The in vitro activity of 10 antimicrobial agents including carbapenem antibiotics biapenem (BIPM), meropenem (MEPM), imipenem (IPM) and panipenem (PAPM), was determined by the agar dilution method against Pseudomonas aeruginosa isolated nationwide in Japan in 2001. MIC₅₀s and MIC₉₀s of carbapenem antibiotics were as follows: BIPM, 1 and 16μg/mL; MEPM, 0.5 and 8μg/mL; IPM, 2 and 32μg/mL; PAPM, 8 and 32μg/mL. BIPM susceptibility was correlated more with IPM than those of other carbapenem agents. The bactericidal effect of BIPM at concentrations above the MIC, against clinical isolates of 6 P.aeruginosa strains, was excellent compared to that of MEPM and ceftazidime (CAZ), and was enhanced in the presence of 10% human fresh serum. The postantibiotic effect (PAE) was demonstrated only when P.aeruginosa strain #8 was treated with BIPM at concentrations above the MIC (1μg/mL) and in the presence of 10% human fresh serum for 2 hours. The binding affinity of 3 agents for penicillin-binding proteins (PBPs) of P.aeruginosa strain #8 was analysed using [³H] benzylpenicillin, with the following results: BIPM, PBP 4 (100%)>>PBP 1A/1B (73.9%)>PBP 3 (69.0%)>PBP 2 (61.2%); MEPM, PBP 3 (92.5%)>PBP 4 (87.1%)>>PBP 1A/1B (60.0%)>PBP 2 (58.9%); CAZ, PBP 3 (100%)>PBP 1A/1B (96.0%)>>PBP 2 (51.4%)=PBP4 (51.2%). PBP binding agreed with morphological changes in P.aeruginosa strain #8 after exposure to the above 3 agents. Following exposure to BIPM at above the MIC, cells lost their rod-like shape, becoming spheroplasts or bulge forms, indicating marked damage to the cell surface. Cell lysis was significantly enhanced in the presence of 10% human fresh serum. Exposure to MEPM induced morphological changes in filament cells in bulge formation and, in CAZ, only filament cells were observed. Cells treated with either MEPM or CAZ showed little surface damaged. The potent bactericidal effect of BIPM observed at concentrations above the MIC in a short time was assumed to be due to its highest affinity for PBP 4 and its high affinity for PBP 1A/1B, PBP3, and PBP 2 at concentrations lower than the MIC.

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The antibacterial activities of telithromycin (TEL), azithromycin, clarithromycin, roxithromycin, levofloxacin (LVFX), ampicillin (ABPC) and erythromycin (EM) were determined against 140 strains of oral streptococci, the major pathogens in dental infbctions. Atthesame time, the antibacterial activities of ketolide-antibiotics were tested against experimentally induced strains that werehighly resistant to macrolides. In the EM-resistant strains, the presence of erm and mef genes was investigated. The MIC₉₀ of each of the fbur 14-or 15-member ring macrolide antibiotics was high against Streptcoccus mitis in the viridans group (1 to 8μg/mL); howeverthe MIC of TEL wasbelow 0.5μg/mL, which was sufficient to inhibit the growth of all the organisms. TEL also did not exhibit cross resistance with macrolides, and displayed the most outstanding antibacterial activity among the test agents, including ABPC and LVFX. No changes were noted in Streptococcus intermedius befbre and after clarithromycin (CAM) resistance induction. After resistance induction, the MIC of CAM against S. mitis rose 16 times. Against two strains of Streptococcus oralis, the MIC of CAM rose to 16 and 256, respectively, after resistance induction. The MIC of TEL rose only slightly (from 0.03 to 0.12μg/mL) against the strains into which CAM resistance had been induced. TEL did not exhibit cross resistance with 14-or 15-member ring macrolides in ermB or mefA gene Carrying Strains.

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We studied carbapenemase gene cloning of anaerobic gram-negative rod Prevotella nigrescens TO 167 (MIC, imipenem resistant>32μg/mL) isolated from odontogenic infection and the distribution of β-lactamase genes in β-lactamase-producing Prevotella. The Prevotella nigrescens TO 167 carbapenemase gene was cloned in Escherichia coli 5 α transcojugants using PCR products of bla_IMP, and the DNA fragment related to this enzyme considered to be extracted from the transconjugant was 1, 493 bp. DNA homologous for this carbapenemase gene and the β-lactamase gene from 13 gram-negative rods, including bla_IMP, was 42.9-50.4%.β-lactamase genes were detected by PCR using Prevotella (81 strains) isolated from oral cavity. The 15 primers used in this study were designed from 14 β-lactamase genes including carbapenemase genes. Amplification by PCR with primers was observed in imipenem-susceptible strains of Prevotella: for Kp CAZ (class A), Ko ampCA (class C), and Ab OXA 21 (class D) from Prevotella intermedia; for Kp CAZ and Ab OXA 21 from Prevotella nigrescens; and for Ko ampCA from Prevotella loescheii. The β-Lactamase gene was not detected in imipenem-resistant strains. These results suggest that the Prevotella nigrescens TO 167 carbapenemase gene cloned differed from previous reported β-lactamase genes. We concluded that carbapenemase genes were different from known carbapenemase genes and that there is variety in Prevotella. And β-lactamase genes of Prevotella were similar to those of Klebsiella and Acinetobacter.

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In vitro and in vivo antibacterial activity of cefteram pivoxil was studied using 37 clinical isolates of cephem-resistant Escherichia coli (cefaclor; MIC>12.5μg/mL) and compared to those of other oral antibacterial agents. MIC₉₀ of cefteram (the active form of cefteram pivoxil) against cephem-resistant E.coli (37 strains) was 3.13μg/mL and less than those of cefiditoren (6.25μg/mL), cefpodoxime (25μg/mL), cefdinir (25μg/mL), cefixime (50μg/mL), amoxicillin (>100μg/mL), and cefaclor (>100μg/mL) and comparable to that of norfloxacin (3.13μg/mL). MIC₉₀s of tested drugs against 25 strains of cephem-susceptible E. coli were as follows: cefditoren (0.2μg/mL), cefixime (0.39μg/mL), cefteram (0.78μg/mL), cefpodoxime (3.13μg/mL), cefdinir (3.13μg/mL), cefaclor (3.13μg/mL), and amoxicillin (3.13μg/mL). The difference between MIC₉₀s against cephem-resistant and susceptible E. coli was lowest for cefteram. No cephem-resistant strains showed hydrolytic activity against the cephems tested except for cefaclor. The therapeutic effect of cefteram pivoxil against an experimental mouse urinary tract infection caused by cephem-resistant E.coli TK-776 was superior to that of cefdinir, cefditoren, cefixime, and cefaclor, reflecting its in vitro activity.

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The production of β-lactamase by pathogens is considered one of the major nonresponse factors to β-lactam antibiotics in bacterial infectious diseases. We conducted this special investigation because cefepime (CFPM, Maxipime _® FOR INJECTION) is extremely stable in β-lactamase production and can be expected to exhibit high clinical efficacy even in nonresponders to β-lactam antibiotics. Of the 563 patients recruited, 423 were analyzed to evaluate clinical efficacy. The overall response rate was 68.6%, and when compared against the type of previous treatment, high efficacy rates of 65.9% in nonresponders to parenteral cephalosporins and 74.0% in nonresponders to parenteral penicillins were obtained. Bacteriological effects demonstrated a high overall eradication of 82.3% in indicated strains and an eradication of 72.4% even in Pseudomonas species, including Pseudomonas aeruginosa. Detected strains were examined to see whether there was a eradication ratio relationship, dependent on the presence or absence of β-lactamase production, but no clear difference was observed with either type. No significant difference was observed in clinical efficacy between those subjects who were β-lactamase positives (72.7%) or β-lactamase negatives (80.9%). All parenteral penicillins used as previous treatment were unstable with β-lactamase, and of those patients treated with such penicillins, the efficacy obtained in detected strains that were β-lactamase positive was high at 88.9%. However, for those nonresponders to penicillins who were β-lactamase negative, CFPM efficacy was even higher, at 100%, suggesting no significant difference occurred in response rate regardless of whether bacteria detected were producing β-lactamase or not. Similarly, those previously treated with parenteral cephalosporins were also examined, and no significant difference in response rate was observed in detected strains, regardless of whether they produced β-lactamase or not. In conclusion, the extreme stability of CFPM is supported by, and can be interpreted from, similar results in efficacy observed in nonresponders to previous treatment with β-lactam antibiotics where strains detected were either producing or not producing β-lactamase. In addition, in the 6 years since its launch, the efficacy of CFPM in those who did not respond to other drugs (β-lactam antibiotics) at CFPM development (1990) remains the same or higher (62.5% overall, 40.0% penicillins, 68.4% cephalosporins), suggesting no obvious increase in bacteria clinically resistant to this drug.

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The first Joint British Society for Antimicrobial Chemotherapy and Japanese Societies Scientific Meeting was held June 7-9, 2001 in Edinburgh, Scotland, giving Japanese and European researchers a chance to meet and exchange information on antimicrobials. This report details the progress made at this meeting. The sessions dealt with chronic respiratory diseases, focusing on diffuse panbronchiolitis, chronic bronchitis, and bronchiectasis. Reports on the latest findings triggered lively discussions in epidemiology, pathogen resistance, clinical trials and guideline development. This report gives an overview of the proceedings in each session.

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