Ritipenem acoxil (RIPM-AC) is a new orally active penem antibiotic. The in vitro antibacterial activities of its active form, ritipenem (RIPM), were compared with those of cefaclor (CCL), cefixime (CFIX), and cefteram (CFTM). The results were as follows.
1. RIPM had a broad spectrum of antibacterial activity and was active against both aerobic and anaerobic gram-positive and gram-negative bacteria. RIPM showed more potent activity than CCL, CFIX, and CFTM against methicillin-susceptible Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Enterococcus faecalis, Citrobacter freundii, Enterobacter cloacae, Morganella morganii, Acinetobacter calcoaceticus, Clostridium spp., and Bacteroides fragilis.
2. RIPM showed potent bactericidal activity (MIC/MBC) against gram-positive and gramnegative clinical isolates. Time-kill studies against S. aureus and E. coli showed potent bactericidal activity of RIPM at concentrations above the MIC level.
3. RIPM was found to possess stronger activity than CCL against β-lactamase-producing strains except Pseudomorzas aeruginosa and Stenotrophomonas (Xanthomonas) maltophilia. In particular, RIPM was more active than CFIX and CFTM against cephalosporinase-producing strains of C. freundii and E. cloacae.
4. RIPM was stable to various types of β-lactamases except for L-1 enzyme from S.(X.) maltophilia. The enzymes from C. freundii GN7391 and E. cloacae GN7471 strains showed a high affinity for and slow hydrolysis of RIPM.

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Ritipenem (in vivo, ritipenem acoxil), a new penem with a broad antibacterial spectrum and potent antibacterial activity, was evaluated for its in vitro and in vivo antibacterial activities in comparison with cefixime, cefpodoxime (in vivo, cefpodoxime proxetil), cefteram (in vivo, efteram pivoxil) and cefaclor. Against genus Staphylococcus including methicillin-resistant Staphyococcus aureus and Enterococcus faecalis, ritipenem showed more potent activity than the reference drugs. Against the family of Enterobacteriaceae, Haemophilus influenzae and Neisseria gonorrhoeae including PPNG, ritipenem was comparable to cefixime, cefpodoxime and cefteram, and superior to cefaclor. Against Pseudomonas aeruginosa, ritipenem had little activity, similar to the reference drugs.
The in vivo efficacy of ritipenem acoxil was superior to that of the reference drugs against experimental septicemia caused by MSSA and imipenem-or quinolone-resistant S. aureus. Against E. coil C 11 and S. marcescens No.2, the efficacy of ritipenem acoxil was superior to that of cefaclor.
These in vivo results indicate that the in vitro activity and stability to β-lactamase of ritipenem is reflected by its in vivo efficacy in mice septicemia caused by gram-positive and gram-negative bacteria.

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Ritipenem (RIPM) is a novel oral penem antibiotic with a broad antibacterial spectrum. The MIC_90s of RIPM against clinical isolates of Staphylococcus aureus (50 strains), methicillin-resistant Staphylococcus aureus (MRSA)(48 strains), coagulase-negative staphylococci (41 strains), Streptococcus pneumoniae (24 strains), Streptococcus pyogenes (50 strains), Enterococcus faecalis (39 strains), Enterococcus faecium (40 strains), Escherichia coli CS2 (R+)(51 strains), Klebsiella, pneumoniae (50), Proteus mirabilis (50 strains), Proteus vulgaris (35 strains), Providencia rettgeri (27 strains), Serratia marcescens (50 strains), Enterobacter cloacae (50 strains), Citrobacter freundii (50 strains), Acinetobacter calcoaceticus (49 strains), Pseudomonas aeruginosa (50 strains), Burkholderia cepacia (40 strains), Xanthomonas maltophilia (50 strains), ABPC-resistant Haemophilus influenzae (26 strains) and Bacteroides fragilis (40 strains) were 0.39, >100, 50, 0.39, 0.05, 6.25, >100, 1.56, 0.39, 1.56, 1.56, 50, 100, 12.5, 25, 3.13, >100, 25, >100, 0.78 and 0.39μg/ml, respectively. RIPM showed stronger anti-staphylococcal activity than other oral cephalosporins tested. RIPM had equal or stronger activity than imipenem (IPM), and stronger activity than cefmetazole (CMZ), flomoxef (FMOX) and cefazolin (CEZ) against heterogeneous MRSA strains. Against E. faecalis, RIPM was the most active among the β-lactams tested. RIPM appeared to be resistant to the wide range of β-lactamases tested. In particular, it was also active against the clinically important β-lactamase-producing strains of H. influenzae. RIPM was also extremely active against B. fragilis strains which produce oxyiminocephalosporinase. RIPM was slightly less active against members of Enterobacteriaceae except for E. cloacae and C. freundii than other β-lactams.
RIPM manifested greater binding affinities to PBPs 2 and 3 of S. aureus 209P than IPM, however, it had lower affinity to PBP2' of an MRSA 6-2 strain than IPM. RIPM showed binding affinities as strong as those of IPM to PBPs of E. coli NIHJ JC-2 and S. marcescens 13.
RIPM showed potent inhibitory activities as strong as those of IPM against β-lactamases of type I c and type V.
RIPM showed moderate synergy with complement, and good synergy with mouse macrophages in the bactericidal effect on E. coli NIHJ JC-2 cells. Cultured mouse macrophages well engulfed and digested E. coli cells in the presence of more than 1/4 MIC of RIPM.
RIPM was more stable against human renal dehydropeptidase- I than IPM.

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The in vitro activity of ritipenem (RIPM) was evaluated by using a total of 360 isolates of anaerobic bacteria including reference strains and fresh clinical isolates. RIPM had a broad antibacterial spectrum against gram-positive and gram-negative bacteria, most of which were inhibited by 1.56 μg/ml. RIPM was superior to cefaclor and other oral reference compounds.
RIPM was especially active against β-lactamase producing isolates including Bacteroides fragilis and Prevotella bivia. This drug showed strong activity against Peptostreptococcus spp., especially P. anaerobius.
RIPM, at or above 1/2 MIC, was bactericidal against B. fragilis GAI 5562 and induced their filamentation. This compound was very stable against the representative, B β-lactamase preparation from B. fragilis GAI 10150, but was unstable against that from B. fragilis GAI 30144, which was resistant to imipenem. Ritipenem acoxil (RIPM-AC) increased the viable counts of Clostridium difficile in the caecum of mice given a daily dose of 100 mg/kg for 5 days orally.

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In this study we tested the in vitro antibacterial activity of ritipenem (RIPM), the parent compound of ritipenem acoxil (RIPM-AC), and the in vivo therapeutic efficacy of RIPM-AC, a new orally active ester derivative of RIPM, against experimental mouse infections in comparison with cefaclor (CCL), cefixime (CFIX), cefotiam (CTM) and cefteram pivoxil (CFTM-PI).
RIPM had a broad antibacterial spectrum against gram-positive and gram-negative bacteria, and its antibacterial activity was superior to those of CCL, CTM and CFIX against the gram-positive bacteria such as Staphylococcus spp. and Streptococcus spp. On the other hand, the activity of RIPM against gram-negative bacteria was superior to that of CCL and inferior to that of CFIX.
In the sensitivity distribution of clinically isolated strains, RIPM showed poor activity against MRSA, but was superior to CCL, CTM and CFIX against the gram-positive bacteria such as Staphylococcus spp. and Enterococcus spp.
RIPM showed good activity against the gram-negative bacteria such as P. vulgaris, M. morganii, P. rettgeri, Enterobacter spp. and S. marcescens, which were resistant to CCL.
The activity of RIPM was largely unaffected by the addition of horse serum and inoculum size, but its activity against S. aureus was enhanced in acidic media. RIPM showed dose-related bactericidal activity against S. aureus, E. coli, K. pneumoniae, S. marcescens, A. calcoaceticus and M. catarrhalis.
The therapeutic efficacy of RIPM-AC in intraperitoneal infections in mice was superior to that of CFIX, comparable to that of cefotiam hexetil (CTM-HE) and inferior to that of CCL. In S. pneumoniae infections in mice, RIPM-AC was comparable to CTM-HE and superior to CFIX and CCL. Against S. pyogenes C203, E. coli KC-14 and K. pneumoniae KC-1, RIPM-AC was inferior to CCL, CTM-HE and CFIX, while RIPM-AC was superior to CCL, CTM-HE and CFIX against A. calcoaceticus Ac-54.
In an experimental pulmonary infection with K. pneumoniae B- 54 in mice, the therapeutic efficacy of RIPM-AC was inferior to that of CFIX and CFTM-PI, but comparable to that of CCL.

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The antibacterial effect of ritipenem (RIPM) against Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Acinetobacter calcoaceticus was examined by phase-contrast, scanning electron and transmission electron microscopy from the viewpoint of morphological alteration. Moreover, the affinity of RIPM for penicillin-binding proteins (PBPs) in E. coli was evaluated.
When E. coli and S. marcescens were exposed to RIPM, bulge cells, spherical cells and cell lysis were observed.
Against K. pneumoniae and A. calcoaceticus, RIPM induced spherical cells and cell lysis.
An inner membrane defect was observed at the swollen site of bulge cells in E. coli and at spherical cells with swollen septa in A. calcoaceticus.
RIPM showed excellent affinity for PBP2 in E. coli.
These results agree with the morphological changes in E. coli treated with RIPM.

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Ritipenem (RIPM) is a new penem antibiotic whose in vitro antibacterial activitywe assessed against 545 strains of clinical isolates of gram-positive and -negative bacteria.
Against gram-positive bacteria, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis, RIPM was superior to cefaclor (CCL), cefixime (CFIX) and cefpodoxime (CPDX).
The activity of RIPM was comparable with that of CFIX and CPDX, and greater thanthat of CCL against gram-negative bacteria.
Fine structures of RIPM-treated methicillin-resistant Staphylococcus aureus (MRSA) revealed that RIPM interfered with cell wall and cross wall formation.

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We investigated the antimicrobial activity of ritipenem acoxil against fresh strains clinically isolated from January to September 1993.
The results were as follows:
1. The distribution of the minimum inhibitory concentrations (MICs) of ritipenem (RIPM) against methicillin (DMPPC)-resistant Staphylococcus spp. showed two peaks.
The MICs of RIPM against DMPPC moderately resistant strains (MIC of DMPPCs≤50μg/ml) were distributed in the low concentration range, and the MICs of RIPM against DMPPC highly resistant strains (MIC of DMPPC≥100 μg/ml) were distributed in the high concentration range.
2. RIPM showed potent antimicrobial activity against benzylpenicilin (PCG)-insensitive Streptococcus pneumoniae and-PCG resistant Streptococcus pneumoniae.
3. RIPM showed strong antimicrobial activity against third-generation cephem-resistant Enterobacteriaceae (Escherichia coli, Klebsiella spp., Proteus group), Moraxella subgenus Branhamella catarrhalis, and Bacteroides fragilis group.
4. The MIC₉₀ of RIPM against Citrobacter freundii was high, and Acinetobacter spp. and Burkholderia cepacia showed some strains that were highly resistant to RIPM.
5. The MIC of RIPM against Haemophilus influenzae was inferior to that of the third-generation cephems. It is important that we consider fully the antimicrobial activity of RIPM against each organism when administering it in the clinical field.

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We carried out a basic study on ritipenem acoxil, a new oral penem antibiotic. Ritipenem acoxil at a dose of 20 mg/kg was orally administered to New Zealand white male rabbits to measure the penetration of ritipenem acoxil in various tissues, and a pharmacodynamic analysis was carried out.
The Tmax of ritipenem in serum was 0.24 hour in the infected group and slightly later in the healthy group, while the Cmax were 12.05 μg/ml and 11.33 μg/ml, respectively. In tissues, the Tmax in the infected group was 0.19-0.26 hour, and the Cmax was 6.74-7.15 μg/g.
The serum level and tissue penetration were similar in both groups. In the case of the infected group, the Tmax was earlier and the Cmax indicated penetration that was 1.0-2.5 times higher than in the healthy group.

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The maximum killing and effective regrowth time (ERT) of ritipenem (RIPM), a novel penem, and cefaclor (CCL) were investigated. The maximum killing of RIPM and CCL against Staphylococcus aureus Smith were-31 and-0.32, respectively, and against Klebsiella pneumoniae BK, 0 and-0.66, respectively.
The durations of the ERT for RIPM and CCL against S. aureus Smith were 3.5 h and 2.9 h, respectively, and against K. pneumoniae BK, 1.0 h and 2.8 h, respectively, in a neutropenic mouse thigh-infection model.
Five neutropenic mice received 25 mg/kg and 50 mg/kg of RIPM by subcutaneous administration. The plasma concentration was fitted to a one-compartment model, and the mean pharmacokinetic parameters were, respectively, T_1/2 8.3 min and 9.0 min, AUC 180.6μg/ml·min and 314.0μg/ml·min.

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Since β-lactams have been reported to induce convulsions, we studied the convulsant activity of ritipenem (RIPM), an active form of ritipenem acoxil (RIPM-AC), and its effect on the receptor binding of γ-aminobutyric acid (GABA), an inhibitory transmitter in the central nervous system. Intraventricular injection of imipenem (IPM), cefazolin (CEZ) and cephaloridine (CER) induced convulsions in mice in a dose-dependent manner, whereas RIPM did not induce convulsion up to 200 nmol/brain. These β-lactams inhibited GABA receptor binding in a concentration-dependent manner. The order of inhibitory activity was IPM>CEZ>CER≥RIPM. These in vivo and in vitro results suggest that RIPM might have weaker convulsant activity than IPM, CEZ and CER.

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The antimicrobial activity of the new oral penem ritipenem (RIPM), the active form of the prodrug ritipenem acoxil (RIPM-AC), was determined against Streptococcus pneumoniae and other recent clinical pathogens in comparison with other agents. The antimicrobial activity of RIPM against both penicillin-sensitive and penicillin-resistant S. pneumoniae, was superior to that of 14 β-lactam agents. MICs of RIPM against S. pneumoniae ranged from≤0.025 to 0.2μg/ml, and MIC_90% was 0.1μg/ml. RIPM also showed good acitivity against Streptococcus pyogenes, Streptococcus agalactiae, almost all species of Enterobacteriaceae except Serratia marcescens, Haemophilus influenzae, Bacteroides fragilis, and Fusobacterium spp., but not against gramnegative glucose-nonfermenters including Pseudomonas aeruginosa and Xanthomonas maltophilia.

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A high performance liquid chromatographic method was developed for determination of ritipenem (RIPM), the active metabolite of ritipenem acoxil (RIPM-AC){(+)-(5R, 6S)-acetoxymethyl 3-carbamoyloxymethyl-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate monohydrate}, in human plasma and urine. Plasma samples were deproteinized by the ultrafiltration method, and the filtrates were analyzed by a reversed-phase column using the two-sided bracketing injection technique. In the plasma samples spiked with RIPM, the calibration curve showed good linearity in the range of 0-5.0 μg/ml. The recovery of RIPM was quantifiable; coefficients of within-day and between-day variation were less than 4.8% and 3.2%, respectively. In the urine samples spiked with RIPM, the calibration curve in the range of 0-1000μg/ml and the reproducibilities were similarly satisfactory. The determination limits were 0.05μg/ml in plasma and 2.5μg/ml in urine. The stability of RIPM in plasma was confirmed at -20°C for a month in addition to stabilizer. Correlations between the proposed method and bioassay were satisfactory for both plasma and urine samples.

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A microbiological assay procedure has been developed for the determination of ritipenem, an active form of ritipenem acoxil, in human plasma and urine.
1) Drug concentrations were determined by Bacillus subtilis ATCC 12432 as the teststrain and nutrient agar supplemented with 5% trisodium citrate dihydrate as the test medium.
2) For the quantitative determination of ritipenem, an equal volume of a stabilizer, 1 M MOPS [3-(N-morpholino)-propanesulfonic acid](pH 5)/ethylene glycol (1: 1), was added to plasma, serum and urine samples. The lowest detectable concentration of ritipenem was 0.04μg/ml, when measured by a paper disk method.
3) The activity of ritipenem in human body fluids mixed with an equal volume of the stabilizer was unchanged during 28 days' storage at-80°C.

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Ritipenem acoxil (RIPM-AC) is a new esterified oral penem antibiotic. When orally administered, ritipenem acoxil is hydrolyzed to ritipenem (RIPM), which has antibacterial activity.
We determined the antibacterial activity of ritipenem against 7 species of 209 clinical isolates, and compared it with those of ampicillin (ABPC), cefaclor (CCL), cefixime (CFIX), cefteram (CFTM) and cefpodoxime (CPDX). RIPM showed better antibacterial activity than 5 comparative antibiotics against Staphylococcus aureus and Klebsiella pneumoniae. The antibacterial activity was similar to that of CCL against Escherichia coli and Proteus mirabilis, similar to that of CFIX and CPDX against Morganella morganii, and similar to that of CFTM and CPDX against Serratia rnarcescens. There was no antibacterial activity against Pseudomonas aeruginosa.
RIPM-AC was administered to 30 patients with respiratory tract infections at doses of 150 to 500mg t. i. d. for 4 to 14 days. The clinical response in 29 patients was excellent in 5, good in 19 and fair in 5. Twenty-one strains were identified as causative organisms in 17 cases: 17 strains were eradicated, 2 were decreased, 1 persisted and 1 was replaced.
As adverse reactions, anorexia and stomach discomfort were observed in 1 patient, and anorexia in another. As abnormal laboratory data, a mild elevation of GOT was observed in 1 patient.

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We investigated the clinical efficacy and safety of ritipenem acoxil (RIPM-AC), a new oral penem antibiotic, in patients with respiratory tract infections.
A daily dose of 600-900mg of RIPM-AC was given orally for 7-15 days to 11 patients after a meal: 4 with pneumonia, 2 with chronic bronchitis and 5 with secondary infections to chronic respiratory disease.
The clinical efficacy was excellent in 2 patients, good in 7 and fair in 2, an efficacy rate of 81.8%.
Eight strains (3 strains of Haemophilus influenzae, 2 strains of Streptococcus pneumoniae and one strain each of Enterobacter aerogenes, Morganella morganii, Pseudomonas aeruginosa) were identified as causative organisms from sputum. Seven strains were eradicated, and the other one (P.aeruginosa) persisted.
Neither side effects nor abnormal laboratory findings were observed.

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A clinical investigation of ritipenem acoxil (RIPM-AC), a new penem antibiotic, was performed, and the results were as follows:
1) Antibacterial activity
MIC₉₀ (the minimum inhibitory concentration at which 90% of isolates were inhibited) values of ritipenem (an active compound of RIPM-AC) at 10⁶cfu/ml were 0.78μg/ml, 0.39μg/ml, and 0.05μg/ml against Haemophilus influenzae, Moraxella (Branhamella) catarrhalis and Streptococcus pneumoniae, respectively.
2) Clinical study
Seventeen patients with respiratory tract infection (chronic bronchitis 7, acute bronchitis 4, bronchiectasis 3, old pulmonary tuberculosis 2, chronic pulmonary emphysema 1) were given 600-900mg per day orally for 7-16 days. The clinical efficacy rate was 70.6%(good 12, fair 3, poor 2). Seven of 10 causative organisms (3/6 S.pneumoniae, 1/1 H.influenzae, 2/2 β-lactamase positive M.(B.) catarrhalis, 1/1 Staphylococcus aureus) were eradicated.
A subjective side effect, nausea, was observed in one patient, while transient slight elevations of total bilirubin and urine protein were seen in two patients.

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We measured the in vitro antimicrobial activity of ritipenem acoxil (RIPM-AC), a new oral penem antibiotic developed in Italy, and evaluated its therapeutic efficacy in respiratory tract infections. The minimum inhibitory concentrations (MICs) of RIPM-AC, cefteram (CFTM) and cefaclor (CCL) against 20 strains each of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa, and 18 strains of Haemophilus influenzae, were determined by the micro-broth dilution method using the Dynatech MIC 2000 system. As shown by the MICs, RIPM-AC was the most active against MSSA and MRSA of the above three antibiotics. Against H.influenzae, E.coli, K.pneumoniae, E.cloacae and S.marcescens, RIPM-AC was more active than CCL, but less active than CFTM. RIPM-AC was considered to be less potent against infections caused by P.aeruginosa. An oral dose of 450-1200mg of RIPM-AC was given daily to 37 patients for 2 to 18 days (mean: 11.7 days): 5 patients with acute bronchitis, 4 patients with chronic bronchitis, 14 patients with bronchiectasis plus infection, one patient each with pulmonary emphysema plus infection and pulmonary fibrosis plus infection, 11 patients with acute pneumonia and one patient with pulmonary tuberculosis. Cl inical efficacy was excellent in 5, good in 22, fair in 6 and poor in 2 patients (efficacy rate: 77.1%). Two cases were excluded from clinical evaluation because one had pulmonary tuberculosis and because treatment in the other case was stopped on the second day due to adverse reaction. Clinical efficacy was poor in cases treated with low doses (450mg), but was good in cases treated with 600, 900 or 1200mg of RIPM-AC. Eighteen strains were identified as causative organisms: 2 strains of S.aureus (one of them was MRSA), 3 strains each of Streptococcus pneumoniae and Moraxella catarrhalis, 8 strains of H.influenzae, and one strain each of P.aeruginosa and Pseudomonas putrefaciens. Eight of them were eradicated by administration of RIPM-AC. Anorexia occurred in one patient. Elevations of s-GOT, s-GPT and eosinophils as well as drug exanthema were observed in one patient. Elevation of s-GOT occurred in one patient. These adverse reactions disappeared after the completion of therapy. From the above results, we conclude that a daily dose of more than 600mg of RIPM-AC is required for the treatment of respiratory tract infections.

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The pharmacokinetics and clinical efficacy of ritipenem acoxil, a new oral penem antibiotic, were studied.
1. Pharmacokinetics: the influence of probenecid was investigated in 6 healthy volunteers orally given 200 mg of ritipenem acoxil with or without 1.5 g of probenecid by cross-over method. With probenecid, the T_1/2 of ritipenem (the active form of ritipenem acoxil) was prolonged from 0.61 h (without probenecid) to 0.91 h, Cmax and AUC increased from 1.88μg/ml and 2.55 μg·h/ml to 2.87μg/ml and 4.53μg·h/ml, respectively, and renal clearance decreased from 139.7ml/min to 32.6ml/min. These results suggest that tubular excretion was involved in the renal excretion of the drug.
2. Clinical efficacy: ritipenem acoxil was administered in daily doses of 450-1500mg (t. i. d.) to seven patients, 1 with tonsillitis, 2 with acute bronchitis and 4 with pneumonia. The clinical response was excellent in 1 patient, good in 4, fair in 1 and poor in 1. No side effects were found. In one patient we observed an increased transaminase level in blood.

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The antibacterial activity of ritipenem (RIPM), a metabolite of ritipenem acoxil (RIPM-AC), a new oral penem, was compared with that of cefotiam (CTM) using an in vitro pharmacokinetic system. The activity of RIPM was higher than that of CTM against Staphylococcus aureus 209 P JC 1 and Streptococcus pneumoniae IID 553, but less than CTM against Escherichia coli NIHJ JC 2 and as active as CTM against Haemophilus influenzae IID 984. The clinical response was excellent in 2 cases, good in 15. The overall efficacy rate was 100%. Seven causative organisms were identified. One strain each of S. pneumoniae, Acinetobacter calcoaceticus, and Pseudomonas aeruginosa, and 2 strains of H. influenzae were eradicated, while1 strain each of S. aureus and P. aeruginosa persisted. No side effects or abnormal changes in laboratory findings attributable to RIPM-AC were observed.

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We carried out basic and clinical studies on ritipenem acoxil, a new oral penem antibiotic, and obtained the following results.
The MICs of ritipenem acoxil (RIPM-AC) were compared with those of other tested antibiotics, clavulanic acid/amoxicillin (CVA/AMPC), sultamicillin (SBTPC), cefotiam (CTM), cefpodoxime (CPDX), cefteram (CFTM), cefixime (CFIX) and minocycline (MINO), in 320 clinical isolates of 16 species. Ritipenem showed stronger antibacterial activity against gram-positive bacteria.
In clinical studies, RIPM-AC was administered to 17 patients with respiratory infections. Clinical efficacy was excellent in 3, good in 11, fair in 1 and poor in 2 patients, an efficacy rate of 82.4%.
Neither side effects nor abnormal laboratory findings were observed.

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Ritipenem acoxil (RIPM-AC) is a new penem antibiotic developed for oral administration. We examined the pharmacokinetic properties and clinical efficacy of RIPM-AC in respiratory infections in elderly patients.
RIRM-AC (200 mg) was administered to 7 elderly subjects, 60 to 81 years of age, to assess its pharmacokinetic properties. The peak blood concentration (Cmax) of RIPM was 2.42 μg/ml, which was reached 0.96 hours after administration. The half-life of blood concentration (T_1/2) of RIPM was 0.79 hours. The area under the blood level-time curve up to 4 hours after administration (AUC_0-4h) was 3.83μg·hr/ml. The urinary recovery rate of RIPM was 17.4%. The subjects' age seemed not to have adversely affected the pharmacokinetic properties of RIPM.
RIPM-AC was administered to 12 patients with respiratory infections to assess the clinical efficacy of the new antibiotic in these infections. A dose of 200 mg to 300 mg of the test antibiotic was orally administered to the study patients 3 times a day after meals. This group consisted of 3 patients with acute bronchitis, 1 with acute tonsillitis, 4 with chronic bronchitis, and 4 with secondary infections of chronic respiratory diseases (2 with bronchial asthma, 1 with bronchiectasis, and 1 with pulmonary emphysema). The efficacy rate was 81.8%(9/11). There were 4 patients in whom a single causative organism was confirmed by serial bacterial cultures to be responsible for the infection. These 4 patients were analyzed with regard to the bacteriologic effect of RIPM-AC.
One strain of Streptococcus pneumoniae, 1 of Klebsiella pneumoniae, 1 of Pseudomonas aeruginosa, and 1 of Moraxella catarrhalis were isolated from the bacterial cultures of clinical specimens obtained from these 4 patients. In 3 cases, the causative organism was eradicated.
No adverse clinical or laboratory events were noted.
Our findings showed that age does not markedly alter the pharmacokinetics o RIPM-AC. Thus, RIPM-AC may be clinically useful in the treatment of respiratory infections in elderly patients.

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We performed bacteriological and clinical studies on ritipenem acoxil (RIPM-AC), a new oral penem antibiotic, with the following results.
1. The MIC₉₀ of ritipenem (RIPM) against Staphylococcus aureus was 0.25 μg/ml, second to that of imipenem/cilastatin Na (IPM/CS) and superior to those of cefotiam (CTM), cefixime CFIX), cefpodoxime (CPDX) and ampicillin (ABPC). The MIC₉₀, against Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were 2 μg/ml, 1 μg/ml, 0.5 μg/ml and 1 μg/ml, respectively. RIPM was, however, weak against methicillin-resist ant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa.
2. Twelve patients with respiratory infections were treated with RIPM-AC. The overall efficacy rate was 81.8%(excellent 1, good 8, fair 1, poor 1, unkown 1). No clinical side effects were observed, but elevation of S-GOT was observed in 2 cases after treatment.

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We performed laboratory and clinical studies on ritipenem acoxil (RIPM-AC), a new oral penem antibiotic, with the following results.
1. Antimicrobial activity
Minimal inhibitory concentrations (MIC) of ritipenem (RIPM) were measured for 223 clinical isolates of 11 species, and its antimicrobial activity was compared with ampicillin (ABPC), cefaclor (CCL), cephalexin (CEX) and cefpodoxime (CPDX). The MIC values of RIPM against gram-positive cocci were equal to those of ABPC, and superior to those of CCL, CEX and CPDX. In contrast, those of RIPM against gram-negative bacteria were superior to those of ABPC, CCL and CEX, but inferior to those of CPDX.
2. Clinical efficacy
The clinical efficacy of RIPM-AC was evaluated in 12 patients: 6 with pneumonia, 1 with bronchopneumonia, 3 with bronchitis, 1 with bronchiectasis and 1 with lung abscess. The patients were given a daily dose of 450-600 mg for 7-28 days. The clinical response was excellent in 2 cases, good in 8, fair in 1, and poor in 1, the efficacy rate being 83.3%. Bacterial strains were eradicated in 1 case, decreased in 4 and unchanged in 1 by treatment with RIPM-AC. As adverse reactions, dyspepsia and eosinophilia and elevation of GPT were observed in one case each.

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We evaluated the in vitro antimicrobial activity and the clinical efficacy of ritipenem acoxil, a newly developed broad-spectrum penem, and obtained the following results.
1. Anitimicrobial activity: Minimal inhibitory concentrations (MICs) of ritipenem, imipenem, cefaclor, cefixime, cefteram, and cefotiam against 515 clinical isolates including 16 different species were determined by the microbroth dilution method. Ritipenem showed excellent antimicrobial activity against gram-positive and -negative bacteria. The MIC values of ritipenem against gram-positive bacteria were the best among the antibiotics tested. Against gram-negative bacteria the antimicrobial activity was slightly inferior to that of imipenem, but superior to those of the other antibiotics tested.
2. Clinical efficacy and adverse reactions: 15 patients with respiratory tract infection were treated with ritipenem acoxil, and the overall efficacy rate was 78.6%(excellent in 2 cases, good in 9, fair in 1, poor in 2, unknown in 1). Regarding adverse reactions, mild diarrhea was observed in one patient. Abnormal laboratory findings were observed in 2 cases (eosinophilia and thrombocytosis), but were mild and transient.
From these data, we conclude that ritipenem acoxil is a useful antibiotic for the treatment of respiratory tract infectious diseases.

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We performed laboratory and clinical studies on ritipenem acoxil, a new oral penem, in order to evaluate its usefulness in respiratory tract infections. We determined the antibacterial activity of ritipenem acoxil against respiratory pathogenic bacteria: its MIC₅₀ and MIC₉₀ were 0.05 and 1.56μg/ml against Streptococcus pneumoniae (50 strains), 1.56 and 3.13μg/ml against Haemophilus influenzae (42 strains), 0.2 and 0.78μg/ml against Moraxella catarrhalis (41 strains), 0.2 and 0.78μg/ml against methicillin-susceptible Staphylococcus aureus (28 strains) and 100 and >100μg/ml against methicillin-resistant Staphylococcus aureus (25 strains). However the MICs of 11 strains of methicillin-resistant Staphylococcus aureus were less than 3.13μg/ml.
The maximal serum level of ritipenem acoxil was 1.41 μg/ml, and its maximal sputum level was 0.12μg/ml after a single dose of 400 mg.
Eleven patients with respiratory infections were studied for the clinical evaluation of ritipenem acoxil, which was administered at a dose of 200 mg, 300 mg or 500 mg t.i.d. The clinical efficacy was excellent in 1, good in 6, fair in 1 and poor in 3 patients. The overall efficacy rate was 63.6%.
The causative bacteria were Streptococcus pneumoniae (3), Haemophilus influenzae (3), Moraxella catarrhalis (5), Staphylococcus aureus (1) and Pseudomonas aeruginosa (2). After ritipenem acoxil administration, 7 of 14 strains (50.0%) were eradicated.
There were no side effects or abnormal laboratory findings in patients after the administration of ritipenem acoxil.
We conclude that a daily dose of ritipenem acoxil in the treatment of acute and chronic respiratory infection was 300 mg (t.i.d.) and 500 mg (t.i.d.), respectively.

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A basic investigation of ritipenem acoxil, a new penem antibiotic developed for oral administration, was conducted. In addition, we examined its clinical efficacy in treating respiratory tract infections.
1. Antimicrobial activity
The minimum inhibitory concentrations (MICs) of 761 strains of bacteria belonging to 19 genera, which were isolated from clinical specimens, were measured according to the standard procedure described by the Japan Society of Chemotherapy. The antimicrobial activity of ritipenem acoxil was compared with that of cefteram (CFTM) and cefpodoxime (CPDX). Ritipenem acoxil showed excellent antimicrobial activity against gram-positive cocci. Its activity against gram negative rods, excluding Proteus mirabilis and Haemophilus influenzae, was equivalent to or greater than that of the other two antibiotics. As with CFTM and CPDX, ritipenem acoxil was ineffective against Pseudomonas aeruginosa and Xanthomonas maltophilia. Ritipenem acoxil was most effective against Moraxella catarrhalis and Bacteroides fragilis.
2. Concentration of ritipenem acoxil in blood and sputum
Ritipenem acoxil was orally administered to 1 patient with chronic bronchitis and another patient with diffuse panbronchiolitis, at doses of 200mg and 400mg, respectively. The drug concentrations in blood and sputum were serially measured. The peak blood concentration was 1.48μg/ml (4 hours after administration) in the patient with chronic bronchitis who received 200mg of ritipenem acoxil. The peak blood concentration was 0.28μg/ml (2 hours after administration) in the patient with diffuse panbronchiolitis who received 400mg of the antibiotic. The concentration of ritipenem acoxil in sputum in both patients was below the detectable level.
3. Clinical results
The clinical efficacy of ritipenem acoxil was evaluated in 9 patients with respiratory tract infections. The orally administered dose of the antibiotic ranged from 200mg to 400mg, and the agent was given 3 times per day. The duration of administration ranged from 3 to 14 days. Ritipenem acoxil was good in 5 patients, fair in 1 patient, and poor in 2 patients. Clinical efficacy of the antibiotic could not be determined in 1 patient. No adverse clinical or laboratory finding was observed during or after the administration of ritipenem acoxil, except for 1 case of eosinophilia which was judged to be clinically insignificant.

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We performed a basic evaluation of ritipenem acoxil (RIPM-AC), a newly developed oral penem, and clinically studied its application in the treatment of respiratory infections, with the following results.
1) Laboratory activity
The minimum inhibitory concentrations (MICs) of ritipenem (RIPM) for a total of 296 strains of 13 clinically isolated species were measured and compared with those of cefaclor (CCL), cefotiam (CTM), cefixime (CFIX), cefteram (CFTM) and amoxicillin (AMPC).
The activity of RIPM against gram-positive bacteria was nearly equal to that of AMPC, and thus more active than that of other antibiotics. Against gram-negative bacteria, its activity was similar to that of the other antibiotics.
2) Clinical efficacy
RIPM-AC was administered to 8 patients with respiratory infections (acute bronchitis 4, acute exacerbation of chronic bronchitis 2, pneumonia 2) at 150-400 mg t.i.d. for 6-14 days.
The clinical efficacy was excellent in 1 case, good in 5 cases, fair in 1 case and was not evaluated in 1 case.
Causative bacteria were Haemophilus influenzae (1) and Enterobacter cloacae (1). Both of 2 strains were eradicated.
No side effects were observed in any patient. As abnormal laboratory findings, eosinophilia in 1 case and elevations of s-Cr, GOT and GPT in 1 case were observed, but they were mild and transient.

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To evaluate the clinically optimal dose of ritipenem acoxil (RIPM-AC), a new oral penem antibiotic, in respiratory tract infections, a dose-finding comparative study was conducted by the double-lind method in patients with bacterial pneumonia using cefotiam hexetil (CTM-HE) as a control drug. Patients were given 200 mg t. i. d. of RIPM-AC (L-group), 300 mg t. i. d. of RIPM-AC (H-group) or 200 mg t. i. d. of CTM-E (C-group). In principle, these drugs were administered for 14 days.
The total number of patients enrolled in this trial was 118, of which 99 cases (L-group: 33, H-group: 31, C-group: 35) were evaluable for clinical efficacy. There were no significant differences in the distribution of background factors.
1) The clinical efficacy rates were 87.9%(29/33) in the L-group and 80.6%(25/31) in the H-group. There was no significant difference between the two groups. The clinical efficacy rate in the C-group was 91.4%(32/35).
2) The bacterial eradication rates (Eradicated+Replaced) were 70.0%(7/10) in the L-group and 72.7%(8/11) in the H-group. There was no significant difference between the two groups. The eradication rate in the C-group was 75.0%(9/12).
3) There were no cases of side effects in the L-group, but there were 2 cases (5.6%) in the H-group. Abnormal laboratory test findings were observed in 8 cases (21.6%) in the L-group and 11 cases (32.4%) in the H-group. There were no significant differences between the two groups in the incidence of side effects and abnormal laboratory test findings. The safety rates were 78.4%(29/37) in the L-group and 63.9%(23/36) in the H-group, with no significant difference. In the C-group, there were no patients with side effects. Abnormal laboratory test findings were observed in 10 cases (26.3%), and the safety rate was 74.4%(29/39).
4) The usefulness rates were 87.9%(29/33) in the L-group and 78.1%(25/32) in the H-group. There was no significant difference between the two groups. The usefulness rate in the C-group was 91.4%(32/35).
From the above findings, we concluded that a daily dose of 200 mg t. i. d. was the clinically optimal dose for RIPM-AC in the treatment of bacterial pneumonia.

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We studied the antibacterial activity and clinical efficacy of ritipenem acoxil (RIPM-AC), a new oral penem, in patients with urinary tract infections. The results were as follows.
1. Antibacterial activity
Using the clinical isolates (30 strains of each of 12 species) preserved at our department and employing the MIC-2000 system, we measured the MICs of RIPM and various other drugs: cefpodoxime (CPDX), cefteram (CFTM), cefaclor (CCL), cefotiam (CTM), imipenem (IPM). The MIC₉₀ of RIPM against methicillin-sensitive Staphylococcus aureus (MSSA), Staphylococcus epidermidis and Enterococcus faecalis were 0.5, 0.25 and 8.0 μg/ml, respectively. Thus, RIPM exerted stronger antibacterial activity against these organisms than the control drugs. On the other hand, the antibacterial activity of RIPM against methicillin-resistant S. aureus (MRSA), E. faecium, Serratia marcescens and Pseudomonas aeruginosa was weak, similar to the other drugs.
2. Clinical study
RIPM-AC was administered to 3 patients with acute uncomplicated cystitis and 10 patients with complicated urinary tract infection. The acute uncomplicated cystitis group received a dose of 150 mg three times a day for 3 days, while the complicated urinary tract infection group received a dose of 200 mg three times a day for 4-7 days. Evaluation of the efficacy, using the criteria of the Japanese UTI Committee, was possible for one case of acute uncomplicated cystitis and 7 cases of complicated urinary tract infection. The clinical response of one case of acute uncomplicated cystitis was excellent. The clinical responses of 7 cases of complicated urinary tract infection were excellent in 6 cases and poor in one. Diarrhea was observed as a side effect in one case. Asan abnormal laboratory finding, slight elevation of GPT was observed in one case.

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We investigated the antimicrobial activity of ritipenem acoxil (RIPM-AC) in human urine, fundamentally, and its clinical efficacy and safety for urinary tract infections, clinically, in order to clarify its usefulness for urinary tract infections.
1. Fundamental study: We measured minimum bactericidal concentrations of ritipenem (RIPM) against Escherichia coil, NIHJ JC-2 and Pseudomonas aeruginosa 18s in nine urine media with different pH, different magnesium concentrations or different calcium concentrations. There was no influence of urine pH, magnesium concentration or calcium concentration on the MBC of RIPM against E. coli. However, the MBC of RIPM against P. aeruginosa in the urine medium with low pH was low.
2. Clinical study: We administered RIPM-AC 600 mg or 900 mg daily, for 5 to 7 days to 8 patients with chronic complicated urinary tract infections. Clinical efficacy was evaluated according to the criteria proposed by the Japanese UTI Committee or by doctors. Clinical efficacy according to the criteria proposed by the Japanese UTI Committee was moderate in 3 patients and poor in 4 patients, and clinical efficacy evaluated by doctors was good in 5 patients, fair in one patient, and poor in 2 patients. No side effects or laboratory abnormalities were seen in the patients after administration of RIPM-AC.
These results indicate that RIPM-AC has moderate efficacy for urinary tract infections.

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We experimentally examined the antibacterial activity of ritipenem, a new penem oral antibiotic, on Neisseria gonorrhoeae and also clinically evaluated its effects on urinary tract infection. The MIC₉₀ of ritipenem was 1.56μg/ml in 40 strains of Neisseria gonorrhoeae. This antibacterial activity was higher than that of cefaclor (CCL) and amoxillin (AMPC) but lower than that of cefixime (CFIX). In the clinical study, an excellent response was observed in all 3 patients with acute simple cystitis that fulfilled UTI criteria for the evaluation of drug efficacy. The response rate was 73.3%(11/15) in the patients with complicated urinary tract infection. Laboratory examinations showed increases in GPT, γ-GTP, and ALP in 1 patient and slight increases in total bilirubin and LDH in 1 patient, but these abnormalities presented no clinical problems. No subjective or objective side effects were observed.

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The following results were obtained for a new oral penem antibiotic, ritipenem acoxil (RIPMAC).
1. Diffusion into human prostatic fluid
The concentration of ritipenem (RIPM) in the prostatic fluid at 1 hour after administration of 400 mg RIPM-AC was less than 0.08 μg/ml in all of 4 human prostatic fluid specimens tested.
2. Clinical study on UTI
The drug was given at daily doses of 450-600 mg divided into 3 times, for a period of 3-7 days in 24 patients with UTI.
According to the Japanese UTI Committee's criteria, the efficacy on 17 patients with chronic complicated urinary tract infection was excellent in 11 patients, moderate in 4 and poor in 2, thus, a response rate being 88.2%. As for side effect, stomach discomfort was found in one patient. There were no particular significant abnormal laboratory values.

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The usefulness of ritipenem acoxil (RIPM-AC, a new oral antibiotic of the penem group) in treating urinary tract infections was studied in vitro and clinically. The following results wereobtained.
1. Antimicrobical activity in vitro: The activity of this drug against microorganisms isolated frompatients with urinary tract infections was assessed in comparison with cefaclor (CCL), cefotiam (CTM) and cefixime (CFIX). Of the gram-positive bacteria examined, methicillin-resistant Staphylococcus aureus was equally sensitive to RIPM, CCL, CTM and CFIX, while methicillin-susceptible Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis weremore sensitive to RIPM than to any control drug. That is, the MIC₅₀, and MlC₉₀ of RIPM againstthe latter three strains were lower than those of any control drug. When the sensitivity ofgram-negative bacteria was assessed, the MIC₉₀ of RIPM against Citrobacter freundii, Klebsiella pneumoniae and Enterobacter cloacae was lower than that of any control drug. The sensitivity of Escherichia coli to RIPM was 3 times higher than its sensitivity to CCL, comparable to itssensitivity to CFIX and lower than its sensitivity to CTM by a factor of one. The sensitivity of Serratia marcescens did not differ between RIPM and any control drug.
2. Clinical study: Seventeen patients with complicated urinary tract infections were orally treatedwith RIPM-AC for 5-7 days (3 doses/day, 200 mg/dose). It was possible to evaluate the clinicalefficacy of this drug in 10 cases, using the UTI criteria proposed by the Japanese UTI Committee (third edition). The drug was regarded as excellent in 5 cases, moderate in 4 cases and poor inlcase. The efficacy rate (percentage of cases in which the drug was excellent or moderate) was 90.0%. One patient developed nausea and vomiting, and another patient complained of heartburn. Allof these subjective and objective adverse reactions were mild. No laboratory parameters changedabnormally in any case.

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We studied ritipenem acoxil (RIPM-AC), a new oral penem, for its clinical efficacy incomplicated urinary tract infection and its pharmacokinetics in patients with impaired renalfunction. The results were as follows.
1. In 10 patients with impaired renal function, blood levels and urinary excretion after oraladministration were investigated. Clear differences were observed between patients with severelyimpaired renal function and healthy volunteers.
2. Ten patients with complicated urinary tract infection were treated with 600 mg per day of RIPM-AC for 5 to 14 days. According to the criteria proposed by the Japanese UTI Committee, theclinical efficacy of RIPM-AC was excellent in 4, moderate in 1 and poor in 2. Neither clinicaladverse effects nor abnormal laboratory findings associated with RIPM-AC treatment wereobserved.

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We studied the antibacterial activity and clinical efficacy of ritipenem acoxil (RIPM-AC), a neworal penem antibiotic, in urinary tract infections.
1) Antibacterial activity: We measured the MICs of ritipenem (RIPM) against 210 clinicalisolates of 14 species from urinary tract infections and compared them with those of cefaclor (CCL), cefixime (CFIX) and cefotiam (CTM). Against gram-positive organisms, the overallantibacterial activity of RIPM was superior to that of other antibiotics. Against gram-negativeorganisms, the activity of RIPM was almost equivalent to that of other antibiotics.
2) Clinical efficacy: Four patients with acute uncomplicated cystitis (AUC) and 30 patients withchronic complicated urinary tract infection were treated with ritipenem acoxil. According to thecriteria of the Japanese UTI Committee, the overall clinical efficacy rate was 100%(2/2) for AUC and 85.7%(24/28) for chronic complicated UTI. Bacteriologically, 28 of 32 strains (87.5%) wereeradicated.
3) Side effects: No side effects were observed. Abnormal laboratory findings, however, wereobserved in 2 cases, one with slight elevations of GOT and GPT and the other with decreases in RBC, Hb and Ht.

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Ritipenem acoxil (RIPM-AC), a new penem, is absorbed into the blood as the active form ofritipenem (RIPM). We studied the in vitro activity and diffusion into prostatic fluid of RIPM andevaluated the clinical efficacy of RIPM-AC in urinary tract infections (UTIs).
With the agar dilution technique, the anitibacterial activity of RIPM was compared with that ofcefaclor (CCL), cefpodoxime (CPDX) and ciprofloxacin (CPFX) against 261 recent clinical isolatesfrom UTIs. RIPM was found to be more active than CCL and CPDX against most of theorganisms tested. The MIC₉₀ values of RIPM were as follows: Staphylococcus aureus 100μg/ml, coagulase negative Staphylococci 12.5μg/ml, Enterococcus faecalis 100μg/ml, Escherichia coli 0.78μg/ml, Citrobacter freundii 6.25μg/ml, Klebsiella pneumoniae 3.13μg/ml, Enterobacter cloacae12.5μg/ml, Serratia marcescens >400μg/ml, Proteus mirabilis 3.13μg/ml, Proteus vulgaris 25μg/ml, and Pseudomonas aeruginosa 400 ug/ml.
The concentration of RIPM expressed in prostatic fluid 90 minutes after administering 200 mg RIPM-AC was 0.06μg/ml, and it was 0.08μg/ml 70 minutes after administering 400 mg, thus indicating little diffusion of RIPM into prostatic fluid in patients with prostatic hypertrophy.
RIPM-AC was administered orally to 17 patients with genitourinary tract infections at a dailydose of 300 mg or 600 mg. Judging from the criteria proposed by the Japanese UTI Committee, theoverall clinical efficacy was excellent or moderate in 4 of 8 cases with chronic complicated UTIs and in one case with acute bacterial prostatitis. Except for two cases whose urethral swab cultureswere positive for Chlamydia trachomatis, two of four cases with acute bacterial epididymitisresponded to RIPM-AC. Neither adverse reactions nor abnormal laboratory findings were observedin these 17 patients.

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To find the optimum dose of ritipenem acoxil (RIPM-AC), a new oral penem, in the treatment ofcomplicated urinary tract infections (UTI), we performed a comparative study using cefotiam hexetil (CTM-HE) as the control drug.
The subjects were patients with complicated urinary tract infections associated with underlying urinarytract diseases. Patients with indwelling catheter and patients within 3 months after prostatectomy were excluded.
RIPM-AC was orally administered at a daily dose of 450mg (RIPM-AC-L group) and 600 mg (RIPM-AC-H group), and CTM-HE was orally administered at a daily dose of 600mg (CTM-HE group), for 7 days.
The overall clinical efficacy was evaluated according to the criteria of the Japanese UTI Committee.
Of the 106 patients evaluated for clinical efficacy, 33 patients received RIPM-AC-L, 39 patients received RIPM-AC-H and 34 patients received CTM-HE. No significant difference in background characteristicswas observed between the RIPM-AC-L and RIPM-AC-H groups.
The overall clinical effectiveness rate was 93.9%(31/33) in the RIPM-AC-L group, 84.6%(33/39) inthe RIPM-AC-H and 70.6%(24/34) in the CTM-HE group. There was no significant difference betweenthe two RIPM-AC groups. However, the rate of patients evaluated as excellent was higher in theRIPM-AC-H group [53.9%(21/39)] than in the RIPM-AC-L group [48.5%(16/33)]. The bacteriologicaleradication rate was 89.1%(49/55) in the RIPM-AC-L group, 92.2%(59/64) in the RIPM-AC-H groupand 75.9%(41/54) in the CTM-HE group, with no statistically significant difference between the twoRIPM-AC groups. However, the eradication rates in gram-positive bacteria species were higher in theRIPM-AC-H group than in the RIPM-AC-L group.
The incidence of adverse reactions was significantly higher in the RIPM-AC-L group [13.5%(7/52)] than in the RIPM-AC-H group [0%(0/48)]. The incidence of adverse reactions in the CTM-HE groupwas 6.0%(3/50). The incidence of abnormal laboratory findings was 2.3%(1/44) in the RIPM-AC-L group, 2.2%(1/46) in the RIPM-AC-H group and 2.1%(1/48) in the CTM-HE group. There was nosignificant difference between the two RIPM-AC groups.
Our results showed that the RIPM-AC-H group was slightly superior to the RIPM-AC-L group in therates of patients evaluated as excellent, the eradication rates in gram-positive bacteria species and theusefulness. We, therefore, concluded that 600mg was the optimum daily dose of RIPM-AC for thetreatment of complicated UTI.

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Ritipenem acoxil (RIPM-AC) is a new oral penem antibiotic. We investigated the pharmacokinetics of RIPM-AC and cefotiam hexetil (CTM-HE) by the cross-over method.
The pharmacokinetics of RIPM-AC and CTM-HE, each orally administrated at a dose of 200 mg, were compared in healthy male volunteers. The Cmax values of ritipenem (RIPM) and cefotiam (CTM) were 2.09μgg/ml and 2.85μg/ml, respectively. The T_1/2 of RIPM and CTM were 0.56 h and 0.71 h, and the AUC_0-12 values were 2.10 μg·h/ml and 4.99 μg·h/ml. The mean urinary recovery rates of RIPM and CTM up to 12 h after a single oral administration were 11.3% and 38.9%.

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We performed basic and clinical studies on ritipenem (RIPM) and its orally absorbed ester, ritipenem acoxil (RIPM-AC), a new semisynthetic penem derivative.
The antibacterial activity of RIPM against clinical isolates was tested and compared with those of cefaclor (CCL), ofloxacin (OFLX) and tosufloxacin (TFLX). Tested organisms were coagulasepositive and-negative Staphylococci (CPS and CNS), methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae.
The MICs of RIPM against tested organisms were lower than those of CCL. The antimicrobial activities of RIPM against CPS, CNS, MRSA and E. faecalis were the same or stronger than those of tested quinolones, OFLX and TFLX. E. cloacae showed susceptibility to RIPM. The MICs of RIPM against E. cloacae ranged from 1.56-25 μg/ml.
RIPM-AC was administered to seventeen patients with surgical infections: seven cases of purulent atheroma, one of infected atheroma, two of phlegmon, two of felon, two of subcutaneous abscess and one each of periproctal abscess, secondary infection and wound infection. Clinical response was excellent in one case, good in thirteen cases, fair in one and poor in two cases, an efficacy rate of 82.4%.
Serum and biliary concentrations of RIPM were measured in a clinical case. The case was acute cholecystolithiasis with cholangitis, so cholecystectomy and biliary drainage of the common bile duct were done two weeks before. With 200 mg oral administration of RIPM-AC, serum and biliary concentrations were measured. Serum concentrations after administration were as follows: 0.5 h, ND (not detected);1 h, ND; 2h, 0.52 μg/ml; and 4 h, 0.08 μg/ml. Biliary concentrations were not detected from 0.5 h to 4h.
In one case, epigastralgia was observed while RIPM-AC was administered, but no additional treatment was needed. No other side effects were noted. It was concluded that RIPM-AC was effective clinically and microbiologically in the treatment of surgical infections.

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We performed a clinical study on ritipenem acoxil (RIPM-AC), a new penem antibiotic, in the surgical field to determine its clinical efficacy. The results were as follows.
RIPM-AC was orally administered to 73 patients with surgical infections. In 71 patients evaluated for clinical efficacy, the clinical response was excellent in 34, good in 24, fair in 10 and poor in 3 patients, and the overall efficacy rate was 81.7% (58/71).
In the bacteriological study, the causative pathogens were isolated from 60 patients, and eradicated in 41, partially eradicated in 2, replaced in 2, persisted in 8 and unknown in 7 patients. The overall eradication rate was 81.1% (43/53).
Side effects were diarrhea in 3 patients, glossitis in 1 and loose stool, glossitis and abdominal discomfort in 1 patient. Abnormal laboratory findings were elevation of GOT and GPT in 4 patients, elevation of GPT in 1 and eosinophilia in 1 patient. All these abnormal changes improved after treatment.

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We gave ritipenem acoxil (RIPM-AC), a new synthetic oral penem, to five patients who were undergoing bile drainage, in a study of its pharmacokinetics. We also treated 59 surgical infections with this drug and evaluated its clinical efficacy in 58 patients.
In the pharmacokinetic study, a single dose of 200 mg or 400 mg was given orally and serial samples were taken from blood and bile. The peak levels of ritipenem (RIPM), the active form of RIPM-AC, in plasma were 0.22-5.40μg/ml at 0.5 to 4 hours. The peak levels of RIPM in bile were 0.16-2.61μg/ml at 1 to 4 hours.
Of the 58 surgical infections, clinical efficacy was excellent in 20, good in 25, fair in 11 and poor in 2, an efficacy rate of 78%. The bacteriological response for each bacterium isolated was evaluated in 86 strains. Eighty-three strains were eradicated and 3 strains persisted, an eradication rate of 97%. The bacteriological response of the host was evaluated in 49 infections. Bacteria were eradicated in 43 infections, decreased in 2, replaced in 3, and persisted in 1. The bacteriological response was evaluated in 86 strains isolated from 104 strains, in which MIC was calculated, and 83 (97%) of them were eradicated, but no correlation was found between MIC and bacteriological response. No side effects or abnormal changes in laboratory data were observed.
RIPM-AC seems to be effective for surgical infection including skin and soft tissue involvement.

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The kinetic profile and clinical efficacy of ritipenem acoxil (RIPM-AC), a new oral penem, were investigated.
RIPM-AC was administered orally to 2 patients at dose of 200 mg t. i. d. for 3 days. At 2-5 hours after the last administration before cholecystectomy, the gallbladder tissue concentration of ritipenem (RIPM), the active form of RIPM-AC, was not detectable. The concentrations in gallbladder bile were 0.12 and 0.64μg/ml, respectively.
RIPM-AC was administered orally to 7 patients undergoing biliary drainage at a single dose of 400 mg. The maximum plasma concentration was 0.16-8.66 μg/ml at 1-2 hours after administration, and the maximum bile concentration was 0.10-17.3μg/ml at 1-4 hours.
RIPM-AC was administered to 31 patients with surgical infections at doses of 150-400 mg t. i. d. for 3-9 days. The clinical efficacy was excellent in 9, good in 18 and fair in 4, with the efficacy rate being 87.1%.
The bacteriological efficacy rates were 93.8% (15/16) in Gram-positive bacteria, 80.0% (20/25) in Gram-negative bacteria and 100% (18/18) in anaerobic bacteria.
As side effects, diarrhea was noted in 1 case, and liver function test values were elevated in 2 cases.

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The antibacterial activity, clinical efficacy and safety of ritipenem acoxil (RIPM-AC), a new oral penem, were evaluated in the treatment of surgical infections.
1) Antibacterial activity
Ritipenem (RIPM), the active form of RIPM-AC, showed potent activity against gram-positive cocci, with an MIC₉₀ of 0.10μg/ml for methicillin-sensitive Staphylococcus aureus, but the activity of RIPM against methicillin-resistant Staphylococcus aureus was inferior. The MIC₅₀ and MIC90 of RIPM against coagulase-negative Staphylococci were 0.20μ/ml and 50μ/ml, respectively. Against Enterococcus spp., the MIC50 and MIC90 were both 6.25μ/ml.
Against gram-negative rods, the MIC₉₀ of RIPM was 0.78μg/ml for Escherichia coli andKlebsiella pneumoniae. Against Klebsiella oxytoca, Enterobacter cloacae, Serratia marcescensandPseudomonas cepacia, the MIC₅₀ were 0.78, 3.13, 3.13 and 0.39μ/ml, respectively. The respective MIC₉₀ of RIPM were 6.25, 25, 100 and 25μg/ml. Against Enterobacter aerogenes, Citrobacter freundiiandProteus mirabilis, the MIC₅₀ were 6.25, 3.13 and 6.25μg/ml. The MIC₉₀ were all 6.25μg/ml. The MIC₅₀ of RIPM was 100 or > 100μg/ml for Pseudomonas aeruginosa, Acinetobacter calcoaceticus and Xanthomonas maltophilia.
2) Clinical study
RIPM-AC was orally dosed to 20 patients: 5 with subcutaneous abscess, 4 with phlegmon, 3 with infected atheroma, 2 with felon, 1 with carbuncle, 1 with folliculitis, 2 with wound infection and 2 with mastitis.
The clinical efficacy of RIPM-AC was excellent in 7, good in 11 and fair in 2, the efficacy rate being 90.0%. No side effects or abnormal laboratory test findngs were observed in any of the cases.

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We investigated a newly developed penem antimicrobial agent, ritipenem acoxil (RIPM-AC), for its clinical efficacy in obstetric and gynecological infections.
RIPM-AC was orally administered to 16 patients. The daily dose of RIPM-AC was 600 mg, and the duration of administration was 7-15 days.
The clinical effect was assessed in a total of 11 patients, 5 with intrauterine infection, 2 adnexitis, 3 infection of the external genitalia, and 1 with mastitis. The efficacy rate was 100%. Bacteriological response was assessed in 8 cases. The causative organisms were eradicated in 4 cases and replaced in 3. Neither subjective or objective side effects nor abnormal findings were observed.
This drug is expected to be useful against infections in the field of obstetrics and gynecology.

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A newly developed synthetic penem antibiotic, ritipenem acoxil (RIPM-AC), was investigated for its antibacterial activity, tissue penetration and clinical efficacy in obstetric and gynecological infections, and the following results were obtained.
1. Antibacterial activity: The MICs of ritipenem (RIPM) against 300 strains of 15 species of clinical isolates from obstetric and gynecological infections were determined and compared with those of cefaclor, cefixime, cefpodoxime, cefteram, ampicillin and imipenem. The MIC₅₀ of RIPM was ≤0.025-> 100μg/ml, and its MIC₉₀ was 0.05->100μg/ml. Compared with other antibiotics, RIPM and imipenem were similar in having excellent activity against gram-positive and anaerobic species.
2. Tissue penetration: Tissue penetration of the drug into genital organ tissues was found to be good, the level in uterine arterial plasma being 0.26-1.61μg/ml and that in the tissues being 0.12-0.42μg/g after a single oral administration of 400 mg.
3. Clinical results: RIPM-AC was orally administered to 34 patients with obstetric and gynecological infections. The clinical efficacy was evaluable in 33 cases (administration at a daily dose of 600 mg for 3-15 days). A clinical efficacy rate of 97.0% (32/33) and an eradication rate against isolated organisms of 93.0% (40/43) were obtained. Neither side effects or laboratory abnormalities were observed.
4. From these findings, RIPM-AC is considered to be a useful antibiotic against obstetric and gynecological infections.

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Basic and clinical studies were conducted on ritipenem acoxil (RIPM-AC), a newly developed oral penem of the ester type, and the following results were obtained.
RIPM-AC was orally administered to puerperal women at a single dose of 400 mg under non-fasting conditions, and the concentration of ritipenem (RIPM) was determined in milk. RIPM could not be detected in milk at 1, 2, 4 and 6 h after administration.
In the clinical trial, RIPM-AC was administered to 21 patients with obstetric and gynecological infections (10 with endometritis, 1 with infectious abortion, 1 with pyometra, 3 with salpingitis and 6 with Bartholin's abscess). Clinical results were evaluated as good in 20 patients and poor in 1, an efficacy rate of 95.2%.
Bacteriologically, 28 causative organisms were isolated, and the eradication rate was 89.3% (eradicated 25, persisted 3).
No subjective side effects or abnormal changes in laboratory values were observed in any of the patients treated with RIPM-AC.

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We performed basic and clinical studies on ritipenem acoxil (RIPM-AC), a new oral penem antibiotic, in the obstetric and gynecological fields, and obtained the following results.
1) The maximum tissue concentration of RIPM in genital organs was 0.56μg/g. The transfer ratio from the uterine artery to the genital organs ranged from 36% to 96%.
2) In our clinical study, RIPM-AC was administered orally to 10 patients with gynecological infections. The clinical results were good in 8 cases and poor in 2 cases, a total efficacy rate of 80%. No critical side effects were observed in any patients.
These results indicated that RIPM-AC was a promising aid in obstetric and gynecological infections.

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The purpose of this study was to evaluate the clinical efficacy of ritipenem acoxil for the treatment of otitis media and external otitis. The patients enrolled in this study consisted of 130 patients with otitis media and 34 with external otitis. The dose of ritipenem acoxil orally administered to these patients ranged from 300 mg to 1200 mg/day. The clinical efficacy rate, as determined by the physician in charge, was 71.4% for otitis media and 90.3% for external otitis. The eradication rates regarding gram-positive cocci, gram-negative bacteria anaerobic bacteria, and all bacterial strains were 87%, 69.2%, 100% and 83.3%, respectively.
Diarrhea was observed in 2 of 154 patients taking the test antibiotic. Laboratory abnormalities were noted in 4 of 62 patients. However, none of these adverse events were of clinical importance.
The overall utility rate of ritipenem acoxil for treating otitis media was 68.4%, that for external otitis was 90.3%.
Our findings have shown that ritipenem acoxil is highly useful in treating otitis media and external otitis.

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Ritipenem acoxil (RIPM-AC) showed an antibacterial spectrum similar to that of cefaclor (CCL), cefpodoxime (CPDX) and cefteram (CFTM), and exhibited wide antibacterial activity against gram-positive and gram-negative bacteria. Twenty strains of clinically isolated Staphylococcus aureus showed sensitivity in the range of 0.05 to 0.2μ g/ml, with a peak at 0.05μ g/ml.
When RIPM-AC was orally administered once at a dose of 100 mg/kg to mature white rabbits, it reached a peak, 0.93μ g/ml, in the anterior aqueous humor in 1 hour. The aqueous humor to blood concentration ratio was 4.92%. The concentration gradually decreased thereafter. It reached 0.16μ g/ml at 4 hours and 0.07μ g/ml at 6 hours after administration. One hour after administration, the concentration in the extraocular tissue was 0.57-8.31μ g/g, and that in the intraocular tissue was 0.08-0.85μ g/g or ml.
The clinical effects of RIPM-AC were investigated in 63 patients: 5 with blepharitis, 11 with hordeolum, 8 with meibomianitis, 12 with dacryocystitis, 14 with keratitis, 12 with corneal ulcer, and 1 with tenonitis. The drug was orally administered at a dose of 150 or 200 mg 3 times a day. The clinical efficacy was excellent in 22 patients, good in 32, fair in 7 and poor in 2. The efficacy rate was 85.7 %. S. aureus, Staphylococcus epidermidis, coagulase-negative staphylococci, Pseudomonas cepacia, Moraxella sp., Klebsiella oxytoca and anaerobes were clinically isolated. The eradication rate was 83.1%.
The side effects observed were a systemic itchy sensation in 1 patient, and itching and rash were reported by 1 patient. The former symptom disappeared after the treatment, and the latter symptoms disappeared 3 days after the discontinuation of treatment.

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