Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration

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The objectives of this study were to assess the safety and tolerance of cefprozil, to characterize the pharmacokinetics of cefprozil after adiinistration of multiple doses of the drug, and to compare these pharmacokinetic parameters with those obtained with cefaclor. The volunteers received 28 doses of 250, 500, or 1,000 mg of cefprozil or 500 mg of cefaclor every 8 h for 10 days. Serial blood samples and the total volume of urine voided by each individual were collected for pharmacokinetic evaluation on days 1, 5, and 10. Both cephalosporins were well tolerated after multiple oral dosing. The greater than that of cefaclor. The half-life of cefprozil was also twofold longer than that observed for cefaclor. Although the urinary recovery of cefaclor (75% of dose) was significantly higher than that of cefprozil (61% of dose), the concentrations of cefprozil in urine remained significantly higher than those of cefaclor from 2 to 8 h postdosing. If the therapeutic concept is maintained that levels of beta-lactam antibiotics in plasma should exceed the MIC for the offending organisms over a period that approximates the dosing interval, then cefprozil would appear to be suitable for twice-daily administration, whereas cefaclor should probably be administered three or even four times a day.

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Phase I study of multiple-dose cefprozil and comparison with cefaclor

Barbhaiya

Shukla

Gleason

et al. 1990

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“…The independent. This is in agreement with the dose-independent kinetics also observed for both drugs in humans (1,16,26).…”

Section: Antibioticssupporting

confidence: 80%

Optimal times above MICs of ceftibuten and cefaclor in experimental intra-abdominal infections

Onyeji

Nicolau

Nightingale

et al. 1994

The duration of time that serum drug levels remain above the MIC (time above the MIC) for the pathogen has been shown to be the most significant parameter determining the efficacies of beta-lactam antibiotics. In the described study, we investigated the optimal time above the MIC of ceftibuten and cefaclor using a nonneutropenic mouse model of intra-abdominal infections caused by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae. The abilities of the drugs to protect mice against the organisms were determined in mouse protection tests, and the doses were fractionated to produce various dosing regimens with different times above the MIC. All drug-organism combinations showed a significant correlation (r > 0.9) between drug efficacy and the time above the MIC. Also, with ceftibuten treatment, the different dosing regimens that produced equal times above the MIC resulted in the same efficacy, whereas with cefaclor, an apparent dose-dependent effect was observed. These results showed that for a 100% recovery from K. pneumoniae and E. coli infections, the optimal times above the MIC with ceftibuten treatment were 2.2 and 1.6 h, respectively. Relatively high doses of both antibiotics were required to ensure recovery from S. pneumoniae infections. In vitro time-kill studies demonstrated that cefaclor exhibits a marked inoculum effect against the pathogens, and there was a concentration-dependent killing at a large inoculum size. On the other hand, ceftibuten showed no inoculum effect. It is suggested that optimization of both dose and time above the MIC appears to be necessary for the treatment of S. aureus infections with cefaclor, and this may apply to other beta-lactams that exhibit marked inoculum effects.The therapeutic efficacies of antimicrobial agents are dependent on a variety of factors, including dosage. To optimize the efficacies of cephalosporins, studies in animals and trials in humans have been undertaken to compare the therapeutic outcomes resulting from different antibiotic dosing regimens. The results of such studies have consistently demonstrated that the major parameter correlating drug efficacy is the duration of time that the serum drug concentration exceeds the MIC (6, 8-10, 14, 18, 19, 24). However, there has been no study to determine the optimal time that drug levels should remain above the MIC in any dosing interval.Ceftibuten, an orally active cephalosporin, has been demonstrated to have antibacterial activity in vitro against a wide range of gram-negative and certain gram-positive bacteria (11, 22). Its activity against common respiratory tract pathogens was found to be superior or comparable to those reported for other oral cephalosporins (12). Cefaclor has been shown to be effective in the treatment of respiratory tract, urinary tract, and skin infections and also has a broad range of activity against gram-positive and gram-negative bacteria (4, 13).The study described here was undertaken to investigate, using an experimentally induced infection...

“…Our data suggest that the absolute bioavailability of cefprozil in dogs is lower than that reported for other oral cephalosporins in humans. Although urinary recovery of cefprozil following oral administration in humans (60 to 70%) is significantly higher (1)(2)(3) than that observed in dogs (40%), the data from this study raise a need to evaluate the fraction of the orally administered dose absorbed and the absolute bioavailability of this new oral cephalosporin in humans.…”

mentioning

confidence: 98%

“…Cefprozil, like other oral cephalosporins, is also well absorbed after oral administration (1-3) in humans. However, urinary recovery accounts for about 60% of the administered dose of cefprozil (1)(2)(3). It appears that cefprozil is incompletely absorbed, is metabolized, and/or is eliminated via biliary excretion in humans.…”

mentioning

confidence: 99%

Absolute bioavailability of cefprozil after oral administration in beagles

Barbhaiya

Wang

Shyu

et al. 1992

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The absolute bioavailability of cefprozil, a new oral cephalosporin, in four beagles was evaluated. In this two-way crossover study, each dog received a 125-mg dose of cefprozil either as an oral aqueous solution or as a 15-min intravenous infusion. A high-performance liquid chromatographic assay with UV detection was employed for the determination of cefprozil concentrations in plasma and urine. Key pharmacokinetic parameters were calculated by noncompartmental methods. Cefprozil was well absorbed after oral administration, and peak concentrations of 17.6 to 26.6 ,ug/ml were attained at 60 min after drug administration. The apparent elimination half-life of cefprozil was about 70 min. The renal clearance was about 60% of total body clearance and is suggestive of significant nonrenal clearance. The absolute bioavailability of cefprozil ranged from 67.1 to 79.1% in the dogs.Cefprozil is a new oral cephalosporin with an antibacterial spectrum that includes important gram-positive and gramnegative organisms (4, 6). It is structurally similar to other cephalosporins in that it has a phenylglycine side chain. Cephalosporins with phenylglycine side chains, such as cephalexin and cefadroxil, are almost completely absorbed and undergo minimal metabolism after oral administration (7, 12). As a result, urinary excretion of these cephalosporins accounts for more than 80% of the administered dose (7, 12). Cefprozil, like other oral cephalosporins, is also well absorbed after oral administration (1-3) in humans. However, urinary recovery accounts for about 60% of the administered dose of cefprozil (1-3). It appears that cefprozil is incompletely absorbed, is metabolized, and/or is eliminated via biliary excretion in humans. The extent of oral absorption of cefprozil in humans is not known at this time. The present two-way crossover study was designed to evaluate absolute bioavailability of orally administered cefprozil in dogs.In a two-way crossover study, four beagles weighing 8 to 12 kg each were administered a 125-mg dose of cefprozil either as an oral aqueous solution or as a 15-min intravenous infusion. There was a 1-week washout period between treatments. The dosing solution was freshly prepared by dissolving 1,000 mg of cefprozil in 200 ml of sterile water. A solution containing 5 mg of cefprozil per ml was filtered through a 0.22-,um-pore-size filter and administered within 2 h of preparation. Food was withheld for about 12 to 14 h prior to dosing and for 4 h after dosing. For intravenous administration of cefprozil, 25 ml of the dosing solution (5 mg/ml) was infused over a 15-min period with a Harvard infusion pump. For oral administration of cefprozil, 25 ml of the dosing solution was administered by gavage through a stomach tube and was followed by 25 ml of tap water to rinse the tube. Blood samples were obtained by saphenous venipuncture just prior to dosing (predose) and at 3, 9, 15 (end of intravenous infusion), 18, 24, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 h after intravenous administration and p...