Veterinary Dermatology 2005, 16, 299 307

A comparative study of two antimicrobial / anti-inflammatory

formulations in the treatment of canine otitis externa

Blackwell Publishing, Ltd.

SANDRINE ROUGIER, DANIELA BORELL, SANDRINE PHEULPIN,

FRDRIQUE WOEHRL and BERNARD BOISRAM
Vtoquinol Research Centre, Magny Vernois, BP 189, 70204 Lure Cedex, France
(Received 10 January 2005; accepted 28 May 2005)

Abstract The efficacy and tolerability of a marbofloxacin-clotrimazole-dexamethasone otic suspension (MCD)

was compared with a standard topical treatment using a phase III clinical trial protocol. In a total of 140 dogs
with clinical signs of acute or subacute otitis externa, Staphylococcus, Pseudomonas, Enterobacteriaceae and
Malassezia were isolated from samples taken at inclusion to identify the causative pathogen; a further sample
was collected in the event of failure or relapse, and from dogs (at day 14) for which Pseudomonas species had been
isolated at inclusion. One group received MCD (10 drops per affected ear) once daily and a second received
Surolan (containing polymyxin B, miconazole and prednisolone) (5 drops per affected ear), twice daily. Each
group received treatment for 7 or 14 days according to the clinical outcome on day 7. Efficacy and tolerability
were evaluated on days 7, 14 and, if necessary, 28 for dogs treated for 14 days. The trial demonstrated equivalence
of both treatments in terms of efficacy, with a cure rate of 58.3% for MCD and 41.2% for Surolan. Both
medications were equally well tolerated by dogs, but MCD was superior in terms of pain relief, decrease in pus
quantity and smell, response rate and investigators assessment on day 14.

IN TRO D U CT ION
Canine otitis externa is one of the most frequently
seen veterinary conditions, and is estimated to affect
between 5 and 20% of dogs.1,2 Otitis has been classified
according to type of exudate as erythemato-ceruminous
(ECO) or suppurative (SO), with the former subgrouped
as parasitic or nonparasitic. 3 Causes of otitis are
classified as: (1) predisposing (such as ear structure,
systemic disease, unsuitable treatment); (2) primary
(ectoparasites, foreign bodies, neoplasms, allergies,
autoimmune disease), and (3) secondary (which contribute to otitis in conjunction with predisposing
and perpetuating factors, such as bacteria, yeasts, histopathological changes, or otitis media).35 The dominant
pathogens in otitis include Staphylococcus intermedius,
and the Gram-negative organisms Pseudomonas
aeruginosa, Proteus mirabilis , Klebsiella spp. and
Escherichia coli. Although these Gram-negative organisms are not routinely cultured from the normal ear
canal, S. intermedius is often present in low numbers,
even in normal ears.3
Topical therapy is an important part of the treatment of otitis externa.3,6 Multipurpose products are
frequently indicated, particularly as a first-line treatment,
because of the mix of micro-organisms and inflammation present in most ears at diagnosis.3 One well-tried
successful therapy for canine otitis externa is topical

Correspondence: S. Rougier, Vetoquinol Research Center,

Magny Vernois, BP 189, 70204 Lure Cedex, France. E-mail:
sandrine.rougier@vetoquinol.com
2005 European Society of Veterinary Dermatology

application of Surolan (containing polymyxin B,

miconazole and prednisolone) (Janssen Animal
Health, Issy-les-Moulineaux, France). However, some
of the antibacterials contained in ear drops are potentially ototoxic if used in the presence of a ruptured
tympanum and/or otitis media, particularly if use is
prolonged and if they include polymyxin B.3,7,8 Moreover, otitis media is considered to be concomitant with
acute otitis externa in 16% of dogs.9 In this instance, if
a tympanum rupture is suspected, topical application
of fluoroquinolone is recommended.10
Marbofloxacin is a third generation fluoroquinolone
developed for veterinary use and is an antibacterial
with potent bactericidal activity against Gram-positive
and Gram-negative organisms.1114 Like other fluoroquinolones,6,15 it is not associated with ototoxicity and
can achieve high local concentrations when used. It is
thus a potentially interesting drug for treatment of
canine otitis externa.
As Malassezia pachydermatis is the predominant
yeast in otitis externa,1618 clotrimazole, a well-known
antimycotic that has often proved effective against
yeasts, appears as a good complementary option in the
treatment of canine otitis.
Topical corticosteroids, such as prednisolone and
dexamethasone, are commonly used in the control of
the otitis due to their anti-inflammatory, antiproliferative, antipruritic, and anti-exudative effects.19
The aim of the present study was to test the efficacy
and tolerability of a marbofloxacin-clotrimazoledexamethasone oily suspension (MCD) in canine acute
otitis externa compared with Surolan using a phase
III clinical trial protocol.
299

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S. Rougier et al.

MATERIALS AND ME T HODS

Test population
Two hundred and four dogs of both sexes, aged from
4 months to 16 years, presenting with acute or subacute otitis externa (in progress for less than 30 days)
were selected from all dogs examined for ear diseases in
15 veterinary practices in France, Belgium, Italy and
Germany. To qualify for inclusion, dogs had to present
either with erythemato-ceruminous otitis (ECO) or
with suppurative otitis (SO). ECO was defined as the
presence of cerumen and erythema (both with scores
2 on a scale of 03) with associated bacterial and
yeast isolates observed microscopically. SO was the
presence of pus (score 2 for quantity) with associated
microscopical evidence of bacteria.
Dogs were excluded from the trial if they had previously received (a) topical treatment (within 10 days),
(b) systemic treatment with an antibiotic, antifungal or
nonsteroidal anti-inflammatory (within 10 days), (c) a
steroidal anti-inflammatory treatment (within 14 days),
or (d) a long acting steroidal anti-inflammatory drug
systemically (within 60 days). They were also excluded
if concurrent auricular diseases such as ear parasites,
foreign bodies, neoplasia or hyperplasia of the meatus
acusticus externus were present, if there was concomitant administration of antibiotics or corticoids during
the study, or if they were gestating or suckling female
dogs. Informed consent was obtained from the owners
of all dogs prior to their participation in the study.

Treatments
All dogs received local treatment consisting of either
the test product, Aurizon (Vtoquinol, Lure, France),
coded MCD (a suspension containing 3 mg of marbofloxacin, 10 mg of clotrimazole and 0.9 mg of dexamethasone acetate per ml) administered once daily as 10
drops per affected ear; or the control product, Surolan (Janssen Animal Health) (also a suspension
containing 5.5 IU of polymyxin B sulphate, 23 mg of
miconazole and 5 mg of prednisolone acetate per ml)
administered twice daily as 5 drops per affected ear
(standard recommended doses).
Both products were administered initially in the clinic
to demonstrate the correct technique, and thereafter by
the dog owners for 7 or 14 days (according to the clinical outcome on day 7). Immediately after application,
the ear was massaged for 12 min to ensure even distribution throughout the entire canal.

Study design
Dogs were assigned to one of the two treatment groups,
according to a block randomization procedure (stratified on the centre). The products were presented in
10-mL vials for MCD or 15-mL vials for Surolan,
labelled A or B and packaged in identical, numbered
cardboard boxes. As the pack sizes and administration
conditions differed, a dual investigator method was
used to ensure blind conditions. A treatment investigator
(nurse or veterinarian) was in charge of the treatment

regime and demonstrated correct use of the test

products, explained treatment and cleaning protocols
to owners, and checked compliance with treatment.
The owner of each included dog was provided with a
copy of the same protocol including a description of
the method of ear cleaning. Each investigation block
had four numbered treatment boxes according to a
randomization list established and kept in the laboratory. At inclusion, a dog was attributed the box with
the lowest number by the treatment investigator; this
number was used also for its identification during the
entire study. When the four cases of the first block were
enrolled, the investigator randomly received another
block of four treatment boxes to include the next four
dogs and so on. And one clinician investigator (compulsorily veterinarian with experience in dermatology)
was responsible for all animal examinations and
scoring evaluations according to the study protocol
requirements.

Schedule
All dogs were examined by the clinician investigator
on days 0 (D0), 7 (D7), 14 (D14) and, if necessary, 28
(D28) for animals treated for 14 days only, in accordance with the recommendations from two European
veterinarian specialists in dermatology. In cases of
bilateral otitis, only the right ear was studied as both
ears were considered to be equally affected.
The affected ear(s) were cleaned with physiological
saline before all applications of the test product: (1) by
the treatment investigator on D0; (2) by the owner on
D2 and D4 for ECO or daily between D1 and D6 for
SO; (3) at each visit until the end of treatment by the
treatment investigator; (4) by the owner (for cases
treated for 14 days), once on D10 for ECO, or twice a
week from D8 to D14 for SO. Holding up the ears
artificially was permitted during the study, and tranquillization or general anaesthesia was employed for
otoscopic examination.

Evaluation
Ears were evaluated at baseline and at each examination time by the clinician investigator for skin erythema
and skin oedema, pruritus, pain, skin ulceration, state
of tympanum, quantity of cerumen/pus and smell
of cerumen/pus. Scores were given for each of these
parameters on a severity scale of 03 (0 = none, 1 =
slight, 2 = moderate, and 3 = severe), except for skin
ulceration (absent/present), state of tympanum (inflamed/
noninflamed) and smell of cerumen/pus (odourless/
slight/foul). Response to therapy and to local and general tolerance was assessed by the clinician investigator
at the end of the treatment (D7 or D14). At the end of
the study and still under blind conditions, an assessment
(excellent, good, average or bad) was made regarding
the course of otitis.
Swab specimens for cytological examination and
microbiological culture and susceptibility testing for
marbofloxacin, polymyxin B, clotrimazole and miconazole were obtained on D0 from the horizontal ear

2005 European Society of Veterinary Dermatology, Veterinary Dermatology, 16, 299 307

Antimicrobial treatment of canine otitis externa

301

canal. Vtoquinol microbiology laboratory staff

contributed to the collection and bacterial isolation.
The strains were isolated on selective and conventional
agars in Petri dishes, and incubated for circa 24 h in
an atmosphere and a temperature appropriate for
their culture: Enterobacteriaceae on MacConkey agar
(Biomrieux, Marcy lEtoile, France) at 35 2 C,
Pasteurella on Columbia blood agar (Biomrieux) at
35 2 C with 6% CO2, Staphylococcus, Bordetella and
Pseudomonas on tryptone-soy agar (Biomrieux) at
35 2 C, Streptococcus and other Gram-positive bacteria on Columbia blood agar (Biomrieux) or on TKT
agar (Merck, Darmstadt, Germany) at 35 2 C, and
Malassezia on Sabouraud agar (Merck) at 25 2 C
for 48 h. After Gram colouration and oxydase (Gramnegative bacilli) or catalase (Gram-positive cocci) test,
the bacteria were characterized by biochemical API
identification systems (Biomrieux), except for Staphylococcus aureus, which was identified with an agglutination system called SlidexStaph kit (Biomrieux).
After identification, the bacterial strains were stored on
cryoballs (AES, Combourg, France) at 80 C. Additional antibiograms were obtained by a disc (Bio-Rad)
diffusion method for enrofloxacin, neomycin, fusidic
acid, gentamicin and nystatin. Organism susceptibility
to the six antibiotics was determined using NCCLS
guidelines20 and Bio-Rad recommendations (Table 1;
inhibition diameters are expressed in mm).
In the event of therapeutic failure or relapse, and at
the end of treatment in each case where Pseudomonas
spp. was isolated on D0, a further swab was required
for laboratory examination.

parameters initially affected]). The development of

clinical parameters was described, and the frequency
of reactions and general adverse effects attributable
to the auricular treatment were calculated for each
group.

Efficacy criteria

R E S U LT S

For both treatment groups, signalment, history (length

of symptoms, previous episodes of, and treatments for
otitis), and the clinical and microbiological data were
compared on D0 to ensure homogeneity before further
comparison.
The primary assessment criterion was the clinical
cure rate (on D7 or D14 according to the length of
treatment). A cure was defined as a return to normal of
all parameters (score = 0), except for cerumen quantity
in ECO for which the score could be 1.
A number of secondary criteria were also analysed,
namely the time to cure, relapse rate, and response rate
(defined as cases cured [see above] or showing clear
improvement [normalization of 50% or more of the
Table 1. Zone diameter interpretive standards breakpoints for
veterinary pathogens
Antibiotics

Susceptible

Intermediate

Resistant

Marbofloxacin
Enrofloxacin
Polymyxin B
Neomycin
Fusidic acid
Gentamycin
Clotrimazole
Miconazole
Nystatin

18
22
15
17
22
16
20
20
> 10

[17 15]
[21 17]

14
16
14
14
14
13
10
10
10

[16 15]
[21 15]
[15 14]
[29 11]
[29 11]

Statistical analysis
The clinical cure rate was compared using an equivalence approach. The 95% confidence interval of the odds
ratio was calculated. Its lower band was then compared
to the a priori equivalence limit, based on the expected
cure rates under the H0 hypothesis of nonequivalence
(20% difference between groups). If the lower band was
superior to the equivalence limit, the H0 hypothesis of
nonequivalence was rejected with P < 0.005.
The other criteria and initial comparability were
performed according to a bilateral approach:
Contingency tables 2 2: Fishers exact test.
Contingency tables 2 n (n > 2): likelihood ratio
chi-square test.
Comparison of means: Students t-test.
Evolution of clinical parameters (scores): generalized linear model (GLM), taking into account
marginal frequencies (after logit transformation),
or mean scores if the number of cases by class was
too low. The model included two factors (time and
treatment) with repeated measures (time).
The significance threshold was set at 5% for comparison between treatments.

Population studied
Only 140 (68.62%) of the 204 dogs presenting with otic
problems were eventually studied, mainly because of
failure to meet the inclusion criteria (38 cases, 18.62%)
and serious deviations in visit times (20 cases, 9.8%).
Others were excluded for reasons of nonrandomization
(two cases), prior local treatment (one case) and
cessation of treatment too early (D7 instead of D14)
irrespective of the protocol requirement (three cases).
The statistical analyses were performed on the data
obtained from these 140 dogs, 83 of which came from
two investigation sites. The 13 other practices recruited
from one to 11 dogs each. Breeds represented included
dwarf and medium size poodles, West Highland white
terriers, Labrador retrievers and mixed breeds. Median
age was 5.8 years and 6.2 years, and average body size
was 18.5 and 19.7 kg for the MCD and control group,
respectively. About half of the animals (54.4% Surolan, 54.2% MCD) had previously suffered episodes
of inflammation of the external ear canal, but only
11.8% in the reference group and 11.3% in the MCD
group had been treated previously. Unilateral and
bilateral otitis occurred equally (bilateral otitis in
54.4% of dogs in the Surolan group and 47.2% in the
MCD group). Symptoms lasted on average from 2 to

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302

S. Rougier et al.

4 weeks (44.1% Surolan and 38.9% MCD). Cases of

SO were more common (61.8% Surolan, 62.5% MCD)
than ECO (38.2% Surolan, 37.5% MCD). There was
also a significant sex difference between groups (Surolan group 27.9% females; MCD group 50%). Apart
from this parameter, both groups were considered to be
equally balanced.

Table 3. Percentage of sensitive, intermediate or resistant strains of

isolated Malassezia pachydermatis

Microbiological results

All the dogs were divided into the following four

subgroups, based on these microbiological results:

Clotrimazole
Miconazole
Nystatin

Evaluation of the prevalence of causal pathogens

revealed Staphylococcus spp. (39.5%), Enterobacteriaceae (17.1%) and Pseudomonas spp. (12.9%) as the
dominant bacteria. Streptococcus spp. and Grampositive bacteria represented 11.4%. Other Gramnegative bacteria represented 10.5%, and 8.6% of
samples was sterile. Of the Staphylococcus spp. isolated,
S. intermedius (82%) represented the great majority
along with, in decreasing order of prevalence, S. aureus,
S. epidermidis, S. sciuri and S. chromogenes (a few strains
of each). The Enterobacteriaceae were represented
mainly by Proteus spp. and E. coli and the Pseudomonas
spp. mainly by P. aeruginosa. Susceptibility patterns of
bacteria isolated prior to treatment, to six antimicrobial agents including marbofloxacin and polymyxin B,
are listed in Table 2. Marbofloxacin proved to be the
most effective antibiotic with 87.5% of sensitive strains
(all bacteria), compared with 45.3% for polymyxin B.
Of the 140 samples examined for the presence of
yeasts (Table 3), 45% were positive, mainly for Malassezia pachydermatis (68.8%), which was found more
frequently in cases of ECO (56.6%) than of SO
(43.4%); 75.5% of M. pachydermatis was susceptible to
clotrimazole and 77.4% to miconazole. Other yeasts
isolated were Malassezia sp., Cryptococcus humicolus
(one strain) and Candida humicola (one strain). Mould
was observed in three cases.

Sensitive

Intermediate

Resistant

75.5
77.4
84.9

9.4
7.5
0

3.8
3.8
3.8

Bacterial otitis (B) with E. coli, Proteus sp., Pseudomonas sp. or Staphylococcus spp. (44.4% of dogs
in the MCD group and 39.7% in the Surolan
group);
Fungal otitis (F) with Malassezia spp. (6.9% MCD
and 8.8% Surolan);
Both bacterial and fungal otitis (BF) with at least
one of the bacterial strains listed previously and
Malassezia spp. (27.8% MCD and 33.8% Surolan);
Nondefined otitis (ND): none of the pathogens
listed previously was found (but other microorganisms were isolated) (20.8% MCD and 17.6%
Surolan).
Of the 27 cases positive for Pseudomonas spp. on D0,
only four samples were taken on D14. Pseudomonas
spp. was found again in two of them and the dogs in
question were treated with Surolan.

Clinical efficacy of treatment

Sixty-nine dogs (95.8%) treated with MCD and 57
dogs (83.8%) treated with Surolan responded satisfactorily (i.e. cured or clearly improved) (statistically
significant difference between groups, likelihood ratio
chi-square test, P = 0.01).

Table 2. Percentage susceptibility to various antibiotics of bacteria isolated from the horizontal ear canals of dogs with otitis externa on day 0
Bacteria

Number of isolates (%)

Staphylococcus spp.

83 (39.5)

Streptococcus spp.

12 (5.7)

Pseudomonas spp.

27 (12.9)

Enterobacteriaceae

36 (17.1)

Other Gram+

24 (11.4)

Other Gram

10 (4.8)

S
I
R
S
I
R
S
I
R
S
I
R
S
I
R
S
I
R

MAR*

ENR*

PMX*

NEO*

FA*

GM*

98.8
0
1.2
66.7
25
0
96.3
0
2.7
100
0
0
25
37.5
0
100
0
0

90.4
4.8
2.4
33.3
58.3
0
37
40.7
22.2
88.9
5.6
2.8
16.7
33.3
12.5
100
0
0

27.7
0
72.3
0
0
100
70.4
0
29.6
100
0
0
4.2
0
58.3
80
0
20

68.7
9.6
19.3
8.3
0
83.3
14.8
11.1
74.1
47.2
19.4
30.6
8.3
0
54.2
80
0
20

84.4
8.4
4.8
8.3
25
58.3
3.7
3.7
92.6
5.6
0
91.7
16.7
25
20.8
20
10
70

95.2
0
2.4
16.7
16.7
58.3
29.6
22.2
48.1
83.3
2.8
11.1
12.5
8.3
41.7
70
0
30

*MAR, marbofloxacin; ENR, enrofloxacin; PMX, polymyxin B; NEO, neomycin; FA, fusidic acid; GM, gentamicin.
S, sensitive; I, intermediate; R, resistant.
Other Gram+: Enterococcus spp. (12), Bacillus spp. (9), Corynebacterium sp. (1), Lactococcus lactis (2).
Other Gram: Pantoea sp. (1), Bacillus Gram-(1), Chryseomonas luteola (1), Pasteurella sp. (1), Acinetobacter (3), Sphingomonas paucimobilis
(2), Stenotrophomonas maltophilia (1).
2005 European Society of Veterinary Dermatology, Veterinary Dermatology, 16, 299 307

Antimicrobial treatment of canine otitis externa

Table 4. Comparison of clinical results according to treatment
groups and otitis types

Table 5. Comparison of percentages of normal scores of the clinical

parameters from D0 to D14

Number (%)

Number (%)

Clear
improvement

Improvement

Failure

12 (34.3)
11 (39.3)

0 (0)
0 (0)

1 (2.9)
7 (25)

1 (16.7)
0 (0)

0 (0)
2 (25)

Both bacterial and fungal otitis

MCD
9 (47.4) 10 (52.6)
Surolan
8 (38.1) 12 (57.1)

0 (0)
0 (0)

0 (0)
1 (4.8)

Nondefined otitis
MCD
6 (54.5)
Surolan
6 (66.7)

0 (0)
0 (0)

1 (9.1)
1 (11.1)

Cure
Bacterial otitis
MCD*
22 (62.8)
Surolan 10 (35.7)
Fungal otitis
MCD
Surolan

4 (66.7)
3 (37.5)

303

1 (16.7)
3 (37.5)

4 (36.4)
2 (22.2)

ECO
MCD
Surolan

14 (51.9)
10 (38.4)

11 (40.7)
12 (46.2)

1 (3.7)
0 (0)

1 (3.7)
4 (15.4)

SO
MCD
Surolan

28 (62.2)
18 (42.9)

16 (35.6)
17 (40.5)

0 (0)
0 (0)

1 (2.2)
7 (16.7)

*MCD, marbofloxacin-clotrimazole-dexamethasone otic

formulation.

Cure was achieved in 58.3% of the MCD group

(42 dogs, eight (19%) on D7 and 34 (81%) on D14), and
in 41.2% of the reference group (28 dogs: seven (25%)
on D7 and 21 (75%) on D14) (non equivalence rejected
with P < 0.05).
MCD was more effective than the reference treatment against both ECO and SO, showing a difference
of 13.4% in cases of ECO and 19.3% in cases of SO.
Analysis of three weight classes (< 10 kg, 1025 kg,
> 25 kg) did not reveal any influence of size on the
efficacy of either product. MCD provided a higher cure
rate in dogs 10 kg (60% vs. 33.3% with Surolan, but
this was statistically nonsignificant, P = 0.07). However,
efficacy rate (association of cures and clear improvements) remained better with MCD whatever the category of weight.
MCD and Surolan proved to be statistically equivalent
in terms of number of cured dogs (P = 0.059 within
each of the four classes of otitis (B, F, BF and ND), Mantel
Haenszel procedure) (Table 4); however, MCD tended
to be superior in cases of bacterial, fungal or mixed otitis.
All clinical parameters gradually improved from D0
to D14 with both products (Table 5). Improvements
in skin ulceration and inflammation of the tympanic
membrane were particularly rapid. The difference
became significant from D7 with MCD being superior
for resolution of pain (GLM, two ways with repeated
measures model, P = 0.005), pus quantity (GLM, P =
0.01) and pus smell (GLM, P = 0.009).
Relapse occurred in 18.5% of dogs treated with
Surolan compared with 9.8% of dogs treated with
MCD, although this difference was not statistically
significant (Fishers exact test, P = 0.47). A second
sample (taken in 11 cases only) evidenced S. intermedius

Clinical parameters

MCD*

Surolan

Total

Skin erythema
D0
D7
D14

0 (0)
13 (18.1)
49 (68.1)

1 (1.56)
11 (17.2)
36 (56.25)

1
24
85

Skin oedema
D0
D7
D14

14 (19.5)
41 (56.9)
67 (93.1)

11 (17.2)
33 (51.6)
49 (76.6)

25
74
116

Pruritus
D0
D7
D14

2 (2.8)
22 (30.6)
57 (79.2)

3 (4.7)
21 (31.8)
41 (64.1)

5
43
98

Pain
D0
D7
D14

5 (6.9)
37 (51.4)
69 (95.8)

2 (3.1)
24 (37.5)
51 (79.7)

7
61
120

Skin ulcerations
D0
D7
D14

38 (52.8)
67 (93.1)
71 (98.6)

28 (43.75)
58 (90.6)
62 (96.9)

66
125
133

Inflammation of the
tympanic membrane
D0
D7
D14

30 (41.7)
64 (88.9)
70 (97.2)

30 (46.9)
52 (81.25)
59 (92.2)

60
116
129

Cerumen quantity
D0
D7
D14

0 (0)
8 (29.6)
23 (85.2)

0 (0)
3 (12.5)
20 (83.3)

0
11
43

Cerumen smell
D0
D7
D14

1 (3.7)
12 (44.4)
23 (85.2)

0 (0)
11 (45.8)
23 (95.8)

1
23
46

Pus quantity
D0
D7
D14

0 (0)
12 (27.9)
40 (93)

0 (0)
9 (21.95)
27 (65.85)

0
21
67

Pus smell
D0
D7
D14

2 (4.7)
30 (69.8)
42 (97.7)

2 (4.9)
19 (46.3)
36 (87.8)

4
49
78

*MCD, marbofloxacin-clotrimazole-dexamethasone otic

formulation.

(two cases), P. mirabilis, P. aeruginosa, Streptococcus

spp. and E. coli (one case for each).
In the cases where treatment failed (two in the test
group and 11 in the control group), the bacteria found
were mainly Staphylococcus spp. (46.1%) and P. mirabilis
(30.8%). All proved to be resistant to polymyxin B but
susceptible to marbofloxacin.
Assessment by clinician investigators of treatment
efficacy resulted in a statistically significantly higher
rating for MCD than the control product on D14
(likelihood ratio chi-square test, P = 0.03).

Tolerability of treatment
Of the 140 cases assessed for local tolerance, two
dogs treated with MCD exhibited local irritation (pain,

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S. Rougier et al.

erythema and pruritus) just after administration of the

product. No local side effects were reported in the control group (statistically nonsignificant, Fishers exact
test, P = 0.25). In addition, 5.9% of dogs treated with
Surolan and 5.6% with MCD suffered transient benign
and nonspecific adverse effects, which generally affected
the digestive system (diarrhoea, vomiting and constipation). Polyuria and/or polydipsia were reported in
three cases (two in the Surolan group and one in the
MCD group), and all were considered to be treatment
related. This did not, however, necessitate discontinuation of the follow-up procedures.

DISCU SSIO N
Topical treatment is the method of choice in otitis
externa because antimicrobial concentrations of the
agents come into direct contact with the pathogens.
The results show that a marbofloxacin-clotrimazoledexamethasone otic suspension (MCD) is as effective
and well tolerated as Surolan (polymyxin B-miconazoleprednisolone otic solution) in the medical management
of otitis externa in dogs.
The results compare favourably with those of another
study that used our reference product;21 a satisfactory
response was achieved in 73.3% of dogs and the recurrence rate was 26.7%. Here, the 7-day treatment was
successful in eight and seven cases treated with MCD
and Surolan, respectively. However, it now seems that
as 34 and 21 dogs, respectively, required 14 days of
treatment to cure, over 1 week of treatment with these
products may be necessary. As has been pointed out
above, the very high local concentration of the active
ingredients and the pharmacokinetic/pharmacodynamic approach2224 do not promote the development
of resistance, and justify a 7- or 14-day treatment
period according to the clinical and microbiological
outcome on D7. MCD and Surolan proved to be
significantly equivalent in efficacy, regardless of the
classification chosen (ECO/SO or B/F/BF/ND). The
active principles act on the otitis mechanisms whatever
the origin of the disease, even when this origin is not
well defined (ND group). They bring about a complete
recovery in the various cases, which is correlated with
very low rates of failure and relapse, particularly with
MCD treatment.
Satisfactory responses were achieved in 95.8% and
83.8% of dogs treated with MCD and control product,
respectively. The same volume of drug (as per label
doses) was used regardless of body size. As only 5 drops
of Surolan as opposed to 10 drops of MCD were
applied at each application interval, it could be supposed that the former would not cover the same surface
area as densely as the latter. However, analysis of three
weight classes revealed no difference in efficacy results.
Thus, as mean weight was similar between both tested
groups, any differences in efficacy between treatments
could probably be attributed more to bacterial resistance to polymyxin B than to a bias in dog size. Relapses

of clinical otitis externa during a 1-month follow-up

period were seen in 9.8 and 18.5% of cases, respectively.
In practice, ototoxicity is rare in small animals and
the risk is probably somewhat overstated.3 Studies
comparing two human-labelled topical fluoroquinolone
products (containing ciprofloxacin and ofloxacin,
respectively) with polymyxin B have shown that
fluoroquinolones are safe and have less ototoxic potential.15,2528 The systemic absorption of fluoroquinolones
is minimal after topical application and therefore
adverse effects should not be observed in dogs receiving MCD. In addition, other components of MCD,
dexamethasone and clotrimazole, are known to be safe
for use in the middle ear.28
Topical glucocorticoids are considered beneficial in
most cases of otitis externa, regardless of the underlying cause of inflammation.2,4,19,2931 They are known to
be very effective against pain and, ethically, pain has to
be treated. It is also easier to treat a dog that is not in pain,
and there is improved compliance with the treatment.
Topical glucocorticoids break the itch-scratch-itch
cycle and reduce hyperplastic and proliferative changes.
Moreover, they are known to have some beneficial
effects against secondary infection by allowing antibiotics to reach the deep canal and reducing discharge
that might inactivate antibiotics.3 Although potentiation of ear infections by topical glucocorticoids is
theoretically possible, studies in humans have shown
that secondary infections such as those occurring in
otitis externa are often controlled more effectively by
combined antibiotic/corticosteroid preparations than
by topical antibiotics or corticosteroids alone.4 Topical
glucocorticoids are relatively safe in practice.3,28 In our
study, polyuria/polydipsia association was reported in
three of the 140 dogs.
The high number of exclusions had no influence on
the evaluation of efficacy. Similarly, the significant
difference found in sex ratio at baseline was not thought
to have any influence on the results with regard to the
aetiology or prognosis of the treated disease. Recruitment was not homogeneous between the 15 veterinarian practices. Indeed, out of the 140 analysed dogs, 83
came from two investigation sites only. However, even
if a bias with the factor practice existed, the randomization procedure used and the use of blind conditions
provided test equally between treatments. Moreover,
because the study began in each veterinarian practice
during the same period, and because of the randomization procedure chosen, both treatments were equally
distributed during the entire 1-year study period.
As recommended by Foster,32 affected ears were gently
flushed with a sterile saline solution to remove ear
wax and purulent material, because fluoroquinolones
are much less effective in an acid medium.33 It is, however, not known exactly how the ears were cleaned by
the owners, even though identical information was
supplied to all participants. Nevertheless, owner compliance with the cleaning protocol and its methodology
was verified at each examination time by the treatment
investigator, and there is no reason to doubt the overall

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Antimicrobial treatment of canine otitis externa

efficacy of this procedure. However, a complete evaluation of the contribution, if any, of ear cleaning to the
efficacy results was not possible because the two treatment groups were not compared with a third group
with solely an ear cleaning protocol. It may, however,
be supposed that any contribution of this cleaning protocol to efficacy is insignificant as saline was used only
to optimize antibiotic action. Nonetheless, bias resulting from the cleaning protocol cannot be completely
ruled out, and may be the reason why the treatment
failed in some instances.
In this study, efficacy criteria were linked to the
clinical symptoms of canine otitis externa as the main
aim was to demonstrate a clinical efficacy and because
microbiological results were considered to be less
revealing of the pathology. Indeed, microbiological
results obtained from the field are dependent on various factors such as quality of sampling and sample
transportation to the laboratory. Thus, the main criterion
was based on clinical signs, and microbiological results
were used only to support and explain clinical findings.
Cytology was used only to distinguish ECO (identification of bacteria and yeast) from SO (bacteria only),
and to exclude animals with parasitic otitis. As this
examination was performed by each veterinarian, it
was considered too subjective for reliable analysis and
group and otitis type comparison. It is also the reason
why no cytology was performed at the end of the treatment. However, bacteria and/or yeast had to be found
initially by investigators for dogs to be included. Culture results were taken into account only for the microbiological criteria. Bacteriological and mycological
examinations were performed at inclusion and in the
event of failure or relapse. These tests allowed assessment of the susceptibility to the active ingredients in
tested products of the isolated strains and analysis of
failure and relapse cases.
As found previously,2,4,16,3436 the most commonly
isolated fungal pathogen in this study was M. pachydermatis, with Candida sp. isolated occasionally. Forty-five
per cent of the dogs proved positive for the presence of
yeast, which is the reason for including an antimycotic
drug in the test preparation. Clotrimazole has been
recommended for clinical application in cases of otitis
externa associated with M. pachydermatis.1618
Staphylococcus spp. was the most common bacterial
isolate, which is consistent with previous reports.16,29,3639
P. aeruginosa, Proteus spp. and E. coli have also been
frequently collected from diseased ears. In human
medicine, the use of fluoroquinolone antibiotic drops
has recently become a popular topical medication to
treat otorrhea owing to their excellent spectrum of
activity against most major pathogens including
P. aeruginosa and Staphylococcus spp.40 However, fluoroquinolone resistance is an acute safety concern both
in veterinary and human medicine. From the results
of a Vtoquinol epidemiological survey performed
between 1994 and 2001,14 no significant increase in
resistance to marbofloxacin was observed for major
zoonotic pathogenic strains such as S. intermedius,

305

S. aureus, P. aeruginosa and P. mirabilis.14 Indeed, it is

most probable that topically administered marbofloxacin is more effective against the pathogens found
because of the high local concentration achieved.6
Nevertheless, it is advisable to reserve products containing fluoroquinolones, such as marbofloxacin, for
individual treatment of clinical conditions that have
responded, or are expected to respond poorly to other
classes of antibiotic (especially P. aeruginosa), and certainly after a positive antibiogram susceptibility test. It
is unfortunate that, out of the 27 cases involving Pseudomonas spp. as a causative agent, only four could be
sampled again on D14. Pseudomonas spp. is known for
its ability to develop antibiotic resistance and it would
have been interesting to follow marbofloxacin susceptibility using these strains. However, development
of marbofloxacin resistance related to these bacteria is
being closely observed by Vtoquinol S.A. during its
European epidemiosurveillance programme, and there
has been no increase in resistance for P. aeruginosa.14
Two cases treated with MCD and 11 cases treated with
Surolan were failures after the 14 days of therapy.
Staphylococcus spp. and P. mirabilis were the main
causative agents involved; all of them proved to be
resistant to polymyxin B but susceptible to marbofloxacin. Although the risk of general increased bacterial resistance from the survey seems very small,
vigilance and a rational policy of antibiotic use by
veterinarian practitioners is required to prevent the
selection of resistant strains to marbofloxacin.
In conclusion, there was a trend for MCD to have a
better cure rate and a lower resistance risk than the
other treatment. This, combined with the benefits of a
need for less frequent dosing, a likelihood of encouraging greater owner compliance, and a lack of ototoxicity,
makes MCD a particularly safe and preferable option
for use when cases of otitis externa are complicated by
an underdiagnosed tympanic membrane perforation.

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307

Rsum Lefficacit et la tolrance dune suspension de marbofloxacine-clotrimazole-dexamethasone auriculaire (MCD) a t compare avec un traitement topique standard en utilisant un protocole de phase III dessai
clinique. 140 chiens prsentant une otite externe aige ou sub-aige, avec isolement de Staphylococcus, Pseudomonas, Enterobacteriaceae et Malassezia ont t inclus; un prlvement supplmentaire a t ralis en cas
dchec ou de rechute et pour les chiens (au jour 14) pour lesquels un Pseudomonas avait t isol linclusion.
Un groupe a reu MCD (10 gouttes dans chaque oreille atteinte) une fois par jour et un second groupe reu
Surolan (contenant de la polymyxine B, du miconazole et de la prednisolone) (5 gouttes par oreille atteinte) deux
fois par jour. Chaque groupe a reu le traitement pour 7 ou 14 jours en fonction de lvolution clinique J7. Lefficacit et la tolrance ont t valus J7, J14 et si ncessaire J28 pour les chiens traits pendant 14 jours. Ltude
a montr une quivalence pour les deux traitements en terme defficacit avec un taux de gurison de 58.3% pour
MCD et 41.2% pour Surolan. Les deux mdicaments ont t bien tolrs par les chiens, mais MCD tait
suprieur en terme de diminution de la douleur, diminution de la quantit de pus et dodeur, taux de rponse et
valutation de linvestigateur J14.
Resumen La eficacia y tolerabilidad a una suspension tica de marbofloxacina-clotrimazol-dexametasona
(MCD) se compar con un tratamiento tpico estndar, siguiendo un protocolo utilizado en fase III de pruebas
clnicas. En un total de 140 perros con signos clnicos de otitis externa aguda o subaguda, Staphylococcus, Pseudomonas, Enterobacteriaceae y Malassezia se aislaron de muestras tomadas al inicio para identificar el agente
causante; una muestra adicional se recogi en previsin de fallo o recidiva, y de perros (al dia 14) en los que Pseudomonas se aisl al inicio. Un grupo recibi MCD (10 gotas en cada odo afectado) una vez al da y un segundo
grupo recibi Surolan (combinado de polimixina B, miconazol y prednisolona) (5 gotas por odo afectado) dos
veces al da. Cada grupo fue tratado durante 7 o 14 das, dependiendo del resultado clnico en el da 7. La eficacia
y tolerabilidad se evaluaron en los das 7, 14 y, cuando fue necesario, en el da 28 en perros tratados durante 14
das. La prueba clnica demostr un resultado similar entre ambos tratamientos a efectos de eficacia, con un ndice
de curacin del 58.3% para MCD y del 41.2% para Surolan. Ambos medicamentos fueron bien tolerados en
los perros, pero MCD fue superior en trminos de control del dolor, reduccin del exudado purulento y mal olor,
ndice de respuesta y evaluacin por el investigador en el da 14.
Zusammenfassung Die Wirksamkeit und Vertrglichkeit einer Marbofloxacin-Clotrimazol-Dexamethason
otischen Suspension (MCD) wurde verglichen mit einer standardisierten topischen Behandlung mittels einem
Phase III klinischen Versuchsprotokol. Bei insgesamt 140 Hunden mit klinischen Symptomen von akuter oder
subakuter Otitis externa wurden Staphylococcus, Pseudomonas, Enterobacteriaceae und Malassezia von Proben
isoliert, die bei der Erstuntersuchung genommen wurden, um das urschliche Pathogen zu bestimmen; eine weitere Probe wurde genommen fr den Fall eines Misserfolgs oder Rckfalls, und von Hunden (am Tag 14), bei
denen Pseudomonas bei der Erstuntersuchung isoliert worden war. Eine Gruppe erhielt MCD (10 Tropfen fr
jedes betroffene Ohr) einmal tglich und einer zweiten Gruppe wurde Surolan (Inhaltsstoffe: Polymyxin B,
Miconazol und Prednisolon) zweimal tglich verabreicht (5 Tropfen fr jedes betroffene Ohr). Jede Gruppe
erhielt eine Behandlung fr 7 oder 14 Tage je nach dem klinischen Erfolg am Tag 7. Wirksamkeit und
Vertrglichkeit wurden an den Tagen 7, 14 und wenn notwendig bei Hunden, die fr 14 Tage behandelt wurden,
am Tag 28 beurteilt. Der Versuch zeigte eine Gleichwertigkeit beider Behandlungsmethoden im Bezug auf die
Wirksamkeit mit einer Heilungsrate von 58.3% fr MCD und 41.2% fr Surolan. Beide Arzneimittel wurden
von den Hunden gleich gut toleriert, aber MCD war besser im Bezug auf Schmerzlinderung, Verminderung von
Eitermenge und Geruch, Reaktionszeit und Beurteilung durch die Untersucher am Tag 14.

2005 European Society of Veterinary Dermatology, Veterinary Dermatology, 16, 299307