Ceftibuten (7432-S, SCH 39720): comparative antimicrobial activity against 4735 clinical isolates, beta-lactamase stability and broth microdilution quality control guidelines.

The antimicrobial activity of ceftibuten, a new oral cephalosporin, was evaluated using 4735 clinical bacterial isolates processed at four medical centers. Ceftibuten inhibited nearly 92% of all Enterobacteriaceae (less than or equal to 8.0 micrograms/ml), thereby being markedly superior to cefixime which inhibited 78.7% at less than or equal to 1.0 microgram/ml and cefuroxime which inhibited 45.1% at less than or equal to 2.0 micrograms/ml. Pseudomonads and staphylococci were not within the spectrum of activity of ceftibuten. Ceftibuten was found to be very stable in the presence of five commonly occurring beta-lactamases of both the chromosomal-mediated (P99, K1) and plasmid-mediated (CARB-2, OXA-1, TEM-1) types. Only Type Ia (P99) beta-lactamase was significantly inhibited by ceftibuten. On the basis of results of a ceftibuten MIC quality control study conducted in five laboratories, a quality control range of 0.12 to 0.5 microgram/ml is recommended for the Escherichia coli ATCC 25922 strain.

In vitro evaluation of ceftibuten (7432-S, SCH 39720), a novel orally administered cephalosporin.

7432-S (SCH 39720) was the most active beta-lactam tested against the Enterobacteriaceae, inhibiting 92% of strains at less than or equal to 8.0 micrograms/ml compared to 82%, 65% and 39% of strains inhibited by cefixime, cefuroxime and cefaclor, respectively. 7432-S was also very effective against Haemophilus influenzae (MIC90, less than or equal to 0.25 microgram/ml), Branhamella catarrhalis (MIC90, 4.0 micrograms/ml) and Neisseria meningitidis (MIC90, less than or equal to 0.25 microgram/ml). Serogroup B streptococci and the penicillin-resistant pneumococci were generally less susceptible to 7432-S and comparison cephems than Streptococcus pyogenes or penicillin-susceptible S. pneumoniae isolates. Pseudomonas spp., enterococci, Acinetobacter spp. and Staphylococcus spp. were routinely resistant to 7432-S (MIC50s, greater than or equal to 32 micrograms/ml).

Cefuroxime axetil.

Cefuroxime axetil is a orally active prodrug formulation of cefuroxime, which upon absorption undergoes immediate deesterification to free cefuroxime. Cefuroxime axetil offers an in vitro antibacterial spectrum against many gram-positive and some gram-negative organisms. Its beta-lactamase stability makes it useful in treating a variety of infections caused by beta-lactamase-producing strains of Haemophilus influenzae, Branhamella catarrhalis, and Staphylococcus aureus. Cefuroxime axetil has good activity against the Enterobacteriaceae and moderate activity against non-Bacteroides fragilis anaerobes. Clinical studies suggest it is at least as effective as ampicillin, amoxicillin, amoxicillin/clavulanic acid, penicillin V, or cefaclor in the treatment of uncomplicated urinary tract infections, acute otitis media, upper respiratory infections, skin and soft tissue infections, and uncomplicated gonorrhea.

Human pharmacokinetics of a new braod-spectrum parenteral cephalosporin antibiotic, ceforanide.

The pharmacokinetics of the l-lysine salt of ceforanide were studied after intravenous administration of 1132 and 2264 mg as 30-min constant-rate infusions and after intramuscular administration of 556 and 1132 mg. The peak intravenous plasma concentrations were 136 and 222 microgram/ml at termination of infusion, and 12-hr trough concentrations were 5.9 and 9.0 microgram/ml, respectively. The peak intramuscular plasma concentrations were 38 and 74 microgram/ml at 1.0-1.3 hr after dosing, and 12-hr trough concentrations were 3.9 and 6.7 microgram/ml, respectively. When 19 successive intravenous and intramuscular doses at these levels were administered at 12-hr intervals, there was no tendency toward drug accumulation. The major drug elimination route was urinary excretion; 85% of the dose was excreted unchanged in the urine within 12 hr, and no metabolites with antibiotic activity were observed in urine. The mean terminal plasma half-life was 2.98 hr, the mean plasma protein binding was 80.6%, the steady-state volume of distribution was 12 liters, the plasma clearance was 45.9 ml/min/1.73 m2, and the renal clearance was 34.9 ml/min/1.73 m2. The pharmacokinetic properties and antibacterial activity spectrum indicate that this antibiotic should be effective in treating human bacterial infections when administered at 12-hr intervals. It is presently under clinical investigation.

Stability of frozen solutions of cefamandole nafate.

The chemical, microbiological and visual stability of frozen solutions of cefamandole nafate was studied. Solutions of cefamandole nafate were prepared by diluting 1 g of drug with 3 ml of Water for Injection, USP, or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP (i.m. dilutions); or with 50 or 100 ml of the latter two diluents (i.v. dilutions). Stability of samples stored in glass and polyvinyl chloride plastic containers for up to 52 weeks at -10 and -20 C was measured by microbiologic, polarographic, iodometric, nephelometric and chromatographic assay and pH was measured. In mice, LD50 tests were performed using the i.m. dilutions. I.M. dilutions of cefamandole nafate were stable for 52 weeks when stored at -20 C; at -10 C, however, some samples did not freeze completely and were turbid when thawed. I.V. dilutions were stable for 26 weeks when stored at -20 C. I.V. dilutions with D5W stored at -10 C developed a transient haze. A gradual decrease in pH, which was a function of storage time, was noted for the frozen solutions. Six months of freezing did not alter the LD50 in mice. Solutions of cefamandole nafate are stable for at least 26 weeks when stored at -20 C in glass or PVC containers.

Comparison of cefamandole nafate to cefamandole by microbiological assay.

Before microbiological assay, cefamandole nafate should be hydrolyzed for 1 h at 37 degrees C in pH 8 buffer (0.1 M) or for 30 min at room temperature in aqueous solutions containing 1.25 molar equivalents of sodium carbonate.

Comparative bactericidal effect of ceforanide (BL-S 786) and five other cephalosporins in an in vitro pharmacokinetic model.

The bactericidal activity of ceforanide was compared, in an in vitro kinetic model, with that of five other cephalosproins: cephalothin, cefazolin, cefamandole, cefuroxime, and cefoxitin. Cultures of various pathogens in 95% human serum were incubated for 12 hours in the presence of the cephalosporins whose concentrations were modified periodically-by addition of a concentrated solution of drug or dilution with unmedicated serum-in order to simulate the variation of antibiotic concentration in human blood after one-gram intramuscular dose. One Gram-positive strain and six Gram-negative strains were used. Bactericidal activity was assessed by monitoring changes in the number of colony-forming units. Tests showed that against Klebsiella pneumoniae, ceforanide was the most active of the six cephalosporins. Proteus mirabilis was more susceptible to ceforanide and cefuroxime than to the other compounds; Enterobacter cloacae to ceforanide, cefuroxime, and cefamandole; Escherichia coli to ceforanide, cefuroxime, cefamandole, and cefazolin. The number of viable cells of Staphylococcus aureus was reduced below detectable levels by all cephalosporins except cefoxitin. On the other hand, Providencia stuartii was virtually unaffected by all of the cephalosporins except cefoxitin.