CLINICAL PHARMACOLOGY
Mechanism Of Action
Levofloxacin is a member of the fluoroquinolone class of
antibacterial agents [see Microbiology].
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 Levofloxacin are summarized in Table 8.
Table 8: Mean ± SD Levofloxacin PK Parameters
Regimen |
Cmax (mcg/mL) |
Tmax (h) |
AUC (mcg•h/mL) |
CL/F* (mL/min) |
Vd/F† (L) |
t½(h) |
CLr (mL/min) |
Single dose |
250 mg oral tablet‡ |
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‡§ |
5.1 ± 0.8 |
1.3 ± 0.6 |
47.9 ± 6.8 |
178 ± 28 |
ND |
6.3 ± 0.6 |
103 ± 30 |
500 mg oral solution¶ |
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 tablet#§ |
9.3 ± 1.6 |
1.6 ± 0.8 |
101 ± 20 |
129 ± 24 |
83 ± 17 |
7.5 ± 0.9 |
ND |
750 mg IV# |
11.5 ± 4.0Þ |
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 infectionβ |
8.7± 4.0à |
ND |
72.5 ± 51.2à |
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 ± 4.1Þ |
ND |
108 ± 34 |
126 ± 37 |
80 ± 27 |
7.9 ± 1.9 |
ND |
500 mg oral single dose tablet, patients with renal ins ufficiency: |
Maleè |
5.5 ± 1.1 |
1.2 ± 0.4 |
54.4 ± 18.9 |
166 ± 44 |
89 ± 13 |
7.5 ± 2.1 |
126 ± 38 |
Femaleð |
7.0 ± 1.6 |
1.7 ± 0.5 |
67.7 ± 24.2 |
136 ± 44 |
62 ± 16 |
6.1 ± 0.8 |
106 ± 40 |
Youngø |
5.5 ± 1.0 |
1.5 ± 0.6 |
47.5 ± 9.8 |
182 ± 35 |
83 ± 18 |
6.0 ± 0.9 |
140 ± 33 |
Elderlyý |
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 sin |
gle 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 |
ND=not determined.
*clearance/bioavailability
†volume of distribution/bioavailability
‡healthy males 18–53 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;
¶healthy males and females 19–55 years of age.
#healthy male and female subjects 18–54 years of age
Þ60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose
β500 mg every 4 8h for patients with
moderate renal impairment (CLCR 20–50 mL/min) and infections of the respiratory
tract or skin
àdose-normalized values (to 500 mg dose), estimated by population
pharmacokinetic modeling
èhealthy males 22–75 years of age
ðhealthy females 18–80 years of age
øyoung healthy male and female subjects
18–36 years of age
ýhealthy elderly male and female subjects 66–80 years of age |
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 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 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. Levofloxacin 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 oncedaily 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
Levofloxacin 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 IV
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 IV routes of administration can be considered
interchangeable (see Figure 2 and Figure 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 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 doses of
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
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 Levofloxacin.
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 [see Use in Specific Populations].
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 (AUC0-24 and Cmax) 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 Levofloxacin to healthy male subjects, the mean terminal plasma elimination
halflife 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 Levofloxacin
are not required following hemodialysis or CAPD [see DOSAGE AND ADMINISTRATION,
Use in Specific Populations].
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 [see Use in Specific Populations].
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 antacids, warfarin, theophylline, cyclosporine,
digoxin, probenecid, and cimetidine has been evaluated [see DRUG INTERACTIONS].
Microbiology
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.
Mechanism of 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).
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 Gram-negative
and Gram-positive bacteria.
Levofloxacin has been shown to be active against most
isolates of the following bacteria both in vitro and in clinical infections as
described in Indications and Usage (1):
Gram-Positive Bacteria
Enterococcus faecalis
Staphylococcus aureus (methicillin-susceptible
isolates)
Staphylococcus epidermidis (methicillin-susceptible
isolates)
Staphylococcus saprophyticus
Streptococcus pneumoniae (including multi-drug
resistant isolates [MDRSP]1)
Streptococcus pyogenes
Gram-Negative Bacteria
Enterobacter cloacae
Escherichia coli
Haemophilus influenza
Haemophilus parainfluenzae
Klebsiella pneumoniae
Legionella pneumophila
Moraxella catarrhalis
Proteus mirabilis
Pseudomonas aeruginosa
Serratia marcescens
Other Bacteria
Chlamydophila pneumoniae
Mycoplasma pneumoniae
1MDRSP (Multi-drug resistant Streptococcus
pneumoniae) isolates are isolates 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.
Gram-Positive Bacteria
Staphylococcus haemolyticus
β-hemolytic Streptococcus (Group C/F)
β-hemolytic Streptococcus (Group G)
Streptococcus agalactiae
Streptococcus milleri
Viridans group streptococci
Bacillus anthracis
Gram-Negative Bacteria
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
Yersinia pestis
Anaerobic Gram-Positive Bacteria
Clostridium perfringens
Susceptibility Tests
When available, the clinical microbiology laboratory
should provide the results of in vitro susceptibility test results for
antimicrobial drug products used in the resident hospitals to the physician as
periodic reports that describe the susceptibility profile of nosocomial and
community-acquired pathogens. These reports should aid the physician in
selecting an antibacterial drug product for treatment.
Dilution Techniques
Quantitative methods are used to determine antimicrobial
minimal inhibitory concentrations (MICs). These MICs 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 (broth or agar)1,2,4 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 9.
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 procedure requires the use of
standardized inoculum concentrations. This procedure uses paper disks
impregnated with 5 mcg levofloxacin to test the susceptibility of bacteria 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 9.
Table 9: Susceptibility Test Interpretive Criteria for
Levofloxacin
Pathogen |
Minimum Inhibitory Concentrations (mcg/mL) |
Disk Diffusion (zone diameter in mm) |
S |
I |
R |
S |
I |
R |
Enterobacteriaceae |
≤ 2 |
4 |
≥ 8 |
≥ 17 |
14-16 |
≤ 13 |
Enterococcus faecalis |
≤ 2 |
4 |
≥ 8 |
≥ 17 |
14-16 |
≤ 13 |
Staphylococcus species |
≤ 2 |
4 |
≥ 8 |
≥ 17 |
14-16 |
≤ 13 |
Pseudomonas aeruginosa |
≤ 2 |
4 |
≥ 8 |
≥ 17 |
14-16 |
≤ 13 |
Haemophilus influenzae |
≤ 2 |
* |
-- |
≥ 17 |
-- |
-- |
Haemophilus parainfluenzae |
≤ 2 |
-- |
-- |
≥ 17 |
-- |
-- |
Streptococcus pneumoniae |
≤ 2 |
4 |
≥ 8 |
≥ 17 |
14-16 |
≤ 13 |
Streptococcus pyogenes |
≤ 2 |
4 |
≥ 8 |
≥ 17 |
14-16 |
≤ 13 |
Yersinia pestis4 |
≤ 0.25 |
-- |
-- |
-- |
-- |
-- |
Bacillus anthracis4 |
≤ 0.25 |
-- |
-- |
-- |
-- |
-- |
S = Susceptible, I = Intermediate, R = Resistant
*The current absence of data on resistant isolates precludes defining any
categories other than “Susceptible.” Isolates yielding MIC/zone
diameter results suggestive of a “nonsusceptible” category should be
submitted to a reference laboratory for further testing. |
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 controls to monitor and ensure the accuracy and precision of
supplies and reagents used in the assay, and the techniques of the individuals
performing the test.1,2,3,4 Standard levofloxacin powder should
provide the range of MIC values noted in Table 10. For the diffusion technique
using the 5 mcg disk, the criteria in Table 10 should be achieved.
Table 10: Quality Control Ranges 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 |
ATCC 35218 |
0.015 - 0.06 |
-- |
Haemophilus influenzae |
ATCC 49247 |
0.008 - 0.03 |
32 - 40 |
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 - 2 |
20 - 25 |
Animal Toxicology And/Or Pharmacology
Levofloxacin and other quinolones have been shown to
cause arthropathy in immature animals of most species tested [see WARNINGS
AND PRECAUTIONS]. 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 at 40 mg/kg/day exhibited clinically severe arthrotoxicity
resulting in the termination of dosing at Day 8 of a 14-day dosing routine.
Slight musculoskeletal clinical effects, in the absence of gross pathological
or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day
(approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis
and articular cartilage lesions were observed at the 10 and 40 mg/kg dose
levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively,
based on AUC comparisons). Articular cartilage gross pathology and
histopathology persisted to the end of the 18-week recovery period for those
dogs from the 10 and 40 mg/kg/day dose levels.
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 nonsteroidal 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 nor inhibitor in the human
therapeutic plasma concentration range; therefore, no drug metabolizing
enzyme-related interactions with other drugs or agents are anticipated.
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 every 6–8 hours daily) followed by
oral ciprofloxacin (750 mg every 12 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 post-therapy 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 are detailed in Table
11.
Table 11: Clinical Success Rates and Bacteriological
Eradication Rates (Nosocomial Pneumonia)
Pathogen |
N |
Levofloxacin No. (%) of Patients Microbiologic/ Clinical Outcomes |
N |
Imipenem/Cilas tatin No. (%) of Patients Microbiologic/ Clinical Outcomes |
MSSA* |
21 |
14 (66.7)/13 (61.9) |
19 |
13 (68.4)/15 (78.9) |
P. aeruginosa† |
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. pneumoniae‡ |
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) |
*Methicillin-susceptible S. aureus
†See above text for use of combination therapy
‡The observed differences in rates for the clinical and microbiological
outcomes may reflect other factors that were not accounted for in the study |
Community-Acquired Pneumonia: 7–14 Day Treatment Regimen
Adult inpatients and outpatients with a diagnosis of
community-acquired bacterial pneumonia were evaluated in 2 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 Chlamydophila pneumoniae, Mycoplasma
pneumoniae, and Legionella pneumophila were 96%, 96%, and
70%, respectively. Microbiologic eradication rates across both studies are
presented in Table 12.
Table 12: Bacteriological Eradication Rates Across 2
Community Acquired Pneumonia Clinical Studies
Pathogen |
No. Pathogens |
Bacteriological 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 Pneumonia Due To Multi-Drug Resistant Streptococcus
pneumoniae
Levofloxacin was effective for the treatment of
community-acquired pneumonia caused by multi-drug resistant Streptococcus
pneumoniae (MDRSP). MDRSP isolates are isolates resistant to two or more of
the following antibacterials: penicillin (MIC ≥ 2 mcg/mL), 2nd
generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and
trimethoprim/sulfamethoxazole). 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 Table
13.
Table 13: Clinical and Bacterial Success Rates for
Levofloxacin-Treated MDRSP in Community Acquired Pneumonia Patients (Population
Valid for Efficacy)
Screening Susceptibility |
Clinical Success |
Bacteriological Success* |
n/N† |
% |
n/N‡ |
% |
Penic illin- 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 |
*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.
†n=the number of microbiologically evaluable patients who were clinical
successes; N=number of microbiologically evaluable patients in the designated
resistance group.
‡n=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically
evaluable patients; N=number of MDRSP isolates in a designated resistance
group. |
Not all isolates were resistant to all antimicrobial
classes tested. Success and eradication rates are summarized in Table 14.
Table 14: Clinical Success and Bacteriologic
Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired
Pneumonia)
Type of Resistance |
Clinical Success |
Bacteriologic Eradication |
Resistant to 2 antibacterials |
17/18 (94.4%) |
17/18 (94.4%) |
Resistant to 3 antibacterials |
14/15 (93.3%) |
14/15 (93.3%) |
Resistant to 4 antibacterials |
7/7 (100%) |
7/7 (100%) |
Resistant to 5 antibacterials |
0 |
0 |
Bacteremia with MDRSP |
8/9 (89%) |
8/9 (89%) |
Community-Acquired Pneumonia: 5-Day Treatment Regimen
To evaluate the safety and efficacy of the 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,
multicenter study comparing Levofloxacin 750 mg, IV or orally, every day for
five days or Levofloxacin 500 mg IV or orally, every day for 10 days.
Clinical success rates (cure plus improvement) in the
clinically evaluable population were 90.9% in the Levofloxacin 750 mg 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 cannot be determined statistically. The
microbiological efficacy of the 5-day regimen was documented for infections
listed in Table 15.
Table 15: Bacteriological Eradication Rates
(Community-Acquired Pneumonia)
S. pneumoniae |
19/20 (95%) |
Haemophilus influenzae |
12/12 (100%) |
Haemophilus parainfluenzae |
10/10 (100%) |
Mycoplasma pneumoniae |
26/27 (96%) |
Chlamydophila pneumoniae |
13/15 (87%) |
Acute Bacterial Sinusitis : 5-Day And 10–14 Day Treatment
Regimens
Levofloxacin is approved for the treatment of acute
bacterial sinusitis (ABS) using either 750 mg by mouth à 5 days or 500 mg by
mouth once daily à 10–14 days. To evaluate the safety and efficacy of a high
dose short course of Levofloxacin, 780 outpatient adults with clinically and
radiologically determined acute bacterial sinusitis were evaluated in a
double-blind, randomized, prospective, multicenter study comparing Levofloxacin
750 mg by mouth once daily for five days to Levofloxacin 500 mg by mouth once
daily for 10 days.
Clinical success rates (defined as complete or partial
resolution of the pre-treatment signs and symptoms of ABS to such an extent
that no further antibiotic treatment was deemed necessary) in the microbiologically
evaluable population were 91.4% (139/152) in the Levofloxacin 750 mg group and 88.6%
(132/149) in the Levofloxacin 500 mg group at the test-of-cure (TOC) visit (95%
CI [-4.2, 10.0] for Levofloxacin 750 mg minus Levofloxacin 500 mg).
Rates of clinical success by pathogen in the
microbiologically evaluable population who had specimens obtained by antral tap
at study entry showed comparable results for the five- and ten-day regimens at
the test-of-cure visit 22 days post treatment (see Table 16).
Table 16: Clinical Success Rate by Pathogen at the TOC
in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute
Bacterial Sinusitis)
Pathogen |
Levofloxacin 750 mg x 5 days |
Levofloxacin 500 mg x 10 days |
Streptococcus pneumoniae* |
25/27 (92.6%) |
26/27 (96.3%) |
Haemophilus influenzae* |
19/21 (90.5%) |
25/27 (92.6%) |
Moraxella catarrhalis* |
10/11 (90.9%) |
13/13 (100%) |
*Note: Forty percent of the subjects in this trial had
specimens obtained by sinus endoscopy. The efficacy data for subjects whose
specimen was obtained endoscopically were comparable to those presented in the
above table. |
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 once daily (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 (VB ) 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 evaluable 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 in Table 17.
Table 17: Bacteriological Eradication Rates (Chronic
Bacterial Prostatitis)
Pathogen |
Levofloxacin
(N=136) |
Ciprofloxacin
(N=125) |
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 ciprofloxacintreated patients (95% CI [-23.40, 2.89]
for Levofloxacin minus ciprofloxacin).
Complicated Urinary Tract Infections And Acute
Pyelonephritis : 5-Day Treatment Regimen
To evaluate the safety and efficacy of the higher dose
and shorter course of Levofloxacin, 1109 patients with cUTI and AP were
enrolled in a randomized, double-blind, multicenter clinical trial conducted in
the US from November 2004 to April 2006 comparing Levofloxacin 750 mg IV or
orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500
mg orally twice daily for 10 days (563 patients). Patients with AP complicated
by underlying renal diseases or conditions such as complete obstruction,
surgery, transplantation, concurrent infection or congenital malformation were excluded.
Efficacy was measured by bacteriologic eradication of the baseline organism(s)
at the posttherapy visit in patients with a pathogen identified at baseline.
The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active
dose of Levofloxacin and 5 to 9 days after the last dose of active
ciprofloxacin.
The bacteriologic cure rates overall for Levofloxacin and
control at the test-of-cure (TOC) visit for the group of all patients with a
documented pathogen at baseline (modified intent to treat or mITT) and the
group of patients in the mITT population who closely followed the protocol
(Microbiologically Evaluable) are summarized in Table 18.
Table 18: Bacteriological Eradication at Test-of-Cure
|
Levofloxacin 750 mg orally or IV once daily for 5 days |
Ciprofloxacin 400 mg IV/500 mg orally twice daily for 10 days |
Overall Difference [95% CI] |
n/N |
% |
n/N |
% |
Levofloxacin- Ciprofloxacin |
mITT Population* |
Overall (cUTI or AP) |
252/333 |
75.7 |
239/318 |
75.2 |
0.5 (-6.1, 7.1) |
cUTI |
168/230 |
73.0 |
157/213 |
73.7 |
|
AP |
84/103 |
81.6 |
82/105 |
78.1 |
|
Microbiologically Evaluable Population† |
Overall (cUTI or AP) |
228/265 |
86.0 |
215/241 |
89.2 |
-3.2 [-8.9, 2.5] |
cUTI |
154/185 |
83.2 |
144/165 |
87.3 |
|
AP |
74/80 |
92.5 |
71/76 |
93.4 |
|
*The mITT population included patients who received study
medication and who had a positive ( ≥ 105 CFU/mL) urine culture
with no more than 2 uropathogens at baseline. Patients with missing response
were counted as failures in this analysis.
†The Microbiologically Evaluable population included patients with a confirmed
diagnosis of cUTI or AP, a causative organism(s) at baseline present at ≥
105 CFU/mL, a valid test-of-cure urine culture, no pathogen isolated
from blood resistant to study drug, no premature discontinuation or loss to
follow-up, and compliance with treatment (among other criteria). |
Microbiologic eradication rates in the Microbiologically
Evaluable population at TOC for individual pathogens recovered from patients
randomized to Levofloxacin treatment are presented in Table 19.
Table 19: Bacteriological Eradication Rates for
Individual Pathogens Recovered From Patients Randomized to Levofloxacin 750 mg
QD for 5 Days Treatment
Pathogen |
Bacteriological Eradication Rate (n/N) |
% |
Escherichia coif |
155/172 |
90 |
Klebsiella pneumoniae |
20/23 |
87 |
Proteus mirabilis |
12/12 |
100 |
*The predominant organism isolated from patients with AP
was E. coli: 91% (63/69) eradication in AP and 89% (92/103) in patients with
cUTI. |
Complicated Urinary Tract Infections And Acute
Pyelonephritis : 10-Day Treatment Regimen
To evaluate the safety and efficacy of the 250 mg dose,
10 day regimen of Levofloxacin, 567 patients with uncomplicated UTI,
mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized,
double-blind, multicenter clinical trial conducted in the US from June 1993 to
January 1995 comparing Levofloxacin 250 mg orally once daily for 10 days (285
patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282
patients). Patients with a resistant pathogen, recurrent UTI, women over age 55
years, and with an indwelling catheter were initially excluded, prior to
protocol amendment which took place after 30% of enrollment. Microbiological
efficacy was measured by bacteriologic eradication of the baseline organism(s)
at 1–12 days post-therapy in patients with a pathogen identified at baseline.
The bacteriologic cure rates overall for Levofloxacin and
control at the test-of-cure (TOC) visit for the group of all patients with a
documented pathogen at baseline (modified intent to treat or mITT) and the
group of patients in the mITT population who closely followed the protocol
(Microbiologically Evaluable) are summarized in Table 20.
Table 20: Bacteriological Eradication Overall (cUTI or
AP) at Test-Of- Cure*
|
Levofloxacin
250 mg once daily for
10 days |
Ciprofloxacin
500 mg twice daily
for 10 days |
n/N |
% |
n/N |
% |
mITT Population† |
174/209 |
83.3 |
184/219 |
84.0 |
Microbiologically Evaluable Population‡ |
164/177 |
92.7 |
159/171 |
93.0 |
*1–9 days posttherapy for 30% of subjects enrolled prior
to a protocol amendment; 5–12 days posttherapy for 70% of subjects.
†The mITT population included patients who had a pathogen isolated at baseline.
Patients with missing response were counted as failures in this analysis.
‡The Microbiologically Evaluable population included mITT patients who met protocol-specified
evaluability criteria. |
Inhalational Anthrax (Post-Exposure)
The effectiveness of Levofloxacin for this indication is
based on plasma concentrations achieved in humans, a surrogate endpoint
reasonably likely to predict clinical benefit. Levofloxacin has not been tested
in humans for the post-exposure prevention of inhalation anthrax. The mean
plasma concentrations of Levofloxacin associated with a statistically
significant improvement in survival over placebo in the rhesus monkey model of
inhalational anthrax are reached or exceeded in adult and pediatric patients receiving
the recommended oral and intravenous dosage regimens [see INDICATIONS AND
USAGE; DOSAGE AND ADMINISTRATION].
Levofloxacin pharmacokinetics have been evaluated in
adult and pediatric patients. The mean (± SD) steady state peak plasma
concentration in human adults receiving 500 mg orally or intravenously once daily
is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total
plasma exposure (AUC0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively.
The predicted steady-state pharmacokinetic parameters in pediatric patients
ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12
hours (not to exceed 250 mg per dose) were calculated to be comparable to those
observed in adults receiving 500 mg orally once daily [see CLINICAL
PHARMACOLOGY].
In adults, the safety of Levofloxacin for treatment
durations of up to 28 days is well characterized. However, information
pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged Levofloxacin
therapy in adults should only be used when the benefit outweighs the risk.
In pediatric patients, the safety of levofloxacin for
treatment durations of more than 14 days has not been studied. An increased
incidence of musculoskeletal adverse events (arthralgia, arthritis,
tendinopathy, gait abnormality) compared to controls has been observed in
clinical studies with treatment duration of up to 14 days. Long-term safety
data, including effects on cartilage, following the administration of levofloxacin
to pediatric patients is limited [see WARNINGS AND PRECAUTIONS, Use
in Specific Populations].
A placebo-controlled animal study in rhesus monkeys
exposed to an inhaled mean dose of 49 LD (~2.7 Ã 106) spores (range
17 – 118 LD50) of B. anthracis (Ames strain) was conducted.
The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax
strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma
concentrations of levofloxacin achieved at expected Tmax (1 hour post-dose)
following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady
state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164
mcg/mL. Mean (SD) steady state AUC0-24 was 33.4 ± 3.2 mcg.h/mL (range 30.4 to
36.0 mcg.h/mL). Mortality due to anthrax for animals that received a 30 day
regimen of oral Levofloxacin beginning 24 hrs post exposure was significantly
lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher's
Exact Test]. The one levofloxacin treated animal that died of anthrax did so
following the 30-day drug administration period.
Plague
Efficacy studies of Levofloxacin could not be conducted
in humans with pneumonic plague for ethical and feasibility reasons. Therefore,
approval of this indication was based on an efficacy study conducted in
animals.
The mean plasma concentrations of Levofloxacin associated
with a statistically significant improvement in survival over placebo in an
African green monkey model of pneumonic plague are reached or exceeded in adult
and pediatric patients receiving the recommended oral and intravenous dosage regimens
[see INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION].
Levofloxacin pharmacokinetics have been evaluated in adult
and pediatric patients. The mean (± SD) steady state peak plasma concentration
in human adults receiving 500 mg orally or intravenously once daily is 5.7 ±
1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma
exposure (AUC0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The
predicted steady-state pharmacokinetic parameters in pediatric patients ranging
in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not
to exceed 250 mg per dose) were calculated to be comparable to those observed
in adults receiving 500 mg orally once daily [see CLINICAL PHARMACOLOGY].
A placebo-controlled animal study in African green
monkeys exposed to an inhaled mean dose of 65 LD50 (range 3 to 145
LD50) of Yersinia pestis (CO92 strain) was conducted. The
minimal inhibitory concentration (MIC) of levofloxacin for the Y. pestis strain
used in this study was 0.03 mcg/mL. Mean plasma concentrations of levofloxacin
achieved at the end of a single 30-min infusion ranged from 2.84 to 3.50 mcg/mL
in African green monkeys. Trough concentrations at 24 hours post-dose ranged
from < 0.03 to 0.06 mcg/mL. Mean (SD) AUC0-24 was 11.9 (3.1) mcg.h/mL (range
9.50 to 16.86 mcg.h/mL). Animals were randomized to receive either a 10-day
regimen of i.v. Levofloxacin or placebo beginning within 6 hrs of the onset of
telemetered fever ( ≥ 39°C for more than 1 hour). Mortality in the Levofloxacin
group was significantly lower (1/17) compared to the placebo group (7/7)
[p < 0.001, Fisher's Exact Test; exact 95% confidence interval (-99.9%,
-55.5%) for the difference in mortality]. One levofloxacin-treated animal was
euthanized on Day 9 post-exposure to Y. pestis due to a gastric complication;
it had a blood culture positive for Y. pestis on Day 3 and all
subsequent daily blood cultures from Day 4 through Day 7 were negative.
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