We compared the antibacterial activity and β-lactamase stability of ME 1206 (the biologically active product of ME 1207, a new oral cephalosporin) with those of cefteram (CFTM), cefixime (CFIX) and cefaclor (CCL).
1) The antibacterial activity of ME 1206 against standard strains of Gram-positive and Gram-negative bacteria was as follows. ME 1206 was more active than CFTM and CCL against Gram-positive bacteria, and it showed almost the same antibacterial activity of CFTM and CFIX against Gram-negative bacteria.
2) ME 1206 was active against most of β-lactamase producing strains. Its activity was comparable to that of CFTM and CFIX. But a small number of resistant strains such as C. freundii strains existed.
3) The relative rate of hydrolysis of ME 1206 by various kinds of β-lactamases was determined. ME 1206 was stable against cephalosporinases (Csase) and penicillinases (PCase) but unstable against oxyiminocephalosporinases (CXase)
4) The β-lactamase inducing activity of ME 1206 was very low and it was comparable to that of CFTM.
5) The time course of ME 1206 bactericidal activity against PCase producing strains of S. aureus and K. pneumoniae was determined. The bactericidal activity of ME 1206 was almost equal to that of CFTM and CCL. But in the case of CCL a more remarkable regrowth was detected

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MIC₅₀s of ME 1206 against 24 to 50 clinical isolates of Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), coagulase-negative staphylococci (CNS), Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus feacalis, Enterococcus faecium, Escherichia coli carrying R plasmids, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa, Pseudomonas cepacia, Xanthomonas maltophilia, Acinetobacter calcoaceticus, ampicillin-resistant Haemophilus influenzae and Bacteroides fragilis were 0.78, 50, 0.78, 50.013, 0.025, >100, >100, 0.2, 0.2, 0.1, 0.2, 3.13, 6.25, 3.13, 100, 3.13, 50, 6.25, >100, 25, S 0.013 and 1.56μg/ml, respectively. ME 1206 manifested stronger activity against gram-positive bacteria than cefdinir, cefaclor, cefteram and cefpodoxime, although it showed weaker activity against Proteus group and S. marcessens than cefixime, cefteram and cefpodoxime. ME 1206 possessed the strongest activity against B. fragilis among cephem antibiotics tested. Since ME 1206 manifested stronger binding affinity to PBPs of S. aureus, E. coli, P. vulgaris, S. marcescens and A. calcoaceticus than cefteram, it was assumed that ME 1206 possesses less penetrability through the outer membrane of gram-negative bacilli than cefteram. Synergy in bactericidal effect between ME 1206 and the complement was not marked, however E. coliliving cells were well engulfed and digested by mouse cultured Mφs in the presence of higher than 1/8 MIC of ME 1206.

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The in vitro and in vivo antibacterial activity of ME 1207, a new oral cephem (a prodrug of ME1206), was compared with that of cefpodoxime proxetil (CPDX-PR, a prodrug of CPDX), cefteram pivoxil (CFTM-PI, a prodrug of CFTM), cefixime (CFIX) and cefaclor (CCL), and the following results were obtained. ME1206 showed the most potent antibacterial activity against Gram-positive organisms among the other drugs. The effects of ME1206 against Gram-negative organisms such as Escherichia coli and Bacteroides fragilis were more effective than those of the comparative drugs and also active against the other Gram-negative bacteria including Haemophilus influenzae and Neisseria gonorrhoeae. ME 1206 was more stable than CCL against β-lactamase. On the other hand, it was slightly more unstable than CPDX, CFTM and CFIX. In experimentally infected mice with Staphylococcus aures Smith, Streptococcus pneumoniae TMS3 and Klebsiella pneumoniae 3K25, ME 1207 showed the excellent therapeutic effects, which were expected from in vitro activity of ME1206. However, the therapeutic effects of ME 1207 against systemic infections in mice with β-lactamaseproducing strains were similar to those of CPDX-PR and CFIX, and superior to those of CFTM-PI and CCL. In respiratory tract infections in mice due to S. pneumoniae TMS3, ME 1207 was more potent than CCL. ME 1207 also showed stronger antibacterial effect than CFTM-PI, CFIX and CCL in urinary tract infections in mice.

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Antibacterial activity of ME 1206, an active form of the novel cephalosporin ME 1207, against anaerobic bacteria of reference and clinical isolates was determined by the agar dilution method. The stability of this compound against β-lactamases derived from three Bacteroides fragilis isolates was also determined. ME 1206 at the concentration of 6.25μg/ml, inhibited the growth of almost all anaerobic species tested except several species including B. fragilis, Bacteroidesthetaiotaomicron, Bacteroides ovatus, Bacteroides unzformis, Fusobacterium varium, Clostridium botulinum and Clostridium difficile. ME 1206 was very active against the strains Prevotella oris, Prevotella oralis, Prevotella intermedia, Perphyromonas sp. and Peptostreptococcus spp. ME 1206 was hydrolyzed to some extent by the β-lactamases from three isolates of B. fragilis, but it was more stable than cefaclor.

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We compared the in vitro and in vivo antibacterial activity of ME 1207, a pivaloyloxymethyl ester of ME1206, with that of cefaclor (CCL), cefteram (CFTM), cefdinir (CFDN) and cefotiam (CTM), and obtained the following results. ME1206 had a broad antimicrobial spectrum against gram-positive and gram-negative organisms. The MIC₉₀ values (μg/ml) of ME1206 against clincal isolates were 0.78 for methicillin-sensitive Staphylococcus aureus, 0.012 for Streptococcus pyogenes, 0.39 for Streptococcus pneumoniae, 1.56 for Escherichia coli, 0.78 for Klebsiella pneumoniae, 0.39 for Proteus mirabilis, 0.78 for Proteus vulgaris, 0.025 for Haemophilus influenzae and 0.39 for Branhamella catarrhalis. ME1206 was the most active drug against S. pneumoniae, P. vulgaris and H. influenzae. ME1206 showed a concentration-dependent bactericidal activity against S. aureus, E. coli, K. pneumoniae and Serratia marcescens. In morphological observation of E. coli, P. vulgaris and S. marcescens treated with ME1206, filamentous formation was observed at low concentrations, and spheroplast and lysis were observed at high concentrations. ME1206 showed high affinities for penicillin-binding proteins (PBPs) 3, 1Aand 1Bs of E. coli, and 2, 1 and 3 of S. aureus. In systemic infections, ME 1207 showed protective effects that were reflected by its in vitro antibacterial activity. Particularly, ME 1207 showed the highest therapeutic activity against systemic infections in mice caused by S.pneumoniae and S. marcescens among the drugs tested.

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ME 1206, the active form of ME 1207, had a potent activity against Gram-positive bacteria except MRSA and Enterococcus spp. The antibacterial activity of ME 1206 was superior to that of cefaclor (CCL) against Staphylococcus aureus and Staphylococcus epidermidis. Against Streptococcus spp., the antibacterial activity of ME 1206 was equal to that of cefteram (CFTM) and superior to that of cefixime (CFIX) and CCL. ME 1206 had a strong activity against Gram-negative bacteria except P.seudomonas aeruginosa and its activity was comparable to that of CFTM and CFIX. However, a part of Enterobacter cloacae, Citrobacter freundii and Serratia marcescens strains was resistant to ME 1206, CFTM and CFIX. The bactericidal activity of ME 1206 against S. aureus and Escherichia coli was almost equal to that of CFTM and CCL. The affinity of ME 1206 to penicillin-binding proteins (PBPs) of S. aureus was high in case of PBPs1, 2 and 3, and to those of E. coli its affinity to PBPs3, 1A and 1B was also high. The permeation activity rate of ME 1206 through the Omp F porin channel was almost equal to that of CFTM and one-third to that of cefazolin. A synergistic effect on the bactericidal activity of ME 1206 was observed with human serum and against E. coli, its activity was as strong as that of CFTM and CCL. Against intraperitoneal infections with S. aureus, Streptococcus pneumoniae, E. coli and Klebsiella pneumoniae in mice, the therapeutic efficacy of ME 1207 was more than that of cefteram pivoxil, CFIX and CCL.

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The MIC distribution and bactericidal activity of ME1206, the active form of a new oral cephalosporin ME 1207, against Haemophilus influenzae, Branhamella catarrhalis and Streptococcus pneumoniae as well as its affinity to penicillin binding proteins (PBPs) were compared with those of other reference compounds.
1. The MIC₈₀ value of ME1206 against 117 strains of H. influenzae was 0.025μg/ml, and almost equal to that of cefteram (CFTM) and cefixime (CFIX) but superior to that of cefaclor (CCL) and ampicillin (ABPC). The MIC₈₀ value of ME1206 against 111 strains of B. catarrhalis was 0.39μg/ml and almost equal to that of CFIX but superior to that of CFTM, CCL and ABPC. The MIC₈₀, value of ME1206 against 94 strains of S. pneumoniae was 0.025μg/ml and its activity was almost equal to that of CFTM and supeior to that of CFIX, CCL and ABPC.
2. The bactericidal activity of ME1206 against the above three pathogens was similar to that of CFTM and CCL at concentrations above the MIC.
3. The affinity of ME1206 to PBP4 and PBP5 among the PBPs of H. influenzae ATCC 9334 was higher than that of CCL and its high affinity was paralleled to its strong antibacterial activity against the same strain. The affinity of ME1206 to PBP3 of B. catarrhalis W-506 was higher than that of CFTM. Affinity of ME1206 to PBP2 and PBP3 of S. pneumoniae IP692 was higher than that of CCL.

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The alteration of the fecal microflora was inspected before, during and after oral administration of ME 1207 (pivaloyloxymethyl ester of ME 1206) to three groups of beagle dogs (12mg/kg/day, 250mg/kg/day and control group) at single dose per day for 14 consecutive days. We investigated the detection of D-1 antigen from Clostridium difficile, the antibacterial activity of ME 1206 and β-lactamase, activity in the feces, and determined the proportion of ME 1206-resistant strains isolated from the feces in the groups administered ME 1207.
1. The feces of three groups each were normal during the experiment, and no changes such as diarrhea were Observed.
2. A slight decrease of Enterobacteriaceae and a transient decrease of anaerobes were observed in the 12mg/kg/day group. A substantial decrease of Enterobacteriaceae was observed and as the results the mained fecal flora was Enterococcus spp. in the 250mg/kg/day group.
3. The detection rate of C. difficile was high in the 12mg/kg/day group.
4. The antibacterial activity as ME 1206 in the feces was low in the 12mg/kg/day group but high (more than 1000μg/g) in the 250mg/kg/day group.
5.β-lactamase activity in the feces was low.
6. The resistant strains were observed in the Enterobacteriaceae but not in the Staphylococcus spp. during administration of ME 1207.

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ME 1207, a newly developed oral cephem-antibiotic, was administered to seven healthy male volunteers in a dose of 200 mg, three times a day after meals for seven days, to study the effects of this drug on the fecal bacterial flora and to determine the fecal concentration of ME 1206, which is the main active form of ME 1207, furthermore, the antibacterial activity against organisms chosen at random from feces isolates was determined. The subjects were monitored for adverse reactions and abnormal laboratory findings. The results were as follows.
1. The mean changes in the bacterial flora consisted decreased counts of Enterobacteriaceae among aerobes, and of Lactobacillus, Peptococcaceae, Veillonellaceae, etc., among anaerobes during the treatment. Other remarkable changes in the fecal bacterial flora were also seen in each of the cases with a high fecal concentration of ME 1206.
2. Clostridium di fficile was isolated from five volunteers in counts of 3.0 × 10²-2.2 × 10⁸ CFU/g from the first day of treatment to the 30 th day after administration, and D-1 antigen was detected in six cases at levels of 250-2, 000 ng/g from the 5 th day before treatment to the 30 th day after administration.
3. The fecal concentrations of ME 1206 were determined by bioassay, and values of 0.12-1, 730μg/g were detected in all cases on the 2 nd, 4 th and 7 th days of treatment.
When assayed by HPLC, values of 210-1, 560 μg/g were detected in three cases on the 2 nd, 4 th and 7 th days. In the other four cases, the fecal concentration was below the limit of detection.
4. The MICs of ME 1206 for some species of Gram-positive cocci were similar to those of cefpodoxime (CPDX) and cefprozil. In case of some species of Enterobacteriaceae, the MICs of ME 1206 were similar to those of cefteram (CFTM), cefpodoxime (CPDX) and cefixime (CFIX). And for Bacteroides fragilis group the MICs of ME 1206 were as high as those of other cephem antibiotics; for C. difficile they were as high as those of CFTM, CPDX, CFIX and cefaclor.
5. As adverse reactions, mild diarrhea occurred during treatment in two cases (Case 5 and 6), and this was thought to have been due to the administration of ME 1207. There were no abnormal laboratory findings.

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The antimicrobial activity of ME 1207 was determined using the urinary samples recovered in the Phase I study. A dose of 200mg of ME 1207 or cefteram pivoxil (CFTM-PI) was administrated three times per day to 8 adult healthy male volunteers by the cross-over method. The urinary samples were recovered on time. The mean peak of urinary levels for the ME 1207 group was 183μg/ml (2-4h) and 227μg/ml (2-4h) for the CFTM-PI group. Antibacterial activity and bactericidal activity in urine against Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae and Serratia marcescens were determined with the above urinary samples. Antibacterial activity and bactericidal activity in the ME 1207 group against S. epidermidis in urine were superior to those in the CFTM-PI group. Against E. coli, K. pneumoniae and S. marcescens, the antibacterial activity and bactericidal activity in the ME 1207 group in urine were almost as strong as those in the CFTM-PI group.

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Microbiological assay methods were examined for the quantitative determination of ME 1206, the active metabolite of ME 1207, in human serum or urine.
ME 1207 is almost completely metabolized to ME 1206, the ultimate active compound, during its absorption through gastrointestinal tract after oral administration. Thus, all the quantitative assays were studied with ME 1206.
The most suitable condition for a bioassay was obtained when combining the test organism Escherichia coli NIHJ with the growth medium Minimum Regulation for Antibiotic Products of Japan (MRAPJ (1): 1% peptone, 0.25% sodium chloride. 0.5% beef extract and 1.5% agar, pH6.5-6.6). This condition was suitable for the cylinder-plate method and the agar well and paper disk methods. As diluents for the standard solutions, normal serum was suitable for dilution of ME 1206 in serum and 0.1M phosphate buffer (pH7.0) for ME 1206 in urine.
The minimal detectable concentrations of ME 1206 in 0.1M phosphate buffer (pH7.0) using these methods, were 0.01μg/ml for the cylinder-plate method, 0.04μg/ml for the agar well method and 0.16μg/ml for the paper disk method.
In human serum, however, they were 0.05μg/ml for the cylinder-plate method, 0.06μg/ml for the agar well method and 0.18μg/ml for the paper disk method.
ME 1206 was stable for at least 60 days in human serum and/or human urine at the temperature of -20°C.

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ME 1207, a novel oral cephem antibiotic, is a prodrug of ME1206 which has a potent activity against a broad spectrum of bacteria. A high-performance liquid chromatographic (HPLC) assay method was established for the determination of ME1206 in human serum and urine. Deproteinized serum or diluted urine was directly injected into a reversed-phase (C₁₈) column. The lower limits of detection in human serum and urine were 0.25μg/ml and 0.50μg/ml, respectively. ME1206 concentration in human serum and urine samples collected during Phase I studies was determined by HPLC and bioassay methods. There was a good correlation between the values obtained by both methods.

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ME 1207, a novel oral cephem antibiotic, is a prodrug of ME1206 which has a potent activity againsta broad spectrum of bacteria.Our preclinical animal studies showed that ME 1207 is a safe antibioticand also has a potent antibacterial effect in in vivo experimental infections. We performed a phase I clinical study in 28 healthy volunteers to determine the safety, tolerance and pharmacokineticprofile of ME 1207. The results obtained were as follows:
1. No alterations attributable to ME 1207 were observed regarding subjective or objective signs, physical examinations or clinical laboratory findings, except for one subject who developed a slightheadache once after a postprandial oral dose of 200mg of ME 1207, which disappeared within 45minutes.
2. Two hours after a postprandial single dose of 100, 200 or 300mg, the mean serum concentrationof ME 1206 reached a peak value at 1.48, 3.17 and 4.42μg/ml, respectively. The half-life rangedbetween 0.80-1.11h and the cumulative urinary excretion ratio was about 20%.
3. Absorpion of ME 1207 was affected by food intake, namely, the absorption underpostprandialconditions was rather higher than under fasting conditions.
4. No accumulation of ME1206 in serum was observed after multiple postprandial administrationof ME 1207 (200mg, t.i.d.) for 8 days.

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The pharmacokinetics of ME 1207, a new oral cephem antibiotic, was studied in mice, rats and dogs.
1. ME 1207 was mainly absorbed from the upper part of the small intestine and transferred to thecirculatory blood as its active form, ME 1206.
2. When ME 1207 was administered orally to mice (10mg/kg), rats and dogs (20mg/kg), the peakplasma concentration of ME 1206 after administration was obtained at 0.5h in mice and rats, and 1 hin dogs.
3. The absolute bioavailability of ME 1207, calculated from the ratio of AUC values after oraladministration of ME 1207 and intravenous administration of ME 1206, was 55.6, 20.2, 9.5% in mice, rats and dogs, respectively.
4. After oral administration of ME 1207 (100mg/kg) to rats, ME 1206 was well distributed to allthe tissues measured, especially to the kidney and liver.
5. The cumulative urinary excretion ratio within 24h after oral administration of ME 1207 (20mg/kg) to mice, rats and dogs, was 21.6, 4.0 and 2.7%, respectively, and the cumulative biliary excretionratio was 11.0% in rats.
6. When ME 1207 was administered to rats and dogs in the non-fasting state, a delay in absorptionoccurred in rats and the extent of absorption increased in dogs compared with that measured in thefasting state.
7. The plasma concentration of ME 1206 after oral administration of ME 1207 to rats with liverdysfunction induced by D-galactosamine, was remained high for longer time than in normal rats.
8. The plasma concentration of ME 1206 after oral administration to 4-day-old rats and 3 or 4-week-old dogs, was higher and remained high longer time than in the adults.
9. No antimicrobially active metabolites other than ME 1206 were observed in the rats urine orbile samples.

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The pharmacokinetics of ME 1207 was studied in rats and dogs after oral administration of (Aminothiazole-2-¹⁴C) ME 1207 at a dose of 20mg which is equivalent to ME 1206/kg.
1. The peak blood concentration of radioactivity was obtained lhr after administration, and were6.00ug/ml for rats and 1.52μg/ml for dogs.
2. There was no marked difference between the blood concentrations in fasting and non-fastingrats, except for a delay in absorption found in the non-fasting animals.
3. The urinary and fecal excretion of radioactivity within 120hr after administration was 11.9% and 84.5% of the dose in rats. It was 4.4% and 93.6% of the dose in dogs.
4. The biliary excretion of radioactivity within 48hr after administration was 11.0% in rats.
5. The radioactivity was well distributed to almost all the tissues measured in rats. The highestconcentration was in plasma, followed by the kidney and liver.
6. The extent of the binding of ME 1206 to plasma protein (in vivo) was high in rats and dogs, however, the binding was reversible.

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Accumulation, placental transfer and transfer to milk of ME 1207 were studied in rats after oraladministration of (Aminothiazole-2-¹⁴C) ME 1207 at a dose equivalent to 20 mg of ME1206/kg.
1. No accumulation of radioactivity was observed in blood or tissues after multiple oral administration (20mg/kg once a day for 21 days).
2. The radioactivity was scarcely transfered to the fetus after single oral administration to 13-day- and 18-day-pregnant rats.
3. The radioactivity concentration in the milk was much lower than the plasma concentrationafter single oral administration to nursing rats.

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A new oral cepharosporin antibiotic, ME 1207, was given in doses of 100mg/kg to beagle dogs inorder to study its distribution to various tissues. The following results were obtained.
1. The maximum plasma concentration of ME 1206, observed 1 hr after oral administration of ME 1207, was 10.03 μg/ml, and then it decreased rapidly.
2. The highest concentration in tissues and body fluids was observed in B-bile followed by liver, gall bladder, stomach, kidney, plasma, small intestine, urinary bladder, vagina, ovarium, uterus, gum, lung, parotid gland, trachea, pericardiac fluid, tonsil, heart, mandibular gland, pancreas, spleen, thymus, muscle, aqueous humor, brain and cerebrospinal fluid, in that order. The maximumconcentrations in all tissues and body fluid except the stomach, small intestine, pancreas andpericardiac fluid, were detected 1 hr after oral administration of ME 1207, and then they declined asthe plasma concentration also decreased.
3. Areas under the tissue concentration curve (AUC) were large for gall bladder, liver, stomach, kidney, vagina, small intestine, Urinary bladder ovarium, uterus, trachea, lung and gum. The orderAUCs was similar to that of the maximum concentrations in the tissues.
4. The pharmacokinetic parameters (K₁₁/K₂₁) derived from plasma and tissue concentration usingthe deconvolution method correlated well with the respective maximum tissue concentrations.

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Acute toxicity in mice and rats, and subacute and chronic toxicity in rats of ME 1207 an oralcephem antibiotic, were investigated. Acute toxicity of ME 1206, an active metabolite of ME 1207, inm ice and rats, and subacute toxicity of ME 1206 in rats were also investigated. ME 1207 was administeredorally at doses of 125, 250, 500 and 1000mg/kg for 4 weeks in the subacute toxicity study andat doses of 31, 63, 125 and 500mg/kg for 26 weeks in the chronic toxicity study. ME 1206 was administeredintravenously at doses of 31, 125 and 500mg/kg for 4 weeks.
In the acute toxicity study, no deaths occured in adult mice, or in adult and infant rats treated orallywith ME 1207 at a dose of 5000mg/kg. Single intravenous administration of ME 1206 to adult mice andrats at a dose of 3000mg/kg and single intraperitoneal administration of ME 1206 to infant rats at adose of 2000mg/kg caused no deaths either. In the repeated dose studies of ME 1207, slightly increased GOT and GPT, transiently increased RBC in urine sediment, and an increase in the kidney weightswas observed, but abnormal microscopic findings were not observed even in high dose groups. In therepeated dose study of ME 1206, slightly abnormal microscopic findings of the kidney were observedin the highest dose group.
The results suggest that the acute toxicity of ME 1207 in mice and rats is low, and the no-effect doselevel of ME 1207 in rats is 250mg/kg in the subacute and chronic toxicity studies and that of ME 1206in rats is 125mg/kg in the subacute toxicity study. The results also indicate that ME 1207 affects thekidney and liver when administered repeatedly for long periods at high dose levels.

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Acute, subacute and chronic toxicity of ME 1207, an oral cephem antibiotic, was investigated in male and female beagle dogs. ME 1207 was administered orally at doses of 125, 250, 500 and 1000mg/kg for 4 weeks in the subacute toxicity study and for 26 weeks in the chronic toxicity study. There were no deaths or toxic signs after single oral administration of 2000mg/kg. At doses of 500mg/kg or higher in the subacute toxicity study and at doses of 250mg/kg or higher in the chronic toxicity study, increases in Cholesterol, GOT, GPT and ALP were observed. Abnormal microscopic findings in liver preparations were also observed in the chronic toxicity study. The results suggest that the no-effect dose level of ME 1207 in dogs is 250mg/kg in the subacute toxicity study and 125mg/kg in the chronic toxicity study, and the most sensitive target organ regarding toxic effects is the liver.

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Three groups of two male beagle dogs each were given ME 1206, an active metabolite of ME 1207, intravenously once at a dose of 500, 1000 or 2000mg/kg, followed by a 2-week observation period to examine its acute toxicity. Four groups of three male and female beagle dogs were given ME 1206 intravenously for 4 weeks at a dose of 125, 250 or 500mg/kg/day to examine subacute toxicity.
1) Acute toxicity study
No deaths occurred in the 2000mg/kg group. On the administration day, licking and vomiting were observed in the 1000 and 2000mg/kg groups, and urine including white precipitate was observed in the 2000mg/kg group. No abnormalities were found in food or water consumption, body weight, ophthalmological examination, auditory examination, electrocardiography, urinalysis or serum biochemical examination. Regarding hematological analysis, a transient prolongation of prothrombin time was noted in all animals, and a shortening of activated partial thromboplastin time as well as a reduction in RBC count, hematocrit value and hemoglobin concentration were noted in the 2000mg/kg group, but these abnormal values tended to normalize. No treatment-related changes were noted in organ weight, gross autopsy or histopathological examination. Therefore, the lethal dose of ME 1206 was considered to be over 2000mg/kg.
2) Subacute toxicity study
No deaths occurred in any group. Vomiting was observed in animals of both sexes in the 500mg/kg group. One female in the 500mg/kg group showed a temporary loss of appetite accompanied by a decrease in water consumption and body weight on the 1st week. No treatment-related changes were found in body temperature, ophthalmological examination, auditory examination or electrocardiography. In serum biochemical examination, female dogs in the 500mg/kg group showed an increase of GOT and GPT also tended to increase. No abnormalities were noted in urinalysis, hematological analysis, kidney function tests, organ weight, gross autopsy or histopathological examination. Under the conditions of this study, the no-effect dose level of ME 1206 was considered to be 250mg/kg, and the toxic target organ was considered to be the liver.

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ME 1207 was orally administered to male and female rats at doses of 125, 250, 500 and 1, 000mg/kg daily in order to assess its effects on the reproductive functions. The test compound was administered before and during the mating period for both sexes and during an early stage of pregnancy for females. None of the parent rats died during this experiment due to administration of ME 1207. Neither males nor females showed any dose-related changes in body weight and food consumption before mating, or in the estrus cycle, copulation and fertility indexes. During the pregnancy period, the body weight of the rats was lower or tended to be lower in the 1, 000mg/kg group than in the control. No effects attributable to ME 1207 were observed regarding the number of corpora lutea, implantations, dead or resorbed fetuses, live fetuses, body weight of fetuses, external, visceral or skeletal findings in the fetuses. From these findings, the non-effect dose of ME 1207 was estimated to be 1, 000mg/kg in male and female rats, 500mg/kg in pregnant rats, and 1, 000mg/kg in embryos and fetuses.

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ME 1207 at doses of 125, 250, 500 and 1, 000mg/kg was orally administered to SD strain rats during the period of fetal organogenesis to investigate its effects on dams, their fetuses and on postnatal development and reproductive function of offspring. The following results were obtained. In dams, suppression of body weight gain was observed in the 250mg/kg and higher dose groups, however, no effects were noted on continuance of pregnancy, delivery or nursing behavior. In embryos and fetuses, no deleterious effects were observed on the implantation rate, number of dead fetuses or resorptions, number (rate) of live fetuses or fetal body weights. Further more, no increase in the development of anomalies or variations related to the administration of ME 1207 was noted by visceral observation. However, in the findings of skeletal observation a decrease in the number of ossified sacrococcygeal vertebrae was observed in the 500mg/kg and higher dose groups. No deleterious effects were observed in postnatal physical and behavioral development, visuoauditory function, learning ability, emotionality or reproductive function. From these results, the non-effect doses are estimated to be 125mg/kg for dams, 250mg/kg for embryos and fetuses and 1, 000mg/kg for the offspring, which suggests that ME 1207 has, potentially, no teratogenic effect in rats.

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Peri- and postnatal study on ME 1207, an oral antibiotic, was carried out with Sprague-Dawley rats. ME 1207 at dose levels of 90, 250 and 750mg/kg/day was administered orally to dams from day 17 of gestation through day 20 of lactation, and its effects on parturition and nursing behavior of dams and growth development of postnatal offspring were investigated. The reference compound 0.1% CMC was given at 10ml/kg in the same manner. In dams, soft stools were observed at the dose of 90mg/kg and higher. Also decrease in food consumption, increase in water consumption and in adrenals weight were noted at the dose of 90mg/kg and higher. Body weight gain, an increase in food consumption, cecum hypertrophy and an increase in kidneys weight were noted at the dose of 250mg/kg and higher. But the gestation period, parturition and nursing behavior were normal in every dose group. ME 1207 did not suppress development of offspring. And there were no changes in viability, external appearence, differentiation, function of sensory organs, behavior, learning ability or reproductive performance attributable to the treatment with ME 1207. From these results, no effect dose levels of ME 1207 were 90mg/kg/day or less for general toxicity in dams and 750mg /kg/day for dams' reproductive performance and for their offspring.

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The nephrotoxicity studies of ME 1207, and ME 1206 which is an active metabolite of ME 1207 were investigated in male rabbits and also in male rats for ME 1207. ME 1207 was administered in a single oral dose to rats pretreated with a nephrotoxicity inducer (furosemide and glycerin) and to rabbits once daily for 5 days. ME 1206 was administered intravenously once daily to rabbits for 5 days. The toxicity of ME 1207 was compared with that of cefteram pivoxil (CFTM-PI) and cefaclor (CCL), and that of ME 1206 with cefteram (CFTM) and cephaloridine (CER). Although definite findings indicating nephrotoxicity were not observed in rats. An increase in BUN, Cre. and the weight of kidneys, as well as renal discoloration and abnormal microscopic findings in the kidneys, were observed in rabbits. The results suggest that the nephrotoxicity of the antibiotics is as follows: CFTM-PI>ME 1207=CCL and CER>CFTM>ME 1206.

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The general pharmacological properties of ME 1207 were investigated in animals. ME 1207 was administered orally (p. o.) or intraduodenally (i. d.); whereas ME 1206, the active metabolite of ME 1207, was utilized for intravenous administration (i. v.) and for in vitro studies. ME 1206 at high concentrations relaxed isolated trachea muscle (3×10^-4g/ml) and potentiated the norepinephrineinduced contraction of isolated was deferens (10^-3g/ml) from guinea pigs. ME 1206 (i. v.) slightly decreased the blood pressure at 250 mg/kg and increased the respiratory rate at 500mg/kg in anesthetized dogs. ME 1206, being infused intravenously (10mg/kg/min), slightly inhibited AChinduced tachycardia. ME 1207 (i. d.) inhibited the gastric secretion at 600mg/kg in rats. Oral administration of ME 1207 decreased the sodium excretion in urine at the dose of 75mg/kg, and also decreased the urinary volume at the dose of 300mg/kg in rats. ME 1206 elongated the whole blood clotting time at 10^-3g/ml in rabbit. ME 1207 or ME 1206 produced no adverse effects on the central nervous or other systems except for the changes mentioned above. From these results, it is concluded that ME 1207 and ME 1206 have no adverse effects at the therapeutic dose.

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ME 1207 is a novel esterified oral cephem prodrug. When orally administered, ME 1207 is hydrolyzed to ME 1206 which has antibacterial activity. ME 1207 was orally administered to 6 healthy volunteers under fasting or non-fasting conditions in a single dose of 200mg, and their pharmacokinetic data was measured. The values of these pharmacokinetic parameters at fasting or non-fasting were 2.68 and 3.12μg/ml for C_max, 1.67 and 1.92 h for T_max, 0.99 and 0.97 h for T_1/2, 7.42 and 8.16μg·h/ml for AUC and recovery rate of urinary excretion 16.2 and 20.3% for within 12hours, respectively. The antibacterial activity of ME 1206 against 180 clinical isolates of 7 species determined. The MIC₉₀ was 25μg/ml against Staphylococcus aureus, 1.56μg/ml against Escherichia coli, 0.78μg/ml against Klebsiella pneumoniae, 0.20μg/ml against Proteus mirabilis, and 12.5μg/ml against Morganella morganii. ME 1207 was particularly effective against S. aureus (MIC₅₀: 0.78μg/ml). The MIC₉₀ against Serratia marcescens and Pseudomonas aeruginosa was 100μg/ml or more. ME 1207 was administered to 17 patients with various types of infections in a dose of 300mg t. i. d. for 3 to 8days. The clinical response of patients with respiratory infections was “excellent” in 2, “good” in 8 and “fair” in 2 cases. The clinical response of patients with urinary tract infections was “good” in 4 and “fair” in 1. The overall rate of effectiveness was 82.4%. The bacteriological response was “eradicated” in 8 patients and “replaced” in 1. No side effects or abnormal laboratory data were observed in any of the patients.

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ME 1207, an ester derivative of ME 1206, has been developed in Japan as a new cephem for oral use. We measured the in vitro antimicrobial activity of ME 1206 by the broth dilution method and evaluated the therapeutic efficacy of ME 1207 in respiratory tract infections. The minimum inhibitory concentrations (MICs) of ME 1206, cefixime (CFIX), cefteram (CFTM), cefaclor (CCL) and ampicillin (ABPC) against 20 strains each of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Haemophilus influenzae and Pseudomonas aeruginosa, and 18 strains each of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Serratia marcescens were determined by the micro-broth dilution method using the Dynatech MIC 2000 system. As shown by the MICs, ME 1206 was more active than the other agents against MSSA. All agents tested had no potent activity against either MRSA or P. aeruginosa. Against H. influenzae and Enterobacteriaceaez, ME 1206 was somewhat more active than CFTM, but less active than CFIX. Daily dose of 300 mg (11 cases) or 600 mg (21 cases) of ME 1207 were given orally to 32 patients for 3 to 14 days (mean: 10.5 days): 1 patient with acute pharyngitis, 2 with acute bronchitis, 8 with chronic respiratory infections and 21 with acute pneumonia. The clinical efficacy was excellent in 9, good in 19, fair in one and poor in one. Two cases were excluded from the clinical evaluation; one case because of Mycoplasma pneumoniae pneumonia and the other because of only two days treatment to develope adverse reactions. Fourteen causative organisms were identified 1 strain of S. aureus, 4 strains of Streptococcus pneumoniae, 1 strain of Streptococcus pyogenes, 3 strains of Branhamella catarrhalis, 4 strains of H. influenzae and 1 strain of P. aeruginosa. Eleven of 13 strains, against which the bacteriological effects could be evaluated, were eradicated. Nausea was observed in one patient. Eosinophilia was observed in three patients and an elevation of transaminase was observed in two patients, but these returned to normal after completion of the therapy. From these results, we conclude that ME 1207 is one of the most useful cephem agents for oral use as first choice drug in the treatment of respiratory tract infections in out-patient clinics.

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We performed basic and clinical studies on ME 1207, a new oral cephalosporin, and obtained the following results. The in vitro antibacterial activity of ME 1206, an active metabolite of ME 1207, against 285 clinical isolates from 17 species was compared with that of cefpodoxime, ceftibuten, cefdinir, cefprozil, ofloxacin, clavulanic acid/amoxicillin, cefixime and cefteram. ME 1206 was more effective against gram-positive bacteria than other cephalosporins except cefdinir, and the MICs of ME 1206 against gram-negative bacteria were equal to that of cefteram. In clinical studies, ME 1207 was administered to 11 patients with respiratory infections; the clinical response was excellent in 3 cases, good in 6, poor in 1 and unknown in 1. Side effects and abnormal laboratory findings were observed in 2 cases.

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Antibacterial activity of ME 1206, a metabolite of ME 1207, a new oral cephalosporin, was compared with that of cefaclor and cefteram using an in vitro pharmacokinetic system. The activity of ME 1206 on Streptococcus pneumoniae II D 533 was higher than that of other two antibiotics. Against Staphylococcus aureus and Escherichia coli, ME 1206 was as active as cefteram, and against Haemophilus influenzae ME 1206 was more effective than cefaclor. The concentration of ME 1206 in sputum was negligible even with the highest concentration (0.06μg/ml). The clinical efficacy rate of ME 1207 was 97.6%(41/42) in respiratory tract infections, with the following breakdown: acute bronchitis 7/7, tonsillitis 1/1, acute pharyngitis 1/1, chronic bronchitis 16/16, diffuse panbronchiolitis 1/2, pneumonia 14/14 and lung abscess 1/1. As a side effect, epigastric distress was found in one case. Elevation of serum transaminases in 4 cases and eosinophilia in one case were noted.

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We studied the pharmacokinetics and clinical efficacy of ME 1207, a new oral cephem, and obtained the following results.
1. Pharmacokinetics
The influence of probenecid was investigated in 6 healthy volunteers orally administered 200mg of ME 1207 with or without 1.5g of probenecid in the fasting state. With probenecid, T_1/2 of ME 1206 (the active form of ME 1207) was prolonged from 1.09 hours (without probenecid) to 2.11 hours, C_max and AUC increased from 1.99μg/ml and 5.12μg·h/ml to 3.16μg/ml and 15.7μg·h/ml, respectively, and Clr decreased from 4.64 l/h to 0.882 l/h. These results suggest that tubular excretion was involved in the renal excretion of the drug.
2. Clinical efficacy
ME 1207 was administered to 8 patients with lacunar tonsillitis (1), pneumonia (1), acute bronchitis (4), chronic pyelonephritis (1) and acute cystitis (1) at a dose of 100-200mg three times a day for 6-14 days. The clinical efficacy was excellent or good in 6 cases, and poor or fair in 2 cases. Side effects were observed in 2 cases (diarrhea in one, and diarrhea and nausea in the other). As to laboratory findings, an increase of eosinophils was observed in one case.

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Pharmacokinetic and clinical studies on ME 1207, a new oral cephem antibiotic of ester type, were performed and the following results were obtained. ME 1207 and cefuroxime axetil were orally administered to five healthy adult male volunteers in single doses of 200mg and 250mg, respectively, after meals. Then the serum and urine levels of the drugs were compared by the crossover method. The serum and urine levels of ME 1206, the active form of ME 1207, and cefuroxime (CXM) were determined by a bioassay. The C_max, T_max, T_1/2 and AUC for ME 1206 were 4.27±1.53μg/ml, 1.59±0.42h, 0.91±0.17h and 12.6±3.7μg·h/ml, respectively. The rate of urinary recovery during 8 hours after administration was 16.11+4.73%. The corresponding values for CXM were 2.93 ±1.35μg/ml, 1.77±0.42h, 0.77+0.14h, 6.9±1.9μg·h/ml, and 50.73+10.03%. In the clinical study 300mg or 600mg/day of ME 1207 was administered for 3-28 days to patients with respiratory or urinary tract infections. Staphylococcus aureus, Haemophilus influenzae and Escherichia coli were isolated. The clinical efficacy was excellent in 3, good in 3 and fair in 3. As to side effects, sleeplessness was observed in one patient. No abnormal laboratory findings were observed.

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ME 1207 is a new oral cephalosporin. The susceptibility of 66 clinical isolates to the drug was determined by two-fold serial dilution of ME 1206, an active form of ME 1207, and compared with that to reference compounds cefaclor (CCL), cefotiam (CTM) and cefixime (CFIX). ME 1206 was more active than the reference compounds against Staphylococcus aureus (methicillin-sensitive), Escherichia coli and Enterobacter cloacae, but less active than CFIX and CTM against Klebsiella pneumoniae. ME 1206 was not active against methicillin-resistant Staphylococcus aureus. ME 1207 was used to treat respiratory tract infections in 4 patients: two had a pneumonia and the other two had acute bronchitis. ME 1207 was administered orally at a dose of 100 to 200 mg three times a day for four to fourteen days. The clinical efficacy was excellent in 1 and good in 3 confirmed by chest X-rays or laboratory data. ME 1207 was very effective in a patient with acute bronchitis induced by Haemophilus influenzae. Neither adverse reaction nor abnormal laboratory findings were found in any case.

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In vitro activity of ME 1206, the active free acid of ME 1207, a newly developed cephalosporin antibiotic for oral use, was studied by determining the minimum inhibitory concentration with the agar two-fold dilution method. ME 1206 was not active against methicillin-resistant Staphylococcus aureus but it showed excellent activity against methicillin-sensitive Staphylococcus aureus among these drugs, cefaclor, cefuroxime, cefteram and cefpodoxime. ME 1206 was more active against Escherichia coli and Klebsiella pneumoniae than cefaclor and cefuroxime, however, it was less active than cefteram. ME 1206 was more active against Escherichia coli and less active against Klebsiella pneumoniae than cefpodoxime and cefixime. Five patients with acute pharyngitis and 5 with acute bronchitis were successfully treated with 300mg or 600mg a day of ME 1207, respectively. Neither significant side effects nor abnormalities of laboratory data were detected with administration of ME 1207.

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The antibacterial activity and clinical efficacy of a novel oral cephem antibiotic ME 1207 were investigated, and the following results were obtained.
1) Antibacterial activity: The activity of ME 1207 against clinical isolates of Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa was determined. The MIC. of ME 1207 was 1.56μg/ml against S. aureus, >100μg/ml against methicillin-resistant S.aureus, 0.39μg/ml against E. coli, 0.78μg/ml against K. pneumoniae, 0.39μg/ml against P. mirabilis and >100μg/ml against P. aeruginosa.
2) Clinical efficacy: ME 1207 was orally administered in a dose of 100 or 200 mg t. i. d. after meals to 11 subjects, including 8 patients with acute bronchitis, 2 with acute tonsillitis, and 1 with chronic bronchitis. The drug was effective in all the patients but one with acute bronchitis. The effectiveness rate was 90.9%(10/11 cases).
The bacteriological effect of ME 1207 could be assessed in 3 patients. The causative organisms isolated were S. aureus in 1 case and K. pneumoniae in 2 and they were eradicated in all the cases after treatment. Side effects or abnormal laboratory findings were not observed.

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We studied ME 1207 a new oral cephem, and obtained the following results.
1) Serum and urinary levels of ME 1206 were determined after oral administration of ME 1207 200mg to 10 patients with renal dysfunction and 3 elderly patients (Ccr ≥70ml/min). In the patients with severe renal impairment, serum concentration decreased more slowly than in those with slight and moderately renal impairment, and high serum levels lasted over a long period. Urinary excretion of ME 1206 diminished depend on the degree of renal function. In the elderly patients, serum concentration and urinary excretion did not differ greatly from those in the patients with slightly renal impairment.
2) Serum and sputum levels of ME 1206 were determined after oral administration of ME 1207 200mg to 3 patients with chronic respiratory infection. The maximum serum concentrations of ME 1206 were 3.32μg/ml, 2.55μg/ml and 2.09μg/ml. The sputum levels of ME 1206 was 0.02μg/g in one case and in the other two it was not detected.
3) Clinical results: Thirty three patients with respiratory tract infections were treated with ME 1207. The clinical response was good in 28, fair in 2, poor in 2 and undetermined in 1. As to adverse reactions, fever and nausea were observed. Laboratory tests revealed elevated GPT in 1, elevated GOT and GPT in 2 and a decline in prothronibin activity in 1. However, these abnormal findings were slight and there were no severe side effects caused by the drug.

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We carried out bacteriological and clinical studies of ME 1207.
1) Antibacterial activity: The MICs of ME 1206 against clinical isolates were measured and compared with those of cefaclor (CCL) and cefixime (CFIX). The MICs of ME 1206 against Staphylococcus aureus were 0.1-56μg/ml, which were superior to those of CCL and CFIX. The MICs of ME 1206 against Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Proteus mirabilis and Morganella morganii were 0.05-25μg/ml, which were superior to those of CCL but inferior to those of CFIX by 1 to 3 dilution steps. Against Serratia marcescens the MICs of ME 1206 were widely distributed from 0.2 to 100μg/ml, which were a little less than those of CFIX. ME 1206, the same as CCL and CFIX, showed low antibacterial activity against Pseudomonas aeruginosa.
2) Clinical study: ME 1207, the ester form of ME 1206, was administered to 21 patients comprising 7 cases of pneumonia, 6 of acute bronchitis, 1 of acute tonsillitis, 6 of acute exacerbation of chronic respiratory tract infection, and 1 of urinary tract infection. The clinical response was excellent in 2, good in 13, fair in 4 and poor in 2, giving an efficacy rate of 71.4%. No adverse reactions were observed. As to laboratory findings, elevated GOT and GPT were observed in 2 cases and elevated ALP and γ-GTP in 1 case.

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We examined the in vitro antibacterial activity and the clinical efficacy of ME 1207, a new oral cephalosporin, which is the prodrug of biologically active ME 1206.
1) Antibacterial activity: The MIC_s of ME 1206 against clinical isolates of Staphylococcus aureus and 7 species of gram-negative rods were determined and compared with those of cefixime (CFIX), cefteram (CFTM) or cefpodoxime (CPDX). Against methicillin-susceptible S. aureus, ME 1206 was 4 to 8 times more active than CFTM or CPDX, and 16 to 32 times more active than CFIX. ME 1206 showed poor antibacterial activity against methicillin-resistant S. aureus, and it was highly effective against gram-negative rods, except for Serratia marcescens and Pseudomonas aeruginosa. Against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Morganella morganii, ME 1206 was, in general, as CFTM.
2) Clinical trial: Eleven cases of respiratory tract infections, and 1 of biliary tract infection were treated with ME 1207. The dosage was 200-600mg per day for 2-12 days. Five of 10 assessable cases responded well to the therapy. No side effects were found in any case. Increase of eosinophilic leukocytes and elevation of serum alkaline phosphatase, leucine aminopeptidase and γ-glutamyltranspeptidase were found in one case.

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We performed bacteriological and clinical studies on ME 1207, a new oral cephem antibiotic, with the following results.
1. The MICs of ME 1206 against Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Branhamella catarrhalis were 0.063-1 μg/ml, which were superior to those of cefaclor (CCL), cefotiam (CTM) and cefteram (CFTM). The MIC₅₀ against methicillin-sensitive Staphylococcus aureus (MSSA) was 0.25 μg/ml, which was superior to those of CCL and CFTM, and the same as that of CTM. All these drugs including ME 1206 were, however, weak against methicillin-resistant S. aureus (MRSA) and Pseudomonas aeruginosa.
2. Sixteen patients with respiratory infections were treated with ME 1207. The overall efficacy rate was 73.3%(excellent in 2, good in 9, fair in 2 and poor in 2). No side effects were observed in any of the patients after treatment. Slight elevations of GOT and GPT were noted in one patient.

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The antimicrobial activity of ME 1206 against 429 clinically isolated strains of 28 species including 6 of gram-positive cocci and 22 of gram-negative bacilli, was compared with that of cephalexin, cefixime (CFIX), cefaclor and cefteram (CFTM). As to gram-positive cocci, the antimicrobial activity of ME 1206 against methicillin-sensitive Staphylococcus aureus and coagulase-negative Staphylococcus was superior to the other cephems and in case of Streptococcus spp. it was somewhat inferior to CFTM. Against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis the activity of all drugs was very weak. As to gram-negative bacilli, the activity of ME 1206, CFIX and CFTM against Enterobacteriaceae was superior to the other drugs. As to other gram-negative bacilli, ME 1206 showed the strongest activity against Vibrio spp., and the activity of ME 1206, CFIX and CFTM against Haemophilus influenzae was excellent. ME 1207 was administered to 8 patients with respiratory tract infections, including 6 cases with pneumonia and 2 with chronic bronchitis, at a daily doses of 200mg-600mg for 7-21 days. The response was excellent in 2 cases with pneumonia and good in the other 6 cases. The causative organisms were detected in 3 cases including one case each of Streptococcus pneumoniae, S. pneumoniae with H. influenzae and Klebsiella pneumoniae. The results of the bacteriological survey after the cessation of the treatment showed that S. pneumoniae and H. influenzae had been eradicated and K. pneumoniae remained. As to adverse reactions, eosinophilia was observed in one case.

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We performed basic and clinical studies on ME 1207, a new oral cephalosporin antibiotic, with the following results.
1) Antimicrobial activity
The MICs of ME 1206, the active substance of ME 1207, were determined with an inoculum size of 10⁶ cells/ml. Its antimicrobial activity against gram-negative rods, except Pseudomonas aeruginosa was as good as that of cefixime and cefteram. Especially, the MIC₉₀ of ME 1206was 0.39-1.56 μg/ml for Escherichia coli, Klebsiella pneumoniae and Proteus spp. Moreover, itsactivity against Staphylococcus aureus was 2-3 times higher than that of cefaclor and cephalexin.
2) Absorption and urinary excretion
The mean serum concentrations of ME 1206 reached a peak of 1.81μg/ml 3 hours after the administration of ME 1207. Its half life was 1.77 hours and the mean urinary excretion rate was 16.13%. Probenecid interfered with the urinary excretion of ME 1206, therefore, its peak level became higher and its half life was prolonged. Dried aluminium hydroxide gel had little influenced on the absorption and excretion of ME 1207, but cimetidine delayed the absorption andtherefore its peak level was lower.
3) Clinical efficacy
Three patients with pneumonia, 5 with bronchitis, 1 with pharyngitis, 3 with cystitis, 1 with epididymitis and cystitis, and 1 with appendicitis were treated with ME 1207. The patients were administered a daily dose of 300 mg or 400 mg for 3-15 days. The clinical response was excellent in 4, good in 7, fair in 1, poor in 1, and unknown in one patient. The efficacy rate was 84.6%. As adverse reactions, abdominal pain, vomiting and diarrhea were seen in a patient, and elevation of GOT, GPT and ALP was observed in another patient.

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ME 1207 was administered to 15 episodes of 13 patients with respiratory infections. The overall efficacy rate was 93.3%. There was no difference in the efficacy rate between bronchitis and pneumonia, nor was there any variation of it with regard to the severity of illness. ME 1207 eradicated Branhamella catarrhalis and Haemophilus influenzae, but in one patient infected with Xanthomonasmaltophilia the strain persisted. Mild diarrhea was noted as a side effect in one patient. Abnormal laboratory data were obtained in another patient (slight elevations of GOT and GPT). ME 1207 was administered to 8 patients with respiratory infections in a dose of 100 or 200 mg and the serum levels were determined at various times after administration. In the patients received 100 mg of ME 1207, its C_max was 1.20±0.59 μg/ml, AUC 6.30 ± 0.32μg·h/ml and T_1/2 1.99±0.54 h. The corresponding values obtained with the dose of 200 mg were 2.28 ±1.12μg/ml, 14.58± 2.88μg·h/ml and 1.76±0.40 h, respectively. In 2 patients with chronic bronchitis receiving 200 mg of ME 1207 the sputum and serum levels were determined, the ratio (sputum/serum) was 3.9% in one case.

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ME 1207, a newly developed oral cephalosporin, was compared in vitro and in vivo with cefaclor, cefixime, cefteram, ofloxacin and ciprofloxacin. The results were as follows:
1. Antimicrobial activity: Minimum inhibitory concentrations (MICs) against 480 clinical isolates of 15 different species were determined by microbroth dilution method. ME 1207 showed excellent antimicrobial activity against gram-positive bacteria, especially against Streptococcus pneumoniae and Streptococcus pyogenes. The MIC of ME 1207 for Staphylococcus aureus (MSSA) were superior to those of the other oral cephems and were comparable to new quinolones. The MICs of ME 1207 for gram-negative bacteria were equal to those of the other oral cephems.
2. Clinical efficacy and adverse reactions: Twenty-four patients with respiratory tract infections were treated with ME 1207, and the overall efficacy rate was 75%(good in 18, fair in 4, poor in 2). As to side effects, one case each of diarrhea and loose stools was observed. Laboratory tests revealed elevations of serum potassium level in one case, GOT in one, GOT and GPT in two, and an increase in the eosinophil in one, but they were mild and transient, and improved rapidly after completion of ME 1207 treatment.

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ME 1207 is a prodrug of ME 1206 which has a chemical structure similar to that of third generation cephems. We performed laboratory and clinical studies to evaluate its usefulness of the drug in respiratory tract infections. The antibacterial activity of ME 1206 against respiratory pathogenic bacteria was superior to those of other oral β-lactam antibiotics: its MIC₅₀ (the minimum concentration at which 50% of isolates are inhibited) at 10⁶cfu/ml was 0.025 μg/ml against Haemophilus influenzae, 0.013μg/ml against Streptococcus pneumoniae, 0.1 μg/ml against Branhamella catarrhalis and 6.25 μg/ml against Staphylococcus aureus. The maximal sputum levels of ME 1206 ranged from <0.025 μg/ml to 0.35 μg/ml in 3patients with respiratory tract infections and the ratios of maximal sputum levels to peak serum levels were 7.4% and 15.4% in 2 patients out of these3 patients during treatment with ME 1207. Twenty-two patients with respiratory infections were studied for clinical evaluation of ME 1207, which was administered at doses of 300mg or 600mg daily for 3 to 14 days. Causative organisms were H. influenzae (9), S. pneumoniae (7), B. catarrhalis (4), S. aureus (1), S. pyogenes (1) and E. cloacae (1). The bacteriological effect was 78.3%, and the clinical efficacy was 81.0%. From these results, we concluded that ME 1207 was one of the effective and useful orally administered antibiotics for the treatment of respiratory tract infections.

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We investigated the antibacterial activity of ME 1207, a newly developed oral cephem antibiotic, against clinical isolates and its clinical efficacy in respiratory infections.
1. Antibacterial activity Against 480 strains of 9 species isolated from clinical specimens (142 strains of Gram-positive cocci, 34 of Branhamella catarrhalis, and 304 of enterobacteria), the MICs of ME 1206, cefteram (CFTM) and cefaclor (CCL) were measured, and the results were compared. Of the three antibiotics tested, ME 1206 was the most active against MSSA (methicillin-sensitive Staphylococcus aureus) and B. catarr Against other species of bacteria, ME 1206 was as active as CFTM.
2. Clinical study
ME 1207 was administered to 12 patients with respiratory infections at doses of 200mg-600mg /day b.i.d. or t.i.d. for 6-14 days. The clinical efficacy was good in 9 cases and fair in 3. We noted no objective or subjective side effects related to the antibiotic, though a mild elevation in GPT was observed in one case.

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We performed a laboratory and clinical evaluation of ME 1207, a new oral cephem, with thefollowing results.
1) Antimicrobial activity: The minimum inhibitory concentrations (MICs) of ME 1207 were determined for 302 clinically isolated strains and compared with those of cefaclor, cefotiam, cefixime, cefteram and amoxicillin, using the MIC-2000 system. ME 1207 showed antimicrobial activity clinical isolates except MRSA, Enterococcus faecalis, Enterobacter cloacae, Citrobacter freundii, Acinetobacter calcoaceticus and Pseudomonas aeruginosa.
2) Clinical efficacy: ME 1207, at a dose of 100 mg t. i. d., was administered to 1 patient with bronchiectasis, 5 patients with chronic bronchitis and 3 patients with acute bronchitis. One patient with chronic bronchitis was treated with ME 1207 at a dose of 200mg t. i. d. Another patient was treated with at a dose of 100mg t. i. d. at first, then the dose was increased to 200mg t. i. d. The clinical response was excellent in 2 patient, good in 8 and fair in 1. The overall clinical efficacy rate was 91%. Three strains of Haemophilus influenzae and two strains of Streptococcus pneumoniae were eradicated. No side effects were observed. As to abnormally altered laboratory findings slight elevation of GOT, GPT was observed in one patient.

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To evaluate the appropriate clinical dose of ME 1207, a new oral cephem, in the treatment of acute exacerbation of chronic bronchitis, we performed a dose-finding comparative study using cefteram pivoxil (CFTM-PI) as the control drug. Patients were given a daily dose of ME 1207 100mg (t. i. d.) or 200mg (t. i. d.) or CFTM-PI 200mg (t. i. d.) for 14 days, in principle. The following results were obtained.
1. The clinical efficacy rates (excellent and good only) as judged by the committee which was organized for the study, were 91.7%(33/36) in the ME 1207 300mg group, 88.6%(31/35) in the ME 1207 600mg group and 82.8%(24/29) in the CFTM-PI group.
2. Bacteriologically, the eradication rates were 80.0%(16/20) in the ME 1207 300mg group, 87.5%(14/16) in the ME 1207 600mg group and 92.3%(12/13) in the CFTM-PI group.
3. As to side effects, mild nausea and upper abdominal pain were observed in the ME 1207 300mg group.
4. The incidence of laboratory abnormalities as judged by the committee were 20.6%(7/34) in the ME 1207 300mg group, 29.4%(10/34) in the ME 1207 600mg group and 18.8%(6/32) in the CFTM-PI group. The majority of the abnormalities were mild eosinophilia and elevation of transaminase.
5. The utility rates (markedly useful and useful only) as judged by the committee were 88.9%(32/36) in the ME 1207 300 mg group, 88.6%(31/35) in the ME 1207 600 mg group and 82.8%(24/29) in the CFTM-PI group. There were no significant differences among the three groups with regard to any of the results presented above. We concluded that a daily dose of 100mg (t. i. d.) is a suitable clinical dosage for ME 1207 in the treatment of acute exacerbation of chronic bronchitis.

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Bacteriological and clinical studies on ME 1207, a new oral cephem, were carried out.
1. Bacteriological study: The MICs of ME 1206, an active metabolite of ME 1207, cefixime (CFIX), cefteram (CFTM) and cefaclor (CCL) against clinical isolates from patients with urinary tract infections, were determined using the MIC 2000 system. The MIC₉₀ of ME 1206 was superior to those of CFIX, CFTM and CCL against Staphylococcus aureus and Staphylococcus epidermidis. Against Enterococcus faecalis, Enterococcus faecium, Serratia marcescens, Enterobacter spp. and Pseudomonas aeruginosa, the MIC₉₀ of all drugs was more than 100μg/ml. Against Neisseria gonorrhoeae, the MIC90 of ME 1206 was less than 0.10μg/ml
2. Clinical study: ME 1207 was administered to 6 patients with acute uncomplicated cystitis (AUC), 5 patients with chronic complicated cystitis (CCC), 15 patients with gonococcal urethritis and 1 patient with gonococcal cervicitis. The response of patients with AUC was excellent in 1 and good in 2 cases, the response of those with CCC was excellent in both 2 cases: the response of patients with gonococcal urethritis was excellent in 3, good in 3 and poor in 1 case and the response of those of gonococcal cervicitis was excellent in 1 case. No side effects or abnormal laboratory findings were observed.

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Eighty patients with urological infections were treated with the novel oral cephem antibiotic, ME127, in doses of 2 to 6 mg/day, and the following results were obtained. The drug was effective in 1% of the 15 patients with acute uncomplicated cystitis and in 69.4% of the 36 patients with chronic complicated urinary tract infection according to the criteria proposed by the Japanese UTI Committee, and in 8 out of 9 male patients with urethritis and in the 1 patient with chronic prostatitis. As to side effects of the drug, two patients had loose stools and 1 had diarrhea. Regarding laboratory finding, 7 patients elevated GOT and GPT, but these values normalized within a week after completion of therapy.

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ME 1207, a new oral cephem, was evaluated for its antimicrobial activity and clinical efficacy in urinary tract infections (UTI) The following results were obtained.
1) The in vitro antimicrobial activity of ME 1206, an active metabolite of ME 1207, against clinical isolates was compared with that of cefteram (CFTM), cefixime (CFIX) and cefaclor (CCL). Against gram-negative bacilli, its activity was similar to that of CFTM and CFIX, and it was superior than that of CCL. Regarding Staphylococcus spp., its activity was superior to all of the other agents.
2) The clinical efficacy of ME 1207 was evaluated in 34 patients with UTI. Five patients with acute uncomplicated cystitis (AUC) were treated with a daily dose of 300mg for 3-5 days. The other 29 patients who had either complicated cystitis or pyelonephritis (complicated UTI) were treated with a daily dose of 300 or 600mg for 4-7 days. According to the criteria proposed by the Japanese UTI Committee, the clinical efficacy of AUC was excellent in 3 and moderate in 1 and the overall clinical efficacy rate was 60%(15/25) in complicated UTI. Bacteriologically all strains were eradicated in AUC and 19 out of 29 strains were eradicated in complicated UTI. Side effects were not observed, and abnormal laboratory findings such as slight elevation of transaminase were found in only three patients. The results suggest that ME 1207 can be an effective antimicrobial agent in UTI.

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We evaluated ME 1207, a new oral cephem antibiotic, bacteriologically and clinically in urinary tract infections, and obtained the following results.
The in vitro antimicrobial activity of ME 1206, an active derivative of ME 1207, was assessed against 483 clinically isolated strains (llspecies) and compared with those of cefaclor (CCL), cefteram (CFTM), cefixime (CFIX), cefdinir (CFDN), cefetamet (CETM) and cefpodoxime (CPDX). ME 1206 was as effective as CFDN against Staphylococcus epidermidis and Enterococcus faecalis, and as effective as CFTM against Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis.
We treated 7 patients with complicated urinary tract infections with ME 1207 300 or 600mg daily in 3 divided doses for 5 days, and assessed the results according to the Japanese UTI Committee's criteria. The clinical efficacy was excellent in 3, good in 2, poor in 2. Bacteriologically, 6 out of 7 strains were eradicated.
As to side effects, heaviness of the head and nausea were noted in one patient and headache in one. No abnormal laboratory findings were observed.

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