Absorption
Moxifloxacin, given as an oral tablet, is well absorbed from the gastrointestinal
tract. The absolute bioavailability of moxifloxacin is approximately 90 percent.
Co-administration with a high fat meal (i.e., 500 calories from fat) does not
affect the absorption of moxifloxacin. Consumption of 1 cup of yogurt with moxifloxacin
does not significantly affect the extent or rate of systemic absorption (AUC).
The mean (± SD) Cmax and AUC values following single and multiple doses
of 400 mg moxifloxacin given orally are summarized below.
| |
Cmax
(mg/L) |
AUC
(mg•h/L) |
Half-life
(hr) |
Single Dose Oral
Healthy (n = 372) |
3.1 ± 1 |
36.1 ± 9.1 |
11.5 - 15.6* |
| Multiple Dose Oral |
|
| Healthy young male/female (n = 15) |
4.5 ± 0.5 |
48 ± 2.7 |
12.7 ± 1.9 |
| Healthy elderly male (n = 8) |
3.8 ± 0.3 |
51.8 ± 6.7 |
|
| Healthy elderly female (n = 8) |
4.6 ± 0.6 |
54.6 ± 6.7 |
|
| Healthy young male (n = 8) |
3.6 ± 0.5 |
48.2 ± 9 |
|
| Healthy young female (n = 9) |
4.2 ± 0.5 |
49.3 ± 9.5 |
|
| * Range of means from different studies |
The mean (± SD) Cmax and AUC values following single and multiple doses
of 400 mg moxifloxacin given by 1 hour I.V. infusion are summarized below.
| |
Cmax
(mg/L) |
AUC
(mg•h/L) |
Half-life
(hr) |
| Single Dose I.V. |
|
| Healthy young male/female (n = 56) |
3.9 ± 0.9 |
39.3 ± 8.6 |
8.2 - 15.4* |
| Patients (n = 118) |
|
|
|
| Male (n = 64) |
4.4 ± 3.7 |
|
|
| Female (n = 54) |
4.5 ± 2 |
|
|
| < 65 years (n = 58) |
4.6 ± 4.2 |
|
|
| ≥ 65 years (n = 60) |
4.3 ± 1.3 |
|
|
| Multiple Dose I.V. |
|
| Healthy young male (n = 8) |
4.2 ± 0.8 |
38 ± 4.7 |
14.8 ± 2.2 |
| Healthy elderly (n =12; 8 male, 4 female) |
6.1 ± 1.3 |
48.2 ± 0.9 |
10.1 ± 1.6 |
| Patients** (n = 107) |
|
|
|
| Male (n = 58) |
4.2 ± 2.6 |
|
|
| Female (n = 49) |
4.6 ± 1.5 |
|
|
| < 65 years (n = 52) |
4.1 ± 1.4 |
|
|
| ≥ 65 years (n = 55) |
4.7 ± 2.7 |
|
|
* Range of means from different studies
** Expected Cmax (concentration obtained around the time of the end of
the infusion) |
Plasma concentrations increase proportionately with dose up to the highest
dose tested (1200 mg single oral dose). The mean (± SD) elimination half-life
from plasma is 12 ± 1.3 hours; steady-state is achieved after at least
three days with a 400 mg once daily regimen.
Mean Steady-State Plasma Concentrations of Moxifloxacin Obtained
With Once Daily Dosing of 400 mg Either Orally (n=10) or by I.V. Infusion (n=12)
Distribution
Moxifloxacin is approximately 30-50% bound to serum proteins, independent of
drug concentration. The volume of distribution of moxifloxacin ranges from 1.7
to 2.7 L/kg. Moxifloxacin is widely distributed throughout the body, with tissue
concentrations often exceeding plasma concentrations. Moxifloxacin has been
detected in the saliva, nasal and bronchial secretions, mucosa of the sinuses,
skin blister fluid, subcutaneous tissue, skeletal muscle, and abdominal tissues
and fluids following oral or intravenous administration of 400 mg. Moxifloxacin
concentrations measured post-dose in various tissues and fluids following a
400 mg oral or I.V. dose are summarized in the following table. The rates of
elimination of moxifloxacin from tissues generally parallel the elimination
from plasma.
Moxifloxacin Concentrations (mean ± SD) in Tissues
and the Corresponding Plasma Concentrations After a Single 400 mg Oral or Intravenous
Dose §
| Tissue or Fluid |
N |
Plasma
Concentration
(μg/mL) |
Tissue or Fluid
Concentration
(μg/mL or μg/g) |
Tissue
Plasma
Ratio: |
| Respiratory |
| Alveolar Macrophages |
5 |
3.3 ± 0.7 |
61.8 ± 27.3 |
61.8 ± 27.3 |
| Bronchial Mucosa |
8 |
3.3 ± 0.7 |
5.5 ± 1.3 |
5.5 ± 1.3 |
| Epithelial Lining Fluid |
5 |
3.3 ± 0.7 |
24.4 ± 14.7 |
24.4 ± 14.7 |
| Sinus |
| Maxillary Sinus Mucosa |
4 |
3.7 ± 1.1 † |
7.6 ± 1.7 |
7.6 ± 1.7 |
| Anterior Ethmoid Mucosa |
3 |
3.7 ± 1.1 † |
8.8 ± 4.3 |
8.8 ± 4.3 |
| Nasal Polyps |
4 |
3.7 ± 1.1 † |
9.8 ± 4.5 |
9.8 ± 4.5 |
| Skin, Musculoskeletal |
| Blister Fluid |
5 |
3 ± 0.5‡ |
2.6 ± 0.9 |
2.6 ± 0.9 |
| Subcutaneous Tissue |
6 |
2.3 ± 0.4# |
0.9 ± 0.3* |
0.9 ± 0.3* |
| Skeletal Muscle |
6 |
2.3 ± 0.4# |
0.9 ± 0.2* |
0.9 ± 0.2* |
| Intra-Abdominal |
| Abdominal tissue |
8 |
2.9 ± 0.5 |
7.6 ± 2 |
7.6 ± 2 |
| Abdominal exudate |
10 |
2.3 ± 0.5 |
3.5 ± 1.2 |
3.5 ± 1.2 |
| Abscess fluid |
6 |
2.7 ± 0.7 |
2.3 ± 1.5 |
2.3 ± 1.5 |
§all moxifloxacin concentrations were
measured 3 hours after a single 400 mg dose, except the abdominal tissue
and exudate concentrations which were measured at 2 hours post-dose and
the sinus concentrations which were measured 3 hours post-dose after 5
days of dosing.
† N = 5
‡N = 7
#N = 12
* Reflects only non-protein bound concentrations of drug. |
Metabolism
Approximately 52% of an oral or intravenous dose of moxifloxacin is metabolized
via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved
in moxifloxacin metabolism, and is not affected by moxifloxacin. The sulfate
conjugate (M1) accounts for approximately 38% of the dose, and is eliminated
primarily in the feces. Approximately 14% of an oral or intravenous dose is
converted to a glucuronide conjugate (M2), which is excreted exclusively in
the urine. Peak plasma concentrations of M2 are approximately 40% those of the
parent drug, while plasma concentrations of M1 are generally less than 10% those
of moxifloxacin.
In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin
does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that
moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized
by these enzymes.
Excretion
Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted
as unchanged drug (~20% in urine and ~25% in feces). A total of 96% ±
4% of an oral dose is excreted as either unchanged drug or known metabolites.
The mean (± SD) apparent total body clearance and renal clearance are
12 ± 2 L/hr and 2.6 ± 0.5 L/hr, respectively.
Special Populations
Geriatric
Following oral administration of 400 mg moxifloxacin for 10 days in 16 elderly
(8 male; 8 female) and 17 young (8 male; 9 female) healthy volunteers, there
were no age-related changes in moxifloxacin pharmacokinetics. In 16 healthy
male volunteers (8 young; 8 elderly) given a single 200 mg dose of oral moxifloxacin,
the extent of systemic exposure (AUC and Cmax) was not statistically different
between young and elderly males and elimination half-life was unchanged. No
dosage adjustment is necessary based on age. In large phase III studies, the
concentrations around the time of the end of the infusion in elderly patients
following intravenous infusion of 400 mg were similar to those observed in young
patients.
Pediatric
The pharmacokinetics of moxifloxacin in pediatric subjects have not been studied.
Gender
Following oral administration of 400 mg moxifloxacin daily for 10 days to 23
healthy males (19-75 years) and 24 healthy females (19-70 years), the mean AUC
and Cmax were 8% and 16% higher, respectively, in females compared to males.
There are no significant differences in moxifloxacin pharmacokinetics between
male and female subjects when differences in body weight are taken into consideration.
A 400 mg single dose study was conducted in 18 young males and females. The
comparison of moxifloxacin pharmacokinetics in this study (9 young females and
9 young males) showed no differences in AUC or Cmax due to gender. Dosage adjustments
based on gender are not necessary.
Race
Steady-state moxifloxacin pharmacokinetics in male Japanese subjects were similar
to those determined in Caucasians, with a mean Cmax of 4.1 μg/mL, an AUC24
of 47 μg•h/mL, and an elimination half-life of 14 hours, following 400
mg p.o. daily.
Renal Insufficiency
The pharmacokinetic parameters of moxifloxacin are not significantly altered
in mild, moderate, severe, or end-stage renal disease. No dosage adjustment
is necessary in patients with renal impairment, including those patients requiring
hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD).
In a single oral dose study of 24 patients with varying degrees of renal function
from normal to severely impaired, the mean peak concentrations (Cmax) of moxifloxacin
were reduced by 21% and 28% in the patients with moderate (CLCR ≥ 30 and
≤ 60 mL/min) and severe (CLCR < 30 mL/min) renal impairment, respectively.
The mean systemic exposure (AUC) in these patients was increased by 13%. In
the moderate and severe renally impaired patients, the mean AUC for the sulfate
conjugate (M1) increased by 1.7-fold (ranging up to 2.8-fold) and mean AUC and
Cmax for the glucuronide conjugate (M2) increased by 2.8-fold (ranging up to
4.8-fold) and 1.4-fold (ranging up to 2.5-fold), respectively.
The pharmacokinetics of single dose and multiple dose moxifloxacin were studied
in patients with CLCR < 20 mL/min on either hemodialysis or continuous ambulatory
peritoneal dialysis (8 HD, 8 CAPD). Following a single 400 mg oral dose, the
AUC of moxifloxacin in these HD and CAPD patients did not vary significantly
from the AUC generally found in healthy volunteers. Cmaxvalues of moxifloxacin
were reduced by about 45% and 33% in HD and CAPD patients, respectively, compared
to healthy, historical controls. The exposure (AUC) to the sulfate conjugate
(M1) increased by 1.4- to 1.5-fold in these patients. The mean AUC of the glucuronide
conjugate (M2) increased by a factor of 7.5, whereas the mean Cmax values of
the glucuronide conjugate (M2) increased by a factor of 2.5 to 3, compared to
healthy subjects. The sulfate and the glucuronide conjugates of moxifloxacin
are not microbiologically active, and the clinical implication of increased
exposure to these metabolites in patients with renal disease including those
undergoing HD and CAPD has not been studied.
Oral administration of 400 mg QD moxifloxacin for 7 days to patients on HD
or CAPD produced mean systemic exposure (AUCss) to moxifloxacin similar to that
generally seen in healthy volunteers. Steady-state Cmax values were about 22%
lower in HD patients but were comparable between CAPD patients and healthy volunteers.
Both HD and CAPD removed only small amounts of moxifloxacin from the body (approximately
9% by HD, and 3% by CAPD). HD and CAPD also removed about 4% and 2% of the glucuronide
metabolite (M2), respectively.
Hepatic Insufficiency
No dosage adjustment is recommended for mild, moderate, or severe hepatic insufficiency
(Child-Pugh Classes A, B, or C). However, due to metabolic disturbances associated
with hepatic insufficiency, which may lead to QT prolongation, moxifloxacin
should be used with caution in these patients. (See WARNINGS
and DOSAGE AND ADMINISTRATION).
In 400 mg single oral dose studies in 6 patients with mild (Child-Pugh Class
A) and 10 patients with moderate (Child-Pugh Class B) hepatic insufficiency,
moxifloxacin mean systemic exposure (AUC) was 78% and 102%, respectively, of
18 healthy controls and mean peak concentration (Cmax) was 79% and 84% of controls.
The mean AUC of the sulfate conjugate of moxifloxacin (M1) increased by 3.9-fold
(ranging up to 5.9-fold) and 5.7-fold (ranging up to 8-fold) in the mild and
moderate groups, respectively. The mean Cmax of M1 increased by approximately
3-fold in both groups (ranging up to 4.7- and 3.9-fold). The mean AUC of the
glucuronide conjugate of moxifloxacin (M2) increased by 1.5-fold (ranging up
to 2.5-fold) in both groups. The mean Cmax of M2 increased by 1.6- and 1.3-fold
(ranging up to 2.7- and 2.1-fold), respectively. The clinical significance of
increased exposure to the sulfate and glucuronide conjugates has not been studied.
In a subset of patients participating in a clinical trial, the plasma concentrations
of moxifloxacin and metabolites determined approximately at the moxifloxacin
Tmax following the first intravenous or oral moxifloxacin dose in the Child-Pugh
Class C patients (n=10) were similar to those in the Child-Pugh Class A/B patients
(n=5), and also similar to those observed in healthy volunteer studies.
Photosensitivity Potential
A study of the skin response to ultraviolet (UVA and UVB) and visible radiation
conducted in 32 healthy volunteers (8 per group) demonstrated that moxifloxacin
does not show phototoxicity in comparison to placebo. The minimum erythematous
dose (MED) was measured before and after treatment with moxifloxacin (200 mg
or 400 mg once daily), lomefloxacin (400 mg once daily), or placebo. In this
study, the MED measured for both doses of moxifloxacin were not significantly
different from placebo, while lomefloxacin significantly lowered the MED. (See
PRECAUTIONS: INFORMATION FOR PATIENTS.)
It is difficult to ascribe relative photosensitivity/phototoxicity among various
fluoroquinolones during actual patient use because other factors play a role
in determining a subject's susceptibility to this adverse event such as: a patient's
skin pigmentation, frequency and duration of sun and artificial ultraviolet
light (UV) exposure, wearing of sunscreen and protective clothing, the use of
other concomitant drugs and the dosage and duration of fluoroquinolone therapy
(See ADVERSE REACTIONS and ADVERSE
REACTIONS/Post-Marketing Adverse Event Reports).
Drug-drug Interactions
The potential for pharmacokinetic drug interactions between moxifloxacin and
itraconazole, theophylline, warfarin, digoxin, atenolol, probenecid, morphine,
oral contraceptives, ranitidine, glyburide, calcium, iron, and antacids has
been evaluated. There was no clinically significant effect of moxifloxacin on
itraconazole, theophylline, warfarin, digoxin, atenolol, oral contraceptives,
or glyburide kinetics. Itraconazole, theophylline, warfarin, digoxin, probenecid,
morphine, ranitidine, and calcium did not significantly affect the pharmacokinetics
of moxifloxacin. These results and the data from in vitro studies suggest
that moxifloxacin is unlikely to significantly alter the metabolic clearance
of drugs metabolized by CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2 enzymes.
As with all other quinolones, iron and antacids significantly reduced bioavailability
of moxifloxacin.
Itraconazole
In a study involving 11 healthy volunteers, there was no significant effect
of itraconazole (200 mg once daily for 9 days), a potent inhibitor of cytochrome
P4503A4, on the pharmacokinetics of moxifloxacin (a single 400 mg dose given
on the 7th day of itraconazole dosing). In addition, moxifloxacin was shown
not to affect the pharmacokinetics of itraconazole.
Theophylline
No significant effect of moxifloxacin (200 mg every twelve hours for 3 days)
on the pharmacokinetics of theophylline (400 mg every twelve hours for 3 days)
was detected in a study involving 12 healthy volunteers. In addition, theophylline
was not shown to affect the pharmacokinetics of moxifloxacin. The effect of
co-administration of a 400 mg dose of moxifloxacin with theophylline has not
been studied, but it is not expected to be clinically significant based on in
vitro metabolic data showing that moxifloxacin does not inhibit the CYP1A2
isoenzyme.
Warfarin
No significant effect of moxifloxacin (400 mg once daily for eight days) on
the pharmacokinetics of R- and S-warfarin (25 mg single dose of warfarin sodium
on the fifth day) was detected in a study involving 24 healthy volunteers. No
significant change in prothrombin time was observed. (See PRECAUTIONS: DRUG
INTERACTIONS.)
Digoxin
No significant effect of moxifloxacin (400 mg once daily for two days) on digoxin
(0.6 mg as a single dose) AUC was detected in a study involving 12 healthy volunteers.
The mean digoxin Cmax increased by about 50% during the distribution phase of
digoxin. This transient increase in digoxin Cmax is not viewed to be clinically
significant. Moxifloxacin pharmacokinetics were similar in the presence or absence
of digoxin. No dosage adjustment for moxifloxacin or digoxin is required when
these drugs are administered concomitantly.
Atenolol
In a crossover study involving 24 healthy volunteers (12 male; 12 female),
the mean atenolol AUC following a single oral dose of 50 mg atenolol with placebo
was similar to that observed when atenolol was given concomitantly with a single
400 mg oral dose of moxifloxacin. The mean Cmax of single dose atenolol decreased
by about 10% following co-administration with a single dose of moxifloxacin.
Morphine
No significant effect of morphine sulfate (a single 10 mg intramuscular dose)
on the mean AUC and Cmax of moxifloxacin (400 mg single dose) was observed in
a study of 20 healthy male and female volunteers.
Oral Contraceptives
A placebo-controlled study in 29 healthy female subjects showed that moxifloxacin
400 mg daily for 7 days did not interfere with the hormonal suppression of oral
contraception with 0.15 mg levonorgestrel/0.03 mg ethinylestradiol (as measured
by serum progesterone, FSH, estradiol, and LH), or with the pharmacokinetics
of the administered contraceptive agents.
Probenecid
Probenecid (500 mg twice daily for two days) did not alter the renal clearance
and total amount of moxifloxacin (400 mg single dose) excreted renally in a
study of 12 healthy volunteers.
Ranitidine
No significant effect of ranitidine (150 mg twice daily for three days as pretreatment)
on the pharmacokinetics of moxifloxacin (400 mg single dose) was detected in
a study involving 10 healthy volunteers.
Antidiabetic agents
In diabetics, glyburide (2.5 mg once daily for two weeks pretreatment and for
five days concurrently) mean AUC and Cmax were 12% and 21% lower, respectively,
when taken with moxifloxacin (400 mg once daily for five days) in comparison
to placebo. Nonetheless, blood glucose levels were decreased slightly in patients
taking glyburide and moxifloxacin in comparison to those taking glyburide alone,
suggesting no interference by moxifloxacin on the activity of glyburide. These
interaction results are not viewed as clinically significant.
Calcium
Twelve healthy volunteers were administered concomitant moxifloxacin (single
400 mg dose) and calcium (single dose of 500 mg Ca++ dietary supplement) followed
by an additional two doses of calcium 12 and 24 hours after moxifloxacin administration.
Calcium had no significant effect on the mean AUC of moxifloxacin. The mean
Cmax was slightly reduced and the time to maximum plasma concentration was prolonged
when moxifloxacin was given with calcium compared to when moxifloxacin was given
alone (2.5 hours versus 0.9 hours). These differences are not considered to
be clinically significant.
Antacids
When moxifloxacin (single 400 mg tablet dose) was administered two hours before,
concomitantly, or 4 hours after an aluminum/magnesium-containing antacid (900
mg aluminum hydroxide and 600 mg magnesium hydroxide as a single oral dose)
to 12 healthy volunteers there was a 26%, 60% and 23% reduction in the mean
AUC of moxifloxacin, respectively. Moxifloxacin should be taken at least 4 hours
before or 8 hours after antacids containing magnesium or aluminum, as well as
sucralfate, metal cations such as iron, and multivitamin preparations with zinc,
or VIDEX® (didanosine) chewable/ buffered tablets or the pediatric powder
for oral solution. (See PRECAUTIONS: DRUG INTERACTIONS
and DOSAGE AND ADMINISTRATION.)
Iron
When moxifloxacin tablets were administered concomitantly with iron (ferrous
sulfate 100 mg once daily for two days), the mean AUC and Cmax of moxifloxacin
was reduced by 39% and 59%, respectively. Moxifloxacin should only be taken
more than 4 hours before or 8 hours after iron products. (See PRECAUTIONS:
DRUG INTERACTIONS and DOSAGE
AND ADMINISTRATION.)
Electrocardiogram
Prolongation of the QT interval in the ECG has been observed in some patients
receiving moxifloxacin. Following oral dosing with 400 mg of moxifloxacin the
mean (± SD) change in QTc from the pre-dose value at the time of maximum
drug concentration was 6 msec (± 26) (n = 787). Following a course of
daily intravenous dosing (400 mg; 1 hour infusion each day) the mean change
in QTc from the Day 1 pre-dose value was 9 msec (± 24) on Day 1 (n =
69) and 3 msec (± 29) on Day 3 (n = 290). (See WARNINGS.)
There is limited information available on the potential for a pharmacodynamic
interaction in humans between moxifloxacin and other drugs that prolong the
QTc interval of the electrocardiogram. Sotalol, a Class III antiarrhythmic,
has been shown to further increase the QTc interval when combined with high
doses of intravenous (I.V.) moxifloxacin in dogs. Therefore, moxifloxacin should
be avoided with Class IA and Class III antiarrhythmics. (See Animal Pharmacology,
WARNINGS, and PRECAUTIONS.)
Microbiology
Moxifloxacin has in vitro activity against a wide range of Gram-positive
and Gram-negative microorganisms. The bactericidal action of moxifloxacin results
from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV required
for bacterial DNA replication, transcription, repair, and recombination. It
appears that the C8-methoxy moiety contributes to enhanced activity and lower
selection of resistant mutants of Gram-positive bacteria compared to the C8-H
moiety. The presence of the bulky bicycloamine substituent at the C-7 position
prevents active efflux, associated with the NorA or pmrA genes
seen in certain Gram-positive bacteria.
The mechanism of action for quinolones, including moxifloxacin, is different
from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore,
microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin
and other quinolones. There is no known cross-resistance between moxifloxacin
and other classes of antimicrobials.
In vitro resistance to moxifloxacin develops slowly via multiple-step
mutations. Resistance to moxifloxacin occurs in vitro at a general frequency
of between 1.8 x 10–9 to < 1 x 10–11 for Gram-positive
bacteria.
Cross-resistance has been observed between moxifloxacin and other fluoroquinolones
against Gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones
may, however, still be susceptible to moxifloxacin.
Moxifloxacin 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 only)
Streptococcus anginosus
Streptococcus constellatus
Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]*)
Streptococcus pyogenes
* MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates
previously known as PRSP (Penicillin-resistant S. pneumoniae), and are
strains resistant to two or more of the following antibiotics: penicillin (MIC
≥ 2 μg/mL), 2nd generation cephalosporins (e.g., cefuroxime), macrolides,
tetracyclines, and trimethoprim/sulfamethoxazole.
Aerobic Gram-negative microorganisms
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
Anaerobic microorganisms
Bacteroides fragilis
Bacteroides thetaiotaomicron
Clostridium perfringens
Peptostreptococcus species
Other microorganisms
Chlamydia pneumoniae
Mycoplasma pneumoniae
The following in vitro data are available, but their clinical significance
is unknown. Moxifloxacin exhibits in vitro minimum inhibitory concentrations
(MICs) of 2 μg/mL or less against most ( ≥ 90%) strains of the following
microorganisms; however, the safety and effectiveness of moxifloxacin in treating
clinical infections due to these microorganisms have not been established in
adequate and well-controlled clinical trials.
Aerobic Gram-positive microorganisms
Staphylococcus epidermidis (methicillin-susceptible strains only)
Streptococcus agalactiae
Streptococcus viridans group
Aerobic Gram-negative microorganisms
Citrobacter freundii
Klebsiella oxytoca
Legionella pneumophila
Anaerobic microorganisms
Fusobacterium species
Prevotella species
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine
antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates
of the susceptibility of bacteria to antimicrobial compounds. The MICs 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 moxifloxacin powder.
The MIC values should be interpreted according to the following criteria:
For testing Enterobacteriaceae and methicillin-susceptible Staphylococcus
aureus:
| MIC (μg/mL) |
Interpretation |
| ≤ 2 |
Susceptible(S) |
| 4 |
Intermediate(I) |
| ≥ 8 |
Resistant(R) |
For testing Haemophilus influenzae and Haemophilus parainfluenzae
a:
| MIC (μg/mL) |
Interpretation |
| ≤ 1 |
Susceptible(S) |
| a This interpretive standard
is applicable only to broth microdilution susceptibility tests with Haemophilus
influenzae and Haemophilus parainfluenzae using Haemophilus
Test Medium1. |
The current absence of data on resistant strains precludes defining any results
other than “Susceptible”. Strains yielding MIC results suggestive
of a “nonsusceptible” category should be submitted to a reference
laboratory for further testing.
For testing Streptococcus species including Streptococcus pneumoniaeb
and Enterococcus faecalis:
| MIC (μg/mL) |
Interpretation |
| ≤ 1 |
Susceptible(S) |
| 2 |
Intermediate(I) |
| ≥ 4 |
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 moxifloxacin powder should provide the following MIC values:
| Microorganism |
|
MIC (μg/mL) |
| Enterococcus faecalis |
ATCC 29212 |
0.06 - 0.5 |
| Escherichia coli |
ATCC 25922 |
0.008 - 0.06 |
| Haemophilus influenzae |
ATCC 49247c |
0.008 - 0.03 |
| Staphylococcus aureus |
ATCC 29213 |
0.015 - 0.06 |
| Streptococcus pneumoniae |
ATCC 49619d |
0.06 - 0.25 |
cThis quality control range is
applicable to only H. influenzae ATCC 49247 tested by a broth microdilution
procedure using Haemophilus Test Medium (HTM)1.
dThis quality control range is applicable to only S. pneumoniae
ATCC 49619 tested by a broth microdilution procedure using cation-adjusted
Mueller-Hinton broth with 2 - 5% lysed horse blood. |
Diffusion Techniques: Quantitative methods that require measurement
of zone diameters also provide reproducible estimates of the 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 moxifloxacin to test the susceptibility of microorganisms
to moxifloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility
test with a 5-μg moxifloxacin disk should be interpreted according to the
following criteria:
The following zone diameter interpretive criteria should be used for testing
Enterobacteriaceae and methicillin-susceptible Staphylococcus aureus:
| Zone Diameter (mm) |
Interpretation |
| ≥ 19 |
Susceptible(S) |
| 16 – 18 |
Intermediate(I) |
| ≤ 15 |
Resistant(R) |
For testing Haemophilus influenzae and Haemophilus parainfluenzaee:
| Zone Diameter (mm) |
Interpretation |
| ≤ 18 |
Susceptible(S) |
| e This zone diameter standard
is applicable only to tests with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium (HTM)2. |
The current absence of data on resistant strains precludes defining any results
other than “Susceptible”. Strains yielding zone diameter results
suggestive of a “nonsusceptible” category should be submitted to
a reference laboratory for further testing.
For testing Streptococcus species including Streptococcus pneumoniae
f and Enterococcus faecalis:
| Zone Diameter (mm) |
Interpretation |
| ≤ 18 |
Susceptible(S) |
| 15 – 17 |
Intermediate(I) |
| ≥ 14 |
Resistant(R) |
| f These interpretive standards
are applicable only to disk diffusion tests using Mueller-Hinton agar
supplemented with 5% sheep blood 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 moxifloxacin. As with standardized dilution techniques, diffusion
methods require the use of laboratory control microorganisms that are used to
control the technical aspects of the laboratory procedures.
For the diffusion technique, the 5-μg moxifloxacin disk should provide the
following zone diameters in these laboratory test quality control strains:
| Microorganism |
|
Zone Diameter (mm) |
| Escherichia coli |
ATCC 25922 |
28 – 35 |
| Haemophilus influenzae |
ATCC 49247g |
31 – 39 |
| Staphylococcus aureus |
ATCC 25923 |
28 – 35 |
| Streptococcus pneumoniae |
ATCC 49619h |
25 – 31 |
g These quality control limits
are applicable to only H. influenzae ATCC 49247 testing using Haemophilus
Test Medium (HTM)2.
h These quality control limits are applicable only to tests
conducted with S. pneumoniae ATCC 49619 tested by a disk diffusion
procedure using Mueller-Hinton agar supplemented with 5% sheep blood and
incubated in 5% CO2. |
Anaerobic Techniques: For anaerobic bacteria, the susceptibility
to moxifloxacin as MICs can be determined by standardized procedures3
such as reference agar dilution methodsi. The MICs obtained should
be interpreted according to the following criteria:
| MIC (ug/mL) |
Interpretation |
| ≤ 2 |
Susceptible(S) |
| 4 |
Intermediate(I) |
| ≥ 8 |
Resistant(R) |
| i This interpretive standard is
applicable to reference agar dilution susceptibility tests using Brucella
agar supplemented with hemin, vitamin K1 and 5% laked sheep
blood. |
Acceptable ranges of MICs (ug/mL) for control strains for reference agar dilution
testingj:
| Microorganism |
|
MIC (ug/mL) |
| Bacteroides fragilis |
ATCC 25285 |
0.12-0.5 |
| Bacteroides thetaiotaomicron |
ATCC 29741 |
1-4 |
| Eubacterium lentum |
ATCC 43055 |
0.12-0.5 |
| j These quality control ranges
are applicable to reference agar dilution tests using Brucella agar
supplemented with hemin, vitamin K1 and 5% laked sheep blood. |
Animal Pharmacology
Quinolones have been shown to cause arthropathy in immature animals. In studies
in juvenile dogs oral doses of moxifloxacin ≥ 30 mg/kg/day (approximately
1.5 times the maximum recommended human dose based upon systemic exposure) for
28 days resulted in arthropathy. There was no evidence of arthropathy in mature
monkeys and rats at oral doses up to 135 and 500 mg/kg/day, respectively.
Unlike some other members of the quinolone class, crystalluria was not observed
in 6 month repeat dose studies in rats and monkeys with moxifloxacin.
No ocular toxicity was observed in a 13 week oral repeat dose study in dogs
with a moxifloxacin dose of 60 mg/kg/day. Ocular toxicity was not observed in
6 month repeat dose studies in rats and monkeys (daily oral doses up to 500
mg/kg and 135 mg/kg, respectively). In beagle dogs, electroretinographic (ERG)
changes were observed in a 2 week study at oral doses of 60 and 90 mg/kg/day.
Histopathological changes were observed in the retina from one of four dogs
at 90 mg/kg/day, a dose associated with mortality in this study.
Some quinolones have been reported to have proconvulsant activity that is exacerbated
with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs). Moxifloxacin
at an oral dose of 300 mg/kg did not show an increase in acute toxicity or potential
for CNS toxicity (e.g., seizures) in mice when used in combination with NSAIDs
such as diclofenac, ibuprofen, or fenbufen.
In dog studies, at plasma concentrations about five times the human therapeutic
level, a QT-prolonging effect of moxifloxacin was found. Electrophysiological
in vitro studies suggested an inhibition of the rapid activating component
of the delayed rectifier potassium current (IKr) as an underlying mechanism.
In dogs, the combined infusion of sotalol, a Class III antiarrhythmic agent,
with moxifloxacin induced a higher degree of QTc prolongation than that induced
by the same dose (30 mg/kg) of moxifloxacin alone.
In a local tolerability study performed in dogs, no signs of local intolerability
were seen when moxifloxacin was administered intravenously. After intra-arterial
injection, inflammatory changes involving the peri-arterial soft tissue were
observed suggesting that intra-arterial administration of moxifloxacin should
be avoided.
Clinical Studies
Acute Bacterial Exacerbation of Chronic Bronchitis
AVELOX Tablets (400 mg once daily for five days) were evaluated for the treatment
of acute bacterial exacerbation of chronic bronchitis in a large, randomized,
double-blind, controlled clinical trial conducted in the US. This study compared
AVELOX with clarithromycin (500 mg twice daily for 10 days) and enrolled 629
patients. The primary endpoint for this trial was clinical success at 7-17 days
post-therapy. The clinical success for AVELOX was 89% (222/250) compared to
89% (224/251) for clarithromycin.
The following outcomes are the clinical success rates at the follow-up visit
for the clinically evaluable patient groups by pathogen:
| PATHOGEN |
AVELOX |
Clarithromycin |
| Streptococcus pneumoniae |
16/16 (100%) |
20/23 (87%) |
| Haemophilus influenzae |
33/37 (89%) |
36/41 (88%) |
| Haemophilus parainfluenzae |
16/16 (100%) |
14/14 (100%) |
| Moraxella catarrhalis |
29/34 (85%) |
24/24 (100%) |
| Staphylococcus aureus |
15/16 (94%) |
6/8 (75%) |
| Klebsiella pneumoniae |
18/20 (90%) |
10/11 (91%) |
The microbiological eradication rates (eradication plus presumed eradication)
in AVELOX treated patients were Streptococcus pneumoniae 100%, Haemophilus
influenzae 89%, Haemophilus parainfluenzae 100%, Moraxella catarrhalis
85%, Staphylococcus aureus 94%, and Klebsiella pneumoniae 85%.
Community Acquired Pneumonia
A large, randomized, double-blind, controlled clinical trial was conducted
in the US to compare the efficacy of AVELOX Tablets (400 mg once daily) to that
of high-dose clarithromycin (500 mg twice daily) in the treatment of patients
with clinically and radiologically documented community acquired pneumonia.
This study enrolled 474 patients (382 of whom were valid for the primary efficacy
analysis conducted at the 14 - 35 day follow-up visit). Clinical success for
clinically evaluable patients was 95% (184/194) for AVELOX and 95% (178/188)
for high dose clarithromycin.
A large, randomized, double-blind, controlled trial was conducted in the US
and Canada to compare the efficacy of sequential IV/PO AVELOX 400 mg QD for
7-14 days to an IV/PO fluoroquinolone control (trovafloxacin or levofloxacin)
in the treatment of patients with clinically and radiologically documented community
acquired pneumonia. This study enrolled 516 patients, 362 of whom were valid
for the primary efficacy analysis conducted at the 7-30 day post-therapy visit.
The clinical success rate was 86% (157/182) for AVELOX therapy and 89% (161/180)
for the fluoroquinolone comparators.
An open-label ex-US study that enrolled 628 patients compared AVELOX to sequential
IV/PO amoxicillin/clavulanate (1.2 g IV q8h/625 mg PO q8h) with or without high-dose
IV/PO clarithromycin (500 mg BID). The intravenous formulations of the comparators
are not FD Aapproved. The clinical success rate at Day 5-7 (the primary efficacy
timepoint) for AVELOX therapy was 93% (241/258) and demonstrated superiority
to amoxicillin/clavulanate ± clarithromycin (85%, 239/280) [95% C.I.
2.9%, 13.2%]. The clinical success rate at the 21-28 days post-therapy visit
for AVELOX was 84% (216/258), which also demonstrated superiority to the comparators
(74%, 208/280) [95% C.I. 2.6%, 16.3%].
The clinical success rates by pathogen across four CAP studies are presented
below:
Clinical Success Rates By Pathogen (Pooled CAP Studies)
| PATHOGEN |
AVELOX |
| Streptococcus pneumoniae |
80/85 (94%) |
| Staphylococcus aureus |
17/20 (85%) |
| Klebsiella pneumoniae |
11/12 (92%) |
| Haemophilus influenzae |
56/61 (92%) |
| Chlamydia pneumoniae |
119/128 (93%) |
| Mycoplasma pneumoniae |
73/76 (96%) |
| Moraxella catarrhalis |
11/12 (92%) |
Community Acquired Pneumonia caused by Multi-Drug Resistant Streptococcus
pneumoniae (MDRSP)*
Avelox was effective in the treatment of community acquired pneumonia (CAP)
caused by multi-drug resistant Streptococcus pneumoniae MDRSP* isolates.
Of 37 microbiologically evaluable patients with MDRSP isolates, 35 patients
(95%) achieved clinical and bacteriological success post-therapy. The clinical
and bacteriological success rates based on the number of patients treated are
shown in the table below.
* MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates
previously known as PRSP (Penicillin-resistant S. pneumoniae), and are
strains resistant to two or more of the following antibiotics: penicillin (MIC
≥ 2 μg/mL), 2nd generation cephalosporins (e.g., cefuroxime), macrolides,
tetracyclines, and trimethoprim/sulfamethoxazole.
Clinical and Bacteriological Success Rates for Moxifloxacin-Treated
MDRSP CAP Patients (Population: Valid for Efficacy)
| Screening Susceptibility |
Clinical Success |
Bacteriological Success |
| n/N a |
% |
n/N b |
% |
| Penicillin-resistant |
21/21 |
100%* |
21/21 |
100%* |
| 2nd generation cephalosporin-resistant |
25/26 |
96%* |
25/26 |
96%* |
| Macrolide-resistant ** |
22/23 |
96% |
22/23 |
96% |
| Trimethoprim/sulfamethoxazole-resistant |
28/30 |
93% |
28/30 |
93% |
| Tetracycline-resistant |
17/18 |
94% |
17/18 |
94% |
a n = number of patients successfully
treated; N = number of patients with MDRSP (from a total of 37 patients)
b n = number of patients successfully treated (presumed eradication
or eradication); N = number of patients with MDRSP (from a total of 37
patients)
* One patient had a respiratory isolate that was resistant to penicillin
and cefuroxime but a blood isolate that was intermediate to penicillin
and cefuroxime. The patient is included in the database based on the respiratory
isolate.
**Azithromycin, clarithromycin, and erythromycin were the macrolide antimicrobials
tested. |
Not all isolates were resistant to all antimicrobial classes tested. Success
and eradication rates are summarized in the table below:
| S. pneumoniae with MDRSP |
Clinical Success |
Bacteriological
Eradication Rate |
| Resistant to 2 antimicrobials |
12/13 (92.3 %) |
12/13 (92.3 %) |
| Resistant to 3 antimicrobials |
10/11 (90.9 %)* |
10/11 (90.9 %)* |
| Resistant to 4 antimicrobials |
6/6 (100%) |
6/6 (100%) |
| Resistant to 5 antimicrobials |
7/7 (100%)* |
7/7 (100%)* |
| Bacteremia with MDRSP |
9/9 (100%) |
9/9 (100%) |
| * One patient had a respiratory isolate resistant
to 5 antimicrobials and a blood isolate resistant to 3 antimicrobials.
The patient was included in the category resistant to 5 antimicrobials. |
Acute Bacterial Sinusitis
In a large, controlled double-blind study conducted in the US, AVELOX Tablets
(400 mg once daily for ten days) were compared with cefuroxime axetil (250 mg
twice daily for ten days) for the treatment of acute bacterial sinusitis. The
trial included 457 patients valid for the primary efficacy determination. Clinical
success (cure plus improvement) at the 7 to 21 day post-therapy test of cure
visit was 90% for AVELOX and 89% for cefuroxime.
An additional non-comparative study was conducted to gather bacteriological
data and to evaluate microbiological eradication in adult patients treated with
AVELOX 400 mg once daily for seven days. All patients (n = 336) underwent antral
puncture in this study. Clinical success rates and eradication/ presumed eradication
rates at the 21 to 37 day follow-up visit were 97% (29 out of 30) for Streptococcus
pneumoniae, 83% (15 out of 18) for Moraxella catarrhalis, and 80%
(24 out of 30) for Haemophilus influenzae.
Uncomplicated Skin and Skin Structure Infections
A randomized, double-blind, controlled clinical trial conducted in the US compared
the efficacy of AVELOX 400 mg once daily for seven days with cephalexin HCl
500 mg three times daily for seven days. The percentage of patients treated
for uncomplicated abscesses was 30%, furuncles 8%, cellulitis 16%, impetigo
20%, and other skin infections 26%. Adjunctive procedures (incision and drainage
or debridement) were performed on 17% of the AVELOX treated patients and 14%
of the comparator treated patients. Clinical success rates in evaluable patients
were 89% (108/122) for AVELOX and 91% (110/121) for cephalexin HCl.
Complicated Skin and Skin Structure Infections
Two randomized, active controlled trials of cSSSI were performed. A double-blind
trial was conducted primarily in North America to compare the efficacy of sequential
IV/PO AVELOX 400 mg QD for 7-14 days to an IV/PO beta-lactam/beta-lactamase
inhibitor control in the treatment of patients with cSSSI. This study enrolled
617 patients, 335 of which were valid for the primary efficacy analysis. A second
open-label International study compared AVELOX 400 mg QD for 7-21 days to sequential
IV/PO beta-lactam/beta-lactamase inhibitor control in the treatment of patients
with cSSSI. This study enrolled 804 patients, 632 of which were valid for the
primary efficacy analysis. Surgical incision and drainage or debridement was
performed on 55% of the moxifloxacin treated and 53% of the comparator treated
patients in these studies and formed an integral part of therapy for this indication.
Success rates varied with the type of diagnosis ranging from 61% in patients
with infected ulcers to 90% in patients with complicated erysipelas. These rates
were similar to those seen with comparator drugs. The overall success rates
in the evaluable patients and the clinical success by pathogen are shown below:
Overall Clinical Success Rates in Patients with Complicated
Skin and Skin Structure Infections
| Study |
Moxifloxacin
n/ N (%) |
Comparator
n/N (%) |
95% Confidence
Interval |
| North America |
125/162 (77.2%) |
141/173 (81.5%) |
-14.4%, 2% |
| International |
254/315 (80.6%) |
268/317 (84.5%) |
-9.4%, 2.2% |
Clinical Success Rates by Pathogen in Patients with Complicated
Skin and Skin Structure Infections
| Pathogen |
Moxifloxacin
n/ N (%) |
Comparator
n/N (%) |
| Staphylococcus aureus (methicillin-susceptible strains) * |
106/129 (82.2%) |
120/137 (87.6%) |
| Escherichia coli |
31/38 (81.6 %) |
28/33 (84.8 %) |
| Klebsiella pneumoniae |
11/12 (91.7 % ) |
7/10 (70%) |
| Enterobacter cloacae |
9/11 (81.8%) |
4/7 (57.1%) |
| * methicillin susceptibility was only determined
in the North American Study |
Complicated Intra-Abdominal Infections
Two randomized, active controlled trials of cIAI were performed. A double-blind
trial was conducted primarily in North America to compare the efficacy of sequential
IV/PO AVELOX 400 mg QD for 5-14 days to IV/ piperacillin/tazobactam followed
by PO amoxicillin/clavulanic acid in the treatment of patients with cIAI, including
peritonitis, abscesses, appendicitis with perforation, and bowel perforation.
This study enrolled 681 patients, 379 of which were considered clinically evaluable.
A second open-label international study compared AVELOX 400 mg QD for 5-14 days
to IV ceftriaxone plus IV metronidazole followed by PO amoxicillin/clavulanic
acid in the treatment of patients with cIAI. This study enrolled 595 patients,
511 of which were considered clinically evaluable. The clinically evaluable
population consisted of subjects with a surgically confirmed complicated infection,
at least 5 days of treatment and a 25-50 day follow-up assessment for patients
at the Test of Cure visit. The overall clinical success rates in the clinically
evaluable patients are shown below:
Clinical Success Rates in Patients with Complicated Intra-Abdominal
Infections
| Study |
Moxifloxacin
n/ N (%) |
Comparator
n/N (%) |
95% Confidence
Interval |
| North America (overall) |
146/183
(79.8 %) |
153/196
(78.1 %) |
-7.4%, 9.3% |
| Abscess |
40/57
(70.2 %) |
49/63
(77.8 %) * |
NA a |
| Non-abscess |
106/126
(84.1 %) |
104/133
(78.2 %) |
NA |
| International (overall) |
199/246
(80.9 %) |
218/265
(82.3 %) |
-8.9 %,4.2% |
| Abscess |
73/93
(78.5 %) |
86/99
(86.9 %) |
NA |
| Non-abscess |
126/153
(82.4 %) |
132/166
(79.5 %) |
NA |
* excludes 2 patients who required additional surgery within the first 48 hours.
a NA - not applicable |
REFERENCES
1. Clinical and Laboratory Standards Institute, Methods for
Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Sixth
Edition. Approved Standard CLSI Document M7-A6, Vol. 23, No. 2, CLSI, Wayne,
PA, January, 2003.
2. Clinical and Laboratory Standards Institute, Performance
Standards for Antimicrobial Disk Susceptibility Tests-Eighth Edition. Approved
Standard CLSI Document M2-A8, Vol. 23, No. 1, CLSI, Wayne, PA, January, 2003.
3. Clinical and Laboratory Standards Institute, Methods for
Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard
CLSI Document M11-A6, Vol. 24, No. 2, CLSI, Wayne, PA, 2004.
Last updated on RxList: 2/18/2009