Cefprozil

Description

Cefprozil is a new orally active cephalosporin useful in the treatment of otitis media, uncomplicated skin and skin structure infections plus upper/lower respiratory tract infections. Although structurally similar to cefadroxil, its spectrum of antibacterial activity is comparable to cefaclor, but exhibits greater activity against S.aureus, S. epidermidis, Listeria monocytogenes, Streptococci, H. influenzae, Propionibacterium acnes. Clostridium perfringens and difficile.

Chemical Properties

Pale Yellow Solid

Originator

Bristol-Myers Squibb (U.S.A.)

Uses

Semisynthetic oral cephalosporin consisting of approx. 90:10 Z/E isomeric mixture. Antibacterial

Definition

ChEBI: A semisynthetic, second-generation cephalosporin, with prop-1-enyl and (R)-2-amino-2-(4-hydroxyphenyl)acetamido groups at positions 3 and 7, respectively, of the cephem skeleton. It is used to treat bronchitis as well as ear, skin and other bacterial infec ions.

Manufacturing Process

A mixture of 4-hydroxy-D-phenylglycine (10 g), ethylene glycol (15 ml) and concentrated sulfuric acid (5 ml) was stirred for 18 hours at 55°C under anhydrous conditions. The solution was cooled, and then ice (10 g) was added to it, and the pH was adjusted to 1.0 with 10 N NH4OH (4.5 ml) giving 40 ml of solution of hydroxyethyl ester of 4-hydroxy-D-phenylglycine.
The enzyme mixture of 20 ml containing immobilized recombinant penicillin G amidase as the enzyme, 10% hydroxyethyl ester of 4-hydroxy-D-phenylglycine, 4% cefprozil (amine source), and 8% enzyme (immobilized recombinant penicillin G amidase, equivalent to 32 IU/ml of enzyme) was made up without buffer. The above prepared ester solution (6.9 ml) was mixed with water (2 ml) and adjusted to pH 7.5 with 10 N NH4OH. Then the amine source (0.8 g) was added to it and the pH adjusted to 7.5 with 1 N NH4OH and the volume to 18.4 ml. Then the mixture was cooled to 5-15°C and solid enzyme (1.6 g; 640 IU) was added to it. The pH was not maintained at 7.5 and fell about 0.6 units during the reaction. The reaction mixture was analyzed by HPLC on a C18 Reverse Phase column. The mobile phase was 10% acetonitrile/0.3% H3PO4. The isomers of cefprozil appeared at 2.9 minutes (cis) and at 5.1 minutes (trans). The final product was obtained with a maximum yield of 92-96%. The whole experiment was completed in 25-50 min.
Synthesis of cefprozil may be carried out at 15°C using Boehringer penicillin G amidase as the enzyme and hydroxyethyl ester of 4-hydroxy-D-phenylglycine. A maximum yield of about 95%. The experiment was completed in 35 minutes.

brand name

Cefzil (Bristol-Myers Squibb).

Therapeutic Function

Antibiotic

Antimicrobial activity

Activity against Gram-positive cocci and Gram-negative bacilli is better than that of cefadroxil (which it structurally resembles) but is not as good as that of group 5 agents . It is moderately stable to hydrolysis by the common plasmid-mediated β-lactamases, but is hydrolyzed by the chromosomal enzymes of Gram-negative bacilli .

Hazard

Moderately toxic by ingestion. Human sys- temic effects.

Pharmacokinetics

Oral absorption: >90%
C_max 250 mg oral: 5–7 mg/L after 1 h
500 mg oral: 10 mg/L after 1
Plasma half-life: 1–1.4 h
Volume of distribution: 15–201
Plasma protein binding: 35–45%
Absorption and distribution
It is almost completely absorbed and well distributed, penetrating well into tonsillar and other tissues and inflammatory exudate. Absorption is unaffected by food or antacids and there is no accumulation on multiple dosing regimens.
Metabolism and excretion
Most of the dose is excreted unchanged in urine, though about 20% is found in feces. Urinary concentrations after a 500 mg oral dose usually exceed 1 g/L. The elimination halflife is prolonged in patients with renal impairment, reaching 6 h in anuric patients. About half the drug is removed in 3 h by hemodialysis.

Pharmacokinetics

Oral absorption: >90%
C_max 250 mg oral: 5–7 mg/L after 1 h
500 mg oral: 10 mg/L after 1
Plasma half-life: 1–1.4 h
Volume of distribution: 15–201
Plasma protein binding: 35–45%
Absorption and distribution
It is almost completely absorbed and well distributed, penetrating well into tonsillar and other tissues and inflammatory exudate. Absorption is unaffected by food or antacids and there is no accumulation on multiple dosing regimens.
Metabolism and excretion
Most of the dose is excreted unchanged in urine, though about 20% is found in feces. Urinary concentrations after a 500 mg oral dose usually exceed 1 g/L. The elimination halflife is prolonged in patients with renal impairment, reaching 6 h in anuric patients. About half the drug is removed in 3 h by hemodialysis.

Clinical Use

Cefprozil (Cefzil) is an orally active second-generationcephalosporin that is similar in structure and antibacterialspectrum to cefadroxil. Oral absorption is excellent (oralbioavailability is about 95%) and is not affected by antacidsor histamine H2-antagonists. Cefprozil exhibits greater invitro activity against streptococci, Neisseria spp., and S. aureusthan does cefadroxil. It is also more active than thefirst-generation cephalosporins against members of theEnterobacteriaceae family, such as E. coli, Klebsiella spp., P. mirabilis, and Citrobacter spp. The plasma half-life of1.2 to 1.4 hours permits twice-a-day dosing for the treatmentof most community-acquired respiratory and urinary tractinfections caused by susceptible organisms.

Clinical Use

It has been used for various infections for which oral cephalosporins are appropriate.

Clinical Use

As for group 2 cephalosporins . It should not be used in infections in which H. influenzae is, or is likely to be, implicated. It should not be used as an alternative to penicillin in syphilis.

Side effects

Nausea, vomiting and abdominal discomfort are relatively common. Pseudomembranous colitis has been described and overgrowth of Candida with vaginitis may be troublesome. Otherwise, mild hypersensitivity reactions and biochemical changes common to cephalosporins occur. Very rare neurological disturbances have been described, particularly in patients in whom very high plasma levels have been achieved. There are rare reports of Stevens–Johnson syndrome and toxic epidermal necrolysis.

Side effects

It is well tolerated. Diarrhea and gastrointestinal discomfort may occur. There have been a few reports of pseudomembranous colitis and serum sickness-like reactions.