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Levaquin Pharmacology, Pharmacokinetics, Studies, Metabolism - Levofloxacin

Levaquin Pharmacology, Pharmacokinetics, Studies, Metabolism - Levofloxacin

CLINICAL PHARMACOLOGY

The mean ±SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral (p. o. ) tablet, oral solution, or intravenous (i. v. ) doses of levofloxacin are summarized in Table 1.

Absorption

Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of a 500 mg tablet and a 750 mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of levofloxacin to healthy volunteers, the mean ±SD peak plasma concentration attained was 6. 2 ±1. 0 µg/mL after a 500 mg dose infused over 60 minutes and 11. 5 ±4. 0 µg/mL after a 750 mg dose infused over 90 minutes. Levofloxacin oral solution and tablet formulations are bioequivalent.

Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or i. v. dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5. 7 ±1. 4 and 0. 5 ±0. 2 µg/mL after the 500 mg doses, and 8. 6 ±1. 9 and 1. 1 ±0. 4 µg/mL after the 750 mg doses, respectively. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily i. v. regimens were approximately 6. 4 ±0. 8 and 0. 6 ±0. 2 µg/mL after the 500 mg doses, and 12. 1 ±4. 1 and 1. 3 ±0. 71 µg/mL after the 750 mg doses, respectively.

Oral administration of 500-mg LEVAQUIN with food prolongs the time to peak concentration by approximately 1 hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, levofloxacin tablets can be administered without regard to food. It is recommended that levofloxacin oral solution be taken 1 hour before, or 2 hours after eating.

The plasma concentration profile of levofloxacin after i. v. administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and i. v. routes of administration can be considered interchangeable. (See following chart. )

Distribution

The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and 500 mg levofloxacin, respectively, to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5- fold higher than plasma concentrations and ranged from approximately 2. 4 to 11. 3 µg/g over a 24-hour period after a single 500 mg oral dose.

In vitro, over a clinically relevant range (1 to 10 µg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.

Metabolism

Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.

Excretion

Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin.

Special Populations

Geriatric

There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects’ differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of levofloxacin to healthy elderly subjects (66 - 80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7. 6 hours, as compared to approximately 6 hours in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. Levofloxacin dose adjustment based on age alone is not necessary.

Pediatric

The pharmacokinetics of levofloxacin in pediatric subjects have not been studied.

Gender

There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when subjects’ differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of levofloxacin to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin was about 7. 5 hours, as compared to approximately 6. 1 hours in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based on gender alone is not necessary.

Race

The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects. Renal insufficiency: Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (creatinine clearance <50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysis or CAPD. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION. )

Hepatic insufficiency

Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.

Bacterial infection

The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.

Drug-drug interactions

The potential for pharmacokinetic drug interactions between levofloxacin and theophylline, warfarin, cyclosporine, digoxin, probenecid, cimetidine, sucralfate, and antacids has been evaluated. (See PRECAUTIONS: Drug Interactions. )

Table 1. Mean ±SD Levofloxacin PK Parameters
	Cmax	Tmax	AUC	CL/F1	Vd/F2	t ½	CLR
Regimen	(µg/mL)	(h)	(µg•h/mL)	(mL/min)	(L)	(h)	(mL/min)
Single dose
250 mg p. o. tablet3	2. 8 ±0. 4	1. 6 ±1. 0	27. 2 ±3. 9	156 ±20	ND	7. 3 ±0. 9	142 ±21
500 mg p. o. tablet3*	5. 1 ±0. 8	1. 3 ±0. 6	47. 9 ±6. 8	178 ±28	ND	6. 3 ±0. 6	103 ±30
500 mg oral solution12	5. 8 ± 1. 8	0. 8 ± 0. 7	47. 8 ± 10. 8	183 ± 40	112 ± 37. 2	7. 0 ± 1. 4	ND
500 mg i. v. 3	6. 2 ± 1. 0	1. 0 ± 0. 1	48. 3 ± 5. 4	175 ± 20	90 ± 11	6. 4 ± 0. 7	112 ± 25
750mg p. o. tablet5*	9. 3 ±1. 6	1. 6 ±0. 8	101 ±20	129 ±24	83 ±17	7. 5 ±0. 9	ND
750 mg i. v. 5	11. 5 ±4. 04	ND	110 ±40	126 ±39	75 ±13	7. 5 ±1. 6	ND
Multiple dose
500 mg q24h p. o. tablet3	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. , patients with bacterial infection6	8. 7 ±4. 07	ND	72. 5 ±51. 27	154 ±72	111 ±58	ND	ND
750 mg q24h p. o. tablet5	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. 14	ND	108 ±34	126 ±37	80 ±27	7. 9 ±1. 9	ND
500 mg p. o. tablet single dose, effects of gender and age:
Male8	5. 5 ±1. 1	1. 2 ±0. 4	54. 4 ±18. 9	166 ±44	89 ±13	7. 5 ±2. 1	126 ±38
Female9	7. 0 ±1. 6	1. 7 ±0. 5	67. 7 ±24. 2	136 ±44	62 ±16	6. 1 ±0. 8	106 ±40
Young10	5. 5 ±1. 0	1. 5 ±0. 6	47. 5 ±9. 8	182 ±35	83 ±18	6.0±0. 9	140 ±33
Elderly11	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 tablet, 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			8 healthy males 22-75 years of age
2 volume of distribution/bioavailability			9 healthy females 18-80 years of age
3 healthy males 18-53 years of age			10 young healthy male and female subjects 18-36 years of age
4 60 min infusion for 250mg and 500mg doses, 90 min infusion for750mg dose			11 healthy elderly male and female subjects 66-80 years of age
5 healthy male and female subjects 18-54 years of age			12 healthy males and females 19-55 years of age
6 500mg q48h for patients with moderate renal impairment(CLCR 20-50mL/min) and infections of the respiratory tract or skin			*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.
7 dose-normalized values (to 500mg dose), estimated by population pharmacokinetic modeling

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 b-lactam antibiotics, 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 multi-drug resistant strains [MDRSP]*)

Streptococcus pyogenes

*MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are strains resistant to two or more of the following antibiotics: penicillin (MIC ³2 µg/mL), 2^nd generation cephalosporins, e. g. , cefuroxime, macrolides, tetracyclines and trimethoprim / sulfamethoxazole.

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 (³90%) 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 method¹ (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)
³8	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)
³8	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 concentrations 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 laboratory 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 49247c	0. 008-0. 03
Pseudomonas aeruginosa	ATCC 27853	0. 5-4
Staphylococcus aureus	ATCC 29213	0. 06-0. 5
Streptococcus pneumoniae	ATCC 49619d	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 cationadjusted 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 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
³17	Susceptible (S)
14-16	Intermediate (I)
£13	Resistant (R)

For Haemophilus influenzae and Haemophilus parainfluenzae: ^e

Zone diameter (mm)	Interpretation
³17	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
³17	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 techniques. 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 49247g	32-40
Pseudomonas aeruginosa	ATCC 27853	19-26
Staphylococcus aureus	ATCC 25923	25-30
Streptococcus pneumoniae	ATCC 49619h	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.

CLINICAL STUDIES

Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7-15 days to intravenous imipenem/cilastatin (500-1000 mg q6-8 hours daily) followed by oral ciprofloxacin (750 mg q12 hours daily) for a total of 7-15 days. Levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1-16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1-19 days).

Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was empirically initiated at study entry in 56 of 93 (60. 2%) patients in the levofloxacin arm and 53 of 94 (56. 4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the levofloxacin arm and 7 days in the comparator. In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa infection, 15 of 17 (88. 2%) received ceftazidime (N=11) or piperacillin/tazobactam (N=4) in the levofloxacin arm and 16 of 17 (94. 1%) received an aminoglycoside in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was added to the treatment regimen of 37 of 93 (39. 8%) patients in the levofloxacin arm and 28 of 94 (29. 8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection.

Clinical success rates in clinically and microbiologically evaluable patients at the posttherapy visit (primary study endpoint assessed on day 3-15 after completing therapy) were 58. 1% for levofloxacin and 60. 6% for comparator. The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-17. 2, 12. 0]. The microbiological eradication rates at the posttherapy visit were 66. 7% for levofloxacin and 60. 6% for comparator. The 95% CI for the difference of eradication rates (levofloxacin minus comparator) was [-8. 3, 20. 3]. Clinical success and microbiological eradication rates by pathogen were as follows:

Pathogen	N	Levofloxacin No. (%) of Patients Microbiologic / Clinical Outcomes	N	Imipenem/Cilastatin No. (%) of Patients Microbiologic / Clinical Outcomes
MSSAa	21	14 (66. 7) / 13 (61. 9)	19	13 (68. 4) / 15 (78. 9)
P. aeruginosab	17	10 (58. 8) / 11 (64. 7)	17	5 (29. 4) / 7 (41. 2)
S. marcescens	11	9 (81. 8) / 7 (63. 6)	7	2 (28. 6) / 3 (42. 9)
E. coli	12	10 (83. 3) / 7 (58. 3)	11	7 (63. 6) / 8 (72. 7)
K. pneumoniaec	11	9 (81. 8) / 5 (45. 5)	7	6 (85. 7) / 3 (42. 9)
H. influenzae	16	13 (81. 3) / 10 (62. 5)	15	14 (93. 3) / 11 (73. 3)
S. pneumoniae	4	3 (75. 0) / 3 (75. 0)	7	5 (71. 4) / 4 (57. 1)
aMethicillin-susceptible S. aureus.
bSee above text for use of combination therapy.
cThe observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study.

Community-Acquired Bacterial Pneumonia

7 to 14 Day Treatment Regimen

Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in two pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies were as follows:

Pathogen	No. Pathogens	Microbiologic Eradication Rate (%)
H. influenzae	55	98
S. pneumoniae	83	95
S. aureus	17	88
M. catarrhalis	18	94
H. parainfluenzae	19	95
K. pneumoniae	10	100. 0

Community-Acquired Bacterial Pneumonia 5-Day Treatment Regimen

To evaluate the safety and efficacy of higher dose and shorter course of levofloxacin, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multi-center study comparing levofloxacin 750 mg, i. v. or p. o. , q. d. for five days or levofloxacin 500 mg i. v. or p. o. , q. d. for 10 days.

Clinical success rates (cure plus improvement) in the clinically evaluable population were 90. 9% in the levofloxacin 750mg group and 91. 1% in the levofloxacin 500 mg group. The 95% CI for the difference of response rates (levofloxacin 750 minus levofloxacin 500) was [-5. 9, 5. 4]. In the clinically evaluable population (31-38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the levofloxacin 750 mg group and 2 out of 147 patients in the levofloxacin 500 mg group. Given the small numbers observed, the significance of this finding can not be determined statistically. The microbiological efficacy of the 5-day regimen was documented for infections listed in the table below.

	Eradication rate
Penicillin susceptible S. pneumoniae	19/20
Haemophilus influenzae	12/12
Haemophilus parainfluenzae	10/10
Mycoplasma pneumoniae	26/27
Chlamydia pneumoniae	13/15

Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae (MDRSP)*

LEVAQUIN was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP)*. Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95. 0%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in the table below.

*MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are strains resistant to two or more of the following antibiotics: penicillin (MIC ³2 µg/mL), 2^nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Clinical and Bacteriological Success Rates for Levofloxacin-Treated MDRSP* CAP Patients (Population: Valid for Efficacy)

Screening Susceptiblity	Clinical Success		Bacteriological Success**
	n/Na	%	n/Nb	%
Penicillin-resistant	16/17	94. 1	16/17	94. 1
2nd generation cephalosporin resistant	31/32	96. 9	31/32	96. 9
Macrolide-resistant	28/29	96. 6	28/29	96. 6
Trimethoprim/ Sulfamethoxazole resistant	17/19	89. 5	17/19	89. 5
Tetracycline-resistant	12/12	100	12/12	100
a n = the number of microbiologically evaluable patients who were clinical successes; N = number of microbiologically evaluable patients in the designated resistance group.
b n = the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients; N = number of MDRSP isolates in a designated resistance group.
* MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are strains resistant to two or more of the following antibiotics: penicillin (MIC ³2 µg/mL), 2nd generation cephalosporins, e. g. , cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
** One patient had a respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and TMP/SMX and intermediate to penicillin and a blood isolate that was intermediate to penicillin and cefuroxime and resistant to the other classes. The patient is included in the database based on respiratory isolate.

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in the table below.

Resistant Streptococcus pneumoniae clinical success and bacteriologic eradication rates
S. pn with MDRSP	Clinical Success	Bacteriologic Eradication
Resistant to 2	17/18 (94. 4%)	17/18 (94. 4%)
Resistant to 3	14/15 (93. 3%)	14/15 (93. 3%)
Resistant to 4	7/7 (100%)	7/7 (100%)
Resistant to 5	0	0
Bacteremias with MDRSP	8/9 (89%)	8/9 (89%)

Complicated Skin and Skin Structure Infections

Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either levofloxacin 750 mg QD (IV followed by oral), or an approved comparator for a median of 10 ±4. 7 days. As is expected in complicated skin and skin structure infections, surgical procedures were performed in the levofloxacin and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the levofloxacin treated patients and 44% of the comparator treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication. Among those who could be evaluated clinically 2-5 days after completion of study drug, overall success rates (improved or cured) were 116/138 (84. 1%) for patients treated with levofloxacin and 106/132 (80. 3%) for patients treated with the comparator.

Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to 90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with comparator drugs.

Chronic Bacterial Prostatitis

Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB₃) or expressed prostatic secretion (EPS) specimens obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind study comparing oral levofloxacin 500 mg, once daily for a total of 28 days to oral ciprofloxacin 500 mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients. A total of 136 and 125 microbiologically evalu-able patients were enrolled in the levofloxacin and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5-18 days after completion of therapy was 75. 0% in the levofloxacin group and 76. 8% in the ciprofloxacin group (95% CI [-12. 58, 8. 98] for levofloxacin minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented below:

	Levofloxacin (N=136)		Ciprofloxacin (N=125)
Pathogen	N	Eradication	N	Eradication
E. coli	15	14 (93. 3%)	11	9 (81. 8%)
E. faecalis	54	39 (72. 2%)	44	33 (75. 0%)
*S. epidermidis	11	9 (81. 8%)	14	11 (78. 6%)
*Eradication rates shown are for patients who had a sole pathogen only; mixed cultures were excluded.

Eradication rates for S. epidermidis when found with other co-pathogens are consistent with rates seen in pure isolates.

Clinical success (cure + improvement with no need for further antibiotic therapy) rates in microbiologically evaluable population 5-18 days after completion of therapy were 75. 0% for levofloxacin-treated patients and 72. 8% for ciprofloxacin-treated patients (95% CI [-8. 87, 13. 27] for levofloxacin minus ciprofloxacin). Clinical long-term success (24-45 days after completion of therapy) rates were 66. 7% for the levofloxacin-treated patients and 76. 9% for the ciprofloxacin-treated patients (95% CI [-23. 40, 2. 89] for levofloxacin minus ciprofloxacin).

ANIMAL PHARMACOLOGY

Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (See WARNINGS. ) In immature dogs (4-5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin for 8 or 9 consecutive days, with an 18-week recovery period, exhibited musculoskeletal clinical signs by the final dose at dose levels 2. 5 mg/kg (approximately >0. 2- fold the potential therapeutic dose (1500 mg q24h) based upon plasma AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (equivalent to and 3-fold greater than the potential therapeutic dose, respectively). All musculoskeletal clinical signs were resolved by week 5 of recovery; synovitis was resolved by the end of the 18-week recovery period; whereas, articular cartilage erosions and chondropathy persisted.

When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones.

While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity.

In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs. In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release.

In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer or inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Sixth Edition. Approved Standard NCCLS Document M7-A6,Vol.23, No.2, NCCLS, Wayne, PA, January,2003.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests Eighth Edition. Approved Standard NCCLS Document M2-A8,Vol.23, No.1, NCCLS,Wayne,PA, January, 2003.

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