The parenteral injection of ciprofloxacin (CPFX), a fluoroquinolone antimicrobial drug, was approved in September 2000 and a re-examination period of 6 years was set at that time. As a special investigation to apply for re-examination of this drug, it has been planned to conduct 3 nationwide surveillances during the re-examination period by collecting clinically isolated bacteria from patients with severe infections, to whom the drug was mainly indicated, and examining drug susceptibilities of the bacteria to various parenteral antimicrobial drugs including CPFX. This time, we determined the minimum inhibitory concentrations (MICs) of various parenteral antimicrobial drugs including CPFX against 1,220 strains isolated from patients with severe infections by the micro-liquid dilution method and compared susceptibilities of various clinically isolated bacteria to CPFX with those to other antimicrobial drugs. Gram-positive bacteria were less susceptible to CPFX than to carbapenems except 2 bacterial species, Enterococcus faecium and Enterococcus avium but susceptibilities of methicillin-susceptible Staphylococcus aureus (MSSA), Staphylococcus epidermidis and Enterococcus faecalis to CPFX were comparable to those to cefozopran. Susceptibility of Streptococcus pneumoniae to CPFX did not differ among ampicillin (ABPC)-susceptible Streptococcus pneumoniae (MIC of ABPC: <0.25μg/ml), ABPC-intermediate S. pneumoniae (MIC of ABPC: 0.25-2μg/ml) and ABPC-resistant S. pneumoniae (MIC of ABPC: ≥4μ/g/ml)(MIC₉₀ of CPFX: 1μg/ml) and a decrease in the antimicrobial activity seen among cephem and carbapenem antimicrobial drugs against penicillin-intermediate strains was not noted with CPFX. Gram-negative bacteria were susceptible to CPFX similarly to carbapenems and the MIC₉₀ values of CPFX were in the range from ≤0.063 to 2μg/ml against strains except Stenotrophomonas maltophilia and Burkholderia cepacia. Pseudomonas aeruginosa was most susceptible to CPFX among the antibacterial drugs examined and the MIC₉₀ was 2μg/ml. CPFX also showed the lowest MIC₉₀ value (0.5μg/ml) against β-lactam-resistant P. aeruginosa among the drugs examined. When extended-spectrum β-lactamase (ESBL) production and class B β-lactamase productionwere examined in 439 strains of Enterobacteriaceae and 168 strains of glucose non-fermentative bacteria out of the Gram-negative bacteria collected this time, 3 strains (0.49%) producing ESBL and 7 strains (1.15%) producing class B β-lactamase were found. The MIC range of CPFX to these 10 strains was between ≤0.063 to 8μg/ml and 5 strains among those showed susceptibilities (MIC of CPFX: 1μg/ml) based on the NCCLS breakpoint. CPFX also showed a satisfactory result concerning susceptibilities of major causal bacteria based on the report of the committee of Japan Society of Chemotherapy on the standard method for determination of susceptibility to antimicrobial agents, the breakpoint of pneumonia. Furthermore, suscepti-bilities of various bacteria isolated clinically from patients with severe infections this time did not differ much from the result of the nationwide surveillance which we conducted in 1997. Thus, it was concluded that the antimicrobial activity of CPFX was maintained in the post-marketing surveillance for its parenteral preparation.

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The antibacterial activity of cefrnetazole (CMZ) against clinical isolates from 15medical institutions all over Japan was evaluated yearly for two years from June 2000 to March 2002 and compared with that of other parenteral β-lactams, cefazolin (CEZ), cefotiam (CTM), sulbactam/cefoperazone (SBT/CPZ), and flomoxef (FMOX). In the first surveillance from June 2000 to March 2001, 575 isolates of 13 species were tested, and 548 isolates of the same 13 species were tested in the second surveillance from April 2001 to March 2002. In these surveillances spanning two years, the MIC₉₀s of CMZ against the bacterial species tested hardly differed. Changes in percent resistance of each species to CMZ (MIC of CMZ ≥32μg/mL) were as follows: methicillin-susceptible Staphylococcus aureus (MSSA, 0%→0%), methicillin-resistant Staphylococcus aureus (MRSA, 73%→87%), Staphylococcus epidermidis (19%→32%), other coagulase-negative Staphylococcus spp.(other CNS, 13%→18%), Escherichia coli (4%→1%), Klebsiella pneumoniae (3%→4%), Klebsiella oxytoca (0%→0%), Proteus mirabilis (2%→2%), Proteus vulgaris (14%→7%), Morganella morganii (7%→0%), Providencia spp.(17%→0%), Peptostreptococcus spp.(0%→0%), Bacteroides fragilis (10%→11%), and other Bacteroides spp.(79%→88%). The change in percent resistance of MRSA, S. epidermidis, other CNS, and other Bacteroides spp. tended to increase. In addition, the percent resistance of B. fragilis was 10%. It is necessary to pay much attention to the 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 of 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. fragilis 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. No remarkable changes in the activity of CMZ were observed in this study compared with studies conducted before CMZ was launched. This result suggests that CMZ still maintains potent activity.

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The bacteria (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa) isolated from patients diagnosed as urinary tract infections (UTIs) in 10 institutions in Japan were supplied between September and December, 2001. Then, the susceptibilities of these bacteria to various antimicrobial agents were examined, and the results were compared with those obtained between 1992 and 2000. Comparison was made by classifying strains isolated from patients into those in uncomplicated UTIs and those in complicated UTIs (including with or without indwelling catheter).
The drug sensitivity of S. aureus in this year was comparable to those in up to the previous year, and S. aureus showed the best susceptibility to vancomycin (VCM). E. faecalis showed good susceptibility to ampicillin and imipenem, and the MIC₉₀s were 2μg/mL. The susceptibility of E. faecalis to VCM was also good. E. coli showed good susceptibility to the test drugs except penicillins. Among cephems, the susceptibility to cefozopran (CZOP) was better (MIC₉₀:≤0.125μg/mL). Just as the last report, the decreases in susceptibility of E. coli to quinolones were also observed in the patients with complicated UTIs. The susceptibility of Klebsiella spp. to all the test drugs did not significantly change in 2001 and was generally good but not to penicillins. Among cephems, Klebsiella spp. showed good susceptibility to flomoxef, cefpirome, cefixime, and CZOP with ≤0.125μg/mL of MIC₉₀s either in uncomplicated or complicated UTIs. Although the drug sensitivity of P. aeruginosa was generally low, the detection of the strains that showed good susceptibility to quinolones and carbapenems (MIC:≤0.125-2μg/mL) were relatively frequent.

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Susceptibility testing of 288 clinical isolates of P. aeruginosa in 2000 was performed by the disk diffusion method with observation at regulax time course. Detailed analysis of the shape of the zones of inhibition gave interesting results, i. e. double zone of inhibition was found in MEPM specifically, unlike BIPM and IPM. The incidence was 50%. Moreover same phenomenon was detected in CAZ. After analyzing this phenomenon from the results of short-time-killing curve and inducibility of AmpC β-lactamase it seems that there is a close relationship between formation of double zone of inhibition and bactericidal activity in sub-MIC drug concentration.

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We determined the antibacterial activities of oral Cephems against isolated from the patients with the respiratory infections, the urinary tract infections, and infections in the obstetrics field of an adult and a child, during the period from 2002 to 2003; Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, Klebsiella pneumoniae and Escherichia coli of 40 strains of each, and Peptostreptococcus spp. 22 strains.
S. pneumoniae and H. influenzae strains that resistant is regarded were collected mainly, penicillin-intermediate S. pneumoniae (PISP), penicillin-resistant S. pneumoniae (PRSP) and β-lactamase negative ampicillin-resistant H. influenzae (BLNAR) strains.
The MICs of Cephems except cefaclor (CCL) were≤0.03 μg/mL against all strains of S. pyogenes.
The MICs of cefteram (CFTM) and cefditoren (CDTR) were≤0.0125 μg/mL activity against 7 strains penicillin-susceptible S. pneumoniae (PSSP).
However the MIC₉₀s of cefditoren (CDTR) was 1 μg/mL, cefteram (CFTM), and cefcapene (CFPN) were 2 μg/mL against PISP and PRSP, were higher than those of other drugs, but showed slightly higher than PSSP.
The MIC₉₀s of Cephems. were 0.5-4 μg/mL against strains of E. coli. The MIC₉₀s of CFTM was 0.5μg/mL, and CDTR, CFPN were 1μg/mL against E. coli were higher than those of other drugs. The four strai of E. coli however were highly-resistant which MIC₉₀s of CCL were more than 32 μg/mL were obtains. Furthermore it is necessary to pay much attention to the trend of resistant such as E. coli of Cephems.
Although all strains showed resistant to AMPC, MIC₉₀ of Cephems were 0.25-1 μg/mL, good activities against K. pneumoniae.
Against β-lactamase negative ampicillin-susceptible H. influenzae (BLNAS) 23 strains the MIC₉₀s of CCL and other Cephems were 64 μg/mL and 0.25-8 μg/mL.
The MIC₉₀s of CDTR and CFTM were≤1 μg/mL of BLNAR (15 strains). However there of CFDN and CPDX were 8 μg/mL and CCL were≤16 μg/mL.
Two strains which were produced β-lactamase were highly-ABPC resistant.
Although B. catarrhalis all strains were prodused β-lactamase and Cephems except for CCL showed better susceptibility than AMPC.
The MIC₉₀s of Cephems were 0.25-2 μg/mL against Peptostreptococcus spp.

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We examined the effects of fosfomycin (FOM), norfloxacin (NFLX), kanamycin (KM), chloramphenicol (CP), and ampicillin (ABPC) on the morphology of E. coli O157: H7, and the accumulation (cell fraction) and release (medium fraction) of Shiga toxins (Stxs: Stx1 and Stx2) in E.colt O157: H7 three hours after treatment with the antibiotics. For each drug, 16 MIC was used for measurement of the activity at a high drug concentration and 1/4 MIC at a low concentration. At 16 MIC, cell wall synthesis inhibitors, FOM and ABPC, strongly induced lysis of the cell of E. coli KU3342, a strain of E. coli O157: H7. The release of Stx1 was observed, but there was no accumulation of Stxs. Nucleic acid synthesis inhibitor NFLX and protein synthesis inhibitor KM induced partial lysis and short filamentation of the cell, and the accumulation and release of Stxs were low. No morphological change was observed after treatment with protein synthesis inhibitor CP, but the accumulation and release of Stxs by CP were low. At 1/4 MIC, FOM induced strong lysis of the cell, and the release of Stx1 was observed, but there was no accumulation of Stxs. ABPC and NFLX had weak lytic reaction, but induced filamentation of the cell, and the accumulation and release of Stxs were observed. In particular, NFLX significantly induced accumulation and release of Stx2. KM and CP had no effect on the morphology of the cells, and the accumulation of Stx1 was not observed, but there was no release of Stxs. The above-mentioned results support the clinical efficacy of FOM in the control of enterohoemorhagic E. coli infections.

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The effectiveness of time-dependent antibiotics such as β-lactams is related to the time above the MIC (TAM, %). We constructed a program to calculate the TAMs of β-lactams using the pharmacokinetic parameters of the Japanese dosing regimen of a phase I study of the Japanese Society for Antimicrobial Chemotherapy (JSAC), and compared them with the MIC breakpoints published by the National Committee for Clinical Laboratory Standards (NCCLS) and JSAC. If the effective TAM was assumed to be more than 40% of the dosing interval, the phaimacokinetic/pharmacodynamic (PK/PD) breakpoints calculated by our program were in agreement with the JSAC breakpoints for pneumonia within 1 dilution MIC. When comparing with the NCCLS breakpoints for Enterobacteriaceae or Staphylococcus, the PK/PD breakpoints dosing three times per day of ampicillin (1g, intravenous dose; iv), piperacillin (2g, iv), cefotaxime (1g, iv) and cefmetazole (1g, iv) were calculated to be less than 2-fold dilution MIC, and those of amoxicillin (0.25g, oral dose; po) and cefaclor (0.5g, po) were calculated to be less than 3-to 4-fold dilution of MIC.
Our program could calculate TAMs and PK/PD breakpoints by inputting the two factors of MIC and dosing interval. If this information is routinely reported to physicians from clinical laboratories, an appropriate dosing s chedule could be proposed for various infectious cases.

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We have examined the antifungal activities of the available antifungal agents including micafungin (MCFG), one of the echinocandin antifungal group, against 92 yeast-like fungi isolated at our hospital during a 3-month period from November 2002 to February 2003. Determination of the antifungal susceptibility was conducted in conformity with the Standards of the Japanese Society for Medical Mycology.
The MIC 80% of the antifungal agents against 4 fungi species including C. albicans (55 strains), C. tropicalis (20 strains), C. glabrata (8 strains), C. krusei (5 strains) were as follows; MCFG: 0.03-0.125μg/ml, amphotericin-B: 0.125-0.25μg/ml, 5-fluorocytosine: 0.125-16μg/ml, itraconazole: 0.25-2μg/ml, fluconazole: 0.5-32μg/ml.
The isolation rate of the drug-resistant fungi was 20% for the fluconazole (FLCZ)-resistant C. tropicalis and 33% when including the susceptible dose dependent (S-DD) class. The rate was 5% for FLCZ-resistant strains of C. albicans and 11% when including the S-DD class. However, MCFG was shown to have an excellent antifungal activity against those azole-resistant strains of Candida species. An analysis of the randomly amplified polymorphic DNA pattern (RAPD) was carried out to assess the fingerprinting of the azole-resistant strains. The results demonstrated a common pattern in 3 of the 6 strains of C. tropicalis that showed MIC of_??_16μg/ml for fluconazole, while all of the 6 strains of C. albicans demonstrated their respective patterns.

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Clarithromycin (CAM) is a new macrolide antibiotic which is active against a wide range of organisms responsible for community-acquired pneumonia (CAP) and has superior pharmacokinetics and tolerance compared to erythromycin. In this study, we evaluated the clinical efficacy and antimicrobial activity of CAM in the empirical treatment of patients with CAP. CAM (200mg given twice daily for 2 weeks) was orally administered to 26 patients with mild or moderate suspected atypical pneumonia, including 15 patients in whom treatment with β-lactam antibiotics was largely ineffective. Causative pathogens were identified on the basis of quantitative sputum cultures, blood cultures, and routine serological testings; M. pneumoniae was most commonly observed in patients with CAP (38.5%; 10/26), followed by H. influenzae (11.5%; 3/26), C. pneumoniae (3.8%; 1/26), and S. constellatus (3.8%; 1/26). Penicillin-resistant, or penicillin-susceptible Streptococcus pneumoniae were isolated from 1 patient (3.8%) and 2 patients (7.7%), respectively out of 26 patients with CAP. There were no detectable pathogens in 8 of 26 patients.
The treatment of CAM resulted in complete resolution of all signs and symptoms of pneumonia in all the patients and was not accompanied with any adverse events. The overall incidence of laboratory abnormalities was not detectable in the patients evaluated. Although it is important to make differential diagnosis of atypical from bacterial pneumonia in designing therapeutic strategy, it is often difficult to make an appropriate diagnosis in patients with CAP. Because of diagnostic difficulties, CAM with a broad antimicrobial spectrum is recommended as the first-line drug for the treatment of lower respiratory infections, particularly in patients with suspected atypical pneumonia.

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The appropriate administration method of levofloxacin in relation to symptoms was investigated by following up 2,353 patients prescribed either levofloxacin (300mg divided into 3 doses) or 400mg (divided into 2 doses) for the treatment of acute upper respiratory tract infection accompanied by fever (temperature (≥38°C) of suspected bacterial infection.
1) The cure rate based on body temperature as an index was significantly higher in the group administered 400mg/day compared with the group administered 300mg/day. No significant difference between the two regimens was observed in patients with a temperature ≤38.5°C at the start of administration, but patients with a temperature ≥38.6°C showed a significantly higher cure rate when administered 400mg/day compared with 300mg/day.
2) No significant difference between the groups was observed with respect to the improvement of quality of life (QOL), assessed using a VAS. In patients with a temperature ≥38.6°C, however, significantly higher improvement rates were demonstrated on days 3, 5 and 6 of treatment at 400mg/day compared with 300mg/day.
3) The reconsultation rate was significantly lower in the group administered 400mg/day compared with the group administered 300mg/day. No significant difference between the groups was observed in patients with atemperature ≥38.5°C. However, in the patients with a temperature ≥38.6°C, treatment at 400mg/day achieved a significantly lower reconsultation rate compared with 300mg/day.
4) Nonsteroidal anti-inflammatory drugs (NSAIDs) were concomitantly administered to 64.3% of the patients, but no significant difference in the cure rate was observed between patients with or without concomitant use of NSAIDs.
5) Among all of the patients, 12.7% were positive for the influenza virus, and anti-influenza drugs were concomitantly administered to 41.3% of them. However, no significant difference in the cure rate was observed between the group administered levofloxacin alone and the group concomitantly administered anti-influenza drugs.
6) The incidence of adverse drug reactions was 0.84% in the group administered 400mg/day and 0.50% in the group administered 300mg/day. No significant difference was observed between these groups and no serious adverse drug reactions occurred.
In conclusion, for treating patients with acute upper respiratory tract infection accompanied by fever (≥38.6°C) and suspected bacterial infection, levofloxacin dosage of 400mg/day (divided into 2 doses) was superior to 300mg/day (divided into 3 doses) in terms of therapeutic effect, QOL, and the reconsultation rate. This was considered to be an administration method worth recommending, including its safety. In patients with a temperature of 38.0°C to 38.5°C, administration of levofloxacin at 300mg/day was confirmed to demonstrate a sufficient therapeutic effect.

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