The antimicrobial activity of a new oxacephem antibiotic 6315 -S (flomoxef), wasbacteriologically evaluated by comparison with latamoxef, cefmenoxime, cefotaxime and ceftazidime.
It was stronger against. Gram-positive bacteria than any other third-generation cephem, being the most effective against methicillin-resistant S. aureus, but as weak as the other drugs against E. faecalis.
As regards Gram-negative bacteria, 6315-S exhibited an MIC similar to that of cefotaxime against E. coli and K. pneumoniae but had weaker activity against P. mirabilis, P. vulgaris, and M. morganii than did the other drugs. It affected P. rettgeri more strongly than did ceftazidime, but slightly less actively than other drugs. Against P. stuartii, it showed stronger activity than did latamoxef, cefmenoxime and ceftazidime.
All strains of P. aeruginosa were resistant to 6315-S, with MIC's of over 100 μg/ml.
Although relatively stable against most β-lactamases, 6315-S was inactivated by the β-lactamase produced by E. coli 35 (Richmond type I).
In experimental mouse infections, 6315-S showed superior therapeutic effects against S. aureus, E. coll., and K. pneumoniae infections.
In mice with mixed infections caused by E. coli and B. fragilis, the lowest ED₅₀ among the drugs tested was that of 6315-S. This may be owing to 1) the slight difference in MIC'S of 6315-S against E. coli and B. fragilis and 2) the long-standing serum level of the compound in mice.

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6315-S (flomoxef) is a new, broad-spectrum, semisynthetic oxacephem compound. Its antibiotic activity against 1, 313 clinical isolates was determined in comparison with those of latamoxef (LMOX), cefotiam (CTM) cefotaxime (CTX) and cefbuperazone (CBPZ). Assays were performed by the serial 2-fold agar dilution technique with inocula added by means of a multiple inoculator apparatus (Sakuma Co., Ltd., Tokyo). With the exception of P. aeruginosa, X. maltophilia and P. cepacia, 6315-S showed potent antibacterial activity against standard strains of Gram-positive and Gram-negative bacteria, including B. fragilis and C. difficile. Notably, most major Gram-positive pathogens were more susceptible to 6315-S than to LMOX, CBPZ, CTX and CTM. 6315-S also showed potent bactericidal activity against clinical isolates of E. coli and S. aureus strains. The stability of 6315-S to various β-lactamases was determined by spectrophotometry using penicillin G and cephaloridine as standards. It proved to be stable to penicillinases, cephalosporinases (CSase) and oxyiminocephalosporinases (CXases) type I, but was slightly hydrolyzed by CSase produced by E. cloacae and CXases type II.
In vivo antibacterial activity of 6315-S was determined by treating systemic infections of mice with E. coli ML 4707, K. pneumoniae GN 6445 or S. marcescens GN 7577, and was approximately equal or slightly less active than LMOX and CTX. Against S. aureus infection, however, it was approximately 16-and 4-times as active as LMOX and CTX, respectively.

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6315-S (flomoxef) is a new parenteral broad-spectrum oxacephem possessing strongantistaphylococcal activity. It is effective even against methicillin and cephem-resistant S. aureus (MRSA).
The MIC's of 6315-S against 22-58 clinical isolates of S. aureus, (MRSA), S. epidermidis, β-streptccccci, S. pneumoniae, E. coli (carrying R plasmids), K pneumoniae, P. mirabilis, P. vulgaris, P. rettgeri, M. morganii, S. marcescens, E. cloacae, A. calcoaceticus, C. freundii, H. influenzae and B. fragilis were 0.39, 6.25, 3.13, 0.78, 0.2, 0.1, 0.1, 0.2, 0.39, 0.39, 3.13, 6.25, 100, 50, 3.13, 1.56, and 1.56 respectively.
6315-S manifested stronger binding affinity to PBP's of S. aureus than CMZ, and equally, high affinity to PBP's of E. coli and S. marcescens as did LMOX. Its binding affinity to PBP's of P. vulgaris and A. calcoaceticus, however, was slightly weaker than that of LMOX.
6315-S was highly stable to all types of penicillinase (IIb, III, IV and V) and cephalosporinase (Ia and Ic). Ki values of 6315-S for those enzymes were rather low.
6315-S showed good bactericidal synergy with serum complement and cultured mousemacrophages.

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6315-S (Flomoxef: FMOX), a new oxacephem cephalosporin, showed a broad spectrum of antibacterial activity against Gram-positive and Gram-negative anaerobic bacteria, including the β-lactamase producing Bacteroides fragilis group and Clostridium difficile.
Its in vitro activity was much stronger than that of CER, CTM, CMX, CMZ, CPZ, CTX, LMOX, CFX and CTT.
It was also resistant to hydrolysis by β-lactamase derived from B. fragilis.
6315-S was the most effective of all the antibiotics tested against intra-abdominal sepsis in mice due to B. fragilis and E. faecalis.

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The in vitro and in vivo antibacterial activities of 6315-S (flomoxef), a new semisynthetic oxacephem antibiotic, were compared with those of cefotiam (CTM), cefmenoxime (CMX) and latamoxef (LMOX). The following results were obtained.
6315-S had a broad antibacterial spectrum against Gram-positive and Gram-negative organisms. Its antibacterial activity was more potent than that of CTM, CMX and LMOX against Staphylococcus aureus, and excellent against β-lactam-resistant Staphylococcus aureus. On the other hand, against Gram-negative bacteria it was superior to that of CTM and equal or only a little inferior to that of CMX and LMOX.
Its antibacterial activity was not affected by the pH of the medium, the addition of horse serum and by inoculum size.
6315-S showed dose-related bactericidal activity against all the bacteria tested.
It also showed a high affinity for (in descending order) PBP 2, 4 and 3 of S. aureus and for PBP 3, 1 A and 1 Bs of Escherichia coli. In a morphological examination of E. coli by phase contrast microscope, exposure to 6315-S resulted in the formation of filamentous cells, spheroplast-like structures and lysis.
Against intraperitoneal infections with β-lactam-resistant or-sensitive S. aureus in mice, the therapeutic efficacy of 6315-S was superior to that of all other antibiotics tested. Moreover, against experimental systemic infections in mice it was almost equal to that of CTM against Streptococcus pyogenes and E. coli, similar to that of LMOX against Klebsiella pneumoniae, superior to that of CTM and only slightly inferior to that of LMOX against Serratia marcescens and Morganella morganii.
Against experimental subcutaneous infections (abscess) induced by β-lactam-resistant S. aureus, the therapeutic efficacy of 6315-S was superior to that of CTM, CMX and LMOX.

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6315-S (flomoxef) is a new semisynthetic oxacephem antibiotic for parenteral use. It proved highly active in vitro against a broad range of Gram-positive and Gram-negative bacteria. These include staphylococci and most Enterobacteriaceae which are resistant to earlier β-lactarn antibiotics.
The susceptibility of clinical isolates of pathogens was tested by the agar dilution method and compared with those of cefazolin (CEZ), cefotiam (CTM), cefmetazole (CMZ), cefotaxime (CTX) and latamoxef (LMOX). A majority of the tested strains of Gram-positive cocci other than enterococci were inhibited at doses of 6315-S lower than 0.78 μg/ml, showing activity similar to CEZ and superior to CMZ, CTX and LMOX. Additionally, methicillin and cefazolin-resistant S. aure.us (MRSA) were generally susceptible to 6315-S at concentrations of 0.78 to 6.25 μg/ml, but only a small portion of MRSA were resistant. Among Gram-negative bacteria, clinical isolates of Branhamella catarrhalis, Escherichia coli, Klebsiella spp., the Proteus group, Alcaligenes, Moraxella and Haemophilus influenzae were susceptible to less than 0.78μg/ml of 6315-S. 6315-S was as effective as LMOX and moreactive than CMZ and CTM against many strains of Gram-negative bacilli other than glucose-nonfermentative bacteria. Bacteroides fragilis and Clostridium difficile were susceptible to less than 6.25 μg/ml of 6315-S. Bacteria susceptible to 6315-S were killed by those MIC's. Medium pH, medium variation, serum supplement and inoculum size of bacteria influenced the antibacterial effectiveness of 6315-S only marginally.

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6315-S (flomoxef), an oxacephem antibiotic, was active against methicillin-resistant Staphylococcus aureus (MRSA), against which cefazolin (CEZ) showed poor activity. Since MIC distribution of 6315-S against 137 strains of MRSA had two peaks, the strains were divided into two groups, L-MRSA (83%) and H-MRSA (17%), against which MIC's of 6315-S were less than 6.3μ g/ml and more than 12. 5μg/ml, respectively. H-MRSA strains were resistant to all other β-lactam antibiotics tested. MRSA strains produced PBP-2', which is associated with bacterial resistance, and the amount of PBP-2' was large in H-MRSA and small in L-MRSA. Although 6315-S, as well as the other β-lactams, showed no affinity at up to 30μg/ml for PBP-2', its ability to induce PBP-2' of penicillinase-producing L-MRSA was very low as compared with those of CEZ, Ceftizoxime, latamoxef and cefmetazole. This characteristic seemed to contribute to the antibacterial activity of 6315-S against L-MRSA. On the other hand, deletion of penicillinase-plasmid from L-MRSA increased PBP-2'production 8-fold. Never-theless, parent and penicillinase-negative variants showed similar susceptibility to 6315-S. This non-correlation between susceptibility and amount of PBP-2', suggests that 6315-S hassome unidentified function in its antibacterial activity against LMRSA. In some L-MRSA strains, penicillinase was involved in the bacterial resistance to CEZ at 37°C, as shown bysynergism between clavulanic acid and CEZ. 6315-S was stable against penicillinase, which also contributed to its activity.

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A new oxacephem antibiotic, 6315-S (flomoxef), was stable against penicillinases of both Staphylococcus aureus and Gram-negative bacteria and cephalosporinase of Proteus vulgaris, while it was hydrolyzed by cephalosporinases of other Gram-negative bacteria, though the hydrolysis rates were low.
6315-S bound to the PBP's-la, -1b, -3, -4.-5 and-6 of E. coli K12. It showed high affinity especially for PBP's-1 a and-3. In this respect it was comparable to latamoxef (LMOX), and both antibiotics had similar antibacterial activity against E. coli.
6315-S and cefazolin (CEZ) showed similar affinity for PBP's-2 and -3 of S. aureus ATCC 25923 and both antibiotics had the same MIC. In addition, 6315-S showed high affinity for PBP-4 while CEZ did not. On the other hand, the affinity of 6315-S for PBP-3 was about ten times higher than that of LMOX and cefotaxime (CTX) and about three times higher for PBP-2 than that of LMOX. This might relate to the anti-staphylococcal activity of 6315-S which is four and sixteen times stronger than that of CTX and LMOX, respectively.

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The preventive effect of 6315-S (flomoxef), a new parenterally active oxacephem antibiotic, against experimental infections in mice was compared with those of latamoxef (LMOX), cefotaxime (CTX), cefotiam (CTM), cefmetazole (CMZ) and cefazolin (CEZ).
6315-S showed excellent in vivo activity against intraperitoneal infection caused by a wide variety of bacteria, reflecting the high in vitro activity of this compound Against Grampositive bacterial infections, the therapeutic activity of 6315-S was 5 to 40 times greater than that of LMOX, but equivalent or slightly inferior to LMOX and CTX against Gram-negative bacterial infections. Against infections with CEZ-resistant Staphylococcus aureus, 6315-S was found to be significantly more active than CTM, CMZ or CEZ, although itsactivity was rather low against infections caused by other strains of S. aureas.
The in vivo activity of 6315-S varied with regimen. Early treatment and frequent administration enhanced its preventive effects strikingly.
Furthermore, 6315-S exhibited potent activity in treatment of mouse infection models such as urinary tract infection caused by E. coli or CEZ-resistant S. aureus and respiratory tract infection caused by K. pneumoniae.

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Assay methods, using E. coli 7437, to measure serum and urine levels of 6315-S (flomoxef), an oxacephem derivative, were established.
Trypto-soy agar inoculated with 2×10⁶ colony-forming units (CFU) per ml proved a suitable medium for the assay. The smallest detectable concentrations of 6315-S were as low as 0.1, 0.3, 0.8 and 0.1 μg/ml by cylinderplate, agar-well, disc-plate, and band-culture assays, respectively. Concentrations of 6315-S were determined by plotting inhibition zones on a standard calibration curve.
To determine 6315-S levels in human plasma, equal amounts of Moni-Trol I or Gonsera were used as diluents of the standard in place of pooled human serum. A 0.1M phosphate buffer (pH 7.0) was used for the standard solution, in which the urine specimens were diluted more than 10-fold.
Concentrations of 6315-S in plasma (n=414) and urine specimens (n=603), obtained from a study using healthy volunteers, were measured by this method and by HPLC assay. The results were compared and no significant differences found.

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We performed three assays for individual determination of 6315 -S (flomoxef) and its metabolite, 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol (HTT), and simultaneous determination f 6315-5, HIT and another metabolite, 6315-S oxide, in human plasma by high-performance liquid chromatography (HPLC).
In each method, after protein precipitation with methanol, the clear supernatant was stored in an ice bath and then placed on HPLC within 1 h. Well resolved chromatograms without superposition of any endogenous components were obtained. Detection limits of 6315-8, HTT and 6315-S oxide were 0.5μg/ml, 0.1μg/ml and 0.1μg/ml plasma, respectively. Correlations between the individual assays and a simultaneous assay of 6315-S and HTT were satisfactory, and excellent linear calibration curves were obtained for both compounds. Concentrations of 6315-S oxide in plasma from volunteers to whom 6315 -S had been administered were below the detection limit.
We also carried out two assays for simultaneous determination of 6315-S and HTT, and individual determination of 6315-S oxide in human urine.
In each method, after defreezing, the urine samples were stored in an ice bath until filtered and placed on HPLC within 4 h. Thoroughly resolved chromatograms were obtained in both assays. Detection limits of 6315-S, HTT and 6315-S oxide were 2μg/ml, 2μg/ml and 0.5 μg/ml urine, respectively. Good linear calibration curves were obtained for those also.

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6315-S (flomoxef), an injectable oxacephem antibiotic newly developed by Shionogi Research Laboratories, was examined for transfer to bone tissue in dogs. The results obtained were as follows:
1) 6315-S was injected i. v, to the anesthetized dogs at a dose of 40 mg/kg. Pharmacokinetic analysis of the serum concentrations using a two-compartment model showed that the halflife of 6315-S was approximately 0.7 h.
2) Tmax values of concentrations in cancellous and cortical bone were calculated to be 4 min and 15-20 min respectively using the parameters obtained by pharmacokinetic analysis. These values suggest that 6315-S can be transferred quickly to bone tissue.
3) Cmax values of concentrations in cancellous and cortical bone were also calculated to be 70 and 10μg/ml respectively.
These results suggest that 6315-S is useful in clinical therapy for bone-tissue infections caused mainly by Gram-positive cocci.

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A study was conducted on 6315-S (flomoxef), a new oxacephem, to test its ability to penetrate into the cerebrospinal fluid (CSF) after i.v. single-dose administration of 100 mg/kg to rabbits with experimental S. aureus meningitis.
Two series of experiments were performed usings 6 rabbits each.
Mean drug concentration in the CSF peaked 30 min. after administration in both series and was 6.07±0.44 in the first and 3.33+0.40μg/ml in the second.
The percentage ratio of maximum CFS concentration to maximum serum concentration was 1.81% in the first series and 1.52% in the second. The percentage ratio of the area under the curve (AUC) for CSF to that for serum was, in the first and second series: 2.7% and 2.80% in 15-60 min, 3.92% and 4.65% in 15-120 min, and 4.61% and 5.96% in 15-180 min. The ratio of half-life in CSF to that in serum was 2. 60 and 4.44.
Drug concentrations in serum and CSF were lower in the second experiment, but the difference between the two experiments in terms of ratio of penetration into CSF and serum was not significant.
From these results, we consider the penetration of 6315-S into the CSF to berelatively low in comparison with other beta-lactams. However, since this agent's serum-binding rate is twice as high in rabbits as in humans, a higher drug-concentration in human CSF may be possible. Nevertheless, before determining whether 6315-S can be used for the treatment of human meningitis, we need to gather and analyze further data on its penetration into human CSF.

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6315-S (Flomoxef), a new parenteral oxacephem antibiotic, was administered to mice, rats, rabbits, dogs and monkeys at doses ranging from 20 to 100 mg/kg, and the time courses of distribution in various body fluids and tissues and of excretion were studied.
After oral administration of 6315-S little absorption was noted. After i. v. injection biological half-life in blood plasma was 16, 11, 29, 50 and 32 min respectively, in the abovementioned species. These values were significantly lower than those of LMOX in all the species except mice. Plasma concentrations of 6315-S in monkeys after i. m. injection reached a peak in 15 min and decreased at a rate similar to that after i. v. administration. 6315-S was rapidly distributed to various tissues in rats with a half-life similar to that of the plasma levels. Concentrations were higher in the liver and kidneys, but lower in the lungs, heart and spleen. The drug penetrated into CSF fluid in rat pups and attained a level of % one-tenth that in plasma. Concentrations of 6315-S in the exudate of inflamed granuloma pouch in rats reached a peak at 2 h and declined slowly maintaing higher levels than in plasma. Protein-binding in serum varied according to species and was highest in rabbits (84%), intermediate in mice, humans, and monkeys (37-32%) and lowest in dogs (8 %).
Biliary excretion of 6315-S was high in rodents (i. e. 22% in mice and 48% in rats), but the drug was eliminated largely via urine in the other (animal) species tested. Since plasmalevels were prolonged significantly in rats and monkeys, by predosing probenecid tubular secretion as well as glomerular filtration appear to be the mechanism of renal elimination. One active metabolite was detected in bile and urine of some animals, but its amount was only 12 % of the dose given. This metabolite was identified as the S-oxide of 6315-S, which is only a quarter as active as 6315-S.

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The distribution, metabolism and excretion of 6315-S (flomoxef) were studied in male rats using two kinds of ¹⁴C-labeled compounds (7-¹⁴C-6315-S and 3-¹⁴C-6315-8).
After i. v. administration of each labeled compound at 20 mg/kg, unchanged 6315-S wee eliminated rapidly from plasma with T1/2 β of c. 11 min and a total body clearance of 19 ml/kg/min. Plasma concentration of 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol (HTT), one of the metabolites of 6315-5, was notably low, but it disappeared more slowly than 6315-S. When 7-¹⁴C-6315-S was administered, unknown radioactive metabolites decreased more slowly than 6315-S or HTT from plasma.
In intact rats, urinary recovery of radioactivity within 72 h was 65. 7% after 7-¹⁴C-6315-Sinjection and 82. 4% after 3-¹⁴C-6315-S injection. Unaltered 6315-S was excreted main by in urine and 22% of the dose was excreted as HTT in the case of 3-¹⁴C-6315-S injection. On the other hand, urinary recovery in bile-duct cannulated rats was 74. 8% with 7-¹⁴C-6315-S and 65. 5% with 3-¹⁴C-6315-S, while only 7. 2% of the dose was recovered as HTT with the 3-¹⁴C compound. Biliary excretion of radioactivity was 23-32% in both labeled compounds, most radioactivity. being excreted as 6315-S, while excretion of HTT was very small. From these excretion profiles, we suppose that 6315-S is transported via bile to the intestinal tract where it is partly decomposed to HTT which is then reabsorbed and excreted in urine.
adioactive intensity in tissues by whole body autoradiography was in the order: kidney>liver>connective tissue>blood, lung, skin>pancreas, spleen, thyroid, hypophysis, bone marrow and others. Radioactivity in all tissues declined rapidly with administration of both compounds, but disappearance of 7-¹⁴C-6315-S was slightly slower.
TLC survey detected a small radioactive spot corresponding to 6315-S oxide as another metabolite. We detected yet another radioactive spot corresponding to des-HTT 7-¹⁴C-6315-S: We did not, however, elucidate their structures.

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Tissue distribution of ¹⁴C-6315-S in male and in pregnant rats and its concentration in the milk of lactating rats were investigated after a single or repeated i. v. administration.
Radioactivity was rapidly distributed throughout the body after a single i. v. administration of 20 mg/kg ¹⁴C-6315-S, and the highest concentration at 5 min was in the kidney (288.9 μg equivalent of 6315-S/g) followed by plasma (67.2), liver (59.7), lung (36.1), heart (12.5) and other tissues. Thereafter, the levels of radioactivity decreased rapidly to below 1μg/g at 24 h in all tissues tested, indicating that the drug has no tendency to accumulate.
Radioactivity in various tissues shortly after the last dose in repeated administrations (20mg/kg ¹⁴C-6315-S once daily for 7 days) was comparable to that after single administra-, tion, but 2-5 times higher at 24 hr after the last dose. However, since its trough level was below 1 μg/g at 168 hr, accumulation obviously did not occur.
Daily excretion of radioactivity in urine and feces under repeated administration was nearly constant: 65% of each dose in urine and 35% in the feces, indicating that the excretion rate was unaffected by repeated administration.
When ¹⁴C-6315-S was administered to pregnant rats, less than 5% of the radioactivity found in the maternal plasma appeared in the fetal tissues at 5 min. When 20 mg/kg 6315-S was was administered to lactating rats, the radioactivity in milk was almost the same or lower than that in plasma.

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The mechanism of renal excretion of 6315-S (flomoxef) was studied in beagles and rabbits by stop-flow analysis and renal clearance methods.
In dogs, total excretion of 6315-S into urine was c. 104% of that estimated for glomerular filtration (GFR). The stop-flow pattern of 6315-S showed no peak corresponding to the paminohippuric acid (PAH) peak which is an indicator of proximal tubular secretion. However, a trough corresponding to the PAH location appeared after pre-treatment with probenecid. This observation suggests that there is bidirectional transport of 6315-S in the proximal tubules and that probenecid inhibits secretion, resulting in a trough due to reabsorption.
In rabbits, total excretion of 6315-S into urine was c. 794% of that estimated for GFR, The stop-flow pattern showed a peak which corresponded to PAH and the peak disappeared, with probenecid-treatment.
These results indicate that renal excretion of 6315 -S takes place primarily through glomerular filtration in beagles. In rabbits, however, 6315-S is excreted mostly by renal tubular secretion.

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Intravenous acute and one-month subacute toxicity studies of 6315 -S (flomoxef), an oxacephem antibiotic, were carried out in rats. In the acute toxicity study, LD₅₀ values of 6315-S were 7.4 and 8.6 g/kg for males and females, respectively. These values were about 2. 5 times those of cefazolin (CEZ), a reference compound. Main toxic signs at lethal doses of 6315-S were exhaustion, ataxia, dyspnea and tono-clonic convulsions, and most deaths occurred within 30 min after administration. At autopsy, edema and congestion of the lungs were seen in all dead animals. These toxic signs, course of death and pathological changes were similar to those found in CEZ-treated rats.
In the subacute toxicity study using dose levels of 750 mg/kg, 1, 500 mg/kg and 3, 000 mg/kg of 6315-S and 1, 500 mg/kg of CEZ, the 6315-S-treated rats showed transient depression within 5 min at 1, 500 mg/kg and sedation, ptosis and ataxia up to 40 min after 3, 000 mg/kg.Soft stools were seen in rats of all drug-treated groups throughout the dosing period. Mortality was 1/20 for the 1, 500 mg/kg group of 6315-S and 8/20 for the CEZ group.
Cecal enlargement without histological changes was seen in all drug-treated rats. Adrenal weight increased in the 3, 000 mg/kg group and some glands showed cortical hemorrhage and necrosis. Local irritation at the injection site in the tail was seen in many rats, including the controls, being more frequent in the 1, 500 and 3, 000 mg/kg groups of 6315-S and the CEZ group than in the control group.
These results indicate that in rats 750 mg/kg/day of 6315-S is a non-effect dose from the toxicological point of view.

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Intravenous acute and subacute toxicity studies of 6315-S (flomoxef), a new oxacephem antibiotic, were conducted in beagles.
Acute toxicity study: Dogs received as a single i. v. infusion 1, 250 mg/kg, 2, 500 mg/kg or 5, 000 mg/kg, of 6315-S or 1, 250 mg/kg, or 2, 500 mg/kg of CEZ as a reference compound. They tolerated 6315-S up to 5, 000 mg/kg, while one of three dogs died after administration of 2, 500 mg/kg of CEZ. Toxic signs were salivation, vomiting and defecation during and immediately after infusion of 6315 -S or CEZ, these signs being more prominent in the CEZ-treated dogs. An other finding was hematuria, which was observed in the dogs treated with 2, 500 mg/kg or more of 6315-S.
Subacute toxicity study: Dogs received 0 (saline), 250 mg/kg, 500 mg/kg or 1, 000 mg/kg of 6315-S, or 1, 000 mg/kg of CEZ i. v. for one month. All dogs tolerated treatment withboth substances. Salivation, vomiting and defecation were observed in those receiving 1, 000 mg/kg of 6315-S or CEZ.
Hematological examination revealed a decrease in platelet count and prolonged clotting time in a few dogs receiving more than 500 mg/kg of 6315-S or 1, 000 mg/kg of CEZ, but the changes were slight and dose-unrelated. The main histological finding was inflammatory reaction at the injection site of all dogs, including the saline-treated group.
The results showed that the maximum tolerated dose of 6315 -S in the acute toxicity study was more than 5, 000 mg/kg and the maximum no-effect dose in the one-month toxicity study was 250 mg/kg/day.

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Adult beagles (4 or 6 per sex per dose group) were given daily i. v. doses (via the cephalic vein) of 6315-S (flomoxef) at 200, 400 and 800 mg/kg/day, the last in divided doses. These groups were compared to the control group, given saline, and dogs dosed with cefazolin sodium (CEZ) at 800 mg/kg/day. All dogs were dosed for 13 weeks, followed by a recovery period of 4 weeks for two males and two females from the group that received 800 mg/kg/day 6315-S.
1) A female dog receiving 800 mg/kg/day 6315-S was killed during week 13 for humane reasons. The dog exhibited severe anemia, subdued behavior and reduced food consumption. There was a body weight loss of 500g during the final 3 days. Liver and spleen weightswere increased. The principal histological findings were extramedullary haemopoiesis and increased haemosiderin deposits in the liver and extramedullary haemopoiesis in the spleen.
2) There were no adverse effects of treatment with 6315-S on weight, food consumption, in;Rphthalmoscopy, auditory function tests or electrocardiographic parameters.
Serum cholesterol and phospholipid concentrations were increased at all dose levels, as was serum alkaline phosphatase. Serum triglycerides and activated partial thromboplastin times were increased at 400 mg/kg/day and at 800 mg/kg/day. Values relating to red cell parameters (RBC, Ht, Hb, MCHC) were lower for animals receiving 800 mg/kg/day for 12 weeks.
Liver weights were increased at 400 mg/kg/day and 800 mg/kg/day, kidney weights were also increased after 800 mg/kg/day. Increased haemosiderin deposits in liver and extramedullary haemopoiesis in liver and spleen were not seen in any dogs which received 6315-S and survived. For dogs which received the reference compound (CEZ) at 800 mg/kg/day, a similar pattern was observed as for those given 6315-S at the same dose. Additional findings were decreased SGPT concentrations and total reducing substances in urine. All differences between controls and those receiving 6315-S showed evidence of reversibility after 4 weeks' withdrawal of treatment for dogs which had received 800 mg/kg/day. We therefore conclude that the maximum non-effect dose of 6315-S was 200 mg/kg/day.

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A chronic toxicity study of 6315-S (flomoxef), a new oxacephem antibiotic, was carried out by administering the compound to rats i. p. once daily for six months at doses of 200, 400, 800 and 1, 600 mg/kg/day. All rats showed abdominal enlargement and loose stools during the administration period.
At autopsy, increased cecal size was observed in all 6315-S treated groups. Mechanical damage in some organs and in the skin at the injection site was also seen in all groups, including controls. A slight increase in renal and adrenal weight was observed, particularly in the higher dosage groups. A slight decrease in ovarian weight was observed in the highest dosage group. Histologically, a number of female rats which had no corpora lutea and hyperplasia of the mammary gland increased in comparison with the control group. In all groups, no remarkable changes were found in hematological examination and urinalysis.
Apart from the increased cecal size and loose stools, the maximal no-effect dose is considered to be 400 mg/kg/day.

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A chronic intravenous toxicity study of 6315-S (flomoxef) was carried out in beagles dosed with 100 mg/kg, 200 mg/kg or 400 mg/kg/day for 6 months.
All dogs of the 6315-S treated groups survived throughout the experimental period without showing any toxic signs other than occasional vomiting in the 400 mg/kg/day dose group. There were no significant group differences in body-weight changes and values relating to hematological parameters; but one male receiving 400 mg/kg/day of 6315-S gained slightly less body weight and showed slight anemia as compared with the control males.
Liver weight in the 400 mg/kg/day dose group increased slightly without any accompanying pathological alterations.
The animals recovered from all of these slight changes after cessation of administration.
Apart from the local irritative effect in the injection sites, the maximum non-effect dose is considered to be 200 mg/kg/day.

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The general pharmacological activity of 6315-S (flomoxef) was studied using various animal species and compared with those of LMOX, 6315-S oxide and hydroxyethyltetrazolethiol (HTT), (two metabolites of 6315-S). The drugs, at 25% concentration, were injected i. v. at a rate of 1 or 5 ml/min.
Intravenous injection of 6315-S to mice caused slight sedation at more than 1 g/kg and decreased spontaneous motor activity at more than 1.75 g/kg. In dogs, 6315-S at more than 0.25 g/kg produced vomiting in relation to dose and rate of injection. In rats, the drug slightly lowered the pyrexia induced byE. coli anti-serum, but in intact rabbits, it had no effect on rectal temperature. In mice and rats, 6315-S had no noticeable effects on the central nervous system and the neuromuscular junction. In anesthetized cats, 6315-S at a dose of 1 g/kg slightly lowered blood pressure and decreased heart-rates, but did not affect the autonomic nervous system. Also, 6315-S did not affect the isolated right atrium of guinea pigs. 6315-S at doses over 0.25 g/kg increased the stomach movement of rabbits, but displayed no significant effects on the passage of a charcoal in the small intestine of mice or in isolated ileum preparations from rabbits and guinea pigs. Doses over 1g/kg slightly decreased uterine motility of pregnant and nonpregnant rats. At the same dose, it slightly decreased urinary Cl excretion in rats. Doses of 0.3g/kg for 8 days to rats decreased the amaunt of bile excreted, but not the secretion of bile acids, cholesterol and phospholipids.
In conclusion, the general pharmacological activity of 6315-S was less than that of LMOX and the same as or higher than those of 6315-S oxide and HTT.

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The effects of 6315-S (flomoxef), a new oxacephem antibiotic on fertility and reproductive performance of Sprigue-Dawley rats were compared with those of rats given CEZ. The daily doses employed were 400, 800 and 1, 600 mg/kg for 6315-S and 800 mg/kg for CEZ. These compounds were injected i. v. to male rats for 9 weeks and to female rats for 16 days prior to cohabitation. The administration regimens to male and female rats were continued during the cohabitation period and, additionally, to impregnated females during the early stage of pregnancy until day 7 of gestation. All pregnant females were autopsied by Cesarean sectionon day 21 of gestation to investigate fetal growth. In male rats treated with 1. 600 mg/kg of 6315-S or 800 mg/kg of CEZ (over a long period), a slight but significant depression of body weight gain was observed during the latter half of the administration period. In female rats, however, body weight slightly increased in comparison with the control group. Food consumption of all groups significantly but transiently decreased at the beginning of administration, but increased thereafter. No effect of 6315-S or CEZ was observed on sexual cyclicity, mating, fertility and other pregnancy performance in female rats. Placental weight decreased slightly but fetal parameters such as gross appearance, viability, and body weight were all normal in the females given 6315-S or CEZ. No defects considered to be owing to the action of 6315-S or CEZ were observed in visceral and skeletal specimens of the fetus. Autopsy of male and female rats revealed marked enlargement of the caecum. These results indicate that 6315-S has no adverse effects on the reproductive performance of male and female rats, although body weight gain was depressed in male rats at the highest dose of 1, 600 mg/kg. Accordingly, the no-effect dose for reproductive performance is considered to be 1, 600 mg/kg/day or more.

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The effects of 6315-S (flomoxef), on Sprague Dawley dams, fetuses and pups were compared with those of cefazolin sodium (CEZ). The 25%(W/V) solutions of the antibiotics were given i. v. once daily for 11 consecutive days beginning on day 7 of pregnancy at doses of 0 (saline, control), 800, 1, 600 and 3, 200 mg/kg/day of 6315-S, or 800 mg/kg/day of CEZ. About 2/3 of the pregnant rats in each group were autopsied on day 21 of pregnancy to examine viability, intrauterine growth and anomalies of fetuses. Skeletal examinations were done on half of le fetuses in each litter after staining with alizarin red-S. Visceral examinations were carried out on the remaining fetuses in each litter by Wilson's freehand section method. Twelve pregnant rats in each group were allowed to deliver and nurse their pups. The pups were examined for viability, growth, development, reflex functions, skeletal system (soft X-ray), behavior (water T-maze and open-field tests), puberty (vaginal opening and penile type), and reproductive performance.
Neither adverse effects on fetal viability nor teratogenic potential were observed in fetuses of the 6315-S groups. Since no dose-related but significant retardation of intrauterine growth of fetuses was found in the 6315-S groups, a supplemental study was done by treatment with low doses of 6315-S. The results showed that the maximum no-effect dose of 6315-S for the intrauterine growth of fetuses was 200 mg/kg/day. Gestation period, parturition and nursing behavior of the mother rats given 6315-S were normal. Body weight gain of newborn pups was suppressed in 6315-S groups in the 1st week, and the suppression continued till about the 10th week in male pups of the 3, 200 mg/kg-treated group. However, the viability, development, reflex and behavioral parameters, sexual maturation, and reproductive performance of the pups born from the 6315-S treated mothers were all normal, suggesting that the suppression of body weight gain in the 6315-S groups exerted no adverse effects on any of the parameters examined. There was no essential difference in the effects attributable to the different treatments in groups given equivalent doses of 6315-S and CEZ.

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In Jcl: SD rats, the effects of 6315-S (flomoxef) on F₀ mothers and offspring in the peri-and post-natal period were compared with those of cefazolin (CEZ) as a reference drug. The antibiotics were administered i. v. to F₀ mother rats once daily from day 17 of gestation through day 20 of lactation at daily doses of 0 (saline; control), 400 mg/kg, 800 mg/kg and 1, 600mg/kg of 6315-S, and 800 mg/kg of CEZ.
Body weight gain in F₀, rats given 1.600 mg/kg of 6315-S and food consumption in all F₀. rats given 6315-S decreased in late pregnancy, but increased during the lactation period. The gestation period, delivery and nursing behavior were normal in F. rats given 6315-S. When F₀ rats were killed on day 21 of lactation, the day of weaning, the weights of the cecum with its contents were higher for the groups given 6315-S.
No adverse effects attributable to 6315-S were found in viability, growth and differentiation, behavior and functions, and reproduction performance in F₁ rats. Intrauterine growth and viability were normal, and no compound-related anomalies occurred in F₂ fetuses of all 6315-S groups. In postpartum observation until weaning, viability and growth and differentiation were normal in F2 pups of the 6315-S groups. There were no qualitative differences between the treatment with 6315-S and that with CEZ for the parameters examined.
The maximum no-effect dose of 6315-S in the peri-and post-natal study is suggested to be 1, 600 mg/kg/day for F₁ and F₂ offspring, although this dose slightly affected body weight gain and food consumption of F₀ rats.

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Immunological properties of a new oxacephem antibiotic agent, 6315-S (flomoxef), and its main metabolite, 6315-S oxide, were studied in animals using latamoxef sodium, penicillin G potassium, cephalothin sodium and cefmetazole sodium as reference compounds.
1. Immnnogenicity.
Immunogenicity of unconjugated antibiotic agents was examined using the corresponding coni4gates with guinea pig serum albumin as polyvalent eliciting antigen. When emulsified with Freund s complete adjuvant, cephalothin and cefmetazole produced active sensitization for anaphylactic shock and IgG, antibodies in the guinea pig. Also in the mouse, these two antibiotics produced IgE antibodies. However, 6315-S and 6315-S oxide as well as penicillin G and latamoxef did not produce these tissue-sensitizing antibodies in either animal species. Enzyme-linked immunosorbent assay for total antibody activity, including tissue-sensitizing and non-sensitizing antibodies, confirmed these results ; definite antibody formation being observed only against cephalothin and cefmetazole.
2. Hypersensitivity-eliciting antigenicity.
Unconjugated cephalothin and cefmetazole provoked PCA and anaphylactic shock in guinea pigs presensitized to homologous antibiotic haptens. In addition, cephalothin, cefmetazole and penicillin G elicited PCA in rats sensitized with mouse IgE antibodies. Again, 6315-S and its metabolite as well as latamoxef lacked the hypersensitivity-eliciting antigenicity.
3. Immunological cross-reactivity.
6315-S and 6315-S oxide haptens did not cross-react with the four reference antibiotic haptens in active anaphylactic shock in the guinea pigs and PCA in the guinea pig and rat.
4. In vitro direct Coomb s reaction
6315-S did not induce in vitro direct Coomb's reaction of human erythrocytes even at the high concentration of 40 mg/ml, while cephalothin and penicillin G caused a positive reaction at 5-20 mg/ml and at 20-40mg/ml
From these results, it can be concluded that 6315-S and its metabolite are immunologically inactive in animals.

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The nephrotoxic potential of 6315-S (flomoxef) was evaluated in four male rabbits after a single i. v. administration at 1, 000mg/kg (via the V. retroauricularis), and compared with that of cefazolin sodium (CEZ). The effects on urinalysis and plasma chemistry parameters were determined. Histological examinations of kidney tissues of all animals were performed after 72 h.
6315-S, produced foci of proximal tubular necrosis without showing any adverse effects on urinalysis or plasma chemistry parameters.
On the other hand, CEZ caused a marked increase in BUN and creatinine, and all animals showed moderate or severe necrosis in proximal tubules accompanied by protein and casts in.urine.
The data indicate that 6315-S has less nephrotoxic potential than CEZ, a compound which does not produce significant nephrotoxicity in human chemotherapy.

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Subcellular localization of several enzymes participating in alcohol metabolism was studied using rat liver. Alcohol dehydrogenase (ADH) activity was detected in cytosol, while aldehyde dehydrogenase (ALDH) activity was detected mainly in both mitochondrial and microsomal fractions. Decreased ADH activity was observed in pyrazole-pretreated rats. On the other hand, administration of disulfiram (Antabuse) resulted in decrease of mitochondrial low-Km ALDH activity. Administration of some antibiotics, reported to have a disulfiram-like action clinically, also caused a depression of mitochondrial low-Km ALDH activity. When the animals received alcohol orally 18-24 h. after the administration of these antibiotics or disulfiram, blood acetaldehyde level increased remarkably. However, mitochondrial low-Km ALDH activity and blood acetaldehyde level were not changed by single and repeated administrations of 6315-S.
Elimination of ethanol from blood was also determined by measuring the blood level in rats following i. v. administration of ethanol. Disappearance rate of ethanol was prolonged remarkably in the animals treated with either pyrazole or disulfiram, while single and repeated administrations of 6315-S had no effect on the disappearance rate. We conclude from these results that 6315-5 does not affect the alcohol metabolizing system in rats.

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The effects of 6315-S (Flomoxef) on blood coagulation factors and platelet aggregation were examined experimentally and the following observations made.
1) 6315-5 (300mg/kg/day), or its side chain 1-(2hydroxyethyl)-1H-tetrazol-5 thiol (HTT, Na salt, 97mg/kg/day), administered once a day for one week by i.v. injection, caused no inhibition of β-glutamylcarboxylase activity in rat liver. In vitro 6315-S decreased enzyme activity at very high concentrations such as 10mM, but the inhibition was less than that produced by latamoxef or cefotaxime.
2) 6315-S had no effect on prothrombin time (PT) in rats fed an ordinary diet, hut increased it in rats fed a vitamin K-deficient diet. Increased in PT was also produced by other antibiotics containing N-methyltetrazolethiol. The hypoprothrombinemia was normalized by vitamin-K injection.
3) 6315-S caused no change in rat platelet aggregation when injected i.v. for one week. In vitro, 6315-S decreased ADP-induced platelet aggregation (rats, rabbits, guinea pigs and humans) at very high concentrations such as 2, 700 or 8, 100μg/ml, but to a lesser extent than latamoxef or cefotaxime. 6315-S showed little inhibition of ADP-induced primary-wave aggregation, but latamoxef or cefotaxime inhibited not only secondary-wave but also primarywave aggregation. 6315-S showed a stronger inhibition of collagen-induced platelet aggregation than did latamoxef or cefotaxime. The inhibition caused by 6315-S, however, was less than 1/80 that caused by aspirin.
4) 6315-S inhibited collagen-or ADP-induced thromboxane A₂, synthesis in rat, rabbit and human platelets in vitro at very high concentrations. The inhibition was also produced by latamoxef or cefotaxime to the same extent, but was about 1/300 that caused by aspirin.

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6315-S (flomoxef), a newly developed injectable antibiotic, was administered to healthy adult volunteers to evalute its clinical pharmacology.
In pharmacokinetic studies of 6315-S after i. v. injection, i. v. drip infusion and i. m. injection, plasma levels were found to correlate well with the dose administered by each method. Half-life was c. 45 min (β-phase) after i. v. injection, 50-60 min (β-hase) after i. v. drip, and 80 min after i. m. injection.
After administration by each method, most of the drug was excreted in urine within 4 h, and the cumulative urinary recovery rate in 12 h was 80-90%.
No tendency to drug accumulation was found in assays of plasma levels or urinary excretion in subjects receiving 1 g or 2 g doses twice daily for 8 days.
No abnormal symptoms or signs, physical or laboratory test results were observed.

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A pharmacokinetic study of 6315 -S (flomoxef) was performed on patients undergoing blood purification.
6315-S was given in a single i. v. dose of 1 g in uremic patients before blood purification.
The half-life of 6315-S in uremic patients who had not undergone dialysis was 24. 75h. Its half-life during hemodialysis (HD), hemofiltration (HF) and continuous ambulatory penitoneal dialysis (CAPD) was 2. 24 h, 2. 60 h and 12. 91 h, respectively.
These findings suggest that 6315-S should be administered to uremic patients undergoing HD or HF at a dose of 1 g before and after termination of blood purification, and to those undergoing CAPD at a dose of 1 g once a day.

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Bacterial susceptibility, pharmacokinetics and clinical tests of 6315-S (flomoxef), a new oxacephem parenteral antibiotic, were evaluated, and the following results obtained.
Susceptibility of 208 clinical isolates of seven species to 6315-S was tested using a plate dilution method with an inoculum size of 10⁶ cells/ml. 6315-S showed a peak MIC at 0.39μg/ml for 104 strains of S. aureus, and superior efficacy to CEZ and CTM. Its efficacy was also superior to that of LMOX or CMX for E. coli and K. pnuemoniae. It was, however, inferior to that of LMOX or CZX for S. marcescens, and showed no efficacy against P. aeruginosa.
Blood and urine concentrations of 6315-S were determined in six healthy male volunteers after a single 1g i.v. injection for 3 min and by drip infusion for 1 h. Mean blood concentration was 121.3μ g/ml 5 min and 1.05μg/ml 6 h after i. v. injection ; 42.6μg/ml 1 h, and 0.48μg/ml 6 h after drip infusion. In CTM, the control, mean blood concentration was 42.5μg/ml 1 h and 0.27μg/ml 6 h after drip infusion. Hence the pharmacokinetics of 6315-S and CTM seem to be similar. Urinary excretion of 6315-S was more than 80% 6 h after both i. v. injection and drip infusion.
Twenty eight patients, (14 with respiratory tract infections, 1 with cholangitis, and 13 withUTI) were treated with 6315-S, mostly by 1 g b.i.d. drip infusion for 5-14 days. Clinical response was excellent in 11, good in 11, and fair in 6 patients. The efficacy rate was calculated as 78. 6%. No side effects were noted, though abnormal laboratory findings (mild anemia and elevation of GOT, GPT) were recognized in 2 patients.

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Clinical efficacy, bacteriological effects and safety of the parenteral oxacephem antibiotic 6315-S (flomoxef) in treatment of respiratory infections were evaluated.
In 78 patients (with acute bronchitis, 1; acute exacerbation of chronic bronchitis, 6; bacterial pneumonia, 56; bronchial pneumonia, 3; secondary infection in chronic respiratory disease, 7; pulmonary suppuration, 2; and other respiratory infections, 3) 6315-S was markedly effective in 15, effective in 42, slightly effective in 13 and ineffective in 8 patients. The efficacy rate was 73.1%. Fourteen cases (e.g., mycoplasma pneumoniae) were excluded as unevaluable.
As causative organisms, 30 strains were detected: S. pneumoniae, 7; S. aureus, 5; Klebsiella spp., 4; Haemophilus influenzae, 4; and 10 other strains. Of 23 strains which could be evaluated bacteriologically, 17 were eliminated by administration of 6315-S.
As regards safety, out of 92 patients treated, three developed allergic symptoms, such as exanthema, and one patient gastrointestinal symptoms. Thus frequency of side-effects was 4.4%(4/92). Abnormal laboratory values were found in 17 cases (18.5%): abnormal liver fuction test, 11, eosinophilia, 4 abnormal liver function with eosinophilia, 1; prolonged prothrombin time, 1. None of these changes was serious, all values having normalized soon after cessation of treatment.

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Clinical efficacy of 6315-S (flomoxef) was evaluated by adminstering the drug to 19 patients: 1 with chronic bronchitis, 10 with bacterial pneumonia, 7 with mycoplasma pneumonia and 1 with primary atypical pneumonia.
Response in chronic bronchitis was good. In bacterial pneumonia it was excellent in 4 cases and good in 6. Of the 19 patients, 6 showed slight elevation of S-GOT and S-GPT or S-GPT. The only side effect observed was drug fever in one patient.

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Clinical efficacy of 6315-S (flomoxef), a new oxacephem antibiotic, was evaluated in 26 patients with respiratory tract infections: 20 with bacterial pneumonia, 3 with bacterial, bronchitis, one each with secondary infection of chronic obstructive lung disease (type B), mycoplasma pneumonia and atypical pneumonia. Response was excellent in 2 patients, good in 13, fair in 7, poor in 3 and undetermined in 1.
Causative organisms, were 1 strain of S. aureus, 2 of H. influenzae, 3 of K. pneumoniae (including 1 case each of mixed infection with E. faecalis and E. cloacae), and I mixed infection of C. freundii and E. cloacae.
Bacteriological efficacy was observed in only 5 cases. In 2 strains of H. influenzae, 1 was eradicated and 1 decreased, 1 strain of C. freundii mixed with E cloacae was eradicated; 1 strain of K. pneumoniae was replaced by E. aerogenes: and 1 case of mixed infection (K. pneumoniae+E. faecalis) was replaced by P. aeruginosa. As adverse reactions, exanthema was observed in 1 patient. As abnormal laboratory findings, GOT, GPT and Al-P were elevated in 8 patients, and WBC decreased in 2.

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In vitro antimicrobial activity of 6315-S (flomoxef), a new oxacephem for parenteral use, was examined by a broth dilution method using the Dynatech MIC 2000 system, and its therapeutic effects in lower respiratory infections were evaluated.
The minimum inhibitory concentrations (MIC's) and minimum bactericidal concentrations (MBC's) of 6315-S, latamoxef (LMOX=moxalactam), ceftizoxiine (CZX), oefmenoxime (CMX), cefmetazole (CMZ), cefazolin (CEZ) and ampicillin (ABPC) against the following 239 clinical isolates were determined: 20 strains each of aureus, S. epidermidis, E. coli, K. pneumoniae, E. cloacae, S. marcescens and P. aeruginosa, 25 strains of S. pneumoniae, 9 strains of S. pyogenes and 65 strains of H. influenzae.
From the determination of MIC's and MBC's, it was found that 6315-S was more active against S. aureus than any other antibiotic, and as active as ABPC against H. influenzae. 6315-S was somewhat less active against S. epidermidis and streptococci than CEZ and ABPC, respectively.
Compared with LMOX, 6315-S was more active against E. coli and K. pneumoniae, but less so against E. cloacae and S. marcescens. 6315-S was also less. active against P. aeruginosa with MIC's above 200μg/ml against all the strains tested. MBC values of 6315-S against a wide variety of pathogens were found to be very close to MIC's.
A daily dose of lg to 4 of 6315-S was given by drip infusion to 21 patients 17 with pneumonia and 2 each with lung abscess and infection in association with bronchiectasis. Clinical effects were excellent in 2 patients, good in 11, fair in 1 and poor in 5. One patient with Mycoplasma pneumoniae infection and one who received 6315-S only twice because of adverse side effects were excluded from clinical evaluation.
Nineteen strains were identified as causative organisms. However, in 4 strains, further bacteriological data were not available for evaluation. Fourteen of the remaining 15 strains were eradicated by 6315-S; only one strain persisted.
Drug exanthema was observed in one patient, and elevation in SGOT and SGPT values was observed in five. These adverse reactions disappeared after completion of the therapy.
From the above results, we conclude that 6315-S is a most useful antibiotic for the treatment of lower respiratory infections.

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Concentrations in serum and sputum and clinical efficacy against respiratory tract infection (RTI) were investigated using 6315-S (flomoxef), a new oxacephem.
One gram of 6315-S was administered twice daily (at 9 p.m. and 6p.m.) to 17 patients with RTI: 11 cases of pneumonia, 3 of chronic RTI, and I case each of lung abscess, D. P. B. and pulmonary tuberculosis.
One case of pneumonia due to chlamydia and one of pulmonary tuberculosis were excluded from the final clincial evaluation.
Serum concentration of 6315-S was 41.6μg/ml and 42.1μg/ml at the end of the first and second drip infusion.
Sputum concentration was 0.98μg/ml and 0.99μg/ml and remained at more than 0.75μg/ml for a long time.
Six potential pathogens were isolated from sputum at the start of the treatment and were eradicated with the exception of one Pseudomonas.
Clinical response was excellent in 5 cases, good in 9 and poor in 1 (efficacy=93.3%).
No side effects were observed. Slight elevation of GPT and GOT·GPT was observed in 1 and 2 cases respectively.
From the above results, we conclude that 6315-S is a highly effective and useful antimicrobial agent.

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Distribution of 6315-S, a new oxacephem, in humans was studied by measuring its levels in serum and lung tissue of nine patients after a single 1 g i. v. injection. The penetration rate from blood into lung tissue was measured, and average ratios of tissue vs. blood level were 39.8% at 1 h, 49.5% at 2 h, and 61.2% at 3 h after i. v. administration.
6315-S was also given by drip infusion (2-4 g b. i. d. for 2 weeks) to 8 patients: 6 with pneumonia, 1 each with pulmonary suppuration and chronic bronchitis. Clinical effects were evaluated as good in 6 and poor in 2 patients. No side-effects occurred during treatment, but abnormal values in hepatic function tests were observed in 2 patients, which returned to normalafter cessation of therapy.

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6315-S (flomoxef), a new cephem, was administered i. v. to 2 patients with bacteremia, 12 with respiratory tract infection, 2 with pyelonephritis, and 1 with fever of unknown origin, The patients received the drug for 5-30 days in a dose of 0.5-6.0 g/day.
Clinical effects were good in 13 cases, poor in 1, and undetermined in 3, showing an efficacy rate 92.9%.
Neither side effects nor abnormal laboratory findings possibly related to this drug were observed in any of these cases.

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Clinical efficacy of 6315-S (flomoxef) was evaluated in 4 patients with respiratory, 3 with biliary, and 1 with urinary tract infection. Effects were good in 6 patients, but poor in the patients with pneumonia and cholecystitis associated with gallstones. Clinical side effects and abnormal laboratory findings were not observed in any of the 12 patients, nor in 4 cases of mycoplasma pneumonia which were excluded from clinical evaluation.

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A new type of oxacephem for injection, 6315-S (flomoxef) was studied, yielding the following results.
1) Antibiotic activity
All MIC's were below 3.13μg/ml, as measured by adding a dilution (1:100) to strains of S. aureus; this was superior to cefazolin (CEZ) and cefoperazone (CPZ) by 3 to 4 and to cefmetazole (CMZ) and latamoxef (LMOX) by 4 to 5 dilution steps. MIC's were below 1.56μg/ml against P. mirabilis and indole-positive Proteus, as good as or slightly better than LMOX, and better than CMZ and CPZ by 2 to 3 steps.
2) Absorption and excretion
Four healthy adult volunteers were i. v. injected once each with 6315-S and LMOX (1, 000mg). The former drug showed a serum level of 90.8±19.5μg/ml 5 min after injection and decreased with a half-life of 56.3±7.7min in serum (β-phase), decreasing to 0.4±0.1μg/ml at 6h. By comparison, the LMOX level was 118.8±11.1μg/ml 5min after injection and then decreased with a serum half-life of 110.4±14.9min (β-phase). Combination with probenecid retarded 6315-S decrease in serum and prolonged serum half-life to 87.2±12.0min. Under these conditions, urinary excretion was retarded, but recovery 8h after administration was 80.3±7.4% with no significant difference from results using 6315-S alone (80. 4±8.5%).
In patients with renal dysfunction, serum levels of 6315-S were maintained longer as renal function diminished. In cases with Ccr of 50ml/min. or less, serum half-life was twice or more that in healthy adults. The present drug was well hemodialyzed.
3) Clinical results
One to four grams of 6315-S per day were given for 5-16 days to 8 patients with internal infections. The results were: effective 5, slightly effective 2, and ineffective 1. The drug removed all isolated pathogenic bacteria;-S. epidermidis, E. coli, K. pneumoniae and E. cloacae-except P. aeruginosa.
No side-effects or abnormal laboratory tests were observed.

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A clinical study on 6315-S (flomoxef), a new cephem derivative, was made in the treatment of 4 patients with respiratory infections (1 with pneumonia, 2 with bronchiectasis and 1 with chronic bronchitis.)
The drug was administered at a dose of 1 g twice daily by drip infusion.
Clinical response was evaluated as good in 2, fair in 1 and poor in 1 case.
As to bactericidal efficacy, a strain of C. freundii was eradicated from sputum, but K. pneumoniae was replaced by P. aeruginosa.
In 1 case of mixed infection K. pneumoniae and P. aeruginosa, K. pneumoniae was eradicated but P. aeruginosa persisted.
No adverse reactions were observed.
From the above results, we consider further clinical evaluation of 6315-S to be useful.

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We performed basic and clinical studies on a new oxacephem derivative, 6315-S (Flomoxef) and obtained the following results:
1) Pharmacokinetics
Mean serum haif-life (β-phase) of this drug was 0.76h. Mean recovery rate in urine within the first 6h was 91.6%.
In combination with probenecid, the serum half-1ife was prolonged, namely, aimost doubled to 1.47h. Recovery rate within lhwas reduced by 20-30%.
A computer simulation revealed that renal tubular secretion, directly after i. v. injection, was nearly indentical with glomerular filtration, but as blood concentration decreased, the former became predominant.
In renal failure cases, the serum half-life was markedly prolonged in cases Ccr was under 5ml/min.
2) 6315-S showed clinical efficacy in 7 cases treated. As a side effect, one patient exhibited exanthema, and another, an increase in GOT, GPT and Al-P.

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A new oxacephem antibiotic, 6315-S (flomoxef) was administered parenterally to 9 patients with various infectious diseases (respiratory, 4; biliary, 2; urinary, 2; gangrene of the toe, 1). The drug was given by drip infusion at a daily dose of 2-4g. The clinical result was good in 8 cases and poor in 1. The efficacy rate was 88.9%. As to side effects, elevation of S-Cr and BUN was observed (in 1 patient), slight elevation of S-Cr in 1, elevation of GOT and GPT in 1, and prolongation of PT in 2 patients.

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Basic and clinical studies on 6315-S (flomoxef), a new parenteral oxacephem antibiotic, were carried out and the following results were obtained.
In vitro antibacterial activity of 6315-S was tested against clinical isolates of Gram-positive and Gram-negative bacteria, (S. aureus, 15 strains; S. epidermidis, 14 S. pneumoniae, 15; S. pyogenes, 15; E. faecalis, 15; E. coli, 15; K. pneumoniae, 15; P. mirabilis, 7; P. vulgaris, 8; H. influenzae, 15; S. marcescens, 15) as compared with that of latamoxef, cefmenoxime, ceftazidime, and cefazolin. 6315-S showed more effective activity against S. aureus, E. coli, and K. pneumoniae than any other antibiotic.
We administered the drug to 8 patients with respiratory and 2 with urinary tract infections at a dose of 2 g daily by i. v. drip infusion. The efficacy rate was 80% in the respiratory and 100% in the urinary tract infections. The organisms isolated from 3 cases were all eradicated.
There were no side-effects or laboratory findings except one case of vomiting and poor appetite.

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Antimicrobial activity of 6315-S (Flomoxef) against 61 strains of C. difficile and 20 blood isolates of CEZ-resistant (MIC>100μg/ml) S. aureus, was determined. MIC's of 6315-S on C. difficile ranged from 3.1-25μg/ml, with MIC₉₀ of 12.5μg/ml. Against CEZ-resistant S. aureus, 4 strains were inhibited at 6.25μg/ml, 7 strains at 12.5μg/ml, and 2 each at 25, 50, 100μg/ml, respectively while 3 strains had MIC's of >100μg/ml. Serum concentration and urinary excretion of 6315-S, were examined on 4 normal adult volunteers and 4 elderly following single i. v. injection of 1g of the drug. T 1/2β was 42 min. with adult volunteers and 84 min. with the elderly. Eighty to ninety percent of the drug was excreted in urine within 6 h. after injection.
Clinical evaluation was performed on 2 patients with septicemia, 3 with biliary tract infection, 1 with erysipelas and 1 with pneumonia. Clinical response was excellent in 5 patients and good in 2. No adverse reactions or abnormal laboratory findings (except slight elevation of GPT) were observed.

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A new antibiotic, 6315-S (flomoxef), was administered for 7-23.5 days at daily doses of 1-3g to 13 patients: septicemia, 1; pneumonia, 3; lung abscess, 1; acute cholecystitis, 1; acute pyelonephritis, 2; acute cystitis, 1; Mycoplasma pneumoniae, 4.
The results were: effective in 6 cases. The overall efficacy rate was 66.7%, excepting the 4 cases of M. pneumoniae.
Side effects were not observed in any of the patients, but abnormal laboratory findings were observed in three (2 cases of GPT, Al-P, 1 case of GOT, GPT).

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Basic and clinical studies on a new oxacephem antibiotic for parenteral use, 6315-S (nomoxef), were performed and the following results were obtained.
The MIC₈₀ of bactericidal activity against clinically isolated S. aureus, E. coli, K. pneumoniae, and P. mirabilis were 0.39, 0.1, 0.1, 0.2μg/ml, respectively, and MIC₅₀ against cefazolin resistant strains of the same organisms were 12.5, 0.78, 25.0, 1.56μg/ml, respectively, Absorption and excretion was studied in 1 case of pyelonephritis with sepsis.
6315-S at a dose of lgwas administered by 1h i. v. drip infusion, and peak serum concentration was 46μg/ml at the end of the infusion. The T1/2 of this case was 1.06 hours.
In a clinical study, we administered the drug to 4 patients with Bacterial pneumonia, acute pyelonephritis, acute prostatitis and acute pyelonephritis with sepsis respectively, for 5-7 days. In all cases clinical efficacy was good or excellent. The organisms of isolated E. coli (3 strains) were all eradicated. Doubtless because the MIC of 6315-S is only 0.1μg/ml.
No side effects a abnormal laboratory findings were observed.

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The oxacephem antibiotic 6315-S (flomoxef) was used in 20 elderly patients with respiratory tract infection (pneumonia, 15: lower RTI, 5) to evaluate its clinical efficacy and side effects. Results of treatment were excellent in 2 patients, good in 14, fair in 2 and poor in 2; the overall efficacy rate being 80%. Bacteriologically, 6315-S was effective against S. pneumoniae, S. aureus, H. influenzae and K. pneumoniae. No side effects were observed. Abnormal laboratory values were decreased WBC, 3 cases; elevated GPT, GOT and GPI, I case each and elevated BUN, 1 case, None were serious.
We therefore consider 6315-S to be a useful antibiotic for elderly patients with respiratory tract infection.

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