[in Japanese]

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Antimicrobial activities of cefazolin (CEZ) against 251 strains of various clinical isolates obtained during 1989 and 1990 were determined using the Mueller-Hinton agar dilution method at an inoculum level 10⁶ CFU/ml. The reliability of the disk susceptility test was also studied using Mueller-Hinton agar and various disks at inoculum levels of 10^3-4 CFU/cm² in estimating approximate values of MICs. In addition, antimicrobical activities of CEZ and cefmetazole (CMZ) or flomoxef (FMOX) in combination were investigated against methicillin-sensitive and-resistant Staphylococcus aureus(MSSA and MRSA) using the checkerboard agar dilution MIC method and the disk diffusion test either with the disks contained CEZ, CMZ, and FMOX alone, or CEZ, and CMZ or FMOX in combination.
In this study, the MICs of CEZ against S. aureus were distributed with the 3 peak values at 0.39μg/ml, 3.13μg/ml and>100μg/ml. MICs against MSSA were 0.39μg/ml to 0.78μg/ml, whereas those against MRSA were greater than 0.78μg/ml. MICs against majority of strains of Enterococcus faecalis were 25 μg/ml. Over 90% of strains of Escherichia coli and Klebsiella pneumoniae were inhibited at the level of 3.13μg/ml. About 60% of isolates of indole negative Proteusspp. were inhibited at the levels of less than 3.13μg/ml and 100% at 6.25μg/ml, but MICs against indole positive Proteus spp.,Serratia spp. and Pseudomonas aeruginosa were over 100μg/ml. The antimicrobial activities of CEZ against these clinical isolates were not significantly different compared to those reported about 15-20 years ago, except for S. aureus. Highly resistant strains of S. aureus to CEZ were more prevalent in this study.
The inhibitory zones obtained with the disk test were compared with MICs. The results of CEZ disk susceptibility test with 30μg disk (Showa) or 10μg disk (prepared in this laboratory) were well correlated with MICs (r=-0.837 and-0.814, respectively), showing the reliavility of the disk method in estimating approximate values of MICs.
In the 4 category classification system currently used in Japan, break points in MIC values proposed are (+++) MIC≤3μg/ml,(++)>3-15μg/ml,(+)>15-60μg/ml,(-)>60μg/ml. The results obtained with 30μg disks showed false positive in 7.7% and false negative in 6.8% of the samples. The disk results with E. faecalis showed a higher ratio of false positive results. With 10μg disks, the results obtained were false positive in 7.2% and false negative results in 10.8% of the samples.
In the 3 category classification system proposed by NCCLS the MIC break points are defined sensitive (S) for MIC≤8 μg/ml, and resistant (R) for MIC≥32μg/ml. In this study, 30μg and 10μg disk test results showed false positive in 3.2% and 2.3% of the samples tested and false negative in 5.4% and 7.7% of the samples, respectively.
MICs of CEZ against MRSA were greater than 0.78μg/ml. To separate strains with MICs of 0.39μg/ml and 0.78μg/ml, results with a higher accuracy were obtained with 10μg disks than with 30μg disks. The former showing false positive results at a lower frequency.
Further study was carried out with respect to antimicrobial activities of CEZ and CMZ or FMOX in combination against clinical isolates of S. aureus(3 MSSA strains and 10 MRSA strains) using the checkerboard MIC method and the disk diffusion test. MICs of CEZ, CMZ and FMOX alone against 10 MRSA strains were 100-400μg/ml, 6.25-100μg/ml, and 6.25-100μg/ml, respectively. In combination of CEZ and CMZ or FMOX, MICs of CEZ, CMZ, and FMOX against MRSA were reduced to 0.78-50μg/ml, 0.39-25μg/ml, and 0.39-50μg/ml, respectively, showing the minimum FIC indexes of 0.094-0.500.

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The in vitro antimicrobial activity of AO-128, an inhibitor of α-D-glucosidase, was evaluated against anaerobic bacteria of 45 reference strains (12 genera, 44 species). AO-128inhibited no strains tested at a concentration of1, 600μg/ml. The results strongly suggested that this compound would not have any influence on the human intestinal microflora, a majority of which is composed of anaerobic bacteria.

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To investigate the skin penetration of cefpiramide (CPM, SM-1652), a broad-spectrum and long acting cephem antibiotic, 1 g of CPM was administered by single bolus intravenous injection to patients under general anesthesia during operations for full-thickness skin grafting. The CPM levels in both the serum and the skin were determined by bioassay at specified time intervals, and the following results were obtained.
1. Peak CPM concentrations in the serum (mean: 292.78μg/ml) were observed 10 minutes after administration, and declined very slowly thereafter.
2. Peak CPM concentrations in the skin (mean: 23.05μg/g) were observed 2 hours after administration, and then also declined very slowly.
3. The ratio of skin to serum concentrations was 16% when the peak CPM concentrations in the skin were obtained (2 hours after the administration).
These results show that effective CPM concentrations were maintained in the skin for a long period, indicating-a good therapeutic action against skin infections.

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A patient of subarachnoid hemorrhage was treated with spinal CSF drainage. Serratia marcescens meningitis occurred because of the spinal CSF drainage. The organism was multiresistant and refractory to antibiotics including piperacillin, imipenem, gentamicin and cephaloridine. It was sensitive to ceftazidime (CAZ).
Treatment with CAZ resulted in clinical improvement associated with rapid clearing of the organism from CSF. CAZ serum level was high enough and CAZ penetration into the CSF was satisfactory. According to the evaluation of CAZ concentrations in serum and CSF, two regimens of treatment were recommended.
One is an administration of CAZ 1g×4 times/day. Another is a combination with CAZ administration 2g×2 times/day and followed by 1g×4 times/day.
The results suggest that CAZ is an extremely effective antibiotic for meningitis caused by CAZ-susceptible bacteria.

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Both aspoxicillin (ASPC) and ceftazidime (CAZ) were administerted together to 55 patients with intractable respiratory tract infections. ASPC and CAZ were administerted at daily doses of 4g and 2 to 4g, respectively. Clinical effects were excellent in 11 cases, good in 33, fair in 7 and poor in 4, thus the efficacy rate was 80.0%. Bacteriologically, identified organisms were eradicated in 14 cases out of 21, decreased in 3, exchanged in 2 and unchanged in 2. The eradication rate was 76.2%. As a side effect, diarrhea was found in only one case, and abnormal laboratory test values were observed in 4 cases. However, these adverse reactions were not severe, therefore it was possible to continue the chemotherapy.
These results indicate that the combination antimicrobial chemotherapy of ASPC and CAZ is effective against intractable respiratory tract infections.

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One hundred thirty-eight patients with severe infections accompanying hematological diseases were treated with cefodizime (CDZM). CDZM was administered by intravenous injection at daily doses ranging from 2g to 8g for about 3 to 18 days.
Clinical efficacies of CDZM were excellent in 30 cases, good in 37 cases, fair in 1 case and poor in 53 cases. The efficacy rate was 55.4%. The efficacy rate was 56.4% in patients from whom causative organisms were not identified. The efficacy rate against Gram-negative bacteria (66.7%) was higher than that against Gram-positivie bacteria (28.6%). No significant differences in the efficacy rates were found among groups of patients with different initial neutrophil counts (less than 100, 100-499, and over 500/μl). Skin eruption caused by CDZM was observed in 2 patients (1.5%). Hepatic disorders, renal dysfunction and urinary test abnormality (protein and urobilinogen) were observed in 7 (5.0%), 1 (0.7%) and 1 (0.7%), respectively.
Therefore, CDZM was considered to be a clinically useful antibiotic for severe infection complicated with hematological diseases.

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Antibacterial effects of combination use of arbekacin (ABK) with cefotiam (CTM) or cefuzonam (CZON) were evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and the following results were obtained.
1. Antibacterial effects of combinations of ABK with CTM and with CZON were equally potent against MRSA at clinically expected 1 MIC of ABK in blood. However, at a sub MIC of ABK the different effects were observed between the 2 combinations. The antibacterial effect of the former was strong and that of the latter was a little weak.
2. In either combination the potency of the antibacterial activity was less dependent on the concentration of CTM or CZON, but was strongly dependent on ABK concentrations. These results suggest that antibacterial effects of the combinations were highly dependent on antibacterial potency and concentration of ABK as previously reported for combinations of ABK with other drugs.
3. The combination use of ABK with CTM appears to be useful in cases of infection by MRSA alone while the combination use of ABK with CZON appears to be useful in cases of double infection with MRSA and Gram-negative bacterium.

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Antibacterial effects of combination use of arbekacin (ABK) with cefmetazole (CMZ) or flomoxef (FMOX) were evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and the following results were obtained.
1. Antibacterial effects of combinations of ABK with CMZ and with FMOX were equally potent against MRSA at clinicaly expected 1 MIC of ABK in blood. However, at a sub MIC of ABK different effects were observed between the 2 combinations. The former combination was slightly less effective than the latter.
2. In either combination the potency of the antibacterial activity was less dependent on the concentration of CMZ or FMOX, but was strongly dependent on ABK concentrations. These results suggest that antibacterial effects of the combinations were highly dependent on antibacterial potency and concentration of ABK as previously reported for combinations of ABK with other drugs.
3. It appears that the antibacterial activity of the combination of the sub MIC of ABK with a β-lactam is an important point in considering the effectiveness of a combination therapy.

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We studied effects of intramaxillary injection of fosfomycin (FOM) on experimental sinusitis in rabbits.
The experimental sinusitis was induced by intramaxillary injection of Staphylococcus aureus to rabbits for 3 successive days.
1. 0.5, 1, 3 or 5% FOM with saline as a control was instilled into the maxillary sinus and the maxillary sinus mucosa were examined macroscoically and light and electron microscopically. 3% and 5% FOM suppressed the damage of mucosa macroscopically and scanning electron microscopically.
2. After administration of 3% FOM and saline twice a week, the maxillary sinus mucosa was examined macroscopically and light and electron microscopically. The maxillary sinus injected with 3% FOM showed almost normal mucosa after 2 weeks while that injected with saline showed severe mucosal damage. S. aureus were decreased by 3% FOM injection and not found in the maxillary sinus in a week.
The results indicate that intramaxillary injection of FOM is very effective in the treatment of sinusitis.

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A new cephalosporin derivative antibacterial agent, DQ-2556, was administered intravenously to 4 healthy adult male volunteers at 2 grams per dosage 2 times a day for 5 days, and degrees of effects of drug concentrations on the fecal microflora were investigated.
1. The total viable count remaind unchanged during the study period due to the minimal change in the number of members of the family Bacteroidaceae, which were the most dominant organisms. In one of the volunteers, however, the total count was remarkably reduced immediately after the end of administration of the drug.
2. Among the obligate anaerobes, most of the organisms decreased except members of the family Bacteroidaceae. A marked increase of lecithinase-positive clostridia was noted in 2 volunteers.
3. The number of aerobes, including facultative anaerobes, members of the family Enterobacteriaceae were suppressed but bacilli and yeasts showed slight increases. In many cases, increases in enterococci were also observed.
4. DQ-2556 was not detected in the feces from any of the volunteers during the study period.
5. Neither Clostridium diificile nor its toxin D-1 was detected in any of the volunteers.
6. Diarrhoea or other side-effects were not noted in any of the volunteers.

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Clinical trials of ofloxacin (OFLX) otic solution, such as an early phase II study, a dose-finding study, a phase III double-blind comparative study and open studies, were conducted in the period from February 1988 to October 1989. In these studies, organisms were isolated from secretions of middle ear in patients with chronic otitis media and acute exacerbation of chronic otitis media, and from secretions of external ear in patients with external otitis. These organisms were subjected to identification, followed by determination of susceptibilities to OFLX and the other antibacterials.
Results obtained are summarized as follows:
1. In total, 746 organisms were defined as the presumable causative organisms in 439 patients with otitis media and 80 with external otitis. Among the isolates, aerobic Gram-positive organisms were most prevalent, with an isolation rate of 66.9%, followed by aerobic Gram-negative organisms (32.4%), and obligate anaerobes (0.7%). Staphylococcus aureus and Pseudomonas aeruginosa were the organisms isolated most frequently among aerobic Gram-positive and Gram-negative bacteria, respectively.
2. The MIC₉₀ of OFLX against the above 746 strains was 6.25μg/ml. At this level, OFLX was 8 times more potent than cefmenoxime (CMX), and 32 times more potent than fosfomycin (FOM) and fradiomycin (FRM). It was postulated that OFLX retained higher local level than the MIC₉₀ of the drug at 2 hours after topical adaptation of the otic solution, and had enough “above the MIC” and “time above MIC”.
3. The MIC₉₀ of OFLX against glucose-nonfermentative Gram-negative rods (GNF-GNR) including P. aeruginosa, which were isolated in 32.6% of the 519 patients, was superior to those of CMX, FOM, and FRM. The well-balanced antibacterial activity of OFLX was thought to be one of the properties of OFLX otic solution.
4. Previously-reported post antibiotic effect of OFLX was thought to be another property of OFLX otic solution.
In conclusion, OFLX otic solution appeared to be clinically useful, because it possessed advantageous properties beyond other clinically-available otic solutions.

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Meropenem (MEPM), a novel parenteral carbapenem antibiotic, was examined in a cooperative study involving 12 pediatric and 1 neonatologic facilities. The results are summarized as follows.
1. Antibacterial activity
Antibacterial activity of MEPM against stock organisms including 31 strains of Streptococcus agalactiae, 14 of Listeria monocytogenes, 4 of Bordetella pertussis and 3 of Neisseria meningitidis ranged from 0.025 to 0.10μg/ml in MIC₉₀'s, which were equal or lower than those of control drugs such as imipenem cefazolin, cefotiam, cefotaxime, ceftazidime and latamoxef.
MICs against clinical isolates were as follows: In Gram-positive bacteria, MICs were 0.20μg/ml to 6.25μg/ml against 3 strains of Staphylococcus aureus, and 0.025μg/ml or less against 4 of Streptococcus pneumoniae. In Gram-negative bacilli, MICs were 0.10μg/ml to 0.20μg/ml against 3 strains of Haemophilus influenzae and 0.78, 0.10 and 0.78μg/ml, respectively, against one strain each of Enterobacter cloacae, Morganella morganii and Pseudomonas aeruginosa. MIC against 1 strain of Peptococcus saccharolyticus was ≤0.025μg/ml.
2. Pharmacokinetics
Maximum plasma concentrations after intravenous infusion of MEPM over 30 minutes at doses of 10, 20 and 40mg/kg, respectively, to 3 different groups of 3 children (total 9 cases) were observed at the completion of the treatment. Mean maximum concentrations in the 3 groups were 36.3, 69.5 and 129.8μg/ml, respectively, exhibiting clear dose response. Mean plasma half lives in beta phase were 0.94, 0.86 and 0.94hours, respectively, exhibiting no difference by doses, and this trend was observed also by HPLC. Urinary excretion rates in the first 6 hours after dose in the 10, 20 and 40mg/kg groups were 67.3, 65.6 and 68.4%, respectively.
Concentrations of MEPM in cerebrospinal fluid were determined in 2 cases of pyogenic meningitis. In 1 case, 500mg (5.9mg/kg) of MEPM was infused intravenously over 30 minutes and concentrations on Days 6, 8 and 15 observed at 190, 60 and 100 minutes after respective doses were 0.13, 0.10μg/ml and less than the detection limit. Cerebrospinal fluid-plasma concentration ratio was determinable only on Day 8 and was 2.8%. In another case to which 250mg (38.5mg/kg) of MEPM was infused intravenously over 30 minutes, the concentration at Days 6, 7 and 10, 1 hour after the dose were less than the detection limit on day 6, and 2.04 and 2.62μg/ml, respectively on days 7 and 10.
3. Clinical efficacy
Clinical efficacies were evaluated in 49 cases and the efficacy rate was 93.9%. Excellent and good effects were obtained in all 3 cases with pharyngitis and tonsillitis, 4 with acute bronchitis, 25 with pneumonia, 2 with purulent meningitis, 1 with peritonitis, 6 with urinary tract infection and 1 with phlegmon. Fair and poor results were obtained in 1 out of 3 cases with staphylococcal scalded skin syndrome and 2 out of 4 with purulent lymphadenitis.
Bacteriological efficacy was examined in 27 strains including Gram-positive bacteria consisting of 7 strains of S. aureus, 1 of S. agalactiae, 5 of S. pneumoniae, and 1 each strain of Enterococcus faecalis and Enterococcus sp, and Gram-negative bacilli consisting of 4 strains of H. influenzae, 2 of Escherichia coli, and 1 each strain of Klebsiella pneumoniae, E. cloacae, Proteus mirabilis, M. morganii and P. aeruginosa as well as 1 strain of anaerobic bacterium P. saccharolyticus. One out of 7 strains of S. aureus, 1 of E. faecalis and 1 of P. saccharolyticus were reduced or unchanged, and all other 24 strains became negative, thus an eradication rate of 88.9% was obtained.
4. Side effects and abnormal laboratory findings
No side effects were observed in 49 cases.

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Meropenem (MEPM, SM-7338), a novel parenteral carbapenem antibiotic, was examined f6r its effect on intestinal flora in children.
Seven children with infectious diseases (3 male and 4 female children of age's ranging from 4 months to 8 years and g months weighing from 7.3 to 23.0kg) were treated with MEPM at doses ranging 10.3 to 40.5mg/kg 3 or 4 times a day for 6 to 12 days. Before, during and after the treatment, identities and numbers of various bacteria contained in 1g of feces were determined and fecal β-lactamase activity and Clostridium difficile D-1 antigen were also assayed.
Changes in fecal flora during MEPM treatment was somewhat different depending on cases. Regarding Enterobacteriaceae among aerobes, all of 7 cases exhibited moderate or pronounced reductions in Escherichia coli. Some of the cases exhibited the tendency to increase in Klebsiella oxytoca, Enterobacter cloacae and Citrobacter freundii. E coli which was reduced during the treatment increased rapidly after the treatment in 5 out of 7 cases, and the initial bacterial counts were restored. Diverse strains were observed within the genus Enterococcus, while the overall bacterial counts of this genus exhibited the tendency to increase during the treatment. As a result, no significant change in total aerobe count was observed in any case except l case where Enterococcus count was somewhat reduced. Among anaerobes, major bacteria such as Bacteroides, Bifidobacterium, Eubacterium and Peptococcaceae exhibited tendencies to decrease in some cases during the antibiotic treatment. Two infants and 1 child exhibited significant decreases in total anaerobe counts. In most of the cases, such changes in major anaerobes were transient and bacterial counts recovered to their initial values rapidly after completion of the treatment.
In no cases, glucose non-fermentative Gram-negative bacilli or fungus became predominant. Although C. difficile D-1 antigen was observed in 4 cases, its changes had no relationship with characteristics of feces. C. difficile was not detected in any of the cases.
MEPM was detected in feces in 4 cases being treatment, in concentrations ranging from 0.35 to 66.0μg/g. Fecal MEPM levels were very low except in l case in whichβ-lactamase was negative.
From these results, effects of MEPM on intestinal flora in children were relatively minor compared to other new β-lactam drugs. However, a care should e taken to minimize diarrhea and bacterial turnover when a prolonged use of the antibiotic, was practiced because of potential significant effects on intestinal flora.

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We performed laboratory and clinical evaluation of meropenem (SM-7338, MEPM), a new carbapenem antibiotics, in pediatric field.
Pharmacokinetics of MEPM was examined with 5 patients, at a dose of 10mg/kg via 30 minutes drip infusion. Mean plasma concentrations at 30 minutes, 1, 1.5, 2.5, 3.5 and 5.5 hours after dose were 18.8, 6.97, 3.62, 1.14, 0.43 and 0.12 μg/ml, respectively, with a half life of 0.96 hour. The urine recovery rate in 6 hours was 70.4%.
Clinical efficacy of MEPM was evaluated in 36 patients with various infectious diseases. MEPM was administered at doses ranging 9.5 to 30.6mg/kg/dosage, 3 to 4 times a day, 2 1/3 to 10 days. Clinical effects were excellent in 24, good in 11, fair in 1, with an efficacy rate of 97.2%. Bacteriologically, all causative organisms except one each of Haemophilus influenzae and Salmonella enteritidis were eradicated, an eradication rate for Gram-positive and Gram-negative bacteria were 100% and 93.3%, respectively.
No side effects were observed. Elevations of GOT and/or GPT were noted in 2 patients.
From the above results, we believe that MEPM is a highly effective and safe drug for patients with various infectious diseases in pediatric fields.

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