Long-term management of recurrent otitis externa in dogs using a two-phase protocol involving ciprofloxacin-clotrimazole-betamethasone and topical hydrocortisone aceponate

Abstract

Background

Recurrent otitis (RO) is characterized by inflammatory or infectious processes in dogs with allergic skin diseases, accompanied by recurrent secondary bacterial and fungal infections. Dogs underwent a combined therapeutic approach for RO, assessing the effect of long-term management during the Stabilization Phase (SP) using a suspension containing ciprofloxacin, clotrimazole, and betamethasone, followed by management in the Proactive Phase (PP) with topical hydrocortisone aceponate (HCA) administration. A total of 45 dogs were evaluated, totaling 90 ears. All animals had a clinical history of bilateral RO with an erythematous-ceruminous clinical presentation, as indicated by the anamnesis, clinical, cytological, and otoscopic evaluations, with three or more relapse episodes of otitis per year.

Results

The SP management reduced bacterial infections and led to an increase in yeast occurrence. There was a decrease in severe otitis cases, while the incidence of moderate scores-Otitis Index Score-3 (OTIS-3) (3 and 4) increased, indicating the persistence of RO with significant changes. In the PP, the topical HCA solution demonstrated efficacy, showing a marked reduction in cytology and clinical assessment over 90 days, with no signs of recurrence or otitis persistence throughout the remaining period. The PP, using HCA, promoted improvement in cytological and clinical outcomes, with most dogs showing no recurrence of otitis.

Conclusions

The likely favorable safety profile of HCA, its local anti-inflammatory effects, and its ability to avoid systemic side effects make it a promising therapeutic option for the long-term management of RO in dogs.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12917-025-05200-1.

Background

Recurrent otitis (RO) is characterized by inflammatory or infectious processes frequently associated with underlying hypersensitivity disorders [1]. It is commonly observed in dogs with allergic skin diseases and is often accompanied by recurrent secondary bacterial and fungal infections [2]. In dogs affected by atopic dermatitis or food hypersensitivity, RO represents a frequent and clinically challenging manifestation [3].

Although initial therapeutic interventions often yield temporary improvement, relapse is common, and infections tend to recur. Therefore, a systematic diagnostic and therapeutic approach is essential to identify and address the underlying cause rather than focusing solely on symptomatic management [3]. In this context, the routine use of antimicrobial agents—antibiotics and antifungals—for otitis externa associated with allergic conditions has been questioned [2]. Evidence suggests that effective clinical control can be achieved without the unnecessary use of these additional medications, thereby reducing antimicrobial exposure and potential resistance [2].

Current management strategies for allergic otitis are typically divided into two phases: an induction phase aimed at achieving clinical remission, followed by a long-term maintenance phase designed to prevent relapse (1). Long-term management using otological formulations of corticosteroids, including vehicles suitable for proactive or pulse therapy, has been shown to reduce inflammation and decrease recurrence rates, ultimately improving patient quality of life (2). In dogs with atopic dermatitis, a combination of antibiotics and topical corticosteroids has been proposed to optimize clinical outcomes and prevent secondary cutaneous lesions (4). Similarly, in humans with atopic dermatitis, proactive topical corticosteroid therapy has been associated with a 3–fivefold reduction in recurrence rates and superior clinical improvement compared to emollient therapy alone (5). These findings support the rationale for revisiting combined therapeutic strategies for RO in dogs.

Given the chronic and recurrent nature of RO, there is a need to investigate long-term, clinically applicable management protocols that integrate both induction and maintenance strategies. Thus, this study evaluated the effects of long-term stabilization phase (SP) management using a ciprofloxacin, clotrimazole, and betamethasone ear drop suspension, followed by a proactive phase (PP) employing topical hydrocortisone aceponate. This combined therapeutic protocol was designed to assess its effectiveness in controlling RO and reducing recurrence in dogs under routine clinical care.

Material and methods

Ethics

This study was approved by the Ethics Committee on the Use of Animals at the University of Brasília (protocol number 23106.107876/2022–17).

Inclusion criteria of animals and experimental design

The animals were recruited from private owners during routine clinical practice (Pet Especialidades – Brasília – DF – Brazil) during the years 2018 to 2023. The owners consented to the participation of their dogs by signing an consent form for the use of animals, which outlined the nature of the study, including its potential risks and benefits, in accordance with Brazilian legislation and institutional guidelines. The investigators were veterinarians working in general practice. The evaluations and treatments were conducted in a blinded manner—Randomized Controlled Clinical Trial. A total of 61 dogs of various breeds, ages, weights, and sexes were evaluated for the study.

The sample size calculation was performed using GPower software (version 3.1.9.7) [4], applying Fisher’s exact test for unequal proportions between two independent groups (Exact – Proportions: Inequality, two independent groups) [4]. The sample size calculation was performed using GPower software (version 3.1.9.7) [4], applying Fisher’s exact test for unequal proportions between two independent groups (Exact – Proportions: Inequality, two independent groups) [4]. Expected proportions of 0.7 and 0.3 were considered, with a Type I error (α) of 0.05 and statistical power (1 − β) of 0.80, resulting in a minimum required sample size of 29 individuals per group (total n = 58; actual power = 0.814). All animals included in the study were evaluated by a veterinary medical team with specialized training in dermatology [5, 6]. Inclusion and exclusion criteria were rigorously applied to minimize potential biases in the experiment [5]. In addition to anamnesis and clinical, cytological, and otoscopic evaluations, the animals also underwent hematological and biochemical analyses to avoid the inclusion of individuals with associated comorbidities.

Pathophysiological conditions related to atopic dermatitis were considered exclusion criteria based on physical examination findings [5]. Furthermore, the Canine Atopic Dermatitis Extent and Severity Index (CADESI-4) and the degree of pruritus, assessed using the Visual Analog Scale (VAS), were applied [6].

All animals had a clinical history of bilateral recurrent otitis externa (RO) with erythroceruminous clinical presentation, as indicated by anamnesis, clinical, cytological, and otoscopic evaluations, multiple otitis episodes over the years, including three or more relapse episodes of otitis per year [1]. Inclusion criteria also required ears with cytological analysis showing ≥ 5 Malassezia spp. yeasts per high-dry × 40 field and/or ≥ 25 cocci and/or bacilli bacteria per high-dry × 40 field [7], along with an Otitis Index Score-3 (OTIS-3) above three [8]. The presence of associated comorbidities (n = 2); clinical conditions compatible with individuals affected by atopic dermatitis (n = 13); application of the Canine Atopic Dermatitis Extent and Severity Index (CADESI-4) and assessment using the Visual Analog Scale (VAS), which allowed classification and exclusion of animals according to severity: mild (n = 1), moderate (n = 10), and severe (n = 2); clinical presentation and medical history not consistent with bilateral recurrent otitis externa (RO) (n = 1), particularly when the evaluated period did not meet the established criteria for classifying a case as bilateral recurrent otitis externa—i.e., not achieving the required number of multiple otitis episodes over the years. All animals receiving topic or systemic treatments were excluded from this study.

A total of 45 dogs met the inclusion criteria, accounting for 90 ears (Table 1, Fig. 1), while the remaining dogs were excluded from the study. The included dogs underwent two phases of therapeutic management: the Stabilization Phase (SP) and the Proactive Phase (PP). Before the ears treatment, all dogs underwent clinical examination with special attention to any systemic alterations or signs of atrophy in the skin and external ear surface.

Table 1.

Description of the experimental design (number of animals, breeds, age, weight) and characterization of the dosage regimen (drops/ear/frequency-times/week) adopted for the different animals in the Stabilization management Phase (SP) with Cortavance →, Virbac SA, Carros, France

Total number of animals	Breeds	Age (years)	Weight (kg)	Dose (pump sprays/ear)	Application frequency (times/week)
7	French Bulldog	3.7	11.9	2	two times/week
1	Chow Chow	7	20.7	2	two times/week
2	Cocker Spaniel	8.5	13.3	2	two times/week
1	Golden Retriever	4	36.6	2	two times/week
3	Lhasa Apso	5.3	8.1	2	two times/week
2	Labrador Retriever	6.5	34	2	two times/week
2	Maltese	5	5.2	2	two times/week
9	Pug	7.5	10.5	2	two times/week
2	Sharpei	4.5	25.8	2	two times/week
12	Shih Tzu	6.6	7	2	two times/week
1	Mixed Breed	10	8.8	2	two times/week
1	Yorkshire Terrier	9	5.8	2	two times/week
2	West Highland White Terrier	7	9.2	2	two times/week

Fig. 1.

Schematic representation of the experimental design, stabilization management phase and proactive management phase

Therapeutic management of recurrent otitis

Stabilization management phase (SP)

The selected dogs (n = 90 ears) received topical treatment with Cipro-otic →, Syntec, Brasil (ciprofloxacin 0.5 g/100 g, clotrimazole 1 g/100 g, and betamethasone 0.172 g/100 g), administered as five drops per ear for dogs weighing up to 15 kg, or ten drops per ear for dogs over 15 kg, every 12 h for 21 days, in accordance with the manufacturer's instructions. The therapeutic protocol was implemented at the following time points: days 0, 90, 180, and 270. Cytological examination and digital otoscopy were performed on all ears at days 0, 90, 180, 270, and 360. Medication administration was performed by the research team. The animals were evaluated at each time point through anamnesis, and clinical, cytological, and otoscopic examinations. Additionally, the presence of any abnormal local or systemic signs was assessed. Owners were instructed to report any adverse events.

Proactive management phase (PP)

All dogs (n = 45, 90 ears) initiated the Proactive Phase (PP) immediately following the final cytological and otoscopic evaluations on day 360, which marked the conclusion of the Stabilization Phase (SP). The data from this evaluation were also designated as the baseline (day 0) for the PP. During the PP, topical ear treatment was administered with hydrocortisone aceponate solution (Cortavance →, Virbac SA, Carros, France) at a dosage of 0.44 mL per ear, applied once daily, twice weekly (on Mondays and Thursdays), at a concentration of 0.058 mg/mL [2]. Cytological examinations and digital otoscopies were performed on days 0, 90, 180, 270, and 360, followed by topical treatment with hydrocortisone aceponate.

Cytological evaluation of ears

Samples were collected from the external ears using sterile swabs for cytological evaluation, spread onto microscope slides, and stained with Panoptic stain for semi-quantitative assessment of bacterial agents and yeast under brightfield microscopy with a 40 × high-power dry objective. The cytological examination for Malassezia spp. included counting 0–4 yeasts per high-power dry field (Objective 400x, HPF) (M1 +), 5–20 yeasts/HPF (M2 +), and more than 20 yeasts/HPF (M3 +). For semi-quantitative evaluation of bacteria (cocci and/or bacilli), the scoring was 0–24 cocci and/or bacilli/HPF (B1 +), 25–40 cocci and/or bacilli/HPF (B2 +), and more than 40 cocci and/or bacilli/HPF (B3 +) [7, 9].

Digital Otoscopy/1–3 Otitis Index Score (OTIS-3)

Digital otoscopy exams were conducted using a Welch Allyn Macroview device [10], assessing erythema, edema/swelling, erosion/ulceration, and exudate in a scale between 0 and 3 included in the clinical score system Otitis Index Score 3 (OTIS-3) [2]. This score ranged from 0–12, with a score of 0 to one observed in healthy ears and a score of 12 representing the most severe degree of otitis [2]. OTIS-3 ≥ 3 has been associated with otitis, failure in treatment, and otitis relapse in dogs [8].

Statistical methods

Cytological results and otoscopy scores (OTIS-3) were presented in relative and absolute terms from the Stabilization and Proactive management phases. The mean values of the 95% confidence intervals (CI) were calculated and presented for the data evaluated in Tables 3 and 4. The normal distribution was assessed using the Kolmogorov–Smirnov test, and comparisons of the frequency of cytological and otoscopy findings were made using Fisher's exact test (p ≤ 0.05) (GraphPad Software, Inc. Prism 9 for Windows. San Diego, CA: GraphPad Software, Inc.).

Table 3.

Mean values of the 95% confidence intervals (CI)- Lower and Upper—Cytological evaluations of the external ears of dogs—Stabilization Phase (SP) management and Proactive Phase (PP) management, (n = 90). Infectious agents: M – Malassezia spp. yeasts and B—bacilli bacteria. Intensity: 1 +, 2 +, and 3 +

Infec-ous agents	Lower (95% CI of mean)	Upper (95% CI of mean)
	SP	PP
M1 +	–1.18–13.98	0.23–10.56
M2 +	28.31–81.29	–26.44–61.64
M3 +	–0.05–25.25	–1.42–3.02
B1 +	2.33–10.87	–0.28–3.48
B2 +	4.90–14.30	–2.13–4.53
B3 +	0.71–4.48	–0.35–0.75

Table 4.

Mean values of the 95% confidence intervals (CI)—Lower and Upper dos scores—Otitis Index scores 3 (OTIS-3)—obtained through digital otoscopy of the external ears of dogs—Stabilization Phase (SP) management and Proactive Phase (PP) management. (n = 90)

OTIS-3	Lower 95% CI of mean	Upper 95% CI of mean
	SP	PP
0	0.00–0.00	15.85–92.15
1	–0.48–4.48	1.81–29.39
2	2.64–24.55	–0.41–9.61
3	28.53–47.07	–15.30–33.30
4	10.77–26.43	–8.96–21.37
5	0.426–15.97	–1.42–3.02
6	1.81–6.58	–1.42–3.02
7	–3.07–11.08	0.00–0.00
8	–3.24–7.64	0.00–0.00
9	–0.71–1.51	0.00–0.00

Results

Cytological evaluation

The cytological examination results (scores) during the Stabilization Phase (SP) indicated a significantly higher frequency of ears with M2 + compared to M1 + and M3 + (p < 0.05) (Table 2). The mean values of the 95% confidence intervals (lower and upper limits) were assessed and presented for the cytological evaluations of the external ears of dogs during the Stabilization Phase (SP) and the Proactive Phase (PP) (Table 3).

Table 2.

Frequency of cytological scores (%) of the external ears (n = 90) of dogs during the Stabilization Phase management (SP) and Proactive Phase management (PP). Sample collection days: 0, 90, 180, 270, and 360. Cytological scores. Infectious agents: M – Malassezia spp. yeasts, and B—bacilli bacteria. Intensity: 1 +, 2 +, and 3 +

Sample collection days: 0, 90, 180, 270, and 360. Cytological scores. Infectious agents: M – Malassezia spp. yeasts, and B - bacilli bacteria. Intensity: 1+, 2+, and 3+

The M2 + and M3 + scores showed significant variations between most evaluated time points (0, 90, 180, 270, and 360 days) (p < 0.05), and M2 + evidenced a marked frequency increase from the beginning to the end of SP (p < 0.05) (Table 2). Despite these variations, M2 + and M3 + scores consistently remained more frequent than M1 + in the affected ears throughout the study (p < 0.05). Similarly, B2 + was more frequent than B1 + and B3 + (p < 0.05), and B2 + showed a significant reduction compared from the beginning to the end of SP (p < 0.05) (Table 2).

The cytological assessment in the Proactive Phase (PP) (Table 2). Most ears showed no detectable yeast, or bacilli (p < 0.05) from 90 to 360-day time points, with a drastic reduction in Malassezia spp. yeasts and bacteria scores since 0-day (p < 0.05) (Table 2). From 90-day, only 3.3% to 12.1% of the ears exhibited M1 +, and 1.1% to 4.4% displayed B1 + (Table 2). The M3 +, B2 +, and B3 + scores were detected in 12.1% of ears in 0-day of PP management, but they were no longer observed throughout the study from the 90-day time point onward (Table 2).

Combined cytological scores of Malassezia spp. and bacteria represented 12.1% of affected ears, mainly before the SP therapeutic management (day 0) (Table 3). The M2 + and B2 + scores (p < 0.05) were more frequent during the SP compared to the PP across most analyzed time points (Fig. 2B and E), similar to what was observed for the M3 + score (Fig. 2C) in most of the study (p < 0.05). In contrast, the frequency of M1 + and B1 + cytological scores (Fig. 2A and D) did not show significant differences between the SP and PP for the majority of the study.

Fig. 2.

Cytological evaluations of the external ears of dogs - Stabilization Phase (SP) management and Proactive Phase (PP) management, (n=90). Times points: 0, 90, 180, 270 and 360 days. Asterisks indicate a statistically significant difference (p≤0.05), as determined by the application of Fisher's exact test. Infectious agents: M – Malassezia spp. yeasts and B - bacilli bacteria. Intensity: 1+, 2+, and 3+. A - Malassezia spp yeasts; Intensity 1+ (M1+). B - Malassezia spp yeasts; Intensity 2+ (M2+). C - Malassezia spp yeasts; Intensity 3+ (M3+). D - Bacilli bacteria; Intensity 1+ (B1+). E - Bacilli bacteria; Intensity 2+ (B2+). F - Bacilli bacteria; Intensity 3+ (B3+)

Digital otoscopy evaluation—1–3 Otitis Index Score (OTIS-3)

During the Stabilization Phase (SP), the evaluated ears exhibited OTIS-3scores ranging from 3 to 9 on day 0 (Fig. 3A-E) (Table 4). The highest scores gradually decreased in subsequent otoscopic assessments, ranging from 2 to 6 by day 360 (Fig. 3A-E). Scores of 3 (42.0%) and 4 (20.7%) were the most frequently observed during the SP (p < 0.05). In contrast, OTIS-3 scores of 0 (75.0%) and 1 (21.7%) were predominant throughout the Proactive Phase (PP) (p < 0.05) from the 90-day time point onward, showing a significant reduction from the initial day-0 evaluation (p < 0.05) (Fig. 4A-J) (Table 4). Only a few otoscopic evaluations revealed OTIS-3 between 2 and 4 (3.9%) during the PP (Fig. 3A-E) (Table 4).

Fig. 3.

Absolute values of the scores - Otitis Index scores 3 (OTIS-3) - obtained through digital otoscopy of the external ears of dogs - Stabilization Phase (SP) management and Proactive Phase (PP) management, (n=90). Times points: 0 (A), 90 (B), 180 (C), 270 (D) and 360 (E) days

Fig. 4.

Graphical representations of Otitis Index scores 3 (OTIS-3); A- score 0; B- score 1; C- score 2; D- score 3; E- score 4; F- score 5; G- score 6; H- score 7; I- score 8; J- score 9 of the external ears of dogs—Stabilization Phase (SP) management and Proactive Phase (PP) management, (n = 90). Time points: 0, 90, 180, 270, and 360 days. Significance index values (p) indicating statistical differences (p ≤ 0.05)—Fisher's exact test

When comparing OTIS-3 between the SP and PP, scores of 2 to 4 (80.9%) predominated during the SP (p < 0.05), and score 5 (9.1%) in most ears from 0 to 180 days (Fig. 4A-J) (Table 4). In contrast, scores of 0 and 1 were more frequent in the PP (96.7%) compared to SP (2.7%) from time point day-90 (p < 0.05) (Fig. 4A-J) (Table 4). There were few ears affected, with scores ranging from 6 to 9, mainly in the SP, with most of the differences observed on day 0 only (p < 0.05) (Fig. 4A-J).

Discussion

Recurrent otitis (RO) externa in dogs is a time-consuming, challenging, and often frustrating condition in small animal practice. ROs are frequently associated with allergic diseases, secondary complications, a guarded prognosis, and limited therapeutic options [1, 3]. In this study, the long-term management of RO in dogs was structured into a Stabilization Phase (SP) with antibiotics + glucocorticoid ear drop suspension to achieve clinical remission, followed by a Proactive Phase (PP) for maintenance with topical hydrocortisone aceponate (HCA) solution to prevent a recurrence, as previously suggested [1, 11, 12].

During the long-term management of the SP, bacterial infections were reduced through the use of a traditional ear drop suspension containing ciprofloxacin, clotrimazole, and betamethasone. However, an increase in cytological scores of Malassezia spp. yeasts was observed throughout the treatment period. These cytological findings were clinically supported by the OTIS-3 evaluation during the SP, which showed a reduction in more severe otitis scores but an increase in moderate scores (3 and 4) from the start to the end of the therapeutic management. Our findings indicate the persistence of recurrent otitis (RO), with notable changes in the severity and between bacterial and Malassezia spp. yeasts cytological scores during the SP.

Long-term otitis therapeutic management during the SP may have induced dysbiosis or a shift in the ear's microbiota, characterized by an increase in Malassezia spp. yeasts, a reduction in bacterial populations, and the persistence of recurrent otitis (RO). Malassezia spp. dysbiosis has been documented in dogs during flares of atopic dermatitis [13]. While healthy dogs typically exhibit a rich fungal microbiota, there is a loss of diversity with Malassezia spp. predominating in dogs with otitis externa [14]. Additionally, more virulent genotypes of Malassezia pachydermatis have been isolated from cases of otitis externa compared to healthy dog ears [15].

Reduced in vitro susceptibility to clotrimazole has been observed in Malassezia pachydermatis isolates from animals with chronic external otitis [16]. In dogs with clinical signs of acute or subacute otitis externa treated with a marbofloxacin-clotrimazole-dexamethasone otic suspension for 28 days, a moderate cure rate of 58.3% was reported [17]. Therefore, the long-term therapeutic protocol, alterations in the ear microbiota, increased virulence, and reduced susceptibility to clotrimazole likely contributed to the elevated cytological scores of Malassezia spp. yeasts and persistence of moderate OTIS-3 observed in dogs with RO at the end of the SP and the beginning of the PP in this study. Despite some improvements, these findings highlight a failure in the therapeutic management during the SP in controlling RO under these experimental conditions.

The proactive long-therm therapy (PP) with topical HCA solution administered to dogs with RO following SP resulted in a marked reduction in both cytological and clinical scores (OTIS-3) in most ears, achieving levels comparable to those considered for healthy animals by the 90-day time point when the treatment's effectiveness could be fully assessed. This improvement was sustained throughout the study period, with nearly all evaluated ears showing no recurrence or persistence of otitis. Similarly, as explored in this study, novel combined therapeutic strategies have been revisited and proposed for the management of recurrent otitis (RO) in dogs [1, 11, 12].

As new affirmative perspectives, the use of diagnostic tools to identify underlying conditions, broad-spectrum treatment of secondary infections, identification of additional predisposing factors, and reversal of chronic alterations is considered appropriate [1]. The recurrent use of HCA has been shown to assist in the prevention and control of relapses in atopic dogs with a history of recurrent otitis externa [11, 12]. Notably, topically administered HCA did not result in adverse effects in animals treated over prolonged periods [11]. Therefore, as a positive clinical implication, topical HCA use did not promote secondary microbial overgrowth or dysbiosis, supporting its preventive application in atopic dogs with recurrent otitis externa [18].

Other studies, such as a 42-day short-term survey involving dogs with erythemato-ceruminous otitis externa, demonstrated improved clinical outcomes by over 90% with the use of an HCA-containing ear spray solution alone, showing comparable results to the application of prednisolone acetate-polymyxin B-miconazole ear drop suspension [2]. Previously, applying a 0.05% solution of betamethasone dipropionate in human patients with external otitis achieved a cure rate of 97% [19]. Furthermore, in a rat model of experimentally induced external otitis, topical treatment with betamethasone dipropionate alone led to the most rapid improvement in ear canal condition compared to those receiving a combination of glucocorticoids and antibiotics [19].

The topical application of glucocorticoids, alone or in combination with other immunomodulatory drugs, has been proposed as an effective strategy for managing certain recurrent diseases. In humans with atopic dermatitis, topical corticosteroids have been shown to reduce recurrence rates by three to five times and improve clinical outcomes compared to the use of emollients alone [20]. In atopic dogs, a combined therapeutic approach involving oclacitinib and topical HCA has been suggested to enhance clinical outcomes and prevent the recurrence of skin lesions [21]. Furthermore, long-term proactive maintenance therapy with HCA spray in dogs with atopic dermatitis significantly prolonged the relapse-free period [22].

Building on previous studies involving the topical treatment of external otitis and atopic dermatitis in dogs using HCA [11, 12, 23, 24], as well as a long-term trial for managing canine atopic dermatitis [22], we implemented a one-year proactive management therapy (PP) following the SP phase for the control RO and prevention of relapse. Although adrenocorticotropic hormone stimulation tests and skin biopsies were not performed during SP and PP, the treatment was well tolerated, and none of the dogs displayed clinical signs of infection or cutaneous atrophy in the external ears or general skin. Additionally, no local or systemic glucocorticoid-related side effects were observed during weekly clinical evaluations or reported by owners throughout the study.

As a challenging perspective for the treatment of external otitis in dogs, cytology proved essential for selecting specific medications targeting the various causative agents. This approach often suggests the prescription of off-label or compounded medications to achieve better therapeutic outcomes [25]. In this context, HCA demonstrated safety, with no adverse effects, ease of application, and long-term efficacy. It did not induce side effects or physiological alterations, as supported by complete blood count, biochemical profile, and adrenocorticotropic hormone concentrations [12, 22, 23]. No cutaneous or systemic effects were observed, in contrast to conventional corticosteroids [21].

External otitis therapy is commonly administered topically. However, systemic treatment with oral prednisolone has been shown to reduce inflammation and hyperplasia of the ceruminous glands [26]. Considering emerging therapeutic perspectives, synthetic DNA-based immunotherapeutic agents have demonstrated significant potential for the treatment of allergic diseases, as they induce modifications in the immune response [27]. With various routes of administration—systemic or topical—these agents enable personalized treatment approaches, depending on the patient’s condition and the location of the inflammatory process [27].

The topical use of HCA has been shown to be well tolerated, without changes in ACTH-stimulation tests, biochemical and hematological parameters, or indications of cutaneous atrophy or secondary infections in dogs treated topically for up to 70 days [1, 23, 28]. A more recent study further supported these findings, demonstrating that long-term proactive maintenance therapy of canine atopic dermatitis with topical HCA for two consecutive days weekly, up to 260 days, was well tolerated [22]. Additionally, proactive treatment with topical mometasone furoate in atopic dogs without clinical signs of otitis for 28 days did not increase the risk of secondary microbial overgrowth [18].

Considering the promising results from this study, which demonstrated the long-term tolerability of treatment in dogs with RO, the topical application of HCA suggests a likely solution to avoid iatrogenic Cushing's syndrome and other adverse effects of glucocorticoids use, a frequent concern in situations like this. The localized anti-inflammatory action of topical HCA at the site of ears' inflammation possibly supported our results and prevented undesired systemic side effects. Moreover, previous studies have shown that the topical application of HCA in dogs with atopic dermatitis enhances skin barrier function, improves hydration and overall clinical condition [29].

HCA is a non-halogenated double-ester Class 3 corticosteroid (moderately potent) topical agent. It was developed mainly for topical use, offering medium to high anti-inflammatory efficacy with fewer side effects and low atrophogenicity [30, 31]. HCA, being an ester of C21-acetate and C17-propionate, effectively permeates the stratum corneum, achieving high dermo-epidermal concentrations while having a lower tendency to enter systemic circulation [31, 32]. In studies involving corticosteroid double esters such as HCA and prednicarbate, no significant reduction in skin thickness was observed in 24 healthy volunteers treated for over six weeks [33], similar to the findings of this study.

The well-tolerated profile and reduced adverse effects of double-ester corticosteroids, which require hydrolysis for activation, are likely due to biotransformation in the keratinocyte layer, where they are converted into inactive metabolites locally. This, combined with a selective impact on cytokine synthesis in the skin, may explain their effectiveness and safety in reducing inflammation without local and systemic undesired effects [30].

Additional limitations may be considered in this study, including the lack of thorough investigation into the potential development of microbial resistance, the absence of a placebo-controlled group, which further limits the evaluation of HCA efficacy, and the failure to monitor long-term recurrence beyond a one-year period. However, the rigorous inclusion and exclusion criteria for animal selection and the absence of observed systemic or local corticosteroid-related side effects in the dogs support the reliability and validity of the reported findings.

Conclusion

This study highlights the challenges in managing RO externa in dogs and underscores the potential of HCA as a long-term proactive therapy. While the initial SP reduced bacterial infections, it revealed a persistent issue with Malassezia spp. yeast overgrowth and moderate clinical scores. However, the subsequent PP with HCA led to significant improvements in cytological and clinical outcomes, with most dogs showing no recurrence of otitis. The likely favorable safety profile of HCA, local anti-inflammatory effects, and ability to avoid systemic side effects make it a promising therapeutic option for the long-term management of RO in dogs. Future studies, including more animals, evaluations of the systemic and local side effects of long-term HCA use, and thorough microbiological assessments of affected ears are necessary to conclusively establish the reliability of proactive long-term treatment of RO in dogs with topical HCA.

Abbreviations

RO

Recurrent Otitis

SP

Stabilization Phase

HCA

Hydrocortisone aceponate

PP

Proactive Phase

CI

Confidence Intervals

Authors’ contributions

Design: F.O.R., R.F., M.A.T., L.H.A.M., M.R.F.A., and A.L.F.M.; Acquisition of data: G.A.L., M.E.N.G., and L.R.S.C.; Analysis and interpretation of data: M.B.C., E.M.M.L., and A.R.C.B.V.; Preparation, drafting, and critical evaluation: M.B.C., E.M.M.L., R.F., A.R.C.B.V., and C.B.M.

Funding

Not applicable.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee on the Use of Animals at the University of Brasília (protocol number 23106.107876/2022–17). All procedures were performed in compliance with Brazil laws and institutional guidelines.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.