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Adv Ther (2009) 26(4):447-454.
ORIGINAL RESEARCH
Rate of Bacterial Eradication by Ophthalmic Solutions
of Fourth-Generation Fluoroquinolones
Michelle C. Callegan ∙ Billy D. Novosad ∙ Raniyah T. Ramadan ∙ Brandt Wiskur ∙ Andrea L. Moyer
Received: February 25, 2009 / Published online: April 16, 2009 / Printed: May 8, 2009
Springer Healthcare Communications 2009
Laboratories, Inc., Fort Worth, TX, USA) is pre-servative-free. Recent studies have demonstrated
Introduction: Antibacterial activity of ophthal-
that the presence of BAK dramatically affects the
mic fourth-generation fluoroquinolones has tra-
antibacterial activity of the ophthalmic formu-
ditionally been evaluated by comparing only
lation of gatifloxacin. This study was designed
their active ingredients, gatifloxacin and moxi-
to compare the kill rates of ophthalmic solu-
floxacin. However, ophthalmic formulations of
tions of fourth-generation fluoroquinolones
fourth-generation fluoroquinolones differ in
against isolates of common ocular bacterial
terms of the inclusion of preservatives. While
pathogens.
Methods: Approximately 5.6 log
gatifloxacin ophthalmic solution 0.3% (Zymar®;
colony-forming units (CFU)/mL of
Haemophilus
Allergan, Inc., Irvine, CA, USA) contains 0.005%
influenzae (
n=1),
Streptococcus pneumoniae (
n=1),
benzalkonium chloride (BAK), moxifloxacin
Staphylococcus aureus (
n=2), methicillin-resistant
ophthalmic solution 0.5% (Vigamox®; Alcon
Staphylococcus aureus (MRSA) (
n=4), methicillin-resistant
Staphylococcus epidermidis (MRSE) (
n=4), and fluoroquinolone-resistant
S. epidermidis (
n=1)
Michelle C. Callegan ( )
Molecular Pathogenesis of Eye Infections Research
were incubated with ophthalmic solutions of
Center, Dean A. McGee Eye Institute, Oklahoma City,
either gatifloxacin or moxifloxacin. Viable bac-
Department of Ophthalmology, Oklahoma Center
teria were quantified at specific time points up
for Neuroscience, and Department of Microbiology
to 60 minutes.
Results: Gatifloxacin 0.3% com-
and Immunology, University of Oklahoma Health
Sciences Center, 608 Stanton L. Young Blvd. DMEI 418,
pletely eradicated
H. influenzae and
Strep. pneu-
Oklahoma City, Oklahoma 73104, USA.
moniae in 5 minutes, one of two
S. aureus isolates
in 15 minutes, and the other
S. aureus isolate in
Billy D. Novosad ∙ Andrea L. Moyer
60 minutes. Gatifloxacin 0.3% completely killed
Department of Microbiology and Immunology,
University of Oklahoma Health Sciences Center,
all MRSA, MRSE, and fluoroquinolone-resistant
S.
Oklahoma City, Oklahoma, USA
epidermidis isolates in 15 minutes. Moxifloxacin
Raniyah T. Ramadan ∙ Brandt Wiskur
0.5% completely eradicated
Strep. pneumoniae
Oklahoma Center for Neuroscience, University of
and one of four MRSA isolates in 60 minutes.
Oklahoma Health Sciences Center, Oklahoma City,
All other isolates incubated with moxifloxacin
Adv Ther (2009) 26(4):447-454.
0.5% retained viable bacteria ranging from 1.8
isolated from suspected cases of bacterial kera-
to 4.4 log CFU/mL.
Conclusions: The ophthal-
titis and endophthalmitis.8,10 However, there are
mic solution of gatifloxacin 0.3% eradicated bac-
few studies that compare the rate of bacterial
teria that frequently cause postoperative ocular
eradication by fourth-generation fluoroquinolo-
infections substantially faster than did the oph-
nes as ophthalmic formulations.
thalmic solution of moxifloxacin 0.5%.
Ophthalmic formulations of fourth-gener-
ation fluoroquinolones differ in terms of the
Keywords: gatifloxacin ophthalmic solution
inclusion of preservatives. While gatifloxacin
0.3%; moxifloxacin ophthalmic solution
0.3% contains 0.005% benzalkonium chlo-
0.5%; ocular surgery prophylaxis; speed of
ride (BAK), moxifloxacin 0.5% is preservative-
bactericidal activity
free.11,12 The presence of BAK, however, appears to dramatically affect the antibacterial activity of
the ophthalmic formulation of gatifloxacin. An in-vitro study demonstrated that BAK lowered
Bacterial keratitis and endophthalmitis are
the minimum inhibitory concentrations (MICs)
serious vision-threatening complications of cat-
of gatifloxacin against methicillin-resistant
aract and refractive surgery.1,2 The causative bac-
Staphylococcus aureus (MRSA) by approximately
teria are commonly
Staphylococcus,
Streptococcus,
2- to 500-fold compared with the MICs of gati-
and
Haemophilus species, which usually origi-
floxacin alone.13 Gatifloxacin plus BAK was also
nate from the patient's ocular surface and peri-
significantly more effective than gatifloxacin
ocular skin.3,4 Perioperative topical antibiotics
alone or BAK alone in eradicating gatifloxacin-
are generally used to reduce bacterial counts in
resistant MRSA in vivo.14
the tear film until the epithelium is healed after
The key to successful eradication of bacte-
surgery.5,6 Rapid and timely eradication of bacte-
ria and infection control is proper use of pro-
ria on the ocular surface before and after surgery
phylactic agents that reduce bacterial numbers
is crucial to a successful prophylaxis of postop-
rapidly. Therefore, this study was designed to
erative ocular infections.
compare the kill rates of ophthalmic formula-
Gatifloxacin ophthalmic solution 0.3%
tions of fourth-generation fluoroquinolones
(Zymar®; Allergan, Inc., Irvine, CA, USA)
against bacteria that frequently cause postoper-
and moxifloxacin ophthalmic solution 0.5%
ative ocular infections.
(Vigamox®; Alcon Laboratories, Inc., Fort Worth, TX, USA) are topical fourth-generation fluoro-
MATERIALS AND METHODS
quinolones that are often used to prevent and treat ocular infections.7 Several studies have
Isolates of
Haemophilus influenzae (
n=1),
evaluated the antibacterial activity of ophthal-
Streptococcus pneumoniae (
n=1),
Staphylococcus
mic fourth-generation fluoroquinolones by com-
aureus (
n=2), MRSA (
n=4), methicillin-resistant
paring only their active ingredients, gatifloxacin
Staphylococcus epidermidis (MRSE) (
n=4), and fluo-
and moxifloxacin. Both fluoroquinolones had a
roquinolone-resistant
S. epidermidis (
n=1) were
broad spectrum of activity and penetrated well
obtained from the collection of bacterial kerati-
into ocular tissues.8,9 In general, gatifloxacin and
tis and endophthalmitis isolates maintained at
moxifloxacin were also equally effective against
the Dean A. McGee Eye Institute in Oklahoma
Gram-positive and Gram-negative organisms
City, Oklahoma, USA. Gatifloxacin ophthalmic
Adv Ther (2009) 26(4):447-454.
solution 0.3% and moxifloxacin ophthalmic
Figure 1. Viability curves of ocular (A)
H. influenzae and
solution 0.5% were used as study drugs. As per
(B)
Strep. pneumoniae incubated with gatifloxacin 0.3%
their commercial formulations, gatifloxacin
or moxifloxacin 0.5%. Suspensions of
H. influenzae
(
n=1) or
Strep. pneumoniae (
n=1) were incubated with
0.3% contained BAK (0.005%) and moxifloxacin
gatifloxacin 0.3% or moxifloxacin 0.5%, and viability was
0.5% was preservative-free.
analyzed in triplicate at 0, 5, 10, 15, 30, and 60 minutes.
H. influenzae was grown from stock cultures
on a chocolate agar while all other bacterial iso-
lates were grown on a blood agar (5% in brain heart infusion agar). Following overnight incu-
H. influenzae
bation at 37°C, bacteria were suspended in sterile
saline to achieve an optical density of 0.13-0.15
at 650 nm. Subsequently, 20 µL of each bacte-
rial suspension with a density of 5.65-5.72 log
colony-forming units (CFU)/mL was inoculated
with 4 mL of study drugs and incubated at 37°C
in a water bath.
To assess bacterial viability, aliquots were
removed from the suspensions of
H. influen-
zae and
Strep. pneumoniae at 0, 5, 10, 15, 30, and 60 minutes, and from the suspensions of
S.
aureus, MRSA, MRSE, and fluoroquinolone-resist-ant
S. epidermidis at 0, 15, 30, and 60 minutes.
Strep. pneumoniae
Aliquots were diluted 1:10 in Dey Engley neutral-
izing broth supplemented with 5% magnesium
chloride and 3.5% Tween 80, and incubated for
10 minutes at room temperature. Aliquots were
then serially diluted, filtered through a 0.45 µm
Supor® filter membrane (Pall Co., Ann Arbor, MI,
USA), and washed with 300 mL of sterile saline
supplemented with 3.5% Tween 80. The filters
10 20 30 40 50 60
were transferred to chocolate or blood agar plates
supplemented with 5% magnesium chloride and 3.5% Tween 80 and were incubated at 37°C in a
by gatifloxacin 0.3% at 5 minutes while
humidified CO chamber. Bacterial colonies were
3.6 log CFU/mL of bacteria were recovered
counted after a minimum of 72 hours. All exper-
from the suspensions incubated with moxi-
iments were carried out in triplicate.
floxacin 0.5% at 60 minutes (Figure 1A). Viable
Strep. pneumoniae were reduced to 0 log CFU/mL
by gatifloxacin 0.3% at 5 minutes and by moxi-floxacin 0.5% at 60 minutes (Figure 1B). Of the
The initial average load of the bacterial suspen-
two
S. aureus isolates tested, one was completely
sions tested was 5.68±0.04 log CFU/mL. Viable
eradicated by gatifloxacin 0.3% at 15 minutes
H. influenzae were reduced to 0 log CFU/mL
while the other
S. aureus isolate was completely
Adv Ther (2009) 26(4):447-454.
Figure 2. Viability curves of ocular
S. aureus isolates incubated
Figure 4. Viability curves of ocular (A) MRSE isolates and
with gatifloxacin 0.3% or moxifloxacin 0.5%. Suspensions
(B) fluoroquinolone-resistant
S. epidermidis incubated
of
S. aureus (
n=2) were incubated with gatifloxacin 0.3% or
with gatifloxacin 0.3% or moxifloxacin 0.5%. Suspensions
moxifloxacin 0.5%, and viability was analyzed in triplicate at
of MRSE (
n=4) or fluoroquinolone-resistant
0, 15, 30, and 60 minutes. CFU=colony-forming units.
S. epidermidis (
n=1) were incubated with gatifloxacin 0.3%
or moxifloxacin 0.5%, and viability was analyzed in triplicate
at 0, 15, 30, and 60 minutes. The lines representing the
viability of four MRSE isolates incubated with gatifloxacin
0.3% are superimposed as the complete kill against all four
isolates was achieved at 15 minutes. CFU=colony-forming
units; MRSE=methicillin-resistant
S. epidermidis.
10 20 30 40 50 60
Figure 3. Viability curves of ocular MRSA isolates incubated
with gatifloxacin 0.3% or moxifloxacin 0.5%. Suspensions
of MRSA (
n=4) were incubated with gatifloxacin 0.3% or
moxifloxacin 0.5%, and viability was analyzed in triplicate at
0, 15, 30, and 60 minutes. The lines representing the viability
of four MRSA isolates incubated with gatifloxacin 0.3% are
10 20 30 40 50 60
superimposed as the complete kill against all four isolates
was achieved at 15 minutes. CFU=colony-forming units;
Fluoroquinolone-resistant
S. epidermidis
10 20 30 40 50 60
10 20 30 40 50 60
eradicated at 60 minutes (Figure 2). None of the
MRSA isolates was reduced to 0 log CFU/mL by
S. aureus isolates were completely killed by moxi-
moxifloxacin 0.5% at 60 minutes (Figure 3). Viable
floxacin 0.5%. At 60 minutes, viable bacteria
bacteria ranging from 2.3 to 2.9 log CFU/mL
ranging from 2.8 to 3.8 log CFU/mL were recov-
were recovered from the remaining three MRSA
ered from
S. aureus suspensions incubated with
suspensions incubated with moxifloxacin 0.5%.
moxifloxacin 0.5%.
Similar to MRSA, all viable MRSE and fluoroqui-
Bacterial counts of all MRSA isolates were
nolone-resistant
S. epidermidis were reduced to
reduced to 0 log CFU/mL by gatifloxacin 0.3% at
0 log CFU/mL by gatifloxacin 0.3% at 15 min-
15 minutes. The bacterial count of one of these
utes. No MRSE or fluoroquinolone-resistant
Adv Ther (2009) 26(4):447-454.
S. epidermidis isolates were completely killed by
pneumoniae and one MRSA isolate, which were
moxifloxacin 0.5% at 60 minutes (Figure 4). Viable
eradicated by moxifloxacin 0.5% at 60 minutes.
bacteria ranging from 1.8 to 4.4 log CFU/mL
Although the time at which moxifloxacin 0.5%
were recovered from suspensions of MRSE
achieved a complete kill was not determined in
and fluoroquinolone-resistant
S. epidermidis
this study, it has been reported that it may take
after 60 minutes of incubation with moxiflox-
moxifloxacin as long as 4 hours to completely
eradicate
S. aureus.19
The underlying reason for the differential
rate of bacterial eradication by ophthalmic formulations of gatifloxacin and moxifloxacin
Endophthalmitis is a devastating complica-
is not known. Recent evidence demonstrat-
tion that may occur following intraocular sur-
ing that BAK enhances the antibacterial activ-
gery. It is known that clear cornea incisions
ity of gatifloxacin against MRSA both in vitro
may allow inflow of tear film into the ante-
and in vivo supports the notion that BAK may
rior chamber and that wounds may leak on the
have contributed to the faster rate of bacte-
first postoperative day.15 Several studies have
rial eradication by gatifloxacin 0.3% in our
shown that most postoperative infections are
study.13,14 The contribution of BAK may also
caused by pathogens originating from the ocu-
explain the in-vivo efficacy of gatifloxacin
lar surface.4,16,17 The primary goal of prophylaxis
ophthalmic solution against
S. aureus isolates
against postoperative infections is to reduce
that were resistant to the gatifloxacin molecule
the bacterial load on the ocular surface and,
thereby, to minimize bacterial penetration into
Bacterial resistance to second- and third-
the deeper ocular tissues and prevent infection.
generation fluoroquinolones is of growing
An ideal prophylactic antibiotic would have
concern.22,23 Resistance to antibiotics may
broad-spectrum antimicrobial coverage and a
enhance the risk of persistent postopera-
rapid kill rate.18
tive infections and seriously jeopardize the
Fourth-generation fluoroquinolones share
outcome of a prophylactic therapy. Fourth-
a similar spectrum of coverage.8 Our findings,
generation fluoroquinolones have a poten-
however, demonstrate that gatifloxacin 0.3%
tially lower propensity to induce resistance
eradicated bacteria that commonly cause ocu-
as two mutations are necessary to render bac-
lar infections considerably faster than moxi-
teria insusceptible to fourth-generation fluo-
floxacin 0.5%. Gatifloxacin 0.3% reduced the
roquinolones, whereas only a single enzyme
viable cell counts of almost all susceptible
mutation may be sufficient for bacteria to
and resistant isolates to 0 log CFU/mL at the
become resistant to the older fluoroquinolo-
first study time point, 5 or 15 minutes, with
nes.24-27 In general, use of the most effective
the exception of one
S. aureus isolate, which
antibiotic with the least propensity to induce
was eradicated after 60 minutes. These find-
resistance is recommended as the first-line
ings suggest that the actual time necessary for
prophylaxis in order to minimize the devel-
a complete kill may be even shorter than 5 or
opment of resistance.28 In our study, among
15 minutes. In contrast, bacterial eradication
fourth-generation fluoroquinolones, gati-
with moxifloxacin 0.5% was incomplete for
floxacin 0.3% eradicated MRSA and MRSE
almost all isolates, with the exception of
Strep.
faster than moxifloxacin 0.5%, suggesting
Adv Ther (2009) 26(4):447-454.
that the ophthalmic formulation of gati-
floxacin may be a more effective prophylac-tic option against postoperative infections
The ophthalmic solution of gatifloxacin erad-
caused by resistant bacteria.
icated bacteria that frequently cause postopera-
Postoperative ocular infections are seri-
tive ocular infections substantially faster than
ous complications that may result in the loss
did the ophthalmic solution of moxifloxacin.
of vision despite therapeutic interventions.29
Further clinical studies are warranted to evaluate
Effective prophylactic strategies are key to
the implication of our findings in the prophy-
preventing ocular infections. Several clinical
laxis against ocular infections in patients under-
studies suggest that gatifloxacin 0.3% may be
going ocular surgery.
more efficacious than moxifloxacin 0.5% in eradicating bacteria in vivo. In patients under-
going cataract surgery, gatifloxacin 0.3% sig-nificantly eliminated conjunctival bacterial
This study was supported by a research grant
flora after both 1-hour and 1-day administra-
from Allergan, Inc. The authors have no finan-
tions whereas moxifloxacin 0.5% was effective
cial or proprietary interest in any material or
only after 1-day administration.30,31 Recent
method mentioned in this study.
studies found that the incidence of endoph-thalmitis presenting during the prophylactic
treatment was lower in patients who received gatifloxacin 0.3% than those who received
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ton J, Miller D. Acute-onset endophthalmitis after
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2. Solomon R, Donnenfeld ED, Azar DT, et al. In-
of bacterial eradication.
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3. Pushker N, Dada T, Sony P, Ray M, Agarwal T, Vaj-
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Source: http://raniyahramadan.com/media/AdvTher2009.pdf
Contents lists available at Artificial Intelligence in Medicine A semantic graph-based approach to biomedical summarisation Laura Plaza , Alberto Díaz, Pablo Gervás Departamento de Ingeniería del Software e Inteligencia Artificial, Universidad Complutense de Madrid, C/Profesor José García Santesmases, s/n, 28040 Madrid, Spain Objective: Access to the vast body of research literature that is available in biomedicine and related
Rule-Based Policy Representation andReasoning for the Semantic Web Piero A. Bonatti and Daniel Olmedilla a di Napoli Federico II, Napoli, Italy L3S Research Center and University of [email protected] Summary. The Semantic Web aims at enabling sophisticated and autonomic ma-chine to machine interactions without human intervention, by providing machinesnot only with data but also with its meaning (semantics). In this setting, traditionalsecurity mechanisms are not suitable anymore. For example, identity-based accesscontrol assumes that parties are known in advance. Then, a machine first determinesthe identity of the requester in order to either grant or deny access, depending on itsassociated information (e.g., by looking up its set of permissions). In the SemanticWeb, any two strangers can interact with each other automatically and thereforethis assumption does not hold. Hence, a semantically enriched process is requiredin order to regulate an automatic access to sensitive information. Policy-based ac-cess control provides sophisticated means in order to support protecting sensitiveresources and information disclosure.