Staphylococcus aureus FDA 209 P JC-1 was passaged 14 times in Mueller-Hinton broth containing serial two-fold dilutions of cefcapane (CFPN) or cefteram (CFTM), as follows. A bacterial suspension of 40μl containing the highest concentration of the drug which allowed full bacterial growth was inoculated into 4ml of broth containing the drug and stationarily grown for 20 to 24 h at 37°C. CFPN MIC increased from 0.78μ g/ml for the parent to 3.13, 12.5 and>200μg/ml for strains passaged 5, 10 and 14 times, respectively, in the broth containing CFPN.Similarly, CFTM MIC increased from 3.13μ g/ml to 6.25, 25 and>200μg/ml. In contrast, only up to four-fold increases were observed for the MICs of cephamycins such as flomoxef and cefmetazole which had high affinities for PBP 4.In the passaged strains, the resistance increase was associated with the elevation of PBP 4 production, suggesting that PBP 4 played an important role in bacterial survival after exposure to cephems.The high-level resistance observed for strains passaged 14 times in the presence of CFPN or CFTM was very unstable and the levels tended to drop during passage in the absence of the drug.The reduction in the resistance level was accompanied by a decrease of the amount of PBP 4 in one strain, but not in the other, suggesting that, in addition to elevated PBP 4 production, there was some unknown factor involved in raising the resistance to such a high level.

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We determined the in vitro combined effects of cefotiam (CTM) plus vancomycin (VCM);of CTM plus arbekacin (ABK);and of minocycline (MINO) plus VCM on 88 methicillin-resistant Stapylococcus aureus (MRSA) by the modified checkerboard method with serial 1.25-fold dilutions. And compared their MICs, MBCs, fractional inhibitory concentration indices (FIC indices), and fractional bactericidal concentration indices (FBC indices). Combinations of CTM plus ABK and CTM plus VCM indicated synergistic effects, an FIC index of≤ 0.50, against 50% and 14% of the strains respectively and additive effects against all other strains. By comparing the FBC indices (12 strains), both combination mainly indicated additive killing effects.In addition, the MICs of ABK and of VCM in combination with CTM of 8 μ g/ml; which concentration could be maintained during about three hours in serum, decreased to 8-83%(mean 39%) and 30-83%(58%) of each MICs in antibiotic alone, respectively. On the other hand, combination of MINO plus VCM was antagonistic, an FIC index of>2.00, against 39%of the strains and showed antagonistic killing effects, an FBC index of >2.00, against all (12) strains. These results suggest that the combination therapy of ABK or VCM with CTM is useful for the treatment of MRSA infection at a site where a penetration of antibiotics is less and may help to reduce a side effects of ABK or VCM in a patient with renal dysfunction, and that the combination therapy of MINO with VCM should be used carefully on MRSA infection.

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We used agar-dilution MIC determinations to assess the activity of 31 antibacterial agents against various clinical isolates (16 Gram potitive cocci, 803 strains), which were isolated in 1994 at 16 facilities in Japan and compared the results with those of a similar study in 1992. We found that 50.4% of the strains of Staphylococcus aureus were methicillin-resistant S. aureus (MRSA), a slight decrease compared to the 58.1% in 1992. Vancomycin (VCM), arbekacin (ABK) and sulfamethoxazole-trimethoprim (ST) proved to have the highest antibacterial activity against these MRSA with an MIC₉₀ of less than 1.56μ g/ml. The agents which showed higher antibacterial activity against Staphylococcus epidermidis were VCM, ABK, minocycline and cephalothin (MIC₉₀≤1.56μg/ml). Most of the agents tested, including β-lactam antibiotics, showed good antibacterial activity against Streptococcus pyogenes and Streptococcus agalactiae. The rate of penicillin-resistant Streptococcus pneumoniae (PRSP) was 43.4%, a small increase compared to 37.0% in 1992. VCM, imipenem (IPM), meropenem, cefpirome and cefcapene displayed a high level of antibacterial activity against PRSP. VCM and IPM had the highest antibacterial activities with an MIC₉₀ of 0.2μ g/ml. The agents which showed higher antibacterial activity against Enterococcus faecalis were ampicillin, IPM, VCM and ST (MIC₉₀≤3.13μg/ml). VCM proved to have the highest antibacterial activity against Enterococcus faecium with an MIC₉₀ of 0.78μ g/ml. VCM, ST and ciprofloxacin showed high antibacterial activity against Enterococcus raffinosus. We did not find any strain highly resistant to VCM (MIC 12.5μg/ml) among any of the isolates of Gram positive cocci including MRSA and Enterococcus species.

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We used agar-dilution MIC determinations to assess the activity of 38 antibacterial agents against various clinical isolates (20 Gram negative aerobic bacteria, 1, 128 strains), which were isolated in 1994 at 16 facilities in Japan and compared the results with those of a similar study in 1992. Most cephems, carbapenems (CBPs), aztreonam, aminoglycosides (AGs) and new quinolones (NQs) exhibited high antibacterial activity against Escherichia coli, Klebsiella spp., Proteus spp., Morganella morganii, Haemophilus influenzae, Branhamella catarrhalis and Neisseria gonorrhoeae with an MIC₉₀ of less than 3.13μ g/ml. However, strains highly resistant to NQs appeared among Proteus spp., H. influenzae and N. gonorrhoeae. β-Lactamase producing H. influenzae strains were detected at 7.0%, which was equivalent to the 10.0% detected in 1992. The agents which showed higher antibacterial activity against Citrobacter spp. and Enterobacter spp. were cefpirome, CBPs, AGs and NQs. CBPs and tosufloxacin showed antibacterial activity against Serratia marcescens with an MIC₉₀ of 1.56-3.13μ g/ml. NQs showed low activity against Providencia spp. with an MIC₉₀ of>100μ g/ml. The agents which showed highest antibacterial activity against Pseudomonas aeruginosa were meropenem (MEPM) and amikacin (MIC₉₀ 12.5μ g/ml) followed by imipenem and ciprofloxacin (MIC90 25μ g/ml). The sensitivity of P. aeruginosa strains to the 11 anti-pseudomonal antibiotics came to 32.8%, which was an increase over the 24.3% found in 1992. IPM-resistant P. aeruginosa strains accounted for 22.1%, a more than two-fold increase over the 8.7% in 1992, but cefsulodin-resistant strains accounted for 19.7%, a great decrease from the 60.2% of 1992. The agents against Burkholderia cepacia with an MIC₉₀ of less than 6.25μ g/ml were ceftazidime, MEPM, ceftizoxime and cefcapene. Minocycline showed the highest antibacterial activity against Stenotrophomonas maltophilia with an MIC₉₀ of 0.78μ g/ml.

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On a survey of 1, 794 bacterial isolates from nine hospitals in Gnnma prefecture in the school year of 1994, we determined the frequency of isolation species and their sensitivity 14 chemotherapeutic agents, especially forcussing on methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae strains. The results were compared with the data obtained during the past five years.
1.The bacterial species isolated at high frequencies were S. aureus (22.3%), Pseudomonas aeruginosa (11.8%), coagulase-negative Staphylococci (CNS)(8.4%), Escherichia coli (6.4%), Haemophilus influenzae (5.4%), and Enterococcus faecalis (5.4%), in order of the isolation frequency. The frequency of isolation of H. influenzae from outpatients and of S. aureus from inpatients was increased by 3% and 5%, respectively, when compared with those in 1993, but no annual changes was observed in other species.
2.Of S. aureus, more than 75% of the MRSA strains were resistant to multiple agents such as penicillins, cephems, aminoglycosides, macrolides, tetracyclines, and new-quinolones, while less than 15% of the methicillin-sensitive S. aureus strains were resistant to these multiple agents except penicillins and none of them were resistant to vancomycin.
3.MRSA strains were isolated at high frequency from special internal medicine wards in larger hospitals with a large number of beds.
4.For S. pneumoniae, the breaking point dividing the sensitive and resistant strains was clearly determined at 6.25μg/ml for cefaclor but was not obvious for benzylpenicillin, ampicillin (ABPC) and piperacillin (PIPC). Penicillin-resistant S. pneumoniae strains were identified by using one-concentration disks for the strains with inhibition zones with diameters less than 30mm, 32 mm, and 29 mm, respectively against benzylpenicillin, ABPC, and PIPC.

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We investigated the penetration of BO-2727, a new parenteral carbapenem antibiotic, into human tears. A peak tear concentration of 2.70μ g/ml was observed 30 min after the initiation of a 30-min drip infusion of BO-2727 (500mg) in human volunteers (n=9). The tear to blood penetration rate was 9.7%.With respect side effects, mild phlebitis occurred in one patient.

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In the early 1980's methicillin-resistant Staphylococcus aureus (MRSA) was reported to be a major source of geriatric hospital infection in Japan.To decrease nosocomial infections some active preventive measures against hospital infection have been taken since October 1991. After the introduction of preventive measures for hospital infection in the geriatric ward (190 beds) nosocomial bacteremia and pneumonia were markedly decreased.However several patients with MRSA colonization were observed every month.The aim of this clinical study was to determine the frequency of MRSA isolated from the skin.MRSA was not observed in any of 102 cultured skin samples. Therefore there is a low frequency of MRSA colonization on skin in our ward that may in part be attributable to our preventive measures.

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In 210 suspected cases of drug hypersensitivity, the identities of the allergenic drugs were delermined by the leucocyte migration inhibition test (LMIT) to investigate the relationship between drug allergy and age-related change. LMIT was positive in 160 cases and negative in 50 cases, a positive rate of 76.2%. However pseudoallergy unassociated with drug allergy was discovered in 20 cases by reinvestigation of 50 cases of negative LMIT. From these results, the number of patients suspected of drug allergy was 190 and the true proportion of positive LMIT was 82.4%. The proportion of positive LMIT in each age category had two peaks of 100% in cases aged less than ten and 97.1% in cases aged 60 to 69 years.This age-associated alternation correlated with observations of the peripheral blood lymphocyte counts of 1, 143 cases (r=0.703, ρ<0.05). The incidence of LMIT-positive patients (drug allergic patients) in each age category was 16.9% in cases aged 50 to 59 years, 20.6% in cases aged 60 to 69 years and 21.9% in cases aged 70 to 79 years. Therefore, incidence of drug allergy increased with age. This age-related change correlated strongly with 10, 571 drug-administered patients (r=0.790, ρI<0.02). The incidence of each individual allergic symptom in 160 LMIT-positive patients was 68.8% with skin eruption, 28.1% with liver damage, 11.9% with fever, 5.0% with blood disorder and 2.5% with gastrointestinal disorder. The age-related change of the incidence in each individual allergic symptom was almost in agreement with that of all drug allergic patients. The incidence of LMIT-positive drugs (allergenic drugs) in each drug category was 41.3% in antibiotic drugs, 31.7% in central nervous system drugs and 13.9% in cardiovascular drugs. Therefore these three drug groups formed more than 85% of the total. The incidence of allergenic drugs in each age category had no age-associated alternation in antibiotic drugs and central nervous system drugs. However the incidence of allergenic cardiovascular drugs was significantly higher in cases aged more than 65 years (ρ<0.005, ratio test). This age-ralated change of cardiovascular drugs in drug allergy almost agreed with that in 7, 642 drug-administered patients. The latent period that elapsed from initial administration of drug to emergence of eruption in 80 cases with drug-induced skin eruption was 5.67 days in 9 cases aged less than 20 years, 9.13 days in 8 cases aged 20 to 39 years, 9.42 days in 26 cases aged 40 to 64 and 15.03 days in 37 cases aged more than 65 years. Therefore, aged persons had a significantly longer latent period (ρ<0.05, t-test) than young persons. Our findings indicate that the aged have a high incidence of drug allergy and allergenic cardiovascular drugs and a long latent period. This age-related. change may come from the high incidence of drug-treated patients, and of administered cardiovascular drugs and from the activity of lymphocytes in the aged.

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To evaluate the regimen for the treatment of RTI, a comparative study using cefotiam (CTM) and cefotiam-hexetil (CTM-HE)(group A) and CTM-HE (group B), was conducted in various clinical institution. Patients were given a single dose of 1 g of CTM (drip infusion) followed by 600 mg per day of CTM-HE for 5-7 days (group A), 600 mg per day of CTM-HE for a period of 5-7 days (group B). CTM-HE was administered three times a day.
1) Clinical efficacy in group A and the group B, was rated of “excellent” in 24.1%(7/29) and 2.9%(1/35) respectively, “good” in 62.1%(18/29) and 62.9%(22/35) respectively, and the overall efficacy rates (“excellent”+ “good”) were 86.2% and 65.7%, respectively.Overall efficacy in group A was superior to overall efficacy in group B, and the difference was significant.
2) There was no significant difference between the two groups in terms of the symptoms or signs, but a trend toward greater efficacy was shown in the early stage in group A.
3) The bacterial eradication rate was 88.2%(15/17) in group A, and 69.2%(9/13) in group B.The difference was not significant.
4) There were no side effects in either group A or group B.
From the above findings, we concluded that a single dose of 1 g CTM (drip infusion) followed by 600 mg of CTM-HE was a better clinical regimen for the treatment of RTI than simple CTM-HE administration.

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Ofloxacin (OFLX) levels in the blood flowing from dental extraction wounds were determined, and evaluated from the aspect of antimicrobial activities. OFLX was administered to a total of 53 patients before extraction at a single dose of 100 mg. Blood samples from the extraction wounds were collected on 8mm thick paper discs and the sampling ranged from 30 minutes to 8 hours after administratin. The blood concentrations of OFLX in the extraction wounds ranged from ND (not detected) to 15.55μ g/ml. The MIC₉₀ of OFLX against Streptococcus sp. isolated at a high frequency from odontogenic infections was 1.56μ g/ml. When the blood concentrtions in the extraction wound was set at the MIC₉₀ as a chemoprophylactic target level, the percentage of cases achieving levels exceeding the target level was 50% between 121 and 210 minutes. It was thus concluded that OFLX should be administered 2 hours before extraction.

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