Following oral administration of levofloxacin (LVFX,(S)-(-)-0floxacin; formerly designated as DR-3355) at 200 mg per dose 3 times a day for 7 days to 6 healthy male volunteers, degrees of disturbance of the fecal microflora and fecal drug concentrations were examined.
The total viable count remained unchanged during the study period due to the minimal change in the number of members of the family Bacteroidaceae, the most predominant organisms. Most of the aerobes including facultative anaerobes were suppressed by LVFX with only a slight increase in yeasts. In particular, the members of the family Enterobacteriaceae were reduced to below the detection limit on and after day 3 through the time of discontinuation of the drug in all subjects but one. Among the obligate anaerobes, peptostreptococci and bifidobacteria decreased or disappeared in some volunteers, but no significant changes were observed in other anaerobes. Neither Clostridium difficile nor its toxin D-1 was detected in any of the volunteers. No side effects attributable to the drug were observed. During administration, LVFX was detected in the feces at high concentrations which correlated well with the decrease of susceptible members of flora as well as to their detection rate.

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Concentrations of levofloxacin (LVFX, DR-3355), optically active (-)-ofloxacin, in the gallbladder tissue and bile were determined in patients, and the results were as follows:
1. A single dose of LVFX (100mg) was administered orally to 6 patients with colelithiasis about 2 to 3 hours before operation. The range in the gallbladder tissues was 0.34 to 1.59μg/g, while the range in sera was 0.20 to 1.05μg/ml. The ranges in the adipose tissues, gallbladder bile, and common duct bile were 0.07 to 0.26μg/g, 1.8 to 12.2μg/ml, and 1.4 to 5.8μg/ml, respectively.
2. A single dose of LVFX (100mg) was administered orally to 5 patients with indwelling T-tube. Concentrations of LVFX in excreted bile samples were 1.2 to 2.4μg/ml, 1.3 to 3.5μg/ml, and 1.3 to 2.4μg/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.

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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 4.02μg/ml of plasma at 2-4 hours after the oral administration, and from 7.5 to 11.3μg/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-eitght (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.

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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 0.64-2.13μg/g after oral administration of 100mg and 0.77-4.86μg/g after administration of 200mg.
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.

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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 100mg. Tissue penetration of LVFX was found to be good, with its tissue levels (C_max) of 1.17-2.16μg/ml or g after inhalation anaesthesia and 1.15-2.17μg/ml or g after lumbar spimal anaesthesia.
LVFX was given to 22 cases of obstetric and gynecological infections with a daily dose of 200-600mg 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.

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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 200mg was found to be good.
2. Sixteen patients with genital infections (endometritis, salpingitis, cervicitis, mastitis) were treated with LVFX at daily doses of 200-300mg for 5-15 days. The efficacy rate was 100% and no side effect was observed.

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Pharmacokinetic, bacteriological and clinical studies were performed on panipenem/betamipron (PAPM/BP) in children.
The results are summarized as follow:
1. Twelve patients with various bacterial infectious diseases were treated with PAPM/BP. Each dose was 20mg/20mg/kg, administered 3 times daily, in 30-minute intravenous drip infusion. Treatments were continued for 5-22 days. Clinical efficacies of PAPM/BP in 12 patients with bacterial infections (1 with suspected sepsis, 5 with pneumonia, 1 with acute maxillary sinusitis, 2 with acute otitis media, 1 with cervical abscess and 2 with urinary tract infection complexed type) were evaluated as excellent in 7, good in 4 and fair in 1, with an efficacy rate of 91.7%. Seventeen causative organisms found in 10 patients (Haemophilus influenzae in 4, Branhamella catarrhalis in 3, Streptococcus pneumoniaein 2, Pseudomonas aeruginosa in 2, Staphylococcus aureus in 1, α-Streptococcus in 1, Corynebacterium sp. in 1, Peptostreptococcus micros in 1 and Klebsiella pneumoniae in 2) were eradicated except 2 strains (S. aureus and P. aeruginosa) from 1 patient (patient No.2). No adverse reactions were observed in any of the 12 patients.
2. MICs of PAPM were examined against 22 clinical isolates (H. influenzae 5, B. catarrhalis 3, α-Streptococcus 3, S. pneumoniae 2, Corynebacterium sp. 2, S. aureus 1, P. aeruginosa 1, P. micros 1, Enterobacter cloacae 1, Escherichia coli 1, Group D Streptococcus 1 and Staphylococcus epidermidis 1) from children with bacterial infections. PAPM showed a good antibacterial activity comparable to the activity of cefoperazone (CPZ) against S. pneumoniae strains relatively tolerant to penicillins. However, the activity of PAPM against H. influenzae was somewhat weaker than that of CPZ.
3. Pharmacokinetic studies. The peak of plasma concentrations of PAPM and BP were 53.39μg/ml (29.04-86.90μg/ml) and 29.91μg/ml (14.28-57.44μg/ml), respectively, at dose of 20mg/20mg/kg administered using a 30-minute intravenous drip infusion. Over a period of 8 hours, the urinary excretions of PAPM and BP were 30.65% (13.3-49.8%) and 74.73% (67.4-78.9%) of the dose administered, respectively.
Plasma half-lives of PAPM and BP in the β-phase were 0.97 hour (0.77-1.15 hours) and 0.61 hour (0.39-0.92 hour), respectively.
Based on the above results and the extremely broad spectrum of antibacterial activities of PAPM/BP, PAPM/BP may be a promising antibiotic which is suitable as a single agent for the primary therapy of severe infections in children and immunocompromized hosts. However, additional investigations in dosage pattern for purulent meningitis due to H. influenzae may be required.

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Panipenem/betamipron (PAPM/BP), a new injectable carbapenem antibiotic, was evaluated for its safety and efficacy in children. Ninety three parcentage (14 in 15 cases) of various infections were cured with PAPM/BP therapy.
Transient skin rash occurred in 1 case, probably due to the histamin-like effect of PAPM/BP. The plasma half life of panipenem was 0.85 ±0.07 hours. PAPM/BP was evaluated to be a less-epileptogenic carbapenem antibiotic.

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Pharmacokinetic and clinical evaluation of panipenem/betamipron (PAPM/BP) were carried out in pediatric patients.
The following results were obtained:
1. Upon 30-minute intravenous drip infusion at a dose of 20 mg/kg, plasma concentrations of PAPM/BP reached their peaks at the end of drip infusion with average values of 62.94/47.32μg/ml, and their plasma half-lives were 1.00/0.51 hour in the β-phase. Upon 30-minute intravenous drip infusion at a dose of 10mg/kg, peak plasma concentrations were 32.10/23.76μg/ml and plasma half-lives were 0.93/0.59 hour.
2. The urinary excretion rates of PAPM/BP after 30-minute intravenous infusion at doses of 20 and 10mg/kg were 25.09/81.04% and 32.14/84.66%, respectively.
3. PAPM/BP was administered to 18 cases (upper and lower respiratory tract infections, pneumonia and urinary tract infections) at daily doses of 30-88.9mg/kg/day divided into 3 dosages using 30-minute intravenous drip infusion. Clinical responses were “excellent” in 12 patients,“good” in 5, and “poor” in 1, hence an efficacy rate of 94.4% was obtained.
4. Bacteria identified from various diseases involved 11 strains of 6 species, and the eradication rate was 90.9%.
5. No side effect was recognized in any patient. Laboratory test results showed abnormalities in including 1 case with leukopenia, and in 2 cases with elevation of GOT and GPT.

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We carried out bacteriological and clinical studies of panipenem/betamipron (PAPM/BP), a newly-developed carbapenem antibiotic, in pediatrics, and the following results were obtained:
1. When antibacterial activities of panipenem (PAPM) were determined, it was found that MICs against such Gram-positive cocci as Staphylococcus aureus and Streptococcus pneumoniae and against such Gram-negative rods as Escherichia coli, Haemophilus influenzae, Pseudomonas aeruginosa, and Branhamella catarrhalis were all sufficiently low.
2. PAPM showed better MIC-correlated antibacterial activities against 215 subcultured strains of methicillin-resistant S. aureus (MRSA) than imipenem.
3. Clinical efficacies were evaluated to be excellent in 23 of 34 patients treated with PAPM/BP, excluding 3 patients from the efficacy evaluation. In addition, good responses were obtained in 10 patients but poor response in one, showing the overall efficacy rate of 97.1%. As for bacteriological efficacies, the eradication rate was also determined to be high, 92.6%.
4. As for side effects, rash appeared in 2 patients, and soft stool and diarrhea occurred in one each. The overall incidence of side effects was calculated to be 10.8%. As for abnormal laboratory findings, increases of eosinophiles in 4 patients, thrombocytes in 2, total bilirubin in 1, and GOT in 1 were observed.
From these results, PAPM/BP was thought to be a highly useful drug in pediatrics.

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Panipenem/betamipron (PAPM/BP), one of the carbapenems, was studied for its absorption and excretion, and clinical efficacy. The following is a summary of the results:
1. Absorption and excretion Fourteen patients with their ages between 2 years and 14 years were administered with PAPM/BP 10mg/kg, 20mg/kg or 30mg/kg, in 30-minute intravenous drip infusion. Maximam serum levels of PAPM, at dose levels of 10mg/10mg/kg, 20mg/20mg/kg and 30mg/30mg/kg of PAPM/BP, were 27.37μg/ml, 59.3μg/ml, 91.7μg/ml, respectively, at the end of infusion. The half-lives of the 3 dose levels were all within 0.90-0.96 hour. Mean peak serum levels of BP, at dose levels of 10mg/10mg/kg, 20mg/20mg/kg and 30mg/30mg/kg, were 21.77μg/ml, 35.29μg/ml, 50.08μg/ml, respectively, with half-lives of 0.55-0.63 hour.
Urinary recovery rates of PAPM in the first 8 hours after administration at dose levels of 10mg/10mg/kg, 20 mg/20mg/kg and 30mg/30mg/kg, were 15.9-31.1%, 15.3-36.9%, 11.0-40.5%, respectively, and those of BP during the same time were 33.1-79.1%, 41.3-93.4%, 12.9-94.4%, respectively.
2. Clinical results
Thirty-nine patients, including 2 with purulent meningitis, 1 with septicemia (suspect), 18 with acute pneumonia, 5 with bronchiolitis, 2 with tonsillitis (unable to receive oral antibiotics), 3 with cervical purulent lymphadenitis, 2 with bacterial enteritis, 6 with urinary tract infections were treated with PAPM/BP at dose levels of 30-100 mg/kg/day. Clinical responses in all the patients were excellent or good. Even 2 patients with purulent meningitis were treated with PAPM/BP at dose levels of no less than 20mg/kg×3 and 33mg/kg×3. Most of respiratory and urinary tract infection cases of moderate severities were treated at dose levels of 30-60mg/kg/day, i.e., 10mg/kg×3 or 20mg/kg×3.
No adverse reaction was observed. One patient suffered from frequent watery diarrhea but the drug was continued to be administered and the patient recovered quickly. Abnormal laboratory findings were noted, in 2 cases with elevation of platelet, in 1 case with elevation of GOT, in 1 case with elevation of monocyte, in 1 with eosinophilia, in 1 with eosinophilia and decrease in platelet count, in 1 with eosinophilia and elevation of GOT and in 2 with elevation of GOT and GPT, but these abnormalities in the 9 cases were slight and transient.

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