The therapeutic efficacy of vancomycin (VCM), a glycopeptide antibiotic, given parenterally in experimental systemic and local infections due to Gram-positive bacteria in rodents, was compared with that of ampicillin (ABPC), flomoxef (FMOX), imipenem/cilastatin (IPM/CS), minocycline (MINO) and tobramycin (TOB). In systemic infections with seven strains of four species of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), VCM showed excellent in vivo activity (ED₅₀: 0.95-17.0mg/kg), reflecting its high in vitro activity. Its effects on infections due to MRSA were superior to those of reference compounds except for MINO. As compared with MINO, the efficacy of VCM was found to be far better in streptococci and Enterococcus faecalis infections. Against subcutaneous infections with MRSA, VCM exhibited greater efficacy than FMOX and IPM/CS, and was slightly better than MINO. In urinary tract infections, VCM was superior to MINO, but inferior to FMOX and IPM/CS in MRSA infection. On the other hand, VCM was comparable with IPM/CS, but slightly less effective than ABPC in E. faecalis infection. In meningitis with Streptococcus pneumoniae, the effect of VCM was twice as high as that of FMOX, and equivalent to that of MINO and ABPC, but significantly less than that of IPM/CS. VCM was also twice as effective as IPM/CS and ABPC, and 14-fold more effective than FMOX against respiratory tract infection with S. pneumoniae in neutropenic mice, but less effective than MINO. Against endocarditis due to MRSA in rats. VCM showed greater efficacy than FMOX and IPM/CS, but was slightly inferior to MINO.

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The effect of serum protein binding of cephem antibiotics on their penetration into the lungs of rats was investigated from the following aspects:(1) Effect of administration method, (2) Penetration into the lungs of rats with pneumonia, (3) Relationship between lung tissue levels and free serum levels.
(1) The penetration rates of cefazolin, ceftriaxon and cefuzonam, which had high protein binding after a bolus intravenous injection into normal rats, were slightly lower than those of ceftizoxime and ceftazidime. But there were no marked differences. On the other hand, the penetration rates of the antibiotics with high protein binding after a continuous drip infusion were 1/2 to 1/3 of those of the antibiotics with low protein binding.
(2) In the rats with pneumonia induced by Klebsiella pneumoniae, the penetration rates of the antibiotics with high protein binding were also lower after a continuous drip infusion, but their penetration rates were 1.5 to 2 times higher in the rats with severe pneumonia than in the normal rats. The penetration rates of the antibiotics with low protein binding in the infected rats, however, were not significantly different from those in the normal rats.
(3) The antibiotic concentrations in the lung tissue after a bolus intravenous injection in the normal rats did not correlate with the free serum levels, but some correlation was seen after a continuous drip infusion.
These results show that protein binding is an important factor for penetration of cephem antibiotics into the lung but the effect depends on some experimental conditions such as serum half life, equilibrium between serum levels and lung levels, or severity of infection, and suggest that these factors should be taken into consideration in addition to free serum levels in evaluation of penetrability of cephem antibiotics into the lung.

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Penetration of levofloxacin (LVFX) and ofloxacin (OFLX) into the human spinal fluid was examined. 200mg of each drug was given to urological patients who required endourological surgery. Spinal fluid and serum were collected 3 hours after oral administration of the drugs. Samples were measured by HPLC and bioassay. Spinal fluid levels of LVFX were 0.16-0.51λg/ml (mean 0.355±0.053λg/ml) and the ratios of spinal fluid levels to serum levels were 0.08-0.24 (mean 0.156± 0.016), while those values for OFLX were 0.10-0. 53λg/ml (mean 0. 374 ± 0. 046λg/ml) and 0.02-0.39 (mean 0.167 ± 0.03) respectively. These results were compared with those for norfloxacin, enoxacin (ENX) and ciprofloxacin. From a statistical point of view spinal fluid levels were not indicated for evaluation. In order to evaluate spinal fluid penetration the ratios of spinal fl uid levels to serum levels were used for statistical analysis. LVFX and OFLX were proved to penetrate into the human spinal fluid better than ENX (0. 01 <P≤0.05).

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The bacterial regrowth-inhibiting activity of antibiotic agents in human uteri was examined by choosing cefminox (CMNX) and dibekacin (DKB) as representatives of, β-lactams and aminoglycosides, administering CMNX, DKB or CMNX plus DKB to puerperae and determining the effective regrowth time (ERT, time required for the viable bacterial count to return to the preantibiotic treatment level) of bacteria in each group. Against Gram-positive cocci except Staphylococcusspp., the bacterial regrowth-inhibiting activity was not markedly different between CMNX and DKB. Against Gram-negative bacilli, the bacterial regrowth-inhibiting activity of DKB was considerably higher than that of CMNX. Against anaerobic bacteria, that bacterial regrowth-inhibiting activity of CMNX against Bacteroides spp. and Prevotella spp. was demonstrated. The combination of CMNX and DKB extended the antibacterial spectrum but did not affect the bacterial regrowthinhibiting activity.

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In the period between January and April, 1991, the effect of inhalation treatment with vancomycin hydrochloride (VCM) on MRSA was studied. The subjects were 16 patients with MRSA in the sputum whose underlying diseases were cerebrovascular disease (12 cases), chronic obstructive lung disease (2 cases) and so on. The MRSA were presumed to be of the colonized type in all the cases, of whom eight had mixed infection with Pseudomonas aeruginosa or Non fermentive bacilli before treatment. The disappearance rate of MRSA within 2 weeks after treatment was 88% of those receiving initial treatment (14 cases), and taking recurrent cases into account, was also 88%(21/24 cases). The duration until disappearance ranged from 2. 44 days (mean: 5.0 days). Moreover, falling bacteria tests in the wards detected no MRSA after inhalation treatment with VCM. On the other hand, 4-28 days (mean: 13. 3 days) after interruption of inhalation, MRSA recurred in 83% of the cases. Many cases had the MRSA with a difference in various characteristics between preinhalation of VCM and post-recurrence, suggesting that the recurrence might be reinfection. Also, as for bacteria in mixed infections after inhalation of VCM, Pseudomonas aeruginosa or Non fermentive bacilli were newly detected in four cases, which were presumed to be superinfection with these bacteria. Inhalation treatment with VCM is useful for temporary elimination and in short-term intermittent administration it may be an effective measure against MRSA in nosocomical infection. However, whether or not MRSA could be completely eliminated greatly depended on various host factors, and it was concluded that the general condition should be improved.

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Clinical efficacy, especially the ability to prevent postoperative methicilline-resistant Staphylococcus aureus (MRSA) infection, of cefuzonam (CZON) for the patients with panperitonitis caused by perforation of the digestive tract was compared with that of the combined therapy with the second generation or the third generation of the cephem family of antibiotics and others, for example, aminoglycosides. Forty-five patients with laparotomy for panperitonitis were studied (in our department) during between January 1987 and December 1990. There were no significant differences in the backgrounds between two groups, a CZON-treated group and a combined-treatment group. The incidence of postoperative infections in the CZON group was 30.0%(9/30), which was significantly lower than that of the combined-treatment group 62.5%(15/24). MRSA was not isolated from the CZON group but it was isolated from 2 patients with wound infection and 3 with intraperitoneal abscess in the combined-treatment group. We think this caused the difference in incidence of postoperative infection between the two groups. Clinical effectiveness assessed by our committee showed efficacy rates of 70.0%(21/30) for the CZON group and 37.5%(9/25) for the combined-treatment group with a significant difference between the groups. There was no significant difference in incidence of side effects between the two groups. The MICs of CZON against 43 strains of MRSA isolated from our patients showed sensitivity in 60.5%(26/43). To prevent postoperative MRSA infection, management of nosocomial infection is indispensable. However, because of the extent of this bacterium in hospitals, it is difficult to diminish the incidence of MRSA infection onl by means of infection control. This study suggests that CZON is useful for preventing postoperative infections, especially those caused by MRSA, for a patient with panperitonitis.

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We examined clinically the penetration of ceftriaxone (CTRX), of which serum half life is long (7.1h), into postoperative wound exudate. CTRX was administered to 15 women after radical mastectomy on the first post-operative day, in three different ways:(a) bolus injection of 1g intravenously (1g i. v.), (b) bolus injection of 2g (2g i. v.) and (c) drip infusion of 2g for 60min (2g d. i.). The concentration of the drug was measured by bioassay with the disc method. Measurement by high performance liquid chromatography (HPLC) was also done in one case. The maximum concentrations of CTRX in wound exudate were 22.6μg/ml (1g i. v.), 37.1μg/ml (2g i. v.) and 39.8μg/ml (2g d. i.). Owing to long serum half life, time-concentration curve of CTRX in exudate showed a very gradual slope. Namely, 3-5h was required to reach the peak, and the half life of CTRX in exudate was about 9h. The concentration of CTRX in exudate remained 10-20% of the peak level at 24h after administration. Thereafter CTRX exhibited the highest area under the curve among 7 cephems which we studied previously; 264 μg·h/ml (1g i. v.), 303μg·h/ml (2g i. v.) and 402μg·h/ml (2g d. i.). After 1g i. v., the level of CTRX was maintained higher than 12.5 μg/ml for 8.68h, 6.25μg/ml for 18.5h and 3.13μg/ml for 27.5h. On measurement by HPLC, the results of ultrafiltrated samples were only 8.85% those of the original samples. So, it was suggested that more than 90% of CTRX was binding to protein in wound exudate. The measurement values of original samples by bioassay were 4 times as high as those of the ultrafiltrated samples by HPLC. Moreover, the results by bioassay were enhanced with sample dilution.

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We evaluated clinical efficacy, MICs and adverse effects of rokitamycin (RKM), a new oral macrolide antibiotic, in the treatment of follicular pyoderma and acne. The results were compared with those of minocycline (MINO) by a single blind test in 95 patients.
1. The clinical efficacy of RKM was equal to that of MINO (no statistical difference).
2. Adverse effects in the gastrointestinal tract were observed in 2 of 62 patients (3.2%) and in 2 of 33 patients (6.1%) in the RKM and MINO groups, respectively. Dizziness was noted in two other patients of the MINO group (6.1%).
3. The MIC distribution of RKM and MINO against Propionibacterium acnes and Staphylococcus epidermidis showed a single peak. RKM inhibited the growth of most strains of Staphylococcus aureus. The MICs of RKM against S. aureus in 16 of 19 strains showed a concentration of 0.78 μg/ml or less. The MIC of one strain was 6.25 μg/ml and the other two strains were 12.5 μg/ml. The MIC distribuions of MINO against S. aureus manifested a single peak at 0.1 μg/ml.
4. RKM and MINO were useful at the same level for the treatment of follicullar pyoderma and acne. The MINO group showed adverse effects more frquently than the RKM group (P<0.1). Weconclude that RKM is more useful than MINO in the treatment of acne and follicular infections.

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With the aim of objectively evaluating the efficacy, safety and usefulness of panipenem/betamipron (PAPM/BP) in the treatment of bacterial pneumonia, a comparative study using imipenem/cilastatin sodium (IPM/CS) as the control drug was undertaken, and the following results obtained. Either PAPM/BP or IPM/CS, in a dose of 1.0 g/1.0 g daily (in 2 divided doses), was administered for a duration of, in principle, 14 days.
1) Clinical efficacy: The efficacy rate in the judgement of the committee was 84.5% in the PAPM/BP group and 91.1% in the IPM/CS group, with no significant difference between the two groups. Judged by the physician in charge, the rate was 85.9% in the PAPM/BP group and 82.1% in the IPM/CS group, with no significant difference between the two groups.
2) Bacteriological efficacy: The eradication rate was 78.3% in the PAPM/BP group and 100% in the IPM/CS group, with no significant difference between the two groups.
3) Side effects and abnormal laboratory data: The incidence of side effects was 3.6% in the PAPM/BP group and 5.7% in the IPM/CS group. Abnormal laboratory data were found in 39.5%and 26.5% respectively, but none was serious and no significant difference was seen between the two groups.
4) Usefulness: The rate of usefulness was evaluated by the committee to be 83.1% in the PAPM/BP group and 85.7% in the IPM/CS group, with no significant difference between the two groups. Judged by the physician in charge, the rate was 84.5% in the PAPM/BP group and 83, 6% in the IPM/CS group, with no significant difference between the two groups.
These results confirm that the administration of PAPM/BP, 1.0g/1.0 g daily in the treatment of bacterial pneumonia is as clinically useful as the administration of IPM/CS, 1.0 g/1.0 g daily.

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