A Single-Blinded Randomized Clinical Trial Comparing Polymyxin

B-Trimethoprim and Moxifloxacin for Treatment

of Acute Conjunctivitis in Children
Lee Williams, DO1,*, Yogangi Malhotra, MD1,5,*, Barbra Murante, NP1, Susan Laverty, RN1, Steve Cook, MD1,
David Topa, MD1,2, Dwight Hardy, PhD3, Hongyue Wang, PhD4, and Francis Gigliotti, MD1,3

Objective To perform a randomized controlled trial comparing moxifloxacin hydrochloride with polymyxin
B-trimethoprim for the treatment of acute conjunctivitis.
Study design Patients ages 1-18 years old with acute conjunctivitis had cultures performed and were random-
ized to receive either moxifloxacin hydrochloride or polymyxin B-trimethoprim ophthalmic solution for 7 days.
Response to treatment was determined by phone query on day 4-6 and by examination with post-treatment con-
junctival culture on day 7-10.
Results One hundred and twenty-four patients were enrolled. Eighty patients (65%) had recognized pathogens
(55 Haemophilus influenzae, 22 Streptococcus pneumoniae, 4 Moraxella catarrhalis) isolated from their conjunctiva.
One hundred fourteen (56/62 moxifloxacin and 58/62 polymyxin B-trimethoprim) completed the 4-6 day evaluation,
with 43/56 (77%) of the moxifloxacin group and 42/58 (72%) of the polymyxin B-trimethoprim group clinically cured
according to parents (noninferiority test P = .04). Eighty-nine (39/56 moxifloxacin and 50/58 polymyxin B-trimeth-
oprim) patients completed the 7-10 day evaluation. Clinical cure was observed in 37/39 (95%) of the moxifloxacin
and 49/51 (96%) of the polymyxin B-trimethoprim treated groups (noninferiority test P # .01). Clinical cure rates for
culture positive and negative conjunctivitis were not different. There was no statistically significant difference in
bacteriologic cure rates between the 2 groups.
Conclusions Polymyxin B-trimethoprim continues to be an effective treatment for acute conjunctivitis with a clin-
ical response rate that does not differ from moxifloxacin. Use of polymyxin B-trimethoprim for the treatment of con-
junctivitis would result in significant cost savings compared with fluoroquinolones. (J Pediatr 2013;162:857-61).

C
onjunctivitis is the most common infectious disease of the eye during childhood.1 The economic impact of bacterial
conjunctivitis is significant. In the US, an estimated 4 million cases occur each year, resulting in direct medical costs
of approximately 500 million dollars.2 Two-thirds of cases occur between the ages of 0 and 19 years and are estimated
to account for 1.5% of ambulatory and emergency room visits.2,3
Conjunctivitis has both infectious and noninfectious causes. In children, bacterial conjunctivitis is the most common type of
acute conjunctivitis, followed by viral, allergic, traumatic, and neoplastic. Haemophilus influenzae, Streptococcus pneumoniae,
and Moraxella catarrhalis are the most common causative bacteria in bacterial conjunctivitis and account for 55%-68% of cases
in children. Interestingly, Staphylococcus aureus is an uncommon pathogen in acute conjunctivitis.4-6
Although conjunctivitis is a self-limited condition, the duration of bacterial conjunctivitis is shortened by topical antibiotic
treatment. In 1984, Gigliotti et al showed that treatment with polymyxin B-bacitracin ointment resulted in significantly more
clinical and bacteriologic cures by 3-5 days than did treatment with the placebo ointment.7 In 1988, Lohr et al compared Poly-
trim (polymyxin B-trimethoprim), gentamicin, and sulfacetamide topical preparations for treatment of conjunctivitis.5 The
clinical response of S pneumoniae infections at 3-6 days was similar for all agents, and polymyxin B-trimethoprim was more
effective for H influenzae infection. Several studies using other antibiotics have shown similar results.
A 2007 Cochrane review assessed the effect of antibiotic therapy in the man-
agement of acute bacterial conjunctivitis and found that clinical cure (relative
1
From the Department of Pediatrics, Golisano Children’s
risk 1.24, 95% CI 1.05-1.45) and microbiologic clearance (relative risk 1.77, Hospital at Strong, University of Rochester School of
8 2
95% CI 1.23-2.54) were accelerated by use of topical antibiotics. No serious out- Medicine and Dentistry, Rochester, NY; Pittsford
3
Pediatrics, Pittsford, NY; Department of Microbiology
comes were observed in either the treatment or the placebo arms. The Cochrane and Immunology, Strong Memorial Hospital, and
4
Department of Biostatistics and Computational Biology,
review concluded that treatment of bacterial conjunctivitis is associated with University of Rochester School of Medicine and
5
Dentistry, Rochester, NY; and Division of Neonatology,
significantly improved rates of clinical and microbiologic cure. Department of Pediatrics, Maria Fareri Children’s
The increasing antibiotic resistance of pathogens associated with acute bacte- Hospital at Westchester Medical Center, Valhalla, NY
*Contributed equally.
rial conjunctivitis has led many authors to propose that topical fluoroquinolones
Y.M. is supported in part by a resident research grant
from the American Academy of Pediatrics. The authors
declare no conflicts of interest.

MIC Minimal inhibitory concentration 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.09.013

857
THE JOURNAL OF PEDIATRICS  www.jpeds.com
are superior to older medications such as polymyxin
B-trimethoprim.9-12 However, the superiority of fluoroqui-
nolones generally is based on interpretation of minimal
inhibitory concentration (MIC) or other in vitro data show-
ing increased potency of the fluoroquinolones compared
with polymyxin B or trimethoprim against bacteria causing
conjunctivitis. Although such drug data have been validated
to predict the outcome of systemic therapy of bacterial
infections, their relevance in topical antibiotic therapy is
unproven.
To provide physicians with clinically relevant data regard-
ing the treatment of acute conjunctivitis, we performed a pro-
spective, randomized, single-blind study of moxifloxacin
compared with polymyxin B-trimethoprim for the treatment
of acute conjunctivitis in children 1-18 years of age.
Methods
Patients were enrolled from the Golisano Children’s Hospital
Pediatric Ambulatory Clinic (resident based hospital clinic)
and Pittsford Pediatrics (a suburban pediatric office in Pitts-
ford, New York) from the fall of 2007 to the fall of 2010.
Patients were enrolled based on a clinical diagnosis of con-
junctivitis by the primary physician. The presence of lid
edema, conjunctival erythema, eye discharge, and/or subcon-
junctival hemorrhage was recorded for each patient enrolled.
Exclusion criteria included a recent history suggestive of
allergies, foreign body or trauma to the eye, and receipt of an-
tibiotics during the previous week or during the study. Non-
English speaking patients were excluded because interpreter
services during the visits and phone follow-up could not be
guaranteed.
Patients were assigned 1:1 to receive 1 of the 2 antibiotics,
using a randomization table. In the research pharmacy,
numbered brown paper bags that contained either poly-
myxin B- trimethoprim or 0.5% moxifloxacin hydrochloride
ophthalmic solution were prepared along with antibiotic-
specific directions for administration.
This was a single-blind study as the study personnel were
unaware of which medication each patient received. Patients
were instructed to follow the written directions contained in
the bag of the antibiotic they received. Polymyxin B-trimeth-
oprim was to be applied 4 times a day for 7 days and moxiflox-
acin was to be applied 3 times a day for 7 days. The patient
and/or parent were asked not to tell the study personnel which
medication they had been assigned. Patient compliance
to treatment was not formally monitored during this study.
At the initial visit (day 0), the patient was evaluated by the
study personnel. Purulent discharge was considered to be
present if parents reported either discharge or eyelids sticking
together on morning rising. The presence of lid edema, con-
junctival erythema, or subconjunctival hemorrhage also was
recorded. The severity of the clinical signs was not graded,
as a validated scoring system is not available. A bacterial cul-
ture of the affected eye was obtained (if both eyes appeared to
be infected, conjunctival was obtained only from one eye) and
was sent to the microbiology lab at Strong Memorial Hospital.
858
Vol. 162, No. 4
A follow-up phone call was made 4-6 days later to assess clin-
ical response. Parents were asked about the same signs and
symptoms assessed at enrollment. The patients then returned
to the office for a follow-up visit at day 7-10. During this visit,
an assessment of physical findings was made by the investiga-
tor and a follow-up conjunctival culture was obtained. Clin-
ical cure required a complete resolution of all signs and
symptoms of conjunctivitis at the time of evaluation.
This study was approved by the Research Subject Review
Board at the University of Rochester School of Medicine
and Dentistry. Parent and/or patient provided informed con-
sent or assent to be included in this study.
Study Microbiology
Conjunctival swab specimens were inoculated onto tryptic
soy agar with 5% sheep blood and GC II Agar supplemented
with hemoglobin and Isovitalex (Becton, Dickinson and Co,
Sparks, Maryland) with incubation at 35 C in ambient air
supplemented with 5% carbon dioxide for 48 hours. S pneu-
moniae was identified as alpha-hemolytic catalase-negative
gram-positive cocci susceptible to desoxycholate or opto-
chin.13 Haemophilus was identified as small gram-negative
bacilli with characteristic growth on supplemented GC II
Agar, no growth on tryptic soy agar supplemented with
blood, and requirement for hemin (X factor) and/or nicotin-
amide adenine dinucleotide (V factor); H influenzae was
typed with type b specific antisera (Becton, Dickinson and
Co).14 M catarrhalis was identified as oxidase-positive, in-
doxyl butyrate-positive, gram-negative diplococci.15
MICs of antimicrobial agents for S pneumoniae and Hae-
mophilus were determined in Muller-Hinton Broth supple-
mented with 2.5% lysed horse blood and haemophilus test
medium broth, respectively, with incubation at 35 C in am-
bient air for 20-24 hours.16 Haemophilus test medium broth
was supplemented with 0.2 IU/mL thymydine phosphorylase
when testing trimethoprim and sulfamethoxazole. MICs for
S pneumonia and H influenzae were interpreted according
to systemic breakpoints established by Clinical and Labora-
tory Standards Institute where available.17
Statistical Analyses
All statistical analyses were conducted using v. 9.2 of the SAS
System for Windows (SAS Institute Inc, Cary, North Caro-
lina). Patient demographics and clinical characteristic were
summarized and compared between treatment groups using
the 2 sample t test (continuous variables) or c2 test (categor-
ical variables). Clinical and microbiologic outcomes of the
polymyxin B-trimethoprim group were compared with the
moxifloxacin group using noninferiority tests of binomial
proportions. Differences in cure rates at 4-6 days, 7-10
days, and associated CIs were estimated.
Results
One hundred and twenty-four patients were enrolled in this
study. Four patients were excluded after enrollment: 2
patients had allergic symptoms, 1 had dacryocystitis, and
Williams et al
April 2013 ORIGINAL ARTICLES

1 had otitis media and was started on amoxicillin. A total of

114 patients completed the 4-6 day follow-up (median day Polymyxin B-
trimethoprim
5), 89 patients completed the 7-10 day follow-up (mean Moxifloxacin
42/58
day 9); 9 patients were lost to follow-up before the 4-6 day 4-6 day clinical cure
visit, and 25 were lost at the final follow-up. Patients who 43/56
missed the 4-6 day phone follow-up were eligible for the 7-
10 day final follow-up in the clinic if they returned.
The 2 groups of subjects were found to be similar at enroll-
ment (Table). Cultures from 80 patients (65%) grew 7-10 day clinical
49/51

recognized pathogens from the initial conjunctival sample cure

(55 H influenzae, 22 S pneumoniae, 4 M catarrhalis
[1 patient’s culture grew both H influenzae and S
pneumoniae]): 35% did not grow a recognizable pathogen.
Sixty-two (50%) patients were randomized to each treatment
group. The number of conjunctival cultures positive for
pathogens was 41/62 (66%) in the moxifloxacin group and
39/62 (62%) in the polymyxin B-trimethoprim group. Of the
114 patients who completed the 4-6 day evaluation, 56/62
(90%) were in the moxifloxacin group and 58/62 (93%) were
in the polymyxin B-trimethoprim group. The median time
to evaluation was 5.1 days for the moxifloxacin group and
4.8 days for those receiving polymyxin B-trimethoprim. At
the 4-6 day follow-up, 43/56 (77%) of the moxifloxacin
group and 42/58 (72%) of the polymyxin B-trimethoprim
group were categorized as clinically cured (Figure 1). The
noninferiority test with a margin of 20% showed that the
clinical cure rate of the polymyxin B-trimethoprim group is
not statistically lower than that of moxifloxacin group
(P = .04, difference: 0.05, 90% CI: 0.20 to 0.11). Cure
rates were not different for the two treatment groups
(P = .59). No patients reported worsening of symptoms at 4-
6 days. A post-hoc power calculation based on noninferiority
was performed. Based on previous work demonstrating
a 62% cure rate with conventional therapy at 4 days (range
3-5 days), we estimated that a 25% improvement in time to
cure would be clinically significant.7 A sample size of 60 per
group would achieve 85% power to detect a noninferiority
margin difference of 25% at 5% significance level.
In the subgroup of initial culture-positive patients, 75
(39/41 in the moxifloxacin group and 36/39 in the polymyxin
37/39
0 20 40 60 80 100
Percentage of patients cured by either moxifloxacin or
polymyxin B-trimethoprim
Figure 1. Clinical outcome of all children enrolled with acute
conjunctivitis.
B-trimethoprim group) completed the 4-6 day evaluation. In
this subgroup, 30/39 (77%) of moxifloxacin treated patients
and 26/36 (72%) of the polymyxin B-trimethoprim treated
patients were clinically cured (P = .10) (Figure 2).
At the final follow-up, a total of 89 patients (39/56 in the
moxifloxacin group and 50/58 in the polymyxin B-trimetho-
prim group) completed the 7-10 day evaluation. The median
time for this evaluation was 9 days for both groups. At 7-10
days, 37/39 (95%) of the entire moxifloxacin group and 49/
51 (96%) of the entire polymyxin B-trimethoprim group
were clinically cured (noninferiority test P < .01)
(Figure 1). From the culture-positive subgroup, a total of
60 patients (28/39 in the moxifloxacin group and 32/36 in
the polymyxin B-trimethoprim group) completed the 7-10
day follow-up. In this subgroup, 26/28 (93%) of the
moxifloxacin group and 30/32 (94%) of the polymyxin B-
Polymyxin B-
trimethoprim
4-6 day clinical 26/36
Moxifloxacin
cure 30/39

30/32
Table. Characteristics of each study group 7-10 day clinical
cure 26/28
Polymyxin
B-trimethoprim Moxifloxacin P
(n = 62) (n = 62) value 7-10 day 19/31*
bacteriologic cure 22/28
Mean age (mo) 73.4 (SD 50) 70.3 (SD 48) .73
Male % 37 (n = 23) 55 (n = 34) .07
Female % 63 (n = 39) 45 (n = 28)
Signs/symptoms initial visit 0 20 40 60 80 100
Purulent discharge % 97 (n = 60) 98 (n = 61) 1.0
Lid edema % 63 (n = 39) 61 (n = 38) .85 Percentage of patients cured by either moxifloxacin or
Erythema % 85 (n = 53) 82 (n = 51) .81 polymyxin B-trimethoprim
Fever % 10 (n = 6) 5 (n = 3) .49
Organism
S pneumoniae % 19 (n = 10) 19 (n = 12) .81 Figure 2. Clinical and microbiologic outcomes of the sub-
H influenzae % 45 (n = 28) 44 (n = 27) 1.0
M catarrhalis % 3 (n = 2) 3 (n = 2) 1.0 group of children with confirmed bacterial conjunctivitis. *One
No pathogen % 37 (n = 23) 34 (n = 21) .85 patient did not have a follow-up culture done.

A Single-Blinded Randomized Clinical Trial Comparing Polymyxin B-Trimethoprim and Moxifloxacin for Treatment of 859
Acute Conjunctivitis in Children
THE JOURNAL OF PEDIATRICS  www.jpeds.com
trimethoprim group patients were considered clinically cured
at 7-10 days (P < .01) (Figure 2). The bacteriologic cure rate
was 22/28 (79%) in the moxifloxacin group and 19/31 (61%)
in the polymyxin B-trimethoprim group (P = .52) (Figure 2).
Of the 6 patients with bacteriologic failure in the moxifloxacin
group, 4 had H influenzae and 2 had S pneumonia isolated.
Among the 12 polymyxin B- trimethoprim bacteriologic
failures, 5 that had H influenzae, 1 had M catarrhalis, and 6
had S pneumoniae isolated.
To determine the potencies of each antibiotic on a micro-
gram per microgram basis, the MIC90 was determined for
moxifloxacin, polymyxin, and trimethoprim to S pneumo-
niae and H influenzae isolates collected from patients en-
rolled in this study. Moxifloxacin had a MIC90 of 0.06
mg/mL for S pneumoniae and 0.015 mg/mL for H influenzae.
Polymyxin B had a MIC90 of 64 mg/mL for S pneumoniae
and 2 mg/mL for H influenzae. Trimethoprim had
a MIC90 of 2 mg/mL for S pneumoniae and 16 mg/mL for
H influenzae.
Discussion
To test the hypothesis, based on frequently published state-
ments, that fluoroquinolones are the preferred treatment
for acute bacterial conjunctivitis, we performed a single-
blind, randomized controlled clinical trial of polymyxin B-
trimethoprim compared with moxifloxacin for the treatment
of acute conjunctivitis in children. Our data do not support
the hypothesis that fluoroquinolones, in this case moxifloxa-
cin, are superior to polymyxin B-trimethoprim.
Our study of 120 children, 80 of whom had microbiolog-
ically confirmed bacterial conjunctivitis, showed that the 4-
to 6-day clinical cure rate after treatment with polymyxin
B-trimethoprim or moxifloxacin was not different.
Seventy-seven percent of all moxifloxacin treated patients
and 72% of all polymyxin B-trimethoprim treated patients
were clinically cured at the first evaluation timepoint, and
those not cured were all improved. These latter patients
were not categorized as cures because complete resolution
of all signs and symptoms was required to be classified as
a clinical cure. There was no difference in the cure rate for
those patients from whom a pathogen was isolated compared
with those from whom no pathogen was isolated. As would
be expected, nearly all patients (95% of moxifloxacin; 96%
of polymyxin B-trimethoprim) had a normal examination
7-10 days after starting topical antibiotics.7
Bacteriologic cure rates, assessed at the 7-10 day visit, ap-
pear to be slightly better for the moxifloxacin group (79%)
compared with the group treated with polymyxin B-trimeth-
oprim (61%). However, this difference was not statistically
significant and did not result in more rapid resolution of con-
junctivitis. This suggests that the antimicrobial activity of
polymyxin B-trimethoprim when applied topically is suffi-
cient, when combined with host defense mechanisms in the
normal eye, to bring about clinical resolution and that there
is little added benefit to the increased potency of the fluoro-
quinolones for the treatment of conjunctivitis.
860
Vol. 162, No. 4
The results of this study differ from those of Granet et al,
who also compared polymyxin B-trimethoprim and moxi-
floxacin.18 They found an accelerated cure rate in the moxi-
floxacin treated children with an 81% clinical cure rate after
only 48 hours of treatment. Several aspects of that study
make interpretations of their results difficult. Most children
in the study did not have a recognized pathogen (H influenzae
or S pneumoniae) isolated from the conjunctiva. The high
cure rate after only 48 hours is unexpected, given the inflam-
matory nature of bacterial components.19,20 The study also is
inconsistent with other fluoroquinolones trials.21,22 McDo-
nald et al reported a clinical cure rate for bacterial conjuncti-
vitis treated with moxifloxacin ophthalmic of 59.4% at day
5.22 This result is consistent with our study’s clinical cure
rate of 77% by day 4-6. In addition, Hwang et al compared
levofloxacin ophthalmic with placebo in a study primarily
of adults and found a 27% clinical cure rate 3-5 days after
initiating treatment.21
Many articles report that fluoroquinolones should be used
for first-line treatment of bacterial conjunctivitis because of
increasing resistance to commonly used antibiotics. In 2007
Lichtenstein et al demonstrated more rapid killing of S au-
reus, S pneumoniae, and H influenzae by fluoroquinolones
compared with polymyxin B- trimethoprim.12 Block et al
showed that H influenzae and S pneumoniae isolated from
the eye often were resistant to the beta-lactam agents, poly-
myxin B-bacitracin, and other drugs commonly used to treat
conjunctivitis and otitis media.23 This study demonstrated
that the 2 topical fluoroquinolones tested possessed the high-
est intrinsic activity, as defined by MIC values. However, the
relationship between MIC and clinical response to topical an-
tibiotic treatment remains undefined.
Furthermore, because of the data showing that fluoroqui-
nolones have lower MICs, there is the perception that therapy
with drugs, such as polymyxin B-trimethoprim, is inferior
and therefore inappropriate for treatment. However, in re-
viewing polymyxin B based treatments over the last 30 years
this does not seem to be the case. A 1984 study by Gigliotti
et al demonstrated a clinical cure rate of 62% at 3-5 days after
treatment with polymyxin B-bacitracin, and a 1988 study by
Lohr et al showed a 47% clinical cure rate at 3-6 days after
treatment with polymyxin B-trimethoprim.5,7 Given the clin-
ical cure rate in this study of 72% on day 4-6 after treatment
with polymyxin B-trimethoprim, there does not appear to be
any decline in the efficacy of polymyxin B based topical treat-
ment of bacterial conjunctivitis. This supports the need to de-
velop a better understanding of how to relate MIC values to
clinical outcomes when using topical antibiotic therapy.
The efficacy of an antibiotic is determined by its antimicro-
bial potency and its concentration at the site of infection. There
is limited information regarding antibiotic tear concentrations
after topical application in the literature. Data are available
for azithromycin, levofloxacin, and moxifloxacin.24-28 Mean
tear concentrations of moxifloxacin at 5 minutes following
the first and last topical doses (1 drop every 8 hours for 10
doses) were 46 and 55.2 mg/mL, respectively.28 Predose
tear concentrations averaged 4 mg/mL. We determined
Williams et al
April 2013
MIC90s for moxifloxacin, polymyxin B, and trimethoprim
against S pneumoniae and H influenzae. Moxifloxacin was
clearly more potent than both polymyxin B and trimethoprim
but as already mentioned, this increased potency did not result
in a superior clinical outcome.
To estimate the financial implications of these results we
searched the 2007 National Ambulatory Medical Care Survey
and National Hospital Ambulatory Medical Care Survey da-
tabases to estimate the number of annual visits for acute bac-
terial conjunctivitis in the US. Using International
Classification of Diseases, 9th Revision codes 372.30, 372.03,
and 372.00 for patients <18 years old, it was estimated that
there were approximately 3 732 322 cases of bacterial con-
junctivitis in 2007. These estimates are consistent with the re-
sults of Smith and Waycaster who used the 2005 National
Ambulatory Medical Care Survey data set searching for Inter-
national Classification of Diseases, 9th Revision codes 372.30,
372.03, and 372.00 and yielding a total 4 016 544 visits.2 Of
these 4 016 544 visits there were 1 356 693 visits by patients
<15 years old.2 To estimate the average cost of polymyxin
B-trimethoprim and moxifloxacin ophthalmic solutions, 9
local pharmacies in Rochester, New York were surveyed.
The average cost of polymyxin B-trimethoprim was $16/10
mL (range $4-$34) compared with moxifloxacin, which
was $105/3 mL (range $101.88-$111.49). Based on these
rough cost estimates using polymyxin B-tremthiprim rather
than a fluoroqunilone would save in excess of $300 million/y
based on an estimated 3.7 million cases each year. n
The authors thank Carl T. D’Angio, MD (University of Rochester), for
his help with statistical analysis of the data.
Submitted for publication Apr 24, 2012; last revision received Aug 1, 2012;
accepted Sep 6, 2012.
Reprint requests: Francis Gigliotti, MD, Department of Pediatrics, Golisano
Children’s Hospital at Strong, University of Rochester School of Medicine and
Dentistry, 601 Elmwood Avenue, Box 690, Rochester, NY 14642. E-mail:
francis_gigliotti@urmc.rochester.edu
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