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The in vitro short-term bactericidal activity and accumulation of NM394, the active metabolite of prulifloxacin, was compared with those of ciprofloxacin (CPFX), levofloxacin (LVFX) and gatifloxacin (GFLX), using Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Of the 4 fluoroquinolones examined, NM394 accumulated to the highest concentration in all three strains. The order of concentration of the fluoroquinolones accumurated in S. aureus 209P JC-1, E. coli NIHJ JC-2 and P. aeruginosa PAO1 were NM394 >> CPFX > GFLX > or = LVFX. The accumulation of fluoroquinolones into bacterial cells correlated with their MICs of the drugs for E. coli and P. aeruginosa, whereas there was no correlation between the accumulation and MICs of the drugs for S. aureus. We also studied the reduction of viable cells after addition of each fluoroquinolones to clarify relationship between the short-term bactericidal activity and the accumulation of the quinolones. The short-term bactericidal activity of NM394 against S. aureus 209P JC-1, E. coli NIHJ JC-2 and P. aeruginosa PAO1 were stronger than those of CPFX, LVFX and GFLX when compared at the same concentration. In conclusion, the strong short-term bactericidal activity of NM394 may be attributed to its high accumulation in bacterial cells.

The levels of levofloxacin (LVFX) in the serum, sputum and lung tissue were measured by a high-performance liquid chromatography method, and the penetration ratio of LVFX into respiratory tissue was investigated. The subjects of this study were 23 patients under pulmonectomy or brochoscopy. LVFX at the dose of 200 mg was given orally and specimens were collected as follows; serum at 2, 3 and 5 hours after, sputum at 2 hours after, and lung tissue at 3 and 5 hours after the administration, respectively. The mean level of LVFX in lung tissue at 3 hours was 3.91 +/- 2.33 micrograms/g, and those in sputum and in serum at 2 hours were 0.71 +/- 0.63 and 2.08 +/- 1.01 micrograms/ml, respectively. A very strong correlation was demonstrated between the level of LVFX in lung tissue and that in serum (p < 0.0001), but correlation between those in sputum and in serum was not significant. The penetration ratio of LVFX into lung tissue was 217.2% and that into sputum was 4.05%. Based on the results of this study, the breakpoints (BPs) of LVFX for pneumonia and chronic respiratory tract infections were calculated to be 4 micrograms/ml and 1 microgram/ml, respectively. It was concluded that penetration of LVFX into lung tissue was satisfactory, and the tissue level of LVFX exceeded greatly the MIC90s against the typical pathogenic bacteria of respiratory tract infections. Taking the excellent BP for pneumonia, 4 micrograms/ml, into consideration, it was thought that LVFX is an effective antibacterial agent against pneumonia and other respiratory tract infections.

An investigation was made on the concentration of levofloxacin (LVFX) in cervical mucus and its clinical effects on cervicitis. The results were as follows: 1) The concentrations of orally administered LVFX in the cervical mucus of 110 subjects were determined by HPLC. During 1-4 hour after the administration the mean concentration of LVFX in the cervical mucus reached a level of 2 micrograms/g, which was higher than the serum level. The transfer of LVFX to the cervical mucus was almost the same as that to other genital organs. 2) When LVFX was given to 102 patients at a dose of 100-200 mg, t.i.d for 4-5 days and the efficacy was evaluated with clinical improvement, the clinical efficacy rate of LVFX was 72/102 (70.6%). Significant bacteriological effects were observed in 70/73 (95.9%), especially, the disappearance rate of C. trachomatis was 18/18 (100%). 3) The administration LVFX did not cause any subjective or objective side effects and any abnormalities were not detected in the laboratory test done in this study. These results demonstrate that LVFX can be sufficiently transferred to the cervical mucus for the treatment of cervicitis due to the infection of C. trachomatis etc.

The ofloxacin (OFLX) concentration in serum, saliva and pleural effusion was measured in 12 patients with pleural effusion after oral administration at a dose of 200 mg three times a day (600 mg daily). Three patients had non-small cell lung cancer and the others had pulmonary tuberculosis. The mean OFLX levels in the serum, saliva and pleural effusion at 2 hours after the first administration on day 3 was 3.15 +/- 1.52, 3.36 +/- 2.23 and 2.86 +/- 1.77 micrograms/ml respectively. There was a strong correlation among these concentrations. The OFLX concentration of pleural effusion was predictable from that of saliva. A 3-day oral administration is sufficient to achieve the OFLX level of pleural effusion similar to that of the serum. It is possible that OFLX is effective for pleuritis caused not only by common infectious pathogens but also by Mycobacterium tuberculosis.

The mechanism of the renal excretion of T-3761, a novel oral fluoroquinolone agent, was studied by renal clearance, stop-flow techniques and analyzing the pharmacokinetics with and without probenecid in rabbits, and which were compared with those of ofloxacin (OFLX). In rabbits probenecid treatment induced increases in the elimination half-life (2.1 times higher) and area under the serum concentration-time curve (3.1 times), and decreases in elimination rate constant (0.44 times) and total body clearance (0.35 times), while volume of distribution showed no significant change. In the stop-flow pattern, a specific peak of T-3761 was observed. On the other hand, a peak of OFLX was observed at the peak of PAH and a small trough at the trough of sodium. And the renal clearance of T-3761 and OFLX were about 4.9 and 3.3 times higher than the corresponding Clcr, respectively. These results suggested that T-3761 was excreted into urine by both glomerular filtration and renal tubular secretion, and was scarcely reabsorbed at distal tubule. The short elimination half-life of T-3761 might be explained by its great ratio of tubular excretion.

The affinity of T-3761 to melanin was examined with synthetic melanin comparing other quinolones. The binding rates with synthetic melanin were from 37% to 48% for tosufloxacin, sparfloxacin, ciprofloxacin and norfloxacin. Binding rate of ofloxacin at 28% was lower and T-3761 was lowest at 22%. Intraocular dynamics of T-3761 and ofloxacin were investigated in pigmented rabbits after a single oral administration at a dose of 20 mg/kg. In both drugs, the concentrations in the melanin bearing tissues were higher and the disappearances from the melanin bearing tissues were more slowly than those of the non-melanin bearing tissues. T-3761 concentrations in the melanin bearing tissues were significantly lower than ofloxacin. In vitro uptake amount to melanin bearing tissue of ofloxacin was 1.4-2.4 times larger than that of T-3761.

Bactericidal activities of isepamicin and ofloxacin against Pseudomonas aeruginosa E7 were examined using an in vitro computer programmed pharmacokinetic simulation system. Concentration of the drugs simulated the pharmacokinetic data obtained in healthy human adult subjects after 200 mg or 400 mg I.M. administration of isepamicin (ISP), and 300 mg P.O. administration of ofloxacin (OFLX). P. aeruginosa cell counts were depressed by ISP or OFLX to -4 log -(-)5 log levels of magnitude below the initial cell counts. The time required in recovery of cell counts to the initial level after treatment with ISP (200 mg) was longer than that after OFLX (300 mg) treatment. An excellent synergistic effect was observed between ISP and OFLX.

1. Minimum inhibitory concentrations (MICs) of levofloxacin (LVFX, DR-3355), ofloxacin (OFLX), tosufloxacin (TFLX), norfloxacin (NFLX) were determined, with an inoculum size of 10(6) cfu/ml, against 122 strains of Staphylococcus aureus isolated from lesions of skin infections. LVFX showed most frequent MIC values of 0.20 micrograms/ml. OFLX, TFLX, and NFLX showed most frequent MIC values of 0.39 micrograms/ml, less than or equal to 0.05 micrograms/ml and 0.78 micrograms/ml, respectively. 2. Serum and skin levels of LVFX after oral administration (10 mg/kg, fasting) were determined in rats. Serum levels were 1.79, 1.29, 0.60, 0.43 and 0.18 micrograms/ml, and corresponding skin levels were 1.63, 1.77, 1.04, 0.87 and 0.64 micrograms/g (wet weight) at 0.5, 1, 2, 4 and 8 hours after administration (n = 5), respectively. 3. LVFX was used clinically in 43 cases at doses of 200-300 mg divided into 2 or 3 doses, and evaluated for final overall clinical efficacy in 41 cases. Cure was observed in 21 cases, remarkable improvement in 13 cases, improvement in 4 cases, unchanged in 1 case, aggravation in 1 case, and remarkable aggravation in 1 case. Diarrhea was observed in 2 cases, diffuse erythema with feverishness in 1 case and slight dyspnea in 1 case. Transient slight eosinophilia, elevation of Al-P, anemia and leukopenia were observed.

Sputum penetration of levofloxacin (LVFX) was evaluated after a single oral dose of 100 mg or 200 mg to 4 patients with copious purulent sputa. The sputum concentration of LVFX reached maximum levels of 1.27 and 4.36 micrograms/ml at 4 hours, and still remained at concentrations of 0.32 and 1.68 micrograms/ml at 8 hours after administration of 100 mg and 200 mg, respectively. The AUC ratio of sputum/serum was 0.9-1.0, indicating good sputum penetration of LVFX in these patients. The clinical efficacy and the safety of LVFX were also evaluated in a total of 13 patients with respiratory tract infections associated with bronchiectasis, diffuse panbronchiolitis, etc. LVFX was administered orally at a daily dose of 200 mg once a day, 100 mg t.i.d. or 200 mg t.i.d. for 7-28 days (mean 14.7 days). The clinical response to the drug was rated as excellent in 1 case, good in 5, fair in 3, and poor in 2 cases in 11 evaluable cases, thus the efficacy rate was 54.5%. All the 3 strains of Haemophilus influenzae were eradicated. Of the 3 strains of Pseudomonas aeruginosa, eradication, decrease, and unchange was observed for 1 strain each. One strain of Streptococcus pneumoniae remained unchanged. No adverse reaction was observed except for 1 case with slight and temporary increase of eosinophils. The above results suggested that LVFX would be clinically useful in the treatment of chronic lower respiratory tract infections.

Evaluations were made on biliary excretion and penetration into the gallbladder tissue of levofloxacin (LVFX, DR-3355), a new quinolone antibacterial agent, and its clinical efficacy in biliary tract infections. 1. Gallbladder tissue concentrations and biliary concentrations of LVFX at 2-6 hours at oral administration of 100 mg were 0.58-1.99 micrograms/g and 0.49-5.63 micrograms/ml, respectively. These tissue and biliary levels are almost equal or somewhat higher than the serum levels (0.55-1.63 micrograms/ml) of the compound. 2. The concentrations of LVFX and optical isomer DR-3354 in the serum, gallbladder tissue, and bile were determined after a single or a concomitant administration of LVFX 100 mg and/or ofloxacin (OFLX) 100 to 200 mg. The concentration ratio of LVFX to DR-3354 paralleled with the ratio of the 2 compounds administrated. 3. At a dose of 100 mg, the glucuronide of LVFX in the common duct bile was detected at proportions between 0.9 and 36.0%. 4. A total of 11 patients with biliary tract infections, including 6 cholecystitis 3 cholangitis, and 1 each of cholecystocholangitis and liver abscess was treated with LVFX at 100-200 mg t.i.d. for 3-14 days. Clinical results were excellent or good in 8 cases and fair in 3 cases, resulting in an efficacy rate of 72.7%. 5. A side effect and an abnormal change in laboratory findings were observed in both 1 case each and they were both mild. It was concluded that LVFX showed good penetration to the biliary tract as does OFLX, and that it would be a useful oral agent for the treatment of biliary tract infections.

We studied a newly developed oral quinolone antimicrobial agent, levofloxacin (LVFX, DR-3355), and obtained the following results. 1. Serum and urine levels of LVFX were determined after oral administration of LVFX 100 mg to 11 elderly patients with various degrees of renal function insufficiencies. The patients were classified according to creatinine clearance (Ccr) values into Group I (n = 1, Ccr greater than or equal to 70 ml/min), Group II (n = 4, 40 less than or equal to Ccr less than 70 ml/min), and Group III (n = 6, Ccr less than 40 ml/min). The peak levels of LVFX did not differ greatly among the 3 groups, but in patients with severely impaired renal functions, serum concentrations decreased more slowly than in those with slightly and moderately impaired renal functions, and high serum levels were maintained over a long period. Urinary excretion of LVFX diminished in relation to degrees of renal failure. 2. LVFX was administered to treat 13 elderly patients with respiratory tract infections. Clinical responses were good in all patients with a high efficacy rate of 100%. Laboratory tests revealed eosinophilia in 1 case. The symptom was mild, however, and no severe side effects due to the drug were observed.

The penetration into bile of a new pyridonecarboxylic acid derivative, levofloxacin (LVFX), was studied in a closs-over method with ofloxacin (OFLX) as the control drug in 6 post-operative patients. The lengths of time to the maximum concentrations in bile and the total areas under the curves were both almost the same for these 2 compounds, although the maximum bile concentration of LVFX was slightly lower than that of OFLX. A stability test for LVFX in human bile revealed that over 95.4% of the initial amount was recovered up to 24 hours after commencement of incubation at a room temperature, thus the stability in bile was similar to that in water. The penetration of LVFX which possesses twice as strong antibacterial activities as OFLX was similar to that of OFLX, suggesting that LVFX is useful against bile duct infections.

A newly developed broad-spectrum fluoroquinolone, levofloxacin (LVFX, DR-3355), was evaluated in vitro and in vivo in comparison with ciprofloxacin (CPFX), ofloxacin (OFLX) and norfloxacin (NFLX). The results were as follows. 1. Antimicrobial activity Minimal inhibitory concentrations (MICs) against 480 clinical isolates including 16 different species were determined using the microbroth dilution method. LVFX showed excellent antimicrobial activities against Gram-positive and -negative bacteria. The MIC values of LVFX for Gram-positive bacteria were superior to those of the other quinolones tested. The MIC values of LVFX for Gram-negative bacteria were comparable to those of CPFX and superior to those of OFLX and NFLX. 2. LVFX concentrations in serum and sputum LVFX was orally administered in a single dose of 200 mg to 2 patients with chronic lower respiratory tract infections, and its concentrations in serum and sputum were measured at intervals using bioassay. The peak concentrations of LVFX in serum were 1.52 and 1.24 micrograms/ml, and 84-95% of serum level were detected in sputum. From these data, it appeared that LVFX penetrate well into the lung. 3. Clinical efficacy and adverse reactions Fifteen patients with respiratory tract infections were treated with LVFX, and the overall efficacy rate was 78.6% (excellent in 3 cases, good in 8, fair in 3, poor in 0). As adverse reactions, anorexia was observed in 2 cases, diarrhea in 1 case and tremor of finger in 1 case. Although an elevation of total bilirubin in serum was observed in a case as an abnormal laboratory finding, it was mild, transient and improved rapidly after the completion of LVFX treatment.

Levofloxacin (LVFX, DR-3355) a new synthetic antibacterial agent, was evaluated pharmacokinetic and clinically in the field of obstetrics and gynecology and the following results were obtained. 1. The transport of LVFX into genital tissues (various regions in the uterus, ovary and oviduct) after a single oral administration of 200 mg was found to be good. 2. Sixteen patients with genital infections (endometritis, salpingitis, cervicitis, mastitis) were treated with LVFX at daily doses of 200-300 mg for 5-15 days. The efficacy rate was 100% and no side effect was observed.

Levofloxacin (LVFX, DR-3355), a new synthetic quinolone derivative antibacterial agent, was evaluated for its pharmacokinetics and clinical efficacy in obstetric and gynecological infections, and the following results were obtained. Concentrations of LVFX in serum and intrapelvic genital organs such as uterine and adnexal tissues were determined following oral administration of 100 mg. Tissue penetration of LVFX was found to be good, with its tissue levels (Cmax) of 1.17-2.16 micrograms/ml or g after inhalation anaesthesia and 1.15-2.17 micrograms/ml or g after lumbar spinal anaesthesia. LVFX was given to 22 cases of obstetric and gynecological infections with a daily dose of 200-600 mg for 3-14 days and its clinical efficacy was 95% and bacteriological response was 100%. No side effect was observed. From these findings, we consider that LVFX will be a useful antibacterial agent against obstetric and gynecological infections.

We performed a fundamental study on levofloxacin (LVFX, DR-3355), a new synthetic antimicrobial agent, in the field of obstetrics and gynecology. Concentrations in serum and intrapelvic genital organs (various regions in the uterus, ovary and oviduct) were determined following single oral administration. The transport of LVFX into genital tissues was found to be good, with the tissue levels of 0.64-2.13 micrograms/g after oral administration of 100 mg and 0.77-4.86 micrograms/g after administration of 200 mg. These tissue levels of LVFX were higher than those in serum and exceeded the MIC90 values against most causative organisms isolated from the lesions of obstetric and gynecological infections. These data indicate that LVFX should be useful in the field of obstetrics and gynecology.

Concentrations of levofloxacin (LVFX, DR-3355), optically active (-)-ofloxacin, in the gall-bladder tissue and bile were determined in patients, and the results were as follows: 1. A single dose of LVFX (100 mg) was administered orally to 6 patients with cholelithiasis about 2 to 3 hours before operation. The range in the gallbladder tissues was 0.34 to 1.59 micrograms/g, while the range in sera was 0.20 to 1.05 micrograms/ml. The ranges in the adipose tissues, gallbladder bile, and common duct bile were 0.07 to 0.26 micrograms/g, 1.8 to 12.2 micrograms/ml, and 1.4 to 5.8 micrograms/ml, respectively. 2. A single dose of LVFX (100 mg) was administered orally to 5 patients with indwelling T-tube. Concentrations of LVFX in excreted bile samples were 1.2 to 2.4 micrograms/ml, 1.3 to 3.5 micrograms/ml, and 1.3 to 2.4 micrograms/ml at 2 to 4, 4 to 6, and 6 to 12 hours after administration, respectively. Therefore, it appears that LVFX may be effective in biliary tract infections, because of its sustained high concentrations in biliary system.

The pharmacokinetics and clinical efficacy of levofloxacin (LVFX, DR-3355), an optically pure S(-)-enantiomer of ofloxacin, were studied in patients after surgery. In the pharmacokinetic study, 4 patients undergoing bile drainage were given 2 100-mg tablets by mouth. Peak levels of LVFX were from 2.22 to 4.02 micrograms/ml of plasma at 2-4 hours after the oral administration, and from 7.5 to 11.3 micrograms/ml of bile at 2-6 hours. Forty-three patients with surgical infections, including 16 skin and soft-tissue infections and 12 wound infections, were treated with LVFX. Twenty-eight (70%) of the 40 patients whose results could be evaluated had excellent or good results; 42 (93%) of the 45 causative organisms identified were eradicated. An episode of diarrhea with chills and fever occurred in a 38-year-old man. The results suggested that LVFX has satisfactory antimicrobial effects in surgical infections.

We studied the intraocular penetration of DR-3355, a new quinolone derivative in white mature rabbits. DR-3355 concentration in the aqueous humor reached the maximum, 1.06 micrograms/ml, at 2 hours after oral administration of 20 mg/kg in single dose. Six hours after it was 0.37 micrograms/ml. At 2 hours, the concentration ratio in the aqueous humor and serum was 23.3%. The pharmacokinetic parameters of DR-3355 levels in both of the aqueous humor and serum were: Cmax, 1.02 micrograms/ml and 4.56 micrograms/ml; Tmax, 1.42 hours and 1.47 hours; T 1/2, 0.96 hours and 1.57 hours; and AUC, 3.91 micrograms.hr/ml and 19.70 micrograms.hr/ml, respectively. At 2 hours after oral administration, the ocular tissue concentrations were 3.84-16.10 micrograms/g in the outer parts of the eye, and 0.70-13.52 micrograms/g or ml in the inner parts of the eye. Those concentrations decreased to about 1/2 to 1/32 in the outer parts, and 1/2 to 1/7 in the inner parts of the eye at 6 hours. Those ocular tissue concentrations of DR-3355 exceeded the MIC90 of the compound against various bacteria of ocular pathogens, such as Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae and Serratia marcescens.

We previously reported a study on the antimicrobial action of a chemically synthesized drug, ofloxacin (OFLX) and on its transfer in. This paper describes the results of our clinical study on OFLX. 1. Only small fractions of intra-blood OFLX were transported into female organs such as uterus, ovary and fallopian tube. Our study with the normal delivery method shows that umbilical cord blood concentrations of OFLX is a third to a sixth of maternal blood concentrations and is achieved through trans-placental transfer. Its transfer into amniotic fluid, however, is very low. 2. Forty-one cases, including cases of female intrapelvic inflammation, urinary tract infection, puerperal mastitis, etc., were administered with OFLX at levels of 200 approximately 400 mg/day for 3 approximately 10 days. OFLX were found to be effective in 35 cases. 3. We observed 113 cases to which OFLX was administered, and found only 4 cases of gastrointestinal disturbance and 1 case of suspicion of drug eruption as side effects. Laboratory tests showed no abnormalities due to OFLX in blood, serum biochemical or urine value in the cases examined (26 to 51 cases depending on test).