S-1108 is a pivalate ester of S-1006 and a new cephem antibiotic. The in vitro and in vivo antibacterial activity of S-1108 (S-1006) was investigated and compared with that of cefteram (CFTM), cefixime (CFIX), cefotiam (CTM) and cefaclor (CCL).
1. S-1006 proved to have a broad antibacterial spectrum, and its in vitro activity against Staphylococcus and Streptococcus was the same as that of CTM and CFTM, and stronger than that of CFIX and CCL. Against the Enterobacteriaceae family and glucosenonfermenting bacteria, except Pseudomoans aeruginosa and Xanthomonas maltophilia, S-1006 was slightly less potent than CFIX, but had the same or greater potency than CTM or CCL.
2. S-1006 showed strong bactericidal activity against various species of bacteria.
3. S-1006 is quite stable to various penicillinases (PCase) and cephalosporinases (CSase), but unstable to oxyiminocephalosporinases (CXase).
4. As to the protective effects in experimental infections with Staphylococcus aureus Smith. S-1108 was more effective than CFTM-PI and CFIX but not as effective as CCL.

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The in vitro and in vivo antibacterial activity of S-1108, a new pivaloyloxymethyl ester of S-1006, was compared with that of cefteram pivoxil (CFTM-PI), cefpodoxime proxetil (CPDX-PR), cefdinir (CFDN) and cefaclor (CCL).
S-1006 had a broad antibacterial spectrum against gram-positive and gram-negative bacteria, and the antibacterial activity of S-1006 against methicillin-sensitive Staphylococcus aureus (MSSA) and Staphylococcus epidermidis was superior to that of CFTM, CPDX and CCL, and its activity against gram-negative bacteria was almost the same as that of CFTM, CPDX and CFDN. S-1006, however, showed weak activity against methicillin -resistant S. aureus (MRSA), Enterococcus spp. and Pseudomonas aeruginosa.
S-1006 showed dose-dependent bactericidal action against the S. aureus, Escherichia coli and Klebsiella pneumoniae used in this study.
In experimental systemic and local infections, S-1108 showed good therapeutic effects reflected well in vitro activity and excellent pharmacokinetic in mice.

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S-1108 is an oral cephem antibiotic of the estertype. The MIC₈₀ values of S-1006 the active form of S-1108, were 3.13, >100, 12.5, <0.013, <0.013, >100, >100, 0.78, 3.13, 0.39, 0.39, 6.25, 100, 100, 0.05 and 50 μg/ml against Staphylococcus aureus, methicillin-resistant S. aureus, coagulase-negative staphylococci, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli CS 2 carrying various R (bla) plasmids, Klebsiella pneumoniae, Proteus mirabilis, Proteus uulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Serratia marcescens, Enterobacter cloacae, Pseudomonas aeruginosa, Pseudomonas cepacia, Xanthomonas maltophilia, Acinetobacter calcoaceticus, ampicillin-resistant Haemophilus influenzae and Bacteroides fragilis, respectively.
S-1006 manifested stronger binding affinity than did cefteram to PBPs of S. aureus, S. pneumoniae and P.uulgaris.
S-1006 was stable to various types of β-lactamases, except for the Ic type of cephalosporinase.
S-1006 manifested marked synergy of its bactericidal effect with serum complemen t. Living cells of E. coli NIHJ JC-2 were well engulfed and digested by mouse- cultured macrophages with more than 1/2 the MIC of S-1006.

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The in vitro activity of S-1006, the active form of a new oral cephalosporin, S-1108, against anaerobic bacteria was compared with other oral cephalosporins, cefteram, cefotiam, and cefaclor. S-1006 had broad spectrum against reference strains of anaerobes, inhibiting many anaerobic bacterial strains at 6.25 μg/ml or less. However, S-1006 showed week activity against Bacteroides thetaiotaomicron, Bacteroides ouatus, Bilophila wadsworthia, Eubacterium lentum, and Clostridium difficile with MICs of 25 μg/ml or more. S-1006 was the most active against fresh clinical isolates. S-1006 exhibited especially strong activity against Prevotella intermedia, Porphydromonas gingivalis, Peptostreptococcus spp., Clostridium perfringens, Mobiluncus spp., and Gardnerella uaginalis, with MIC₅₀s of 0.39 μg/ml or less. S-1006 displayed comparatively strong activity against Bacteroides fragilis, with an MIC₅₀ of 3.13 μg/ml. S-1006 was more stable than cefaclor and less stable than cefteram agai nst hydrolysis by β-lactamases derived from B. fragilis. A 5-day administration of S-1108 induced the emergence of C. difficile in mouse cecum 1 day after completion of administration of the compound, but no or little C. difficile was detected 7 days after completion.

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In this study we tested the in vitro antibacterial activity of S-1006, the parent compound of S-1108, and the in vivo therapeutic efficacy of S-1108, a new orally active ester derivative of S- 1006, against experimental mouse infections in comparison with cefaclor (CCL), cefuroxime (CXM), cefixime (CFIX), cefteram (CFTM), FK-482 and BMY-28100.
S-1006 had a broad antibacterial spectrum against gram-positive and gram-negative bacteria and it's antibacterial activity was almost equal to that of CXM against gram-positive bacteria, and superior to those of CCL and BMY-28100 and equal to that of CFTM against gram-negative bacteria.
In the sensitivity distribution of clinically isolated strains, S-1006 showed weak activity against MRSA and Enterococcus spp. of gram-posittive bacteria, while being similar to CFTM and CXM and superior to CCL and CFIX against Streptococcus spp. The activity of S-1006 against gram-negative bacteria was equal to that of CFTM and superior to that of CCL.
The activity of S-1006 was largely unaffected by the type of culture medium, inoculum size or addition of horse serum, but its activity against S. aureus was enhanced in acidic media.
S-1006 showed dose-related bactericidal activity against all the bacteria tested.
In morphological examinations by phase-contrast microscopy, S-1006 induced the formation of filamentous cells in E. coli KC-14, K. pneumoniae KC-1 and S. marcescens T-55. In one strain of the three P. mirabilis strains tested, S-1006 induced spheroplastlike structures, but did not result in the production of filamentous forms of the bacteria. On the other hand, CFTM and CCL gave rise to filamentous infections in mice, and the therapeutic effects of S-1108 were superior to those of CFTM-PI against gram-positive bacteria and almost equal to those of CCL and BMY-28100 against E. coli and K. pneumoniae of gramnegative bacteria. In S. marcescens T-55 infections in mice, S-1108 was similar to CFTM and FK-482 and superior to CCL and CXM-AX. S-1108 and CXM-AX showed good therapeutic efficacies against A. caloaceticus AC-54, but no other antibiotics tested showed any effects.
In an experimental pulmonary infection with K. pneumoniae B-54 in mice, the therapeutic efficacy of S-1108 was inferior to that of CFIX and similar to that of CFTM-PI.

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The in vitro activity of S-1006, active form of oral cephem antibiotic S-1108, against standard bacterial strains and 1, 464 clinical isolates of bacteria was determined by the agar dilution method and compared with that of cefteram (CFTM), cefotiam (CTM), cefaclor (CCL), and amoxicillin (AMPC).
S-1006 was highly active against staphylococci (excluding strains resistant to methicillin), streptococci, species of Klebsiella, Proteus and Providencia, Escherichia coli, Citrobacter freundii, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis and Peptostreptococcus spp.
It was moderately active against species of Enterobacter, Morganella morganii, Pseudomonas cepacia, Alcaligenes faecalis and Bacteroides fragilis.
However, its activity against methicillin-resistant staphylococci, enterococci, Pseudomonas aeruginosa, Pseudomonas putida, Acinetobacter calcoaceticus, Xanthomonas maltophilia, Flavobacterium spp. and Clostridium difficile was poor. Its overall activity was approximately equal to that of CFTM, its activity against streptococci, species of Proteus, M. morganii, H. influenzae and M.(B.) catarrhalis was superior to that of CTM, its activity against the isolates tested with the exception of enterococci, was superior to that of CCL, and its activity against gram-negative bacterial isolates tested was superior to that of AMPC.
S-1006 did not show cross-resistance with a new quinolone antibacterial agent, ofloxacin.
The bactericidal activity of S-1006 against Streptococcus pneumoniae Type I was slightly superior to that of CFTM, and markedly superior to that of CTM and CCL, and its activity against Escherichia coli NIHJ JC-2 was equal to that of CFTM, and superior to that of CCL, but slightly inferior to that of CTM.

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The therapeutic efficacy of S-1108, a new orally absorbable cephem antibiotic, was evaluated against experimental systemic and local infections in mice and compared with that of cefteram pivoxil (CFTM-PI), cefaclor (CCL) and amoxicillin (AMPC).
In systemic infections with various gram-positive and gram-negative bacteria, including β-lactamase-producing strains, S-1108 showed excellent in vivo activity, reflecting the high in vitro activity of S-1006, the active form of S-1108. S-1108 had a broader antibacterial spectrum against gram-negative bacteria than CCL or AMPC. Compared with CFTM-PI, the antibacterial spectrum and efficacy of S-1108 were found to be almost the same, but its activity against staphylococci and some β-lactamase-producing bacteria, such as Proteus vulgaris and Klebsiella oxytoca, were far better.
The antibacterial activity of S-1108 tended not to be affected by the challenge dose ofbacteria.
S-1108 also exhibited good activity against local infections, such as subcutaneous infection with Staphylococcus aureus, meningitis due to Streptococcus pneumoniae, respiratory tract infection caused by Klebsiella pneumoniae and urinary tract infection with Proteus mirabilis, and its effect was highest among the antibiotics tested against the infections, except for respiratory tract infection.

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S-1108 is an oral cephem antibiotic of the prodrug-type. S-1108 is de-esterified to an active form, S-1006, after being absorbed from the intestine. S-1006 showed high affinity for various cephalosporinases produced by gram-negative bacteria, except the enzyme of cefuroximase, but Vmax values remained very small. S-1006 was hydrolyzed by penicillinases of both the Klebsiella oxytoca and OXA-1 type, but S-1006 showed very low affinity against the enzymes of other the gram-negative bacteria tested, so it was very stable against them.
S-1006 exhibited high affinity for the penicillin-binding protein (PBP)-3 of Escherichia coil K12 as well as affinity for PBP-1a, -1bs and-2. In the case of affinity for the PBPs of Staphylococcus aureus ATCC 25923, S-1006 showed IC₅₀ values of less than 0.2μg/ml for PBPs-1, -2 and-3. This value correlated with the MIC value.

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Phase I studies of S-1108, a new ester-type oral cephem antibiotic, were conducted on 61 healthy male volunteers. In single-dose studies, S-1108 was administered under fasting and non-fasting conditions in various amounts. In multiple-dose studies, 150 mg of S-1108 was administered three times daily for 8 days. Plasma concentrations and urinary recoveries of the active form S-1006 were determined in these studies. The results for tolerance, safety and pharmacokinetic profile of S-1108 in these studies are summarized below.
1. S-1108 was well tolerated and this drug was found to be safe in these studies.
2. Elimination half-lives and urinary recoveries of S-1006 were shown to be almostconstant regardless of dose administered in the single-dose studies. The Cmax and AUC of S-1006 were proportional to the dose, suggesting linearity of the pharmacokinetics of S-1108.
3. AUC and urinary recovery increased significantly when S-1108 was given after a meal, suggesting that absorption of S-1006 under non-fasting conditions is greater than under fasting conditions.
4. No abnormal accumulation or changes in the pharmacokinetic parameters of S-1108 were found in the multiple-dose study.
5. After administration of S-1108, S-1006 and trace amounts of trans-S-1006 were found in the blood and urine. No unchanged S-1108 or other active metabolites were found.

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Pharmacokinetics of S-1108 were investigated in the elderly. The serum Concentrations of S-1006 were determined after oral administration of 100mg and 150mg of S-1108 to ten aged subjects (mean age=76.5±7.4 years). In the 100mg dose group, the maximal serum concentration was attained 2 to 6 hours after administration, and the mean value ranged from 0.56 to 2.16μg/ml (mean=1.12±0.61μg/ml). In the 150 mg dose group, the maximal serum concentration was attained 2 to 6 hours after administration, and the mean value ranged from 0.56 to 2.23μg/ml (mean=1.47±0.65μg/ml). Urinary recovery of S-1108 within 24 hours in the 100mg dose group and in the 150mg dose group was 22.2% and 25.4%, respectively. Thus, the maximal serum concentration of S-1006 in the elderly was nearly equal to that in the adult. However, the half life of S-1006 in the elderly was slightly longer than in the adult. This indicates that the administration intervals of the drug should be longer in the elderly than those in the young.
With regard to carnitine (CRN) metabolism, urinary recovery of CRN within 4 hours in the 100mg dose group and in the 150mg dose group was 35.7μ mol and 226 μ mol, respectively. Serum concentration of CRN 4 hours after administration of 100mg S-1108 and 150mg S-1108 were 63.9±1.9 nmol/ml and 60.4±24.6 nmol/ml, respectively. Additionally, the ratio of acyl CRN to free CRN in serum in the 100mg dose group and the150mg dose group was 0.38 and 0.27, respectively. It therefore appears that CRN body stores are little influenced by S-1108 administration even in the elderly. Moreover, no adverse reactions were observed in any ot the subjects.

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Pharmacokinetics studies of S-1108, an ester-type oral cephem antibiotic, were evaluated in 5 elderly patients (mean aeg: 76y). The plasma concetrations and urinary excretions of S-1006, the active compound of S-1108, were measured after 100mg administration under non-fasting conditions. The peak plasma levels were 1.35-2.60μg/ml at 2-3 hours after administration, and in 2 patients of moderate real failure (mean S-Cr: 2.1mg/dl) the levels were 1.67 and 2.60μg/ml which were higher than those in 3 mind renal failure patients (mean S-Cr: 1.0). The mean C_max, urinary excretions, T1/2 and AUC were 1.73μg/ml, 26.5%, 1.79 hr and 8.18μg·hr/ml, respectively, indicating the adsorptions was delayed a little and urinary excretion was also lower compared with young adult volunteers.

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The aim of this study was to determine the transfer of the antibiotic, S-1108, administered orally, from serum to lung tissue and bile juice. In sixteen patients with lung diseases, 200mg of S-1108 was given just before surgery. In four patients with biliary diseases, it was given about two weeks after cholecystectomy and T-tube drainage. The concentration of S-1006 in serum, lung tissue and bile juice was determined at intervals of 1, 2, 4, 6, 8 and 12 hr after administration of S-1108. The concentration of S-1006 in serum was 0.49μg/ml 1 hour later, reached a maximum of 0.72μg/ml 2 hours later, and gradually decreased to 0.14μg/ml 12 hours later. The mean rates of transfer of S-1108 from serum to lung tissue and bile juice during the 12 hours after oral administration were 44.1% and 548.9%, respectively. S-1108 appeared to be useful for treatment of lung and biliary tract infections.

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Microbiological assay methods were investigated for quantitative determination of S-1108 in body fluids.
S-1108 concentration in body fluids was determined as the concentration of S-1006, the bioactive form of S-1108. The concentrations of S-1006 were assayed by the band-culture, cylinder-plate, agar-well and disc-plate methods using E. coli 7437 as the assay organism and trypto-soy agar (Eiken) as the assay medium. The minimal detectable concentrations for these bioassay methods were 0.01, 0.08, 0.16 and 0.16μg/ml, respectively.
To determine S-1006 levels in human plasma, consera were employed as diluents of the standard solutions instead of pooled human serum. When the urine specimens were diluted more than 10-fold, the standard solution was prepared with 0.1 M phosphate buffer (pH 7.0).
The concentrations of S-1006 in human plasma and urine obtained by the band-culture assay method were in good agreement with those obtained by HPLC analysis.
S-1006 in body fluids was stable at -20°C for at least 28 days.

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A high-performance liquid chromatographic method with ultraviolet detection was developed for determination of S-1006, the active component of S-1108 {Pivaloyloxymethyl (+)-(6R, 7R)-7-[(Z)-2-amino-4-thiazoyl)-2-pentenamido] 3-carbamoyloxym ethyl-8-oxo-5-thia-1-azabicyclo [4. 2. 0.] oct-2-ene-2-carboxylate, hydrochloride, hydrate}, in human plasma and urine. S-1006 and a possible metabolite, δ²-S-1006, were selectively fractionated from plasma or urine on a disposable reversed-phase column. Recovery of both compounds was quantitative, and coefficients of within-day variation were less than 9, 5% and 5, 8% in the concentration ranges of 0.05-2 μg/ml for plasma and 5-200 μg/ml for urine, respectively. Detection limits were 0.02 μg/ml for both compounds in plasma, and 1 μg/ml and 2 μg/ml for S-1006 and δ²-S-1006 in urine. Correlations between this method and microbiological assay were satisfactory for both plasma and urine samples.

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We studied the pharmacokinetics of S-1108, a new esterified oral cephem, in experimental animals. The oral absorption of S-1108 varied from species to species, and bioavailability in terms of ratio of oral/intravenous AUC was 33.7% in mice, 13.6% in rats, 5.7% in dogs and 21.0% in monkeys.
The peak plasma levels (Cmax) of S-1108 after oral administration of 20 mg/kg were 4.7 in mice, 1.8 in rats, 2.3 in rabbits, 1.2 in dogs and 3.6 μg/ml in monkeys, and the corresponding AUCs were 3.4, 5.8, 4.5, 4.4, and 10.6 μg·h/ml, respectively. In mice, rats and rabbits, the plasma levels of S-1108 were lower in comparison with cefteram pivoxil (CFTM-PI), but they were higher than with CFTM-PI in monkeys, and equal to those of CFTM-PI in dogs.
The tissue levels of S-1108 in rats after oral administration were highest the kidney, followed in descending order by the plasma, liver, lung, heart and spleen.
Urinary excretion rates of S-1108 were 7.1% in mice, 22.7% in rats, 23.9% in rabbits, 15.9% in dogs and 16.0% in monkeys.
Biliary excretion rates of S-1108 after oral administration were 2.0% in rats.
Plasma levels of S-1108 after oral administration in the non-fasting state were increased in rats and dogs, but decreased in monkeys.
No antimicrobially active metabolites except S-1006, the bioactive farm of S-1108, were detected in the plasma or urine samples.
The binding of S-1006 to serum protein was 27% in mice, 28% in rats, 62% in monkeys and 46% in humans, and their values were all lower than in the case of CFTM.

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The absorption, excretion and metabolism of S-1108, an ester-type prodrug of S-1006, have been examined in rats and dogs by administering ¹⁴C-labeled S-1108 or S-1006 in a dose of 20 mg/kg.
In non-fasted rats, the plasma concentration of radioactivity after oral administration of [7-¹⁴C]-S-1108 reached a maximum of 2.4 μg equiv./ml 30 min after administration, then decreased with a half-life of 0.8 h until 4 h. The AUC was 7.09 μg equiv.·h/ml. The same maximum concentration time, but lower maximum concentration, 1.7 μg equiv./ml, and smaller AUC, 5.12μg equiv.·h/ml, were obtained in fasted rats.
After oral administration of [7-¹⁴C]-S-1108, 28.1% and 70.8% of th radioactivity was excreted in the urine and feces, respectively, of non-fasted rats, while the corresponding values in fasted rats were 18.4% and 80.5%. Biliary excretion in fasted bile duct-cannulated rats was 7. 8%. The calculated absorption ratio was 40% in non-fasted rats and 25% in fasted rats.
Urinary and biliary metabolites in rats were examined by TLC-autoradiography, and it was concluded that hardly any biotransformation of 5-1006 occurred. The plasma concentration of radioactivity after oral administration of [7-¹⁴C]-S-1108 to fasted dogs reached a maximum of 5.76 μg equiv./ml 1-1.5 h after administration, then declined with a halflife of 17 h. The AUC was 33.0μg equiv.·h/ml. Excretion of radioactivity at this dose was 25.3% in the urine and 70.2% in the feces up to 24 h after administration. When [7-¹⁴C]-S-1108 was administered at 400 mg/kg reduction of the absorption ratio was observed.
Serum protein binding of [7-¹⁴C]-S-1006 in vitro was rather low in all animal species examined and in man, and in vivo binding after oral administration of [7-¹⁴C]-S-1108 to rats and dogs was also low.

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Tissue distribution of radioactivity in male, female and pregnant rats, and its levels in the milk of lactating rats were investigated after single or repeated oral administration of ¹⁴C-labeled S-1108, [7-¹⁴C]-S-1108, to rats.
Tissue concentration in non-fasted rats after a dose of 20 mg/kg was investigated by radioactivity determination and whole-body autoradiographic methods. Maximum radioactivity was obtained 1 h after administration in most of tissues. Excluding the intestinal tract the highest levels were in the kidney followed by the liver. All other tissues and organs exhibited lower levels than in plasma. Radioactivity in these tissues, including the kidney and liver, diminished to very low levels 24 or 48 h after administration. Similar distribution patterns were obtained in both males and females.
Repeated administration of [7-¹⁴C]-S-1108 to rats 15 doses twice a day did not alter urinary or fecal excretion, plasma or tissue radioactivity levels. Nor was any accumulation in tissue observed by whole-body autoradiography.
Placental transfer and secretion of radioactivity into milk after oral administration of [7-¹⁴C]-S-1108 to pregnant or lactating rats were both estimated to be low.

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S-1108 is a novel esterified oral cephem prodrug. When orally administered, S-1108 is hydrolyzed to S-1006 which has antibacterial activity.
The antibacterial activity of S-1006 against 180 clinical isolates of 7 species was determined. The peak MIC against Staphylococcus aureus was 1.56μg/ml, and superior to that of cefaclor (CCL), cefixime (CFIX), cefteram (CFTM) and cefpodoxime (CPDX). Antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii and Serratia marcescens was similar to that of CFIX, CFTM and CPDX, however, there was no antibacterial activity against Pseudomonas aeruginosa.
S-1108 was orally administered to 6 healthy male volunteers immediately after a meal or 30 minutes after a meal in a single dose of 200 mg, and the pharmacokinetic data were measured. The values of the pharmacokinetic parameters when ingested immediately or 30 minutes after a meal were 2.39 and 2.44 μg/ml, respectively, for Cmax, 2.83 and 3.17 hours, respectively, for Tmax, 1.06 and 0.96 hours, respectively, for T1/2, 8.22 and 7.66μg·h/ml, respectively, for AUC, and the urinary excretion recovery rates were 42.6 and 42.8%, respectively, within 10 hours. There were no significant differences in plasma levels or urinary recoveries of S-1006 between the two administration regimens.
S-1108 was administered to 31 patients with respiratory tract infections in doses of 75 to 200 mg t. i. d. for 4 to 15 days. Clinical response was excellent in 1, good in 28, and fair in 2. The overall efficacy rate was 93.5%. Twenty strains isolated from 20 patients were eradicated bacteriologically.
No side effects or abnormal laboratory data were observed in any of the patients.

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Clinical studios on S-1108, a new ester-type oral cephalosporin antibiotic, were performed, and the results obtained are as follows.
1. Concentrations of S-1006 in sputum and plasma were measured in 3 patients with old pulmonary tuberculosis 3 hours after administration of S-1108, 200 mg t. i. d. for 3 days.
Mean sputum levels of S-1006 were 0.11μg/ml after the second dose, 0.10μg/ml after the 5 th dose and 0.16μg/ml after the 8th dose, while the mean plasma levels were 2.01μg/ml, 2.10μg/ml and 2.83μg/ml, respectively.
2. Twenty patients, including 4 patients with bacterial pneumonia, 2 with acute bronchitis, 9 with chronic bronchitis, 3 with infection secondary to bronchiectasis and 2 with infection secondary to bronchial asthma were treated with S-1108 in doses of 100-200 mg t. i. d. for 6-14 days. Clinical efficacy was excellent in 2 patients, good in 17 and fair in 1, and the efficacy rate was 95%. Bacteriologically, 10 strains were isolated from 10 patients, and all strains were eradicated.
3. No side effects were observed. Abnormal laboratory findings consisted of slight elevation of CPK in one patient.

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We measured the in vitro antimicrobial activity, and serum and sputum concentrations of S-1108, a new oral cephem developed in Japan, and evaluated its therapeutic efficacy in respiratory tract infections. The minimum inhibitory concentrations (MICs) of 5-1006, cefixime (CFIX), cefteram pivoxil (CFTM-PI) and cefaclor (CCL) against 20strains each of methicillin-susceptible Staphylococcs aureus (MSSA), methicillin-resistant Stphylococcus aureus (MRSA), Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa were determined, . by the micro-broth dilution method using the Dynatech MIC 2000 system. As shown by the MICs, S-1006 was more active than the others against MSSA, H. influenzae and P. aeruginosa. Against Enterobacteriaceae, 5-1006 was as active as cefteram and cefixime. No agents tested displayed potent activity against either MRSA or P. aeruginosa. The concentration of S-1006 in the serum of the three patients with bronchiectasis was highest 2 to 3 hours after oral administration of 200 mg (2.17, 1.08 and 0.66 μg/ml). Thereafter, the maximum concentrations of S-1006 achieved in sputum were 0.04, 0.06, and 0.03 μg/ml, respectively. Thus, the maximum penetration rates were 1.84, 5.56 and 4.55%, respectively (mean: 3.98%). An oral dose of 300-600 mg of S-1108 was given daily to 25 patients for 5 to 15 days (mean: 9.3 days): 4 with acute bronchitis, 5 with chronic respiratory infections, 14 with acute pneumonia and one each with pulmonary tuberculosis and secondary infection in lung cancer. Three patients were excluded from clinical evaluation because one patient was diagnosed as having active pulmonary tuberculosis and two were seen in the outpatient clinic only once. Clinical efficacy was excellent in 2 patients and good in 20 (efficacy rate: 100%). Nineteen strains were identified as causative organisms: 1 strain of S. aureus, 6 strains of Streptococcus pneumoniae, 6 strains of Branhamella catarrhalis, 3 strains of H. influenzae, 1 strain of K. pneumoniae and 2 strains of P. aeruginosa. Fourteen out of 18 strains against which bacteriological effects could be evaluated were eradicated by administration of S-1108. Diarrhea was observed in three patients. Eosinophilia and elevation of transaminase values were observed in four patients each, but the adverse reactions disappeared after completion of therapy From the above results, we conclude that S-1108 is one of the most useful cephems for oral use as an agent of first choice in the treatment of respiratory tract infections in outpatient clinics.

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Pharmacokinetic and clinical studies of S-1108, a new oral cephem, produced the following results:
1) Pharmacokinetic study
Serum and sputum concentrations of S-1006 were measured in two patients with respiratory tract infection (RTI) who were orally given 100 or 200 mg×3/day for 3 days. Peak serum levels were 1.07.μg/ml 8 hours after administration of the lower dose and 1.56.μg/ml at 2 hr after administration of the higher dose. Sputum levels were undetectable at the lower dose, but at the higher dose, levels peaked at 0.08μg/ml 8 hr after administr ation on Day 1 and at 0.75.μg/ml at 2 hr on Day 3.
2) Clinical study
Ten patients with RTIs (acute pharyngitis 1, pharyngolaryngitis 1, acute bronchitis 2, chronic bronchitis 2, infection of old pulmonary tuberculosis 2, infection of chronic pulmonary emphysema 1 and infection of pulmonary fibrosis 1) were given 100mg×3/day orally for 6-14 days. Clinical efficacy was excellent in 1 patient, good in 7 and fair in 2. Eight of the 9 causative organisms (4/4 S. pneumoniae, 3/3 B. catarrhalis, 1/2 H. influenzae) were eradicated, however, one of the 4 strains of S. pneumoniae was replaced by K. pneumoniae.
No adverse reactions were observed clinically, but slight elevations of GOT, GPT, etc, were detected transiently in the laboratory findings of 5 patients. S-1108 was found to be an effective and useful oral antibiotic for the treatment of RTIs, particularly those caused by B. catarrhalis, S. pneumoniae and H. influenzae.

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The in vitro activity of S-1108, newly developed oral cephem antibiotic, against 400 clinical isolates and its clinical effects were evaluated.
In the evaluation of the in vitro activity of S-1108 against gram-positive bacteria, S-1108 showed strong activity against methicillin-sensitive Staphylococcus aureus (less than 1.58μg/ml against all clinical isolates). Against another 5 gram-positive bacteria, including Staphy lococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae, S-1108 had activity similar to or greater than that of cefteram. Against such gram-negative bacteria as Escherichia coli, Enterobacter cloacae, Haemophilus influertzae, and Citrobacter freundii, S-1108 had activity similar to those of ceftibuten and cefixime.
In the clinical evaluation, S-1108 was given three times a day in daily doses 225-600mg for 4-14 days to 19 patients, 18 with respiratory tract infections and one with urinary tract infection (males, 11; females, 8; age; 16-80 years).
Clinical efficacy was evaluated “excellent” in 7 cases, “good” in 11 cases and “poor” in 1 case.
Adverse reactions, consisted of one case of diarrhea as a side effect, and three cases of slight elevation of GOT and GPT, and one case of eosinophilia among the laboratory test results.

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The antibacterial activity and clinical efficacy of a novel oral cephem antibiotic, 5-1108, were investigated, and the following results were obtained.

1) Antibacterial activity: The activity of 5-1008, a metabolite of S-1108, against clinical isolates of Staphylococcus aureus, methicillin-resistant S. aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Haemophilus influenzae was determined and compared with that of cefaclor (CCL), cefprozil (CFPZ), cefotiam (CTM), cefpodoxime (CPDX), and cefteram (CFTM). The MIC₉₀ of 5-1006 was 1.56μg/ml against S. aureus, which was superior to that of CCL, CPDX and CFTM but inferior to that of CFPZ and CTM, >100μg/ml against methicillin-resistant S. aureus, 12.5μg/ml against S. aureus≤0.05 μg/ml against S. pneumoniae, which was superior to that of the others except CFTM, >100μg/ml against E. faecalis, 0.78μg/ml against E. coli, which was superior to that of CCL and CFPZ but inferior to that of CTM, >100μg/ml against P. aeruginosa and ≤0.05μg/ml against H. influenzae, which was superior to that of the others.
2) Clinical efficacy: The clinical efficacy rate of S-1108 in respiratory tract infections and urinary tract infections was 90.7% (39/43), with the following breakdown: pneumonia 11/12, acute bronchitis 6/6, bronchiectasis 2/2, chronic bronchitis 18/21, pyelonephritis 1/1 and cystitis 1/1. Side effects were anorexia in one patient and diarrhea and abdominal pain in one patient. Elevation of GPT in one patient and GOT and GPT in another patient was noted.

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We stuied the pharmacokinetics and clinical efficacy of S-1108, a new oral cephem, and the following results were obtained.
1) Pharmacokinetics
The influence of meals and probenecid were investigated in 6 healthy volunteers given 200 mg of S-1108 orally, in fasting, and with and without 1.5g of probenecid in the nonfasting-state.
The peak serum levels and AUCs were 1.42, 2.06, 2.74g/ml and 4.80, 7.37, 13.05μg·hr/ml, respectively. These results indicated that absorption was higher in the non-fasting state, and suggested that tubular excretion is involved in the renal excretion of the drug.
2) Clinical efficacy
S-1108 was administered to 11 patients with different infections, i. e., pneumonia (3), bronchitis (4), acute tonsillitis (2), pyelonephritis (1) and appendicitis (1), in doses of 100-200 mg three times a day for 4-13 days. Clinical efficacy was good in 9 cases, and poor in 2 cases. There were no side effects in any of the patients, but abnormal laboratory findings were observed in 2 (Eos. 3→8%, GPT 16→87).

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We determined the serum and sputum concentrations of S-1108, a newly developed oral cephem, in 4 patients with chronic bronchitis, and evaluated its efficacy and safety in 30 patients with respiratory tract infection.
1) Serum and sputum concentrations of S-1108: The concentration of S-1108 in serum reached a peak, 1.43μg/ml, 2 hours after 200mg of S-1108 was administered orally and then gradually decreased to 0.11μg/ml by 6 hours. In sputum, it reached a peak of 0.05μg/ml at 3 hours and the concentration was still 0.04μg/ml at 6 hours.
2) Clinical efficacy: Clinical efficacy was evaluated in 30 patients (13 males and 17 females, 21 to 80 years old) with respiratory tract infections. Different doses f S-1108 were given orally for 4 to 15 days: 100mg×3/days in 12 cases, 150 mg×3 in 6 cases, 200 mg×3 in 12 cases.
Two strains each of Haemophilus influenzae, Streptococcus pnuemoniae, Klebsiella pnuemoniae and Klebsiella oxytoca and one strain each of Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Klebsiella ozaenae and Haemophilus aphrophilus were isolated from the patients' sputum. Eleven of the 12 strains were eradicated by treatment.
The clinical efficacy rate was 100% in the 26 evaluable cases: excellent in 7 and good in 19 cases.
Diarrhea and serum GOT and GPT elevations were observed in one case each. Serum BUN elevations, decrease of leukocyte and proteinuria developed in one case. The other laboratory findings observed were decreased Hb in one case and eosinophilia in two cases.

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The in vitro activity of S-1006, the active free acid of S-1108, a newly developed cephalosporin antibiotic for oral use, was studied by determining minimum inhibitory concent rations by the agar two-fold dilution method. S-1006 was not active against methicillinresistant Staphylococcus aureus but showed excellent activity against methicillin-sensitve Staphylococcus aureus compared with cefteram, cefpodoxime, cefaclor and methicillin. S-1006 was equally active effective Escherichia coli as cefpodoxime and cefixime. S-1006 was more active than cefaclor and less active than cefteram and cefixime against Klebsiella pneumoniae.
Among 4 patients with acute bronchitis, 3 were successfully treated by administration of S-1108, 300mg a day.
Neither significant side effects nor abnormalities of laboratory data were detected after administration of S-1108, except for one case of soft stools.

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S-1108 is a new ester-type oral cephem antibiotic developed at Shionogi Laboratories, We evaluated its activity against clinical isolates and its clinical efficacy.
The MICs of S-1006 against methicillin-sensitive Staphylococcus aureus (MSSA)(9 strains) ranged from 0.8 to more than 100μg/ml, one dilution less active than that of CTM and one or two dilutions more active than that of CCL.
The MICs of S-1006 against Escherichia coli (20 strains) ranged from 0.2 to 12.5μg/ml, almost equal to that of CFIX, and the MICs of S-1006 against Klebsiella pneurnonicte (20 strains) ranged from 0.2 to 6.25μg/ml, and two dilutions less active than CFIX and CTM.
Regarding clinical respones, S-1108 was orally administered in dose of 75-150mg t. i. d. for 6 to 10 days to 7 patients with respiratory tract infection (acute bronchitis in 3 patients, acute tonsillitis in 1, acute pharyngitis in 1, pneumoniae in 1, infection with bronchial asthma in 1).
Clinical efficacy was excellent in 2 and good in 5.
Bacteriologically, S-1108 eradicated one isolate of Haemophilus influenzae andone isolate of Streptococcus pneumoniae.
No side effects were observed throughout the study, however, laboratory tests showed a slight elevation of GPT in two cases, which returned to normal after therapy.
On the basis of these results, we consider S-1108 to be a useful oral cephem antibiotic in the treatment of patients with mild and moderate respiratory tract infections.

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Basic (absorption and excretion) and clinical studies of S-1108, a new oral cephem antibiotic, were performed, and the following results were obtained.
1) Absorption and excretion: S-1108 was administered to 5 patients (Mean age 57.6 years) in doses of 150mg (n=3) and 300mg (n=2).
The peak serum concentrations were 0.76 and 1.53μg/ml, respectively, and half times were 0.99 and 1.25 hours, respectively. The urinary excretion rates were 12.4% and 15.9%, respectively, within 8 hours.
2) Clinical studies: S-1108 was given to 4 patients with chronic respiratory tract infections in a dose of 300mg three times a day for 8-14 days.
The clinical response was excellent in 2 cases and good in 2 cases. The following organisms were isolated (Staphylococcus aureus 1, Branhamella catarrhalis 1, Streptcoccus pneumoniae 1) and 1 case (S.aureus) ilas persisted
No side effects or abnormal laboratory findings were observed.

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We performed clinical studies to evaluate the usefulness of S-1108 in respiratory tract infections. The maximal sputum level of S-1108 was 0.11μg/ml in patient DPB, and the maximal sputum level was 7.8% of the peak serum level. Nineteen patients with respiratory tract infections were studied for clinical evaluation of S-1108, which was administered in doses of 225mg to 600mg daily for 3-14 days. Clinical efficacy was 78.9%, and 6 strains of causative organisms (Streptococcus pneumoniae (1), Streptococcus pyogenes (1), Staphylococcus aureus (1), Kiebsiella pneumoniae (2), and Haemophilus influenzae (1)) were eradicated, and K. pneumoniae were exchanged for Pseudomonas aeruginosa after treatment, respectively.
Based on these results, we concluded that S-1108 is an effective and useful antibiotic for the treatment of respiratory tract infections.

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We performed basic and clinical studies on S-1108, a new oral cephalosporin, in respiratory infections, with the following results.
1, The MICs of S-1006 for causative organisms were measured by the agar dilution method using an inoculum size 10⁸CFU/ml.
The MIC for 15 strains of Haemophilus influenzae was ≤0.1μg/ml; for 15 strains of Branhamella catarrhalis, ≤0.05-1.56μg/ml; for 20 strains of Streptococcus pneurnoniae, ≤0.05-0.78μg/ml; and for 20 strains of methicillin-sensitive Staphylococcus aureus, 0.1-3.13μg/ml.
2. Clinical evaluation of S-1108 in 5 patients with respiratory infections was good in 4 and poor in 1. No adverse reactions nor abnormal laboratory findings were observed in any of the cases.

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We performed bacteriological and clinical studies on S-1108, a new oral cephem antibiotic, with the following results.
1. The MICs of S-1006 against Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis and Klebsiella pneumoniae were 0.063μg/ml and superior to those of cefaclor (CCL), cefotiam (CTM) and cefteram (CFTM). The MIC₅₀ against methicillin-sensitive Staphylococcus aureus (MSSA) was 1μg/ml and superior to that of CCL and CFTM. S-1006, however, was weak against methicillin-resistant S.aureus (MRSA) and Pseudomonas aeruginosa.
2. Thirteen patients with respiratory infections were treated with S-1108. The overall efficacy rate was 69.2% (good in 9, fair in 4). No clinical side effects were observed in any of the patients after treatment. There were 4 patients with laboratory abnormalities (elevation of BUN in 1, eosinophilia and elevation of GOT, GPT and ALP in 1, eosinophilia in 2).

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The clinical efficacy and safety of S-1108, a new oral cephalosporin antibiotic, were studied in 15 patients with pneumonia, and respiratory and urinary tract infections. The drug was given in a dose of 300mg daily for an average of 12.6 days.
The clinical response in 15 patients, 11 with respiratory tract infections and 4 with urinary tract infections, was excellent in 1, good in 13, and fair in 1. The overall efficacy rate was 93.3%(14/15).
No side effects were detected. A mild elevation of serum GPT was observed in 1 patient, eosinophilia in 2, and CK and aldolase elevations in 1.
The pleural fluid concentrations of S-1006 after a single oral 200 mg dose were analyzed in 3 patients with carcinomatous pleurisy. The peak concentration was 0.90 μg/ml (mean level) at five hours after administration. The ratio of mean peak pleural fluid level to mean peak serum level was 0.75 (0.90/1.20), and the penetration of S-1006 into pleural fluid was remarkably good.

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The efficacy and safety of the new ester-type oral cephem antibiotic S-1108 was studied in treating various infections.
There were 20 subjects (13 males and 7 females) ranging in age from 29 to 77 years (mean age: 59.7 years). The target diseases included pneumonia in 5 cases, bronchitis in 2 cases, acute exacerbation of chronic bronchitis in 4 cases, bronchial asthma+lower respiratory infection in 2 cases, bronchiectasis and acute exacerbation of chronic pulmonary emphysema in 2 cases, upper respiratory tract infection in 3 cases, and periproctitis and cystitis in 1 case each, for a total of 20 cases. S-1108 was administered 3 times daily in doses of 100 mg, and the treatment period ranged from 3 to 25 days (mean 10.5days).
S-1108 was judged effective in 14 cases, fair in 3 cases, poor in 2 cases, and in 1 case was unevaluable, for an efficacy rate of 73.7%.
In 7 of the 8 cases evaluated for bacteriological efficacy the bacteria were eliminated. Side effects consisted of dizziness in 1 patient.
No abnormal changes in laboratory findings were observed.

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We performed basic and clinical studies on S-1108, a new oral cephalosporin antibiotic, with the following results.
1) Antimicrobial activity
The MICs of S-1006, the active substance of S-1108, were determined with an inoculum size of 10⁶ cells/ml. The MIC₉₀ of S-1006 was 0.78μg/ml for Staphylococcus aureus, 100<for Enterococcus faecalis, 0.78 for Escherichia coli, 6.25 for Klebsiella pneumoniae, 25 for Enterobacter spp., 50 for Serratia marcescens and Citrobacter freundii, and 100 for Pseudomonas aeruginosa. Its activity against S. aureus was greater than that of the new oral cephems. On the other hand, its activity against gram-negative bacilli was the same as that of the new oral cephems and there were few strains highly-resistant to S-1006.
2) Clinical efficacy
Four patients with pneumonia, 2 with acute bronchitis, 5 with chronic bronchitis, 2 with tonsillitis, and 1 with cystitis were treated with S-1108. The patients were treated with a daily dose of 150-600 mg for 2-40 days. The clinical response was, excellent in 3, good in 5, fair in 3. poor in 1, and unknown in one patient. The efficacy rate was 69.3%. Adverse reactions were dysphoria (1 patient), and swelling of the vulva and nipple (1 patient), but there were no changes in the laboratory findings.

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We investigated the efficacy and safety of S-1108 in 9 patients with respiratory tract infections. Overall clinical efficacy was excellent in 1 and good in 8.
Organisms isolated were identified in 4 patients. Two strains of Haemophilus sp. and one strain of Branhamella catarrhalis were eradicated, but in one patient infected with Pseudomonas aeruginosa+Xanthomonas maltophilia the outcome was unknown.
Mild diarrhea was noted as a side effect in one patient.
Abnormal laboratory data were found in another patient (slight elevation of GOT). S-1108 was administered to 9 patients with respiratory infections in doses of 100 or 200mg, and serum levels were determined at various times after administration. In the patients who received 100mg of S-1108, Cmax was 0.96±0.14 μg/ml, AUC_0-8 4.35±0.65μg·h/ml and T1/2 2.17±0.31h. The oorresponding values obtained with the 200 mg dose were 2.01 ± 0.36 μg/ml, AUC_0-8 7.98±2.16 μg·h/ml and T1/2 1.53 ± 0.23h. These results suggest that S-1108 is useful in the treatment of mild respiratory tract infections.

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A newly developed broad-spectrum cephem, S-1108, was evaluated in vitro and in vivo. The results were as follows.
1. Antimicrobial activity: Minimal inhibitory concentrations (MICs) against 3 standard strains and 298 clinical isolates, including 10 different species, were determined and compa red with three other antibiotics, CFTM, CTM and CCL. S-1006, an active form of S-1108, showed excellent antimicrobial activity against both gram-positive and gram-negative, bacteria, except E. cloacae and P. aeruginosa, and the MICs were the same or greater than those of the other three drugs.
2. S-1006 concentration in serum and sputum Two patients with chronic bronchitis were given 200 mg of S-1108 orally, and its concentrations in serum and sputum were measured at intervals using HPLC or bioassay. The peak concentrations of S-1006 in serum were 2.42μg/ml and 2.94μg/ml, while, the peak concentration in sputum was 0.07μg/ml in the former patient, and the penetration ratio was 2.9%.
3. Clinical efficacy and adverse reactions: Eighteen patients with respiratory tract infections were treated with S-1108, and the overall efficacy ratio was 83.3%(excellent in 3 cases, good in 12, fair in 2 and poor in 1). Adverse reactions were cutaneous pruritus in one patient, anorexia in 1, nausea in 1 and diarrhea in 1. Elevation of CPK was observed in 1 case as an abnormal laboratory finding. All of the above were mild and improved repidly after completion of S-1108 treatment, indicating that S-1108 is a very safe agent.

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The antibacterial activity of S-1108, serum and sputum concentrations, and the clinical effect of S-1108 in bacterial respiratory infections were assessed. The in vitro potency of S-1006 was excellent against 46 strains of Haemophilus influenzae (MIC₈₀: 0.025 μg/ml) and 41 strains of Streptococcus pneumoniae (MIC₈₀:≤0.05 μg/ml) and moderate against 45 strains of Branhamella catarrhalis (MIC₈₀: 0.39 μg/ml), while highly-resistant strains consisted of 54 strains of Pseudomonas aeruginosa (MIC₈₀:>100 μg/ml) and 49 strains of Staphylococcus aureus (MIC₈₀:>100μg/ml). The maximum concentration of S-1006 after an oral dose of 200 mg of S-1108 was 0.94 μg/ml in serum and 0.041μg/ml in sputum. A daily dose of 450 mg to 600 mg for three to seven days were given to 14 patients with respiratory infections. Good outcomes were seen in 71% of the cases treated with S-1108. In those cases, 3 out of the 3 H. influenzae strains, 5 out of the 5 S. pneumoniae strains, and 4 out of the 6 B. catarrhalis strains were eradicated, while eradication failed in one strain of S. aureus. On the other hand two strains of P. aeruginosa superinfected without exacerbating symptoms. There were no severe side effects observed among the patients treated. These results indicate the usefulness of S-1108 treatment of bacterial respiratory tract infections due to H. influenzae, S. pneumoniae and B. catarrhalis.

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We evaluated S-1108, a newly developed cephem antibiotic, for its in vitro antimicrobial activity, serum and sputum levels and clinical efficacy in patients with respiratory infections.
The results were as follow:
1. Antimicrobial activity
The minimum inhibitory concentrations (MICs) of S-1006 against 521 strains of 15 species isolated from clinical material were measured by the standard method designated by the Japan Society of Chemotherapy, and compared with those of cefteram (CFTM) and cefaclor (CCL). S-1006 showed similar or superior activity to other competitive antibiotics against methicillin -susceptible Staphylococcus aureus (MSSA). Streptococcus pneumoniae and Branhamella catarrhalis. Against gram-negative rods and Bacteroides fragilis, it showed almost the same activity as CFTM.
2. Serum and sputum levels
Serum and sputum levels of S- 1006 were measured in three patients with chronic bronchitis after a single 200 mg oral dose of S-1108. The maximum serum levels were 2.1-2.6μg/ml at 2-3h after ad ministration.The maximum sputum levels were 0.11-0.20μg/ml at 2-5h after administration. The ratio of the maximum sputum level to the maximum serum level was 4.4-8.3%.
3. Clinical efficacy in respiratory infections
We administered S-1108 150 mg b. i. d. for 7-14 days to 9 patients. Clinical efficacy was good in 7, fair in 1 and poor in 1. No adverse reactions or abnormal laboratory findings were observed.

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We performed bacteriological and clinical evaluations of S-1108, a new oral cephem antibiotic, with the following results:
1) Antimicrobial activity of S-1108
The minimum inhibitory concentrations (MICs) of S-1108 for total 302 clinicaly isolated strains, were determined and compaired with those of cefteram, cefotiam, cefixime, cefaclor and amoxicillin using the MIC-2000 system.
S-1108 had broad antimicrobial activity against those clinical strains, except MRSA, Enterococcus faecalis, Serratia marcescens, Acinetobacter calcoaceticus and Pseudomonas aeruginosa.
2) Clinical efficacy
S-1108, 100mg×3 (300mg/day), was administered to 3 patients with chronic bronchitis for 7-14 days. Two patients with chronic bronchitis and a patients with bronchiectasis were treated with S-1108 in a dose of 150mg ×3 (450mg/day), for 7-14 days, and S-1108, 200mg-3 (600mg/day), was given to 3 patients with chronic bronchitis for 7-21 days.
Clinical responses were good in 7 patients and fair in one patient.
All strains of Haemophilus influenzae, Klebsiella pneumoniae, Streptococcus pneumoniae and Branhamella catarrhalis were eradicated, but one strain of S. pneumoniae was not eradicated.
There was superinfection by H. influenzae and S. aureus in one case.
No side effects were observed and no abnormally altered laboratory findings were observed.

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To investigate the appropriate clinical dose of S-1108, a new ester-type oral cephem antibiotic, in the treatment of chronic respiratory tract infections excluding diffuse panbronchiolitis, we conducted dose-finding studies using cefteram pivoxil (CFTM-PI) as a reference drug at collaborating institutions. Daily doses were S-1108 450mg (S450 group), S-1108 600mg (S600 group) and CFTM-PI 600 mg (C600 group) divided into three equal doses for 14 days. The clinical responses were as follows
1) The number of patients assessed by the investigator was 55 (S450 group: 19, S600 group: 19, C600 group: 17). The number of patients in which clinical efficacy was evaluated by the committee was 46 (S450 group: 14, S600 group: 17, C600 group: 15). The number of patients in which side effects were evaluated was 55 (S450 group: 19, S600 group: 19, C600 group: 17). The number of patients in which laboratory findings were evaluated was 52 (S450 group: 17, 5600 group: 19, C600 group: 16). The number of patients in which the utility of the drug was reported was 48 (S450 group: 16, S600 group; 17, C600 group: 15).
2) The clinical efficacy rates (“good” or better) judged by the committee were 85.7% for S450 group, 94.1% for S600 group and 73.3% for C600 group, with no significant differences among the three groups.
3) There were significant difference among the three groups with respect to the degree of improvement in cough (C600 group>S450 group) and WBC (5450 group, S600 group>C600 group).
4) The number of patients judged as an elimination of causative organism were 6 out of 7 on S450 group, 7 of 10 on S600 group and 3 of 5 on C600 group, with no significant differences among the three groups.
5) Side effects were observed in 2 patients (10.5%) on S450 group, 2 patients (10.5%) on S600 group and 1 patient (5.9%) on C600 group. Abnormal changes in laboratory findings were also observed in 1 patient (5.9%) on S450 group, I patient (5.3%) on S600 group and 1 patient (6.3%) on C600 group. There were no significant differences among the three groups which regard to either of these items.
6) The satisfactory rate (“satisfactory” or better) judged by the committee was 75% for S450 group, 82.4%(14/17) for S600 group and 73.3%(11/15) for C600 gorup, with no significant differences in incidence among the three groups.
On the basis of these clinical results, we concluded that S-1108, 150mg, three times a day is an appropriate clinical dose in the treatment of chronic respiratory tract infections.

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Fundamental and clinical studies on S-1108 were carried out, and the results were as follows.
1. Antimicrobial activity of S-1006
The MICs against clinical isolates from urine were determined and compared with those of cefixime (CFIX), cefteram (CFTM) and cefaclor (CCL). The antimicrobial activity of S-1006 against Staphylococcus aureus and Staphylococcus epidermidis was superior to that of CFIX, CFTM and CCL. Its activity was similar to that of CFIX and CFTM against Escherichia coli, Klebsiella pneumoniae Proteus mirabilis and indole-positive Proteus spp. Activity against Enterococcus faecalis, Enterococcus faecium, Enterobacter spp., Serratia marcescens and Pseudomonas aeruginosa was low, but similar to that of CFIX and CFTM.
2. Clinical efficacy of S-1108
S-1108 was administered in the treatment of complicated urinary tract infections (UTI) without indwelling catheters, including 1 patient with complicated pyelonephritis and 21 with complicated cystitis, to investigate its therapeutic effect and safety.
Efficacy was judged according to the criteria of the Japanese UTI Committee. The clinical response in the 15 evaluable cases with complicated UTI was excellent in 11, good in 2 and poor in 2, and the overall efficacy rate was 86.7%. Side effects were skin eruption and itching in one of the 22 patients, and no abnormal laboratory findings were observed.
We concluded that S-1108 is a useful drug in the treatment of complicated UTI without a catheter.

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The clinical response of S-1108 was evaluated in 30 male patients with gonococcal urethritis using dosage regimens of single dose of 300 mg (10 patients, including 2 patients with PPNG infection) or for 2 to 4 days (20 patients, including 3 patients with the PPNG) between September 90 and February 91.
In 20 patients on the 100mg t. i. d. for 2 to 4 day regimen, S-1108 eradicated Neisseria gonorrhoeae isolated from the patients, and the clinical efficacy rate was 100%. In 10 patients on the single dose of 300 mg regimen, S-1108 also eradicated the bacteria in 9 cases, while they presisted in one case in which they were identified as non-PPNG, and the efficacy rate was 9/10. No adverse reactions were observed in any patients. The MICs of PCG, CCL, CFTM and S-1006 were determined against a total 29 clinical isolates of N. gonorrhoeae (5 strains PPNG, 24 strains non-PPNG). The MICs of PCG against the 29 strains, ranged from 0.025 to 100μg/ml, and those of CCL ranged from 0.20 to 6.25μg/ml. The MICs of S-1006 and CFTM had a narrower range, 0.02-0.20μg/ml, and were superior to PCG and CCL. Thus, the activities of S-1006 and CFTM were more potent than those of PCG or CCL. Based on these findings, we consider S-1108 to be a useful and safe oral antibiotic in the repeated treatment of urinary tract infections, such as male gonococcal urethritis.

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Forty-six patients with urological infections were treated with the newly synthesized oral cephem antibiotic, S-1108, in daily doses of 150 to 300mg for 3-5 days, and the following results were obtained.
The drug was effective in 95.7% of the 23 patients with acute uncomplicated cystitis after 3 days of treatment and 52.4% of the 23 patients with chronic complicated urinary tract infections according to the criteria proposed by the Japanese UTI committee.
The average levels of the agent in prostatic fluid (PF) 2 hours after a 200mg dose of S-1108 were 0.03μg/ml±0.03μg/ml (n=3).
Neither side effects nor adverse laboratory findings were observed in all cases.

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We evaluated the clinical efficacy of S-1108 in the treatment of urinary tract infection (UTI) and measured the in vitro antibacterial activity of S-1006.
1. The antibacterial activity of S-1006 against clinical isolates from patients with UTI was compared with that of control drugs cefaclor (CCL), cefixime (CFIX) and cefteram (CFTM). The antibacterial activity of 5-1006 was higher than that of the control drugs against gram-positive cocci and similar to that of CFIX and CFTM against gramnegative rods.
2. Six patients with uncomplicated cystitis were treated with S-1108 75mg or 100mg t.i.d., and forty patients with complicated UTI were treated with 75mg, 100mg or 150mg t.i.d. According to the criteria proposed by the Japanese UTI Committee, the overall clinical efficacy of 5-1108 was 81% in complicated UTI and S-1108 was effective in all patients with uncomplicated cystitis.
Urticaria, vomiting and diarrhea were observed in three patients, but diminished soon after the medication was stopped.
Elevation of GPT was noted in one patient and a decrease in WBC and neutrophil count was noted in one patient.
We concluded that 5-1108 is an effective and safe drug for UTI.

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S-1108, a novel oral prodrug of the cephalosporin type, was administered to 26 patients with uncomplicated or complicated urinary tract infection (UTI).
The clinical efficacy in 26 patients with various types of UTI was evaluated by oral ad ministration of 150-300mg three times daily for 3-5 days.
According to the criteria of the Japanese UTI Committee, the overall clinical efficacy rate was 100%(18/18) in acute uncomplicated cystitis or pyelonephritis, and was excellent in 6/6 in complicated UTI.
The bacteriological eradication rate was 100%(26/26). No side effects were observed.
Based on these findings, we consider S-1108 a useful antibiotic in UTI.

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We studied S-1108, a new oral cephem, for its antibacterial activity, absorption and excretion, as well as clinical pharmacology, clinical efficacy and side effects.
1) The in vitro antimicrobial activity of S-1006 was compared with that of ceftibuten and cefteram (CFTM) against 2 gram-positive cocci and 9 gram-negative rods from a total of 483 clinical isolates. Its activity against Proteus mirabilis, Staphylococcus epidermidis, Morganella rnorganii and Proteus vulgaris was clearly superior to that of CFTM. It showed no activity against Enterococcus faecalis or Pseudomonas aeruginosa.
2) Six healthy male volunteers received 100 mg each of either S-1108 or CFTM-PI in the non-fasting state, and serum and urinary concentrations were determined. The serum concentration of S-1006 by bioassay was similar to that of CFTM: Cmax 1.28μg/ml, T_max 1.33h, T_1/2 1.0h and AUC (0-42) 3.86μg·h/ml. The urinary recovery rate within 24 h was 43.7%, which was higher than that of CFTM. The serum concentration of pivalic acid was similar to that of CFTM Cmax 0.546μg/ml, Tmax 3.00 h, T_1/2 2.65 h. The urinary recovery rate of total pivalic acid within 24 h was over 90%. Urinary levels of free carnitine were not very different from those of the controls.
3) Three patients with acute uncomplicated cystitis and 17 patients with chronic complicated cystitis were treated with S-1108, and the therapeutic results were evaluated in accord ance with the criteria proposed by the Japanese UTI Committee. In acute uncomplicated cystitis, the overall efficacy rate was 3/3, while in chronic complicated cystitis, it was 82.4%. In the latter cases, P. aeruginosa and Serratia marcescens persisted after treatment.
No side effects were observed in any of the cases.

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We studied the antibacterial activity and efficacy of S-1108, a new cephem antibiotic, in urinary tract infections.
1) Antibacterial activity: The MICs of S-1006 were measured against 202 clinical isolates of 14 species from urinary tract infections and compared with those of cefaclor (CCL), cefixime (CFIX) and cefterarn (CFTM). In general, the antibacterial activity of S-1006 was almost equal to that of CFIX and CFTM, but superior to that of CCL.
2) Clinical efficacy: According to the criteria of the Japanese UTI Committee, the overall clinical efficacy rate was 84.2%(16/19) for chronic complicated UTI. Bacteriologically, 21 of the 22 strains isolated (95.4%) were eradicated.
3) Side effects: No clinical adverse reactions and no abnormal laboratory findings were observed.

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We studied S-1108, on antibacterial activity and clinical efficacy against urinary tract infections in order to clarify its usefulness for urinary tract infections.
The in vitro antimicrobial activity of S-1006, an active form of S-1108 was assessed against 205 clinically isolated strains (4 species) and compared with those of cefaclor (CCL) and cefixime (CFIX).
The MIC₉₀ of S-1006 was similar to that of CFIX against Escherichia coli and Proteus mirabilis. Against Klebsiella pneumoniae, the MIC₉₀ of S-1006 was superior to that of CCL and inferior to that of CFIX. Against Serratia marcescens, both the MIC₉₀ and MIC₅₀ of S-1006 were superior to those of CFIX.
We-administered S-1108 to 3 patients with acute uncomplicated cystitis (AUC) and 14 patients with chronic complicated urinary tract infections (UTI). According to criteria of the Japanese UTI Committee, clinical efficacy of AUC was excellent in 2 patients, and the efficacy of chronic complicated UTI was excellent in 4 patients, moderate in 1 and poor in 2. No side effects were observed.
Laboratory findings showed slightly elevated GOT and GPT in 1 patient.

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S-1108, a new oral cephem, was administered to 44 patients consisting of 14 patients with acute uncomplicated cystitis, 29 with chronic complicated UTI and one patient with acute prostatitis in appropriate doses of 50 to 150 mg t. i. d. for 3 to 7 days appropriate for these infections.
The results were as follows
1. Nine of the 14 patients with acute uncomplicated cystitis were assessable according to the criteria of the Japanese UTI committee. Clinical efficacy was excellent in 8 and moderate in 1 patients, and the ovevall clinincal efficacy rate was 100%.
2. Twenty eight of the 29 patients with chronic complicated UTI were assessable accord ing to the same criteria. Clinical efficacy was excellent in 8, moderate in 11 and poor in 9 patients. The overall clinical rate was 67.9%. Bacteriologically, 28 of the 37 strains were eradicated. The eradication rate was 78%.
3. The one patient with acute prostatitis was excluded based on the criteria of the Japaese UTI Committee.
4. No adverse reactions were observed in any of the patients. Abnormal laboratory findings were eosinophilia in 1 patient, and elevation of GOT, Na and K in 1 patient. Based on these results, we consider S-1108 highly useful as an oral treatment for acute uncomplicated cystitis and chronic complicated UTI.

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We assessed the antimicrobial activity and clinical efficacy of S-1108, a new oral cephalosporin, and the following results were obtained.
1. Antibacterial activity of S-1108
The antibacterial activity of S-1108 against 10 species of pathogenic isolates from patients with urinary tract infection was assesssed and compared with those of KT-3777, cefaclor (CCL), cefteram (CFTM) and cefotiam (CTM). S-1108 was superior to the other drugs in antibacterial activity against Citrobacter freundii, Enterobacter cloacae, Proteus mirabilis and Proteus uulgaris, Its acfivity against Escherichria coli and Klebsiella pneumoniae was equal to that of CFTM and CTM. The antimicrobial activity of S-1108 against Serratia marcescens and Pseudomonas aeruginosa was not very strong. Staphylococcus spp. and Enterococcus faecalis were generally resistant to S-1108, but some strains of Staphylococcus showed susceptibility.
2. Clinical efficacy
S-1108 was administered orally in daily doses of 75 mg to 150 mg for 3 to 5 consecutive days to 58 patients with genitourinary infections. According to the criteria of the Japanese UTI Cornmittiee, the overall clinical efficacy rate in acute uncomplicated cystitis was 95.5%(20/21), in complicated UTI 80%(20/25) and in gonococcal urethritis 100%(2/2).
3. Bacteriological response
Fifty-three of 59 strains (89.8%) isolated from patients with UTIs including 16 grampositive cocci and 43 gram-negative rods were eradicated.
4. Adverse reactions
No adverse reactions were observed, but abnormal laboratory changes were noted in two patients. Slight elevation of GOT and GPT in one patient and elevation of CPK (77-204) in anrther patient were noted after administration of S-1108.
These data normalized soon after treatment was stopped.

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