In 1983 and 1986, we studied the susceptibility of Staphylococcus aureus to antimicrobial agents at the Clinical Laboratory of Saga Medical School Hospital. The organisms were isolated from clinical materials, and the former study (1983) included 150 and the latter (1986) 205 strains of Staphylococcus aureus. Five antimicrobial agents (ampicillin (ABPC), cefazolin (CEZ), minocycline (MINO), gentamicin (GM) and clindamycin (CLDM)) were tested in both studies. Eight other drugs (methicillin (DMPPC), oxacillin (MPIPC), dicloxacillin (MDIPC), cefmetazole (CMZ), cefmenoxime (CMX), cefuzonam (CZON), amikacin (AMK) and ofloxacin (OFLX)) were added to the latter study.
The microdilution method, using the MIC-2000 system, and the triple concentration disk method were employed to determine the susceptibility of Staphylococcus aureus to each drug.
Comparing both studies, the percentage of the resistant strains (MIC) 12.5 /temp against ABPC, CEZ, GM and CLDM was higher in 1986 than in 1983, increasing from 18 to 50% for ABPC, from 15 to 34% for CEZ, from 20 to 27% for GM and from 14 to 24% for CLDM. However, resistant strains against MINO were not detected in either study. In the latter study, the percentages of resistant strains were 26% for DMPPC, 22% for MPIPC, 5% for MDIPC, 9% for CMZ, 24% for CMX, 17% for CZON, 13% for AMK and 0.5% for OFLX. With the disk method, moreover, 46% of the total strains were resistant against both jS-lactams and aminoglycosides. About 50% were resistant against CEZ (cefazolin-resistant-Staphylococcus aureus CRSA).
These data suggest that multiple-resistant strains of Staphylococcus aureus are increasing rapidly, and that the management of these resistant strains may be of great clinical importance.

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Fifty-seven strains of Nocardia asteroides and thirty-four of Nocardia brasiliensis were tested by agar dilution for their susceptibility to 17 aminoglycoside antibiotics (AGs). The inoculum used in the study was prepared by increasing the homogeneity of the organism suspension using sterile glass beads in Erlenmeyer flasks.
Both N. asteroides and N. brasiliensis were generally insensitive to SM, KM, AKM, FRM, PRM and RBSM group AGs. 3'-Deoxy type AGs, such as GM, DKB, MCR, SISO and TOB were effective against N. brasiliensis, whereas most of them were not effective against N. asteroides. C-1-NAcylated or acetylated AGs, such as AMK, HBK, HAPA-B and NTL, were highly effective against both N. asteroides and N. brasiliensis and no resistant strains were observed.
These results indicate that all N. brasiliensis strains have an inactivating enzyme, APH (3') and about 50% of N. asteroides strains have either adenyltransferase ADD (2'') or phosphotransferase A AC (3').
Among the 17 AGs tested, HBK was found to be most effective, followed by AMK, and the MICH values of HBK against N. asteroides and N. brasiliensis were 1.25 and 1.46μg/ml, respectively.
Our studies suggest that a test for the susceptibility of Nocardia to aminoglycosides is useful to differentiate between species of N. asteroides and N. brasiliensis. Our data also suggest that strains of N. asteroides sensu stricto could be divided into at least two subgroups by their reaction to 3'-cleoxy type aminoglycoside antibiotics.

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We clinically examined the fosfomycin (FOM) susceptibility of 192 strains of clinically isolated Pseudomonas aeruginosa. FOM-inactivating enzyme was detected in two strains (T-75 and T-92) showing high FOM-resistance. The enzymological properties were investigated using strain T-75. We suspected that the FOM-inactivating enzyme was located near the inner membrane of the cell. The enzyme was purified to 810-fold. Molecular weight of the enzyme estimated by Sephadex G-100 gel filtration and SDS-polyacrylamide gel electrophoresis was 32 Kdal and 11 Kdal, respectively. The optimum temperature, optimum pH for the inactivation of FOM and isoelectric point of the enzyme, were 25°C, pH 7.8, and pl 5.4, respectively.

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Our major objective in this study was to clarify the transfer of antibiotics into the bronchoalveolar lumen. Bronchoalveolar lavage (BAL) was performed in 18 patients with various respiratory dis. eases: 5 with pneumonia (cured phase), 4 with lung cancer, 3 with chronic inflammation, 3 with interstitial pneumonia or pulmonary fibrosis, 2 with diffuse panbronchiolitis and one with pneumoconiosis. BAL was performed 60 min after i. v. injection of 1 g of CMX. CMX concentration, total protein and albumin were measured in serum and in BAL fluid (BALF). CMX concentration was tested by bioassay. The following conclusions were obtained.
1) CMX concentrations ranged from 0.035-0.962μg/ml in BALF and from 13.5-65.2μg/ml in serum.
2) Mean value and standard deviation of CMX concentration were 0.289±0.271μg/ml in BALF and 41.5±16.10μg/ml in serum.
3) CMX/albumin ratio showed a higher value in BALF than in serum.
4) CMX concentration in BALF was higher than those of cefotiam and sulbenicillin.

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A quantitative analysis of TE-031 (A-56268) and its metabolites in serum, urine and feces was established by high performance liquid chromatography (HPLC) with an electrochemical detector (for TE-031, M-4, M-5, M-6 and M-7) and a fluorescence detector (for the NBD-F derivative of M-1).
The detection limit of TE-031 and its metabolites in serum, urine and homogenized feces was below 0.05, 1.0and 1.0μg/ml. Good linear calibration curves were also obtained for these metabolites.

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To study the pharmacokinetics and safety of TE-031 in tablet form, a new macrolide antibiotic, we examined its absorption and excretion in 56 healthy male volunteers by bioassay.
At oral doses of 100, 200 and 400 mg, peak serum levels were attained at 1.20-2.74 h, suggesting rapid absorption from the gastro-intestinal tract. C_max was O.73, 1.16 and 2.24μg/ml at doses of 100, 200 and 400 mg, respectively, and AUC values were roughly proportional to the doses. Disappearance of TE-031 from serum was relatively slow, with a T_1/2 of 3.77-4.36 h and activity was clearly observed even 12 h after dosing.
Urinary excretion revealed an almost constant rate at these doses, which accounted for 38.3-46.3% of the dose within 24 h. Fecal excretion was 11.3% of the dose within 48 h.
It was demonstrated that the pharmacokinetic profile of TE-031 was scarcely influenced by food intake, owing to its high acid stability, and showed little inter-individual variation in serum level and urinary excretion.
During repeated clinical doses of TE-031 200 mg (2 times/day for 14 days, 27 times in total), both serum level and urinary excretion rapidly reached a steady-state and no accumulation was observed.
Levels in saliva were about 1/2 those in serum and AUC values about 58% that in serum.

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To study the pharmacokinetics of TE-031 tablets in humans, we measured TE-031 and its metabolites in serum, urine and saliva by HPLC and compared the results with the preceeding bioassay data.
After oral administration of TE-031, roughly equal concentrations of TE-031 and its active metabolite, (14R)-14-hydroxy TE-031 (M-5), were mainly detected in serum, urine and saliva. Also, at 400 mg, the proportion of TE-031 increased over that of M-5, suggesting metabolic saturation of TE-031 at higher doses.
The total concentration of TE-031 and M-5 in each sample was generally in agreement with the value measured by bioassay.
As for the other metabolites, small amounts of N-demethyl TE-031 (M-1), decladinosyl TE-031 (M-4) and the isomer of M-5 (M-6) were detected in the serum and urine. These results indicate that 14-hydroxylation of TE-031 is the principal metabolic pathway in humans.
With repeated administration of TE-031 at 200 mg × 2/day for 14 days, the composition of metabolites was not significantly changed in serum and urine, suggesting that metabolic changes scarcely occured during repeated administration.

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We observed a rapid and drastic decrease in blood pressure when DNR and MINO were alternately or simultaneously injected into cats at clinical doses. The percentage decrease against His standard was 22.2-76.5% for alternate and 28.6-150% for simultaneous administrations. Experiments in which we used pure minocycline showed that other agents were not responsible for the decrease in blood pressure. Other antibiotics, GM, LCM and MMC, had no effect on the decrease in blood pressure when administrated before injection of DNR and MINo.No decrease in blood pressure occurred if the interval between injection of DNR and MINO was sufficiently wide, e. g., one Ihour. In simultaneous administration with 3.33 mg/kg of MINO, blood pressure did not decrease up to 2mg/kg of DNR, but it drastically decreased at 3 mg/kg of DNR.
These results suggest that this drastic decrease in blood pressure can be avoided if the concentrations of the two drugs are lower than the threshold value and the interval between administrations is sufficiently wide.

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Multiple combination chemotherapy mainly consisting of aminoglycosides is commonly used for severe infections. We clinically studied the protective effect of piperacillin on the renal toxicity ofaminoglycosides and other antimicrobial agents, using urinary N-acetyl-beta-D-glucosaminidase (NAG) as a parameter. In the population receiving aminoglycosides, cephems, and amphotericin B with piperacillin, the rate of patients in whom the NAG value increased was 43% while the rate in that receiving no piperacillin was 74%. The difference was statistically significant with a risk factor of 1%. In the population receiving no piperacillin the higher the NAG value before therapy, the higher it was after therapy also. The reductive effect of piperacillin on the renal toxicity of aminoglycosides was not influenced by the type of aminoglycoside or other combined antibiotics. These results suggest that piperacillin decreases the renal toxicity of aminoglycosides.

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We report thirteen cases of tsutsugamushi disease, which was endemic in Nagasaki Prefecture from October to December 1987. All patients showed fever, skin rash and eschar. All cases were diagnosed serologically by indirect-immunofluorescense technique and treated with minocycline. Rickettsia tsutsugamushi was isolated from five cases.
In a survey of anti-Karp, Kato, Gilliam, and newly discovered serotype (Kawasaki, Kuroki) antibodies, seven patients showed the highest antibody titers against the Kuroki strain and six against the Kawasaki strain. These findings suggest the prevalence of two serotypes of R. tsutsugamushi in Nagasaki Prefecture.
The in vitro activities of six antibiotics against three clinically isolated strains of R. tsutsugamushi were determined by a cell culture method. Tetracycline, minocycline, dimethylchlortetracycline, and leucomycin showed stronger activity than chloramphenicol against R. tsutsugamushi.

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