Three hundred seventy five isolates of Streptococcus pneumoniae were collected from 14 medical institutions in the Kinki region of Japan between November 2003 and February 2004. We determined the minimum inhibitory concentration (MIC) of penicillin G (PCG) and 25 of other antimicrobial agents against these isolates according to the National Committee for Clinical Laboratory Standards (NCCLS). Overall, 71.5% of all isolates were resistant to PCG (intermediate and resistant categories were 51.7% and 19.8%, respectively). For the carbapenems and penem, the rank order of activity was PAPM (MIC₉₀, 0.12μg/ml) >IPM (0.25μ g/ml) >MEPM (0.5μg/ml) =FRPM (0.5μg/ml). For the cephems, the overall rank order of activity was CPR (MIC₉₀, 0.5μg/ml) =CDTR (0.5μg/ml) >CTRX (1μg/ml) =CTX (1μg/ml) =CZOP (1μg/ml) =CFPN (1μg/ml). Rank order activity for six of fluoroquinolones was TFLX=MFLX (MIC₉₀, 0.25μg/ml) >GFLX (0.5μg/ ml) =SPFX (0.5μg/ml) >LVFX (1μg/ml) >PZFX (4μg/ml). The rate of resistance to fluoroquinolones per the NCCLS criteria were very low, ranging from 0.7% to 2.6%. Rate of resistance to other antimicrobiotics were CAM, 77.0%; CLDM, 41.7%; TEL, 0%; VCM, 0%; ST, 32.7%, and CP, 21.4%.

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For the post-marketing surveillance of panipenem/betamipron (PAPM/BP, Carbenin®), MICs of injectable β-lactam antibacterials including PAPM against clinical isolates from 15 medical institutions all over Japan are measured yearly and the incidence ratesof resistance in various species are also evaluated. In the first surveillance from June 2000 to March 2001, 1,356 isolates of 28 species weretested, 1,221 isolates of the same 28 species were tested in the second surveillance from April 2001 to March 2002, and 1,403 isolates of the same 28 species were tested in the third surveillance from April 2002 to March 2003.
No remarkable changes in the activity of PAPM were observed in these surveillances spanning three years. The activity of PAPM in this study was comparable to that in the studies conducted before Carbenin® was launched. This result suggests that PAPM still maintains potent activity.
In these surveillances spanning three years, the incidence rates of resistance in various species were as follows (2000.6-2001.3→2001.4-2002.3→2002.4-2003.3): methicil lin-resistant Staphylococcus aureus (39.3%→43.9%→47.3%), penicillin-intermediate Streptococcus pneumoniae (48.9%→44.2%→25.7%), penicillin-resistant S. pneumoniae (PRSP, 13.8%→26.3%→43.2%), extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (0.9%→0%→1.4%), ESBL-producing Klebsiella pneumoniae (3.4%→1.3%→3.1%), β-lactamase-producing Haemophilus influenzae (19.2%→8.9%→2.9%), β-lactamase-negative ampicillinresistant H. influenzae (BLNAR, 22.1%→30.7%→33.0%), and metallo-β-lactamase-producing Pseudomonas aeruginosa (1.0%→4.4%→1.0%). PAPM showed the most potent activity among tested drugs against PRSP, whose incidence rate increased notably.BLNAR, whose incidence rates also increased, exhibited low susceptibility to all tested drugs and metalloβ-lactamase-producing P. aeruginosa also exhibited high resistance. The findings of this surveillance indicate that it is necessary to pay careful attention to the trends of resistant bacteria such as PRSP, BLNAR, and metalloβ-lactamase producing strains.

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For the post-marketing surveillance of cefpodoxime proxetil (CPDX-PR, Banan®), MICs of oral cephem antibacterials including CPDX against clinical isolates from 15 medical institutions all over Japan are measured yearly and the incidence rates of resistance in various species are also evaluated. In the first surveillance from June 2000 to March 2001, 1,091 isolates of 22 species were tested, 993 isolates of the same 22 species were tested in the second surveillance from April 2001 to March 2002, and 1,115 isolates of the same 22 species were tested in the third surveillance from April 2002 to March 2003.
No remarkable changes in the activity of CPDX were observed against most of the species in these surveillances spanning three years and in comparison with that in the studies conducted before Banan® was launched.
In the study, CPDX as well as other cephem antibacterials showed a gradual decrease in activity against all the strains of Streptococcus pneumoniae and Haemophilus influenzae in proportion to the increase in the incidence rates of penicillin-resistant S. pneumoniae (PRSP) and β-lactamase-negative ampicillin-resistant H. influenzae (BLNAR). A small percentage of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, which are high-resistant strains, were isolated. The findings of this surveillance indicate that it is necessary to pay careful attention to the trends of resistant bacteria such as PRSP, BLNAR, and ESBLproducing strains.

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The susceptibility of clinical strains isolated from patients with infection to ceftriaxone (CTRX) and injectable β-lactam antibiotics was determined in Japanese medical institutions in 2004. The in vitro antibacterial activity of the above antibiotics against clinical strains isolated in 2004 was compared with that against part of the clinical strains isolated about ten years ago (1994-1996).
The antibacterial activity of CTRX against Streptococcus including penicillin-intermediate and penicillinresistant Streptocuccus pneumoniae was potent and there were no large differences between clinical strains isolated in 1994-1996 and those in 2004 in the antibacterial activity of CTRX. CTRX inhibited the growth of all the strains of Haemophilus influenzae including β-lactamase-negative, ampicillin-resistant (BLNAR) strains at 0.5 μg/mL or less and showed the potent antibacterial activity against these strains. In addition, since there are no large differences between strains isolated in the past and those isolated in 2004 in the antibacterial activity, CTRX is considered to be a useful antibiotic in the treatment of BLNAR infections which are increased by the causative organism of infections especially in the field of pediatrics in recent years. CTRX showed the excellent antibacterial activity against Escherichia coli and Klebsiella pneumoniae but one of the 50 strains of E coli tested was highly resistant. The antibacterial activity of CTRX against Neisseria gonorrhoeae was the most potent in all the antibiotics tested.
These results indicate that CTRX shows excellent antimicrobial activity against fresh strains isolated from patients with infections. CTRX is thus useful as a therapeutic antimicrobial for the treating a variety of infections.

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We analyzed Haemophilus influenzae isolates in Gifu prefecture between May 2003 and August 2003. We conducted molecular-level epidemiological studies for 313 strains using PCR to identify resistant genes in H. influenzae. Our four sets of primers are as follows: (i) p6 gene of P6 membrane protein,(ii) TEM-1 type β-lactamase gene (bla),(iii) normal PBP 3 gene (ftsl), and (iv) mutational ftsl gene detected in β-lactamase-nonproducinga mpicillin (ABPC) resistant H. influenzae (BLNAR). H. influenzae strains were classified into 6 types based on PCR: (i) β-lactamase-nonproducin ABPC-susceptibles trains (BLNAS; n=85) with no any resistant genes,(ii) TEM-1 type β-lactamase-producing ABPC resistant strains (BLPAR; n=6),(iii)-lactamase-nonproducing and low-level ABPC-resistant strains (Low-BLNAR; n=77) possessing β Asn-526→Lys-526 amino acid substitution,(iv) BLNAR strains (n=138) possessing Asn-526→Lys-526 and 3 amino acids substitutions detected around the Ser-Ser-Asn conserved motif,(v) β-lactamase-producing amoxicillin-clavulanate resistant strains (BLPACR-I; n=3) possessing TEM-1 and Low-BLNAR resistant genes, and (vi) β-lactamase-producing amoxicillin-clavulanate resistant strains (BLPACR-II; n=4) possessing TEM-1 and BLNAR resistant genes. Amoxicillin (AMPC) MIC₉₀s in Low-BLNAR was 4 μg/mL and in BLNAR was 16, μg/mL. In oral cephalosporins, cefditoren MIC₉₀ was the most excellent with 0.5μg/mL against BLNAR. The prevalence of H. influenzae type b isolates in Matsubara Otorhinolaryngology Clinic was 66.7%. Selection of appropriate antimicrobial agents should be performed to prevent resistant microorganisms. Also, the vaccination for H. influenzae type b would be strongly recommended in near future.

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For the post-marketing surveillance of cefmetazole (CMZ, Cefmetazon®), MICs of injectable β-lactam antibacterials including CMZ against clinical isolates from 15 medical institutions all over Japan are measured yearly and the incidence rates of resistance in various species are also evaluated. In the first surveillance from June 2000 to March 2001, 574 isolates of 13 species were tested, 548 isolates of the same 13 species were tested in the second surveillance from April 2001 to March 2002, and 654 isolates of the same 13 species were tested in the third surveillance from April 2002 to March 2003.
No remarkable changes in the activity of CMZ were observed in these surveillances spanning three years. The activity of CMZ in this study was comparable to that in the studies conducted before Cefmetazon® was launched. This result suggests that CMZ still maintains potent activity.
Changes in percent resistance of each species to CMZ (MIC of CMZ≥32μg/ml) were as follows: methicillin-susceptible Staphylococcus aureus (MSSA, 0.0%→0.0%→0.0%), methicillin-resistant Staphylococcus aureus (MRSA, 72.9%→87.2%→88.7%), Staphylococcus epidermidis (18.5%→31.6%→14.3%), coagulase-negative Staphylococcus spp.(CNS, 13.3%→418.2%→21.4%), Escherichia coli (3.6%→0.8%→2.1%), Klebsiella pneumoniae (3.4%→3.8%→2.1%), Klebsiella oxytoca (0.0%→0.0%→0.0%), Proteus mirabilis (2.3%→2.1%→ 0.0%), Proteus vulgaris (13.6%→6.7%→0.0%), Morganella morganii (7.3%→0.0%→14.0%), Providencia spp.(12.5%→0.0%→18.2%), Peptostreptococcus spp.(0.0%→0.0%→0.0%), Bacteroides fragilis (10.3%→10.8%→ 17.1%), Bacteroides spp.(78.6%→87.5%→62.5%). The Change in percent resistance of MRSA, other CNS, and B. flagiris tended to increase. It is necessary to pay much attention to trends observed in these species. Compared to other drugs tested, against MSSA, the activity of CMZ was inferior to that of CEZ, CTM, and FMOX and superior to that SBT/CPZ. Against MRSA, S. epidermidis, and CNS, the tested drugs exhibited little activity. Against Gram-negative bacteria, the activity of CMZ was almost superior to that of CEZ and CTM, and inferior to that of FMOX. Against B. flagiris and other Bacteroides spp., the activity of CMZ was almost superior to that of CEZ and CTM, and comparable to or inferior to that of SBT/CPZ and FMOX.

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In vitro antibacterial activity of telithromycin (TEL) against the isolates of Neisseria gonorrhoeae (212 isolates) derived from urine or genital secretion in 2002 (April to December) was examined in comparison with those of macrolides (erythromycin [EM], clarithromycin [CAM]), penicillins (penicillin G [PCG]), cephems (cefodizime [CDZM], cefixime [CFIX]), quinolones (levofloxacin [LVFX]), tetracyclines (minocycline [MINO]), and aminoglycosides (spectinomycin [SPCM]).
The MIC of TEL was ranged from≤0.039 to 0.25μg/mL and the MIC₅₀ and MIC₉₀ of TEL were respectively 0.125 and 0.25μg/mL, which were the lowest values compared with those of other oral antibacterial agents measured. When compared TEL with other agents in the order of the MIC₅₀ and MIC₉₀, TEL was more superior to EM and CAM (both eight times), MINO (four times and twice), and LVFX (16 and 64 times). The MIC₉₀ of TEL was superior in twice though the MIC₅₀ was the same in comparison with CFIX. The CDZM resistant strain did not exist and SPCM also inhibit growth with 32μg/mL or less that was the breakpoint MIC excluding one stock though the PCG sensitive strain was only 1.4% in the injection drug.
However, clinical breakpoint MIC is not established, but the efficacy of TEL is prospective because of its high antibacterial activity to inhibit growth of all stocks for gonococcus with 0.25μg/mL.
It is expected that TEL can become an oral antibiotic recommended for treatment of gonococcus if dosage and administration are considered.

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From October 2003 to September 2004, we collected the specimen from 399 patients with lower respiratory tract infections in 12 institutions in Japan, and investigated the susceptibilities of isolated bacteria to various antibacterial agents and patients' characteristics. Of 474 strains that were isolated from specimen (mainly from sputum) and assumed to be bacteria causing in inflammation, 469 strains were examined. The breakdown of the isolated bacteria were: Staphylococcus aureus 76,Streptococcus pneumoniae 81, Haemophilus influenzae 84, Pseudomonas aeruginosa(non-mucoid) 56, P aeruginosa(mucoid) 11,Klebsiella pneumoniae 36,Moraxella subgenus Branhamella catarrhalis 24,etc.
Of 76 S. aureus strains, those with 2μg/ml or less of MIC of oxacillin (methicillin-susceptible S. aureus: MSSA) and those with 4μg/ml or more of MIC of oxacillin (methicillin-resistant S. aureus:MRSA) were both 38 strains (50.0%). Against MSSA, imipenem had the most potent antibacterial activity and inhibited the growth of all the strains at 0.063μg/mL. Against MRSA, vancomycin showed the most potent activity and inhibited the growth of all the strains at 2μg/mL. Arbekacin also showed the potent activity and inhibited the growth of all the strains at 4μg/mL. Carbapenems showed the most potent activities against S. pneumoniae and inhibited the growth of all the strains at 0.125-0.5μg/mL. Cefozopran (CZOP) also had a preferable activity (MIC₉₀: 2μg/ mL) and inhibited the growth of all the strains at 4μg/mL. In contrast, there were high-resistant strains (MIC: 128μg/mL or more) for cefaclor (11.1%), erythromycin (43.2%), and clindamycin (40.7%). Against H. influenzae, levofloxacin showed the most potent activity and inhibited the growth of 83 of all the strains (98.8%) at 0.063μg/mL. Tobramycin showed the most potent activity against P aeruginosa (both mucoid and nonmucoid) and its MIC₉₀ was 2μg/mL. The activity of CZOP also was preferable and its MIC₉₀ was 4 μg/mL for the mucoid-type and 8μg/mL for the non-mucoid type. CZOP was the most potent activities against K pneumoniae and inhibited the growth of all the strains at 0.125μg/mL. Also, all the agents-generally showed potent activities against M (B.) catarrhalis and the MIC₉₀ of them were 4μg/mL or less.
The approximately half the number (54.1%) of the patients with respiratory infection were aged 70 years or older. Bacterial pneumonia and chronic bronchitis accounted for 46.1% and 30.6% of all the respiratory infection, respectively. The bacteria frequently isolated from the patients with bacterial pneumonia were S. aureus(18.6%) and H. influenzae (18.1%). In contrast, S. aureus(16.9%) and S. pneumoniae(14.9%) were frequently isolated from the patients with chronic bronchitis. Before the drug administration, the bacteria frequently isolated from the patients were S. pneumoniae (20.6%) and H. influenzae (21.5%). The bacteria relatively frequently isolated from the patients treated with cephems or macrolides were P aeruginosa, and S. aureus was relatively frequently isolated from the patients treated with quinolones.

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Monte Carlo simulation was employed forthis comparative study to determine the optimal Carbapenem and its dosing strategy to cure the infections by Escherichia coli and Pseudomonas aeruginosa and to consider how the difference of each Carbapenems in dosing regimens and antibiotic activityinfluenced to maximize %T>MIC.
This result revealed that it was important to increase a dose and a number of doses a day, in addition to great antibiotic activity for maximizing %T>MIC.

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