Broad-spectrum antibacterial agent.
Ofloxacin is a broad-spectrum antibacterial agent of pyridonecarboxylic acid derivative originated in Daiichi Pharmaceutical Co., Ltd. It shows more potent antibacterial activities against gram-negative bacteria eg, E. coli, K. pneumoniae, Serratia
spp, P. aeruginosa
and H. influenzae
than other formerly developed derivatives of pyridonecarboxylic acid. Moreover, it has antibacterial activities against gram-positive bacteria eg, Staphylococcus
sp, hemolytic streptococci and enterococci.
Tarivid, which is transferred rapidly to each tissue in high concentrations without accumulation, is mostly excreted in the urine almost unchanged. Tarivid also shows good effects clinically on respiratory tract, genital-urinary tract, biliary tract and enteric tract infections; and other various infections in the dermatological, otorhinolaryngological and ophthalmological fields.
Mechanism of Action:
Tarivid, which is considered to specifically inhibit DNA synthesis in microorganism, is bactericidal, and causes bacteriolysis at minimum inhibitory concentration (MIC).
Pharmacology: Pharmacokinetics: Absorption:
The serum concentration of Tarivid increases dose-dependently when orally administered to healthy adults in a single dose.
When Tarivid was administered orally after meals at doses of 100, 200 and 300 mg the maximal serum levels (1, 1.65 and 2.8 mcg/mL, respectively) were reached 2 or 3 hrs after administration. Its biological half-life at each dose was 3.6, 4.5 and 5.5 hrs, respectively. (See figure.)
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When ofloxacin was administered to healthy adults or patients in a single dose of 200 mg, the drug transferred to the following tissues in high concentrations: Skin (2.24 mcg/g 2 hrs later), tonsil (4.58 mcg/g approximately 1 hr later), sputum (3.08 mcg/mL 1 hr later), prostate (6.25 mcg/g 2 hrs later), prostatic fluid (1.66 mcg/mL 2 hrs later), bile (2.57 mcg/mL 4 hrs later), gallbladder (2.3 mcg/g 4 hrs later), tears (1.36 mcg/mL 2 hrs later), otorrhea, maxillary sinus mucosa and saliva (2.51 mcg/mL 2 hrs after administration at a dose of 300 mg). The drug passed into milk as well.
Metabolism and Excretion:
The urinary concentration increases dose-dependently when orally administered to healthy adults in a single dose. Following administration of 100 mg, the urinary concentration peaked at 115 mcg/mL within 2-4 hrs and declined to 36 mcg/mL within 12-24 hrs after administration. The majority of the drug is not metabolized in the body. More than 90% of the administered dose is excreted in urine as an unchanged form and approximately 4% in feces by 48 hrs after administration. In subjects given Tarivid orally in a single dose of 200 mg, the cumulative urinary excretion rates during the first 12 hrs after administration were 74% in the subjects with normal renal function (CrCl≥70), 43% in those in the middle level of renal insufficiency (50>CrCl≥30), and 20% in those in the severe stage of renal insufficiency (CrCl<30), demonstrating the decreasing urinary excretion rates relative to the decreasing renal function.
Clinical Studies: Clinical Efficacy:
The results of the clinical trials carried out in Japan in 3701 cases of various infections of each field and those of the double-blind comparative tests with 1084 cases in the 8 fields are summarized in the following: Respiratory Tract Infections:
Clinical efficacy rate was 80.7% (668/828) in patients with respiratory tract infections eg, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis with infection, diffuse panbronchiolitis, secondary infections of chronic respiratory diseases and pneumonia. The main causative organisms were Staphylococcus
spp, S. pneumoniae, K. pneumoniae, P. aeruginosa
and H. influenzae
. Most of the patients received a daily dose of 300-600 mg. Moreover, usefulness of the drug in acute lacunar tonsillitis, in chronic respiratory tract infections and pneumonia, and in bronchitis were confirmed by respective double-blind comparative studies.
Urinary Tract Infections:
Clinical efficacy rate was 85.6% (1339/1564) in patients with urinary tract infections eg, pyelonephritis, cystitis, prostatitis, gonococcal and non-gonococcal urethritis. The main causative organisms were Staphylococcus
sp, S. faecalis, E. coli, Citrobacter
sp, K. pneumoniae, Enterobacter
spp, P. aeruginosa
and N. gonorrhoeae
. Most of the patients received a daily dose of either 300 or 400 mg. Moreover, usefulness of the drug in acute simple cystitis and in complicated urinary tract infections has been confirmed by respective double-blind comparative studies.
Soft Skin Tissue Infections:
Clinical efficacy rate was 85.7% (323/377) in patients with soft skin tissue infections eg, folliculitis, furuncle, phlegmon, felon, SC abscess and infectious atheroma. The main causative organism was Staphylococcus
sp. Most of the patients received a daily dose of 300 mg. Moreover, usefulness of the drug in these infections has been confirmed by a double-blind comparative study.
Infections in the Field of Surgery and Orthopedics:
Clinical efficacy rate was 75.8% (72/95) in patients with surgical and orthopedical infections eg, secondary infections of trauma, burns and surgical trauma. The main causative organism was Staphylococcus
sp. Most of the patients received a daily dose of either 300 or 400 mg.
Biliary Tract Infections:
Clinical efficacy rate was 73.9% (68/92) in patients with biliary tract infections eg, cholecystitis and cholangitis. The main causative organisms were E. coli, K. pneumoniae
sp. Most of the patients received a daily dose of either 300 or 600 mg.
Infections in the Field of Otorhinolaryngology:
Clinical efficacy rate was 71.7% (76/106) in patients with otorhinolaryngological infections eg, otitis media and sinusitis. The main causative organism was Staphylococcus
sp. Most of the patients received a daily dose of 600 mg. Moreover, usefulness of the drug in otitis media has been confirmed by a double-blind comparative study.
Infections in the Field of Ophthalmology:
Clinical efficacy rate was 94.6% (141/149) in patients with ophthalmological infections eg, hordeolum, dacryocystitis, tarsadenitis and keratohelcosis. The main causative organism was Staphylococcus
sp. Most of the patients received a daily dose of 400 mg.
Clinical efficacy rate was 99.1% (107/108) in patients with infectious enteritis eg, bacillary dysentery and colitis. The main causative organisms were Shigella
spp. Most of the patients received a daily dose of either 400 or 600 mg. Moreover, usefulness of the drug in these infections has been confirmed by a double-blind comparative study.
Adverse Reactions and Abnormal Laboratory Findings:
A total of 4785 cases were treated with Tarivid and adverse reactions were observed in 198 cases (4.1%). The major adverse reactions were gastrointestinal system disorders (131 cases; 2.7%) eg, nausea/vomiting, stomach/abdominal discomfort and diarrhea/soft stool, disorder in the central nervous system (CNS) (35 cases; 0.7%) eg, insomnia and dizziness and hypersensitivity (29 cases; 0.6%) eg, eruption. The major abnormalities observed in the laboratory findings were elevation in S-GOT (2.2%; 58/2678), S-GPT (2.4%; 64/2625), BUN (0.9%; 23/2442), and eosinophiles (1.9%; 35/1811) and decrease in leucocytes (0.5%; 15/2799).
Toxicology: Preclinical Studies: Absorption and Distribution: 14
C-Ofloxacin, when administered orally to rats at a dose of 20 mg/kg, was absorbed primarily from the small intestine, and the maximum tissue concentrations were reached 2 hrs after administration. Except for the levels in the central nervous system, the drug concentrations in all tissues of the body were higher than the blood level (2.59 mcg/mL), demonstrating the ready transference to tissues. Regarding the drug concentrations in the main organs, the maximal level of 14 mcg/g in the kidney was followed by 8.2 mcg/g in the liver and 3.3 mcg/g in the lung.
values after oral administration were 5450 mg/kg in mice, 3590 mg/kg in rats, >200 mg/kg in dogs and 500-1000 mg/kg in monkeys.
Following 4-week administration to rats, no changes were observed up to 90 mg/kg in general condition, hematology, urinalysis and histology. At a dose of ≥270 mg/kg, rats showed roughened fur, soft stool and depression of body weight gain. In addition to these changes, rare fraction of articular cartilage matrix was observed in rats given 810 mg/kg. When dogs were orally administered for 4 weeks, no noticeable changes were observed at a dose of 12.5 mg/kg. However, at 50 and 200 mg/kg, vomiting, salivation and blister or erosion of the articular cartilage were observed.
Following 6-month administration to rats, no noticeable changes were observed up to 30 mg/kg. At 90 and 270 mg/kg, salivation, soft stool, enhancement of spontaneous lesions in the cartilage and enhancement of lipid deposition in cortical cells of the adrenal glands were observed.
Reproductive Studies: Fertility Study:
No effects were observed on fertility of both sexes and on the fetuses after administration of 360 mg/kg to rats.
In rats, growth retardation in the fetuses at not <90 mg/kg and skeletal variations in the fetuses at a dose of 810 mg/kg were observed. However, no teratogenesis was observed up to 810 mg/kg. In rabbits, no teratogenesis was observed up to 160 mg/kg.
Perinatal and Postnatal Study:
No effects were observed in the female parturition and on the pups after administration of 360 mg/kg to rats.
No antigenicity was suggested from the systemic anaphylaxis test, PCA reaction, hemagglutination reaction and precipitation reactions in rat, from the PCA reaction and hemagglutination reaction in rabbits and from the detection test of specific IgE antibodies in mice.
The sister chromatid exchange test, unscheduled DNA synthesis test, reverse mutation test, chromosomal abberation test (in vitro
and in vivo
), micronucleus test and dominant lethal test showed no mutagenic potential of the drug.
Effects on Kidney:
Following oral administration to rabbits for 10 days, no abnormalities were observed in renal functional parameters and morphological studies up to 200 mg/kg.
Effects on Eye:
Following oral administration to rats for 4 weeks, no abnormalities were observed in ophthalmological tests and morphological studies up to 100 mg/kg.
Effects on Articulation:
When Tarivid was administered orally to immature rats (4 weeks of age) or immature dogs (3-4 months of age) for 7 days, blisters or erosions occurred in the articular cartilage in rats on ≥300 mg/kg and in dogs on ≥10 mg/kg. After termination of administration, however, it was confirmed that these symptoms tended to subside gradually without showing any signs of deterioration. In mature rats (8-10 weeks) and mature dogs (12-13 months), repeated administration did not cause any change.
Microbiology: Antibacterial Activity:
Ofloxacin has a wide range of antibacterial spectrum against various gram-positive and gram-negative bacteria. Antibacterial activities of Tarivid are 2-4 fold stronger than those of norfloxacin against Staphylococcus
sp, hemolytic Streptococci and Enterococci. Meanwhile, ofloxacin has satisfactory activities as those of norfloxacin against Enterobacteriaceae including E. coli, K. pneumoniae, Serratia
spp, glucose-nonfermentative gram-negative rods, P. aeruginosa, H. influenzae
and N. gonorrhoeae
. Furthermore, it has good effects against nalidixic acid-resistant Enterobacteriaceae, ABPC-resistant N. gonorrhoeae
and GM-resistant P. aeruginosa
The median effective doses (ED50
) of ofloxacin in experimentally produced infectious diseases in mice were between ¼ and ½ of norfloxacin and between 1
of pipemidic acid, thus indicating a good effect of this drug in the prevention of infections.
Appearance of microorganism with naturally developed drug-resistance has not been confirmed.