Professional Documents
Culture Documents
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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Benitez-del-Castillo et al.
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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
545
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
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
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
547
100
90
80
70
60
50
40
30
20
10
0
133
Scotland
108
Spain
215
Netherlands
Benitez-del-Castillo et al.
548
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
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
20
40
c
Surviving H. influenzae CFUs (%)
1000
100
10
1
0.1
0.01
0.001
0.0001
0.00001
0
20
40
60
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.
Benitez-del-Castillo et al.
550
Ofloxacin
Levofloxacin
Moxifloxacin
Control
1000
100
10
1
0.1
0.01
0.001
0.0001
0
20
40
60
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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
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
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
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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
Health Care System costs (covers nearly all costs of treatment of bacterial conjunctivitis in Spain).
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
Benitez-del-Castillo et al.
554
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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.