A survey was conducted to determine the antimicrobial activity of fluoroquinolones and other antimicrobial agents against 8,474 clinical isolates obtained from 37 Japanese medical institutions in 2000. A total of 25 antimicrobial agents were used, comprising 4 fluoroquinolones, 13β-lactams, minocycline, chloramphenicol, clarithromycin, azithromycin, gentamicin, amikacin, sulfamethoxazole-trimethoprim, and vancomycin.
A high resistance rate of over 85% against fluoroquinolones was exhibited by methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium. Isolates showing resistance to fluoroquinolones among methicillin-resistant coagulase-negative Staphylococci, Enterococcus faecalis, and Pseudomonas aeruginosa from UTI accounted for 30-60%. However, many of the common pathogens were still susceptible to fluoroquinolones, such as Streptococcus pneumoniae (including penicillin-resistant isolates), Streptococcus pyogenes, methicillin-susceptible S. aureus (MSSA), methicillin-susceptible coagulase-negative Staphylococci, Moraxella catarrhalis, the Enterobacteriaceae family, and Haemophilus influenzae (including ampicillin-resistant isolates). About 85% of P. aeruginosa isolated from RTI were susceptible to fluoroquinolones.
In conclusion, this survey of sensitivity to antimicrobial agents clearly indicated trend for increasing resistance to fluoroquinolones among MRSA, Enterococci, and P. aeruginosa isolated from UTI, although fluoroquinolones are still effective against other organisms and P. aeruginosa from RTI as has been demonstrated in previous studies.

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From October 2001 to September 2002, we collected the specimen from 370 patients with lower respiratory tract infections in 16 institutions in Japan, and investigated the susceptibilities of the isolated bacteria to various antibacterial agents and antibiotics and patientsrsquo; characteristics. Of 458 strains that were isolated from specimen (mainly from sputum) and assumed to be bacteria causing in inflammation, 456 strains were investigated. The breakdown of the isolated bacteria were: Staphylococcus aureus 69, Streptococcus pneumoniae 72, Haemophilus influenzae 85, Pseudomonas aeruginosa (non-mucoid) 44, P. aeruginosa (mucoid) 13, Klebsiella pneumoniae 32, Moraxella subgenus Branhamella catarrhalis 32, and others.
Of 69 S. aureus strains, those with 4μg/mL or more of MIC of oxacillin (methicillin-resistant S. strains: MRSA) occupied 43.5%. Vancomycin and arbekacin showed the most potent activities against MRSA as observed in 2000. The frequency of S. pneumoniae exhibiting low sensitivity to penicillin (penicillin-intermediate S. pneumoniae: PISP+penicillin-resistant S. pneumoniae: PRSP) was 59.7% and both rates of PISP and PRSP were the highest after 1992. Carbapenems had strong activities against S. pneumoniae. Especially, panipenem and imipenem inhibited the growth of all 72 strains at 0.125 and 0.5μg/mL, respectively. Generally, all drugs had strong activities against H. influenzae with MIC₉₀s of 16μg/mL or less. The drug that had the strongest activity against H. influenzae was levofloxacin, which inhibited the growth of 80 of the 85 strains at 0.063μg/mL.Against P. aeruginosa mucoid strain, meropenem had a strong activity with MIC₉₀ of 0.5μg/mL while, against non-mucoid strain, tobramycin had a strong activity with MIC₉₀ of 2μg/mL. K. pneumoniae showed good susceptibilities to all drugs except ampicillin and minocycline, and the MIC₉₀s were 4μg/mL or less. Particularly, cefmenoxime, cefpirome, and imipenem had the strongest activity (MIC₉₀: 0.125μg/mL), and cefozopran had a strong activity, inhibiting the growth of all strains at 0.25μg/mL. Also, all drugs generally had strong activities against M.(B.) catarrhalis. MIC₉₀s of all drugs were 4μg/mL or less. The drug that had the strongest activity was minocycline and levofloxacin inhibiting all 32 strains at 0.063μg/mL.
Most of the patients with respiratory infection were aged 70 years or older, accounting for approximately a half of the total (40.5%). As for the incidence by the diseases, bacterial pneumonia and chronic bronchitis were the highest, being noted in 39.2% and 37.3% of all the patients, respectively. The bacteria frequently isolated from the patients with bacterial pneumonia were S. aureus (19.3%) and S. pneumoniae (19.9%). In contrast, H. influenzae (22.0%) were frequently isolated from the patients with chronic bronchitis. Before the drug administration, the bacteria frequently isolated from the patients were S. pneumoniae (20.8%) and H. influenzae (21.5%).S. pneumoniae and H. influenzae decreased after the initiation of drug administration while S. aureus increased.The isolation frequency of P. aeruginosa was higher after than before the initiation of drug administration. The bacteria were frequently isolated from the patients who had already treated with cephems were S. aureus and P. aeruginosa. From the patients who had already treated with macrolides, S. pneumoniae was the most frequently isolated while S. aureus was the most frequently isolated from the patients pre-treated with quinolones.

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The bacterial strains isolated from patients diagnosed as having urinary tract infections (UTIs) in 10 institutions in Japan were supplied between the period of September and December 2001. Then, the susceptibilities of them to a variety of antimicrobial agents were investigated. The number of them were 496 strains. The breakdown of these strains was Gram-positive bacteria as 29.6% and Gram-negative bacteria as 70.4%.
Susceptibilities of these bacteria to antimicrobial agents were as follows; against Staphylococcus aureus, vancomycin (VCM) showed a strong activity, and this drug also had a strong activity against MRSA in preventing growth of all strains at 1μg/mL. In addition, arbekacin (ABK) showed strong activity with the MIC₉₀ of 2μg/mL against MRSA and prevented growth of all strains at 4μg/mL. ABK also showed a strong activity against Staphylococcus epidermidis in preventing growth of all strains at 0.5μg/mL. Ampicillin (ABPC) and cefozopran (CZOP) showed a relativly strong activity against S. epidermidis (MIC₉₀: 8μg/mL). ABPC, imipenem (IPM), and VCM showed strong activities against Enterococcus faecalis. No increase of low-susceptible strains in E. faecalis was observed against these antimicrobial agents. Against Escherichia coli, carbapenems showed the highest activities: meropenem (MEPM) prevented growth of all strains at 0.25μg/mL, IPM prevented growth of all strains at 0.5μg/mL. CZOP and cefotiam (CTM) also showed strong activities against E. coli: MIC₉₀ of CZOP was within 0.125μg/mL; MIC₉₀ of CTM was within 0.5μg/mL. Quinolone-resistant E. coli was detected at frequency of 9.3%, which was lower than that in the last year, and was higher level than those in up to 1999. MEPM showed the strongest activity against Citrobacter freundii in preventing growth of all strains at 0.125μg/mL. Almost all drugs showed strong activities against Klebsiella pneumoniae and Proteus mirabilis, and MEPM prevented growth of all strains within 0.125μg/mL. Against Serratia marcescens, the MIC₉₀ of gentamicin (GM) was the lowest value being 2μg/mL, and those of IPM and carumonam were 8 and 16μg/mL, respectively. Against Pseudomonas aeruginosa, almost all drugs were not so active. The MIC₉₀ of GM was 8μg/mL, those of IPM and amikacin were 16μg/mL, and those of all other drugs were over than 32μg/mL.

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Five-hundred thirty one bacterial strains isolated from 412 patients diagnosed as having urinary tract i nfections (UTIs) in 10 institutions in Japan were supplied between September and December 2001. Then, the clinical background of patients were investigated such as sex, age, and type of infections, infections and kind of bacteria, frequency of bacteria isolation by age and infections, bacteria and infections by timing of antibiotics administration, and bacteria and infections by surgical procedures.
With regard to the relationship between age and sex of patients and type of infections, the number of cases aged lower than 50 years was few and complicated UTIs without indwelling catheter was the most frequent in male patients. In females, the number of patients aged lower than 20 years was few. Most of female patients aged lower than 80 years had uncomplicated UTIs. As for the relationship between type of infections and kind of bacteria, Escherichia coli decreased as the infections were more compli ated, and Pseudomonas aeruginosa and Enterococcus faecalis increased as the infections were more complicated. In relation of these results to age of patients, isolation frequency of E. coli gradually decreased with aging in patients aged 20 years and older with uncomplicated UTIs. The isolation frequencies of E. faecalis decreased with aging in the patients with complicated UTIs without indwelling catheter while P. aeruginosa decreased with aging in the patients with complicated UTIs with indwelling catheter. E. coli was isolated a few after administration of antibiotics, and P. aeruginosa and E. faecalis were frequently isolated after administration in the patients with all types of infections. As for type of causative organisms in UTIs and with or without surgical operation, E. coli was frequently isolated in the patients without surgery in the patients with uncomplicated UTIs and complicated UTIs without indwelling catheter, while P. aeruginosa was frequently isolated in the patients who underwent surgery in the patients with uncomplicated UTIs and complicated UTIs with indwelling catheter. In uncomplicated UTIs, isolation frequencies of Klebsiella spp., P. aeruginosa, and E. faecalis were significant in the patients withsurgery. In complicated UTIs without indwelling catheter, Klebsiella spp. was frequently isolated in the patients with surgery. In complicated UTIs with indwelling catheter, S. aureus and Staphylococcus spp. were frequently isolated in the patients without surgery.

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As a post-marketing surveillance, the in vitro antibacterial activities of cefozopran (CZOP), an agent of cephems, against various clinical isolates were yearly evaluated and compared with those of other cephems, oxacephems, penicillins, and carbapenems. Changes in the bacterial susceptibility for CZOP were also evaluated with the resistance ratio calculated with breakpoint MIC. Sixteen species (2,363 strains) of Gram-positive bacteria were isolated from the clinical materials annually collected from 1996 to 2001, and consisted of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus epidermidis (MSSE), methicillin-resistant Staphylococcus epidermidis (MRSE), Staphylococcus haemolyticus, Staphylococcus saprophyticus, Enterococcus faecalis, Enterococcus faecium, Enterococcus avium, Streptococcus pyogenes, Streptococcus agalactiae, penicillinsusceptible Streptococcus pneumoniae (PSSP), penicillin-intermediate resistant S. pneumoniae (PISP), penicillin-resistant S. pneumoniae (PRSP), Streptococcus milleri group and Peptostreptococcus spp.
The antibacterial activity of CZOP either against MSSA or MSSE was preferable (MIC₉₀: 2 or 0.5 μg/mL) and comparable to those of other cephems. CZOP was also effective on MRSE (MIC₉₀: 16 μg/mL) but not on MRSA. CZOP and other cephems had low antibacterial activity against S. haemolyticus (MIC₉₀: 64 μg/mL). The antibacterial activity of CZOP against S. saprophyticus was comparable to or higher than those of other cephems, but the MIC₉₀ of CZOP in 2001 was higher than those in 1996-2000 (32 vs 1-2μg/mL). The antibacterial activity of CZOP against E. faecalis was comparable to that of cefpirome (CPR; MIC₉₀: 16 μg/mL) and higher than those of other cephems. No antibacterial activity of CZOP against E. faecium and E. avium was observed, like other drugs. The antibacterial activity of CZOP against S. pyogenes was as potent as those of cefotiam and CPR (MIC₉₀:≤0.063 μg/mL), and, against S. agalactiae, was also preferable (MIC₉₀: 0.125 μg/mL). CZOP indicated preferable antibacterial activity either against PSSP, PISP, or PRSP (MIC₉₀: 0.25, 1, or 2 μg/mL). The antibacterial activity of CZOP against S. milleri group was also preferable, but the MIC₉₀ of CZOP in 2001 was higher than those in 1996-2000 (4vs 0.5 μg/mL). The antibacterial activity of CZOP against Peptostreptococcus spp. was preferable but weaker than those of cefazolin and cefmetazole. The resistance ratio estimated from breakpoint MIC of CZOP was 95.9% in MRSA, 93.5% in PRSP, 63.3% in PISP, 35.8% in S. haemolyticus, 27.9% in E. faecalis, and 13.3% MRSE. Those resistance ratios were comparable to those for cefepime (CFPM), but E. faecalis showed 91.2% for CFPM. The difference in the resistance ratio of E. faecalis demonstrated that CZOP successfully maintained its antibacterial activity against these species. In correlation of drug susceptibility, 40.3% of PRSP was not inhibited at breakpoint MIC either CZOP or CFPM while 69.2% at breakpoint MIC either CZOP or ceftazidime.
In conclusion, the antibacterial activities of CZOP against the Gram-positive bacteria obtained from the 6-year duration study were consistent with the results from the studies performed until the new drug application approval. A decline in the sensitivities of S. saprophyticus, S. milleri group, PISP, and PRSP to CZOP, however, was suggested.

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As a post-marketing surveillance, the in vitro antibacterial activities of cefozopran (CZOP), an agent of cephems, against various clinical isolates were yearly evaluated and compared with those of other cephems, oxacephems, carbapenems, monobactams, and penicillins. Changes in CZOP susceptibility among bacteria were also evaluated with the bacterial resistance ratio calculated from the breakpoint MIC. Twenty-five species (4,154 strains) of Gram-negative bacteria were isolated from the clinical materials annually collected from 1996 to 2001, and consisted of Moraxella (Branhamella) catarrhalis, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Serratia liquefaciens, Citrobacter freundii, Citrobacter koseri, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia spp., Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida, Acinetobacter baumannii, Acinetobacter lwoffii, Burkholderia cepacia, Stenotrophomonas maltophilia, Bacteroides fragilis group, and Prevotellal Porphyromonas. CZOP preserved its antibacterial activity against M.(B.) catarrhalis (MIC₉₀: 4μg/mL) and showed comparable activity to carbapenems against H. influenzae (MIC₉₀: 1μ g/mL). The antibacterial activity of CZOP against E. coli was preferable (MIC₉₀: 0.125μ g/mL) and comparable to those of cefpirome (CPR), cefepime (CFPM), and imipenem (IPM). The MIC₉₀ of CZOP against K. pneumoniae and K. oxytoca was 1 and 0.25μ g/mL, respectively. The MIC₉₀ of CZOP against E. cloacae increased during 6 years (32 to 128μ g/mL).
The antibacterial activity of CZOP against E. aerogenes was preferable (MIC₉₀: 1μ g/mL). The antibacterial activities of CZOP against S. marcescens and S. liquefaciens were relatively potent (MIC₉₀: 0.5 and 0.25μ g/mL) and comparable to those of CPR, CFPM, and carumonam. CZOP preserved comparable antibacterial activity to CPR against C. freundii and C. koseri (MIC₉₀: 8 and 0.125μ g/mL). The MIC₉₀ of CZOP against P. mirabilis, P vulgaris, and M. morganii was 0.25, 16, and 2μ g/mL, respectively. The antibacterial activity of CZOP against Providencia spp. was moderate (MIC₉₀: 64 μ g/mL). The antibacterial activity of CZOP against P. aeruginosa was the most potent (MIC₉₀: 16μg/mL) among the test agents and comparable to those CFPM, IPM, and MEPM. CZOP had low activity against P. fluorescens and P. putida (MIC₉₀: 128μg/mL). The antibacterial activity of CZOP against A. baumannii was comparable to those of ceftazidime (CAZ), CPR and CFPM (MIC₉₀: 32μg/mL) and against A. lwoffii was moderate (MIC₉₀: 64μg/mL). Most of the test agents including CZOP had low antibacterial activity against B. cepacia, S. maltophilia, and B. fragilis group. The MIC₉₀ of CZOP against Prevotella/Porphyromonas was 64 μg/mL. Bacterial cross-resistance ratio between CZOP and other agents was low in most of the species, ranging from 0.0 to 15.1%. In non-glucose fermentative bacteria, however, the bacterial cross-resistance ratio between CZOP and CFPM, CAZ, CPR, or IPM was high, being 36.8%, 28.0%, 38.7%, or 31.1%, respectively.
In conclusion, the 6-year duration study suggested that the antibacterial activity of CZOP against E. cloacae possibly decreased, but against other Gram-negative bacteria was consistent with the study results obtained until the new drug application approval.

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