Clarithromycin dry syrup, a new drug preparation, was clinically evaluated in the pediatric field and the following results were obtained:
1. Absorption and excretion
In infants administered with single oral dose of 5mg (potency)/kg and 10mg/kg, the C_max was 2.26±0.42 and 3.23μg/ml; T_max, 1.6±0.1 and 2.0 hours; T 1/2, 3.89±0.52 and 2.06 hours; AUC (0-∞), 13.48±1.93 and 13.84μg·hr/ml, respectively.
Urinary concentrations peaked in 2-4 hours after administration at 5mg/kg and 0-2 hours at 10mg/kg. Urinary recovery rates in the first 6 hours were 25.8±3.9% at 5mg/kg and 20.7% at 10mg/kg.
2. Clinical results
The clinical efficacy of the drug was evaluated in 150 patients with various infections. Clarithromycin dry syrup was administered to all the patients at daily doses of 10-15mg/kg divided into 2-3 equal doses.
The overall clinical efficacy rate was 98.0%, and this drug was effective in 98.9% of 90 patients for whom the causative pathogens were identified and in 96.7% of the other 60 patients for whom the causative pathogens were unknown.
The bacteriological eradication rate was 88.5%.
The efficacy and eradication rates for 19 patients who had not responded to previous chemotherapy that lasted for more than three days were 94.7% (18/19) and 75.0%, respectively.
Side effects occurred in 4 (2.4%) of 169 patients subjected to safety analyses, but none was serious. As to abnormal laboratory test results, moderate increases of eosinophils and elevations of transaminases were observed in 5.9% of the cases. No particular and serious problems were associated with administration of this drug.
Based on the above results, clarithromycin dry syrup is considered to be very useful and have a good compliance at a daily dose of 10-15mg/kg divided into 2-3 doses.

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We conducted a multicenter trial to determine the clinical usefulness of the combined therapy with flomoxef (FMOX) and fosfomycin (FOM)(FF therapy) as an empirical therapy in the treatment of intractable respiratory tract infections, because FF therapy has clinically been proved to be very useful for the treatment of severe infections including MRSA infections. The overall efficacy rate of FF therapy was 69.2%. The efficacy rate for “pneumonia/lung abscess,” which occupy the largest portions of respiratory tract infections, was 70.0%, showing a statistically significant difference from the efficacy rate for FMOX alone (56.7%) found in a previous study (P=0.09 by chi-squared test). Although MRSA was eradicated in only 3 cases (37.5%) including superinfection cases, of 8 patients, from whom MRSA had been isolated as causative or ganisms, none of our patients were superinfected with MRSA. Thus it has been concluded that FF therapy is clinically very useful when used as an empirical therapy in the treatment of respiratory tract infections.

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Twenty-eight patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were clinically studied for the effectiveness of the time-difference combination use of netilmicin (NTL) and minocycline (MINO). The patients were treated with NTL 100mg and two hours later, with MINO 100mg intravenously, twice daily, in the morning and evening for 14 days. Of 26 patients, MRSA was eradicated in 16 (61.5%), decreased in one, and unchanged in nine. Superinfections occurred with Serratia marcescens and Pseudomonas aeruginosa in two patients. The clinical efficacies were assessed in two patients with septicemia, 16 with pneumonia, and eight with chronic bronchitis. The obtained results were excellent in four patients, good in 15, fair in six, and poor in one patient. The rate of effectiveness was 73.1% (19/26). The overall clinical effectiveness judged by the commitee was good in 19, fair in five, and poor in two patients. The efficacy rate was also 73.1% (19/26). Coagulase type II of MRSA was found in 23 patients, and coagulase type III in three patients, with overall clinical efficacy rates of 73.9% (17/23) and 66.7% (2/3), respectively. A side effect of eruption was observed in one patient, and its incidence was 3.6% (1/28). Abnormal laboratory test results were observed in 16 patients (57.1%), including abnormal liver function in 14 patients, abnormal kidney function in three, and increased eosinophils in three. Laboratory abnormalities occurred twelve of 16 bedridden patients, and this rate was higher than that in non bedridden patients. However, these abnormalities were all mild, transient, and immediately recovered after the treatment. In conclusion, the time-difference combination therapy using NTL and MINO was effective in the treatment of MRSA infections.

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Using the envelope method, we allocated 125 patients with infections accompanied by hematopoietic disorders into two groups treated with imipenem/cilastatin sodium (IPM/CS) at a daily dose of 1g/1g b. i. d.(group BID) or 0.5g/0.5g q. i. d.(group QID), and obtained the following results.
1. In group BID, ANLL was observed in 25 patients; ALL in 6;and NHL in 12. In group QID, ANLL was observed in 27 patients; ALL in 7; and NHL in 13.
2. In group BID, efficacy rates were 54.5% (6/11) in sepsis, 63.0% (17/27) in fever of undetermined origin and 50.0% (4/8) in pneumonia, thus the overall efficacy was 61.8% (34/55). In group QID, efficacy rates were 66.7% (4/6) in sepsis, 76.0% (19/25) in fever of undetermined origin and 35.7% (5/14) in pneumonia, thus the over all was 61.1% (33/54). No significant difference in response rates were observed between the two groups.
3. Bacteriologically, 22 bacterial strains were isolated in group BID and 21 strains, in group QID. The eradication rates after treatment with IPM/CS was 100% in group BID and 66.7% in group QID.
4. Side effects were observed in 8 patients in group BID and 3 in group QID. Laboratory examination revealed abnormal values in 9 patients in group BID and 6 in group QID. However, all of the side effects desappeared after the suspension or discontinuation of IPM/CS.
The efficacies of IPM/CS therapy for severe infections in patients with hematopoietic disease were similar between 1g/1g b. i. d. and 0.5g/0.5g q. i. d. groups.

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Bacteria isolated from intraabdominal infections during the period from July 1982 to June 1993 were investigated with regard to their classifications according to a joint research by 9 university hospitals in Japan. The following results were obtained.
1. A total of 971 strains were isolated from 684 out of 597 patients with peritonitis, and 287 strains out of 971 were isolated from postoperative peritonitis.
2. The most predominant organism isolated from patients with acute peritonitis was Escherichia coli (28%), followed by Bacteroides fragilis group (17%), Gram-positive anaerobic cocci (16%), Enterococcus spp.(9%) and Klebsiella spp.(8%).
3. Against E. coli, cefmenoxime, cefuzonam, cefozopran, aztreonam and carumonam showed MIC₅₀ less than 0.05μ/ml. Against B. fragilis group, erythromycin, clindamycin, imipenem, lincomycin and latamoxef showed MIC₅₀ less than 0.78μ/ml.
4. The most predominant organism isolated from patients with postoperative peritonitis was Enterococcus spp.(20%) and followed by Pseudomonas spp.(14%), and Staphylococcus spp.(13%), E. coli (9%), Enterobacter spp.(8%) and Klebsiella spp.(8%).
We suggest that cefazolin, cefmetazole, flomoxef, cefmenoxime, cefuzonam and latamoxef are the first choice agents in empiric therapy for the treatment of acute peritonitis.

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The specific ladder pattern on polyacrylamide gel electropholesis of lipopolysaccharide (LPS) extracted from Pseudomonas aeruginosa was clearly shown by using the complex methods of the PAS staining, re-periodate oxidation and then Ag-staining method. Accordingly, it was concluded that the new method was grately useful for a detail analysis of LPS changes in Gram-negative bacteria. And it was shown by this method that no changes in LPS occurred between the impermeability-type drug resistant P. aeruginosa mediated by R plasmid and a drug susceptible strain. The absence of changes indicated that the LPS of P. aeruginosa K-Ps102 had no role inthe mechanism of the high drug resistance.

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We investigated in vitro synergistic effects of tazobactam/piperacillin (TAZ/PIPC), a combination drug of tazobactam (TAZ) and piperacillin (PIPC) in the ratio of 1:4, with several other antibiotics against Pseudomonas aeruginosa, Serratia marcescens and methicillin-resistant Staphylococcus aureus (MRSA).
Synergistic effects of TAZ/PIPC with each of tobramycin (TOB), netilmicin (NTL), fosfomycin (FOM), ciprofloxacin, minocycline or cefoperazone were observed against all bacteriatested in the checkerboard dilution method. No antagonistic effect was observed in combination of TAZ/PIPC with other antibiotics. Against P. aeruginosa, a combination of TAZ/PIPC with NTL was the most effective, with an average fractional inhibitory concentration (FIC) index of 0.459. And a combination of TAZ/PIPC with FOM was the most the effective against S. marcescens and MRSA.
TAZ/PIPC combined with TOB or FOM showed bactericidal effect against P. aeruginosa No.11, S. marcescens No.39 and S. aureus O-62 at concentrations of the drugs that showed only bacteriostatic activity individually.
Phase-contrast micrographic observations of P. aeruginosa No.11 and S. marcescensNo.39 demonstrated that the bacterial cells treated with TAZ/PIPC were in filamentous forms and those treated with TOB or FOM were nearly normal. Thecombination of TAZ/PIPC with TOB or FOM induced filamentous cells with spheroplast-like structures and lysis.
Those results suggest that the combination of TAZ/PIPC with aminoglycosides or FOM were useful in the treatment of infections by P. aeruginosa, S. marcescens and MRSA, especially those caused by β-lactamase-producing strains.

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We analyzed the results of bacteriological tests on patients with MASA infections admitted to Osaka Prefectural Hospital, for the past 10 years. The conclusions obtained are as follows.
1. In our hospital, MRSA infections accounted for 50% or more of all Staphylococcus aureus infections in 1983 and 1984 (in the first half of the 1980's), markedly decreased to about 10%after 1988, because of the preventive measures taken against nosocomial infections and initiation of anti-MRSA treatment. During the latter period, use of antibiotics including third generation cephems was not especially restricted.
2. Glucose non-fermentative Gram-negative rods (GNF-GNR) or yeasts co-isolated with S. aureus were more frequent in MRSA infected patients, than those in MSSA infected patients. 70 to 80% of GNF-GNR were P. aeruginosa.
3. Sensitivities of MRSA to drugs were studied. VCM was most active, followed by arbekacin and rifampicin. Effectiveness against co-isolated GNF-GNR was high with ofloxacin, netilmicin and ceftazidime (CAZ).
Therefore, is expected that, to prevent the replacement of opportunistic infections, combination therapies using vancomycin and CAZ would be effective.

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To examine the antimicrobial activity of cefditoren (CDTR) against strains clinically isolated from outpatients at this hospital from November, 1993 to February, 1994, the minimum inhibitory concentrations (MICs) were determined including those of the control drugs. The results were as follows;
1. CDTR showed strong antimicrobial activities against Staphylococcus aureus subsp. aureus, Streptococcus pyogenes and Streptococcus pneumoniae. The MICs of CDTR against benzylpenicillininsensitive or-resistant S. pneumoniae distributed in the lowest concentration range even compared to those of the control drugs.
2. CDTR showed strong antimicrobial activities against Haemophilus influenzae, Moraxella subgenus Branhamella catarrhalis, Escherichia coli, and Klebsiella spp. The MIC of CDTR against CEPs-resistant E. coli was lower than those of most control drugs.
3. Since the microbes described above are major pathogens for the community-acquired infections, CDTR will be effective against infectious diseases transmitted at outpatient visits.

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In order to investigate antibacterial activities of new quinolones (NQs) against a number of clinical isolates obtained in our laboratory during a period from February, 1993 to January, 1994, minimum inhibitory concentrations (MICs) were determined using most of the NQs available in the market as of December, 1993.
The obtained results are summarized as follows:
1. Noticeable differences were observed among the antibacterial activities of 8 different NQs tested against Gram-positive bacteria, i. e., there were large differences in their MIC distributions. Some differences were also observed among different NQs in ratios of NQ-resistant strains among Staphylococcus spp. From these results, it seems necessary to further study tolerance mechanisms of these Gram-positive bacteria toward different NQs and also to examine possible differences in antibacterial activities among different NQs against Gram-positive bacteria in clinical settings.
2. MIC distributions against Gram-negative bacteria were also different among the 8 NQs tested. Though elevated MICs were observed against NQ-resistant Gram-negative bacteria in many cases, and somewhat higher, though not exceedingly high, MIC values than those against NQsensitive bacteria were found in other cases, patterns of MIC values against different NQ-resistant Gram-negative bacteria were similar for all of the 8 NQs tested. This may explain the fact that most of NQ-resistant Gram-negative bacteria showed similar resistant patterns to the 8 NQs tested.
3. Among the NQ-resistant bacteria, were found Haemophilus influenzae and Neisseria gonorrhoeae strains. Ratios of resistant strains were approximately 10% or lower for the former and approximately 20% for the latter.
4. With MICs of ampicillin and cefaclor used as control, it appears that benzylpenicillin (PCG)-insensitive or PCG-resistant Streptococcus pneumoniae (PISP or PRSP) and CEPs-resistant Escherichia coli are increasing.

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In order to perform a preclinical evaluation of effectiveness of oral terbinafine (TBF) in tinea pedis, an animal model was produced using guinea pigs by experimentally infecting the plantar skin with Trichophyton mentagrophytes. TBF was administered orally to groups of the infected guinea pigs once-a-day for 4 consecutive weeks. The therapeutic efficacy was assessed on the basis of recovery of fungal cultures from the plantar skin. The group of guinea pigs treated with 12.5mg/kg/day of TBF resulted in complete cure. The animal group treated with 3.13mg/kg/day of TBF showed significantly better mycological response to the therapy than the group treated with 12.5mg/ kg/day of griseofulvin. These results suggest clinical usefulness of oral TBF for the treatment of tinea pedis.

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The effectiveness of topical terbinafine (TBF) to tinea pedis was evaluated an animal model in which guinea pigs were experimentally infected through their planta pedis with Trichophyton mentagrophytes, then a 1% TBF or butenafine (BTF) cream was administered topically once daily for 4 consecutive weeks. The therapeutic efficacy was assessed on the basis of recovery of fungal cultures from the planta pedis. The cured guinea pigs were reared in a clean environment that protected the animals from reinfection. The dermal tissues were cultured 2, 4, and 8 weeks post-treatment to examine for relapse of tinea. Complete cure was achived after 4 weeks of administration of TBF or BTF cream. In animals receiving 4 weeks of treatment with TBF, relapse was not observed up to 8 weeks after the termination of treatment. In animals treated with BTF for 4 weeks, while no relapse occurred 4 weeks after cessation of the treatment, relapse was detected in 2 out of 10 feet at 8 weeks after the termination of treatment.
These results suggest that topical TBF is effective in curing the infection and in preventing relapse in a guinea pig model of tinea pedis.

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Two different flucytosine (5-FC) treatment regimens, one by itself and the other in combination with fluconazole (FLCZ) were compared in chemotherapy against mycotic infections in 60 patients with hematological diseases.
The patients in a randomized fashion were assigned to the two treatments.
In the combination regimen, the two drugs were used in half doses. β-D-Glucan and D-arabinitol in the sera of patients were measured to document mycotic infections, and bacterial examinations were also performed.
The efficacy of the combination therapy was 60.0% (18/30) and that of 5-FC alone was 65.5% (19/29). The stratified evaluation indicated that no factor was found to contribute to the efficacy in the two treatments with statistical significance. The side effects occurred in few cases and none of those was serious; including, one case of subjective symptom in each groups and two episodes of liver dysfunction in combination treatment. Changes in β-D-glucan concentrations in the sera reflected well the pathophysiology of mycotic infections and clinical improvement. These results suggested that a combination of 5-FC and FLCZ at half doses provided a clinical benefit comparable to 5-FC alone at the ordinary dose, and the safety was considered satisfactory.

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