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REVIEW ARTICLE

Clin Drug Investig 2011; 31 (8): 543-557


1173-2563/11/0008-0543/$49.95/0

2011 Adis Data Information BV. All rights reserved.

The Role of Topical Moxifloxacin, a New


Antibacterial in Europe, in the Treatment
of Bacterial Conjunctivitis
Jose Benitez-del-Castillo,1 Yves Verboven,2 David Stroman3 and Laurent Kodjikian4,5
1 Ocular Surface and Inflammation Department, Ophthalmology, Hospital Clinico de San Carlos, Madrid,
Spain and Universidad Complutense, Madrid, Spain
2 Alcon Research Ltd, Puurs, Belgium
3 Alcon Research Ltd, Fort Worth, TX, USA
4 Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon and
University of Lyon, Lyon, France
5 Laboratory of Biomaterials, Medical Devices and Matrix Remodelling, Claude Bernard Lyon I University,
Lyon, France

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1 Burden on Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2 Burden on Society . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Management of the Health Issue: A Clinical and Healthcare Utilization Perspective in European
Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1 Treatment by a General Practitioner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Treatment by a Specialist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Use of Topical Moxifloxacin for Bacterial Conjunctivitis in Clinical Practice . . . . . . . . . . . . . . . . . . . . . .
3.1 Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2 Antibacterial Resistance and Topical Moxifloxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3 Adverse Effect Profile and Acceptability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Cost to the Healthcare System of Treatment with Topical Moxifloxacin. . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Reduction in Treatment Failures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Healthcare Resources and Cost of Treatment Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3 Healthcare Cost-Effectiveness Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4 Impact on the Healthcare Budget . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

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This article discusses current practice in the treatment of conjunctivitis and


how the use of topical moxifloxacin can increase therapeutic effectiveness,
reduce treatment failures and, consequently, be cost effective and reduce the
societal burden of the disorder. Current practice and effectiveness data were
derived from the literature. Data on healthcare utilization as a result of treatment failure were collected by survey and the cost of treatment was defined
using national costings. A decision-analytic model to assess cost effectiveness

Benitez-del-Castillo et al.

544

was developed and the impact on the healthcare budget was calculated to
define the health economic impact.
Bacterial conjunctivitis represents a significant health problem and accounts for an estimated 11.5% of primary-care consultations. The disorder is
highly contagious and causes a substantial healthcare and societal burden.
Bacterial conjunctivitis is generally self-limiting, resolving within 12 weeks.
However, the use of antibacterials significantly improves clinical and microbiological remission, shortens symptom duration, and enables more effective
use of healthcare resources, compared with placebo. From a health economic
perspective this benefits the healthcare system and society, since fewer
healthcare resources are needed and the adult affected, or the parent/caregiver of the child affected, can return to full work capacity sooner, reducing
loss of productivity.
Treatment strategies vary significantly between countries. Most patients
are first seen in primary care, where wait-and-see, lubrification and antiseptic or antibacterial treatment is provided. In Europe, when antibacterials
are prescribed most general practitioners (GPs) prescribe a broad-spectrum
topical antibacterial. The most commonly used drugs are chloramphenicol
and fusidic acid, with fluoroquinolones rarely reported as first-line treatment
by GPs. At the specialist (ophthalmologist) level, or for second-line treatment
at the GP level, topical antibacterials are frequently used. However, in most
countries, topical fluoroquinolones, particularly those recently approved by
the European Medicines Agency, such as topical levofloxacin and topical
moxifloxacin, are rarely used and instead are reserved for use as a last resort.
In other parts of the world topical lomefloxacin, gatifloxacin and/or besifloxacin are also available. The strategy of using novel topical fluoroquinolones as a last resort reflects a belief that the use of topical fluoroquinolones
may enhance the development of resistance, jeopardizing future availability
of antibacterial treatment for ocular infections. In fact, most cases of bacterial resistance arise as a result of systemic treatment. Thus, this concern
should not be extrapolated to topical use of fluoroquinolones, which results
in antibacterial concentrations at the ocular surface that can significantly
exceed mutant prevention concentrations. In addition, with products such as
topical moxifloxacin, a dual-step mutation is required for resistance to
emerge. Moxifloxacin restricts the selection of resistant mutants, meaning
that emergence of resistance is unlikely.
The strategy of not using the most effective fluoroquinolones such as topical
moxifloxacin may lead to more patients with no improvement or worsening
of symptoms, requiring re-intervention, additional examination and new treatment; these outcomes are defined as treatment failures. Treatment failures
cause an extra societal burden and increased costs due to the extra healthcare
resources required (additional GP/specialist visits, laboratory tests, additional
treatment, etc.).
Compared with non-fluoroquinolones, topical moxifloxacin has a higher
potency and faster in vitro speed-to-kill. It has also been shown that, within
the fluoroquinolone class, topical moxifloxacin and besifloxacin achieve the
highest mean concentrations in conjunctival tissue, have the longest residence
times and display favourable area under the concentration-time curve from
time zero to 24 hours (AUC24)/minimum inhibitory concentration ratio required
to inhibit the growth of 90% of organisms (MIC90) and thus favourable

2011 Adis Data Information BV. All rights reserved.

Clin Drug Investig 2011; 31 (8)

Moxifloxacin in the Treatment of Bacterial Conjunctivitis

545

pharmacokinetic/pharmacodynamic characteristics. This can result in reduced


time-to-cure and a lower number of treatment failures, leading to better disease management and a healthcare-economic benefit arising from the associated reduction in utilization of healthcare resources.
The high potency and mean concentration in conjunctival tissue combined
with the long residence time of topical moxifloxacin enables a dosing strategy
of three times daily for 5 days. Topical moxifloxacin is also the first ophthalmic
antibacterial in Europe provided as a multidose, self-preserved, topical
solution, thus avoiding the risk of benzalkonium chloride preservativerelated allergic reactions and swelling. In addition, topical moxifloxacin has a
near neutral pH (6.8) and is well tolerated by patients.
Given the characteristics of the novel topical fluoroquinolones, a change
in the healthcare treatment strategy for acute infectious conjunctivitis is to be
recommended. Topical application of fluoroquinolones, such as moxifloxacin multidose self-preserved solution, should be considered earlier in the
treatment path for conjunctivitis. Notwithstanding the premium price attached to this novel topical antibacterial, use of topical moxifloxacin for
bacterial conjunctivitis can be cost effective and even generate total healthcare budget savings by reducing both the costs of managing treatment failures
and the use of clinicians time to manage such failures.

1. Introduction
Conjunctivitis is used to describe any inflammation of the conjunctiva. It is generally characterized
by irritation, itching, foreign body sensation, and
tearing or discharge.[1,2] Severe symptoms may
also include burning and swelling, and the condition is commonly referred to as red eye or pink
eye. Conjunctivitis may be infectious (caused by
bacteria or viruses) or allergic.[3]
1.1 Burden on Patients

Conjunctivitis occurs worldwide and affects all


age groups, but is especially prevalent in children.
In Western countries the estimated prevalence of
conjunctivitis is 1315 cases per 1000 persons per
year.[4-6] In children incidences of up to 80 per
1000 children up to 1 year of age have been reported.[7] Estimates of the proportion of infective
conjunctivitis that is bacterial vary widely among
studies. Recent studies in primary care estimate
that between 33% and 78% of cases are bacterial
in origin.[8] Bacterial conjunctivitis is estimated to
be one of the most common ophthalmic conditions
in the developed world, accounting for 11.5% of
annual consultations in primary care.[9-11]
2011 Adis Data Information BV. All rights reserved.

In adults, the most common microbial pathogens associated with bacterial conjunctivitis are
Staphylococcus aureus and Streptococcus pneumoniae,
followed by Haemophilus influenzae.[1,12-14] In
children, bacterial conjunctivitis is more common
than viral. Approximately 80% of cases of
conjunctivitis in children are bacterial in origin,
being caused mainly by H. influenzae and
S. pneumoniae.[15,16] Bacterial conjunctivitis may
also result from a systemic infection with Neisseria
gonorrhoeae or Chlamydia trachomatis in sexually
active individuals and in neonates.[17] These causes
of extremely severe conjunctival disease, however,
have a low incidence in European countries.[17]
Although mostly bacterial conjunctivitis is selflimiting,[18,19] resolving within 12 weeks of
onset,[15,20] in rare cases, serious, permanent damage
to the eye can occur.[21] Bacterial conjunctivitis
that is not rapidly diagnosed represents an ocular
problem, which, unless managed appropriately,
may progress to infectious keratitis and endophthalmitis.[2,22-25] Other more common complications include otitis media, which may develop in
25% of children with H. influenzae conjunctivitis.[26]
The symptoms of bacterial conjunctivitis cause
both pain and irritation for sufferers. Due to its
highly contagious nature,[27] it may be recommended
Clin Drug Investig 2011; 31 (8)

Benitez-del-Castillo et al.

546

that sufferers are kept in isolation, i.e. stay away


from daycare facilities, school or the workplace.[28]
While epidemics or outbreaks of conjunctivitis
are usually caused by viruses, recent studies have
implicated bacteria, especially S. pneumoniae, in
such cases.[29,30]
1.2 Burden on Society

As mentioned in section 1.1, conjunctivitis is


highly contagious,[27] particularly among children
and the elderly.[31-33] In a recent study, over 40%
of the conjunctival bacteria collected in a clinical
setting were obtained from patients aged <5 years.[34]
Due to its highly contagious nature, children with
the condition are usually recommended not to
attend school or daycare. A survey of ophthalmologists found that 4080% of children were
advised to stay away from school and up to 100%
of adults had sick leave certified by some ophthalmologists in some countries, with the average
duration of absence or leave being 5 days.[28] These
measures have a health economic impact on society,
since the adult affected, or the parent/caregiver of
the affected child, will then not be able to attend
work, resulting in a loss of productivity.
2. Management of the Health Issue:
A Clinical and Healthcare Utilization
Perspective in European Countries
2.1 Treatment by a General Practitioner

The majority of conjunctivitis patients are first


seen in primary care. It is estimated that between
2% and 5% of all general practice consultations
concern eye problems.[9,31,35,36] Acute bacterial
conjunctivitis is the eye disease most commonly
seen by general practitioners (GPs).[9,10,35]
Management of conjunctivitis, however, varies
between countries, and in some countries patients
may directly consult an ophthalmologist or be
referred via an optician/optometrist. Differences
in the management strategies in different countries may also be due to the availability of ophthalmologists in different countries. For example,
in the Netherlands there are a limited number of
registered ophthalmologists (593) for a population of 16 584 127.[37] In addition, these ophthal 2011 Adis Data Information BV. All rights reserved.

mologists are always located at hospitals, which


makes them less accessible to the general public
compared with other European countries, such as
Belgium or Spain. In the latter country, there
were an estimated 4466 ophthalmologists for
a population of 45 989 016 in 2009.[38]
The treatment approach following a treatment
failure (defined as no improvement or a worsening of symptoms during the treatment period requiring re-intervention and possible additional
examination) also varies between different countries, with the patient either being referred to an
ophthalmologist or continuing to be managed
and treated by the GP.[39]
Clinicians often face a high degree of difficulty
in differentiating between viral and bacterial
conjunctivitis based solely on signs and symptoms.[40] No clear criteria to differentiate these
aetiologies have been developed to date. In fact,
a recent survey found that only 36% of GPs felt
able to discriminate between acute bacterial and
viral conjunctivitis.[11]
In order to diagnose the viral or bacterial cause,
and to determine the specific pathogen, eye swabs
(requiring up to 7 days for culture growth) and
microbiological examination may be performed.
However, in practice, eye swabs are rarely taken
as treatment is usually started immediately. Also,
most cases of bacterial conjunctivitis are selflimiting and benign and begin to resolve with use
of a broad-spectrum antibacterial before the results of any laboratory tests are available.[20]
Spontaneous cure of bacterial conjunctivitis
has been reported to be likely to occur within
12 weeks in around 65% of cases,[15,20] so there is
the potential option to wait-and-see or delay the
use of antibacterials.[41] However, this strategy
leads to concerns relating to the contagious
character of the disease, the risk of complications[19] and the increased healthcare professional
resources associated with this approach.[42] This
is due to the higher number of treatment failures,
which is the major cost driver in the management
of bacterial conjunctivitis.[43]
A Cochrane systematic review of the use of
antibacterials for bacterial conjunctivitis found
that, compared with placebo treatment, antibacterials significantly improved clinical and
Clin Drug Investig 2011; 31 (8)

Moxifloxacin in the Treatment of Bacterial Conjunctivitis

2.2 Treatment by a Specialist

Strategies for the management of conjunctivitis


by specialists (ophthalmologists) also differ among
countries. The generally accepted strategy is a stepwise approach to antibacterial use, reserving the
most potent for last. Therefore in many countries
topical fluoroquinolones, especially those approved
recently, are not used early in management by
specialists,[28] but are rather reserved for later use.
This strategy, however, still results in a relatively
high number of treatment failures at the specialist
2011 Adis Data Information BV. All rights reserved.

level and, as a consequence, to extra costs associated with these failures.[28] Treatment failures
may occur because the antibacterial used does
not cover the pathogen causing the conjunctivitis
and/or because of emergence of resistance in some
pathogens to certain antibacterials.[47,48] In most
cases, the latter involves the emergence of plasmidmediated resistance genes or single-step chromosomal mutations in a setting of insufficient
antibacterial concentrations.[47,48]
Treatment failures accompanied by no improvement or worsening of the patients symptoms are
associated with a substantial increase in costs due
to the additional healthcare resources required
(additional GP/specialist visits, laboratory tests,
etc.)[43] [figure 1]. Therefore, a need for an effective antibacterial agent that reduces the incidence
of treatment failures and negates the requirement
for additional healthcare resources is apparent.
Use of potent, broad-spectrum antibacterials
ensures rapid and effective resolution of acute
bacterial conjunctivitis.[49] Using a novel topical
fluoroquinolone as a first choice rather than as
a last resort whenever the patient is seen by a

Receptrule1
Chlamydia test
Swab culture
Switch drug
Ophthalmology visits

Percentage

microbiological remission[19] and could be used


to shorten the duration of symptoms and reduce
the chance of sequelae.[20] Use of antibacterials is
also thought to limit the spread of contagious
bacterial strains and thus may prevent epidemics
of bacterial conjunctivitis.[18,44]
Given the difficulty in determining whether
conjunctivitis has a viral or bacterial cause, most
GPs (as many as 95%) usually prescribe a broadspectrum topical antibacterial in most cases of
acute infectious conjunctivitis, whether viral or
bacterial.[7,10,11,45]
In the UK and the Netherlands, up to 64% of
GPs used chloramphenicol as their drug of choice,
while up to 27% primarily used fusidic acid, with
use of fluoroquinolones being rarely reported as a
first line of treatment at the GP level.[7,8,10,11,28]
However, marked differences in the treatment
administered were observed between different
countries with, for example, Spanish GPs using
aminoglycosides as first-line treatment in 30% of
cases.[28] Recent studies evaluating use of chloramphenicol[15] and fusidic acid[4] in clinical practice were not able to demonstrate improvements
with treatment, and such findings have led to different recommendations in different countries.[46]
Referral by the GP to a specialist at the time of
a treatment failure is country specific. The action
taken by the GP can range from immediate
referral (e.g. in Spain) to further examination
and the trial of a new antibacterial (e.g. in
Scotland).[28] The choice of therapy by a GP after
a treatment failure in countries where the patient
is not referred to a specialist (ophthalmologist) is
similar to that by a specialist.

547

100
90
80
70
60
50
40
30
20
10
0

133

Scotland

108

Spain

215

Netherlands

Fig. 1. Average overall cost (year of costing 2009) and distribution


of costs when initial treatment fails to improve symptoms of infectious conjunctivitis based upon a survey of ophthalmologists in
different countries. For individual ophthalmologists, treatment failure
costs ranged from h94 to h279.[28] 1 The receptrule is specific to the
Netherlands and refers to the extra payment that the pharmacist
receives from the Government when he/she provides the medication
that is on the prescription.

Clin Drug Investig 2011; 31 (8)

Benitez-del-Castillo et al.

548

specialist would result in faster symptom relief


and a lower rate of treatment failures.[50] This
would then lower the consumption of healthcare
resources, thereby reducing costs.[43] Furthermore, use of, for example, topical moxifloxacin
as a preferred choice of treatment at the specialist
level would not be expected to lead to a significant increase in bacterial fluoroquinolone
resistance (see section 3.2).[51,52]
3. Use of Topical Moxifloxacin for
Bacterial Conjunctivitis in Clinical
Practice
The data on topical moxifloxacin for the
treatment of bacterial conjunctivitis discussed in
this section were derived from a PubMed search
using the terms moxifloxacin and conjunctivitis
and from all trials reported to the European
Medicines Agency to obtain market authorization for the approved indication of bacterial conjunctivitis. Publications evaluating use outside the
approved indication or not considering moxifloxacin as therapy were excluded. Healthcare
utilization data at the time of treatment failure
were collected by survey and the cost of treatment
was defined using national costings. A decisionanalytic model to assess cost effectiveness was
developed and the impact on the healthcare budget
was calculated to define the health economic impact.
When evaluating the potential effectiveness of
topical antibacterials, not only the potency but also
the mean concentration in conjunctival tissue,
residence, speed-to-kill and bactericidal ability,
along with the compliance with prescribed dosing,
need to be considered. All of these factors contribute to rapid eradication of bacteria, decrease the
risk of disease transmission, and shorten symptom and disease duration.
Moxifloxacin achieves concentrations in the
conjunctiva well above the minimum inhibitory
concentration (MIC) for S. aureus, S. pneumoniae
and H. influenzae,[53-56] which are some of the most
common causes of acute bacterial conjunctivitis.
The MIC for moxifloxacin for most pathogens
is lower than that of other commonly used antibacterials, such as gentamicin, tobramycin, polymyxin B, trimethoprim, chloramphenicol, fusidic
2011 Adis Data Information BV. All rights reserved.

acid, erythromycin and azithromycin.[50,57] At a


1 : 1000 dilution, which simulates concentrations
in the eye a few minutes after topical moxifloxacin
has been instilled, moxifloxacin demonstrated a
more effective kill rate compared with other commonly used non-fluoroquinolones[52,58] (figure 2)
and fluoroquinolones[59] (figure 3) available in
Europe. Moxifloxacin demonstrated a 99.9% kill
rate within 3 hours for S. aureus (figure 2a and
figure 3), 2 hours for S. pneumoniae (figure 2b)
and 30 minutes for H. influenzae (figure 2c)[52,58]
and susceptible and fluoroquinolone-resistant
Gram-positive conjunctival pathogens.[60] In clinical practice we observed complete resolution of
ocular signs and symptoms at 48 hours in 81% of
patients treated with moxifloxacin.[49]
Beyond trial-based clinical efficacy data or
real-life effectiveness data, pharmacodynamic/
pharmacokinetic parameters can predict the efficacy of antibacterials. For fluoroquinolones, the
maximum plasma drug concentration (Cmax)/
MIC required to inhibit the growth of 90% of
organisms (MIC90) ratio and/or the area under
the concentration-time curve from time zero to
24 hours (AUC24)/MIC90 ratio have been used
for this purpose. For S. aureus, S. pneumoniae
and H. influenzae, the conjunctival AUC24 :
MIC90 ratios ranged from 625 to 1355 for topical
moxifloxacin,[49] which is well above the concentrations required to eradicate bacteria.
After administration of a single drop of each
medication, the mean concentrations of moxifloxacin in conjunctival tissue (18.0 mg/g) were higher
than for ciprofloxacin (2.65 mg/g), gatifloxacin
(2.54 mg/g), ofloxacin (1.23 mg/g) and levofloxacin
(2.34 mg/g) in healthy subjects 20 minutes after
receiving a single dose of these ophthalmic solutions.[61] Compared with besifloxacin,[62,63] a mean
peak concentration for moxifloxacin of 10.7 mg/g
was reported versus 2.3 mg/g for besifloxacin, although besifloxacin had a higher mean residence
time of 4.7 h versus 3.0 h and a lower concentration decrease over time than moxifloxacin in
conjunctival tissue, resulting in a higher AUC.[64]
On the other hand, moxifloxacin penetrated
better into corneal epithelium, stroma and endothelium and achieved significantly higher levels in
the aqueous and vitreous humour of infected eyes
Clin Drug Investig 2011; 31 (8)

Moxifloxacin in the Treatment of Bacterial Conjunctivitis

549

Control
Azithromycin 10 g/mL
Gentamicin 3 g/mL
Trimethoprim 1 g/mL
and polymyxin B 10 U/mL
Tobramycin 3 g/mL
Moxifloxacin 5 g/mL
a

b
10 000
Surviving S. pneumoniae CFUs

Surviving S. aureus CFUs (%)

1000
100
10
1
0.1
0.01
0.001
0.0001

1000
100
10
1
0.1
0.01
0.001
0.0001

20

40

60

80 100 120 140 160 180


Time (min)

20

40

60 80 100 120 140 160 180


Time (min)

c
Surviving H. influenzae CFUs (%)

1000
100
10
1
0.1
0.01
0.001
0.0001
0.00001
0

20

40

60

80 100 120 140 160 180


Time (min)

Fig. 2. Pharmacokinetics of bacterial kill by moxifloxacin compared with other non-fluoroquinolone antibacterials for (a) Staphylococcus
aureus, (b) Streptococcus pneumoniae and (c) Haemophilus influenzae, based on a 1 : 1000 dilution.[52] Reproduced with permission.
CFU = colony forming unit.

than ofloxacin (p < 0.01), ciprofloxacin (p < 0.05),


lomefloxacin (p < 0.01) and levofloxacin (p < 0.05);
furthermore, the levels reached exceeded the MIC90
values of clinically relevant pathogens in these
tissues and fluids.[65-72]
Increased residence time through use of a delivery system[73] such as that used with besifloxacin[64]
or addition of a retention-enhancing agent as in the
case of a recently US FDA-approved formulation of moxifloxacin[74] will further improve these
pharmacodynamic/pharmacokinetic parameters,
2011 Adis Data Information BV. All rights reserved.

ensuring even better bactericidal characteristics.


In a recent study, microbial eradication at day
5 occurred in 93.3% of patients receiving besifloxacin and in 91.1% receiving moxifloxacin
(p = 0.1238).[75-77] This further confirms previous
findings on the efficacy of moxifloxacin.[50,78,79]
3.1 Dosage and Administration

Because of its potency and pharmacodynamic


and pharmacokinetic properties, use of topical
Clin Drug Investig 2011; 31 (8)

Benitez-del-Castillo et al.

550

Ofloxacin
Levofloxacin
Moxifloxacin
Control

Surviving S. aureus CFUs (%)

1000
100
10
1
0.1
0.01
0.001
0.0001
0

20

40

60

80 100 120 140 160 180


Time (min)

Fig. 3. Pharmacokinetics of bacterial kill by moxifloxacin compared


with other fluoroquinolone antibacterials for Staphylococcus aureus,
based on a 1 : 1000 dilution.[59] Reproduced with permission.
CFU = colony forming unit.

moxifloxacin ensures that the required drug


concentrations are achieved in the conjunctiva
with fewer drops, thereby avoiding the need for
frequent dosing, even in the first days of treatment. This means that only three times daily
installation of moxifloxacin topical solution is
required, less than the usual treatment regimen
for other fluoroquinolones of up to eight applications per day (i.e. every 2 hours) on days 1 and
2 followed by three to four treatments per day
from day 3 onwards. Further developments in the
formulation of topical moxifloxacin designed
to allow twice-daily treatment instillation are
ongoing.[74]
Standard topical antibacterial treatments are
multidose products, allowing the same bottle to
be used throughout the treatment. However, in
order to maintain sterility and avoid contamination of the ophthalmic solution, a preservative is
normally used. Since preservatives such as benzalkonium chloride (BAK) have known cytotoxicity[80] and adverse effects, including allergic
reactions, swelling and effects on the tear film,[81]
BAK-free or preservative-free products are desirable.[81] Until recently the only preservativefree antibacterial products available in Europe
for the treatment of conjunctivitis were in a uni 2011 Adis Data Information BV. All rights reserved.

dose formulation (available for ofloxacin, levofloxacin, azithromycin, chloramphenicol and


gentamicin). Moxifloxacin, because of its potency,
is the first, and currently the only, self-preserved
topical antibacterial supplied in a multidose
bottle to be approved by most European countries, having met European Pharmacopoeia requirements for preservative effectiveness.
Topical moxifloxacin is provided as a 5 mL
bottle for multidose self-preserved application, with
a dropper that dispenses, on average, 38.9 3 mL
per drop. Once opened, the product can be used
for up to 4 weeks. For a patient adhering to a
regimen of three times daily installation in both
eyes, a single bottle is sufficient for a 14-day treatment period. Since ophthalmologists often prescribe a minimum treatment period of 57 days,[28]
the product provides full coverage of the treatment period. This is important in economic terms,
since the multidose bottles are less expensive than
the unidose vials for health authorities, patients
in most countries and manufacturers.
3.2 Antibacterial Resistance and Topical
Moxifloxacin

The emergence of bacterial resistance during


the use of antibacterial treatment in general is a
concern because, over time, this can lead to products no longer being effective for treatment.[82]
Bacterial resistance is mainly caused by the use
of antibacterials in animal food and their systemic
use by humans.[83] Bacterial resistance has been
reported, not only to fusidic acid[4] and chloramphenicol,[84] which are two of the most commonly used treatments for conjunctivitis,[10,28] but
also to other antibacterials[85] and fluoroquinolones (e.g. ciprofloxacin and ofloxacin).[14,86] However, emergence of resistance to moxifloxacin (in
contrast to ciprofloxacin and ofloxacin) depends
on the development of two mutations in the DNA
gyrase and topoisomerase genes, which means
resistance to moxifloxacin develops at a slower
rate.[51,62,87]
Nevertheless, due to the systemic use of
fluoroquinolones (and the selective pressure they
exert on species colonizing the respiratory tract),
increases in fluoroquinolone-resistant, methicillin
Clin Drug Investig 2011; 31 (8)

Moxifloxacin in the Treatment of Bacterial Conjunctivitis

(meticillin)-resistant S. aureus (MRSA) isolates


have been reported, particularly in patients with
nosocomial infections.[88] Increased recovery
of MRSA isolates from conjunctival infections
has been reported in the elderly population
(aged >65 years),[34,89] although not in younger
patients.[90] Continued development of antibacterials is therefore needed.
Following topical application, development of
resistance to moxifloxacin is not a major concern,
due to the fact that local application of moxifloxacin 5000 mg/mL results in high ocular surface
concentrations.[51,52] These concentrations exceed the MIC and bactericidal concentration for
bacterial pathogens, including those isolates with
an acquired resistance to fluoroquinolones,[51,52]
and are well above the mutant prevention concentrations (MPCs).[54] The MPC, which represents
a threshold above which the selective proliferation
of resistant mutants is expected to occur only rarely, has been shown to be very low for moxifloxacin
compared with other fluoroquinolones and nonfluoroquinolones.[91-93] This means that moxifloxacin restricts the selection of resistant mutants,
meaning emergence of resistance is unlikely.
A recent clinical study supported by Alcon
Research Ltd (Fort Worth, TX, USA) assessed
fluoroquinolone-resistance development at the
ocular and distal sites (e.g. the nose and throat).[87,94]
The study showed that a course of moxifloxacin
treatment for bacterial conjunctivitis consisting
of instillations three times daily over 7 days did
not cause or select for any changes in the moxifloxacin susceptibility of isolates of the primary
ocular pathogens S. pneumoniae, S. aureus or
H. influenzae. This was true irrespective of whether the pathogenic isolates were recovered from
the eye or from body sites distal to the site of the
moxifloxacin instillation.[87,94]
3.3 Adverse Effect Profile and Acceptability

Topical treatments for acute conjunctivitis can


be associated with adverse reactions.[95-98] In a
clinical study environment, topical moxifloxacin
has been shown to be safe and well tolerated by
both children and adults. A review of studies
by Silver et al.[48] that included a total of 918
2011 Adis Data Information BV. All rights reserved.

551

paediatric and 1060 adult patients found that the


most frequent adverse event in the overall population was transient ocular discomfort with
an incidence of 2.8%, which was similar to the
incidence observed in the placebo group. No
treatment-related changes in ocular signs or visual acuity were observed.
Moxifloxacin topical solution also has a near
neutral pH (6.8), is well tolerated by patients[48,61]
and is generally well accepted.[99]
4. Cost to the Healthcare System of
Treatment with Topical Moxifloxacin
4.1 Reduction in Treatment Failures

Differences in treatment failure rates amongst


different products compared with moxifloxacin
have been reported in a meta-analysis.[50] The
meta-analysis included results from five clinical
trials involving 2099 patients. In this meta-analysis the number of patients with no improved or
worsened symptoms (treatment failure) who were
applying topical moxifloxacin 0.5% was consistently low within the different trials (mean
2.9% [95% CI 1.4, 4.3]) and was 3.61 times lower
than with placebo treatment. In a comparative
trial, ofloxacin had a 7.6% treatment failure rate
and a relative risk of treatment failure 1.75 times
higher than moxifloxacin.[50]
4.2 Healthcare Resources and Cost
of Treatment Failure

A recent survey captured the treatment patterns and healthcare resources associated with
treatment failure rates for conjunctivitis.[28] The
survey was conducted in the Netherlands,
Scotland and Spain by way of a questionnaire and
interviews with GPs and ophthalmologists. Local
health economists estimated the unit costs that
were necessary for the valuation of the resources
used, as declared by the physicians. The costs considered were the direct costs for health authorities.
The costs associated with productivity losses are
provided for information purposes only.[28]
During the survey, data were collected on:
 The management of conjunctivitis in clinical
practice by GPs and ophthalmologists.
Clin Drug Investig 2011; 31 (8)

Benitez-del-Castillo et al.

552

 The antibacterial treatment prescribed.


 Whether a swab (with or without culture
examination) was taken to identify the pathogen and whether tests for Chlamydia were
requested.
 How treatment failures were handled.
The healthcare resources required to manage
patients with a treatment failure were hypothesized to be independent of any previous treatment
provided.[28]
A total of 39 GPs (21, 5 and 13 in Scotland,
Spain and the Netherlands, respectively) and
14 ophthalmologists (4, 5 and 5 in Scotland,
Spain and the Netherlands, respectively) were interviewed. Table I provides details of the survey
results relating to the healthcare resources required when treatment failures occurred.[28]
Treatment failures seen by GPs resulted in an
immediate switch in treatment. Additional examinations varied between countries, occurring
in 1250% of cases. In approximately 30% of cases
an extra follow-up visit was scheduled. Treatment
failures seen by an ophthalmologist also resulted
in a switch or repeat treatment. Additional examinations were performed and additional follow-up visits were scheduled in more than 75% of
cases (table I).[28]
The costs of treating a treatment failure varied
between GPs and ophthalmologists due to the
differences in healthcare resources associated
with a treatment failure (table II). The average

costs of a treatment failure when the patient was


being treated by an ophthalmologist were h133,
h108 and h215 (year of costing 2009) in Scotland,
Spain and the Netherlands, respectively (table II,
figure 1). The most conservative and most
healthcare-resource demanding approaches described by individual ophthalmologists fell within
a range of 30%.[28]
The low occurrence of treatment failures with
moxifloxacin minimized the cost of the healthcare resources required to treat conjunctivitis.
Compared with ofloxacin, a cost of h6.3, h5.1 and
h10.13 could have been avoided per patient treated by an ophthalmologist in Scotland, Spain and
the Netherlands, respectively, when using moxifloxacin at the same price. To test the robustness
of the calculation, evaluation of different scenarios, all within the 95% confidence interval (CI),
representing different reductions in treatment
failures with moxifloxacin and ofloxacin showed
that the cost avoided per patient for treatment
failure was within 30% of the average cost avoided. When only patients with a bacterial cause
were considered, an additional cost of 1138%,
depending on the country, could have been
avoided.[28]
4.3 Healthcare Cost-Effectiveness Analysis

To determine if treatment with topical moxifloxacin could be cost effective for the healthcare

Table I. Healthcare resources utilized in association with bacterial conjunctivitis treatment failuresa[28]
Healthcare resource

GP

Ophthalmologist

Netherlands

Scotland

Spain

Netherlands

Scotland

Spain

GP visit

100.0

100.0

100.0

NA

NA

NA

GP referral

NA

NA

NA

NA

44.0

76.0

Ophthalmologist visit

NA

NA

NA

100.0

100.0

100.0

Switch to another antibacterial

100.0

100.0

100.0

100.0

100.0

100.0

0.8

4.4

0.2

12.2

1.0

40.0

12.3

39.1

0.8

60.8

79.0

27.0

Swab
Swab + culture
Chlamydia test
Additional FU GP visit
Additional FU ophthalmologist visit
a

1.2

6.8

33.1

32.9

NA
27.0

2.4

0.9

15.4

30.0
NA
86.3

17.4
NA

67.0
NA

76.5

105.0

Data are percentage of patients.

FU = follow-up; GP = general practitioner; NA = not available.

2011 Adis Data Information BV. All rights reserved.

Clin Drug Investig 2011; 31 (8)

Moxifloxacin in the Treatment of Bacterial Conjunctivitis

553

Table II. Cost of treatment failures when patients with bacterial conjunctivitis are treated by a general practitioner (GP) or ophthalmologist[28]
Use of healthcare resources

GP
Netherlands (h)

Ophthalmologist
Scotland (ha)

Spain (h)b

Netherlands (h)

Scotland (ha)

Spain (h)b
108.46

Average use

53.47

72.30

38.53

215.56

133.81

Lowest user

32.42

40.90

26.15

169.55

103.38

94.45

Highest user

119.53

124.19

40.83

279.42

160.30

135.83

Exchange rate used 1 = h1.13907 (25 May 2009).

Health Care System costs (covers nearly all costs of treatment of bacterial conjunctivitis in Spain).

system a decision-analytic model was developed


using the TreeAge software.[100] The model considered a treatment path where (i) a fluoroquinolone is offered by a GP and the healthcare use
upon failure of the treatment is evaluated;
(ii) where the fluoroquinolone is offered by the ophthalmologist and the healthcare use upon failure
of the treatment is evaluated. Both paths resulted
in a treatment cost. Comparisons were then made
between the different types of fluoroquinolones
that can be offered and the total cost (which
varies with the different cost for each product and
for dealing with treatment failures). The model
was populated with data taken from previously
described findings (see sections 4.1 and 4.2) and
available market data. Cost data were obtained
from publicly available price information.[100]
A comparison of moxifloxacin multidose and
ofloxacin unidose, both of which are preservativefree fluoroquinolones, showed that treating the
patient with moxifloxacin would result in avoidance
of a mean 4.7 treatment failures per 100 patients
treated.[100] In the Netherlands, treatment with
fluoroquinolones is primarily prescribed by ophthalmologists, with only 9.8% being prescribed
by GPs. Since the price of preservative-free
ofloxacin in the Netherlands at the time of the
analysis (2009) was h9.78 and that for moxifloxacin h17.55, this would have resulted in an average cost per patient treated with ofloxacin of
h25.47 (taking into account the average costs of
both treatment and of treatment failure), compared with h23.54 for treatment with moxifloxacin. A saving of h1.93 per patient treated with
moxifloxacin could therefore be made compared
with patients treated with preservative-free
ofloxacin because of the reduction in treatment
failures with moxifloxacin.[100]
2011 Adis Data Information BV. All rights reserved.

To test the robustness of the results, the uncertainty around the differences in treatment failure, i.e. the 95% CI and the range of healthcare
resources used by different GPs and ophthalmologists to correct a treatment failure, were considered. Different scenarios using a random value
for each of the parameters, within the indicated
CIs, were evaluated and the outcomes calculated.
This process was repeated 50 000 times (a Monte
Carlo simulation offered within the TreeAge
modelling software) and showed that 86% of the
simulations with moxifloxacin at the premium
price of h17.55 were cost saving for the healthcare
system in the Netherlands. As it is to be expected
that not only the preservative-free ofloxacin, but
also the preserved ofloxacin, will be replaced,
these simulations considered not only h17.55 but
also a price of h14.04 for topical moxifloxacin
compared with a weighted average price of h3.74
for ofloxacin (based on yearly sales of 110 953 units
of preserved and 15 554 units of preservative-free
ofloxacin). This analysis showed that topical
moxifloxacin was cost effective, i.e. it provided
the best value-for-money, in 87% of simulations.[100]
An assumption made was that the public considers the value of avoiding a treatment failure to
be the same as the value considered acceptable to
avoid allergic reactions during topical treatment
with BAK-preserved products.[81] This value was
derived from the price difference between preservative-free and preserved products.[81]
4.4 Impact on the Healthcare Budget

Self-preserved topical moxifloxacin multidose,


even at a higher price, can be expected to be cost
saving for the healthcare system, given the healthcare costs avoided because of less frequent treatment
Clin Drug Investig 2011; 31 (8)

Benitez-del-Castillo et al.

554

failures and the smaller amount of healthcare


resources required.
Unidose applications of ofloxacin and levofloxacin require 16 treatments in the first 2 days
and four treatments each day over the following
3 days, i.e. a total of 28 vials. Therefore the current pack size of 30 vials limits treatment to 5 days,
requiring a second pack if the conjunctivitis is not
yet resolved and adding extra costs to the treatment.
For example in Spain, treatment with fluoroquinolones is primarily prescribed by ophthalmologists. Given the public price (which is partly
paid by the health authorities, partly paid by the
patient) in Spain of h3.53 for Exocin (ofloxacin)
and h9.02 for Vigamox (moxifloxacin), and assuming 52 000 prescriptions of moxifloxacin
(16% of the 318 217 expected Exocin sales), this
would have resulted in a budget for the strategy in
2010 of h4 240 131 versus h4 457 015 if moxifloxacin was not used, yielding savings of 4.9%.
To test the robustness of the outcome, different reductions in treatment failures seen in clinical trials were tested (3.3% and 5.4%). When the
whole population with confirmed bacterial conjunctivitis was considered, these scenarios resulted in cost savings ranging from 0.79% to
6.13%. Converting 25% of the prescriptions to
moxifloxacin resulted in savings of 210% for the
healthcare system in Spain. For the same healthcare system, use of moxifloxacin would save between h0.72 and h6.92 per patient being treated
for conjunctivitis. Where the price for moxifloxacin was lower than h9.02, further savings would
occur.
5. Conclusions
The use of moxifloxacin reduces the time to
symptom resolution and the number of treatment
failures in the treatment of acute infectious conjunctivitis compared with both placebo and other
antibacterial treatments available in the majority
of European countries. This leads to a reduction
in the amount of healthcare resources required
and thus to a reduction in healthcare costs.
Topical moxifloxacin can be offered as a multidose, self-preserved, topical product, at near
neutral pH (6.8), instilled three times daily for
2011 Adis Data Information BV. All rights reserved.

78 days. This formulation avoids the potential


adverse effects associated with the use of BAKpreserved products and reduces the costs associated with treatment with unidose formulations.
The risk of emergence of antibacterial resistance due to use of topical moxifloxacin has been
demonstrated to be minimal at both the eye and
distal sites because of the high local concentrations achieved and the fact that a dual-step mutation is required for the emergence of bacterial
resistance. Risk of resistance is therefore not a
reason to withhold topical moxifloxacin early in
the treatment path of bacterial conjunctivitis.
Therefore, in order to both improve outcomes
and reduce the number of healthcare resources
required to treat acute infectious conjunctivitis, a
change in the healthcare treatment strategy in
Europe for this condition is recommended. Multidose, self-preserved, topical moxifloxacin or other
fluoroquinolones with proven comparable effectiveness should be considered earlier in the treatment path for conjunctivitis. Even if a premium price
is requested for this novel topical antibacterial,
management of conjunctivitis with topical moxifloxacin can be cost effective. Furthermore, this
strategy can also deliver total healthcare budget
savings by avoiding multiple tests and treatments
and saving time for those clinicians who initiate
treatment with the most effective topical antibacterial, i.e. moxifloxacin, early in the treatment
path for bacterial conjunctivitis.
Acknowledgements
The authors would like to thank Antoine Lafuma and
Julien Robert of Cemka, Max Brosa of Oblique Consulting,
Mark Nuijten of Ars Accessus Medical, Elizabeth Gylee of
Abucus Int. and Ana Vieta of IMS Health Spain for the
healthcare resources and costing data collection.
The authors would also like to thank Michelle Derbyshire
of MD Writing Services for providing assistance with the
preparation of the manuscript.
Yves Verboven and David Stroman are employed by
Alcon. The other authors have no conflicts of interest that are
relevant to the content of this review.

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Correspondence: Prof. Laurent Kodjikian, Hopital de la


Croix-Rousse, Service dOphtalmologie, 103, Grande Rue
de la Croix-Rousse, Lyon 69004, France.
E-mail: kodjikian.laurent@wanadoo.fr

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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

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