Phase I Clinical Studies of 7432‐S, a New Oral Cephalosporin: Safety and Pharmacokinetics

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...

show abstract

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

Section: Antibioticssupporting

confidence: 91%

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

Onyeji

Nicolau

Nightingale

et al. 1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…As was true in the study reported by Nakashima et al (9), we found that the CFB dose did not appear to alter the pharmacokinetic parameters of CFB (Table 2). Comparison of CFB pharmacokinetic parameters in our pediatric subjects with those previously reported by Nakashima et al (9) from a study with healthy adults suggests both similarities and differences. The apparent elimination t112 of CFB in our subjects (2.1 + 0.5; range = 1.2 to 3.7 h; Table 1) was in agreement with values reported for adults receiving a single CFB dose of 25.0 (1.1 + 0.2 h), 50.0 (1.6 + 0.2 h), 100.0 (1.5 + 0.2 h), and 200.0 (1.8 + 0.3 h) mg.…”

Section: Discussionsupporting

confidence: 81%

“…While we could not demonstrate a difference in VSS/F for CFB between the age subgroups in our investigation (Table 3) or a correlation between age and V,/IF, the mean values from subjects in our initial (n = 49) and validation (n = 11) studies (0.42 ± 0.23 and 0.49 ± 0.12 liter/kg, respectively) were considerably larger than those in adults (range = 0.13 to 0.18 liter/kg) reported by Nakashima et al (9). Although these two studies cannot be directly compared on the basis of experimental design, subject number and composition, or methods used for data analysis, the apparent increase in the VsS/F for CFB in younger subjects has been previously reported for many cephalosporins and beta-lactam antimicrobial agents (15) and may result from age-related changes in extracellular fluid and total body water spaces (8) and/or changes in the protein binding of CFB, as have been previously described for ceftriaxone (4).…”

Section: Discussioncontrasting

confidence: 58%

“…CFB is relatively inactive against enterococci and staphylococci and is only weakly active against Pseudomonas aeruginosa and obligate anaerobes (18). It is also stable in the presence of most ,B-lactamase-producing organisms except Bacteroides fragilis (9). Additionally, CFB has recently been shown to be very active against strains of the family Enterobacteriaceae (mean MIC for 90% of strains = 0.25 ,ug/ml) but less active * Corresponding author.…”

mentioning

confidence: 99%

“…against Campylobacterjejuni (mean MIC for 90% of strains = 16.0 ,ug/ml) (13). Nakashima et al (9) have recently described CFB pharmacokinetics in 40 healthy adult volunteers after single oral doses of 25, 50, 100, and 200 mg. They found apparent peak concentrations in plasma (Cmax) of 1.9, 3.6, 5.6, and 11.6 ,xg/ml at 2.1 to 3.0 h after administration of the 25-, 50-, 100-, and 200-mg doses, respectively.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Single-dose pharmacokinetics of ceftibuten (SCH 39720) in infants and children

Kearns

Reed

Jacobs

et al. 1991

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Ceftibuten (CFB), a new broad-spectrum cephalosporin for oral administration, possesses potent activity in vitro against a wide range of gram-negative and certain gram-positive pathogens frequently encountered in pediatric patients. Its antimicrobial spectrum and dosage formulation suggest a use for CFB in the treatment of otitis media and upper and lower respiratory and urinary tract infections in infants and children. To assess the pharmacokinetic characteristics of CFB in pediatric patients, we completed a multicenter investigation of 49 children (26 females) between the ages of 6 months and 17 years who had normal hepatic and renal functions and no evidence of chronic disease. Pharmacokinetic parameters were determined from repeated blood samples (n = 12) and, when possible, quantitative urine collections (n = 7) obtained over a 12-to 24-h period following a single oral CFB dose of either 4.5 or 9.0 mg/kg of body weight. CFB was quantitated from plasma and urine samples by using a sensitive, microanalytical high-pressure liquid chromatography method. The drug was rapidly absorbed (mean time to maximum concentration in serum = 140 min) and produced apparent peak concentrations in plasma (Cm,.) ranging from 5.0 to 19.0 mg/liter. Average CFB pharmacokinetic parameters (±standard deviations) were as follows: apparent elimination half-life, 2.0 + 0.5 h; mean residence time, 3.9 ± 1.1 h; apparent steady-state volume of distribution, 0.4 ± 0.2 liter/kg; and apparent total plasma clearance (CL/F), 2.5 ± 0.9 m/min/kg. No significant differences in any of the pharmacokinetic parameters were observed between the two dosing groups. Significant (P < 0.05) negative correlations were found between patient age and CFB elimination half-life and CL/F and between the estimated creatinine clearance and renal clearance and CL/F. Apparent age dependence of CFB disposition was also reflected by a greater CL/F in children from 0.5 to c5 years of age (3.1 ± 1.1 ml/min/kg) than in children >10 years of age (2.0 ± 0.6 ml/min/kg; P < 0.005). The increased CL/F for CFB (3.0 ± 0.5 ml/min/kg) was corroborated by a validation study performed with 11 infants (6 to 26 months) who were given a single 9.0-mg/kg oral dose. Comparison of renal clearance (1.0 ± 0.5 ml/min/kg) with CL/F for 19 subjects suggested that appreciable nonrenal clearance (1.3 + 0.6 ml/min/kg) of CFB occurred in children, a finding different from preliminary data for adults.Ceftibuten (CFB; 7432-S, SCH 39720; Schering Corp., Bloomfield, N.J.) is a recently synthesized broad-spectrum oral cephalosporin which has the structural formula 7-3-[(Z)-2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylic acid. It exhibits antimicrobial activity against a wide range of gram-negative bacteria and certain gram-positive organisms which frequently represent serious bacterial pathogens in infants and children. In vitro, CFB is highly active against Haemophilus influenzae, Escherichia coli, Klebsiella sp., and Proteus sp. and moderately active against Serratia sp. and ...

show abstract

Intestinal Transporters

2012

Biopharmaceutics Modeling and Simulations

View full text Add to dashboard Cite

Phase I Clinical Studies of 7432‐S, a New Oral Cephalosporin: Safety and Pharmacokinetics

Cited by 38 publications

References 8 publications

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

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

Single-dose pharmacokinetics of ceftibuten (SCH 39720) in infants and children

Intestinal Transporters

Contact Info

Product

Resources

About