Clinical Therapeutics/Volume 32, Number 3, 2010

454 Volume 32 Number 3

Accepted for publication February 16, 2010.
doi: 10.1016/j.clinthera.2010.03.013
0149-2918/$ - see front matter
2010 Excerpta Medica Inc. All rights reserved.
ABSTRACT
Background: Besifloxacin is a topical ophthalmic
fluoroquinolone that was approved by the US Food
and Drug Administration (FDA) in May 2009 for the
treatment of bacterial conjunctivitis caused by suscep-
tible bacterial strains.
Objective: This article provides an overview of the
pharmacology, clinical efficacy, and tolerability of
ophthalmic besifloxacin when used for the treatment
of bacterial conjunctivitis.
Methods: Relevant reports pertaining to the phar-
macology, efficacy, and tolerability of besifloxacin were
identified through a search of MEDLINE (1985
December 2009) and International Pharmaceutical
Abstracts (1985December 2009) using the terms besi-
floxacin, BOL-303224-A, ophthalmic fluoroquinolones,
and bacterial conjunctivitis. Additional publications
were identified by reviewing the reference lists of iden-
tified articles and searching the FDA Web site.
Results: Besifloxacin has potent in vitro inhibitory
activity against most common ocular bacterial patho-
gens (MIC
90
values generally 4 g/mL), including
Staphylococcus aureus, Streptococcus pneumoniae,
and Haemophilus influenzae. In an ocular pharma-
cokinetic study in 64 healthy volunteers, the C
max
in tears (mean [SD], 610 [540] g/mL) was reached
10 minutes after a single ocular instillation of besi-
floxacin; concentrations 1.6 g/g of tear were sus-
tained for at least 24 hours; and the elimination t
1/2
was ~3.4 hours. In a study in 24 patients with a
clinical diagnosis of bilateral bacterial conjunctivitis,
systemic exposure (C
max
) after administration of besi-
floxacin ophthalmic suspension 3 times daily for 5 days
was <0.5 ng/mL. In 2 randomized, double-masked,
vehicle-controlled clinical trials, besifloxacin ophthal-
mic suspension was well tolerated and significantly
more efficacious than vehicle in achieving clinical
resolution (73.3% vs 43.1%, respectively, in one of
the studies [P < 0.001]; 45.2% vs 33.0% in the other
[P = 0.008]) and microbial eradication (88.3% vs
60.3% [P < 0.001] and 91.5% vs 59.7% [P < 0.001],
respectively). In a randomized, double-masked, parallel-
group, noninferiority trial comparing besifloxa-
cin ophthalmic suspension 0.6% with moxifloxacin
ophthalmic solution 0.5%, besifloxacin was found
to be noninferior to moxifloxacin (predefined cutoff
for noninferiority = 15), with no significant differ-
ences in rates of clinical resolution (58.3% and
59.4%, respectively; 95% CI, 9.48 to 7.29) or mi-
crobial eradication (93.3% and 91.1%; 95% CI,
2.44 to 6.74). Besifloxacin was generally well toler-
ated in these clinical trials, with the most common
(1.5%) ocular adverse events being nonspecific
conjunctivitis (2.6%), blurred vision (2.1%), bacteri-
al conjunctivitis (1.8%), and eye pain (1.5%). The
recommended dose of besifloxacin is 1 drop in the
affected eye(s) 3 times daily (412 hours apart) for
7 days.
Conclusion: Besifloxacin ophthalmic suspension
0.6% appeared to be well tolerated in the populations
studied and was efficacious in the treatment of bacterial
conjunctivitis caused by susceptible isolates. (Clin Ther.
2010;32:454471) 2010 Excerpta Medica Inc.
Key words: besifloxacin, bacterial conjunctivitis,
ophthalmic fluoroquinolones.
INTRODUCTION
Conjunctivitis is an inflammation of the conjunctiva
due to infectious or noninfectious causes.
1,2
Infec-
tious etiologies include bacterial, viral, and fungal
New Drug
Besifloxacin: A Topical Fluoroquinolone for the Treatment of
Bacterial Conjunctivitis
Mei H. Chang, BA, PharmD; and Horatio B. Fung, PharmD, BCPS
Pharmacy Service, James J. Peters Veterans Affairs Medical Center, Bronx, New York
March 2010 455
M.H. Chang and H.B. Fung
Routine culturing of eye swabs is impractical in
most settings and is not commonly performed.
1,4
Once
a clinical diagnosis of bacterial conjunctivitis has been
made, the choice of empiric therapy usually involves a
broad-spectrum, bacteriocidal, topical ophthalmic
antibiotic.
1,2
The presence of severe pain, decreased
vision, or hazy cornea, as well as lack of improvement
after 24 hours of antibiotic treatment, suggest a more
serious condition that requires referral to an ophthal-
mologist for further evaluation.
1
At least 6 different classes of topical antibiotics are
available in the United States for the treatment of
bacterial conjunctivitis: fluoroquinolones, aminogly-
cosides, polymyxin B combinations (with trimetho-
prim, with bacitracin, or with neomycin and grami-
cidin), macrolides, sulfacetamide, and bacitracin
ophthalmic ointment.
1,10
No significant differences in
clinical outcomes between these agents have been re-
ported.
1
A randomized, double-blind study comparing
trimethoprim-polymyxin (n = 55), gentamicin (n = 57),
and sulfacetamide (n = 46) administered for 10 days in
patients aged <21 years found no significant dif-
ferences in cure rates, either at 3 to 6 days after ini-
tiation of treatment (47.3%, 49.1%, and 41.3%,
respectively) or at 2 to 7 days after the completion of
treatment (83.6%, 87.7%, and 89.1%).
11
The choice
of a topical ophthalmic antibiotic is generally made
based on cost, local resistance data, risk of adverse
effects, and spectrum of activity.
1,8
Polymyxin B com-
bination products have broad-spectrum coverage and
have been reported to have good tolerability
profiles.
12,13
Sulfacetamide has good coverage against
gram-positive organisms; however, it stings on contact
and has been associated with severe allergic reactions,
including Stevens-Johnson syndrome.
1214
Aminogly-
cosides provide broad coverage against gram-negative
organisms, but are not as effective against streptococci
as are other agents and can cause corneal ulceration
with prolonged use.
12,13
Erythromycin has good
gram-positive coverage but poor activity against Hae-
mophilus and Staphylococcus species.
8,12,13
With the
exception of ciprofloxacin and ofloxacin, most oph-
thalmic fluoroquinolones are not available in generic
formulations.
10
Ophthalmic fluoroquinolones are
more expensive than other available options, but have
a broader spectrum of activity and fewer adverse ef-
fects.
8,15,16
The growing threat of multidrug-resistant
strains of ocular pathogens has increased the need for
new ophthalmic antibiotics.
organisms; noninfectious causes may be allergic,
chemical, or mechanical.
1
Acute infectious conjunc-
tivitis is one of the most common eye infections seen
in the primary care setting.
3,4
Estimates of the rate of
conjunctivitis in adults vary widely. Conjunctivitis
has been reported to account for ~0.9% of all emer-
gency department visits.
2,5
The 2005 National Ambu-
latory Medical Care Survey estimated the incidence
of bacterial conjunctivitis at 1.35%.
6
Conjunctivitis
is the most common infection during the first month
of life, affecting 2% to 8% of infants in industrialized
countries.
7
Acute conjunctivitis has been estimated to
have a bacterial cause in >70% of cases in children
and ~50% of cases in adults.
4
Patients may present
with unilateral or bilateral eye involvement, along
with erythema, inflammation, pruritus, foreign-body
sensation, and ocular discharge.
1,2
Although bacterial
conjunctivitis is typically self-limiting, topical antibi-
otic treatment may bring faster clinical and microbio-
logic improvement, reduce contagious spread, and
lower the risk of reinfection and complications.
13
The most common causative pathogens in bacte-
rial conjunctivitis are Staphylococcus aureus, Strepto-
coccus pneumoniae, and Haemophilus influenzae.
14
Other bacterial causes can range from susceptible
organisms to such resistant strains as methicillin-
resistant S aureus (MRSA) and vancomycin-resistant
enterococci. In neonates, the most common causative
organisms are Chlamydia trachomatis and Neisseria
gonorrhoeae.
8
Gonococcal conjunctivitis in neonates
must be treated with systemic antibiotics, as topical
therapy alone is insufficient and unnecessary; without
systemic therapy, the affected eye may develop scar-
ring and other complications involving the cornea,
potentially leading to blindness.
8
Fortunately, neona-
tal bacterial conjunctivitis due to N gonorrhoeae is
rarely seen today because of the routine instillation of
ocular prophylaxis with silver nitrate, erythromycin,
or tetracycline at birth.
8
This prophylaxis does not
prevent chlamydial conjunctivitis in neonates; when
this infection occurs, the patient is treated with oral
antibiotics.
8
C trachomatis and N gonorrhoeae are
also known to cause bacterial conjunctivitis in sexu-
ally active patients; in these cases, systemic treatment
is required to ensure eradication of the infection and
prevent potential complications.
1
Pseudomonas
aeruginosa is the organism most commonly involved
in bacterial conjunctivitis in individuals who wear
contact lenses.
8,9
456 Volume 32 Number 3
Clinical Therapeutics
MECHANISM OF ACTION
Fluoroquinolones are bacteriocidal agents that selec-
tively inhibit bacterial DNA gyrase and topoisomer-
ase IV.
22
Inhibition of DNA gyrase and topoisomer-
ase IV interferes with transcription, replication, and
separation of bacterial chromosomal DNA during cell
division.
23
DNA gyrase is the primary target for an-
tibiotic therapy in most gram-negative bacteria, and
topoisomerase IV is the primary target for antibiotic
therapy in gram-positive bacteria.
22
Cambau et al
24
investigated the in vitro activity of
besifloxacin against bacterial DNA gyrase and topo-
isomerase IV in S aureus and S pneumoniae, using
Escherichia coli as the reference. They found that be-
sifloxacin inhibited supercoiling of DNA gyrase and
the decatenation activity of topoisomerase IV with a
50% inhibitory concentration (IC
50
) of 2.5 and 1 M,
respectively. They also found that DNA gyrase was
the primary target in all 3 species studied, with topo-
isomerase IV the secondary target. Inhibition of DNA
gyrase and topoisomerase IV by besifloxacin was com-
parable to that of moxifloxacin, another broad-spectrum
ophthalmic fluoroquinolone, which had IC
50
values
of 10 and 2.5 M.
Some fluoroquinolones may possess anti-
inflammatory activity, although the exact underlying
mechanism is not clearly defined.
25,26
Ciprofloxacin,
moxifloxacin, and gemifloxacin may modulate cytokine
synthesis and release from immune and inflamma-
tory cells.
26
Besifloxacin has also been reported to pos-
sess such anti-inflammatory effects.
25,26
At 10 g/mL,
besifloxacin inhibition of interleukin-1induced cyto-
kines was observed in primary human corneal epithelial
cells.
25
In human THP-1 monocytes, cytokine inhibitory
Besifloxacin is a topical ophthalmic fluoroquinolone
that was approved by the US Food and Drug Admin-
istration (FDA) on May 28, 2009, for the treatment of
bacterial conjunctivitis caused by susceptible bacterial
strains.
17,18
It is the only ophthalmic fluoroquinolone
that was not first studied for systemic use, and there
is no intention to market it for this purpose.
19
Besi-
floxacin is available as a 0.6% topical ophthalmic sus-
pension formulated with DuraSite technology to help
extend drug residence time on the ocular surface.
4,18
This article provides an overview of the pharmaco-
logic and pharmacokinetic properties, clinical efficacy,
and tolerability of besifloxacin ophthalmic suspension
0.6% when used for the treatment of bacterial con-
junctivitis caused by susceptible organisms.
METHODS
Relevant reports pertaining to the pharmacology, ef-
ficacy, and tolerability of besifloxacin were identified
through a search of MEDLINE (1985December
2009) and International Pharmaceutical Abstracts
(1985December 2009) using the terms besifloxa-
cin, BOL-303224-A, ophthalmic fluoroquinolones,
and bacterial conjunctivitis. Additional publications
were identified by reviewing the reference lists of the
identified articles and searching the FDA Web site.
Also consulted were posters and/or abstracts pre-
sented and/or published as of December 2009 at sci-
entific meetings of the European Society of Clinical
Microbiology and Infectious Diseases, Association
for Research in Vision and Ophthalmology, Associa-
tion for Ocular Pharmacology and Therapeutics,
American Optometric Association, American Acade-
my of Ophthalmology, American Society for Microbi-
ology, and Federation of European Microbiological
Societies.
CHEMICAL STRUCTURE
Besifloxacin is a chiral synthetic fluoroquinolone with
an N-cyclopropyl group to provide enhanced activity
against aerobic bacteria and an 8-chloro substituent
to provide improved potency against bacterial DNA
gyrase and topoisomerase IV.
20,21
Chemically, besi-
floxacin is (+)-7-[(3R)-3-aminohexahydro-1H-azepin-
1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,
4-dihydroquinolone-3-carboxylic acid. Its chemical
formula is C
19
H
21
ClFN
3
O
3
, and its molecular weight
is 430.40.
18
The chemical structure of besifloxacin is
depicted in the figure.
O
N
F
Cl
O
OH
N
H
H
2
N
Figure. Chemical structure of besifloxacin.
18
March 2010 457
M.H. Chang and H.B. Fung
which moxifloxacin was more active, besifloxacin
had more potent activity overall against gram-positive
bacteria, including resistant strains, compared with
moxifloxacin, ciprofloxacin, and levofloxacin (Table I).
MIC
90
values for besifloxacin were generally 2- to 16-
fold lower than those for the other fluoroquinolones.
Even among multidrug-resistant pathogens such as
vancomycin-resistant Enterococcus faecalis, vancomycin-
resistant Enterococcus faecium, ciprofloxacin-
susceptible MRSA, and ciprofloxacin-resistant
MRSA, MIC
90
values for besifloxacin were low
relative to the other fluoroquinolones (2, 8, 0.12,
and 4 g/mL, respectively). Besifloxacin also had po-
tent activity (MIC
90
0.5 g/mL) against Strep-
tococcus species, including Streptococcus agalactiae;
Lancefield group C, F, and G streptococci; levofloxacin-
susceptible and levofloxacin-resistant S pneu-
moniae; Streptococcus pyogenes; and viridans group
streptococci.
In contrast to its gram-positive activity, besifloxa-
cin was no more potent than the comparator fluoro-
quinolones against gram-negative organisms.
30
MIC
90
values for besifloxacin were comparable to those of
the other fluoroquinolones or were within 1 to 4 dilu-
tions difference (Table II). Ciprofloxacin and levo-
floxacin generally had lower MIC
90
values against
gram-negative isolates compared with besifloxacin and
moxifloxacin. Of note, the MIC
90
values for besifloxa-
cin against multidrug-resistant strains, specifically
Acinetobacter spp, Enterobacter aerogenes, Proteus
mirabilis, ciprofloxacin-resistant P aeruginosa, and
levofloxacin-resistant Stenotrophomonas maltophilia,
were 8 g/mL.
30
However, ophthalmic antibiotics,
including besifloxacin, are often formulated at a con-
centration of active drug that greatly exceeds these
MIC
90
values (eg, 6000 g/mL for besifloxacin).
18,30
The range of MIC
90
values for besifloxacin against
anaerobic isolates in the study by Haas et al
30
was
between 0.25 and 4 g/mL. Table III summarizes in
vitro MIC
90
values for besifloxacin and the comparator
antibiotics against anaerobes in this study.
Overall, besifloxacin had comparable or better in
vitro activity against gram-positive and anaerobic iso-
lates compared with moxifloxacin, ciprofloxacin, and
levofloxacin, and had comparable activity against
gram-negative organisms.
30
Besifloxacin inhibited
most ocular bacterial pathogens with MIC
90
values
generally 4 g/mL. However, whether a several-fold
difference in MIC
90
values will translate into a clinical
effects were detected at besifloxacin concentrations as
low as 0.1 g/mL.
26
Based on clinical pharmacokinetic
data, this concentration is well below predicted ocular
concentrations after ocular administration.
26
In a rab-
bit model of MRSA-induced endophthalmitis, besi-
floxacin was associated with a significant reduction in
ocular inflammation compared with placebo (mean
[SD] clinical inflammation score, 6.67 [1.37] vs 9.83
[2.33], respectively; P = 0.035).
25
At present, the clini-
cal significance and relevance of the anti-inflammatory
effect of besifloxacin are not fully understood and
require further investigation.
SPECTRUM OF ACTIVITY
Fluoroquinolones are derived from nalidixic acid, which
has activity only against gram-negative aerobes.
22
Improved understanding of the structureactivity rela-
tionship of fluoroquinolones has led to the development
of newer fluoroquinolones with a broader spectrum
of activity. Resistance to fluoroquinolones is becom-
ing more common
27
; for example, Shigemura et al
28
reported a >7.5-fold increase in fluoroquinolone-
resistant isolates of E coli between 2000 and 2006
(from 3.5% to 26.4%). This increase probably cor-
responds to an increase in the overall use of quino-
lones
27
; based on data from IMS Health, Neuhauser et
al
29
reported a >2.5-fold increase in fluoroquinolone
use between 1990 and 2000. Known mechanisms of
resistance to fluoroquinolones involve point mutations
in genes encoding the subunits of DNA gyrase and
topoisomerase IV, as well as changes in membrane
efflux proteins.
22
Compared with other fluoroquino-
lones, besifloxacin has the theoretical advantage of
being available only for topical ophthalmic use, which
should limit overall exposure and potentially reduce
the development of resistance. Nevertheless, in vitro
studies have already found cross-resistance between
besifloxacin and fluoroquinolones such as gatifloxa-
cin and moxifloxacin.
18
Haas et al
30
studied the in vitro activity of besifloxa-
cin against clinical isolates of aerobic and anaerobic
bacterial species, including resistant strains, from the
United States, mostly from 2005 to 2008. They ana-
lyzed a total of 2690 clinical isolates (2535 aerobic,
155 anaerobic) of ocular and respiratory origin when-
ever possible. All susceptibility testing was conducted
according to the current reference methods of the
Clinical and Laboratory Standards Institute. With the
exception of ciprofloxacin-susceptible MRSA, against
458 Volume 32 Number 3
Clinical Therapeutics
pharmacokinetic parameters included C
max
, AUC
0t
,
and mean residence time in tears, conjunctiva, aque-
ous humor, and plasma. A concentration gradient was
noted from the tear film through the conjunctiva to
the aqueous humor and plasma. Conjunctival concen-
trations of besifloxacin (C
max
, 62.79 g/mL; AUC
0t
,
5569 min g/mL) were above the MIC
90
for most
gram-negative and gram-positive organisms (MIC
90
range, <0.064 g/mL) and were maintained for at
least 12 hours after a single dose (Table IV). Very low
concentrations of besifloxacin (<10 ng/mL) were de-
tected in plasma after a single dose, confirming mini-
mal systemic exposure after ocular administration.
In a number of experiments in rabbits, monkeys,
and humans, Proksch et al
31
evaluated ocular penetra-
difference remains unknown, as the amount of drug
delivered topically to the ocular surface is at concen-
trations well above the MIC against common causative
pathogens in conjunctivitis. Besifloxacin was active
against the resistant isolates studied and against a
broad range of streptococci.
30
Based on these results,
besifloxacin appears to have a spectrum of activity
sufficient for the empiric treatment of acute bacterial
conjunctivitis.
PHARMACOKINETICS AND
PHARMACODYNAMICS
Ward et al
21
studied the ocular and systemic pharma-
cokinetics of besifloxacin after a single dose of besifloxa-
cin ophthalmic suspension 0.6% in rabbits. Ocular
Table I. In vitro MIC
90
values for besifloxacin and comparator fluoroquinolones against gram-positive bacteria.
30
Gram-Positive Organism
(No. of Isolates; % Phenotype) Besifloxacin Moxifloxacin Ciprofloxacin Levofloxacin
Enterococcus faecalis (130; 20.0% VRE) 2 16 64 64
Enterococcus faecium (110; 12.7% VRE) 8 64 >128 128
Listeria monocytogenes (25) 0.12 0.12 1 1
Staphylococcus aureus
Ciprofloxacin susceptible (19; 21.1% MRSA) 0.12 0.06 0.5 0.25
Ciprofloxacin resistant (11; 63.6% MRSA) 4 >8 >8 >8
Staphylococcus haemolyticus (101) 1 8 >8 >8
Staphylococcus hominis (50) 1 4 >8 >8
Staphylococcus lugdunensis (15) 0.5 2 >8 >8
Staphylococcus saprophyticus (101) 0.12 0.12 0.5 0.5
Staphylococcus warneri (50) 1 4 >8 >8
Streptococcus agalactiae (100) 0.06 0.25 1 1
Lancefield group C, F, and G streptococci (50) 0.06 0.12 0.5 0.5
Streptococcus pneumoniae
Levofloxacin susceptible (16) 0.06 0.12 2 0.5
Levofloxacin resistant (85) 0.5 4 64 16
Streptococcus pyogenes (101) 0.06 0.25 0.5 0.5
Viridans group streptococci* (156) 0.12 0.25 4 1
VRE = vancomycin-intermediate (as defined in reference 30) and vancomycin-resistant enterococci; MRSA = methicillin-
resistant S aureus.
*Two isolates of Streptococcus anginosus, 13 of Streptococcus bovis, 7 of Streptococcus constellatus, 28 of Streptococcus intermedius,
51 of Streptococcus mitis, 22 of Streptococcus oralis, 2 of Streptococcus salivarius, 17 of Streptococcus sanguinis, and 14 of other
viridans group streptococci.
MIC
90
, g/mL
March 2010 459
M.H. Chang and H.B. Fung
centrations generally ranging from 0.1 to 10 g/mL
over time.
Ward et al
21
used individual single-dose conjunctival
concentrationtime data from rabbits to perform phar-
macokinetic and pharmacodynamic dosing simulations.
The results of these simulations indicated that a thrice-
daily dosing regimen was sufficient to achieve conjunc-
tival besifloxacin concentrations of >2 g/g that were
consistently above the MIC
90
for most ophthalmologic
isolates over a 7-day course of treatment.
Proksch et al
31
conducted a single-center, open-
label study of the ocular pharmacokinetics of besi-
tion and systemic exposure to besifloxacin. Besifloxa-
cin ophthalmic suspension 0.6% was rapidly absorbed
(T
max
= 0.5 hour), and sustained concentrations in
tears of >0.05 g/g were maintained through 24 hours
after a single topical ocular administration. Similar to
the findings of Ward et al,
21
ocular exposure to besi-
floxacin (C
max
and AUC) was highest in tears, fol-
lowed by the conjunctiva and aqueous humor. The
terminal t
1/2
of besifloxacin was comparable in tears
of rabbits and monkeys, ranging from 5.3 to 13.9 hours.
Systemic exposure to besifloxacin was low but
measurable in both species, with mean plasma con-
Table II. In vitro MIC
90
values for besifloxacin and comparator fluoroquinolones against gram-negative
bacteria.
30
Gram-Negative Organism
(No. of Isolates) Besifloxacin Moxifloxacin Ciprofloxacin Levofloxacin
Acinetobacter baumannii (53) 32 32 >128 64
Acinetobacter calcoaceticus (27) 16 8 128 8
Acinetobacter lwoffii (50) 16 4 16 4
Citrobacter freundii (100) 4 4 2 2
Citrobacter koseri (100) 0.25 0.25 0.06 0.12
Enterobacter aerogenes (50) 8 16 16 16
Enterobacter cloacae (50) 2 2 0.5 0.25
Haemophilus influenzae
Ciprofloxacin susceptible (15) 0.03 0.06 0.015 0.015
Ciprofloxacin resistant (11) 2 16 64 16
Klebsiella oxytoca (50) 1 2 0.5 0.5
Klebsiella pnuemoniae (100) 4 2 2 2
Legionella pneumophila (50) 0.03 0.06 0.03 0.03
Moraxella catarrhalis (101) 0.03 0.03 0.015 0.03
Morganella morganii (51) 4 >8 >8 8
Neisseria meningitidis (20) 0.015 0.008 0.004 0.015
Proteus mirabilis (50) 16 16 32 8
Proteus vulgaris (50) 0.25 0.5 0.03 0.06
Pseudomonas aeruginosa
Ciprofloxacin susceptible (105) 4 4 0.5 1
Ciprofloxacin resistant (96) 64 >128 64 64
Serratia marcescens (100) 1 1 0.5 0.5
Levofloxacin susceptible (48) 4 1 4 2
Levofloxacin resistant (52) 64 32 64 32
MIC
90
, g/mL
460 Volume 32 Number 3
Clinical Therapeutics
These authors conducted a multicenter, open-label
study to investigate systemic exposure to besifloxacin
after topical ocular administration in human sub-
jects
31
and to obtain additional pharmacokinetic and
pharmacodynamic data.
21
Twenty-four patients (mean
[SD] age, 38.9 [14.5] years) with a clinical diagnosis
of bilateral bacterial conjunctivitis received 1 drop of
besifloxacin ophthalmic suspension 0.6% in each eye
3 times daily for 5 days, with a final dose on the morn-
ing of day 6.
31
Serial blood samples were collected for
6 days. Blood samples from 3 healthy volunteers were
used to assess the plasma protein binding of besi-
floxacin.
21
Systemic exposure to besifloxacin was gen-
erally minimal, with a mean plasma C
max
<0.5 ng/mL
(Table V). Of note, the mean plasma concentration
was 12- to 15-fold lower in humans than in the ex-
periments in rabbits and monkeys.
31
In vitro protein
binding of besifloxacin in human plasma ranged from
38.5% to 44.0%, and did not vary substantially
across besifloxacin concentrations ranging from 10 to
10,000 ng/mL.
21
Successful bacterial eradication with fluoroquino-
lones has been reported to be associated with
C
max
:MIC
90
ratios 10, AUC:MIC
90
ratios 30 against
gram-positive bacteria, and AUC:MIC
90
ratios 100
against gram-negative bacteria.
21,31
In the single-dose
study in a rabbit ocular model by Ward et al,
21
con-
junctival C
max
was ~63 g/mL and conjunctival resi-
dence time was ~8 hours. Proksch et al
31
found that
repeated dosing was associated with a proportional
increase in AUC, with little effect on C
max
. Using
MIC
90
values for nonresistant organisms from the
study by Ward et al, the desired C
max
:MIC
90
ratios
floxacin in 64 healthy volunteers (mean [SD] age,
23.7 [4.2] years). Volunteers received a single instilla-
tion of besifloxacin ophthalmic suspension 0.6% in
the conjunctival sac of each eye, after which a single
tear sample was collected from the right eye of each
subject. In addition, tear samples from a subgroup of
subjects were collected for further analysis at 8 predeter-
mined times from 10 minutes to 24 hours after dosing.
The mean (SD) C
max
in tears (610 [540] g/mL) was
observed at 10 minutes after dosing, and concentrations
1.6 g/g were sustained for at least 24 hours after
dosing. Total exposure (AUC
024h
) was 1232 g h/g.
The elimination t
1/2
of besifloxacin in human tears
was ~3.4 hours.
Table III. In vitro MIC
90
values for besifloxacin and comparator antibiotics against gram-positive and gram-
negative anaerobes.
30
Anaerobic Organism
(No. of Isolates) Besifloxacin Moxifloxacin Ciprofloxacin Gatifloxacin Metronidazole
Bacteroides fragilis (20) 1 2 NA 4 2
Clostridium perfringens (21) 0.25 0.5 NA 1 4
Fusobacterium spp (21) 1 2 NA 4 1
Peptostreptococcus spp (52) 0.5 0.5 4 NA 1
Prevotella spp (20) 4 8 NA 16 4
Propionibacterium acnes (21) 0.25 0.25 NA 0.5 >16
NA = not available.
MIC
90
, g/mL
Table IV. Pharmacokinetic parameters of besi-
floxacin ophthalmic suspension 0.6%
after a single instillation in rabbit ocu-
lar tissues.
21
Mean
C
max
, AUC
0t
, Residence
Site g/mL min g/mL Time, min
Tears 2756 194,580 923
Conjunctiva 62.79 5569 458
Aqueous
humor 1.692 125 422
Plasma 0.0198 2.55 NA
NA = not available.
March 2010 461
M.H. Chang and H.B. Fung
were generally higher than those reported for other
ophthalmic fluoroquinolones (eg, ciprofloxacin, oflox-
acin, norfloxacin, levofloxacin).
31
Discounting differ-
ences associated with variations in fluoroquinolone
dose and concentration, the sustained high concentra-
tions of besifloxacin can be partly explained by the
vehicle formulation.
CLINICAL TRIALS
A review of the literature identified 3 Phase III studies
of the clinical efficacy and tolerability of besifloxacin
topical ophthalmic suspension 0.6% in the treatment
of bacterial conjunctivitis.
3,4,32
Two trials compared
besifloxacin with its vehicle,
4,32
and the other com-
pared besifloxacin with moxifloxacin.
3
Results of these
studies are summarized in Table VI.
Comparisons of Besifloxacin and Vehicle
Karpecki et al
32
conducted a prospective, random-
ized, double-masked, vehicle-controlled, parallel-group
trial to evaluate the clinical and microbiologic efficacy
of besifloxacin ophthalmic suspension 0.6% adminis-
tered 3 times daily for 5 days in the treatment of bacte-
rial conjunctivitis. The study was conducted at 35 cen-
ters in the United States. Eligible patients had a clinical
diagnosis of acute bacterial conjunctivitis, were aged
1 year, and had pinhole visual acuity 20/200 in
each eye. Reasons for exclusion were pregnancy, known
hypersensitivity to the study medications, use of topical
ophthalmic products within 48 hours or antibacterial
medications within 72 hours of the start of the study,
and suspected nonbacterial conjunctivitis, iritis, cor-
neal erosion, or keratitis.
The primary efficacy outcomes were clinical resolu-
tion and eradication of the baseline bacterial infection
on day 8 in patients with a culture-confirmed diagno-
sis.
32
Clinical resolution was defined as the absence of
conjunctival discharge and bulbar conjunctival injec-
tion at visit 3 (day 8 or 9). Eradication was defined as
the absence at visit 3 of bacterial species that had been
present at or above threshold on day 1. The tolerability
of besifloxacin was assessed based on adverse events,
changes in visual acuity, and biomicroscopic and oph-
thalmoscopic findings in all patients who received
1 dose of besifloxacin or vehicle. Compliance with
therapy was assessed by weighing medication bottles.
Two hundred sixty-nine patients were randomized
to treatment (137 besifloxacin, 132 vehicle), of whom
256 completed the trial (134 and 122, respectively).
32
were exceeded for all organisms except P aeruginosa.
Based on concentration data from tear samples from
human subjects who received ocular besifloxacin oph-
thalmic suspension 0.6% 3 times daily, the simulation
by Proksch et al predicted attainment of pharmacody-
namic targets against S aureus (MIC
90
= 0.25 g/mL),
S pneumonia (MIC
90
= 0.125 g/mL), Staphylococcus
epidermidis (MIC
90
= 0.5 g/mL), and H influenzae
(MIC
90
= 0.06 g/mL). The C
max
:MIC
90
ratio was
1220 (range, 122010,167) and the AUC:MIC
90
ra-
tio was 7602 (range, 760263,350), both well above
the respective targets. It appears that ocular adminis-
tration of besifloxacin 3 times daily would be ade-
quate to achieve microbiologic cure of bacterial con-
junctivitis caused by these pathogens.
Besifloxacin ophthalmic suspension is formulated
with DuraSite, a synthetic polymer that helps stabilize
small molecules in an aqueous mixture.
18
DuraSite
also contains a polycarbophil-based vehicle that in-
creases viscosity and allows besifloxacin to remain on
the ocular surface for a longer time.
31
In the pharma-
cokinetic studies by Proksch et al,
31
a single topical
administration of besifloxacin ophthalmic suspension
0.6% provided sustained concentrations >0.05 and
1.6 g/g in animals and humans, respectively, over a
24-hour period. Thus, use of DuraSite in the besi-
floxacin suspension formulation appeared to help ex-
tend drug residence time on the ocular surface. These
authors stated that besifloxacin concentrations in tears
Table V. Ocular pharmacokinetic parameters of
besifloxacin ophthalmic suspension 0.6%
in human tears.
31
Parameter Value
C
max
, mean (SD), g/mL* 610 (540)
T
max
, min 10
AUC
024h
, g h/g* 1232
Elimination t
1/2
, h* ~3.4
Systemic exposure, ng/mL

<0.5
* Measured in tears of volunteers who received a sin-
gle ocular administration of besifloxacin ophthalmic
suspension.

Measured in plasma from patients who received besi-
floxacin ophthalmic suspension 3 times daily for 5 days.
462 Volume 32 Number 3
Clinical Therapeutics
On day 4 (visit 2), the rate of eradication of bacte-
rial infection in the culture-confirmed intent-to-treat
(ITT) population was significantly greater in the besi-
floxacin group than in the vehicle group (90.0% vs
46.6%, respectively; P < 0.001).
32
There was no sig-
nificant difference in clinical resolution of conjunctivi-
tis (33.3% vs 17.2%). At visit 3, the besifloxacin
group had significantly greater rates of both clinical
resolution of conjunctivitis (73.3% vs 43.1%; P <
0.001) and eradication of bacterial infection (88.3%
Of note, only 60 patients allocated to receive besi-
floxacin and 58 allocated to receive vehicle had a
culture-confirmed diagnosis of bacterial conjunctivi-
tis. There were no significant differences in demo-
graphic characteristics between groups. The majority
of patients were female (60.2%) and white (82.5%);
the mean age was 34.2 years (range, 192 years besi-
floxacin; 181 years vehicle). Based on the weight of
the medication bottles, >90% of patients in both
groups were 80% compliant with treatment.
Table VI. Summary of Phase III clinical efficacy studies of besifloxacin ophthalmic suspension 0.6%.
Authors/
Study Design Intervention* Clinical Microbiologic Major Adverse Events*
Karpecki et al
32

MC, R, DM,
VC, PG,
prospective
Besifloxacin TID
for 5 d (n = 137)
Vehicle TID for 5 d
(n = 132)
44/60 (73.3)

25/58 (43.1)
53/60 (88.3)

35/58 (60.3)
>5%: Eye pain (10.5%
besifloxacin, 6.9% vehicle),
blurred vision (10.5% and
11.7%, respectively), eye
irritation (7.4% and 12.2%)
Tepedino et al
4

MC, R, DM,
VC, PG,
prospective
Besifloxacin TID
for 5 d (n = 473)
Vehicle TID for 5 d
(n = 484)
90/199 (45.2)

63/191 (33.0)
182/199 (91.5)

114/191 (59.7)
>1%: Conjunctivitis (2.6%
besifloxacin vs 5.0% vehicle; P =
0.015), blurred vision (1.2% and
2.2%, respectively), eye pruritus
(1.2% vs 0.3%; P = 0.036), eye
irritation (1.1% and 0.4%),
bacterial conjunctivitis (0.8%
and 2.1%)
McDonald et al
3

MC, R, DM,
AC, PG,
prospective,
noninferiority
Besifloxacin TID
for 5 d (n = 582)
Moxifloxacin TID
for 5 d (n = 579)
147/252 (58.3)

167/281 (59.4)
235/252 (93.3)

256/281 (91.1)
1%: Conjunctivitis (2.8%
besifloxacin, 3.9%
moxifloxacin), bacterial
conjunctivitis (2.1% and 2.6%,
respectively), blurred vision
(1.0% and 0.5%), eye pain (0.6%
and 1.1%), eye irritation (0.3%
vs 1.4%; P = 0.020)
MC = multicenter; R = randomized; DM = double masked; VC = vehicle controlled; PG = parallel group; AC = active
controlled.

*

Numbers and rates represent the intent-to-treat (ITT) population, which included all patients who received 1 dose
of study medication. The efficacy results represent data from visit 3 (day 8 or 9) in the study by Karpecki et al, visit 2
(day 5) in the study by Tepedino et al, and day 5 in the study by McDonald et al.

Numbers represent the modified ITT population, which included all patients with a culture-confirmed diagnosis of
bacterial conjunctivitis in 1 eye at baseline.

P < 0.001 versus vehicle.

P = 0.008 versus vehicle.

95% CI for noninferiority, 9.48 to 7.29.

95% CI for noninferiority, 2.44 to 6.74.
Efficacy, n/N (%)

March 2010 463

M.H. Chang and H.B. Fung
eradication of the baseline infection was defined as the
absence of all bacterial species present at or above
threshold at baseline. Individual clinical outcomes, in-
cluding tolerability, were also assessed. The ITT/safety
population included all patients who received 1 dose
of study drug; the modified ITT (mITT) population
included those patients with baseline bacterial levels at
or above threshold in 1 eye. Compliance with treat-
ment was assessed by measuring bottle weight.
The ITT population included 957 patients (473 be-
sifloxacin, 484 vehicle).
4
Eight hundred seventy-four
patients completed the study (442 and 432, respec-
tively). In the ITT population, the majority of patients
were female (62.9%) and white (65.2%). The mean age
of the population was 27.3 years (range, 198 years
besifloxacin, 10 months97 years vehicle). At least
80% of patients in both arms were 70% compliant
with study medication.
The mITT population included 390 patients (199 be-
sifloxacin, 191 vehicle).
4
Both rates of clinical resolu-
tion and microbial eradication were significantly higher
in the besifloxacin group compared with the vehicle
group at visit 2 (clinical resolution: 45.2% vs 33.0%,
respectively [P = 0.008]; microbial eradication: 91.5%
vs 59.7% [P < 0.001]) and visit 3 (clinical resolution:
84.4% vs 69.1% [P = 0.001]; microbial eradication:
88.4% vs 71.7% [P < 0.001]). Findings for individual
clinical outcomes (eg, ocular discharge, bulbar con-
junctival injection) were consistent with those for the
primary outcomes. Patients treated with besifloxacin
compared with vehicle had significantly greater rates
of resolution of ocular discharge at visit 2 (73.9% vs
57.6%; P = 0.001) and visit 3 (93.0% vs 79.1%; P <
0.001). Normalization of bulbar conjunctival injec-
tion also was significantly greater in those treated with
besifloxacin compared with those who received vehi-
cle at visit 2 (52.3% vs 36.1%; P = 0.001) and visit 3
(84.9% vs 70.7%; P = 0.001).
Rates of clinical resolution and microbial eradica-
tion were further analyzed based on bacterial etiolo-
gy.
4
In infections caused by gram-positive bacteria,
rates of clinical resolution with besifloxacin and ve-
hicle at visit 2 were 43.0% and 28.2%, respectively
(P = 0.006). At visit 3, the respective rates were 81.5%
and 69.5% (P = NS). In infections caused by gram-
negative bacteria, rates of clinical resolution were 48.6%
and 45.8% at visit 2, and 88.9% and 72.2% at visit 3
(both comparisons, P = NS). Based on these results,
those who received besifloxacin had significantly higher
vs 60.3%; P < 0.001). Commonly isolated bacterial
species were H influenzae (31.7%), S pneumoniae
(27.6%), S aureus (13.8%), and S epidermidis (4.8%),
with corresponding besifloxacin MIC
90
values of 0.06,
0.125, 0.25, and 0.06 g/mL.
Although no statistical analysis was performed,
ocular adverse events appeared to be comparable be-
tween the besifloxacin and vehicle groups.
32
One pa-
tient receiving vehicle withdrew due to cellulitis in
both eyes, and another lost consciousness due to de-
hydration that was deemed unrelated to besifloxacin
treatment. Overall rates of adverse events were 34.7%
in the besifloxacin group and 38.8% in the vehicle
group. The most common (>5%) adverse events in-
cluded eye pain (10.5% besifloxacin, 6.9% vehicle),
blurred vision (10.5% and 11.7%, respectively), and
eye irritation (7.4% and 12.2%).
In summary, in the study by Karpecki et al,
32
besi-
floxacin appeared to have activity beyond the contri-
butions of vehicle and normal host immune processes.
Rates of clinical resolution and eradication of baseline
bacterial infection at visit 3 were higher with besi-
floxacin than with vehicle. Besifloxacin MIC
90
values
were low for most clinical isolates identified (range,
0.061 g/mL). Treatment with besifloxacin was re-
ported to be well tolerated, with no apparent differ-
ences compared with vehicle in terms of clinically sig-
nificant changes in visual acuity or treatment-emergent
events on biomicroscopy or direct ophthalmoscopy.
Tepedino et al
4
conducted a prospective, random-
ized, double-masked, vehicle-controlled, parallel-group
trial to evaluate the clinical and antimicrobial efficacy
of besifloxacin ophthalmic suspension 0.6% adminis-
tered 3 times daily for 5 days in the treatment of
bacterial conjunctivitis. The study was conducted at
58 sites in the United States. The inclusion and exclu-
sion criteria were the same as in the study by Karpecki
et al.
32
This study also excluded patients who had par-
ticipated in a research study of an ophthalmic drug or
device within the previous 30 days, those with uncon-
trolled or debilitating systemic disease, and those who
were immunocompromised or likely to require anti-
microbial therapy for systemic infection.
The primary end points were clinical resolution of
conjunctivitis and eradication of the baseline bacterial
infection at visit 2 (day 5 [1]).
4
Clinical and antimi-
crobial efficacy were evaluated at visit 3 (day 8 or 9).
Clinical resolution was defined as the absence of ocu-
lar discharge and bulbar conjunctival injection, and
464 Volume 32 Number 3
Clinical Therapeutics
ma (0% and 0.5%). Nonocular adverse events oc-
curred in 7% of all patients, with headache being
the most frequently reported (2.3% and 1.2%; P =
NS). One patient in the vehicle group developed pneu-
monia that was considered unrelated to study drug.
Based on biomicroscopy or ophthalmoscopy, <3% of
all study eyes in either group developed treatment-
emergent abnormalities.
In summary, Tepedino et al
4
found besifloxacin to
be well tolerated in patients with bacterial conjuncti-
vitis. Rates of clinical resolution and microbial eradi-
cation were higher with besifloxacin than with vehicle.
The authors stated that these rates were comparable
to those reported for other ophthalmic fluoroquino-
lone preparations used to treat bacterial conjunctivitis.
The results suggest that besifloxacin may be more ef-
fective than its vehicle in treating bacterial conjuncti-
vitis caused by gram-positive organisms. This obser-
vation is consistent with the results of in vitro studies
of besifloxacin MIC
90
values against gram-negative
organisms commonly involved in bacterial conjuncti-
vitis.
30
This study did not report MIC
90
values for the
organisms cultured from ocular infections; therefore,
it is not possible to assess the correlation between
besifloxacin MIC values and outcomes.
Comparison of Besifloxacin and Moxifloxacin
McDonald et al
3
conducted a prospective, random-
ized, double-masked, active-controlled, parallel-group,
noninferiority trial comparing the clinical and anti-
microbial efficacy of besifloxacin ophthalmic suspen-
sion 0.6% and moxifloxacin 0.5% ophthalmic solu-
tion, both administered 3 times daily for 5 days, in the
treatment of bacterial conjunctivitis. The study was
conducted at 84 sites in the United States and Asia.
The inclusion and exclusion criteria were the same
as in the study by Tepedino et al.
4
Also excluded were
patients who had undergone ocular surgery within
6 weeks of study entry.
The primary end points were clinical resolution
and microbial eradication of the baseline bacterial
infection at day 5 (1) in patients with baseline bacte-
rial cultures at or above threshold in 1 eye (mITT
population).
3
Clinical resolution was defined as ab-
sence of ocular discharge and bulbar conjunctival in-
jection. Microbial eradication was defined as the ab-
sence at day 5 of ocular bacterial species present at or
above threshold at baseline. The predefined noninferi-
ority limit in the difference between besifloxacin and
rates of clinical resolution of infections caused by gram-
positive organisms after 4 to 6 days of study medication
compared with those who received vehicle; this was not
the case after 8 or 9 days of treatment. Rates of clinical
resolution of infections caused by gram-negative organ-
isms did not differ between besifloxacin and vehicle,
regardless of the duration of treatment.
In gram-positive infections, rates of microbial
eradication at visit 2 were 92.6% for besifloxacin and
58.8% for vehicle (P < 0.001); at visit 3, the respective
rates were 89.6% and 73.3% (P = 0.009).
4
In gram-
negative infections, rates of microbial eradication were
87.5% and 66.7% at visit 2 (P = 0.025), and 84.7% and
72.2% at visit 3 (P = NS). Thus, besifloxacin was associ-
ated with significantly greater rates of microbial eradica-
tion compared with vehicle in gram-positive infections,
regardless of the duration of treatment. However, rates
of microbial eradication in gram-negative infections
were significantly higher after 4 to 6 days of besifloxacin
therapy but not thereafter.
A total of 480 bacterial organisms were isolated
from the mITT population.
4
The most common patho-
gens were S pneumoniae (29.2%), H influenzae
(26.9%), S aureus (11.5%), and S epidermidis (7.1%).
With the exception of S epidermidis, against which
eradication rates were 94.4% for besifloxacin and
68.8% for vehicle, rates of eradication of these organ-
isms at visit 2 were significantly greater with besi-
floxacin compared with vehicle: 90.4% versus 59.7%,
respectively, for S pneumoniae (P < 0.001), 87.3%
versus 65.2% for H influenzae (P = 0.008), and 95.8%
versus 41.9% for S aureus (P = 0.003).
Treatment-emergent ocular adverse events were gen-
erally comparable between the besifloxacin and vehi-
cle groups.
4
More patients receiving vehicle reported
1 ocular adverse event compared with those receiv-
ing besifloxacin (13.9% vs 9.2%, respectively; P =
0.005); the vehicle group also had a higher incidence
of conjunctivitis (conjunctivitis: 5.0% vs 2.6% [P =
0.015]; bacterial conjunctivitis: 2.1% vs 0.8% [P =
NS]). Patients receiving besifloxacin had a higher inci-
dence of eye pruritus (1.2% vs 0.3%, respectively; P =
0.036) and viral conjunctivitis (0.7% vs 0%; P =
0.029). Other ocular adverse events, which were com-
parable between the besifloxacin and vehicle groups,
included blurred vision (1.2% and 2.2%), eye irrita-
tion (1.1% and 0.4%), conjunctival hyperemia (0.5%
and 0.3%), eye pain (0.3% and 0.5%), conjunctival
hemorrhage (0.1% and 0.5%), and conjunctival ede-
March 2010 465
M.H. Chang and H.B. Fung
eradication of these organisms on days 5 and 8. Spe-
cific eradication rates at day 5 with besifloxacin and
moxifloxacin were 95.1% and 94.3%, respectively,
against H influenzae; 96.6% and 89.1% against
S pneumoniae (P = 0.023); 87.9% and 82.5% against
S aureus; and 96.6% and 85.4% against S epidermidis.
The corresponding values at day 8 were 90.1% and
88.6%; 86.2% and 85.9%; 82.8% and 80.7%; and
86.2% and 75.6%.
The safety analysis was based on the ITT popula-
tion, which included all patients randomized to study
treatment.
3
Both medications were well tolerated.
There were no significant differences between the be-
sifloxacin and moxifloxacin groups with regard to the
frequency of eyes with 1 ocular adverse event (12%
and 14%, respectively). Two serious adverse events
occurred, 1 in each group (severe congestive heart
failure in the besifloxacin group, acute viral syndrome
in the moxifloxacin group); neither was considered
related to the study medications. The most common
(1%) adverse events were conjunctivitis (4.9% and
6.5%), blurred vision (1.0% and 0.5%), eye pain (0.6%
and 1.1%), and eye irritation (0.3% and 1.4%). Eye
irritation was reported significantly more frequently in
the moxifloxacin group than in the besifloxacin group
(0.3% vs 1.4%, respectively; P = 0.020). Treatment-
emergent abnormalities on biomicroscopy occurred in
<3% of patients. Although no statistical analysis was
presented, the incidence of worsening conjunctival
chemosis on day 5 was reported to be significantly
higher in patients treated with besifloxacin than with
moxifloxacin (2.3% vs 0.7%). Most cases of chemo-
sis were considered mild. One patient in each group
had worsening cataracts. There were no treatment-
emergent abnormalities on ophthalmoscopy. Less than
5% of the ITT population reported treatment-
emergent nonocular adverse events. Headache was the
only nonocular adverse event occurring in >1% of
patients (1.2% besifloxacin, 1.6% moxifloxacin). No
significant differences in nonocular adverse events
were reported.
In summary, McDonald et al
3
found besifloxacin
ophthalmic suspension to be noninferior in tolerabil-
ity and efficacy to moxifloxacin ophthalmic solution,
both administered 3 times daily for 5 days, in the
treatment of bacterial conjunctivitis. There were no
significant differences in rates of clinical resolution or
microbial eradication between the 2 treatment groups.
The only treatment-emergent adverse event that oc-
moxifloxacin was 15%, assuming a microbial eradi-
cation rate of 90% and clinical resolution rate of 66%
in both groups. Adverse events were documented, and
compliance was assessed by weighing medication
bottles.
One thousand one hundred sixty-one patients were
randomized to treatment (582 besifloxacin, 579 moxi-
floxacin), of whom 1109 completed the study (555 besi-
floxacin, 554 moxifloxacin).
3
The mITT population
consisted of 533 patients (252 and 281, respectively),
with comparable demographic characteristics between
treatment groups. Most patients were female (53.5%)
and white (70%). The mean (SD) age of the besifloxa-
cin group was 31.6 (26.2) years (range, 192 years),
and the mean age of the moxifloxacin group was
38.3 (27.7) years (range, 11 months100 years). Chil-
dren aged <2 years constituted 5.6% of patients
(7.1% besifloxacin, 4.3% moxifloxacin). Most pa-
tients were reported to be >70% compliant. Mean
exposure to study medications was ~5 days in both
groups.
Besifloxacin was found to be noninferior to moxi-
floxacin at both days 5 and 8.
3
At day 5, rates of clini-
cal resolution were 58.3% and 59.4%, respectively
(difference, 1.1%; 95% CI, 9.48% to 7.29%), and
rates of microbial eradication were 93.3% and 91.1%
(difference, 2.2%; 95% CI, 2.44% to 6.74%). At day 8,
rates of clinical resolution were 84.5% and 84.0%
(difference, 0.5%; 95% CI, 5.67% to 6.75%), and
rates of microbial eradication were 87.3% and 84.7%
(difference, 2.6%; 95% CI, 3.32% to 8.53%).
Although statistical data were not presented, there
were reported to be no significant differences between
treatment groups in terms of clinical resolution or
microbial eradication of infections caused by gram-
positive or gram-negative organisms.
3
The exception
was the rate of microbial eradication of S aureus on
day 8, which was significantly greater with besifloxa-
cin than with moxifloxacin (84.5% vs 70.2%, respec-
tively; P = 0.029).
A total of 699 bacterial isolates were identified in
the mITT population.
3
The most common (>10%) or-
ganisms isolated at baseline were H influenzae (24.2%),
S pneumoniae (17.5%), S aureus (16.5%), and S epi-
dermidis (10.0%). When clinical resolution was evalu-
ated by the most commonly isolated organisms, besi-
floxacin was found to be noninferior to moxifloxacin
(statistical analysis not reported). Besifloxacin also
was found to be noninferior to moxifloxacin in the
466 Volume 32 Number 3
Clinical Therapeutics
receiving vehicle developed possible vehicle-induced
corneal infiltrates and discontinued therapy.
4
The most frequently (0.5%) reported adverse
events were ocular events of predominantly mild se-
verity.
19
Patients who received vehicle had a higher
incidence of ocular adverse events compared with
those who received besifloxacin (19.8% vs 13.8%,
respectively; P < 0.001). The most common (>1.5%)
ocular adverse events in patients receiving besifloxa-
cin ophthalmic suspension were nonspecific conjunc-
tivitis (2.6%), blurred vision (2.1%), bacterial con-
junctivitis (1.8%), and eye pain (1.5%). Eyes treated
with besifloxacin rather than vehicle had a higher in-
cidence of viral conjunctivitis (0.6% vs 0%, respec-
tively; P = 0.019) but a lower incidence of conjuncti-
vitis (2.6% vs 4.3%; P = 0.022), blurred vision (2.1%
vs 4.1%; P = 0.004), eye irritation (1.4% vs 2.8%;
P = 0.019), and increased lacrimation (<0.1% vs
0.6%; P = 0.009). Differences in the incidence of all
other adverse events were not statistically significant.
19
Table VII summarizes ocular adverse events occurring
in 0.5% of eyes treated with besifloxacin, vehicle,
and moxifloxacin.
Nonocular adverse events were relatively rare, with
no significant differences between besifloxacin oph-
thalmic suspension and vehicle. Headache was the
most frequently reported nonocular adverse event in
all groups.
19
The most common (0.5%) nonocular
adverse events are summarized in Table VIII.
Other safety assessments in the 3 clinical trials in-
cluded visual acuity, biomicroscopy, and ophthal-
moscopy.
3,4,32
Changes in visual acuity were detected
in only 7 patients overall (0.003%), 4 who received
besifloxacin, 2 vehicle, and 1 moxifloxacin.
19
There
were no significant differences in findings on biomi-
croscopy or ophthalmoscopy.
3,4,32
Besifloxacin is classified as a pregnancy category C
drug.
18
Oral doses of up to 1000 mg/kg/d were not
associated with malformations in rat pups. This dose
was, however, associated with maternal toxicity and
mortality, as well as reduced body weight gain and
food consumption. There have been no studies in
pregnant women, and concentrations of besifloxacin
in human milk have not been assessed. Based on its
pharmacokinetic profile (ie, <0.5 ng/mL in plasma
after administration 3 times daily for 5 days),
21,30
a
small amount of besifloxacin may be excreted in hu-
man breast milk after ocular administration. Based on
these risks and the available data, the approved pre-
curred more frequently in one group than the other
was eye irritation in the moxifloxacin group.
ADVERSE EVENTS
In the studies reviewed,
3,4,32
2387 patients received
1 dose of study medication and provided data for the
assessment of tolerability: 1192 who received besi-
floxacin ophthalmic suspension, 616 who received
vehicle, and 579 who received moxifloxacin ophthal-
mic solution. No deaths were reported during the
studies. Four serious adverse events were reported in
4 separate patients: loss of consciousness from dehy-
dration (besifloxacin), severe congestive heart failure
(besifloxacin), pneumonia (vehicle), and acute viral
syndrome (moxifloxacin). None of these events were
considered related to study medication.
Of the 2387 patients who received 1 dose of study
medication, 174 (7.3%) discontinued study treatment.
The primary reason for discontinuation was inade-
quate therapeutic response (27/174 [15.5%]). In the
study by Karpecki et al,
32
significantly more patients
who received vehicle than besifloxacin withdrew from
the study (10/132 [7.6%] vs 3/137 [2.2%], respec-
tively; P = 0.048), primarily because of an insufficient
response. In the study by Tepedino et al,
4
26 patients
in the mITT population discontinued therapy, 8 of
199 (4.0%) in the besifloxacin group and 18 of 191
(9.4%) in the vehicle group (P < 0.05), again mainly
because of lack of efficacy. In the study by McDonald
et al,
3
52 patients withdrew, 27 of 582 (4.6%) in the
besifloxacin group and 25 of 579 (4.3%) in the moxi-
floxacin group. The main reasons for discontinuation
were adverse events (1.9% and 0.9%, respectively)
and loss to follow-up (1.7% and 1.4%). There were
no significant differences between groups in rates of
discontinuation or reasons for discontinuation.
Overall, discontinuations due to adverse events oc-
curred in 15 of 1192 patients (1.3%) who received besi-
floxacin, 7 of 616 patients (1.1%) who received ve-
hicle, and 5 of 579 patients (0.9%) who received
moxifloxacin.
19
Adverse events leading to discontinua-
tion were considered possibly related to study drug in
5 patients. Two patients treated with besifloxacin dis-
continued therapy, one due to dermatitis in the study
by Tepedino et al
4
and the other due to photophobia
in the study by McDonald et al.
3
One patient treated
with moxifloxacin discontinued therapy because of
iritis and decreased visual acuity, and another discon-
tinued because of an allergic response.
3
One patient
March 2010 467
M.H. Chang and H.B. Fung
Table VII. Ocular adverse events (AEs) occurring in 0.5% of all treated eyes.
19
*
Besifloxacin Vehicle Moxifloxacin
Variable (n = 1810 eyes) (n = 961 eyes) (n = 855 eyes) P

Total no. of AEs 327 258 153

Eyes with 1 AE, no. (%) 249 (13.8) 190 (19.8) 120 (14.0) <0.001
Individual AEs, no. (%)
Conjunctivitis 47 (2.6) 41 (4.3) 33 (3.9) 0.022
Blurred vision 38 (2.1) 39 (4.1) 4 (0.5) 0.004
Bacterial conjunctivitis 32 (1.8) 27 (2.8) 22 (2.6) 0.074
Eye pain 28 (1.5) 17 (1.8) 9 (1.1) 0.640
Eye irritation 26 (1.4) 27 (2.8) 12 (1.4) 0.019
Eye pruritus 18 (1.0) 18 (1.9) 3 (0.4) 0.076
Conjunctival hyperemia 10 (0.6) 3 (0.3) 0 0.561
Viral conjunctivitis 10 (0.6) 0 1 (0.1) 0.019
Conjunctival hemorrhage 7 (0.4) 5 (0.5) 4 (0.5) 0.762
Eye discharge 6 (0.3) 6 (0.6) 3 (0.4) 0.362
Eyelid edema 6 (0.3) 4 (0.4) 5 (0.6) 0.746
Ocular hyperemia 6 (0.3) 5 (0.5) 1 (0.1) 0.529
Dry eye 5 (0.3) 2 (0.2) 4 (0.5) 1.000
Punctate keratitis 5 (0.3) 3 (0.3) 5 (0.6) 1.000
Corneal staining 4 (0.2) 1 (0.1) 4 (0.5) 0.665
Limbal hyperemia 4 (0.2) 3 (0.3) 4 (0.5) 0.699
Increased lacrimation 1 (<0.1) 6 (0.6) 2 (0.2) 0.009
* Data include the number of AEs in all eyes, each of which may have had >1 AE. For individual AEs, both of a patients
eyes could be counted if the event occurred in both eyes.

Based on the Fisher exact test for the comparison of besifloxacin ophthalmic suspension and vehicle.
Table VIII. Nonocular adverse events (AEs) occurring in 0.5% of all patients.
19
*
Besifloxacin Vehicle Moxifloxacin
Variable (n = 1102) (n = 616) (n = 579) P

Total no. of AEs 107 64 45

Patients with 1 AE, no. (%) 75 (6.8) 48 (7.8) 31 (5.4) 0.238
Individual AEs, no. (%)
Headache 21 (1.9) 11 (1.8) 9 (1.6) 1.000
Pharyngolaryngeal pain 8 (0.7) 5 (0.8) 3 (0.5) 0.773
Pyrexia 6 (0.5) 4 (0.6) 1 (0.2) 0.742
Cough 4 (0.4) 4 (0.6) 1 (0.2) 0.456
Streptococcal pharyngitis 3 (0.3) 3 (0.5) 1 (0.2) 0.416
Upper respiratory tract infection 2 (0.2) 2 (0.3) 4 (0.7) 0.609
* Patients may have had >1 AE per body system and term. For individual AEs, a patient reporting 1 AE was counted only once.

Based on the Fisher exact test for the comparison of besifloxacin ophthalmic suspension and vehicle.
468 Volume 32 Number 3
Clinical Therapeutics
spills over immediately, as the conjunctival cul de sac
can hold no more than 20 to 30 L of liquid. In addi-
tion, reflex tearing and blinking induced by instilla-
tion will further increase spillage of the drop from the
eye and drainage through the nasolacrimal duct to the
nose. It takes 2 to 5 minutes after instillation for the
tear film to return to its normal volume of 7 to 9 L.
Therefore, instillation of drops at intervals of <2 to
5 minutes will result in a disproportionate loss of drug
from the site of infection. This phenomenon frequent-
ly occurs when 2 different ophthalmic solutions are
instilled separately over a short interval; the product
that was instilled first is displaced from the eye due to
the rapid addition of the second product. For this
reason, a droplet of besifloxacin ophthalmic suspen-
sion should not be instilled <5 minutes after a previous
droplet or after application of another topical oph-
thalmic agent.
33
DOSING AND ADMINISTRATION
Besifloxacin is available as a 0.6% sterile ophthalmic
suspension formulated with DuraSite.
18
A total of 5 mL
of product is packaged in a 7.5-mL bottle with a con-
trolled dropper tip and cap. Tamper evidence is pro-
vided by a shrink band around the cap and neck of the
bottle. Each milliliter of suspension contains 6.63 mg
of besifloxacin hydrochloride equivalent to 6 mg of
the base. Bottles should be stored at 15C to 25C
(59F77F) and protected from light. The recom-
mended dose is 1 drop to the affected eye(s) 3 times a
day, administered 4 to 12 hours apart, for 7 days.
Besifloxacin is indicated for topical ophthalmic use
only and should not be injected or introduced directly
into the anterior chamber of the eye.
18
When handling the bottle of besifloxacin ophthal-
mic suspension, patients should avoid contaminating
the applicator tip.
18
If a rash or allergic reaction oc-
curs, patients are instructed to discontinue use and
contact their physician immediately. Patients who wear
contact lenses should not wear them during the course
of therapy or if they have signs and symptoms of bac-
terial conjunctivitis. Before instillation of drops, pa-
tients should wash their hands thoroughly, invert the
closed bottle, and shake once before using.
PHARMACOECONOMIC CONSIDERATIONS
The literature review identified no pharmacoeconomic
analyses of besifloxacin ophthalmic suspension. Sev-
eral ophthalmic fluoroquinolones have a spectrum of
scribing information states that besifloxacin should be
used during pregnancy only if the potential benefit
justifies the potential risk to the fetus, and that cau-
tion should be exercised when administering besi-
floxacin to nursing mothers.
18
The 3 clinical trials included patients as young as
1 year and as old as 100 years. Although no overall
differences in tolerability were observed in these pa-
tients, data were not analyzed by age. The safety pro-
file of besifloxacin ophthalmic suspension in infants
aged <1 year has not been established.
18
In summary, the most common (1%) adverse
events reported with besifloxacin were ocular events
typically found in patients with acute bacterial con-
junctivitis, such as nonspecific conjunctivitis (2.6%),
blurred vision (2.1%), bacterial conjunctivitis (1.8%),
eye irritation (1.5%), eye pain (1.5%), and eye pruri-
tus (1.0%).
19
These adverse events were mainly mild
and transient. No deaths were reported. Serious ad-
verse events were few, nonocular, and considered un-
related to study medication. There were no significant
differences in visual acuity, biomicroscopic, or oph-
thalmoscopic measures between the besifloxacin, ve-
hicle, and moxifloxacin groups. Overall, besifloxacin
ophthalmic suspension appeared to be well tolerated,
with minimal ocular adverse effects. However, tolera-
bility data were based on <1200 patients who received
1 dose of besifloxacin in the clinical trials. The true
nature and incidence of adverse events associated with
besifloxacin use remain to be characterized. Further-
more, it should be noted that besifloxacin ophthalmic
suspension was administered for 5 days in the clinical
studies, whereas the prescribing information recom-
mends a treatment duration of 7 days.
18
DRUG INTERACTIONS
A literature search identified no published drug-
interaction data for besifloxacin ophthalmic suspen-
sion. This is not to say that besifloxacin has no poten-
tial for drug interactions. Ocular application of another
topical ophthalmic medication within 2 to 5 minutes
of a first medication in the same eye will likely affect
drug concentration, distribution, and elimination. An-
tibiotic ophthalmic drops usually deliver 40 to 60 L
of aqueous fluid to the surface of the eye. This results
in rapid distribution of the agent through the tear film,
delivering high concentrations of antibiotic to the
cornea and conjunctiva. However, the drug also dis-
sipates rapidly. Approximately half of a typical drop
March 2010 469
M.H. Chang and H.B. Fung
besifloxacin, suggesting that besifloxacin had activity
beyond the contribution of normal immune process-
es.
3
A noninferiority trial comparing besifloxacin with
moxifloxacin found that the 2 products were compa-
rable in terms of rates of clinical efficacy and micro-
bial eradication.
3
Besifloxacin ophthalmic suspension was well toler-
ated in the populations studied, with minimal ocular
adverse effects.
3,4,19,32
Besifloxacin was associated with
fewer ocular adverse events and similar rates of non-
ocular adverse events compared with its vehicle.
4,19,32
In addition to its broad spectrum of activity, ac-
ceptable clinical efficacy, and good tolerability, besi-
floxacin has been found to have anti-inflammatory
activity through inhibition of proinflammatory cyto-
kines.
25,26
Immunomodulatory effects have also been
reported for other broad-spectrum fluoroquinolones
(eg, gatifloxacin, moxifloxacin).
25
In an in vitro study
using human corneal epithelial cells, besifloxacin was
reported to have anti-inflammatory activity through
inhibition of the nuclear factor B and mitogen-
activated protein kinase pathways.
25
However, there
are no published data on the ability of this anti-
inflammatory effect to reduce the inflammatory se-
quelae of ocular infections.
25
The clinical relevance of
the anti-inflammatory activity of besifloxacin remains
to be elucidated.
Successful fluoroquinolone treatment of ophthal-
mic infections is based in part on the ability to achieve
sustained and adequate concentrations at the site
of infection.
31
Rates of absorption, distribution, and
elimination of available fluoroquinolones are depen-
dent on the physicochemical properties of the com-
pound, the characteristics of the formulation, the fre-
quency of application, the presence of ocular defects,
and the measurement technique.
22,30
Besifloxacin is
formulated with DuraSite drug delivery technology to
help prolong the residence time of drug on the ocular
surface, which is intended to enhance clinical efficacy
and minimize the need for frequent application of the
product. In one of the pharmacokinetic studies by
Proksch et al,
31
a mean (SD) C
max
in human tears as
high as 610 (540) g/mL was attained at 10 minutes
after dosing with topical besifloxacin ophthalmic sus-
pension 0.6%. This confirms that the drug is delivered
topically to the ocular surface at concentrations well
above MIC values against the common causative patho-
gens in bacterial conjunctivitis. A pharmacodynamic
study in humans found that besifloxacin administered
antibacterial activity comparable to that of besifloxacin,
including gatifloxacin, moxifloxacin, and levofloxacin.
Based on the 2009 average wholesale price in US dollars,
the acquisition cost of a bottle of besifloxacin ophthal-
mic suspension 0.6% is $77.38.
16
This is comparable
to the acquisition costs of a bottle of the other broad-
spectrum ophthalmic fluoroquinolones that are indi-
cated for the treatment of bacterial conjunctivitis:
$74.54 for gatifloxacin,
16
$74.94 for moxifloxacin,
16
and $70.56 for levofloxacin.
15
Further studies are need-
ed to determine which agent is more cost-effective in the
treatment of bacterial conjunctivitis.
DISCUSSION
Besifloxacin is a new topical ophthalmic fluoroquino-
lone with a broad spectrum of activity. It is approved
by the FDA for the treatment of bacterial conjunctivitis
caused by susceptible organisms. Like other fluoro-
quinolones, besifloxacin has potent inhibitory activity
against both bacterial DNA gyrase (IC
50
= 2.5 M) and
topoisomerase IV (IC
50
= 1 M).
24
It has good activi-
ty against a broad range of common ocular bacterial
pathogens, including S aureus, S pneumoniae, and
H influenzae, and some resistant strains, including
MRSA and vancomycin-resistant E faecalis.
14,22,25,30
In vitro data for >2500 bacterial isolates indicated
that besifloxacin generally had equivalent or lower
MIC
90
values than other fluoroquinolones currently
available for the topical treatment of ocular infections
(specifically moxifloxacin, ciprofloxacin, and levo-
floxacin).
30
In an analysis of resistant isolates by
Karpecki et al,
32
besifloxacin was found to have lower
MICs against methicillin- and ciprofloxacin-resistant
S aureus, ciprofloxacin-resistant S epidermidis, and
methicillin- and ciprofloxacin-resistant S epidermidis
compared with gatifloxacin and moxifloxacin. The
clinical relevance of this finding remains to be eluci-
dated. Besifloxacin is being developed exclusively for
ophthalmic use,
32
minimizing overall drug exposure
and theoretically helping to minimize development of
besifloxacin-resistant strains due to selective pres-
sure. However, limiting besifloxacin exposure does
not necessarily eliminate cross-resistance with other
fluoroquinolones.
In clinical trials, besifloxacin treatment was associ-
ated with faster clinical resolution and higher rates of
microbial eradication compared with its vehicle.
4,32
Rates of clinical resolution and microbial eradication
were ~10% to 30% lower with vehicle compared with
470 Volume 32 Number 3
Clinical Therapeutics
bial eradication. In another trial, besifloxacin admin-
istered for 5 days was well tolerated and was found
to be noninferior to moxifloxacin in the treatment of
bacterial conjunctivitis.
ACKNOWLEDGMENT
The authors have indicated that they have no conflicts
of interest with regard to the content of this article.
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3
; therefore, it can be consid-
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18,30
Besifloxacin has only recently been approved by the
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17
This review had several limitations. There were
limited published data on the pharmacology, spectrum
of activity, tolerability, and efficacy of besifloxacin.
The published trials were sponsored by the manufac-
turer of besifloxacin, introducing the potential for bias.
There were no published drug-interaction or pharma-
coeconomic studies; therefore, the discussion of drug
interactions was mainly theoretical, and the discussion
of cost considerations was based on a comparison
of the price of besifloxacin with those of ophthalmic
fluoroquinolones having a comparable spectrum of
antibacterial activity. In addition, because this was not
a systematic review, the potential for publication bias
cannot be ruled out.
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Besifloxacin is a new broad-spectrum, bacteriocidal,
topical ophthalmic fluoroquinolone approved for the
treatment of bacterial conjunctivitis caused by suscep-
tible organisms. In an era of growing bacterial resis-
tance, besifloxacin ophthalmic suspension 0.6% is a
welcome addition to the armamentarium of topical
antibiotics. In 2 clinical trials comparing besifloxacin
with its vehicle, both administered 3 times daily for
5 days, besifloxacin was well tolerated and was associ-
ated with higher rates of clinical resolution and micro-
March 2010 471
M.H. Chang and H.B. Fung
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Address correspondence to: Horatio B. Fung, PharmD, BCPS, Pharmacy
Service, James J. Peters Veterans Affairs Medical Center, 130 West Kings-
bridge Road (119), Bronx, NY 10468. E-mail: horatio.fung@va.gov
Reproducedwith permission of thecopyright owner. Further reproductionprohibited without permission.