The activity of various antibacterial agents against clinical isolates of 919 strains of gram-positive cocci (22 species), and 170 strains of anaerobic bacteria (22 species) was assessed using agar-dilution MIC determination. The clinical isolates were isolated in 1998 at 14 facilities in Japan. Methicillin-resistant Staphylococcus aureus (MRSA) accounted for 51.7% of all S.aureus isolates. Vancomycin (VCM) teicoplanin (TEIC), arbekacin (ABK) and sulfamethoxazole-trimethoprim (ST) had the highest antibacterial activities against MRSA, with an MIC₉₀ of 1.56μg/mL. VCM, ABK, minocycline and cefotiam were effective Staphylococcus epidermidis (MIC₉₀≤3.13μg/mL). Penicillin (PC)-intermediate and PC resistant Streptococcus pneumoniae (PISP+PRSP) accounted for 46.8% of all S. pneumoniae strains. Cefpirome, cefoselis, carbapenems (CBPs), tosufloxacin, TEIC and VCM displayed the highest antibacterial activities against PISP+PRSP, inhibiting all strains at less than 0.39μg/mL. VCM and TEIC were effective against Enterococcus faecalis and Enterococcus faecium (MIC₉₀≤3.13μg/mL). No VCM-resistant strains were found in any of the gram-positive cocci isolates tested, including MRSA and Enterococcus species. However, TEIC-resistant strains of Staphylococcus haemolyticus and other cocci were present. Regarding the anaerobes, cefcapene exhibited the highest antibacterial activity against Peptostreptococcus spp., while VCM and benzylpenicillin were effective against Clostridium difficile, and S-1090 was effective against Propionibacterium acnes. CBPs, faropenem (FRPM) and flomoxef exhibited the highest antibacterial activity against the Bacteroides fragilis group and Prevotella spp. CBPs and FRPM were potent antibacterial inhibitors for all anaerobic bacteria. However, the reduction in susceptibility of B. fragilis to CBPs should be noted.

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The activity of various antibacterial agents against clinical isolates of 1, 069 strains of gram-negative aerobic bacteria (18 species) was assessed by agar-dilution MIC determination. The clinical isolates were isolated in 1998 at 14 facilities in Japan. Most of the β-lactams showed no decrease in antibacterial activity against Enterobacteriaceae (excluding Klebsiella oxytoca and Proteus vulgaris) when compared with our previous reports. However, strains producing extended spectrum β-lactamases (ESBLs) were found among Escherichia coli, Proteus mirabilis and other species. The antibacterial activity of the β-lactams against K. oxytoca and P.vulgaris was lower than in previous reports. The number of newquinolones (NQs) resistant Enterobacteriaceae strains also increased. Most of the agents exhibited a high antibacterial activity against Neisseria gonorrhoeae and Branhamella catarrhalis. The rate of NQsresistant N. gonorrhoeae strains was high (50.0%), but remained unchanged from that of previous reports.β-Lactamase producing Haemophilus influenzae strains were detected at a rate of 14.6%, which is a slightly higher percentage than that found in previous reports. On the other hand, the rate of β-lactamase-negative ampicillin-resistant (BLNAR) H.influenzae increased greatly from 3.3% in 1992 and 3.5% in 1994, to 15.6% in 1996 and 24.4% in 1998. Tobramycin, S-4661, meropenem and imipenem exhibited a comparatively high antibacterial activity against Pseudomonas aeruginosa, with an MIC₈₀ of less than 6.25μg/mL. The number of multi-resistant P. aeruginosa strains has increased compared to the data of previous reports. Only a few agents exhibited a high antibacterial activity against other species of glucose non-fermentative gram-negative rods, illustrating the difficulty in selecting drugs to treat these infections.

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The pharmacokinetics of a new quinolone, pazufloxacin (PZFX) mesilate, were evaluated in 10 elderly volunteers. Five hundred milligrams of PZFX mesilate were administered by intravenous drip infusion over a period of 30 minutes. The concentrations of PZFX in the serum and urine were then determined using high-performance liquid chromatography. The pharmacokinetic parameters were calculated for groups of elderly subjects aged 65-74 years, ≥75 years and≥65 years using a two-compartment model, Higher peak concentration (C_max) and area under the curve (AUC) levels, lower systemic and renal clearance values, and a lower steady state of distribution volume were observed in the≥75 group. However, a longer elimination half-lives (T_1/2β) value was not observed. The average urinary excretion rate of PZFX after 24 hours was 83.5%. Renal clearance accounted for the major form of PZFX elimination, confirming that PZFX is primarily excreted in the urine in the elderly. No significant correlation was observed between the systemic clearance and creatinine clearance (CL_CR). The effects of repeated administrations of PZFX mesilate (500 mg× 2-3 times per day for 7 days) were simulated using the observed parameters. Based on these calculations, the accumulation of PZFX seems unlikely. None of the elderly subjects experienced any adverse effects or produced any abnormal laboratory data. PZFX mesilate tolerance was good for a Cmax of up to 23 μg/mL. However, we recommend that the administration of PZFX mesilate in elderly subjects be carefully monitored to prevent a significant decrease in renal function.

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The pharmacokinetics of pazufloxacin (PZFX) were evaluated in patients with reduced renal function. The optimum administration interval was examined, and the ability of hemodialysis to remove PZFX from the bloodstream was assessed. In patients with reduced renal function (aged, 37 to 58 years), 300 mg of PZFX was administered by drip intravenous injection (d.i.v.) over a period of 30 minutes. The serum and urinary levels of the drug were then determined at specific time intervals. The pharmacokinetic parameters were calculated, and changes in the serum level of PZFX following repeated administrations, were predicted. In some patients, hemodialysis was started 24 hours after the administration of PZFX, and the serum level of PZFX was determined after 4 hours of hemodialysis to assass the rate at which PZFX was removed. Elimination half-lives (T_1/2β) and areas under the serum concentration-time curve from time zero to infinity (AUC_0-inf) increased as the degree of renal function decreased. In particular, the T_1/2β was 20 hours or longer in patients receiving hemodialysis. This value is much larger than the T_1/2β value of healthy subjects (about 2 hours). Renal clearance also showed signs of reduction in patients with reduced renal function, suggesting a delay in urinary excretion. PZFX was removed from the blood by hemodialysis relatively easy; the apparent half-life of PZFX during hemodialysis was 2.78-4.00 hours. This value is about one sixth of the value during non-dialysis periods. About 59-66 mg of the administered PZFX was eliminated from the blood after 4 hours of hemodialysis. The pharmacokinetics of PZFX after repeated administration was simulated in individual patients using the experimental data. In the patients with a creatinine clearance (Ccr) value of 44.7 and 13.6 mL/min, 300 mg of PZFX could be safely administered twice daily with no adjustments to the administration interval necessary. In the 3 patients receiving hemodialysis (Ccr=0 mL/min), however, the administration interval required adjustment. These findings suggest that the administration interval should be carefully adjusted in patients with severely reduced renal function.

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Pazufloxacin mesilate (PZFX mesilate, T-3762), a newly developed intravenous fluoroquinolone antibacterial agent, was clinically evaluated for use against obstetric and gynecological infections, that have penetrated the genital tissues and retroperitoneal exudate. The following results were obtained.
1. A drip infusion of 300 mg over a period of 30 minutes was given to ten patients scheduled for a radical hysterectomy. PZFX concentrations in the serum, genital tissues (portio vaginalis, cervix uteri, endometrium, myometrium, oviduct, ovary), and retroperitoneal exudate were measured at periodic intervals.
1) In cases 1-5, the concentrations of PZFX in the serum and genital tissues peaked at 0.83 hours after administration. The concentrations of PZFX in the uterine artery blood and the peripheral vein blood were 6.72 μg/mL and 6.21 μg/mL, respectively, at 0.83 hours. The maximum PZFX concentrations were 5.00 g in the portio vaginalis, 7.79 gi g in the cervix uteri, 13.9μg/g in the endometrium, 12.9 gieg in the myometrium, 9.34 μg/g in the oviduct and 5.65 μg/g in the ovaryies.
2) In cases 6-10, the serum PZFX concentrations peaked at 0.25 to 0.5 hours, and the retroperitoneal exudate PZFX concentrations peaked 1 to 4 hours after administration. The mean maximum serum concentration and retroperitoneal exudate concentration were 7.83 μg/mL and 3.18 μg/mL, respectively.
2. Three hundred milligrams or 500 mg of PZFX mesilate was administered to 49 patients with adnexitis, parametritis or pelvic peritonitis two or three times a day for 7 days.
1) The clinical efficacy of the PZFX treatment in 42 patients who qualified for evaluation was evaluated as excellent in 4 patients, good in 33 patients and poor in 5 patients. The overall rate of clinical efficacy was 88.1%(37/42). When classified according to the type of infection, the clinical efficacy of the PZFX treatment was 95.2%(20/21) for patients with adnexitis, 80.0%(8/10) for patients with parametritis and 81.8%(9/11) for patients with pelvic peritonitis.
2) The clinical efficacy rates (6/8) and 90.6%(29/32) for the administration of 300 and 500 mg of PZFX, respectively.
3) The clinical efficacy of the PZFX treatment in 8 patients, who had not responded to antibiotic treatment was 6/8.
4) The bacteriological effects of the PZFX treatment were evaluated in 30 patients in whom the infective organism had been isolated. The clinical efficacy against monomicrobial infections and polymicrobial infections was 83.3%(10/12) and 88.9%(16/18), respectively. The eradication rate for 60 strains isolated in 30 patients was 90.0%(54/60). The eradication rates of gram-positive species, gram-negative species and anaerobes were 85.2%(23/27), 94.1%(16/17) and 93.8%(15/16), respectively.
5) Side effects were observed in 5 out of 48 patients and were mild to moderate in severity. Diarrhoea was observed in 2 patients, rash in one patient, watery feces in one patient, and loose stools in one patient.
6) Abnormal laboratory findings were observed in 8 out of 46 patients. Most of the abnormal findings consisted of an elevated transaminase level.
The above results suggest that the administration of PZFX mesilate is a seful treatment for moderate to severe adnexitis, parametritis and pelvic peritonitis, particularly in patients who have not responded to antibiotics.

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The clinical efficacy, safety and usefulness of pazufloxacin (PZFX) mesilate, a new quinolone for injection, were evaluated in a clinical study of patients with sepsis, infectious endocarditis and empyema resulting in severe refractory infections. PZFX mesilate was administered by intravenous drip infusion at a dose of 500 mg two or three times a day. A total of 9 cases were enrolled in this study, and the clinical efficacy of PZFX mesilate was evaluated in 7 cases. Eight cases were evaluated for side effects, laboratory fi ndings and overall safety, and 7 cases were evaluated for utility. The clinical efficacy rate was 2/2 for sepsis and 3/5 for empyema. The efficacy rate in patients who had responded poorly to other antibiotic treatments was 2/2. The causative organisms were detected in 2 patients with sepsis. One case was caused by a monomicrobial infection of Escherichia coli, while the second case was caused by a polymicrobial infection of E. coli and Enterococcus faecalis. The monomicrobial infection was eradicated by the PZFX treatment, but the outcome of the polymicrobial infection is unknown because bacteriological tests were not performed after the administration of PZFX. The elimination rate of the causative organisms was thus 1/1. The causative organisms were detected in 1 patient with empyema, who had a monomicrobial infection of Streptococcus intermedius. The infection persisted despite treatment, so the elimination rate of the causative organisms was 0/1. Delirium was observed as a side effect in 1 case, and the incidence of all side effects was 1/8. Abnormal laboratory findings were observed in 2 cases, and the incidence of abnormal laboratory findings was 2/8. Eosinophilia was observed in one case, while the second case had an elevated Al-P level. The overall safety of the treatment was evaluated to be 5/8. The utility of PZFX treatment was evaluated to be 1/2 for sepsis and 3/5 for empyema. These results indicate that PZFX mesilate is an effective drug for the treatment of severe refractory infections, especially to sepsis and empyema.

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