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: effects of coumarins may be enhanced.

Metabolism

Cefradine is excreted unchanged in the urine by glomerular filtration and tubular secretion, over 90% of an oral dose or 60-80% of an intramuscular dose being recovered within 6 hours. Probenecid delays excretion.

Metabolism

Not Available