Susceptibility to β-lactam antibiotics, affinity of penicillin-binding proteins (PBPs), and the detection of the PBP 2 B gene (penA) by the polymerase chain reaction (PCR) were studied using 30 clinical strains of pneumococci isolated in 1993. The following results were obtained:
1) Fifteen of strains were identified as penicillin (PCG)-rsistant strains of pneumococcus (PRSP), with minimum inhibitory concentrations (MIC) of PCG≥0.125μg/ml.
2) The MICs of oxacillin, ampicillin, cefotaxime, cefdinir, and imipenem clearly differed in PRSP and PCG-sensitive strains of pneumococcus (PSSP).
3) PCR was performed by preparing three sets of primers for amplification of part of the PBP 2 B gene in order to differentiate between PRSP and PSSP. DNA from 15 strains with a PCG MIC <0.125 μg/mL was amplified using primers for detection of sensitive strains. The strains for which DNA was amplified with primers for PRSP detection all had MICs ≥ 0.125 μg/ml. These strains consisted of one class A strain and ten class B strains. However, DNA was amplified by primers for PSSP even in four PRSP strains.
4) In PRSP strains, the affinity of [³H]-PCG for PBP 2 B was reduced, and affinity for PBP-1 A or PBP-1 B was also reduced in many strains. Some PSSP strains showed reduced affinity for PBP-1 A or PBP 1 B, and PBP-2 X newly appeared in some strains.
These results suggest that many PRSP in Japan are variable strains with an altered PBP 2 B gene belonging to class B, that there are few class A strains, and that there are PCGresistant strains with changes in the PBP-2 B gene that have not yet beem reported.

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Antibacterial activities of four carbapenem antibiotics, imipenem (IPM), panipenem (PAPM), meropenem (MEPM) and biapenem (BIPM) were examined against fresh isolatesfrom complicated urinary tract infections. Tested species were methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa and Acinetobacter calcoaceticus. These carbapenems showed good antimicrobial activities against the tested strains except for MRSA, IPM showed better activity against gram-positivecocci such as MSSA, S. epidermidis and E. faecalis than other carbapenems. MICs of PAPM to P. aeruginosa were slightly larger than the others. MEPM and BIPM had better activities against gram-negative rods.

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The effect of cefclidin (CFCL) on experimental respiratory tract infection caused by Pseudomonas aeruginosa was studied in mice and compared with the effects of cefepime (CFPM) cefpirome (CPR), ceftazidime (CAZ) and imipenem/cilastatin (IPM/CS). Mice were rendered neutropenic by 5-FU administration. Experimental respiratoty tract infection was produced with an intranasal inoculation of P. aeruginosa into each neutropenic mouse. The infected mice which received the E 03575 or E 03585 strain of P. aeruginosa died of pneumonia. Using this experimental infection, the effects of cefclidin (CFCL), and other drugs were evaluated. Consequently, the CFCL (P<0.01) and CAZ (P<0.05) groups showed significantly enhanced survival rates against respiratory tract infection with P. aeruginosa E 03575 at 7 days after inoculation. Against respiratory infection with P. aeruginosa E 03585, the CFCL, CFPM, CPR and IPM/CS groups showed significantly higher survival rates (P<0.01) than the untreated control group, and CFCL produced the highest survival rate (100%). Mice did not die as a result of respiratory infection with P. aeruginosa E 03408, the antibiotics could, however, be evaluated on the basis of viable cell counts in the lungs. Treatment with CFCL (P<0.01) CFPM (P<0.05) and IPM/CS (P<0.01) led to significant reductions in the numbers of viable orgarisms in the lungs, as compared with the numbers in the lungs of untreated mice.

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The efficacy of tazobactam/piperacillin (TAZ/PIPC) in mice urinary tract infections with β-lactamase-producing bacteria were compared with those of piperacillin (PIPC) and sulbactam/cefoperazone (SBT/CPZ). TAZ/PIPC administration decreased the viable cell counts in kidney as effectively as SBT/CPZ, and their activities were superior to PIPC in infections with β-lactamase-producing Escherichia coli, Proteus vulgaris and Serratia marcescens. In mixed infection with β-lactamase-producing Staphylococcus aureus and PIPC-sensitive E. coli, concentration of PIPC following PIPC administration in kidney was lower than that following TAZ/PIPC administration. This result reflected the different efficacies of PIPC and TAZ/PIPC. From these results, it was suggested that TAZ/PIPC possessed as potent activity as SBT/CPZ against urinary tract infection, including polymicrobial infection.

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We treated 5 patients with respiratory tract MRSA infections with arbekacin administered by inhalation of 100mg to investigate its clinical efficacy, serum levels and pharmacokinetics. The results were as follows:
1) The serum level of the drug reached the maximum concentration of 0.366μg/ml in 1 patient 3h after inhalation, but was below the detection limit in 4 other patients.
2) The maximum daily urinary excretion was 2.33 mg, suggesting that the in vivo absorption rate would be 3.9% as the maximum, taking into consideration the fact that the urinary recovery rate was about 60% after the intravenous administration.
3) Bacteria disappeared in 2 patients and decreased in one after inhalation of arbekacin.
4) One patient complained of slight pharyngeal discomfort 4 days after the initiation of treatment, but therapy was continued and the symptom disappeared rapidly after treatment was finished.
5) Inhalation of arbekacin at a daily dose of 100mg was therefore thought to be effective in patients who do not respond to systemic antimicrobial therapy.

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The antibacterial and clinical efficacies of roxithromycin (RXM) were evaluated in 12 patients with infection and colonization in the respiratory tract caused by erythomycin (EM)-sensitive MRSA: 5 with pneumonia, 1 with bronchitis, 1 with lung abscess, and 5 with MRSA colonization. All patients received a dose of 150mg twice a day (total 300mg/day) orally. Clinical efficacy was 71.4%(5/7) and bacterial efficacy was 100%(12/12) for EM-sensitive MRSA. However, other bacteria such as Pseudomonas aeruginosa, Enterococcus faecalis, and even EM-resistant MRSAformed superinfection in 9 patients, although neither clinical symptoms nor inflammatory reactions were observed. After the completion of therapy, colonization by EMresistant MRSA strains was seen in three patients. Thus, RXM showed good clinical and antibacterial efficacies against EM-sensitive MRSA infection and colonization of the respiratory tract, but it did not always prevent superinfection by other bacteria, including EM-resistant MRSA.

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In order to find the optimal dose Of biapenem (BIPM), a carbapenem antibiotic, for the treatment of chronic respiratory tract infections, a comparative study was performed using imipenem/cilastatin sodium (IPM/CS) as a control drug, and the following results were obtained. BIPM at 0.3 (group L) or 0.6 (group H) g/day in two-divided doses and IPM/CS at 1.0g/1.0g/day (group C) in two-divided doses were systemically administered for 14days.
1) Clinical effects: The rates for excellent efficacy and efficacy rates were 10.7%(3/28) and 82.1%(23/28), respectively, in group L, 25.0%(6/24) and 83.3%(20/24) in group H, and 17.4%(4/23) and 78.3%(18/23) in group C. There were no significant differences among the 3 groups.
2) Bacteriological effects: The bacterial eradication rates were 76.2%(16/21) in group L, 81.3%(13/16) in Group H and 93.3%(14/15) in C group. There were no significantdifferences among the 3 groups.
3) Side effects were observed at a rate of 3.6%(1/28) in group L, 3.8%(1/26) in group H and 8.0%(2/28) in C group. None of these side effects were serious.
4) Abnormal laboratory findings were observed at a rate of 17.9%(5/28) in group L, 19.2%.(5/26) in group H and 28.0%(7/25) in group C. These abnormal findings were not serious.
5) Usefulness: Very useful and useful rates were 10.7%(3/28) and 82.1%(23/28), respectively, in group L, 20.0%(5/25) and 80.0%(20/25) in group H, and 16.7%(4/24) and 70.8%(17/14) in group C. There were no significant differences among the 3 groups.
Based on these results, we concluded that 0.6 g a day was the optimal dosage of BIPM in the treatment of chronic respiratory tract infections from the point of view of efficacy and safety.

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In order to investigate a more effective method of Arbekacin sulfate (ABK) administration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection, 15 cases of respiratory MRSA infection in 13 patients were studied. Dosage, duration of administration and serum concentration of ABK, sputum culture for MRSA, body temperature and CRP were checked to assess clinical efficacy. When the maximal serum ABK level was less than 7 μg/ml, the improvement of inflammation was 29%(2/7 cases), the clinical efficacy was 57%(4/7 cases), and the rate of eradication of MRSA, datermined from a series of three or more sputum cultures was 43%(3/7 cases). On the other hand, when the maximal serum ABK concentration was 7μg/ml or more, the improvement of inflammation was 75%(6/8 cases), the clinical efficacy was 100%(8/8 cases), and MRSA was eradicated in 63%(5/8 cases). We therefore concluded that a maximal serum ABK concentration of 7μg/ml is the effective level for respiratory MRSA infection, and that ABK should be used for 2 weeks at maximum, because in all effectively treated cases, MRSA disappeared within 11 days. In contrast, in failed cases, MRSA was still present even after more than 3 weeks of administration. About the proper daily dosage of ABK, the efficacy was only 57% at 200 mg/day, which is the officially recommended dose for ABK injection, in contrast with 100% at 400mg/day. It appears that the clinical efficacy of ABK is dependent whether the effective serum ABK level was achieved, because an effective serum ABK level was demonstrated in 71% of patients given 400mg of ABK per day, but only 29% of those given 200 mg/day. In terms of pharmacokinetic parameters for ABK, the mean distribution volume (Vd) was 24.4 L/man, which was larger than that reported previously, and the average elimination rate constant (Ke) was 0.109/hr. Simulation curves based on the mean values of the Vd and Ke in this study demonstrated that ABK at a dose 200mg twice per day with a 6-hour interval resulted in the highest serum concentration of 13μg/ml, which was over the effective level, but the trough serum concentration did not exceed 2μg/ml, which was expected to increase adverse reactions.

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The present authors investigated the utility and mechanism of long-term chemotherapy with erythromycin (EM) in the treatment of chronic lower respiratory tract infections. In parallel, we found that EM-clarithromycin (CAM) possesses properties as a biological response modifier (BRM), stimulating the activities of natural killer cells and producing various cytokines. Given these characteristics of CAM, investigations were performed on the effects of CAM on the survival of lung cancer patients receiving long-term administration of CAM. The subjects were 50 inpatients with primary lung cancer not indicated for surgical operation. They consisted of 43 males and 7 females, 41-82 years of age (64.5±9.8). Patients received concomitant application of radiotherapy with chemotherapy including CDDP; after discharge, they were allocated randomly into a CAM administration group and nonadministration group at their initial visit to the outpatient clinic, and subsequent survival times were compared between the two groups. Survival rate data were analyzed using the Kaplan-Meier method and differences between the two groups were compared by the generalized Wilcoxon method and LongranK method. There were no significant differences between the two groups in terms of age, sex, stage, tissue type, basic treatment or efficacy rate. Results indicated that the survival curves of patients with small cell cancer were not significantly different between the two groups, but the 50% survival time of patients with non-small cell cancer was 930 days in the CAM administration group and 299 days in CAM non-administration group, indicating significant prolongation of survival in the CAM administration group (p=0.003). In conclusion, CAM was suggested to have potential as a BRM in eliciting prolongation of survival time in patients with lung cancer.

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Sixty-nine patients with hematopoetic malignancies who were complicated with severe opportunistic infection were studied. Ten of them were diagnosed as having mycosis, and 33 of the remaining 59 patients were suggested to have fungal infections.β-D-glucan was positive in 12 (17.4%) of the patients. The positivity rates for β-D-glucan in patients who were diagnosed as having mycosis, in those whose infection was strongly suspected to be mycosis were 80.0% and 12.1% respectively. The differences inthe positivity rates of β-D-glucan among those three groups were statistically significant. These results suggest that the measurement of β-D-glucan is useful for diagnosing deep mycosis. β-D-glucan was more frequently detected during the neutropenic state in patients with acute myeloid leukemia, while the frequency of positive β-D-glucan was higher during the lymphopenic state in patients with malignant lymphoma. Fluconazole (FLCZ) was effective against fungal infections in 27 (65.1%) of 43 patients in whom it was administered. Combined therapy with FLCZ and G-CSF was effective in 11 (61.1%) of 18 patients, while treatment with FLCZ alone was effective in 17 (68.0%) of 25 patients. These results suggest that G-CSF has no significant additive benefit to FLCZ against fungal infections. Although the measurement of β-D-glucan is useful for diagnosing deep mycosis, it was positive in only a few patients with localized fungal infection. In such patients, it is important to confirm the diagnosis by using the combination of several tests for fungal infection. FLCZ was considered effective for the treatment of mycosis associated with hematopoietic malignancies.

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