The combined action of netilmicin (NTL) with latamoxef (LMOX), cefoperazone (CPZ), ceftizoxime (CZX), cefmenoxime (CMX) or ceftazidlme (CAZ) was studied against Escherichia coil, Serratia marcescens, Pseudomonas aeruginosa and Moraxella (Branhamella) catarrhalis. The following results were obtained
1. The antibacterial activity of each antibiotic by itself against E. coil and M.(B.) catarrhaliswas strong.
2. Synergistic action of NTL with each of LMOX, CPZ, CZX, CMX and CAZ was observed on all bacteria, especially S. marcescens and P. aeruginosa. The combination of NTL with CPZ was most effective.
3. Bactericidal activity of NTL with LMOX or CAZ was observed on S. marcescens T-55 and P. aeruginosa E-2 at concentrations in which the respective drugs alone showed only bacteriostatic activity.
4. Phase-contrast microscopic observation of P. aeruginosa E-2 demonstrated that the bacterial cells treated with LMOX or CAZ showed a filament-like form and those treated with NTL almost a normal form. In each combination lysed cells were observed.

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The sensitivity to methicillin (DMPPC) and cefazolin (CEZ) of 378 strains of Staphylococcus aureus isolated in 12 institutions in the Tohoku district of Japan in 1987, was examined by a microbroth dilution method using the Dynatech MIC-2000. The incidence of methicillin-resistant strains (MIC≥12.5μg/ml) of S. aureus (MRSA) was 34.4%(130/378), and that of cefazolin-resistant strains (MIC≥12.5 μg/ml) 32.5%(123/378). Of 130 MRSA strains, 107 were resistant also to cefazolin. There was astatistically significant specimen-to-specimen difference in the incidence of MRS A, which was higher in aspirated sputum, blood and urine than in expectorated sputum, pus, otorrhea and throat swab. The incidence of MRSA among institutions was found to vary between 0% and 75%. This difference was statistically significant. MRSA incidence among institutions with more and those with less than 500 inpatients was 44.3% and 14.4%, respectively, the difference being again statistically significant. The incidence of MRSA among departments was found to vary between 12.1% and 75.0%.The incidence of MRSA in urology, neurosurgery and general surgery departments was higher than in otorhinolaryngology and respiratory departments. The above results suggest that the increase in the incidence of MRSA can, for the most part, be ascribed to hospital infection.

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The in vitro combined effect of cefuzonam (CZON) plus minocycline (MINO) against 403 strains of Staphylococcus aureus (152 MRSA and 251 MSSA strains) isolated in the Tohoku district of Japan in 1987, was examined by a checkerboard microbroth dilution method using the Dynatech MIC-2000. The mean FIC (fractional inhibitory concentration) index of this combination for all 403 strains of S. aureus was 0.652, being 0429 for MRS A, and 0.764 for MSSA. This combination was more effective against highly-resistant MRSA strains (MIC>25μg/ml), as revealed by the mean FIC index of 0.405, than against moderately-resistant MRSA strains (MIC=12.5 and 25 μg/ml), whose mean FIC index was 0.485. It was also more effective against cefuzonam-resistant than against cefuzonamsensitive MRSA strains: the mean FIC index being 0.388 for those strains whose MIC exceeded 6.25 μg/ml; 0.520 for those whose MIC was 6.25, 3.13 or 1.56μg/ml; and 0.625 for those whose MIC was below 1.56μg/ml. On the other hand, when the MIC of minocycline against MRSA was high, the mean FIC index of the combination was not markedly decreased by the addition of cefuzonam. Based on our results, we conclude that minocycline made a more significant contribution to this combination Than did cefuzonam.

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Since methicillin-resistant S. aureus (MRSA) occupies a prominent position in nosocomial infections, we studied it by coagulase-typing of 214 strains of S. aureus isolated from clinical specimens on the ward from 1983 to 1988 and of 62 strains isolated in the operating room.
In the study on the ward strains, highly methicillin-resistant S. aureus strains (H-MRSA, MIC >100 μg/ml) which was not detected in 1983, showed a significant increase in isolation frequency, and accounted for c. 60% of MRSA (MIC12.5 μg/mp) in 1987. Then, with the medical staff's awareness of the prevalence of MRSA on the ward, countermeasures, such as sterilization with chlorhexidine alcohol from 1987 on, significantly decreased the isolation frequency of MRSA and H-MRSA in 1988.
In the study on coagulase type, MRSA type IV strains were predominantly isolated until 1984, but after 1986 most MRSA belonged to type II. The characteristics of the current epidermic strain type II were the following.
1. It proved highly resistant to DMPPC and other p-lactam antibiotics.
2. The isolation frequency of highly β-lactamase-producing strains was less than that of the other coagulase types of S. aureus.
3. It was sensitive to MINO and OFLX.
4. GM-sensitive, AMK-resistant strains were circulating from the second half of 1986.
In the operating room, all the strains isolated were methicillin-sensitive S. aureus (MSSA), thecurrent epidermic coagulase type there being type VII. We therefore presume that cross-infection with MRSA did not take place in the operating room but on the ward.

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We studied the intrarenal retention of the aminoglycoside antibiotics, netilmicin (NTL) and dibekacin (DKB) and their nephrotoxicity under consecutive daily administrations to rats.
Both drugs were given intramuscularly to male Sprague-Dawley rats weighing approximately 200g in doses of 30, 90 or 120 mg/kg for 21 days. The following results were obtained.
(1) There were no dose-related changes in serum concentration for the groups treated with NTL, but a significant increase in renal tissue was noted. For groups treated with DKB, there was a doserelated increase in serum concentration, but accumulation in renal tissue was less than during treatment with NTL.
(2) In a histopathological study of the epithelial cells of the proximal convoluted tubuli in rats receiving NTL or DKB, we observed dilation, regeneration, pyknosis, karyorrhexis and swelling of the renal tubules and renal casts. The degree of these changes in the proximal tubules was doserelated for both drugs, but was more remarkable with DKB at 90 and 120 mg/kg.
Consequently, NTL exhibited milder nephrotoxicity than DKB, although NTL tends to accumulate in renal tissue.

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The purpose of this study was to induce an experimental urinary tract infection, pyelonephritis, in mice by using a urethral stricture followed by intravesical inoculation of bacteria. Viable cells in the kidney were studied and histopathological observations made for 14 days.
Urinary retention was observed in all mice at 24 hours after the inoculation. A large number of bacteria remained in the kidney: 10⁶cells/kidney at 7 days and 10⁵cells/kidney at 14 days. Histopathologically, inflammatory cells were observed in the renal cortex at day 1 and in the renal cortex, medulla and renal pelvis at day 3. Inflammatory cells were observed in the renal pelvis but not in the renal cortex and medulla at day 7. Subsequently, all inflammatory cells decreased at day 14. Vesicoureteral reflux was frequently observed at 12 hours.
Thus, in the urethrally strictured mice bacteriuria continued which derived from vesicoureteral reflux. Histopathologically, however, pyelonephritis developed differently in three animals. Further investigation is under consideration.

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We studied the susceptibility of mice with experimentally-induced diabetes or granulocytopenia to microbial infection, and the therapeutic effects of cefixime, cefaclor and cefadroxil using a model of ascending urinary tract infection with E. coli. Streptozotocin (STZ) at an i. v. dose of 200mg/kg caused diabetes-like symptoms and prolonged high glucose levels in the blood. In the mice with diabetes, the test drugs suppressed chemotaxis and NBT reduction of peritoneal PMN leukocytes, though these mice tended to have the same susceptibility to urinary tract infection due to E. coli as normal mice. There were no significant differences between diabetic and normal regarding the effects of cefixime, cefaclor and cefadroxil against ascending urinary tract infection.
In contrast, granulocytopenia caused by cyclophosphamide (CY) readily developed into infection, and the antibiotics were markedly less effective in these mice. The therapeutic effect of cefixime against both diabetes and granulocytopenia was the most potent, followed in descending order by cefaclor and cefadroxil. This therapeutic improvement was mainly due to cefixime's strong antibacterial activity and long-lasting renal concentrations.

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Forty patients undergoing transurethral prostatectomy were successfully treated by an oral antimicrobial quinolone, ofloxacin. All 5 patients who showed significant bacteriuria before surgery were sterile on the 4 th post-operative day. The results were comparable with patients treated with intravenous cephalosporins.

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In order to objectively evaluate the efficacy, safety and usefulness of TE-031 (A-56268)(hereinafter abbreviated as TE), a new oral macrolide antibiotic, in the treatment of superficial suppurative skin and soft tissue infections, a double-blind comparative clinical trial was conduc ted using erythromycin (EM) as the control drug.
The daily dosage was 400 mg (in two divided doses) for TE and 1, 200 mg (in four divided doses) for EM. The administration period was set at 10 consecutive days for Disease Groups I-IV and VI and 14 consecutive days for Disease Group V.
A total of 265 patients (TE Group: 131; EM Group: 134) were administered the test articles (TE and EM), and 225 patients (TE Group: 110; EM Group: 115) were evaluated for clinical efficacy, 245 patients (TE Group: 117; EM Group: 128) for overall safety and 230 patients (TE Group: 111; EM Group: 119) for usefulness. The following results were obtained.
1. The clinical efficacy rate (good plus excellent) was 82.7%(91/110) in the TE Group and 79.1%(91/115) in the EM Group, and the difference between the two groups was not statistically significant. The clinical efficacy evaluated as a function of the Disease Group was significantly higher in the TE Group for Disease Group II and the EM Group for Disease Group III.
2. The bacteriological efficacy in terms of the eradication rate was 92.2%(59/64) in the TE Group and 93.0%(66/71) in the EM Group. There was no statistically significant difference between the two drug groups.
3. Side effects were recorded in 3 of the 117 patients (2.6%) in the TE Group and 12 of the 128 patients (9.4%) in the EM Group. The incidence of side effects was significantly lower in the TE Group than in the EM Group. Abnormal laboratory test values were seen in 2 of 75 patients (2.7%) in the TE Group and 2 of 82 patients (2.4%) in the EM Group. None of these differences were statistically significant. The overall safety rate evaluated on the basis of both side effects and abnormal laboratory test values was 95.7%(112/117) in the TE Group and 89. 8%(115/128) in the EM Group. No significant difference was present between the two drug groups. 4. The usefulness was evaluated on the basis of overall consideration of clinical efficacy and safety, and the usefulness rate (useful plus remarkably useful) was 81.1%(90/111) in the TE Group and 76.5%(91/119) in the EM Group. The difference was not statistically significant.
In the final analysis, TE-031 was considered to be an extremely safe, useful drug in the treatment of superficial suppurative skin and soft tissue infections. Efficacy equal to that of erythromycin can be expected with TE-031 administered at only one-third the dosage of erythromycin.

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To evaluate the clinical efficacy, safety and usefulness of TE-031 in the treatment of pneumonia, We carried out a multi-center double-blind comparative clinical study using midecamycin acetate (MOM) as the control drug. TE-031 was administered orally in a daily dosage of 400 mg (in two doses of 200 mg each), while MOM was administered orally in a daily dosage of 600 mg (in three doses of 200 mg each). As a rule, the duration of administration was 14 days. The following results were obtained.
1) The clinical efficacy was judged by the attending committee, and the efficacy rates were 90.2% in the TE-031 group and 73.9% in the MOM group. The clinical efficacy in the TE-031 group was significantly higher.
2) When the clinical efficacy was evaluated by the doctors in charge, the efficacy rates were 91.5% in the TE-031 group and 77.9% in the MOM group. The efficacy rate in the TE-031 group was significantly higher.
3) The bacteriological efficacy rates were 90.5% in the TE-031 group and 76.2% in the MOM group.Although the eradication rate in the TE-031 group was higher, the difference was not statistically significant.
4) The improvement in the signs/symptoms, laboratory test values and chest X-rays was evaluated. The improvement in both body temperature and CRP was significantly superior in the TE-031 group, but none of the other parameters showed any significant differences between the two drug groups.
5) The incidence of side effects was 5.5% in the TE-031 group and 6.5% in the MOM group, while the incidence of laboratory test abnormalities was 12.1% and 9.1%, respectively. These differences were not statistically signifcant.
6) Usefulness, evaluated by the committee, showed satisfactory rates of 86.1% in the TE-031 group and 70.4% in the MOM group, the TE-031 group's rate being significantly higher. In theevaluation by the doctors in charge, the usefulness rates were 86.1% in the TE-031 group and 75.0% in the MOM group but the difference was not found to be statistically significant.
7) On the basis of the results summarized above, it was confirmed that, in comparison with MOM (at 600 mg/day), TE-031 (at 400 mg/day) showed a high degree of clinical usefulness as an antibiotic in the treatment of pneumonia.

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