Field Comparison of the Impact of Different Treatment Durations in the Treatment of Acute Otitis Externa

doi:10.4236/ojvm.2013.36047

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Open Journal of Veterinary Medicine, 2013, 3, 289-296

http://dx.doi.org/10.4236/ojvm.2013.36047 Published Online October 2013 (http://www.scirp.org/journal/ojvm)

Field Comparison of the Impact of Different Treatment

Durations in the Treatment of Acute Otitis Externa

in the Dog

Erik Grandemange1, Florence Pillet2, Olivier Roy2, Frédérique Woehrlé1

1Vétoquinol Research Centre, Lure Cedex, France

2CEBIPHAR, 1 rue de la Bodinière, Fondettes, France

Email: [email protected]

Received June 27, 2013; revised July 27, 2013; accepted August 17, 2013

cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: Acute otitis externa is a common multi-factorial disorder in the dog. Several topical preparations are

available on the veterinary market, which are licensed for an either specified duration of treatment or for a discretionary

period that is determined by the clinician. Objectives: To compare the efficacy of two topical products, both licensed

for the treatment of otitis externa in the dog, but with different treatment durations. Animal Population: One hundred

and sixty dogs were enrolled in this multicentre field study from which 157 dogs were analysed in the Per Protocol sam-

ple (73 Aurizon® treated animals and 84 Easotic® treated animals). Method: Dogs were randomly assigned to Aurizon® or

Easotic® treatment groups. Aurizon® (Vétoquinol SA: marbofloxacin, clotrimazole, dexamethasone) was administered

daily in the affected ear(s) for 7 or 14 days, and was compared with a daily administration of Easotic® (Virbac SAS:

gentamicin, miconazole, hydrocortisone aceponate) for 5 days. General and localised clinical signs were scored on days

0 (D0), 3 (D3), 7 (D7), 14 (D14) and 21 (D21). Results: Clinical cure rates at the end of treatment were 56.3% and

48.8% (p = 0.35) in the Aurizon® and Easotic® groups respectively and 81.2% versus 74.7% one week after completing

the course of treatment (p = 0.34). Twenty-one days after initially presenting for the study, cure rates were 84.3% in the

Aurizon® group and 73.8% in the Easotic® (p = 0.12). A relationship between severity of clinical signs and treatment

duration was observed. Conclusion and Clinical Significance: At the end of the trial period, cure rates showed a ten-

dency to be higher in the Aurizon® treated animals. The flexible dosage and the veterinary monitoring permitted treat-

ment duration to be adjusted based upon the severity of otitis externa thus increasing the likelihood of clinical cure.

Keywords: Acute Otitis Externa; Topical Ear Treatment; Efficacy; Field Clinical Trial

1. Introduction

Acute otitis externa is a common pathology seen on a

daily basis in small animal practice (8.7%, Masuda et al.

[1]) and is characterized by acute inflammation of the

epithelium of the external auditory canal, often associ-

ated with an increase in cerumen production. Head shak-

ing, pruritis and other behaviours suggestive of aural pain

are also common features [2]. When otitis externa is

suspected, typical diagnostic procedures include a gen-

eral clinical examination followed by otoscopic inspec-

tion of the ear canal and the collection of aural exudates

for cytology and/or culture and sensitivity testing [3].

Potential primary causes of otitis externa include foreign

bodies; ectoparasites; dermal hypersensitivity; keratinisa-

tion defects; endocrinopathies; autoimmune disease and

neoplasia. Otitis externa, regardless of aetiology may be

exacerbated by factors such as abnormally stenotic or

torturous ear canals, pendulous pinnae, excessive mois-

ture or trauma of the ear [4-6]. Even though bacteria and

yeast are rarely primary causes, they are commonly iso-

lated (alone or in combination) in cases of otitis externa.

Malassezia pachydermatis, Staphylococcus pseudinter-

medius and Pseudomonas aeruginosa are particularly

common microbiological isolates and play a role in per-

petuating otitis externa [1,7-10]. Treatment of this condi-

tion consists of identifying and addressing both primary

and predisposing factors; cleaning the ear canal; ad-

dressing secondary infection with topical therapy (with

adjunctive systemic therapy where necessary); client

education; follow up; preventive and maintenance ther-

apy (where required) [3,11,12]. In cases where parasitic

infection has been excluded by cytologic examination

E. GRANDEMANGE ET AL.

290

[13], the majority of topical treatments indicated for the

treatment of otitis externa combine an antimicrobial

agent with an antifungal agent and a glucocorticoid, the

latter component providing rapid symptomatic relief and

accelerating resolution of inflammation [14]. The li-

censed treatment duration of most products is often at

least 7 days, which may be extended to 2 or 3 weeks un-

der certain circumstances. Boda et al. [15] compared the

licensed treatment protocol of a new ear treatment (Ea-

sotic®, Virbac, 1 pump application per day, 5 day course

of treatment) to the one of a reference product (Surolan®,

Janssen, 3 - 5 drops applied twice daily for 7 days) and

concluded that simplifying dosing regimen and method

of administration improved owner compliance when

treating canine otitis externa. The authors reported satis-

faction rates but did not comment upon clinical response.

In a previous study [16], a comparison of clinical resolu-

tion following Aurizon® and Surolan® therapy demon-

strated a trend for better results in the Aurizon® treated

animals. The aim of this study was to compare the effi-

cacy of two therapeutic options for the treatment of otitis

externa in dogs that have different treatment durations:

Easotic® (5 days) versus Aurizon® (7 or 14 days of treat-

ment dependant on clinical response).

2. Materials and Methods

2.1. Experimental Design

This was a randomised, parallel controlled, multi-centre

study, conducted in compliance with VICH (International

Cooperation on Harmonisation of Technical Require-

ments for Registration of Veterinary Medicinal Products)

guidelines for Good Clinical Practice [17] and involved

twenty one French veterinary practices. The study con-

formed to local animal welfare standards and informed

consent was obtained from the owners of all participating

dogs. Microbiological analysis of samples collected fol-

lowing otoscopic examination was performed by a single

reference laboratory. For the purposes of assessing gen-

eral clinical condition and response to treatment, the ex-

perimental unit was the patient. The ear was the design-

nated experimental unit for the evaluation of local clini-

cal signs evaluation (some dogs suffered from bilateral

otitis at the time of inclusion in the study).

2.2. Selection of Animals

One hundred sixty animals were recruited from 21 vet-

erinary practices throughout France. Twelve of these

patients were examined at breeding sites and 148 at the

practice premises. Animals were included in the trial

based upon the following criteria:

 Good general physical condition on the basis of a

clinical examination

 Presented to the clinician with acute uni- or bilateral

otitis externa with fungal or bacterial involvement.

◦ Presence of moderate/severe inflammation of the

external acoustic meatus with moderate/severe

aural discharge (pus and/or cerumenous material).

The assessment score was >2 for both parameters

(for at least one ear in cases with bilateral in-

volvement).

◦ Chronic/recurrent cases of otitis externa and those

associated with ectoparasite infestation were ex-

cluded.

 No constraints were placed upon signalment, origin or

home environment.

2.3. Clinical Examination

Each animal was assessed over the course of three weeks

(21 days). The study calendar is presented in Table 1.

2.4. Laboratory Examination

The investigator collected a sample from the ear at D0

(prior to treatment only one ear was sampled even in

cases of bilateral disease). Samples were stored between

Table 1. Individual calendar.

DAY EVENT DAY EVENT

Clinical examination and inclusion/non

inclusion criteria check.

Informed consent obtained from owner

Sample obtained from ear for microbiological analysis.

First administration of the study treatment.

Clinical examination.

Clinician given the option to extend the treatment

period with Aurizon®.

If no further treatment required, sample obtained

from ear for microbiological analysis.

D1, D2 Application of treatment by the owner once daily. D7 to D13Application of treatment by the owner once daily

(animals receiving extended Aurizon® therapy).

D3 Local and general clinical examination.

Treatment compliance check. D14 + 1Clinical examination.

Sample obtained from ear for microbiological analysis (all patients)

D3, D4 Application of treatment by the owner once daily.

D4: End of treatment with Easotic®. D21 ± 1

Clinical examination.

Owner assessment of response obtained.

Sample obtained from ear for microbiological analysis

(animals receiving extended Aurizon® therapy).

D5, D6 Application of treatment by the owner once daily

(Aurizon® group only).

E. GRANDEMANGE ET AL. 291

+2˚C and +8˚C pending shipment at ambient temperature

to the laboratory within 72 hours. Staphylococcus pseu-

dintermedius, Pseudomonas aeruginosa, Escherichia coli,

Proteus mirabilis, beta-haemolytic streptococci, Malas-

sezia pachydermatis and other yeasts than Malassezia

pachydermatis were identified if present.

2.5. Treatment Administration

Dogs were allocated to one of the two treatment groups

according to the randomisation list. Prior to initiating

treatment, an otoscopic examination was performed to

confirm the integrity of the tympanic membrane and to

ensure that there was no ectoparasite involvement. Prior

to each application of trial therapy, the external ear canal

was cleaned with Otifree® (Vétoquinol SA, France) and

dried. This procedure was performed by the clinician for

the first application; subsequent daily cleaning was the

responsibility of the pet owner for the remainder of the

trial period.

Trial products were administered topically to the ex-

ternal auditory canal of the affected ear(s) as follows:

 Aurizon® (Vétoquinol SA, France): a single admini-

stration of 10 drops once daily for 7 days (D0 to D6).

At D6, the clinician could extend treatment by further

7 days if they considered additional therapy was re-

quired (D7 to D13).

 Easotic® (VIRBAC SAS, France): a single admini-

stration of 1ml (one actuation of the dosing pump)

once daily for 5 days (D0 to D4).

2.6. Assessment Criteria

Patient assessment during the study consisted of a full

clinical examination by the investigator to obtain scores

for selected local and general parameters. These values

were processed to provide a General Clinical Score (GCS)

and a Local Clinical Score per ear (LCS) for each patient

(Table 2).

At D7, D14 + 1 and D21 ± 1, the clinical response of

each patient was characterised as follows:

 Cured:

-All local parameters scored  1 for each treated ear

and the Local Clinical Score < 3, and absence of itching

from auricular origin,

-General Clinical Score at end of treatment (D7 or D14)

less than the GCS at D0.

 Failure:

-Lack of improvement in local or clinical parameters,

relapse following an initial improvement or a worsening

of the condition that necessitated alternative therapy.

2.7. Statistical Analysis

Statistical analysis of results was performed using “Stat-

view” software (version 5.0, SAS Institute Inc., USA,

1992-1998). The primary criterion was clinical cure rate

at the end of treatment (D7 or D14), one week after

treatment was discontinued (D14 or D21) and on D21 for

all animals. Cure rates were compared using a Chi-square

test. The progression of clinical signs over time was the

secondary efficacy criteria.

Table 2. Clinical parameters.

General parameters (summarized by a general clinical score) (GCS)

 General behaviour

0 = Normal

1 = Subdued

2 = Depressed

 Appetite

0 = Normal

1 = Slightly decreased (<50%)

2 = Strongly decreased (>50%)

 Locomotion (excepting musculoskeletal disease)

0 = Normal

1 = Slightly abnormal

2 = Ataxic

 Head carriage

0 = Normal

1 = Slightly modified

2 = Abnormal

 Pruritis (ext ernal auditory meatus and/or pinna)

0 = Absent

1 = Intermittent, low-intensity

2 = Frequent, high-intensity

Local parameters (summarized by a local clinical score, LCS)

 Pinna lesions

0 = Absent

1 = Present

 Malodour

0 = Absent

1 = Present

 Pain on handling

0 = Absent

1 = Slight

2 = Moderate

3 = Severe

 Inflammation of external acoustic meat us

0 = Absent

1 = Slight

2 = Moderate

3 = Severe

 Exudate quantity

0 = Nil

1 = Slight

2 = Moderate

3 = Severe

 Exudate character

Ceruminous

Purulent

E. GRANDEMANGE ET AL.

292

Data obtained from the study were analysed as fol-

lows:

 Mean, standard deviation, minimum and maximum

age and body weight at date of inclusion (D0) was

calculated for animals in each treatment group. These

parameters were compared between groups using a

one-way analysis of variance. Distribution of patient

sex was compared using a Chi-square test.

 General and local clinical scores at inclusion were

described for each treatment group; the distributions

of unilateral versus bilateral otitis and suppurative

versus erythemato-ceruminous otitis at D0 were

compared using a Chi-square test. Rectal temperature

prior to the initiation of treatment was compared be-

tween groups using a one-way analysis of variance.

Clinical progression of the cases was compared using

an analysis of variance for repeated measurements, with

time and treatment-time-interaction designated as the

within-subject effects and the therapy utilised assigned to

the between-subject effect. To account for significant

interaction between time and treatment, a comparison

was carried out at each re-examination interval (D3, D7,

D14 and D21). In order to preserve sample size, any

missing values were replaced using the last observation

carried forward (LOCF) approach.

The type I error rate was set to 5% two-sided for all

comparisons, i.e. α = 0.05.

3. Efficacy Results

3.1. Evaluation and Completion of Dogs

Three enrolled animals were removed (two lost to follow

up and one where the owner did not comply with treat-

ment protocols). A total of 157 dogs (73 Aurizon®

treated animals and 84 Easotic® treated animals) was

kept in the Per Protocol analysis. The distribution of dogs

across treatment groups at inclusion was comparable

based upon demographics (Table 3) and clinical signs

(Table 4), although patients within the Aurizon® treat-

ment group tended to present with a higher GCS at the

time of enrolment. Thirty dogs with bilateral otitis were

enrolled per group and the total number of ears treated

was 103 in the Aurizon® group and 114 in the Easotic®

group. Otitis externa was characterised as suppurative in

63 ears (29 within the Aurizon® group, 34 in the Easotic®

group) and erythemato-ceruminous in 154 ears (74 ears

in the Aurizon® group, 80 in the Easotic® group). Bacte-

riological findings prior to treatment are presented in

Table 5.

3.2. Efficacy Assessments

No significant difference (p > 0.05) in treatment efficacy

was found at any point during the study, although a trend

in favour of better results was encountered in animals

treated with Aurizon® (p = 0.12 on D21, Figure 1). A

similar trend was also present for the rate of animals for

which a new auricular therapy was to be performed (13

within the Easotic® group versus 9 Aurizon® treated

animals; not statistically significant). A sub-analysis,

which took into account Aurizon® treatment duration,

suggested that there were two subpopulations enrolled

within this group. Furthermore, there appeared to be a

positive clinical correlation between the severity of

clinical signs at inclusion and the duration of treatment

chosen by the clinician. This relationship was observed

for GCS (Figure 2) but was absent for LCS (Figure 3).

3.3. Safety Assessments

Only one adverse event was detected during the course of

the study. One Easotic® treated animal was presented as

an emergency on D12 with ataxia and epileptiform sei-

zures. A hepatic tumour was diagnosed based on the re-

sults of imaging studies (ultrasonography); the owner

subsequently elected for euthanasia of the patient. No

causative link with the treatment was suspected.

4. Discussion

Blind conditions could not be implemented within this

Table 3. Demographic summary.

Aurizon® Easotic® Total

Number of animals 73 84 157

Age* (years) 6.6 ± 3.79

(min: 0.5; max: 15.7)

6.5 ± 3.79

(min: 0.3; max: 16.0)

6.5 ± 3.78

(min: 0.3; max: 16.0)

Body weight* (kg) 17.5 ± 11.14

(min: 4.0; max: 48.0)

20.7 ± 13.23

(min: 3.6; max: 72.0)

19.2 ± 12.37

(min: 3.6; max: 72.0)

Sex 42 females (11 neutered) and

31 males (5 neutered)

43 females (20 neutered) and

41 males (6 neutered)

85 females (31 neutered) and

72 males (11 neutered)

Otitis (affected ears)

Erythemato-ceruminous

Suppurative

103

114

217 ears

154 ears

63 ears

Breed The main pure breeds were Labrador retriever (n = 17), poodle (n = 13), golden retriever (n =8),

cocker spaniel (n = 8) and bull terrier (n = 8)

E. GRANDEMANGE ET AL. 293

Table 4. Clinical scores at inclusion.

Aurizon® Easotic®

Appetite (score) 0: 91.8%

1: 8.2%

0: 96.4%

1: 3.6%

Behaviour (score) 0: 93.2%

1: 6.8%

0: 97.6%

1: 2.4%

Locomotion (score) 0: 97.3%

1: 2.7%

0: 97.6%

1: 2.4%

Head carriage (score)

0: 68.5%

1: 27.4%

2: 4.1%

0: 76.2%

1: 21.4%

2: 2.4%

Pruritis (score)

0: 5.5%

1: 42.5%

2: 52.0%

0: 5.9%

1: 39.3%

2: 54.8%

Pinnal lesions (score) 0: 31.1%

1: 68.9%

0: 26.3%

1: 73.7%

Malodour (score) 0: 31.1%

1: 68.9%

0: 28.9%

1: 71.1%

Pain on handling (score)

0: 2.9%

1: 19.4%

2: 42.7%

3: 35.0%

0: 7.9%

1: 23.7%

2: 44.7%

3: 23.7%

Inflammation of external meatus (score) 2: 57.3%

3: 42.7%

2: 49.1%

3: 50.9%

Exudate quantity (score) 2: 57.3%

3: 42.7%

2: 50.9%

3: 49.1%

Table 5. Microbiological results prior to treatment and

clinical characterization of otitis.

Number of ears concerned

Pathogens Suppurative

otitis

Erythemato-ceruminous

otitis

Number of ear sampled 49 108

Staphylococcus

pseudintermedius 26 36

Streptococcus canis 12 2

Pseudomonas aeru gi n os a 9 3

Escherichia coli 3 0

Proteus mirabilis 3 0

Staphylococcus aureus 1 0

Streptococcus dysgalactiae

spp equisimilis 1 0

Malassezia pachydermatis 30 65

Other yeasts 0 3

study due to differences in the presentation of the treat-

ments and non-conformity of the licensed durations of

therapy.

The pathogens isolated from clinically affected ears at

inclusion were typical of those described in the literature

and the breeds of dog enrolled in the study were varieties

generally considered to have a predisposition for otitis

externa (e.g. Labrador, Golden Retriever, Poodle and

Cocker Spaniel) [4,5,8].

An ear cleaning was performed prior to administration

of topical therapy in order to remove ear wax and/or pu-

rulent material. The primary endpoint for the study was

clinical resolution of otitis externa as this was considered

to be a more common indicator of treatment success than

microbiological cure for the vast majority of owners and

clinicians within general practice.

The results of this multicentre field study confirmed

that Aurizon® is an effective treatment of otitis externa

with 84.3% of cure rate on D21, which confirmed previ-

ous findings [16]. This was 10% greater than that en-

countered in the Easotic® group (73.8% cure rate,

non-significant difference). The Easotic® results ob-

served in the study were consistent with efficacy results

previously published on the European Medicine Agency

(EMA) website (72.2% at D14) [18] and by Rigault

(74.7%) [19]. This difference between groups was mir-

rored by a non-significantly higher number of animals in

the Easotic® group requiring an additional therapy due to

relapse/failure before or on D21 (13 versus 9 animals in

the Aurizon® group). An increase in the cure rate be-

tween the end of treatment and at re-assessment 7 days

after completing treatment was observed in both groups.

Further improvement beyond the post-treatment exami-

nation was noted in the Aurizon® treated animals; this

finding was not replicated in the Easotic® group.

A sub-analysis of inclusion criteria based upon the

Aurizon® treatment duration selected by the clinician (7

or 14 days) showed that there were 2 populations of dogs

presenting with otitis externa: a population with a low

GCS which only required a 7 day course of therapy and a

second population with a higher GCS which necessitated

14 days of treatment. This confirmed that the duration of

treatment was influenced by the severity of disease at

initial presentation as opposed to the clinicians taking a

conservative approach and using the longest duration of

treatment available, regardless of the clinical picture. In

addition, it may indicate that in this study treatment dura-

tion was related to the clinical disease at inclusion and

not to differences in the progression of cases of otitis

externa which had a similar baseline. No variations were

observed for the LCS scores between animals who re-

ceived 7 or 14 days of treatment, but these scores were

already very high at the time of inclusion. Licensing re-

strictions (5 day treatment duration and instructions to

discard the medication 10 days after opening) prevented

a similar flexible dosing schedule being adapted for the

Easotic® group. Furthermore, studies have indicated that

a longer duration would not improve the cure rate [18]

which validates the licensed 5 day treatment duration.

The consequences of inadequate therapy in cases of otitis

externa are largely dependant upon the underlying aeti-

ology but can include relapse of clinical signs within

weeks of completing therapy, selection for antimicrobial

resistance in key pathogens or a progression to chronic

otitis externa.

E. GRANDEMANGE ET AL.

294

56.3%

81.2% 84.3%73.8%

48.8%

74.7%

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

Cure rate at the end of treatmentCure rate one week after the end of the

treatment Cure rate on D21

Percentages

Aurizon Easotic

Figure 1. Clinical progression of treatment groups relative to date of examination.

1.3

1.5

1.8

2.3

D0D3D7D14 D21

AURIZON 7 days

EASOTIC 5 days

AURIZON 14 days

study day

General clinical score

Figure 2. Progression of the GCS relative to treatment group and duration of therapy.

Despite the lack of statistical significance, the differ-

ence observed between groups on D21 suggests that re-

assessment of cases 7 days after starting treatment and

subsequent adaptation of the treatment duration based

upon clinical response could improve therapeutic success

rate. Clinical cure is rarely possible unless the owner

complies with treatment protocols and this variable was

closely monitored by the investigators during the course

of this study. Boda [15], comparing Easotic® to another

ompound which required twice daily administration for c

E. GRANDEMANGE ET AL. 295

D0D3 D7 D14 D2 1

AURIZON 7 days

EASOTIC 5 days

AURIZON 14 days

study day

Local clinical score

Figure 3. Progression of the LCS relative to the treatment group and duration of therapy.

7 days, concluded that its simplified dosing regimen and

method of administration improved the owner compli-

ance. Another variable that must be considered is on-

going monitoring of otitis externa cases until the veteri-

narian decides that clinical cure has been achieved.

The results of this study suggest that when selecting an

appropriate therapy for otitis externa, clinicians should

consider not only ease of administration, but also effi-

cacy and the availability of extended durations of therapy

where needed to achieve clinical cure in the face of sig-

nificant clinical disease. Owner assessment of clinical

cure is unreliable as the glucocorticoid incorporated in

many ear preparations leads to resolution of easily ob-

servable markers of disease such as pain, pruritis, hyper-

plastic and proliferative. This may lead to an owner

electing to discontinue therapy before a true clinical cure

has been achieved.

A longer duration study (e.g. 6 months) would be an

interesting exercise and would enable the monitoring of

the frequency of relapses and/or the development of

chronic otitis externa.

No safety problem related to the investigated products

was reported throughout the study.

5. Conclusion

In conclusion, Aurizon® administered for 7 to 14 days

showed a non-significant tendency towards superior cli-

nical resolution than Easotic® administered for 5 days in

the treatment of acute otitis externa in the dog. The

treatment duration of Aurizon® prescribed by the inves-

tigator showed correlation with the severity of the gen-

eral clinical signs observed at inclusion.

6. Acknowledgements

This work was funded by Vétoquinol SA, Lure, France.

During the time of the study conduct, Erik Grandemange

and Frédérique Woehrlé were employed by Vétoquinol

SA, R&D Department, Lure, France. The authors ac-

knowledge the assistance of the staff at the clinics and

the laboratory involved and the cooperation of the own-

ers. The authors would like to thank Adrian Ward,

MRCVS for the English review of this article.

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