|
Multiple dose
500 mg q24h p. o. 3 5.7 ± 1.4 1.1 ± 0. 4 47.5 ± 6. 7 175 ± 25 102 ± 22 7.6 ± 1. 6 116 ± 31
500 mg q24h i. v. 3 6.4 ± 0. 8 ND 54.6 ± 11.1 158 ± 29 91 ± 12 7.0 ± 0. 8 99 ± 28
500 mg or 250 mg q24h i. v., 8.7 ± 4. 0 7 ND 72.5 ± 51.2 7 154 ± 72 111 ± 58 ND ND
patients with bacterial infection 6
750 mg q24h p. o. 5 8.6 ± 1. 9 1.4 ± 0. 5 90.7 ± 17.6 143 ± 29 100 ± 16 8.8 ± 1. 5 116 ± 28
750 mg q24h i. v. 5 12.1 ± 4. 1 4 ND 108 ± 34 126 ± 37 80 ± 27 7.9 ± 1. 9 ND
500 mg p. o. single dose, effects of gender and age:
Male 8 5.5 ± 1. 1 1.2 ± 0. 4 54.4 ± 18.9 166 ± 44 89 ± 13 7.5 ± 2. 1 126 ± 38
Female 9 7.0 ± 1. 6 1.7 ± 0. 5 67.7 ± 24.2 136 ± 44 62 ± 16 6.1 ± 0. 8 106 ± 40
Young 10 5.5 ± 1. 0 1.5 ± 0. 6 47.5 ± 9. 8 182 ± 35 83 ± 18 6.0 ± 0. 9 140 ± 33
Elderly 11 7.0 ± 1. 6 1.4 ± 0. 5 74.7 ± 23.3 121 ± 33 67 ± 19 7.6 ± 2. 0 91 ± 29 500 mg p. o. single dose, patients with renal insufficiency:
CLCR 50-80 mL/ min 7.5 ± 1. 8 1.5 ± 0. 5 95.6 ± 11.8 88 ± 10 ND 9.1 ± 0. 9 57 ± 8
CLCR 20-49 mL/ min 7.1 ± 3. 1 2.1 ± 1. 3 182.1 ± 62.6 51 ± 19 ND 27 ± 10 26 ± 13
CLCR <20 mL/ min 8.2 ± 2. 6 1.1 ± 1. 0 263.5 ± 72.5 33 ± 8 ND 35 ± 5 13 ± 3
Hemodialysis 5.7 ± 1. 0 2.8 ± 2. 2 ND ND ND 76 ± 42 ND
CAPD 6.9 ± 2. 3 1.4 ± 1. 1 ND ND ND 51 ± 24 ND 1 clearance/ bioavailability Text Continues Below
2 volume of distribution/ bioavailability 3 healthy males 18-53 years of age 4 60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose 5 healthy male and female subjects
18-54 years of age 6 500 mg q48h for patients with moderate renal impairment (CLCR 20-50 mL/ min) and infections of the respiratory tract or skin 7 dose-normalized values (to 500 mg
dose), estimated by population pharmacokinetic modeling 8 healthy males 22-75 years of age 9 healthy females 18-80 years of age 10 young healthy male and female subjects 18-36 years of age 11 healthy elderly male and female subjects 66-80 years of age *Absolute bioavailability; F = 0.99 ± 0.08 from a 500-mg tablet and F= 0.99 ± 0.06 from a 750-mg tablet; ND = not determined. MICROBIOLOGY Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin 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. Levofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations. Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and -lactam antibi-otics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials. Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10 -9 to 10 -10 ). Although cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin. Levofloxacin 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 Enterococcus faecalis (many strains are only moderately susceptible) Staphylococcus aureus (methicillin-susceptible strains)
Staphylococcus epidermidis (methicillin-susceptible strains)
Staphylococcus saprophyticus
Streptococcus pneumoniae (including penicillin-resistant strains*)
Streptococcus pyogenes *Note: penicillin-resistant S. pneumoniae are those strains with a penicillin MIC value of
2 µg/ mL Aerobic gram-negative microorganisms Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Escherichia coli Legionella pneumophila Serratia marcescens
Haemophilus influenzae Moraxella catarrhalis
Haemophilus parainfluenzae Proteus mirabilis As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin. Other microorganisms Chlamydia pneumoniae Mycoplasma pneumoniae The following in vitro data are available, but their clinical significance is unknown. Levofloxacin 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 levofloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. Aerobic gram-positive microorganisms Staphylococcus haemolyticus Streptococcus (Group G) Streptococcus milleri Streptococcus (Group C/ F) Streptococcus agalactiae Viridans group streptococci Aerobic gram-negative microorganisms Acinetobacter baumannii Enterobacter aerogenes Proteus vulgaris Acinetobacter lwoffii Enterobacter sakazakii Providencia rettgeri Bordetella pertussis Klebsiella oxytoca Providencia stuartii Citrobacter (diversus) koseri Morganella morganii Pseudomonas fluorescens Citrobacter freundii Pantoea (Enterobacter) agglomerans
Anaerobic gram-positive microorganisms Clostridium perfringens Susceptibility Tests Susceptibility testing for levofloxacin should be performed, as it is the optimal predictor of activity. Dilution techniques Quantitative methods are used to determine antimicrobial minimal 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 method 1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of levofloxacin powder. The MIC values should be interpreted according to the following criteria: For testing Enterobacteriaceae, Enterococci, Staphylococcus species, and Pseudomonas aeruginosa:
MIC (µg/ mL) Interpretation
2 Susceptible (S) 4 Intermediate (I) 8 Resistant (R) For testing Haemophilus influenzae and Haemophilus parainfluenzae: a MIC (µg/ mL) Interpretation
2 Susceptible (S) a These interpretive standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.
1 The current absence of data on resistant strains precludes defining any categories other than "Susceptible." Strains yielding MIC results suggestive
of a "nonsusceptible" category should be submitted to a reference laboratory for further testing. For testing Streptococcus spp. including S. pneumoniae: b MIC (µg/ mL) Interpretation 2 Susceptible (S) 4 Intermediate (I) 8 Resistant (R) b 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 con-centrations 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 concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of labora-tory control microorganisms to control the technical aspects of the laboratory procedures. Standard levofloxacin powder should give the following MIC values: Microorganism MIC (µg/ mL)
Enterococcus faecalis ATCC 29212 0.25-2 Escherichia coli ATCC 25922 0.008-0.06 Escherichia coli ATCC 35218 0.015-0.06 Haemophilus influenzae ATCC 49247 c 0.008-0.03
Pseudomonas aeruginosa ATCC 27853 0.5-4 Staphylococcus aureus ATCC 29213 0.06-0.5
Streptococcus pneumoniae ATCC 49619 d 0.5-2 c
This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM). 1 d
This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a broth 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 suscepti-bility of bacteria to antimicrobial compounds. One such standardized procedure 2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-µg levofloxacin to test the susceptibility of microorganisms to levofloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg levofloxacin disk should be interpreted according to the following criteria: For testing Enterobacteriaceae, Enterococci, Staphylococcus species, and Pseudomonas aeruginosa: Zone diameter (mm) Interpretation
17 Susceptible (S) 14-16 Intermediate (I) 13 Resistant (R) For Haemophilus influenzae and Haemophilus parainfluenzae: e Zone diameter (mm) Interpretation
17 Susceptible (S) e These interpretive standards are applicable only to disk diffusion susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium. 2 The current absence of data on resistant strains precludes defining any categories other than "Susceptible." Strains yielding zone diameter results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing. For Streptococcus spp. including S. pneumoniae: f
Zone diameter (mm) Interpretation 17 Susceptible (S) 14-16 Intermediate (I) 13 Resistant (R) f These zone diameter standards for Streptococcus spp. including S. pneumoniae apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2 . Interpretation should be as stated above for results using dilution tech-niques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for levofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-µg levofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:
Microorganism Zone Diameter (mm)
Escherichia coli ATCC 25922 29-37 Haemophilus influenzae ATCC 49247 g 32-40
Pseudomonas aeruginosa ATCC 27853 19-26 Staphylococcus aureus ATCC 25923 25-30
Streptococcus pneumoniae ATCC 49619 h 20-25 g
This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM). 2 h
This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2 . Page: << Prev | 1 | 2 | 3 | 4 | 5
|
.gif)
