The enhancing or synergistic effect on the growth-inhibitory activity of antibiotics and Japanese green tea (Camellia sinensis) extract was examined against clinically isolated strains of methicillin-resistant Staphylococcus aureus (MRSA). Using a disk method, growth-inhibition of MRSA was clearly observed in distinct areas where sub-MIC concentrations of the tea extract and β-lactam antibiotic had been applied.β-lactam antibiotics included cefazolin (CEZ), cefotiam (CTM), cefmetazole (CMZ), ceftizoxime (CZX), flomoxef (FMOX), imipenem (IPM) and ampicillin (ABPC).This suggested that there was an enhancing or co-operative effect between the tea extract and the β-lactams. Lower levels of growth-inhibition or no inhibition were seen with MPIPC, CRMN, and non-β-lactam antibiotics including clindamycin (CLDM), vancomycin (VCM), netilmicin (NTL), levofloxacin (LVFX), chloramphenicol (CP), minocycline (MINO), erythromycin (EM) and fosfomycin (FOM). The MICs against MRSA of CEZ, CTM, CMZ, CZX, FMOX, IPM and ABPC were significantly decreased by treatment with the tea extract.

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Agar dilution was used to compare the in vitro activity of tosufloxacin (TFLX) with that of levofloxacin (LVFX), norfloxacin (NFLX), ciprofloxacin (CPFX), fleroxacin (FLRX) and sparfloxacin (SPFX) against 1, 112 fresh bacterial clinical isolates. The MIC of all drugs for 90% of the MSSA strains tested was 1.56μg/ml, but almost all the MRSA were resistant to these drugs.Ten to 20% of the Staphylococcus epidermidis and Enterococci isolates were resistant at>12.5μg/ml. TFLX and SPFX were active against all Streptococci, but a few strains of Streptococcus pyogenes and Streptococcus pneumoniae were resistant to NFLX and FLRX.These six fluoroquinolones were active against all Enterobacteriaceae strains, but some Serratia marcescens strains, and some providlemta strains were less susceptible.TFLX, CPFX and SPFX were active against all strains of glucose non-fbrmentative rods, but 10% of Pseudomonas aeruginosa isolates were resistant to TFLX.Peptostreptococci and Propionibacterium were more susceptible than the Bacteroides fragilis to all of the fluoroquinolones tested.These results suggest that tosufloxacin has an excellent in vitro antibacterial activity against fresh clinical isolates and is a promising drug which is clinically usefUl for the treatment of bacterial infbctions.

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We investigated the in vitro and in vivo antimicrobial activities of new fluoroquinolones against Pseudomonas aeruginosa.The in vitro antimicrobial activities of ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX), sparfloxacin (SPFX), levofloxacin (LVFX), and NM 394, the active form of prodrug NM 441, were examined against 100 clinical isolates of P.aeruginosa.The MIC₅₀s for CPFX, TFLX and NM 394 (0.25μg/ml) were superior to that of LVFX (1.0μg/ml) and OFLX (2.0μg/ml).The in vivo therapeutic efficacies of fluoroquinolones (OFLX, CPFX, LVFX, and NM 441) were evaluated by using a normal and a neutropenic murine model of P.aeruginosa pneumonia.Neutropenia was induced by the single administration of cyclophosphamide at a dose of 200mg/kg of body weight on day 0. Experimental pneumonia was established by intratracheal inoculation of P.aeruginosa on day 3. Antibiotics were administered orally twice a day for 7 days after bacterial challenge.There was no significant difference between the therapeutic effects of CPFX, LVFX, and NM 441 when using normal ddY mice. However, when neutropenic ddY mice were infected with 9×10⁷ CFU of P.aeruginosa, the survival rates of mice were 67%, 33%, and 25% after treatment with NM 441, CPFX, and LVFX, respectively.The difference in survival rates between the NM 441-treated group and the LVFX-treated group was statistically significant (P<0.05).These results suggest that NM 441 has potent antimicrobial activity against P.aeruginosa which shows reduced susceptibility to other fluoroquinolone agents.

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Cisplatin (CDDP), an anti-cancer drug, and arbekacin (ABK) and vancomycin (VCM) which are approved antibiotics for methicillin-resistant Staphylococcus aureus (MRSA) were administrated. individually or in combination to compare toxicity.Fosfomycin (FOM) was also included to estimate the effect of this drug in preventing toxicity.Doses of each drugs were set up as follows: 1mg/kg of CDDP, 80mg/kg of ABK, 200mg/kg of VCM, 80mg or 320mg/kg of FOM, and were administered to rats intravenously for 7 days.In the monotherapy, treatment with CDDP resulted in toxicity in the liver, bone marrow, kidney and digestive mucosa.VCM treatment was followed by toxicity in the kidney and bone marrow, and treatment with ABK produced toxicity in the kidney.ABK treatment resulted in the lowest levels of nephrotoxicity.The nephrotoxic effects of CDDP treatment were significantly potentiated with combine administration of VCM.The toxic effects that developed following combined administration of the anti-cancer drug and antibiotics were remarkably alleviated by concurrent treatment with FOM.On the basis of these findings, we conclude that concurrent use of CDDP and antibiotics (anti MRSA) should be avoided as far as possible.Where the conbined of there drugs in unvoidable, ABK should be the antibiotic of choice. Furthermore, ABK treatment combined with FOM may result in reduced the toxicity.

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The clinical efficacy, safety and usefulness of cefoselis (FK 037, CFSL), a new parenteral cephalosporin, were evaluated in bacterial pneumonia in a comparative study with ceftazidime (CAZ).Each drug was administered by intravenous drip infusion at a dose of 1.0g (potency), twice daily for 14 days.The following results were obtained.
1. Of the total 178 patients enrolled, 138 were evaluated for clinical efficacy and the efficacy rates (“good” and better responses) were 91.9%(68/74) in the CFSL group and 92.2%(59/64) in the CAZ group.
2. Bacteriological effects (eradication rates) were 100%(18/18) in the CFSL group and 96.0%(24/25) in the CAZ group.
3. Adverse reactions occurred in 3 of the 86 patients (3.5%) in the CFSL group and in 3 of the 84 patients (3.6%) in the CAZ group.The incidence of abnormal laboratory findings was 20.9%(18/86) in the CFSL group and 19.0%(15/79) in the CAZ group.The safety rate (“safe” in the overall safety rating) was 77.9%(67/86) in the CFSL group and 81.0%(64/79) in the CAZ group.
4. Usefulness rates (“useful” and better responses) were 89.2%(66/74) in the CFSL group and 87.5%(56/64) in the CAZ group.
No significant difference was observed between the two groups in any of the above ratings.The results indicate that cefoselis is as useful as ceftazidime for the treatment of bacterial pneumonia.
This paper reports clinical results excluding cases violating Good Clinical Practice (GCP) found after publication of our previous paper in “Jpn.J. Chemother.” (Vol.43, No.4, 1995).

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The clinical efficacy, safety and usefulness of cefoselis (FK 037, CFSL), a new parenteral cephalosporin, were evaluated in chronic respiratory tract infection in a comparative study with ceftazidime (CAZ).Each drug was administered by intravenous drip infusion at a dose of 1.0g (potency), twice daily for 14 days.The following results were obtained.
1.A total of 167 patients were enrolled in this study.Efficacy rates (“good” and better responses) were 90.3%(65/72) in the CFSL group and 89.7%(61/68) in the CAZ group.
2.Bacteriological effects (eradication rates) were 89.2%(33/37) in the CFSL group and 94.1%(32/34) in the CAZ group.
3.Adverse reactions occurred in 6 of the 81 patients in the CFSL group and in 2 of the 76 patients in the CAZ group.The incidence of abnormal laboratory findings was 11.1%(9/81) in the CFSL group and 13.3%(10/75) in the CAZ group.
4.Usefulness rates (“useful” and better responses) were 84.9%(62/73) in the CFSL group and 86.8%(59/68) in the CAZ group.
No significant difference was observed between the two groups in any of the above items.
The results indicate that cefoselis is a useful drug in the treatment of chronic respiratory tract infections.
This paper reports clinical results excluding cases violating Good Clinical Practice (GCP) found after publication of our previous paper in “Jpn.J. Chemother.” (Vol.43, No.4, 1995).

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To clarify the clinical features of acute severe pneumonia, we compared 51 pneumonic patients who required therapy in the ICU with 52 patients treated in the medical ward.We also studied pneumonic patients who did not survive, in spite of intensive care, to determine the prognostic factors.The following results were obtained, and were considered to be clinical features of acute severe pneumonia.The first was the presence of clinical symptoms, such as dyspnea and central nervous system symptoms.The second was abnormal physical signs, such as tachycardia and tachypnea.The third was abnormal laboratory data, such as hypoalubumiemia.The last was the presence of massive pulmonary infiltrations on chest roentgenograms.The presence of acidosis was an important prognostic factor.When these features present in pneumonic patients, these patients may be expected to experience severe difficulties and careful treatment is adviced.

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We investigated the clinical efficacy and incidence of adverse reactions, especially photosensitivity reactions, to tosufloxacin tosilate (TFLX).We collected a total of 2, 552 patients treated with TFLX from 304 hospitals throughout Japan during the period between August 1992 and March 1994, in order to exclude any biases in geographical and seasonal distributions of the patients.
1) Clinical efficacy was evaluated in 2, 447 patients.The efficacy rates (“excellent” and “good” responses) were 81.5%(662/812) for respiratory tract infections, 86.0%(606/705) for superficial suppurative diseases, 88.0%(529/601) for urinary tract infections and the overall efficacy rate was 84.2%(2, 060/2, 447).
2) A total of 2, 543 cases were evaluated for the safety of TFLX.Adverse reactions were noted in 21 patients (0.83%); gastrointestinal symptoms were predominant in 8 patients (0.31%), and allergic reactions were observed in 5 (0.20%).Photosensitivity reactions were noted in 3 (0.12%).
3) In 2 out of 3 patients with photosensitivity reactions, the confirmatory tests were performed after obtaining informed consent.In both, who had negative MED tests, the patch and photo-patch tests were also negative.On the other hand, the p.o.-photosensitive test was positive in one patient, while the other case remained negative.The former positive case also had a history of photosensitivity reaction to enoxacin (ENX).
4) Studies were conducted on the cases with photosensitivity reactions among 11 cases including 8 reported by patients themselves, focusing on items, such as their ages and administration durations. The results revealed the incidence of photosensitivity reaction to be low, the major administration period for manifestation of photosensitivity reaction being less than 7 days, while the relationship with age was unclear.

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We studied changes in thymidylate synthase (TS) activity and 5-fluorouracil (5-FU) incorporated into RNA (F-RNA) after a bolus dosage of 5-FU, using a human stomach cancer xenograft to nude mice (SC-1-NU).The TS inhibition rate (TSIR) reached high levels (40mg/kg;93.4%, 10 mg/kg;74.9%) soon after dosage of 5-FU.F-RNA took 12 hours to reach a peak (40mg/kg;111 ng/mg-RNA, 10 mg/kg;21.8ng/mg-RNA).After the peaks, both TSIR and F-RNA decreased slowly. Especially at a bolus dosage of 40mg/kg of 5-FU, TSIR and F-RNA maintained certain levels (TSIR;40.1%, F-RNA; 31.1ng/mg-RNA) even at 96 hours after dosage of the drug.TSIR and F-RNA increased gradually after successive doses of 5-FU (40mg/kg q4d and 10mg/kg qd). Bolus dosage (especially large doses) of 5-FU showed a prolonged effects on DNA and RNA, suggesting that intermittent bolus dosage of 5-FU could be expected to have good antitumor effects.

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Thirty-six cases of methicillin-resistant Staphylococcus aureus (MRSA) infection determined from fecal culture were recorded in our hospital between January and December of 1994.Only 4 cases were postoperative.The third generation cephalosporin antibiotics were used from the onset in the most cases.Twenty of 36 cases (56%) were administered with H₂-blocker agents, 17 (47%) retained a stomach tube at the onset, and twenty-two of the cases (61%) were MRSA-positive from sputum culture.Twenty-eight symptomatic patients were cured whether or not antibiotics were administered.These results suggest that MRSA in the respiratory tract may gain easy access to the gastrointestinal tract and caused enterocolitis.

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