Bacteria isolated from respiratory tract infections were collected in cooperation with institutions located throughout Japan, since 1981, and IKEMOTO et al. have been investigating susceptibilities of the isolates to various antibacterial agents and antibiotics, and the relationships between the isolates and backgrounds of the patients and so forth each year. We discuss the results in detail.
In 20 institutions around the entire Japan from October 1993 to September 1994,584 strains of bacteria were isolated mainly from sputa of 473 patients with respiratory tract infections and presumed to be the etiological agents. MICs of various antibacterial agents and antibiotics were determined against 91 strains of Staphylococcus aureus, 98 strains of Streptococcus pneumoniae, 122 strains of Haemophilus influenzae, 91 strains of Pseudomonas aeruginosa (non-mucoid), 34 strains of Pseudomonas aeruginosa (mucoid), 42 strains of Moraxella subgenus Branhamella catarrhalis, 25 strains of Klebsiella pneumoniae etc., and the drug susceptibilities of these strains were measured except the strains which died during transportation.
1. S. aureus
S. aureus strains for which MICs of methicillin were higher than 4, ug/ml (methicillin-resistant S. aureus) accounted for 56.0%, but this frequency of the drug resistant bacteria was lower than the previous year's 61.4 %. Arbekacin and vancomycin showed the highest activities against MRSA and MIC₈₀s were 1μg/ml.
2. S. pneumoniae
Benzylpenicillin among the penicillins showed potent activities against S. pneumoniae. Cefuzonam, cefotaxime and cefmenoxime among the cephems showed excellent antimicrobial activities against S. pneumoniae. Imipenem; carbapenems, showed the most potent activity, and MIC₉₀ was 0.063μg/ml.
3. H. influenzae
All the drugs tested were quite active against H. influenzae. Cefotaxime, cefmenoxime, cefuzonam and cefixime among the cephems showed the most potent activities, and MIC₉₀ were 0.063μg/ml against H. influenzae. Ofloxacin also showed MIC₉₀ of 0.063μ/ml.
4. P. aeruginosa (mucoid)
Tobramycin showed the most potent activity against P. aeruginosa (mucoid), and MIC₈₀ was 1 u /ml. Ceftazidime, cefsulodin, imipenem, aztreonam, gentamicin and ciprofloxacin showed potent activities with MIC₈₀s of 2μg/ml.
5. P. aeruginosa (non-mucoid)
Tobramycin showed the highest activity against P. aeruginosa (non-mucoid), and MIC₈₀ was 1 ug/ml, followed by ciprofloxacin with MIC₈₀ of 2μg/ml. Comparing to activities against P. aeruginosa (mucoid), all the drugs tested had relatively low activities against P. aeruginosa (nonmucoid).
6. K. pneumoniae
The activities of all drugs except ampicillin and minocycline were high against K. pneumoniae. Cefozopran, imipenem and carumonam showed the highest activities and MIC₈₀s were 0.125μg/ml. Flomoxef showed the next highest activities with an MIC₈₀ of 0.25μg/ml.
7. M (B.) catarrhalis
Imipenem showed the most potent activity against M (B.) catarrhalis, with an MIC₈₀ of 0.063 ug/ml, followed minocycline and ofloxacin with their MIC₈₀s of 0.125μg/ml.
We also investigated year to year changes in the background of patients, as well as types of respiratory infectious diseases, and the etiological agents.
As for patients backgrounds, there were many infectious diseases found among patients a high age bracket, and the patients over age 60 accounted for 61.3% of the diseases.

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To objectively evaluate the efficacy, safety and usefulness of the newly developed penem oral antibiotic, ritipenem acoxil (RIPM-AC), against bacterial pneumonia, we conducted a multi-center double-blind comparative study using cefotiam hexetil (CTM-HE) as the control drug. Both RIPM-AC and CTM-HE were orally administered at 200 mg t.i.d. for 14 days, in principle. The results were as follows:
The total number of patients enrolled in this trial was 208, of which 152 cases (RIPM-AC group: 73, CTM-HE group: 79) were evaluable for clinical efficacy.
1. The clinical efficacy rates (excellent +good) were 91.8% (67/73) in the RIPM-AC group and 94.9% (75/79) in the CTM-HE group. There was no significant difference between the two groups, and the clinical equivalency of RIPM-AC to CTM-HE was demonstrated.
2. In the patients enrolled in the evaluation of clinical efficacy, the eradication rates of the causative organisms were 84.6% (22/26) in the RIPM-AC group and 91.7% (22/24) in the CTM-HE group, with no significant difference between the two groups.
3. Side effects were noted in 9 cases (9.6%) of the RIPM-AC group and 5 cases (4.9%) of the CTM-HE group. Abnormal laboratory test findings were observed in 23 cases (26.7%) of the RIPM-AC group and 15 cases (15.6%) of the CTM-HE group. There were no significant differences between the two groups in the incidence of side effects nor of abnormal laboratory test findings. In the safety evaluation, RIPM-AC was judged to be safe in 64 cases (68.1%) and CTM-HE in 82 cases (80.4%), with no significant difference.
4. The usefulness rates (markedly useful + useful) were 86.5% (64/74) in the RIPM-AC group and 92.5% (74/80) in the CTM-HE group. There was no significant difference between the two groups.
Since RIPM-AC showed clinical efficacy similar to those of CTM-HE and posed no particular safety problems, it is expected to be a useful antibiotic for the treatment of bacterial pneumonia.

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In order to evaluate antimicrobial activity of meropenem (MEPM), minimum inhibitory concentrations (MICs) of MEPM and control drugs were determined against clinical isolates in 1993.
The results were as follows;
1. Antimicrobial activities of MEPM against Gram-positive bacteria were stronger than those of cephems (CEPs), were approximately equal to those of panipenem (PAPM), and were weaker than those of imipenem (IPM).
2. Carbapenems showed strong antimicrobial activities against Enterobacteriaceae, glucose non-fermentative Gram-negative rods and Bacteroides fragilis group that were multiple drug resistant including the third generation CEPs. Antimicrobial activities of MEPM against these organisms were stronger than those of IPM and PAPM.
3. MIC-ranges of MEPM against Enterobacteriaceae and Haemophilus influenzae were lower than those of IPM and PAPM. We observed that MEPM had better permeability into the cells of H. influenzae, higher affinities to 3 to 5 different penicillin-binding protein and high stablity against β-lactamase than those of IPM and PAPM.

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In order to evaluate antibacterial activities of combination uses of isepamicin (ISP) and β-lactams in vitro, minimum inhibitory concentrations (MICs) these drugs were examined singly and in combination against clinically isolated Staphylococcus aureus.
The results are summarized as follows;
1. MICs of ISP+cefazolin (CEZ), ISP+cefotiam (CTM) and ISP+flomoxef (FMOX) were low and the activities against methicillin (DMPPC)-susceptible S. aureus (MSSA) were dependent on the concentration of ISP. Combined effects were observed when the concentrations of ISP were at sub-MIC levels (1/2-1/4 MIC concentrations).
2. MICs of ISP+CEZ, ISP+CTM, ISP+FMOX, ISP+imipenem and ISP+panipenem were low and the activities against DMPPC-resistant S. aureus(MRSA) were dependent on the concentration of ISP, and were similar to those against MSSA. Combined effects were observed when the concentrations of ISP were at sub-MIC levels of ISP. Lower MIC₅₀ or MIC₉₀, was observed at ISP concentrations of 4-16ug/ml.
3. The blood C_max of ISP exceeded 20ug/ml at one-time administration of ISP 400 mg, and these results suggested that antibacterial activities of combination uses of ISP and β-lactams was clinically effective against MRSA infections.

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The usefulness of a newly developed imipenem/cilastatin powder-and-diluent kit packed in non-glass container was compared to that packed in commercially available glass vials. The imipenem/cilastatin powder-and-diluent kit container is made of a polyolefin bag with two chambers that contain imipenem/cilastatin powder and diluent (0.9% saline, 100 ml), respectively.
The convenience of use of the kit and the time required for the preparation of the dosing solution were evaluated by nurses and pharmacists at the Kitasato University East Hospital. The newly developed kit received higher scores with regard to convenience of use and led to a 46-59% reduction in the time required for preparation as compared to the commercially available glass vials.

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The usefulness of a kit consisting of non-glass packaging was evaluated in terms of accuracy of reconstitution. The newly developed imipenem/cilastatin powder-and-diluent kit consists of a polyolefin bag with two chambers that contain imipenem/cilastatin powder and diluent (0.9% saline, 100 ml), respectively.
The accuracy of reconstitution was determined by nurses and pharmacists at the Kitasato University East Hospital by measuring the amount of materials remaining in vials after reconstitution using the syringe dilution method and the transfer-needle dilution method.
The mean percent amounts of imipenem and cilastatin remaining after preparation by the syringe dilution method were 5.58±2.60% and 4.08±1.77%, respectively. The mean percent amounts of imipenem and cilastatin remaining after preparation by the transfer-needle dilution method were 3.99±2.28% and 3.71±2.09%, respectively. The amount of imipenem/cilastatin remaining in the newly developed kit should be negligible, because the kit serves as both a vial and a dosing package.
Therefore, greater accuracy in terms of reconstitution is expected with the newly developed kit than with the traditional syringe dilution or transfer-needle dilution methods.

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