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CLINICAL PHARMACOLOGY

Following oral administration, the bioavailability of ofloxacin in the tablet formulation is approximately 98%. Maximum serum concentrations are achieved one to two hours after an oral dose. Absorption of ofloxacin after single or multiple doses of 200 to 400 mg is predictable, and the amount of drug absorbed increases proportionately with the dose. Ofloxacin has biphasic elimination. Following multiple oral doses at steady-state administration, the half-lives are approximately 4-5 hours and 20-25 hours. However, the longer half-life represents less than 5% of the total AUC. Accumulation at steady-state can be estimated using a half-life of 9 hours. The total clearance and volume of distribution are approximately similar after single or multiple doses. Elimination is mainly by renal excretion. The following are mean peak serum concentrations in healthy 70-80 kg male volunteers after single oral doses of 200, 300, or 400 mg of ofloxacin or after multiple oral doses of 400 mg.

Oral Dose Serum Concentration 2 Hours After Admin. (μg/mL) Area Under the Curve (AUC(0-8)) (μg•h/mL)
200 mg single dose 1.5 14.1
300 mg single dose 2.4 21.2
400 mg single dose 2.9 31.4
400 mg steady-state 4.6 61.0

Steady-state concentrations were attained after four oral doses, and the area under the curve (AUC) was approximately 40% higher than the AUC after single doses. Therefore, after multiple-dose administration of 200 mg and 300 mg doses, peak serum levels of 2.2 μg/mL and 3.6 μg/mL, respectively, are predicted at steady-state.

In vitro, approximately 32% of the drug in plasma is protein bound.

The single dose and steady-state plasma profiles of ofloxacin injection were comparable in extent of exposure (AUC) to those of ofloxacin tablets when the injectable and tablet formulations of ofloxacin were administered in equal doses (mg/mg) to the same group of subjects. The mean steady-state AUC(0-12) attained after the intravenous administration of 400 mg over 60 min was 43.5 μg•h/mL; the mean steady-state AUC(0-12) attained after the oral administration of 400 mg was 41.2 μg•h/mL (two one-sided t-test, 90% confidence interval was 103-109). (See following chart.)

Single dose and steady-state plasma profiles - Illustration

Between 0 and 6 h following the administration of a single 200 mg oral dose of ofloxacin to 12 healthy volunteers, the average urine ofloxacin concentration was approximately 220 μg/mL. Between 12 and 24 hours after administration, the average urine ofloxacin level was approximately 34 μg/mL.

Following oral administration of recommended therapeutic doses, ofloxacin has been detected in blister fluid, cervix, lung tissue, ovary, prostatic fluid, prostatic tissue, skin, and sputum. The mean concentration of ofloxacin in each of these various body fluids and tissues after one or more doses was 0.8 to 1.5 times the concurrent plasma level. Inadequate data are presently available on the distribution or levels of ofloxacin in the cerebrospinal fluid or brain tissue.

Ofloxacin has a pyridobenzoxazine ring that appears to decrease the extent of parent compound metabolism. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Studies indicate that less than 5% of an administered dose is recovered in the urine as the desmethyl or N-oxide metabolites. Four to eight percent of an ofloxacin dose is excreted in the feces. This indicates a small degree of biliary excretion of ofloxacin.

The administration of FLOXIN® (ofloxacin) with food does not affect the Cmax and AUC∞ of the drug, but Tmax is prolonged.

Clearance of ofloxacin is reduced in patients with impaired renal function (creatinine clearance rate ≤ 50 mL/min), and dosage adjustment is necessary. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION.)

Following oral administration to healthy elderly subjects (65-81 years of age), maximum plasma concentrations are usually achieved one to two hours after single and multiple twice-daily doses, indicating that the rate of oral absorption is unaffected by age or gender. Mean peak plasma concentrations in elderly subjects were 9-21% higher than those observed in younger subjects. Gender differences in the pharmacokinetic properties of elderly subjects have been observed. Peak plasma concentrations were 114% and 54% higher in elderly females compared to elderly males following single and multiple twice-daily doses. [This interpretation was based on study results collected from two separate studies.] Plasma concentrations increase dose-dependently with the increase in doses after single oral dose and at steady state. No differences were observed in the volume of distribution values between elderly and younger subjects. As in younger subjects, elimination is mainly by renal excretion as unchanged drug in elderly subjects, although less drug is recovered from renal excretion in elderly subjects. Consistent with younger subjects, less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites in the elderly. A longer plasma half-life of approximately 6.4 to 7.4 hours was observed in elderly subjects, compared with 4 to 5 hours for young subjects. Slower elimination of ofloxacin is observed in elderly subjects as compared with younger subjects which may be attributable to the reduced renal function and renal clearance observed in the elderly subjects. Because ofloxacin is known to be substantially excreted by the kidney, and elderly patients are more likely to have decreased renal function, dosage adjustment is necessary for elderly patients with impaired renal function as recommended for all patients. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION.)

Microbiology

Ofloxacin is a quinolone antimicrobial agent. The mechanism of action of ofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.

Ofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Ofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Fluoroquinolones, including ofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and β-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.

Resistance to ofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-11). Although cross-resistance has been observed between ofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to ofloxacin.

Ofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE Section:

Aerobic Gram-positive Microorganisms

Staphylococcus aureus (methicillin-susceptible strains)
Streptococcus pneumoniae
(penicillin-susceptible strains)
Streptococcus pyogenes

Aerobic Gram-negative Microorganisms

Citrobacter (diversus) koseri
Enterobacter aerogenes

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Neisseria gonorrhoeae

Proteus mirabilis

Pseudomonas aeruginosa

As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ofloxacin.

Other Microorganisms

Chlamydia trachomatis

The following in vitro data are available, but their clinical significance is unknown.

Ofloxacin exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 μg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of ofloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-positive Microorganisms

Staphylococcus epidermidis (methicillin-susceptible strains)
Staphylococcus saprophyticus

Streptococcus pneumoniae
(penicillin-resistant strains)

Aerobic Gram-negative Microorganisms

Acinetobacter calcoaceticus
Bordetella pertussis

Citrobacter freundii

Enterobacter cloacae

Haemophilus ducreyi

Klebsiella oxytoca

Moraxella catarrhalis

Morganella morganii

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Serratia marcescens

Anaerobic Microorganisms

Clostridium perfringes

Other Microorganisms

Chlamydia pneumoniae
Gardnerella vaginalis

Legionella pneumophila

Mycoplasma hominis

Mycoplasma pneumoniae

Ureaplasma urealyticum

Ofloxacin is not active against Treponema pallidum (See WARNINGS.)

Many strains of other streptococcal species, Enterococcus species, and anaerobes are resistant to ofloxacin.

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC values). These MIC values provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ofloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa:

MIC (μg/mL) Interpretation
≤ 2 Susceptible (S)
4 Intermediate (I)
≥ 8 Resistant (R)

For testing Haemophilus influenzae:a

MIC (μg/mL) Interpretation
≤ 2 Susceptible (S)

a This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae using Haemophilus Test Medium1

The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Neisseria gonorrhoeae:b

MIC (μg/mL) Interpretation
≤ 0.25 Susceptible (S)
0.5-1 Intermediate (I)
≥ 2 Resistant (R)

b These interpretive standards are applicable only to agar dilution tests using GC agar base and 1% defined growth supplement incubated in 5% CO2.

For testing Streptococcus pneumoniae and Streptococcus pyogenes:c

MIC (μg/mL) Interpretation
≤ 2 Susceptible (S)
4 Intermediate (I)
≥ 8 Resistant (R)

c These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ofloxacin powder should provide the following MIC values:

Microorganism   MIC Range ( g/mL)
Escherichia coli ATCC 25922 0.015-0.12
Haemophilus influenzae ATCC 49247d 0.016-0.06
Neisseria gonorrhoeae ATCC 49226e 0.004-0.016
Pseudomonas aeruginosa ATCC 27853 1-8
Staphylococcus aureus ATCC 29213 0.12-1
Streptococcus pneumoniae ATCC 49619f 1-4
d This quality control range is applicable to only H. influenzae ATCC 49247 tested by a microdilution procedure using Haemophilus Test Medium (HTM)1.
e This quality control range is applicable only to N. gonorrhoeae ATCC 49226 tested by an agar dilution procedure using GC agar base with 1% defined growth supplement incubated in 5% CO2.
f This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-μg ofloxacin to test the susceptibility of microorganisms to ofloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-μg ofloxacin disk should be interpreted according to the following criteria:

For testing Enterobacteriaceae, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa:

Zone Diameter (mm) Interpretation
≥ 16 Susceptible (S)
13-15 Intermediate (I)
≤ 12 Resistant (R)

For testing Haemophilus influenzae:g

Zone Diameter (mm) Interpretation
≥ 16 Susceptible (S)

g This zone diameter standard is applicable only to disk diffusion tests with Haemophilus influenzae using Haemophilus Test Medium (HTM)2 incubated in 5% CO2.

The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Neisseria gonorrhoeae:h

Zone Diameter (mm) Interpretation
≥ 31 Susceptible (S)
25-30 Intermediate (I)
≤ 24 Resistant (R)

h These zone diameter standards are applicable only to disk diffusion tests using GC agar base and 1% defined growth supplement incubated in 5% CO2

For testing Streptococcus pneumoniae and Streptococcus pyogenes:i

Zone Diameter (mm) Interpretation
≥ 16 Susceptible (S)
13-15 Intermediate (I)
≤ 12 Resistant (R)

i These zone diameter standards are applicable only to disk diffusion tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO2.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ofloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-μg ofloxacin disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism   Zone Diameter (mm)
Escherichia coli ATCC 25922 29-33
Haemophilus influenzae ATCC 49247j 31-40
Neisseria gonorrhoeae ATCC 49226k 43-51
Pseudomonas aeruginosa ATCC 27853 17-21
Staphylococcus aureus ATCC 25923 24-28
Streptococcus pneumoniae ATCC 49619l 16-21
j This quality control range is applicable only to H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM)2 incubated in 5% CO2.
k This quality control range is applicable only to N. gonorrhoeae ATCC 49226 tested by a disk diffusion procedure using GC agar base with 1% defined growth supplement incubated in 5% CO2.
l This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO2.

Animal Pharmacology

Ofloxacin, as well as other drugs of the quinolone class, has been shown to cause arthropathies (arthrosis) in immature dogs and rats. In addition, these drugs are associated with an increased incidence of osteochondrosis in rats as compared to the incidence observed in vehicle-treated rats. (See WARNINGS.) There is no evidence of arthropathies in fully mature dogs at intravenous doses up to 3 times the recommended maximum human dose (on a mg/m² basis or 5 times based on mg/kg basis), for a one-week exposure period.

Long-term, high-dose systemic use of other quinolones in experimental animals has caused lenticular opacities; however, this finding was not observed in any animal studies with ofloxacin.

Reduced serum globulin and protein levels were observed in animals treated with other quinolones. In one ofloxacin study, minor decreases in serum globulin and protein levels were noted in female cynomolgus monkeys dosed orally with 40 mg/kg ofloxacin daily for one year. These changes, however, were considered to be within normal limits for monkeys.

Crystalluria and ocular toxicity were not observed in any animals treated with ofloxacin.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically - Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January 1997.

Last reviewed on RxList: 4/15/2011
This monograph has been modified to include the generic and brand name in many instances.

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