LEVAQUIN (levofloxacin 750 mg) Dailymed

12 Clinical Pharmacology

12.1 Mechanism of Action

Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [seeClinical Pharmacology (12.4)].

12.3 Pharmacokinetics

The mean ± SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of LEVAQUIN^® are summarized in Table 10.

Table 10: Mean ± SD Levofloxacin PK Parameters

Regimen	Cmax	Tmax	AUC	CL/Fclearance/bioavailability	Vd/Fvolume of distribution/bioavailability	t1/2	CLR
	(mcg/mL)	(h)	(mcg∙h/mL)	(mL/min)	(L)	(h)	(mL/min)
ND=not determined.
Single dose
250 mg oral tablethealthy males 18–53 years of age	2.8 ± 0.4	1.6 ± 1.0	27.2 ± 3.9	156 ± 20	ND	7.3 ± 0.9	142 ± 21
500 mg oral tablet Absolute bioavailability; F=0.99 ± 0.08 from a 500 mg tablet and F=0.99 ± 0.06 from a 750 mg tablet;	5.1 ± 0.8	1.3 ± 0.6	47.9 ± 6.8	178 ± 28	ND	6.3 ± 0.6	103 ± 30
500 mg oral solutionhealthy males and females 19–55 years of age.	5.8 ± 1.8	0.8 ± 0.7	47.8 ± 10.8	183 ± 40	112 ± 37.2	7.0 ± 1.4	ND
500 mg IV	6.2 ± 1.0	1.0 ± 0.1	48.3 ± 5.4	175 ± 20	90 ± 11	6.4 ± 0.7	112 ± 25
750 mg oral tablethealthy male and female subjects 18–54 years of age	9.3 ± 1.6	1.6 ± 0.8	101 ± 20	129 ± 24	83 ± 17	7.5 ± 0.9	ND
750 mg IV	11.5 ± 4.060 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose	ND	110 ± 40	126 ± 39	75 ± 13	7.5 ± 1.6	ND
Multiple dose
500 mg every 24h oral tablet	5.7 ± 1.4	1.1 ± 0.4	47.5 ± 6.7	175 ± 25	102 ± 22	7.6 ± 1.6	116 ± 31
500 mg every 24h IV	6.4 ± 0.8	ND	54.6 ± 11.1	158 ± 29	91 ± 12	7.0 ± 0.8	99 ± 28
500 mg or 250 mg every 24h IV, patients with bacterial infection500 mg every 48h for patients with moderate renal impairment (CLCR 20–50 mL/min) and infections of the respiratory tract or skin	8.7± 4.0dose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modeling	ND	72.5 ± 51.2	154 ± 72	111 ± 58	ND	ND
750 mg every 24h oral tablet	8.6 ± 1.9	1.4 ± 0.5	90.7 ± 17.6	143 ± 29	100 ± 16	8.8 ± 1.5	116 ± 28
750 mg every 24h IV	12.1 ± 4.1	ND	108 ± 34	126 ± 37	80 ± 27	7.9 ± 1.9	ND
500 mg oral tablet single dose, effects of gender and age:
Malehealthy males 22–75 years of age	5.5 ± 1.1	1.2 ± 0.4	54.4 ± 18.9	166 ± 44	89 ± 13	7.5 ± 2.1	126 ± 38
Femalehealthy females 18–80 years of age	7.0 ± 1.6	1.7 ± 0.5	67.7 ± 24.2	136 ± 44	62 ± 16	6.1 ± 0.8	106 ± 40
Youngyoung healthy male and female subjects 18–36 years of age	5.5 ± 1.0	1.5 ± 0.6	47.5 ± 9.8	182 ± 35	83 ± 18	6.0 ± 0.9	140 ± 33
Elderlyhealthy elderly male and female subjects 66–80 years of age	7.0 ± 1.6	1.4 ± 0.5	74.7 ± 23.3	121 ± 33	67 ± 19	7.6 ± 2.0	91 ± 29
500 mg oral 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

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 levofloxacin from a 500 mg tablet and a 750 mg tablet of LEVAQUIN^® are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of LEVAQUIN^® to healthy volunteers, the mean ± SD peak plasma concentration attained was 6.2 ± 1.0 mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 ± 4.0 mcg/mL after a 750 mg dose infused over 90 minutes. LEVAQUIN^® Oral Solution and Tablet formulations are bioequivalent.

Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV 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 mcg/mL after the 500 mg doses, and 8.6 ± 1.9 and 1.1 ± 0.4 mcg/mL after the 750 mg doses, respectively. The mean ± SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4 ± 0.8 and 0.6 ± 0.2 mcg/mL after the 500 mg doses, and 12.1 ± 4.1 and 1.3 ± 0.71 mcg/mL after the 750 mg doses, respectively. Oral administration of a 500 mg dose of 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, LEVAQUIN^® Tablets can be administered without regard to food. It is recommended that LEVAQUIN^® Oral Solution be taken 1 hour before or 2 hours after eating.

The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for LEVAQUIN^® Tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable (seeFigure 2andFigure 3).

Figure 2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mg

Figure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg

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 buler fluid of healthy subjects at approximately 3 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the buler fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and 500 mg doses of LEVAQUIN^®, 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 mcg/g over a 24-hour period after a single 500 mg oral dose.

In vitro, over a clinically relevant range (1 to 10 mcg/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 LEVAQUIN^®.

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 LEVAQUIN^® 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. LEVAQUIN^® dose adjustment based on age alone is not necessary [seeUse in Specific Populations (8.5)].

Pediatrics

The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose were investigated in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposures than adults for a given mg/kg dose. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC_0–24 and C_max) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours.

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 LEVAQUIN^® 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 Impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in adult 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 LEVAQUIN^® are not required following hemodialysis or CAPD [seeDosage and Administration (2.3),Use in Specific Populations (8.6)].

Hepatic Impairment

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 [seeUse in Specific Populations (8.7)].

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 LEVAQUIN^® and antacids, warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [seeDrug Interactions (7)].

12.4 Microbiology

MECHANISM OF ACTION SECTION

Mechanism of Action

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.

Drug Resistance

Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.

Fluoroquinolones, including levofloxacin, 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 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.

Activity in vitro and in vivo

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.

Levofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in Indications and Usage (1):

•   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]MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole.)
  •   Streptococcus pyogenes

•   Aerobic Gram-Negative Microorganisms
  •   Enterobacter cloacae
  •   Escherichia coli
  •   Haemophilus influenzae
  •   Haemophilus parainfluenzae
  •   Klebsiella pneumoniae
  •   Legionella pneumophila
  •   Moraxella catarrhalis
  •   Proteus mirabilis
  •   Pseudomonas aeruginosa As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with LEVAQUIN^®.
  •   Serratia marcescens

•   Other Microorganisms
  •   Chlamydophila pneumoniae
  •   Mycoplasma pneumoniae

Levofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of plasma levels as a surrogate marker in a rhesus monkey model for anthrax (post-exposure) [seeIndications and Usage (1.13),Clinical Studies (14.9)].

The following in vitro data are available, but their clinical significance is unknown: Levofloxacin exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of LEVAQUIN^® in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

•   Aerobic Gram-Positive Microorganisms
  •   Staphylococcus haemolyticus
  •  β-hemolytic Streptococcus (Group C/F)
  •  β-hemolytic Streptococcus (Group G)
  •   Streptococcus agalactiae
  •   Streptococcus milleri
  •  Viridans group streptococci

•   Aerobic Gram-Negative Microorganisms
  •   Acinetobacter baumannii
  •   Acinetobacter lwoffii
  •   Bordetella pertussis
  •   Citrobacter koseri
  •   Citrobacter freundii
  •   Enterobacter aerogenes
  •   Enterobacter sakazakii
  •   Klebsiella oxytoca
  •   Morganella morganii
  •   Pantoea agglomerans
  •   Proteus vulgaris
  •   Providencia rettgeri
  •   Providencia stuartii
  •   Pseudomonas fluorescens

•   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 criteria outlined in Table 11.

• 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 mcg 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 mcg levofloxacin disk should be interpreted according to the criteria outlined in Table 11. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for levofloxacin.

Table 11: Susceptibility Interpretive Criteria for LEVAQUIN^®

	Minimum Inhibitory Concentrations (mcg/mL)			Disk Diffusion (zone diameter in mm)
S = Susceptible, I = Intermediate, R = Resistant
Pathogen	S	I	R	S	I	R
Enterobacteriaceae	≤2	4	≥8	≥17	14–16	≤13
Enterococcus faecalis	≤2	4	≥8	≥17	14–16	≤13
Methicillin-susceptible   Staphylococcus species	≤2	4	≥8	≥17	14–16	≤13
Pseudomonas aeruginosa	≤2	4	≥8	≥17	14–16	≤13
Haemophilus influenzae	≤2These 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 /zone diameter results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.	--	≥17These interpretive standards are applicable only to disk diffusion susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.2	--	--
Haemophilus parainfluenzae	≤2	--	--	≥17	--	--
Streptococcus pneumoniae	≤2These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.	4	≥8	≥17These 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.	14–16	≤13
Streptococcus pyogenes	≤2	4	≥8	≥17	14–16	≤13

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.

• Quality Control:

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard levofloxacin powder should give the MIC values provided in Table 12. For diffusion technique, the 5 mcg levofloxacin disk should provide zone diameters provided in Table 12.

Table 12: Quality Control for Susceptibility Testing

Microorganism	Microorganism QC Number	MIC (mcg/mL)	Disk Diffusion (zone diameter in mm)
Enterococcus faecalis	ATCC 29212	0.25 – 2	--
Escherichia coli	ATCC 25922	0.008 – 0.06	29 – 37
Escherichia coli Careful maintenance of this organism is required as the strain may lose its plasmid.	ATCC 35218	0.015 – 0.06	--
Haemophilus influenzae	ATCC 49247	0.008 – 0.03This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM).1	32 – 40This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM).2
Pseudomonas aeruginosa	ATCC 27853	0.5 – 4	19 – 26
Staphylococcus aureus	ATCC 29213	0.06 – 0.5	--
Staphylococcus aureus	ATCC 25923	--	25 – 30
Streptococcus pneumoniae	ATCC 49619	0.5 – 2This 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.	20 – 25This 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.