The antibacterial activities of CS-807, a new orally absorbable cephalosporin, were compared with those of cephalexin (CEX), cefadroxil (CDX), cefaclor (CCL), amoxicillin (AM PC), cefixime (CFIX), and T-2588. The results are as follows.
1) R-3763, active compound of CS-807, possessed broad antibacterial spectra together with potent activities against both Gram-positive and Gram-negative pathogens, namely, C.freundii, indole-positive Proteus sp., M.morganii, E.cloacae, and S.marcescens insusceptible to CEX, CDX, CCL, and AMPC. Moreover, R-3763 was very active against S.pneumoniae, S.pyogenes, and H.influenzae.
2) The activity of R-3763 was scarcely influenced by changes in pH of medium or co-existence of horse serum in medium, but was slightly affected by an increase in inoculum size.
3) R-3763 showed the potent bactericidal activity (MBC/MIC) against various species of bacteria including β-lactamase-producing strains. Time-kill studies against S.aureus, E.coli, and K.pneumoniae showed potent bactericidal activity of R-3763 at concentrations above the MIC level.
4) R-3763 was highly resistant to hydrolysis by, β-lactamases from various organisms, and its β-lactamase stability was much higher than that of CEX, CDX, CCL, and AMPC.
5) R-3763 showed high affinity for penicillin-binding proteins (PBPs) 1, 3, 4 of S. aureus, and PBPs 1A, 1 Bs, 3 of E. coli.
6) The therapeutic efficacy of CS-807 against experimental intraperitoneal infections caused by Gram-positive cocci such as S.pneumoniae and S.pyogenes, and Gram-negative bacilli was superior to that of CEX, CDX, CCL, and AMPC. In addition, CS-807 was very active against systemic infection caused by S.marcescens, a β-lactamase-producing strain, on which orally available β-lactam antibiotics were not effective.

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CS-807 is an orally active prodrug of an oxime-type cephem antibiotic. The MIC₆₀ of R-3746, the active form of CS-807, were 3.13, 6.25, 0.05, 0.38, 0.2, 0.1, 3.13, 3.13, 6.25, 6.25, 0.1, and 12.5 μg/ml against S.aureus, coagulase (-) staphylococci (CNS), S.pneumoniae, E.coli (R⁺), P. vulgaris, P. rettgeri, C. freundii, S. marcescens, A. calcoaceticus, P. cepacia, ABPC-resistant H. influenzae, and B. fragilis, respectively. Its activity was stronger than that of cefaclor (CCL) and ampicillin (ABPC). CS-807 manifested little activity against P.aeruginosa, MRSA, and Enterococcus spp.
CS-807 showed stronger binding affinity than CCL with PBP 2 of S. aureus, PBPs la, lbs, 2, and 3 of E. coli, PBPs, lb, lc, 2, and 3 of P.rettgeri, and PBP 3 of P.aeruginosa than CCL.
Synergy of bactericidal effect between R-3476 and serum complement was moderate, although the cells of E. coli NIHJ-JC2 and S. aureus 209P were well engulfed and rapidly digested by mouse-cultured macrophages in the presence of higher than 1/8 MIC of R-3746. Good clinical efficacy can be expected of CS-807, if its pharmacokinetics proved good.

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We compared the antibacterial activity of R-3763 (the active form of CS-807) with that of cefaclor (CCL), cephalexin (CEX), cefixime (CFIX), T-2525, amoxicillin (AMPC), ampicillin (ABPC), minocycline (MINO), chloramphenicol (CP), and sulfamethoxazole-trimethoprim (ST), against 1431 clinical isolates (collected Jan. 1985 to May 1987).
The results are as follows.
1) Against S.aureus and coagulase-negative staphylococci, antibacterial activity of R-3763 was almost equivalent to that of CCL, T-2525 and ABPC. CFIX was less active against these strains. R-3763 and other drugs had quite number of resistant strains.
2) R-3763 exhibited potent antibacterial activity against S.pyogenes, S.agalactiae, Group C and G streptococci and S. pneumoniae. Its activity against these organisms was generally equal to those of AMPC and T-2525, and higher than those of CCL and CFIX.
3) Antibacterial activity of R-3763 and other drugs except ABPC was weak against E. faecalis, E. faecium and E.avium.
4) Against B. catarrhalis, R-3763 was stronger than CCL, but was inferior than CFIX and T-2525.
5) Against H.influenzae including ABPC-resistant and CP-resistant strains, R-3763 was most effective, almost all strains being inhibited by MIC values of ≤0.10μg/ml.
6) Against P.mirabilis, P.vulgaris, P.stuartii and P. rettgeri, R-3763 showed strong antibacterial activity. In M.morganii, R-3763-resistant strains were observed more frequently, and ST was stronger than β-lactams.
7) R-3763 showed weak antibacterial activity against glucose non-fermentative gram-negative bacilli, including P. aeruginosa, P. fluorescens, P. putida, P. maltophilia, P. cepacia, A. antitratus, A. lwoffi, A. faecalis, A. xylosoxidans, F. meningosepticum, F. odoratum and F.indologenes. But against A.putrefaciens, R-3763 showed strong antibacterial activity.
8) R-3763 showed weak antibacterial activity against C.perfringens, B.fragilis, and other Bacteroides group bacteria.

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The in vitro and in vivo antibacterial activities of CS-807 (R-3746: active form) were compared with those T-2588 (T-2525), cefixime, cefaclor, and augmentin.
The antibacterial activity of R-3746 against various Gram-negative bacteria, except P.aeruginosa, was the most potent of all the antibiotics tested. R-3746 was extremely stable against various types of β-lactamase from Gram-negative bacilli, and its stability was superior to that of cefaclor.
The therapeutic effect of CS-807 against systemic infections due to β-lactamase-producing bacteria in mice was almost the same as that of cefixime and T-2588, and was superior to that of cefaclor and augmentin. augmentin.

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The in vitro activity of R-3746 a bioactive derivative of CS-807, a new oral cephalosporin, was determined against 38 strains of reference organisms and a total of 152 strains of clinical isolates of anaerobic bacteria by agar dilution technique using GAM agar as basal media. The in vivo activity of CS-807 was also determined against B. fragilis GAI-5562 using rat pouch model.
R-3746 was very active against many kinds of anaerobic bacteria tested and had a very similar spectrum to that of T-2525. R-3746 was more stable than cefaclor (CCL) against the β-lactamase from two strains of B. fragilis tested, and showed stronger activity against B. fragilis than CCL. MIC values were raised by increasing the inoculum size, but were not influenced by the kind of basal medium. The oral administration of CS-807 at a dose of 20mg/kg twice daily for 2 days had no effect on B.fragilis GAI-5562 which was growing exponentially in the rat pouch. The MIC of R-3746 to B. fragilis GAI-5562 was 3.13μg/ml at a concentration of 10⁶ CFU/ml. At 6 hours after the initial administration, a maximal concentration 2.0μg/ml of R-3746 was detected in the aspirate of rat pouch.
The influence of CS-807 on caecal flora of mice was also determined with a special attention to Clostridium difficile. CS-807 was given orally to mice at a dose of 2 mg/mouse for 5 days. Growth of C. difficile was observed on the 1st. day, but not on the 5th day after withdrawal of the compound.

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We compared the in vitro and in vivo activities of CS-807 (R-3763), a new oral cephem antibiotic, with those of cephalexin, cefaclor, cefadroxil, T-2588 (T-2525) and amoxicillin, with the following results.
R-3763 had a broad antibacterial spectrum against Gram-positive and-negative bacteria, and was especially active against S. pneumoniae, S.pyogenes and Gram-negative bacteria. It was also potent against Enterobacter spp., S.marcescens and indole-positive Proteus spp., which were insensitive to older oral cephems. R-3763 showed bactericidal activity at low concentrations. Morphological observation revealed that E. coli and S.marcescens became filamentous, spheroplast-like structures and were lysed relative to the increasing concentration of R-3763.
R-3763 showed relatively high affinity with penicillin-binding proteins (PBPs) 3 and 2 of S. aureus, but a low affinity with PBPs 2' and 4. On the other hand, the affinity of R-3763 with PBPs of E. coli decreased in the order 1A, 3, 2, 1Bs. R-3763 was stable against β-lactamases produced by Gram-negative bacteria.
The therapeutic efficacy of CS-807 in experimental infections in mice was inferior to those of cephalexin and cefaclor against S. aureus, but much superior against S.pneumoniae and Gram-negative bacteria. CS-807 showed ED₅₀ values several times lower than even T-2588, whose antibacterial activity in vitro was similar. CS-807 also produced higher serum levels than T-2588 and cefaclor.

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CS-807 is a new oral cephem antibiotic whose in vitro antibacterial activity we assessed against 529 strains of recent clinical isolates of both Gram-positive and nagative bacteria.
Its activity was compared with those of cephalexin, cefaclor, T-2525, cefixime and amoxicillin. The antibacterial spectrum and activity of CS-807 were similar to T-2525 and cefixime.
Against Staphylococcus aureus (50 strains) it was superior to cefixime and cephalexin, and similar to AMPC, cefaclor and T-2525.
Against Gram-negative bacteria, Escherichia coli (70), Klebsiella pneumoniae (57) and Proteus species (76), it was very superior to cephalexin, cefaclor or amoxicillin but similar to T-2525 and cefixime.
CS-807 was also more active than cephalexin, cefaclor or amoxicillin against Enterobacter aerogenes (53), Enterobacter cloacae (42), Citrobacter freundii (66), Serratia marcescens (60), and Acinetobacter calcoaceticus (55).

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CS-807 is an orally-active third generation cephalosporin antibitic. Its activity compared with those of cefaclor, cephalexin, cefatrizine, amoxicillin and clindamycin. R-3763, the active metabolite of CS-807, had activity comparable to those of cefaclor and amoxicillin. for S.aureus. It was more active than cefaclor, cephalexin, and cefatrizine, inhibiting the S.pneumoniae, S.pyogenes, beta-streptococci, E. coli, K.pneumoniae, K. oxytoca, P. mirabilis, P. vulgaris, M. morganii and H. influenzae, at concentration of≤1.56ug/ml. R-3763 had an activity against S.epidemidis, P.rettgeri, E. cloacae, E.aerogenes and Y. enterocolitica, but not against E. faecalis, P.aeruginosa and beta-lactamase-producing B. fragilis.

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To elucidate the excellent antibacterial activity of CS-807, a new oral cephalosporin, we investigated its mechanism of action, compared with those of several β-lactam antibiotics.
1) R-3763, the active compound of CS-807, was highly resistant to hydrolysis by both penicillinases and cephalosporinases derived from various species of bacteria, but scarcely inhibited the hydrolyzing activity of the enzymes on the substrate.
R-3763 showed low β-lactamase inducing activity against organisms possessing inducible cephalosporinase similar to those of cephalexin (CEX), cefadroxil (CDX), cefaclor (CCL) and amoxicillin (AMPC).
2) R-3763 showed high affinity for PBPs 1, 3 of S.aureus, and PBPs 1A, lBs, 3 of E. coli compared with CEX and CCL.
3) R-3763, at a wide range of concentrations, induced filamentous forms in E. coli and K. pneunzoniae cells, and spheroplast-and/or bulge-like structures were observed.
Cell lysis after exposure to R-3763 was found to be more marked than that after exposure to CEX and CCL.
4) R-3763 showed the synergistic effect with human serum on its bactericidal activity against E. coli, and moreover bactericidal activity was enhanced by co-existence of human leukocyte.

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The in vivo antibacterial activity of CS-807 was evaluated against various experimental infections in mice or rats and compared with that of cephalexin (CEX), cefatrizine (CFT), cefaclor (CCL) and amoxicillin (AMPC). Serum and organ levels of R-3763, the active metabolite of CS-807, in mice and rats were also investigated.
In mice, CS-807 showed good therapeutic efficacy against intraperitoneal infections induced by 32 strains of 13 species of Gram-positive and-negative bacteria, but was not effective against those induced by E.faecalis, B.cereus or P.aeruginosa.
In rats, its efficacy against infective endocarditis induced by S. aureus was almost equal to that of CEX or CCL.
In mice, CS-807 also showed good efficacy against subcutaneous infections induced by 3 strains of S.aureus. Its efficacy against 2 β-lactamase-producing strains was markedly superior to those of CEX, CCL and AMPC.
Against intra-uterine infections in rats caused by E. coli, CS-807 showed better efficacy than CCL.
Its efficacy against E. coli-induced urinary tract infections in mice was equal or slightly superior to those of CEX or CCL.
CS-807 showed better therapeutic effect than CEX and CCL against pulmonary infections in mice induced by 2 strains of K.pneumoniae.
Organ levels of CS-807 in mice and rats were rather good.

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Based on the susceptibility to methicillin and the profile of penicillin-binding proteins (PBPs), we have classified 1, 000 fresh clinical isolates of S. aureus into methicillin-resistant (MRSA) strains and methicillin-susceptible (MSSA) strains. Furthermore, in vitro and in vivo antibacterial activities of CS-807 against MSSA were investigated as compared to those of cephalexin (CEX), cefaclor (CCL), and amoxicillin (AMPC).
1) One thousand strains of S. aureus isolated clinically in recent years were divided into 3 classes on the basis of their susceptibility to methicillin (DMPPC) examined by using two-fold plate dilution method with Mueller-Hinton agar on which a 10⁶ CFU/ml suspension was spotted, followed by incubation at 37°C for 20 h.(1) Strains with DMPPC-susceptibility of 1.56μg/ml retained almost the same susceptibility even by inoculation of 10' CFU/ml or incubation at 30°C.(2) Approximately 30% of strains with DMPPC-susceptibility of 3.13μg/ml showed a greater than four-fold reduction in their susceptibility by change of inoculum size or incubation temperature.(3) Susceptibility of strains to which MIC of DMPPC was more than 6.25μg/ml was decreased markedly by change of inoculum size or incubation temperature.
2) PBP2' fraction specific for MRSA was detected in the strains with DMPPC-susceptibility of more than 6.25μg/ml, while no PBP2' was detectable in the strains with DMPPC-susceptibility of 1.56μg/ml. The strains with DMPPC-susceptibility of 3.13μg/ml, whose susceptibility was influenced by inoculation of 10⁸ CFU/ml or incubation at 30°C, were confirmed to possess PBP2'.
3) From the shift of DMPPC-susceptibility with change in inoculum size or incubation temperature, and from the presence of PBP2' in the resistance mechanism, 270 strains (27%) with DMPPC-susceptibility of more than 6.25μg/ml were demonstrated to be MRSA. The remaining 730 strains (73%) with DMPPC-susceptibility of less than 3.13μg/ml, in which MRSA strains were a little included, were regarded as being MSSA.
4) R-3763, an active metabolite of CS-807, exerted the same in vitro activity as CEX against 730 MSSA strains, and its MIC.0 to those was 3.13μg/ml.
5) CS-807 was found to have a constant therapeutic effect (ED₅₀: 6.8-29.4 mg/kg) on intraperitoneal infections in mice caused by 15 MSSA strains without any relation to their penicillinase (PCase)-production and-nonproduction.
The therapeutic effect of CCL and AMPC on infections by 3 PCase-nonproducing MSSA strains was superior to that of CS-807. Whereas, against the infections by 12 PCase-producing MSSA strains, both CCL and AMPC only displayed an instable therapeutic efficacy.
6) R-3763, CCL, and AMPC exhibited a growth inhibitory effect on about 90% of the PCase-nonproducing MSSA strains after exposure to 2.5μg/ml in a liquid medium. On the other hand, as much as 87% of the PCase-producing MSSA strains had their growth inhibited by treatment with R-3763 at a concentration of 2.5μg/ml, but 25% and only 4% of the MSSA strains treated with the same concentration of CCL and AMPC, respectively, had their growth inhibited.
From the results described above, we have concluded that CS-807 possesses potent in vitro and in vivo activities against S. aureus, except for the DMPPC-resistant strains, without any bearing on PCase-production or-nonproduction.

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Microbiological assay methods were investigated for quantitative determination of CS-807 in body fluids. CS-807 is almost completely metabolized to the active metabolite R-3763 during absorption through the gastrointestinal wall after p.o. administration. CS-807 concentration was determined as the concentration of R-3763.
R-3763 in body fluids was assayed by agar-diffusion microbiological assay using M. morganii IFO 3848, P. rettgeri IFO 3850 and E. coli NIHJ as test organisms. Minimal detectable concentrations for these bioassays were 0.078μg/ml, 0.019μg/ml and 0.156μg/ml, respectively. The inhibition zones of M. morganii IFO 3848 and E. coli NIHJ were more defined than those of P. rettgeri IFO 3850. The assay sensitivity was, however, very high in the case of P. rettgeri IFO 3850.
Standard solutions prepared with human serum, bile and 1% phosphate buffer (pH6.0) were used for the assay of serum, bile and urine samples. R-3763 in serum and urine was sufficiently stable and no reduction in activity was observed after 4 weeks' storage at-20°C.

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The following results were obtained by high-performance liquid chromatography (HPLC) of R-3763, the active metabolite of CS-807, in human serum and urine.
1) We devised a fast, specific and sensitive HPLC method for determining R-3763 in human serum and urine. Deproteinized serum or diluted urine was directly injected into a reverse-phase column.
2) By our HPLC method, R-3763 was efficiently separated without interference from human serum and urine components; good linear calibration curves were obtained.
3) Our HPLC method provided a high degree of accuracy, the determination limit in human serum and urine being 0.1μg/ml and 1.0μg/ml.
4) R-3763 concentrations in serum and urine samples collected from healthy male volunteers following CS-807 administration in Phase I studies was determined by HPLC and bioassay. A good correlation was observed between the results.
5) R-3763 was stable for at least 14 days in human serum and 21 days in human urine when stored at-20°C.

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CS-807, a new cephalosporin for oral administration, is metabolized to an active metabolite (R-3763) by nonspecific esterase in the gut wall.
R-3763 has been shown to have not only potent broad-spectrum antibacterial activity in addition for Enterobacter, Serratia, indole (+) Proteus but also remarkable stability against β-lactamase. The purpose of this study was to determine the safety, tolerance and pharmacokinetic profile of CS-807 (R-3763) following single oral administration (50, 100 and 200mg) and a multiple dosing regimen (200mg, b. i. d. for 14 days) in healthy male volunteers.
The concentrations of R-3763 in plasma and urine were determined by the HPLC method.
The dose-related plasma concentration-time curves were obtained following a single dose (50, 100 and 200 mg) under postprandial administration rather than under fasting condition and also the increased Cmax's, AUC's and cumulative urinary excretion ratio's of R-3763 were observed under postprandial administration. After multiple postprandial administration of CS-807 (200mg, b.i.d.) for 14 days, no accumulation of R-3763 in plasma was found.
The pharmacokinetic parameters of R-3763 obtained under postprandial administration of 100mg CS-807 for Tmax, Cmax, AUC, t1/2 and cumulative urinary excretion ratio were 2.7hr, 1.7μg/ml, 8.7μg·r/ml, 1.8hr and 50.8%, respectively and plasma protein binding was about 30%.
Administration of CS-807 in single or multiple dose regimens had no significant effects on vital signs (blood pressure, heart rate, body temperature) and ECG, and subjective symptoms or clinical laboratory test data in this study. However, some of the hepatic functional laboratory tests (GOT, GPT etc.) showed slight increases after multiple dosing.
The results of the phase I studies of CS-807 show that CS-807 has a relatively long t1/2 and good renal excretion and no significant side-effects which would prohibit the continuation of clinical trials.

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Influence of CS-807 on the human fecal microflora was studied, in 5 healthy male volunteers who were given the drug in an oral dose of 200mg b.i.d. for 14 consecutive days. The total counts of fecal organisms slighly decreased in one volunteer. Enterobacteriaceae and Bacteroidaceae were decreased, but returned to normal soon after the end of treatment. Clostridium difficile was detected in one volunteer at the end of treatment. No diarrhoea occurred in any of the 5 volunteers during the period of study.

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Absorption, distribution, excretion and biotransformation of ¹⁴C-labeled CS-807 was studied after oral administration to Wistar-Imamichi rats, beagle dogs and Cynomolgus monkeys, at the dose of 13mg/kg.
CS-807-¹⁴C was mainly absorbed from the upper part of the small intestine and the absorption rate was approximately 70% in rats. During absorption, CS-807 was rapidly hydrolyzed to its active form, R-3763, by non-specific esterase in the intestinal epithelium, and transferred to the circulatory blood. The plasma concentration of radioactivity was the highest in dogs (23.4μg/ml), followed by rats (8.4μg/ml) and monkeys (3.9μg/ml).
R-3763 was mainly excreted to the urine after being distributed to the kidney, liver, lung, skin or extracellular space in the whole body. Approximately 3% of the dose was excreted in the bile as the active acid.
Bioautography showed that R-3763 was the only active substance in the plasma and urine. Serum protein binding ratio in the human was approximately 40% and was lower than those in the experimental animals.

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¹⁴C-CS-807 was administered orally to rats at a dose of 10mg equiv.of R-3763/kg to study its accumulation, placental transfer, excretion into milk and influence of a diet. The following results were obtained
1) Repeated administration did not show accumulation and retention of radioactivity.
2) In pregnant rats on days 12 and 18 of pregnancy, a little radioactivity was transfered to the fetuses.
3) The concentrations of radioactivity in the milk reached a peak at 4 hr and declined rapidly. The concentration at 24hr was lowe than the detection limit.
4) After single administration to fasting male rats, blood concentrations of radioactivity reached a peak at and declined with a half-life of 0.98hr until nhr. The concentration at 48hr was lower than the detection limit. The blood concentrations in non-fasting male rats did not show marked difference from that in fasting male rats. zu fasting femalm rats, the blood concentrations reached a peak ot zur and declined with uhalf-life of 0.90hr until 6yr The concentration at 48hr was lower than the detection limit, being similar an that ummale rats.
5) After single administration, the urinary and fecal excretion oe radioactivity during zuhr was 58.1% and 38.1% of the dose in fasting male rats, 61.6% and 33.9% of the dose in non-fasting male rats and 55.3% and 42.3% of the dose in fasting female rats, respectively.

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CS-807, a new oral cephem antibiotic, is a pro-drug of R-3763 which has antimicrobial activity. The effect of food on absorption and excretion of CH-807 was studied under three conditions, that is, fasting, after a light meal and after a heavy meal. CS-807 was administered orally to six healthy male volunteers at a dose of 200mg (equimolar to R-3763). The pharmacokinetic parameters of CS-807 were: Cmax values during fasting, after a light meal and after a heavy meal, were 2.1μg/ml, 3.0μg/ml and 2.7μg/ml. Tmax values were 2.7h, 2.6h and 3.5h. T_1/2 was almost the same in all three conditions: 1.8h, 1.8h, and 1.9h.(AUC) ¹² values were 12.5μgh/ml, 16.9μgh/ml and 14.8μgh/ml.
Urinary recovery rates within 12h after administration were 31.7%, 50.2% and 42.1%.
These results indicate that absorption of CS-807 is affected by food intake, namely, the absorption rate after a light meal is higher than during fasting, and almost the same as after a heavy meal.

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Antimicrobial activity of orally administred CS-807 (R-3763) was compared with those of CCL, AMPC, and L-CEX using an in vitro pharmacokinetic system.
The activities of these four drugs were almost the same against S. aureus 209p.
Against E. coli 3229, 200mg of orally administred of CS-807 was more effective than any of the other three drugs. Of the four drugs, all of which eradicated S. pneumoniae 2132, CS-807 was quickest in eradicating the strain.

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CS-807 and T-2588 were administered orally to five healthy adults in a dose of 200 mg fasting and after breakfast; cefixime was given in the same dose but only during fasting. Afterwards serum and urine levels of the drugs were measured by HPLC and compared.
Peak serum levels of cefixime, CS-807 and T-2588 during fasting were 2.5, 2.4 and 1.7μg/ml on average; cefixime had the longest serum retention, followed by CS-807 and T-2588. The highest recovery rate in urine was achieved by CS-807 (33.5%), followed by cefixime (17.8%) and T-2588 (16.6%).
Peak levels of CS-807 after p.c. oral administration ranged from 3.1-4.8μg/ml, being on average. lμg/ml higher than that during fasting. Six hours after administration, however, CS-807 levels were lower than those of cefixime. Peak levels of T-2588 ranged from 2.1-3.0μg/ml. Mean recovery rates in urine were 49.0% for CS-807 and 31.7% for T-2588. These rates were 1.5 and 2 times those during fasting, indicating that absorption is better after meals. Mean T_1/2 before and after meals, calculated using a one-compartment open model, was 2.4 h and 2.1 h for CS-807, 2.1 h and 2.4 h for T-2588 and 3.1 h for cefixime during fasting. The AUC before and after meals was 15.5μg·h/ml and 19.7μg·h/ml for CS-807, 5.9μg·h/ml and, 8.5μg·h/ml for T-2588 and 23.9μg·h/ml for cefixime.
These results indicate that CS-807 and cefixime b.i.d. maintain higher serum levels than three administrations of T-2588 per day.

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Acute toxicity studies on CS-807, a cephalosporin antibiotic for per oral administration, were conducted in RFVL mice and Wistar-Imamichi rats by oral, intraperitoneal and subcutaneous treatments. LD₅₀ values obtained after oral, intraperitoneal and subcutaneous administration were: in mice, more than 8000mg/kg in both sexes; 3502mg/kg in the male and 2535mg/kg in the female; and more than 10000mg/kg in both sexes. In rats, more than 4000mg/kg; more than 4000mg/kg; and more than 2000mg/kg. There were no drug-related changes both in general symptoms and increasing of mean body weights the course of the experiments and any gross findings by autopsy of animals who died during or sacrificed at the end of the experiments. ments.

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The toxicity of CS-807 was evaluated in male and female Wistar rats after administration by gavage for 13 weeks at doses of 30, 80, 200, 500 and 1000mg/kg, followed by 4 weeks' withdrawal and for 1 year at doses of 250, 500 and 1000mg/kg. The results are summarized as follows:
1) No death occurred and no changes in general condition were observed throughout the experimental period except for soft stool early in the treatment or after withdrawal at doses of more than 80mg/kg.
2) No abnormal findings were obtained by urinalysis or ophthalmoscopic examination after a dose of 1000mg/kg.
3) Slight decrease in body weight gain was observed in several groups compared with the controls during treatment, and a transient decrease in body weight was observed soon after withdrawal, but no change was noted in food intake.
4) A dose-dependent increases in cecum weight, which is generally noticed after administration of antibiotics, was noted at autopsy. There were, however, no histopathological abnormalities in organs or tissues after one year's treatment at doses up to 1000mg/kg. We found no abnormalities attributable to the changes in intestinal flora, nor did CS-807 show any toxic effects on specific organs in the rat.

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CS-807 was orally administered to beagles for 1 day (at a dose of 800mg/kg/day), 28 days (100, 200 or 400mg/kg/day) and 6 months (25, 100 or 400rng/kg/day). There were no treatment-related changes in physical signs, body weight, food and water intake, urinalysis, ophthalmoscopic examination, serum chemistry, hematological parameters, fecal occult blood test, liver and renal function tests, gross or histopathological findings. Dosage levels of 800mg/kg/day and 400mg/kg/day were the maximum doses which could be administered singly and serially. From our results, we estimate that the maximum no-effect doses of CS-807 in beagles are 800mg/kg/day for 1 day, and 400mg/kg/day for 28 days or 6 months.

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CS-807 was administered orally to Wistar-Imamichi rats during fetal organogenesis and studied for its influence on dams, the development of embryos and fetuses, and postnatal growth of newborns. The drug was administered successively from day 7 to day 17 of pregnancy at dosage levels of 500, 100 and 20mg/kg.
Result; Soft stool and diarrhea were observed in dams of the 100mg/kg and higher dosage groups. Also, food consumption was significantly decreased and body weight gain was suppressed. However, no effect was observed on the duration of pregnancy, delivery or fostering in any of the groups. As to its influence on embryos and fetuses, the number of caudal ossification centers decreased in the 500mg/kg group. However, neither lethal nor teratogenic effects were observed, nor was any abnormality noted in the postnatal growth of newborns.
Based on the above results, we consider the no-effect dose in dams, concerning general toxicity to be 20mg/kg, concerning reproduction to be more than 500mg/kg. and concerning development of offspring to be 100mg/kg.

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We studied the pharmacology of CS-807 and R-3746, an active metabolite. Cefaclor was used as a reference compound.
The doses of CS-807 administered, orally or intraduodenally, were up to 2000mg/kg in mice and rats, and 1000mg/kg in rabbits, cats and dogs.
The concentrations of R-3746 in vitro were up to 10^-4 or 10^-3g/ml.
On the central nervous system, CS-807 showed no significant effect. Namely, gross behavior, locomotor activity, thiopental-induced anesthesia, electroshock-or bemegride-induced convulsions, and muscle coordination in mice, gross behavior and spontaneous electroencephalogram in rats and body temperature in rabbits were not influenced by CS-807.
On the respiratory, cardiovascular and autonomic nervous systems, CS-807 showed no significant effect. Namely, respiration, blood pressure, heart rate, carotid blood flow, electrocardiogram and blood pressure response to norepinephrine, acetylcholine or carotid artery occlusion in anesthetized dogs, contraction of the nictitating membrane induced by electrical stimulation of the cervical sympathetic nerve in anesthetized cats, and the beat rate and contractile force of isolated guinea pig atrium and papillary muscle were not influenced by CS-807 or R-3746.
Movement and tone of isolated guinea pig tracheal muscle, rabbit ileum, rat was deferens, and pregnant or non-pregnant uterus were not influenced by R-3746. R-3746 showed no spasmolytic effect against acetylcholine, histamine or norepinephrine in isolated guinea pig ileum or rat was deferens.
Gastric secretion in rats was slightly but significantly reduced by an intraduodenal dose of 2000mg/kg of CS-807, though at 500mg/kg no significant effect was observed. Intestinal propulsion and defecation time in mice were not influenced by CS-807.
On the urinary excretion system, an oral dose of 2000mg/kg of CS-807 caused a slight but significant decrease in urine volume and increase in potassium excretion and urine osmotic pressure in rats. At 500mg/kg, a slight increase in urine osmotic pressure was observed.
On the blood, CS-807 showed no significant effect. Namely, haemolysis of human blood, coagulation and platelet aggregation in rats were not influenced by CS-807 or R-3746. Isolated rat phrenic nerve-diaphragm preparation and blood glucose levels in rats were not influenced by CS-807 or R-3746. CS-807 or R-3746 caused neither local anesthesia in guinea pig cornea nor local irritation in rabbit eye mucosa.
As shown above, significant effects of CS-807 were observed only at 2000mg/kg but not at 500mg/kg, which presumably would be 60-120 times the clinical dose (200-400mg/day). This suggests that CS-807 would not cause any serious adverse effects clinically.

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Susceptibility to R-3763, the active free acid of a new oral cephem antibiotic CS-807, was tested in 137 clinical isolates of 6 species using the agar dilution method with an inoculum size of 10⁶ cells/ml. The MIC range of R-3763 was biphasic for S. aureus, and peaked at 1.56μg/ml and at more than 50/μg/ml; it was 0.1-1.56μ/g/ml for E. coli, 0.1-0.78μg/ml for K. pneumoniae, less than 0.39μg/ml (79%) and 3.13-50μg/ml for M. morganii, 0.1μg/ml (93%)->100μg/ml for P. mirabilis and 0.39->100 μg/ml for S. marcescens.
The antimicrobial activity of R-3763 against S. aureus was as good as that of four reference drugs, CEX, CCL, CFT and T-2525, and superior to CFIX. R-3763 against E. coli, K. pneumoniae, M. morganii, P. mirabilisand S. marcescens was superior to CEX, CCL and CFT and almost equal to CFIX and T-2525.
Thirty patients with bacterial infections were treated with CS-807 at a daily oral dose of 200mg or 400mg for 3-14days. Clinical efficacy was excellent in 17, good in 12 and fair in 1. The total efficacy rate was 96.7%. Twenty-three pathogens-principally S. aureus, S. pneumoniae, E. coli and H. influenzae were isolated.
All were eradicated after treatment with CS-807, except one strain of E. coli in a patient with chronic bronchitis. No adverse reactions or abnormal laboratory findings were observed.

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CS-807 was administered to 22 patients with respiratory tract infection (RTI)(acute pharyngitis 1, acute bronchitis 10, pneumonia 1, pneumonia and pyothorax 1, bronchial asthma and infection 1) and urinary tract infection (UTI)(chronic cystitis 2, acute pyelonephritis 3). CS-807 at 200mg or 100mg was administered twice daily. Overall efficacy was evaluated as 77.3%, being 76.5% and 80.0% for RTI and UTI.
Side-effects were: diarrhea in one case. Laboratory abnormalities were: slight eosinophilia, slight elevations of GOT and GPT, and slight increase in BUN and serum creatinine in one patient each.

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The clinical efficacy and the safety of CS-807, a new oral cephalosporin, were studied in 16 patients with bacterial respiratory tract infections. The results obtained were as follows;
1) Efficacy of fourteen patients with respiratory tract infections were estimated. Six of these cases were suffering from bacterial pneumonia, 1 from mycoplasma pneumonia, 2 from an acute exacerbation of chronic bronchitis, 2 from a secondary infection of bronchiectasis and also secondary infection of each one from idiopathic interstitial pneumonia, chronic pulmonary emphysema and bronchial asthma.
2) Two cases were excluded because one was severe underlying disease and the other was symptom of infection was unclear. Isolated organisms were S. pneumoniae (3), S. aureus (1), H. influenzae (3) and P. aeruginosa (1). All strains except one strain of P. aeruginosa were eradicated.
3) Clinical response was good in 11, fair in 2, poor in 1 and unknown in 2 cases.
4) No adverse reactions were observed, but elevation of platelet, mild eosinophilia and transient elevations of serum GPT, BUN and creatinine value were observed in respective patient.
From the above results, CS-807 is considered to be useful oral antibiotic for the treatment of the patients with the respiratory tract infections.

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Pharmacokinetic and clinical studies of CS-807, a new oral cephem, produced the following results:
1) Pharmacokinetic study
Serum and sputum levels of CS-807 were measured in three patients with respiratory tract infection (RTI), who were given 200mg orally. Peak serum levels were 1.85, 2.42 and 3.03μg/ml 6, 4 and 2 hours after administration. At 6 hours the peak sputum levels was 0.10μg/ml in one patient, 0.16μg/ml in the second, and in the third patient no sputum level was detectable.
The ratio of peak sputum to peak serum level was 5.4 and 6.6%.
2) Clinical study
Seven patients with RTI (Chronic pulmonary emphysema 3, bronchiectasis 2, bronchial asthma 1, lung cancer 1) were given 200 or 400mg per day orally for 7-16 days. The clinical efficacy rate was 57.1%. Four of six causative organisms (2/2 H. influenzae, 2/2 β-lactamase positive B. catarrhalis, 0/1 S. aureus, 0/1 P. aeruginosa) were eradicated. No subjective side-effects were observed, though a transient slight elevation of laboratory test values (GOT, GPT, LDH, BUN or γ-GTP) was seen in four patients.
From these results, we concluded that CS-807 is an effective and useful oral antibiotic for the treatment of RTI, particularly if caused by H. influenzae or β-lactamase positive B. catarrhalis.

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CS-807, an ester derivative of R-3763, has been developed in Japan as a new cephem for oral use. We investigated the in vitro antimicrobial activity of R-3746, a sodium salt of R-3763, by broth dilution method using the Dynatech MIC 2000 system, and evaluated its therapeutic efficacy in lower respiratory tract infections.
The minimum inhibitory concentrations (MIC's) of R-3746, cefaclor (CCL), cefixime (CFIX) and amoxicillin (AMPC) against 165 clinical isolates consisting of 20 strains each of S. aureus, B. catarrhalis, E. coli, K. pneumoniae, E. cloacae, S. marcescens and P. aeruginosa, and 25 of H. influenzae were determined.
Results: we found that against S. aureus, R-3746 was more active than CFIX, and as active as CCL and AMPC. Against H. influenzae and B. catarrhalis, R-3746 was somewhat less active than CFIX, but much more so than CCL and AMPC. R-3746 was almost as active as CFIX against E. coli, K. pneumoniae, E. cloacae and S. marcescens. On the other hand, R-3746 was less active against P. aeruginosa, MIC's being above 100/4g/ml against all the strains tested, except one. A daily dose of 200 or 400mg of CS-807 was administered orally to 9 patients: acute bronchitis 1, acute pneumonia 2, infected bronchiectasis 5, and infection in association with pulmonary emphysema 1. Clinical effects were excellent in 1 patient, good in 6, fair in 1 and poor in 1. Six strains of H. influenzae and one each of S. aureus and S. pneumoniae were identified as causative organisms. All were eradicated by CS-807. Neither adverse reactions nor abnormal laboratory data were observed.
From the above results, we conclude that CS-807 is a most useful antibiotic for the oral treatment of lower respiratory tract infections.

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Clinical evaluation of CS-807 was performed in nine patients with acute exacerbation of chronic bronchitis.
They consisted of six males and three females aged from 46 to 74 years old. CS-807 was given orally to four patients in daily doses of 200mg and five patients in daily doses of 400mg in two divided portions. The duration of administration were four days in one patient, seven days in five and 10 days, 11 days and 14 days in one each.
A total of five strains comprising H. influenzae two strains, S. pneumoniae two strains and S. aureus one strain were isolated from the sputum and identified before administration. All strains were eradicated.
The clinical efficacy rate was 88.9%(8/9): Excellent in three cases, good in five cases and poor in one case.
There were no side effects and abnormal findings in laboratory test values in any of the patients.
From the above results, it is concluded that CS-807 is effective, safe and useful new oral cephem.

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CS-807, a new orally absorbed pro-drug of R-3763, was evaluated for its clinical efficacy in five cases of acute bronchitis, one case of chronic bronchitis and 3 cases of acute cystitis.
CS-807 was administered orally at a daily dose of 200mg in two divided doses. The duration of treatment ranged from 5-20 days, and the total dose from 1.0g-4.0g.
The clinical effects were excellent in two, good in six and poor in one case.
Bacteriologically, strains of β-streptococcus, E. coli and S. epidermidis were eliminated.
Neither side-effects nor abnormal laboratory values were observed.
Our results suggest that CS-807 is an effective and safe drug against infectious diseases.

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Basic and clinical studies were performed on CS-807, a newly developed cephalosporin for oral use.
The MICs of R-3763 for 285 strains of 17 species of clinical isolates were compared with those of AMPC, AMPC-CVA and CCL. The antibacterial activity of R-3763 against S. aureus was as high as that of CCL and those of S. pneumoniae and S. pyogenes were comparable to those of AMPC and AMPC-CVA and higher than that of CCL. Against all gram-negative bacilli studied, antibacterial activity of R-3763 was the highest.
In the clinical studies, a daily dose of 200-400mg of CS-807 administered b.i.d.was given orally for 7-23 days to 18 patients including 16 cases with respiratory tract infections and 2 cases with urinary tract infections.
The clinical efficacy rate was 88.2% on 17 patients excluding 1 case who took CS-807 only 1 day because of vertigo.
As side-effects, vertigo was observed in 1 case as stated above. BR>As abnormal laboratory findings related to CS-807, slightly elevated s-GOT, s-GPT and s-Al-P were observed in 1 case and basophilia was observed in 1 case.
In conclusion, CS-807 is an effective antibiotic in the treatment of respiratory tract infections.

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We studied the clinical efficacy of CS-807, a new oral cephalosporin antibiotic in eight patients, three with acute bronchitis, one with chronic bronchitis, one with diffuse panbronchiolitis, two with acute tonsillitis and one with pyelonephritis.
The drug was administered orally at 100-200mg twice a day for 6-14 days.
The clinical results were good in four, fair in two, and poor in two cases.
The causative organisms were eradicated in three, and unevaluated in five cases.
No side-effects were observed, but transient elevation of S-GPT was noted in one case.

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We studied CS-807, a cephalosporin antibiotic, to determine its clinical efficacy and safety by the oral route in five patients with respiratory infection: one case of acute bronchitis, two of chronic bronchitis, one of bronchiectasis and one of diffuse pulmonary bronchitis.
The clinical response was good in four cases, and fair in one. No adverse reaction was noted. From our results, we consider CS-807 to be useful in the treatment of respiratory tract infections.

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We administered CS-807, a new oral cephem antibiotic, to 35 patients with a variety of infectious diseases pneumonia 20, acute bronchitis 4, acute pharyngitis 1, exacerbation of chronic bronchitis 6 and pulmonary fibrosis with infection 1.
Our clinical evaluation was: 3 cases excellent, 27 good, 2 fair and 3 poor. No adverse effect was observed. The transaminase levels were higher than normal in three patients.

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CS-807 was administered in doses of 100-200mg twice daily for 3-30 days, to 16 patients with respiratory tract infections. In acute bronchitis (4 cases), clinical responses was: good in 3 cases and fair in 1 case. In pneumonia (5): good in 4 and poor in 1. In diffuse pulmonary bronchitis (1): good in 1 case. As to adverse reactions, coating of the tongue was observed in one case.

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A new oral cephem antibiotic, CS-807 was administered to 12 patients with respiratory infections, 10 of outpatients and 2 of inpatients. The drug was given a daily dose of 400mg, b. i. d. in 8 patients, 200mg, b. i. d. in 3 patients, and 300mg, t. i. d. in one patient for 5 to 14 days. The clinical result was good in 8 cases and fair in 4 cases. In all cases, normalize of fever, WBC, CRP and ESR, and amelioration of sputum property and decrease of sputum volume were observed in several days after medication. Moreover, in 4 cases with pneumonia marked recovery of chest X-ray findings was found. Bacteriologically, isolates of S. aureus were eradicated in 3 cases and not evaluable in one case, and isolate of H. influenzae was decrease in one case. No side-effect was observed in all cases. Abnormal laboratory values were increase of eosinophile number and slightly elevated GOT, GPT in one case each. None were serious.

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Clinical and adverse effects of CS-807, a new cephem antibiotic, were studied in 15 patients with respiratory tract infections receiving orally 100-200mg b. i. d.
Of these, 1 patient had pneumonia, and 14 had lower respiratory tract infections (bronchiectasis 8, diffuse panbronchiolitis 2, bronchial asthma 3, and pulmonary emphysema 1, as underlying disease).
Clinical effects were: excellent in 1 case, good in 10, fair in 2 and poor in 2.
The efficacy rate was 73.3%.
As to causative organisms, results were: of four strains of S. aureus, three were eradicated and one persisted; two strains each of S. pneumoniae, B. catarrhalis and H. influenzae were all eradicated.
As to adverse effects, stomach discomfort was observed in one case.
Laboratory findings revealed no abnormality.
From these results, we conclude that CS-807 is a useful drug for the treatment of respiratory infections.

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The absorption, excretion and clinical efficacy on CS-807 were investigated and the following results were obtained.
1) Absorption and excretion
Serum levels of CS-807 in six healthy male volunteer reached a peak of 1.97μg/ml 2h after an oral dose of 200mg 30 min after meals and then declined gradually with a serum half-life of 1.9h.
In a pharmacokinetic study of CS-807, cefaclor (CCL) and ampicillin (AMPC), both at doses of 250mg, serum half-life of CS-807 was longer and its AUC was higher.
The 0-12 h cumulative urinary recovery rate of CS-807 was 39.6% and for CCL and AMPC, 62.6% and 48.1% in 0-8 h.
2) Clinical results
CS-807 was administered to five patients with internal infections, at a daily dose of 200mg for 6-15 days. Clinical response was good in all cases. Bacteriologically, all strains of E. coli and P. mirabglis, except S. saprophyticus, were eradicated.
No side-effect or abnormal laboratory value were observed.

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CS-807 is a new oral cephalosporin derivative developed by Sankyo Co., Ltd. We evaluated its clinical efficacy and safety in 18 patients: 6 with upper and 12 with lower respiratory tract infection. The dose was 100mg or 200mg 30 min after meals twice or thrice daily for 3-21 days, so that the total dose was 1.0g-8.4g.
The drug was effective in two cases of acute pharyngitis, four of acute tonsillitis, four out of five cases of acute bronchitis, in two cases of chronic bronchitis, three of bronchiectasis, and two of pneumonia. The total efficacy rate was 94.4%.
Bacteriological efficacy was evaluated in six cases. One each of H. influenzae, (GPR), S. aureus, Enterococcus sp., S. pyogenes and Streptococcus sp. was eradicated, but one each of K. pneumoniae and P.aeruginosa persisted.
No side-effect were found. In laboratory findings, LDH or BUN were slightly elevated in two cases. Our conclusion from these results is that CS-807 is an effective and a safe antibiotic.

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CS-807, a newly developed cephalosporin antibiotic for oral use, was administered to 5 male and 6 female patients with suspected bacteriological infection.
Two patients with acute pharyngitis, 3 with acute tonsillitis, 2 with acute bronchitis, 1 with infected bronchiectasis, 1 with acute cystitis and 2 with acute pyelonephritis were successfully treated with 100mg or 200mg b.i.d. for 4 to 9 days. Out of three patients, no causative organism were isolated before CS-807 administration.
Coagulase negative staphylococci was isolated from a patient with acute cystitis before CS-807 administration and this strain was disappeared after treatment.
No significant side-effect was observed. Slight elevation of serum GPT level was observed in one patients.

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CS-807 was studied clinically in respiratory tract infections: pneumonia 1, acute bronchitis 1, chronic bronchitis 2, secondary infection of pulmonary emphysema 1, socondary infection of bronchiectasis 1, and secondary infection of bronchial asthma 1. All patients were given 100-600mg CS-807 daily for 1-14 days. Clinical efficacy was evaluated as good in 4 cases, fair in 1, poor in 1, and unknown in 1. The clinical efficacy rate was 66.7%. Three patients given a unit dose of 400mg CS-807 were evaluated as showing good clinical effect. The clinical efficacy rate in lower respiratory tract infections was lower than in pneumonia and acute bronchitis. The bacteriological effect in five cases in whom the causative organisms were evaluated was: eradication in two cases, replacement in one, unchanged one and unknown one.
As to side-effects, diarrhea was observed in one case. CS-807 was discontinued immediately, and after three days, the patient had recovered from diarrhea without treatment. No abnormal clinical tests were observed. These results suggest that CS-807 is a useful antibiotic in respiratory tract infections.

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CS-807, a new cephem antibiotic, was administered to 14 patients with respiratory and 5 with urinary tract infections. The patients were given the drug for 3-4 days in a dose of 200-400mg/day.
Clinical efficacy was excellent in 6 cases, good in 11, fair in 1, and undetermined in 1, showing an overall efficacy rate of 94.4%. As to abnormal laboratory findings possibly related to the drug, eosinophilia was observed in one case. No side-effects were found.

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CS-807 was administered to 13 patients with various infections. Good effects were observed in one case of acute streptococcal pharyngitis, one of chronic bronchitis, five of pneumonia, one of secondary pulmonary infection with pneumoconiosis and four of pyelonephritis. In only one case of chronic bronchitis were the clinical effects fair. Causative organisms were isolated from six patients. One strain each of S. pyogenes, P. mirabilis and K. pneumoniae, and two of E. coil were eradicated, but one of P. rettgeri was replaced by P. aeruginosa.
No side-effects were observed. Abnormal laboratory findings were leucopenia, elevation of GOT and GPT in one case, and elevation of GOT and GPT in another. In the second case, the leucocyte migration inhibition test was positive against R-3763.

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We used a new oral cephem antibiotic, CS-807, to treat 26 patients with respiratory and 3 with urinary tract infections, and to evaluate its efficacy and safety. The study was carried out from December 1985 to April 1986. The patients consisted of 17 adult males and 12 adult females, aged 29-95, the mean age being 67.8.
CS-807 was given b.i.d. at 100mg or 200mg to the patients with respiratory tract infection, and similarly at 50mg or 100mg to the patients with urinary tract infaction. Therapy lasted from 3.5-17 days and the total dose was 0.4-5.6 g.
The therapeutic effect was good in 21 patients, fair in 3, and undetermined in 5, with a high efficacy rate of 87.5%. An adverse reaction was diarrhea in one case, and laboratory tests revealed GOT elevation in two cases. These findings were slight, however, and disappeared immediately after withdrawal of the drug.

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We evaluated the clinical efficacy and safety of CS-807 in 16 patients with respiratory tract infections: two with tonsillitis, two with acute bronchitis, eight with acute exacerbation of chronic bronchitis, and four with bronchiectasis.
The clinical response was excellent in 2 cases, good in 11 and fair in 3; the clinical efficacy rate being 81. 3%. The clinical response of the 200mg b.i.d. group was better than that of the 100mg b.i.d. group.
As to adverse reactions, GPT was slightly elevated in one case, but this normalized in a week following withdrawal.

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1) Antibacterial activity: the MIC of R-3746 against clinically isolated bacteria was measured and compared with those of cephalexin (CEX), cefaclor (CCL) and amoxicillin (AMPC). Against 27 strains of E. coli, R-3746 showed a distribution of 0.1-25μg/ml with a peak of 0.39μg/ml, and against 27 strains of K. pneumoniae a distribution of 0.05-0.2μg/ml with a peak of 0.2μg/ml. Against both, antibacterial activity of R-3746 proved superior by 2 steps and 4-5 steps, compared with CCL and CEX. Against 27 strains of P. mirabilis, R-3746 showed a distribution of 0.05-50μg/ml with a peak of 0.05μg/ml an antibacterial activity superior to CCL and AMPC by five steps. Against 27 strains of P. vulgaris, R-3746 showed a distribution of 0.05-50μg/ml with a peak of 0.1μg/ml, and against 27 strains of M. morganii, it showed a distribution of 0.1-25μg/ml with a peak of 0.2μg/ml. Against 27 strains of Serratia, it showed a wide distribution of 0.1-100μg/ml and more. Against P. vulgaris, M. morganii and Serratia marcescens, R-3746 was antibacterial, compared with CEX, CCL and AMPC.
2) Clinical study: CS-807 was used in the treatment of 24 cases: 10 of pneumonia, 4 of acute bronchitis with underlying pulmonary disease, 9 of acutely exacerbated chronic airway infection and 1 case of middle-lobe syndrome. All cases, except the last, were evaluted for clinical efficacy. Twelve males and 12 females, aged 37-78, were given a daily dose of 0.2-0.4g (b.i.d. or q.i.d.) for 4-15 days (average 11.5). Clinical effects were: better than good 78.3% and better than fair 91.3%. Adverse effects observed were diarrhea and abdominal pain in one case. Abnormal clinical values observed were increase in eosinophilia in one case, decrease in leukocytes in two and elevated GOT and GPT in one case, all of which were, however, moderate.

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We undertook basic and clinical studies on the new oral cephem CS-807, and obtained the following results.
1) Serum levels reached a peak 4h after administration of 200mg to healthy adults: the mean peak level was 2.8ug/ml, and the mean halflife 1.6h. When CS-807 was administered to elderly subjects, serum levels reached a mean peak of 2. 9/ig/ml after 6h, and the mean halflife was 3.3h.
2) Mean recovery rates in urine up to 24h after administration were 51.5% in healthy adults and 25.6% in the elderly.
3) In the clinical evaluation of 30 patients (urinary tract infection 24, respiratory tract infection 5, and sepsis 1), excellent, good, fair and poor responses were seen in 1, 19, 6 and 4 patients, showing an efficacy rate of 66.7%.
4) As to bacteriological efficacy, 24 of 36 strains (66.7%) were eradicated, among them E. coli, K. pneumoniae, Enterobacter and P. mirabilis.
5) Rash occurred in one patient. Abnormal laboratory findings were anemia and thrombopenia, increased GOT and GPT, increased Al-P, and increased BUN in one patient each. All of these findings abated after discontinuation of treatment with CS-807.
These results suggest that CS-807 is a useful drug for the treatment of infections in elderly patients, especially for urinary tract infections.

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CS-807, a new cephem antibiotic for oral use, was evaluated for its antibacterial activity, absorption and clinical efficacy.
The following results were obtained:
1) Antibacterial activities: MIC₈₀s of CS-807 for clinically isolated S. aureus (27 strains), P. mirabilis (21), E. coli (66), K. pneumoniae (34), S. marcescens (19), and E. cloacae (6) were 6.25, 0.1, 0.39, 0.1, 25, and 1.5μg/ml, respectively.
2) Clinical results: CS-807 was administered to 14 patients (bacterial pneumonia 6, chronic bronchitis 6, acute bronchitis 2) at a dose of 200-400mg b. i. d. for 5-14 days. Clinical efficacy was assessed as good in four of six cases of bacterial pneumonia, four of six cases of chronic bronchitis and one of two cases of acute bronchitis.
No adverse effect attributable to the drug was observed, except a slight elevation of GOT, GPT and Al-P values in one case.

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