Bacteriological, pharmacokinetic and clinical studies of 5% and 10% granules of cefdinir in the pediatric field]

Bacteriological, pharmacokinetic and clinical studies on cefdinir (CFDN, FK482), a new oral cephalosporin, 5% and 10% granules, were performed in the field of pediatrics. The results are summarized below. 1. Antibacterial activities Antibacterial activities of CFDN against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, Escherichia coli and Klebsiella pneumoniae were studied in comparison with those of cefaclor (CCL), cefixime (CFIX) and amoxicillin (AMPC). MIC80's of CFDN against S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, B. catarrhalis, K. pneumoniae and E. coli were 0.78, 0.20, less than or equal to 0.025, 0.39, 0.10, 0.20 and 0.10 micrograms/ml, respectively. These results show that CFDN has high antibacterial activities against these organisms. MIC80's of CFDN against Gram-positive bacteria were similar to those of AMPC, and was lower than those of CCL and CFIX. As for antibacterial activities against Gram-negative bacteria (GNB), the MIC80 of CFIX against H. influenzae was 0.05 micrograms/ml, which was slightly lower than that of CFDN. THe MIC80's of CFDN against other GNB were similar to those of CFIX. 2. Absorption and excretion Blood concentrations and urinary excretion rates of CFDN 5% and 10% granules and 100 mg capsule were determined. The data on CFDN 10% granules were similar to those on CFDN 5% granules. At a dose of 3 mg/kg, peak blood concentrations (Cmax's) of CFDN ranged from 0.20 to 2.12 micrograms/ml with 5% granules and from 0.50 to 1.15 micrograms/ml with 10% granules at 2 to 3 hours after dosing. At a dose of 6 mg/kg, peak concentrations were 0.66-2.06 micrograms/ml and 0.70-1.52 micrograms/ml with 5% granules and with 10% granules, respectively. At 8 hours after dosing, blood concentrations were 0.04-0.54 micrograms/ml at 3 mg/kg and 0.06-0.27 micrograms/ml at 6 mg/kg. Blood half-lives were 1.33-4.36 hours at 3 mg/kg and 1.14-3.27 hours at 6 mg/kg. AUC's were 1.7-11.0 micrograms.hr/ml with 3 mg/kg and 2.4-8.7 micrograms.hr/ml with 6 mg/kg. With administration of single 100 mg capsule, Cmax's, blood concentrations after 8 hours, T1/2's and AUC's were 0.79-1.88 micrograms/ml, 0.20 micrograms/ml, 1.54-2.72 hours, and 5.2 micrograms.hr/ml, respectively. Urinary recovery rates in the first 8 hours ranged from 6.85 to 39.2% with 3 mg/kg and 6.08-25.5% with 6 mg/kg.(ABSTRACT TRUNCATED AT 400 WORDS)     

Synthesis and biological activity of novel 3-(2-propenyl)-cephalosporins. I

The synthesis, antibacterial activity and oral absorption of novel cephalosporins (3a-3d) having a 2-propenyl group at the C-3 position are described. Diphenylmethyl 7-amino-3-(2-propenyl)-3-cephem-4-carboxylate HCl (4) prepared from 7-aminocephalosporanic acid in 12 steps was acylated with various acid moieties to give cephems 3a-3d. The cephems 3a-3c showed similar antibacterial activities as cefixime. However, these cephems were not well absorbed orally.     

Pharmacokinetic and clinical studies on cefdinir fine granules in children

A new oral cephem, cefdinir (CFDN) was evaluated for its efficacy, safety and pharmacokinetics in 13 children. The results are summarized as follows. Plasma concentration peaked at 3-4 hours after administration of 3 mg/kg of CFDN with Cmax ranging from 0.57-0.89 microgram/ml except 1 case in which the absorption of the drug was poor. Recovery rates in urine averaged at 13.4%, with a large individual variation. Ten children with 12 bacterial infections were treated with 9 mg/kg/day of CFDN fine granule. Clinical responses were good in 10 patients and fair in 1 patient, with an efficacy rate of 90.9%. No clinical adverse reactions nor abnormal laboratory findings were encountered.     

Studies on cephalosporin antibiotics. IV. Synthesis, antibacterial activity and oral absorption of new 3-(2-substituted-vinylthio)-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2- (carboxymethoxyimino)acetamido]cephalosporins.

A series of new 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)ace tamido] cephalosporins (1) having various substituted-vinylthio groups at the C-3 position of the cephen nucleus was synthesized and evaluated for antibacterial activity and oral absorption in rats in comparison with cefixime. Of these, the cephalosporins (1a and 1c) with a lower alkoxycarbonylvinylthio group (Z-form) at the C-3 position showed a potent antibacterial activity against Gram-negative bacteria, improved activity against Staphylococcus aureus as well as good oral absorption in rats. The structure-activity relationships of 1 are also presented.     

Studies on cephalosporin antibiotics. V. Synthesis, antibacterial activity and oral absorption of new 3-[(Z)-2-methoxycarbonylvinylthio]-7 beta- [(Z)-2-(2-aminothiazol-4-yl)-2-(oxyimino)acetamido]cephalosporins.

A series of new 3-[(Z)-2-methoxycarbonylvinylthio]-7 beta-[(2- aminothiazol-4-yl)acetamido]-cephalosporins (1) having various oxyimino groups (Z-form) at the alpha position of the C-7 side chain was synthesized and evaluated for antibacterial activity and oral absorption in rats. Of these, the cephalosporin (1a) with a hydroxyimino group in the C-7 side chain showed a potent antibacterial activity against Gram-negative bacteria and Gram-positive Staphylococcus aureus as well as good oral absorption in rats. The structure-activity relationships of 1 are also presented.     

Studies on cephalosporin antibiotics. III. Synthesis, antibacterial activity and oral absorption of new 3-(substituted-alkylthio)-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2- (carboxymethoxyimino)acetamido]cephalosporins

The synthesis, antibacterial activity and oral absorption in rats of new 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)ace tamido] cephalosporins (1) having various substituted-alkylthio groups at the C-3 position of the cephem nucleus are described. Of these, the cephalosporins with a cyanomethylthio group (1d) and fluoroethylthio group (1p) at the C-3 position showed a potent in vitro antibacterial activity against Gram-positive and Gram-negative bacteria as well as good oral absorption in rats. When administered orally to mice infected with Klebsiella pneumoniae, 1d had stronger protective effect than 1p. The structure-activity relationships of 1 are also presented.     

7-酰氨基-3-(1,2,3-三唑甲基)头孢菌素衍生物的合成及其抗菌活性

本文以青霉素G扩环而得的7-苯乙酰氨基-3-甲基-3-头孢烯-4-羧酸(Ⅰ)为原料,合成了12个C₃位上有1,2,3-三唑甲基取代的新头孢菌素衍生物(Ⅷ_1～12),并经分析确证了各化合物的结构。体外抑菌试验结果表明,其中6个化合物,即Ⅶ_2～4,9～11,不仅对革兰氏阳性菌有较高的抑制作用。而且对革兰氏阴性菌也有高度敏感性。     

Clinical studies on cefdinir granules in pediatric field

Cefdinir (CFDN, FK482) granules, a new oral antibiotic for children, were given to children with infections. The results obtained are summarized as follows. 1. The plasma level of CFDN peaked at 0.38-0.88 microgram/ml in 2-3 hours after administration of the drug at a dose of 3 mg/kg. Meanwhile, the plasma level peaked at 1.85 micrograms/ml in 3 hours after administration of 6 mg/kg. The plasma level was higher in the 6 mg/kg group than that in the 3 mg/kg group, thus a dose response was clearly observed. 2. The 8 hour urinary excretion accounted for 10.3-17.4% of administered amount of the drug in children with 3-6 mg/kg dosage. 3. CFDN granules were administered to a total of 42 children with upper or lower airway infections or with urinary tract infections at daily doses of 9.0-20.7 mg/kg in 3 divided portions. The clinical efficacy was "excellent" in 28 patients, "good" in 13, and "fair" in 1, hence an efficacy rate of 97.6% was obtained. 4. Bacteria identified from various diseases were 29 strains of 9 species, and the eradication rate was 82.8%. 5. No. side effects were noted in any of the children. Laboratory test results showed an abnormality in 1 case each with a rise of platelet count and eosinophilia.     

Studies on beta-lactam antibiotics. XIII. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-aryl-2-carboxymethoxyiminoacetamido]-3-vinylcepha losporins

The synthesis, antibacterial activity and oral absorption of the 7 beta -[(Z)-2-aryl-2-carboxymethoxyiminoacetamido]-3- vinylcephalosporins are described. Of these cephalosporin derivatives, 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-carboxymethoxyiminoacetamido]- 3-vinylcephalosporin exhibited the highest activity against Gram-negative bacteria and showed also good excretion after oral administration to rats. In addition, the effects on the antibacterial activity and oral absorption of the amino function on the thiazole ring are discussed.     

Laboratory and clinical studies of cefdinir 5% and 10% fine granules in pediatric field]

We have carried out laboratory and clinical studies on cefdinir (CFDN) 5% and 10% fine granule preparations. The results are summarized as follows. CFDN 5% fine granule preparation was given via oral route to each of 2 children in the fasting state at a single dose of 3 mg/kg. After administration, the mean peak plasma level of CFDN was 0.76 micrograms/ml at 4 hours and the mean half-life was 1.77 hours. The mean urinary excretion rate of CFDN was 31.5% in the first 12 hours after oral administration. CFDN 10% fine granule preparation and CFDN 100 mg capsule were given via oral route 3 children and to another child in the fasting state at single doses of 3 mg/kg and 2.63 mg/kg, respectively. After administration of 10% granules the mean peak plasma level of CFDN was 0.73 micrograms/ml at 2 hours and the mean half-life was 1.62 hours. The peak serum level obtained after administration of CFDN 100 mg capsule was 0.91 micrograms/ml at 2 hours and the half-life was 1.08 hours. The mean urinary excretion rate obtained with CFDN 10% fine granules was 26.2% in the first 8 hours after oral administration and the urinary excretion rate obtained with CFDN 100 mg capsule was 19.7% in the first 12 hours after oral administration. Treatment with CFDN 5% fine granules was made for a total of 48 cases of pediatric bacterial infections including 21 cases of tonsillitis, 12 cases of scarlet fever, 3 cases of pharyngitis, 5 cases of impetigo, 1 case of subcutaneous abscess, 1 case of furuncle, 5 cases of UTI. Results obtained were excellent in 30 cases, good in 18 cases. Treatment with CFDN 10% fine granules was made for a total of 16 cases of pediatric bacterial infections including 6 cases of tonsillitis, 3 cases of pneumonia, 4 cases of scarlet fever, 2 cases of impetigo, 1 case of UTI. Results obtained were excellent in 8 cases, good in 7 cases, poor in 1 case. No significant side effects due to the drugs were observed except 2 cases (1 case with 5% preparation and another with 10%) with eosinophilia, 3 cases (all with 5%) with diarrhea and 1 case each of elevated GOT & GPT (with 5%) and elevated GOT, GPT & Al-P (with 10%).     

Studies on cephalosporin antibiotics. VI. Synthesis, antibacterial activity and oral efficacy in mice of new 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)-acetamido]-3- (substituted alkylthio)cephalosporins.

A series of new 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] cephalosporins (1) having various substituted alkylthio groups at the C-3 position of the cephem nucleus were prepared and evaluated for antibacterial activity and oral absorption in rats. Of these, the cephalosporin with a cyanomethylthio group (1a) showed the greatest activity against Staphylococcus aureus and Gram-negative bacteria. Its pivaloyloxymethyl ester (6a), a representative prodrug, exhibited good in vivo efficacy in mice by oral administration. The structure-activity relationships of 1 are also presented.     

Clinical evaluation of cefdinir 10% granules in children]

Cefdinir (CFDN, FK482) was evaluated in children with infections. CFDN was given at a daily dose of 6.4-19.8 mg/kg in 2 or 3 divided portions. CFDN was effective in 94% of 32 cases with respiratory tract, middle ear, urinary tract or skin structure infections. Side effects were loose stool and diarrhea (12.5%). In a pharmacokinetic study, 6.0 mg/kg of CFDN was given to each of the subjects before meal. Cmax was 0.81 +/- 0.38 microgram/ml, T 1/2 was 2.31 +/- 0.77 hours. Antibacterial activity against Staphylococcus aureus was the most excellent of oral cephem antibiotics tested. The data suggest that CFDN 10% granular preparation is safe and effective when used in children with infections caused by susceptible bacteria.     

A clinical evaluation of cefdinir in pediatric infections

Cefdinir (CFDN), a new oral cephalosporin, was administered to 10 patients with various infections and the following results were obtained. 1. Clinical responses in 10 patients (1 patient with rhinitis, 2 with sinusitis, 1 with pharyngitis, 1 with tonsillitis, 4 with scarlet fever and 1 with abscess) were excellent in 6 and good in 4 with an efficacy rate of 100%. 2. Eleven species of bacteria were isolated (3 of Staphylococcus aureus, 6 of Streptococcus pyogenes and 2 of Haemophilus influenzae) and all of them were eradicated by the treatment with CFDN. 3. No side effects or abnormal laboratory test values were noted. None of the patients refused to take the drug.     

Studies on the alpha-glucoside hydrolase inhibitor, adiposin. III. alpha Glucoside hydrolase inhibitory activity and antibacterial activity in vitro

Adiposin-1 and -2 exhibited potent inhibitory activities against alpha-amylase, human salivary alpha-amylase and disaccharidases isolated from porcine small intestine. The effect of adiposin-1 and -2 on hydrolysis of glucoamylase was non-competitive. Adiposin showed antimicrobial activities against some Gram-positive bacteria, Gram-negative bacteria belonging to Enterobacteriaceae, Some anaerobic bacteria and some phytopathogenic fungi, and showed a synergistic effect on the antibacterial activity with some maltooligosaccharides. However, these antibacterial activities were suppressed by addition of various other saccharides.     

Studies on FK482 (Cefdinir). III. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-aryl-2-hydroxyiminoacetamido]-3-vinyl-3- cephem-4-carboxylic acid derivatives

The synthesis, antibacterial activity and oral absorption of the 7 beta-[(Z)-2-aryl-2-hydroxyiminoacetamido]-3-vinylcephalosporins (Ia--e) are described. All of these compounds exhibited excellent activity against Staphylococcus aureus. Against Gram-negative bacteria FK482 exhibited more excellent activity than the other compounds (Ia--e). These compounds except Ie showed good oral absorption. The relationship between the oral absorption rates and the lipophilicity of these cephalosporins is discussed.     

Orally active cephalosporins. I. Synthesis and structure-activity relationships of 7 beta-[2-(R)-amino-2-phenylacetamido]-3-(1H- 1,2,3-triazol-4-yl)alkylthiomethyl-3-cephem-4-carboxylic acid and related compounds]

The synthesis, antibacterial activity and oral absorbability of 7 beta-[2-(R)-amino-2-phenylacetamido]-3-(1H-1H-1,2,3-triazol- 4-yl)methylthiomethyl-3-cephem-4-carboxylic acid (1a) and related compounds (1b-p and 2) are described. The replacement of 1,2,3-triazole at the C-3 position of 1a with other heteroaromatics such as 1,2,4-triazole, imidazole and so on decreased its oral absorbability in mice (1b-j). The oral absorbability was also influenced by the spacer length between C-3 of cephem nucleus and C-4 of 1,2,3-triazole. The quantitative relationship between the bioavailability and the spacer length of cephalosporins (1a and 1k-p) is discussed. These results suggest that 1,2,3-triazole in the side chain at the C-3 position of cephems plays an important role in good oral absorption through its interaction with the transport system of small intestine.     

Clinical studies on cefdinir in pediatric infections

Pharmacokinetic, bacteriological and clinical studies on cefdinir (CFDN), a newly developed oral cephalosporin, were performed on children with infections. The pharmacokinetics was examined in 3 patients. The peak plasma concentrations were 1.97 micrograms/ml, 0.84 microgram/ml and 1.67 micrograms/ml in the 3 patients. The 0 to 6 or 8-hour urinary excretion rates were 22.2%, 18.1%, and 32.7%, respectively. These results were similar to those in adult patients. Clinical response to CFDN was evaluated in 21 patients, 4 patients with pharyngitis (an efficacy rate of 100%), 7 with tonsillitis (85.7%), 1 with bronchitis (excellent), 1 with pneumonia (fair), 6 with scarlet fever (100%), 1 with staphylococcal scaled skin syndrome (good) and 1 with urinary tract infection (good). Thus, an overall efficacy rate of 90.5% was achieved. With regard to microbiological effect on pathogens, 14 of the 15 strains identified as pathogens were eradicated, with an eradication rate of 93.3%. The safety was evaluated in a total of 23 cases. Diarrhea, elevated eosinophil count and elevated S-GPT were observed in one patient each. The side effect and abnormalities in laboratory tests were not serious, however. It was concluded that CFDN, with its excellent antibacterial effect, was an efficacious and safe drug for the treatment of pediatric infections.     

Studies on beta-lactam antibiotics. X. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido] cephalosporin derivatives

The synthesis of 7 beta-([Z) -2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-cephalosporins (2a-h) modified at the C-3 position of a cephem nucleus and the effect of the C-3 substituents on the antibacterial activity, oral absorptivity and therapeutic activity are discussed. The cephems (2a and 2b) having a C-3 substituent such as hydrogen or vinyl were more potent than other cephalosporins against Gram-negative bacteria. However, the cephalosporin (2f) having methylthio group at the 3-position showed the highest absorption rate in rats. These three cephalosporins (2a, b and f) exhibited equally good protective activities in mice infected. Furthermore, the serum levels of these cephalosporins (2a, b and f) were examined in dogs, and 2b and 2f showed outstanding high and prolonged serum levels.     

Pharmacokinetic, bacteriological and clinical evaluations of cefdinir 10% fine granules in pediatrics]

Pharmacokinetic, bacteriological, and clinical studies on cefdinir (CFDN, FK482) (10% fine granules), a new oral cephem, were performed in pediatrics. 1. Bioequivalencies of plasma concentrations and urinary excretions of CFDN 5% and 10% fine granules were investigated on 3 pediatric patients with ages between 5 to 13 years administered with a drug in fasting state at a dose level of 3 mg/kg using a cross over method. Average plasma concentrations in a group of patients administered with 5% fine granules peaked at 3 hours after administration with a level of 1.05 +/- 0.29 micrograms/ml (mean +/- S.E.) and decreased to 0.12 +/- 0.05 micrograms/ml at 8 hours with a half-life of 1.48 +/- 0.09 hours. In the group administered with 10% fine granules, average plasma concentrations peaked at 2 hours after administration with a level of 1.32 +/- 0.12 micrograms/ml, and decreased to 0.20 +/- 0.11 microgram/ml at 8 hours with a half-life of 1.68 +/- 0.28 hours. The first 8-hour urinary recovery rates of CFDN in the 5% and 10% fine granules groups averaged 19.64 +/- 5.69% and 23.37 +/- 2.36%, respectively. Both average and individual plasma concentrations and urinary recovery rates in the patients of the 10% fine granules group were somewhat higher than those of the 5% fine granules group, but no significant differences were observed between the 2 groups including areas under concentrations. 2. CFDN 10% fine granule preparation was administered to 33 pediatric patients with ages between 1 to 13 years with various infections, and its clinical effects, bacteriological effects and safety were assessed. In 31 of the 33 patients (2 patients were excluded since they were with non-bacterial infections) clinical effects were excellent in all of 9 patients with scarlet fever (3), acute pharyngitis (3) or impetigo (3), excellent in 12 and good in 3 of 15 patients with acute purulent tonsillitis, and excellent in 4 and good in 3 of 7 patients with acute pneumonia. The overall efficacy rate was 100%. Bacteriological effects against causative organisms were evaluated. All the identified Staphylococcus aureus (4 strains) and Streptococcus agalactiae (1) were eradicated. Of 10 strains of Streptococcus pyogenes, 9 strains were eradicated and the other one was reduced. Of 7 strains of Haemophilus influenzae 4 were eradicated, 1 persisted and the fate of the remaining 2 were unknown. The overall eradication rate was 90.0%. Microbial substitutions were observed in 5 patients. The new, replacing bacteria were all Haemophilus spp.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical study on cefdinir in pediatric field

We studied pharmacokinetics and clinical effects of cefdinir (CFDN), a newly developed oral cephalosporin, and the following results were obtained. 1. Pharmacokinetics of CFDN in 2 patients were investigated. The 2 patients with ages of 8 years (36.5 kg, body weight) and 6 years (26.5 kg, body weight) were administered with 3 mg/kg of fine granules of CFDN on empty stomachs. Peak plasma levels of CFDN were 0.85 microgram/ml in one patient and 0.56 microgram/ml in the other. The 8-hour urinary recovery rate was 21.6% of the administered dose in one and was not calculable in the other. 2. Clinical effects of CFDN were studied in 25 children with various infectious diseases: 11 with acute pharyngitis, 1 with acute tonsillitis, 2 with acute laryngitis, 3 with acute bronchitis, 2 with acute bronchopneumonia, 4 with scarlet fever, 1 with acute otitis media, 1 with acute lymphadenitis. The efficacy rate was 96% (24/25), and the bacteriological eradication rate was 83.3% (10/12). 3. No side effects were noted. Clinical laboratory test values were investigated in 14 patients. There were no seriously abnormal laboratory test findings except a slight elevation of eosinophile and GPT.