一种含氢化可的松醋丙酯的耳喷雾剂治疗红斑性耵聍性外耳炎的疗效 ...

王帆

Efficacy and safety of a hydrocortisone aceponate-containing ear spray solution in dogs with erythemato-ceruminous otitis externa: A randomised, multicentric, single-blinded, controlled trial

一种含氢化可的松醋丙酯的耳喷雾剂治疗红斑性耵聍性外耳炎的疗效和安全性：一项随机、多中心、单盲、对照试验

 

作者：Delphine Rigaut | Philippe Briantais | Pierre Jasmin | Alice Bidaud

 

翻译：叶精精

 

Abstract

Background: Erythemato-ceruminous otitis externa (ECOE) is frequently seen in dogs affected with an allergic skin disease, with recurrent secondary bacteria and yeast overgrowths (detected on cytological examination).

背景：红斑性耵聍性外耳炎（ECOE）常见于患有过敏性皮肤病的犬，伴有复发性继发性细菌和酵母菌过度增殖（可以在细胞学检查检测到）。

Objectives: The objective of the study was to compare the efficacy and safety of an ear spray containing only hydrocortisone aceponate glucocorticoid diester (HCA) to a control product (CTRL), an approved otic formulation containing prednisolone-miconazole-polymyxin combination, in dogs with ECOE.

目的：本研究的目的是比较仅含氢化可的松醋丙酯（HCA）的耳喷雾剂与对照产品（CTRL）在ECOE犬的有效性和安全性，CTRL是一种已批准的含有醋酸泼尼松龙-咪康唑-多粘菌素组合的耳药。

Animals: In total, 97 and 104 dogs with ECOE were respectively randomly assigned to the tested ear treatment product group (HCA) or the commercially available ear treatment control product group (CTRL).

动物：共97只和104只ECOE犬分别被随机分配到试验耳治疗产品组（HCA）或更常见的耳治疗对照产品组（CTRL）。

Materials and Methods: Dogs were treated for 7–14days, as needed. At Day (D)0, D7, D14, D28 and D42, Otitis Index Score-3, hearing test, pruritus and pain visual analogue scales, and cytological scores were graded. The overall response to treatment also was assessed.

材料和方法：根据需要对犬进行治疗7-14天。在第(D)0天、D7、D14、D28和D42天，对耳炎指数评分-3、听力测试、瘙痒和疼痛视觉模拟量表和细胞学评分进行评分。对治疗的总体反应也进行了评估。

Results: All clinical parameters decreased rapidly and in a similar way without any significant difference at any time between treatment groups. A goodto-excellent response to treatment was seen in >90% of dogs of both groups as early as D14. The treatment was considered safe in all dogs.

结果：所有临床参数均快速下降，无显著差异。早在D14，两组中>90%的对治疗反应良好。这种治疗被认为对所有的犬都是安全的。

Conclusions and Clinical Relevance: A 7- to 14-day ear topical application of HCA alone to dogs with ECOE accompanied with bacterial and/or fungal (yeast) overgrowth was safe and led to no statistical difference in improvement of clinical scores relative to the CTRL combination. Based on these results, it may be necessary to reconsider the routine use of antimicrobial drugs such as antibiotics and antifungals as a first-line treatment for ECOE that is likely to have been caused by an allergic reaction.

结论和临床相关性：单独应用HCA治疗伴有细菌和/或真菌（酵母菌）过度增殖的ECOE犬7-14天是安全的，与CTRL组相比，临床评分改善方面没有统计学差异。基于这些结果，可能有必要重新考虑常规使用抗菌药物，如抗生素和抗真菌药物，作为可能是由过敏反应引起的ECOE的一线治疗方法。

KEYWORDS

atopic dermatitis, atopy, dog, glucocorticoid, hydrocortisone aceponate, otitis

特应性皮肤病，特应性皮炎，犬，糖皮质激素，氢化可的松醋丙酯，耳炎

 

INTRODUCTION

引言

Otitis externa (OE) is a common problem that affects dogs, with various clinical presentation. Three studies, two prospective and one retrospective, have reported that erythemato-ceruminous OE (ECOE) was by far the most common phenotype of canine OE, as it was diagnosed in 75%, 79% and 85% of 752,844 and 82 dogs with OE, respectively.

外耳炎（OE）是一种犬常见的问题，有多种临床表现。两项前瞻性和一项回顾性的三项研究，报道了红斑性耵聍性OE（ECOE）是迄今为止犬OE最常见的表型，在752、844和82只OE犬中诊断率分别为75%、79%和85%。

 

In the retrospective case series where this information was clearly specified, it was found in 75% of dogs with ECOE not related to ear parasites, that an allergic dermatitis [including atopic dermatitis (AD), flea bite allergy and food allergy] was the most commonly identified underlying disease. The other two prospective studies reported that AD was the most common pre-existing disease diagnosed in dogs with OE.

在这些信息的回顾性病例系列中，明确指出在75%的犬ECOE与耳部寄生虫无关，过敏性皮肤病[包括特应性皮炎（AD）、跳蚤叮咬过敏和食物过敏]是最常见的潜在疾病。另外两项前瞻性研究报道，AD是OE犬中最常见的原发疾病。

 

The studies above allowed the comparison of ear cytological results with the phenotype of canine OE. In dogs with ECOE not related to parasites of the ears, the cytological examination of otic cerumen revealed Malassezia yeast in 79%–82% of cases and Staphylococcus bacteria in 50%–57% of cases. The microscopic detection of Malassezia alone (40% in two studies ) was common. A different study showed that an increasing excess of cerumen was associated with a higher probability of culture of Malassezia spp.

这些研究还比较了OE的临床表型与耳道分泌物细胞学。在与耳寄生虫无关的ECOE犬中，79%-82%的病例检出马拉色菌，50%-57%的病例检出葡萄球菌。在显微镜下仅检出马拉色菌是常见的（在两项研究中占40%）。另一项研究表明，耵聍的增加与马拉色菌培养增多相关。

 

One abstract supported the benefit of a commercial hydrocortisone aceptonate (HCA) solution in dogs with allergic OE. The HCA was applied in the ear canals of dogs with OE of allergic origin, once daily for 7–14days: both erythema and cytological scores were reduced significantly. A study on the treatment of AD skin lesions in humans showed that topical glucocorticoids alone improved the bacterial microbiota in lesional skin (mainly Staphylococcus aureus) to a level similar to that found in atopic yet nonlesional skin. However, that study did not examine the impact on fungal flora, and microbial overgrowth in dogs, especially in the ear canal, that may be of more pathophysiological significance and difficult to reduce with topical glucocorticoids alone.

一份摘要支持商业氢化可的松醋丙酯（HCA）溶液对过敏型OE犬的益处。将HCA应用于过敏性OE犬的耳道，每日1次，持续7-14天：皮肤异常发红和细胞学评分均显著降低。一项关于治疗人类AD皮肤疾病的研究表明，局部单独使用糖皮质激素可以改善病变皮肤中的细菌微生物群（主要是金黄色葡萄球菌），达到与特应性皮炎无皮肤病变时水平相似。然而，该研究并没有研究对真菌菌群和微生物过度增殖的影响，特别是在耳道中，这可能具有更多的病理生理意义，且很难仅用外用糖皮质激素来减少。

 

This study aimed to assess the effectiveness and safety of a corticosteroid ear spray solution for treating canine ECOE. The tested spray contained only one active ingredient, hydrocortisone aceponate (HCA at 0.584mg/mL) and did not include any specific antibiotic or antifungal components. The diester chemical form of HCA has particular pharmacodynamic properties that increase the efficacy/safety ratio.

本研究旨在评估一种皮质类固醇耳喷雾剂治疗犬ECOE的有效性和安全性。测试的喷雾剂只含有一种活性成分氢化可的松醋丙酯（HCA为0.584mg/mL），不包括任何特定的抗生素或抗真菌成分。HCA的二酯化学形式具有特殊的药效学特性，可以提高疗效/安全比。

 

The objective was to demonstrate that the tested product was not inferior to a commercial ear drop suspension used as a control product which contained a combination of corticosteroid (prednisolone acetate at 5mg/mL), antibiotic and antifungal active ingredients.

目的是证明测试产品不逊色于含皮质类固醇（醋酸泼尼松龙5mg/mL）、抗生素和抗真菌活性成分的复方商业滴耳剂。

 

MATERIALS AND METHODS

材料和方法

Ethics

伦理

In this multicentre study, which had been approved by an ethics committee (EU-ERC I 201906–09), all animals were recruited within the clientele of investigators' clinics in Spain (5 clinics), France (4 clinics) and Ireland (2 clinics). Investigators were veterinary surgeons working in general practice, they assessed efficacy and safety in a blinded manner.

这项多中心研究经过伦理委员会（EU-ERCI20190906-09）批准，所有动物都是在西班牙（5个诊所）、法国（4个诊所）和爱尔兰（2个诊所）的客户中招募的。研究人员是在全科诊所工作的兽医，他们以盲法评估了有效性和安全性。

 

Animals

动物

We enrolled dogs of any breed or sex, older than seven months, exhibiting clinical signs of ECOE with a minimum Otitis Index Score (OTIS)-3 score of 5 (of a maximum score of 12). Bacteria and/or yeast had to be easily visible on the cytological examination of a smear of the otic exudate on Day (D)0. Dogs had to be in good general health or with stable chronic conditions. When two ears were affected, both were treated, yet only the most severely affected (based on OTIS-3 score) was followed during this trial. Allergen-specific immunotherapy was permitted if used for more than a year; nonsteroidal anti-allergic drugs were allowed if used for longer than two months, provided that the treatment would remain unchanged and the clinical signs had been stable with these interventions.

我们登记了任何品种和性别，年龄超过7个月的犬，有ECOE的临床症状，最低耳炎指数评分（OTIS）-3分为5分（最高评分12分）。在(D)0天的细胞学检查中，必须容易可见细菌和/或酵母菌。犬的总体健康状况良好或有稳定的慢性疾病。当两只耳患病时，两只耳朵都接受了治疗，但在本试验中只跟踪了患病最严重的耳朵（基于OTIS-3评分）。如果使用一年以上，允许过敏原特异性免疫治疗；允许使用非甾体抗过敏药物超过两个月，前提是治疗保持不变，且临床症状稳定。

 

Pregnant or lactating bitches, dogs with suppurative OE (SOE), or with parasites in the ears or with OE caused by a foreign body, were excluded from enrolment. We likewise did not enrol dogs with a clinical suspicion, or evidence, of a ruptured tympanic membrane on careful otoscopic examination. Also eliminated from consideration were dogs with other diseases not controlled at enrolment, or those with a known allergy to any of the ingredients contained in the administered products. Finally, dogs that had been treated with topical or systemic antifungals, antibiotics, glucocorticoids or nonsteroidal anti-inflammatory drugs in the two weeks preceding potential enrolment and dogs treated previously with long-acting glucocorticoids (as defined by >1week of activity) within two months of potential enrolment also were excluded.

怀孕或哺乳期的母犬，患有化脓性OE（SOE），或耳朵内有寄生虫或由异物引起的OE的犬，被排除在登记之外。同样，我们也没有纳入那些耳镜检查中发现鼓膜破裂的病例。此外，患有其他疾病的犬，或那些已知对产品中所包含的任何成分过敏的犬也都被排除在外。最后，两周内接受局部或全身抗真菌，抗生素，糖皮质激素或非甾体抗炎药物和两个月内接受长效糖皮质激素（至少>1周有效）的犬也被排除在外。

 

Interventions

干预治疗

After clinical and otoscopic examinations, selected dogs were randomly allocated 1:1 to be treated with an HCA ear spray solution (Cortotic; Virbac) or with a prednisolone acetate-polymyxin B-miconazole ear drop suspension combination (CTRL; Surolan, Elanco Animal Health).

在临床和耳镜检查后，随机选择的犬1：1分配给HCA耳喷雾液或醋酸泼尼松龙-多粘菌素B-咪康唑滴耳悬浊液组合（CTRL）治疗。

 

For the first seven days, the HCA was applied in the external ear canal at 0.44mL (two pump sprays) once daily, while the CTRL was given as per the registered instructions for use, five drops twice daily in the external ear canal. On D7, if the OTIS-3 score was ≥4, the treatment was continued for another week until D14. Ear cleaning was performed in all dogs of both groups only once on D0 using Epiotic S.I.S (Virbac), just before the first treatment. Throughout the entire trial, to keep the primary investigator blinded to the nature of treatment, a different investigator was responsible for group allocation, first ear cleaning, drug dispensing to the owner and contact with clients regarding any drug-related concern.

前7天，每天使用0.44 mL（每天2泵喷剂）HCA，按照CTRL注册的使用说明给予，每天在外耳道滴5滴。在第7天，如果OTIS-3评分为≥4，则继续治疗一周，直到第D14天。在第一次治疗前，两组犬均使用耳漂进行一次耳朵清洁。在整个试验过程中，为了让主要研究者对治疗的性质一无所知，另一名研究者负责小组分配、第一次洗耳、向主人分配药物，以及任何与药物相关的客户沟通。

 

Efficacy outcomes

疗效结果

On D0, D7, D14±1, D28±2 and D42±2, the investigator performed a general physical evaluation and assigned an OTIS-3 score and a pain grade using a four-point Visual Analog Scale (0=‘no pain’ to 3=‘painful when the pinna is raised’). The owner also was asked to rate the pain and the pruritus using a VAS ranging from 0 to 10, once daily from D0 to D6, and then at each reevaluation visit. Finally, both investigators and owners provided a subjective overall assessment of the response to treatment (poor, moderate, good, excellent) at each visit from D7 to the end of the trial

在D0、D7、D14±1、D28±2和D42±2上，研究者进行了常规体格检查，并使用4点视觉模拟量表进行OTIS-3评分和疼痛评分（0=无疼痛到3=“牵拉耳朵时感到疼痛”）。主人还被要求使用从0到10的VAS对疼痛和瘙痒进行评分，从D0到D6每天一次，然后在每次回访中再评估。最后，研究人员和主人在从D7到试验结束的每次就诊中都对治疗的反应（差、中等、良好、优秀）进行了主观的总体评估。

 

On D28, we defined treatment success as an OTIS-3 score of ≤3. However, treatment failure was considered to be an OTIS-3 score of ≥4; this included cases of withdrawal of the dog before D28. Between D28 and D42, an otitis relapse was defined if the OTIS-3 score was >3 in any dog that had been a treatment success on D28.

在D28，我们认为OTIS-3评分≤3是成功的。OTIS-3评分≥4是失败的；这包括在D28之前退出的病例。在D28和D42之间，如果任何一只犬在D28的OTIS-3评分为>3，则定义为耳炎复发。

 

At each evaluation visit, and before ear cleaning at D0, an ear swab was taken and sent to a central laboratory for semiquantitative cytological evaluation. For each smear, five single fields of vision at ×400 magnification were examined. Each field of vision received a single scoring for bacteria and yeast based on the Budach and Mueller scoring (0–4+ scale). Then, the mean of the five single scorings was calculated and rounded to the nearest value on the 0–4+ scale. In addition, micro-organisms were cultured and identified: The identification of bacteria was carried out using a combination of matrix-assisted laser desorption ionisation–time-of-flight–mass spectrometry (MALDI-TOF-MS), biochemical testing (VITEK), rapid detection of cytochrome oxidase or catalase, or serological testing (e.g. Wellcolex). This procedure was repeated in case of treatment failure or OE relapse.

在每次评估就诊中，在D0时洗耳之前，取耳拭子并送往中心实验室进行半定量细胞学评估。对于每一块涂片，在400×放大下检查5个视野。每个视野根据Budach和穆勒评分（0-4+量表）对细菌和酵母菌进行单一评分。然后，计算5个单次评分的平均值，并在0-4+量表上四舍五入到最接近的值。此外，对微生物进行了培养和鉴定：采用基质辅助激光解吸电离-飞行时间质谱（MALDI-TOF-MS）、生化检测（VITEK）、细胞色素氧化酶或过氧化氢酶的快速检测或血清学检测（如韦尔科利克斯）进行细菌鉴定。在治疗失败或OE复发的病例中，重复此步骤。

 

The primary efficacy end-point was the change in OTIS-3 score from baseline to D28. Secondary efficacy outcome measures were changes from baseline of the following: OTIS-3 score on D7 and D14, each of the clinical signs of the OTIS-3 score at each visit, the semiquantitative cytological score, ear pain assessments by the investigator and ear pain and pruritus VAS assessments by the owner. The overall assessment of response to treatment, the percentage of recovery (OTIS-3 score≤3) at each visit and the relapse rate also were considered.

主要疗效终点是OTIS-3评分从基线到D28的变化。次要效果测量从基线的变化如下：D7和D14的OTIS-3评分，每次就诊时对应OTIS-3评分的临床症状，半定量细胞学评分，研究者对耳朵疼痛评分和主人对耳朵疼痛和瘙痒VAS评分。同时还考虑了对治疗反应的总体评估、每次就诊时的恢复百分比（OTIS-3评分≤3）和复发率。

 

Safety evaluation 

安全评价

A clap test, a subjective evaluation of the dog's hearing ability, was performed at each visit. The investigators clapped their hands in a location outside the dog's field of vision and the ability of the dog to turn its head towards the noise was observed. The results of this test were recorded either as positive or negative response.

每次就诊时都要进行拍手测试，即对犬的听力能力进行主观评估。调查人员在犬的视野外的一个地方鼓掌，并观察到犬的头部转向噪音的能力。该测试的结果被记录为阳性或阴性反应。

 

Haematological, serum biochemical and urine analyses were performed before treatment administration on D0, and at the end of the study. At each visit, investigators assessed the dogs for any abnormal systemic and local (i.e. ears) signs, and the owners were instructed to report any perceived adverse events.

在D0治疗给药前和研究结束时，分别进行血液学、血清生化和尿液分析。在每次就诊中，调查人员评估了犬的任何异常系统性和局部（即耳朵）症状，并提示主人报告任何感知到的不良事件。

 

An adverse event was defined as any observation in the animals that was unfavourable, unintended and occurred after the use of the veterinary product or investigational veterinary product, whether or not the event was considered to be product-related. Therefore, any observations made by the owner or investigator were reported from D0 until the end of the follow-up of the dog. The causality assessment of all adverse events was subsequently performed by the Virbac pharmacovigilance department following the ‘Guideline on procedures for competent authorities for pharmacovigilance information for veterinary medicinal products’ from the European Agency for the Evaluation of Medicinal Products.

不良事件定义为在使用兽医产品或发明了兽医产品后对动物进行不良、意外和治愈的任何观察，无论该事件是否被认为与产品相关。因此，主人或调查人员的任何观察从D0到犬的随访结束都被报告。因此，维克药物警戒部门按照欧洲药品评估局的“兽医药品药物警戒信息主管当局程序指南”进行了所有不良事件的因果关系评估。

 

Statisticsn.

统计学

The randomisation for dogs inclusion was performed by site of investigation and provided by an independent statistician. Dogs were included from November 2019 to September 2020 and the maximum percentage of the total dogs included in one clinic was 25%. Each individual dog was considered a separate experimental unit. Sample size calculation was based on a previous pilot study, and the noninferiority margin of 15% was selected, as used previously. A mixed model with repeated measures (MMRM) was generated for OTIS-3 percentage change from baseline values, and the least squares means difference between treatments with their 95% confidence intervals (CIs) were reported. Noninferiority was claimed if the lower bound of the difference between HCA and CTRL did not exceed −15% on D28, while all of the other time points were considered secondary. Analyses were conducted on both full analysis set (FAS) population (presented here), and per protocol (PP) population (which leads to the same conclusions). Changes from baseline owner-assessed ear pain and pruritus also were examined using a MMRM method, and we determined the difference in least-squares means between treatments at each time point. All other secondary efficacy outcomes were analysed using Cochran Mantel Haenszel stratified by site with ridit transformation, general association or row mean score statistics.

犬的随机分组由调查地点进行，并由一个独立的统计学家提供。2019年11月至2020年9月，犬被纳入研究，一家诊所纳入的犬总数的最大比例为25%。每只犬都被认为是一个单独的实验单元。样本量的计算是基于之前的试点研究，并选择了15%的非劣效界值，如前所述。建立了一个重复测量的混合模型（MMRM），计算OTIS-3与基线值的百分比变化，并报告了具有95%置信区间（ci）的处理之间的最小二乘均值差异。如果HCA和CTRL之间的差异下限不超过−15%，则认为是非劣效性，而其他所有时间点则认为是次要的。对完整分析集（FAS）人群（此处所述）和每个方案（PP）人群（得出相同的结论）进行了分析。我们还使用MMRM方法检查了与基线主人评估的耳朵疼痛和瘙痒之间的变化，并且我们确定了不同治疗之间的最小二乘均值的差异。所有其他次要疗效结果采用科克伦曼特尔汉恩泽尔分层，采用疗效比较转换、一般关联或行平均评分统计。

 

All analyses were performed using SAS software v9.4 (Cary, NC, USA), and the significance was reached at the p=0.05 two-sided level.

所有分析均采用SAS软件v9.4（Cary，NC，USA）进行，在p=0.05双侧水平上达到显著性。

 

RESULTS

结果

Animals

动物

In total, 201 dogs with ECOE were admitted to the study, 97 were assigned to the tested ear treatment product group (HCA), and 104 were assigned to the commercially available ear treatment control product group (CTRL).

共有201只ECOE犬被纳入研究，97只被分配到被试验的耳治疗产品组（HCA），104只被分配到市售的耳治疗对照产品组（CTRL）。

 

At the start of the study (D0), the two treatment groups were similar in terms of age, sex, body weight, breed and OTIS-3 scores (Table 1). The majority (71%) of the enrolled dogs were purebred, with seven breeds making up 31% of the total: Yorkshire terrier (7%), Golden or Labrador retriever (5%), West Highland white terrier (4%), English cocker spaniel (4%), German shepherd dog (3%), French bulldog (3%) and Dogue de Bordeaux (3%). Over 75% of dogs in both groups had bilateral ECOE.

在研究开始时（D0），两个治疗组在年龄、性别、体重、品种和OTIS-3评分方面表现相似（表1）。大多数（71%）是纯种犬，其中7个品种占总数的31%：约克夏犬（7%）、金毛犬或拉布拉多猎犬（5%）、西高地白㹴犬（4%）、英国可卡犬（4%）、德国牧羊犬（3%）、法国斗牛头犬（3%）和波尔多公犬（3%）。两组中超过75%的犬都患有双侧ECOE。

 

The majority of dogs with ECOE (88.6%) had yeast as the predominant micro-organisms identified on cytological examination at baseline (D0), while bacteria were present in 53.7% of dogs. Malassezia pachydermatis was the most common type of yeast isolated, representing 98.8% of yeast cultures. For bacteria, Staphylococcus pseudintermedius was identified in 32.3% of dogs, Pseudomonas spp. in 11.9%, Escherichia coli in 5.0% and Proteus mirabilis in 5.0%. The distribution of micro-organisms between the HCA and CTRL treatment groups was similar.

大多数ECOE犬（88.6%）在基线（D0）细胞学检查中以酵母菌为主要微生物，而53.7%的犬存在细菌。厚皮马拉色菌是最常见的酵母菌分离类型，占酵母菌培养物的98.8%。对于细菌，32.3%的犬鉴定出假中间葡萄球菌，假单胞菌占11.9%，大肠杆菌占5.0%，奇异变形杆菌占5.0%。HCA处理组和CTRL处理组之间的微生物分布相似。

 

In the HCA group, one dog was withdrawn from the study owing to an adverse event, one dog because of withdrawal of owner's consent, and two dogs were lost to follow-up; in the CTRL group, one dog was withdrawn from the study because of the administration of a forbidden treatment and five additional dogs were lost to follow-up. Thus, 93 dogs in the HCA group and 98 dogs in the CTRL group completed the study.

在HCA组中，一只犬因不良事件退出研究，一只犬主人不同意继续研究，两只犬失去随访；在CTRL组中，一只犬因禁止治疗而从研究中抽取，另外五只犬失去随访。因此，HCA组93只犬和CTRL组98只犬完成了研究。

 

Outcome

效果

OTIS-3 scores. After D7, 57.7% of dogs in the HCA group and 57.3% of dogs in the CTRL group required an additional week of treatment as they had not fully recovered (OTIS-3 still >3).

OTIS-3分数。D7后，HCA组57.7%的犬和CTRL组57.3%的犬需要额外一周的治疗，因为它们还没有完全恢复（OTIS-3仍然是>3）。

 

Mean OTIS-3 scores evolved favourably and in a similar way in both groups (Figure 1).

平均OTIS-3分数在两组中以相似的方式进化（图1）。

 

Percentages of reduction of mean OTIS-3 scores at each visit are detailed in Table S1. On D28, the noninferiority in the percentage reductions in OTIS-3 scores from baseline was established. The observed difference between HCA and CTRL was +2.74% and the lower bound of the 95% CI of that difference was −4.23% which was above the pre-defined noninferiority margin of −15%.

每次就诊时平均OTIS-3评分的下降百分比详见表S1。在第28天，建立了OTIS-3评分较基线下降百分比的非劣效性。HCA与CTRL之间的观察差异为+2.74%，该差异的95% CI的下限为−4.23%，高于预定义的−15%。

 

Similar favourable evolution of the proportion of treatment success at D28 and recovery at D7, D14 and D42 (i.e. dogs with an OTIS-3 score of ≤3) was recorded in both groups over time with no significant difference between groups at any visit (Figure 2).

随着时间的推移，两组在D28和D7和D14和D42（即OTIS-3评分为≤3的犬）的治疗成功比例相似，在任何就诊时组间没有显著差异（图2）。

 

Treatment failure was observed in six of 97 (6.2%) HCA-treated dogs and in nine of 104 (8.7%) CTRLtreated dogs. An otitis relapse (OTIS-3 score>3 after a treatment success on D28) was recorded in seven of 87 (8.0%) and four of 89 (4.5%) dogs from the HCA and CTRL groups, respectively.

97只接受HCA治疗的犬中有6只（6.2%）治疗失败，104只接受CTRL治疗的犬中有9只（8.7%）治疗失败。HCA和CTRL组的87只（8.0%）和89只（4.5%）治疗成功后出现耳炎复发（OTIS-3评分>3）。

 

TABLE 1 Study subject demographics.

表1：研究对象的统计学数据。

 

 

 

FIGURE 1 Evolution of Otitis Index Score (OTIS)-3 scores over time in both groups. Data presented are the means±SDs. Blue line, hydrocortisone aceponate (HCA) ear spray solution; orange dotted line, prednisolone acetate-polymyxin B-miconazole ear drop suspension combination (CTRL).

图1 两组患犬耳炎指数评分（OTIS）-3随时间的演变情况。所提供的数据是平均±SDs。蓝线，氢化可的松醋丙酯（HCA）耳喷；橙色虚线，醋酸泼尼松龙-多粘菌素B-咪康唑耳滴悬液组合（CTRL）。

 

 

FIGURE 2 Evolution of the percentages of recovery over time (percentage of dogs with an Otitis Index Score (OTIS)-3 score≤3). Blue columns, hydrocortisone aceponate (HCA) ear spray solution; orange columns, prednisolone acetate-polymyxin B-miconazole ear drop suspension combination (CTRL).

图2恢复的百分比随时间的演变（患有耳炎指数评分（OTIS）-3≤3的犬的百分比）。蓝色柱，氢化可的松醋丙酯（HCA）耳喷雾液；橙色柱，醋酸泼尼松龙-多粘菌素B-咪康唑耳滴悬液组合（CTRL）。

 

 

FIGURE 3 Evolution of owner-assessed pruritus scores over time (Visual Analog Scale from 0 to 10). Blue line, hydrocortisone aceponate (HCA) ear spray solution; orange dotted line, prednisolone acetate-polymyxin B-miconazole ear drop suspension combination (CTRL).

图3主人评估的瘙痒评分随时间推移的演变（视觉模拟量表从0到10）。蓝线，氢化可的松醋丙酯（HCA）耳喷雾液；橙色虚线，醋酸泼尼松龙-多粘菌素B-咪康唑耳滴悬液组合（CTRL）。

 

Pain scores. On D14, a complete relief of pain, assessed by the investigators (Figure S1), was obtained in 83.2% and 69.6% of the dogs from the HCA and CTRL groups, respectively. No pain was detected in 84.9% and 89.8% of dogs from the HCA and CTRL groups, respectively, at the end of the trial. There were no significant differences between groups at any of the re-evaluation visits.

疼痛评分。在第14天，根据研究人员的评估（图S1），在HCA组和CTRL组中分别有83.2%和69.6%的犬的疼痛完全缓解（图S1）。在试验结束时，HCA组和CTRL组中分别有84.9%和89.8%的犬未检测到疼痛。在任何一次重新评估访问中，各组间都没有显著差异。

 

The VAS pain score assessed by the owners (Figure S2) evolved in a similar manner to that graded by the investigators: as soon as D5, they were reduced by half in both groups. There were no significant differences in scores between groups on any of the rated days. Pruritus scores. Pruritus scores (Figure 3) were reduced likewise in both groups and there were no significant differences between scores of the two groups at any of the days evaluated.

患犬评估的VAS疼痛评分（图S2）的演变方式与研究人员的评分相似：第五天时，两组患犬都减少了一半。在任何评分天数，两组之间的得分都没有显著差异。瘙痒评分。两组患犬的瘙痒评分（图3）也同样降低，两组患犬的评分在任何一个被评估的天数内都没有显著差异。

 

Overall assessment of treatment response. A goodto-excellent treatment response was recorded by investigators and by owners (Figure 4) as soon as D7 in both groups and their percentages increased regularly up to the end of the study. There were no significant differences between groups.

对治疗反应的总体评估。根据主人和研究人员的评估，两组从第七天到结束，百分比定期增加，就记录了良好到极好的治疗反应（图4）。各组间无显著性差异。

 

Cytological scores

细胞学评分

Cytological subgroup analyses were performed on dogs with only yeast overgrowth, or with only bacteria overgrowth, or both on D0. These analyses were descriptive only, statistical comparisons were not relevant owing to the inadequate number of dogs in each subgroup. Further studies would be required on a larger number of dogs to specifically analyse the microbial outcome.

对D0当天，只有酵母菌过度增殖或只有细菌过度增殖或两者都过度增殖的犬进行分离培养。这些分析仅是描述性的，由于每个亚组的犬的数量不足，统计比较不相关。需要对更多的犬进行进一步的研究来专门分析微生物的结果。

 

On D0, 43 (45.3%) and 47 dogs (46.5%), respectively, in the HCA and CTRL groups, had both yeast and bacterial overgrowth and 43 (45.3%) and 45 dogs (44.6%), respectively, in the HCA and CTRL groups exhibited only yeast overgrowth. Only nine dogs from both groups (representing 9.5% and 8.9%, respectively, in the HCA and CTRL groups) had only bacterial overgrowth (Figure 5).

在D0上，HCA和CTRL组有43只（45.3%）和47只（46.5%）出现酵母菌和细菌过度增殖，HCA和CTRL组分别有43只（45.3%）和45只（44.6%）出现酵母菌过度增殖。两组中只有9只犬（在HCA组和CTRL组中分别占比9.5%和8.9%）只有细菌过度增殖（图5）。

 

Yeast cytological scores (Figure S3). When both yeast and bacterial overgrowth was recorded on D0, the mean yeast cytological scores decreased from 2.3 to 1.4 and 2.4 to 1.0 on D28, respectively, in the HCA and CTRL groups.

酵母菌细胞学评分（图S3)。当D0同时记录酵母菌和细菌过度增殖时，HCA和CTRL组的酵母菌平均细胞学评分分别从2.3下降到1.4，2.4下降到1.0。

 

When only yeast overgrowth was recorded on D0, the mean yeast cytological scores decreased from 2.6 to 1.2 and 2.6 to 1.7 on D28, respectively, in the HCA and CTRL groups

当D0组仅记录酵母菌过度增殖时，HCA组和CTRL组的酵母菌细胞学平均评分分别从2.6下降到1.2，2.6下降到1.7

 

When only bacterial overgrowth (nine dogs only in each group) was recorded on D0 (yeast score=0), yeast scores increased to 0.1 and 0.2 on D28, respectively, in the HCA and CTRL groups.

当在D0（酵母菌评分=0），只记录细菌过度增殖（每组只有9只犬）时，HCA和CTRL组的酵母菌评分在D28上分别增加到0.1和0.2。

 

Bacteria cytological scores (Figure S4). When both yeast and bacterial overgrowth was recorded on D0, the mean bacteria cytological scores decreased from 1.8 to 0.8 and 2.3 to 0.9 on D28, respectively, in the HCA and CTRL groups.

细菌细胞学评分（图S4)。当D0同时记录酵母菌和细菌过度增殖时，HCA和CTRL组的平均细菌细胞学评分分别从1.8下降到0.8和2.3下降到0.9。

 

When only bacterial overgrowth (nine dogs only in each group) was recorded on D0, the mean bacteria cytological scores decreased from 2.8 to 2.1 and 3.3 to 2.4 on D28, respectively, in the HCA and CTRL groups.

当D0组仅记录细菌过度增殖（每组9只犬）时，HCA组和CTRL组的平均细菌细胞学评分分别从2.8下降到2.1，3.3下降到2.4。

 

FIGURE 4 Evolution of the overall response to treatment assessed by investigators and owners. Blue columns, hydrocortisone aceponate (HCA) ear spray solution; orange columns, prednisolone acetate-polymyxin B-miconazole ear drop suspension combination (CTRL).

图4 由调查人员和主人评估的对治疗的总体反应。蓝色柱，氢化可的松醋丙酯（HCA）耳喷雾液；橙色柱，醋酸泼尼松龙-多粘菌素B-咪康唑耳滴悬液组合（CTRL）。

 

 

FIGURE 5 Percentages of dogs with bacteria and/or yeast in the smear of the otic exudate at Day 0.

图5 第0天耳部渗出物涂片中带有细菌和/或酵母菌的犬的百分比。

 

When only yeast overgrowth was recorded on D0 (bacteria score=0), bacteria scores increased to 0.4 on D28, in both groups

当D0仅记录有酵母菌过度增殖时（细菌评分=0），两组D28的细菌评分均增加到0.4

 

Safety

安全性

Overall, 16 dogs experienced 22 adverse events. 10 dogs (10.3%) from the HCA group experienced 14 adverse events (two digestive disorders, three anaemia, one elevated protein/creatinine ratio, two dermatitis and eczema, two otitis appearing in the nonaffected ear at D0, one conjunctivitis, one neoplasia, one trauma, one ataxia), while six (5.8%) from the CTRL group experienced eight adverse events (three digestive disorders, one dermatitis and eczema, one blepharitis, one mammary gland disorder, one lameness, one gynaecomastia). All adverse events were rated as not related to the ear treatments, except for one dog with head tilt in the HCA group, for which a relationship with the treatment could neither be confirmed nor excluded. In this case, the treatment was not stopped and the patient experienced a rapid, spontaneous and complete recovery without any additional medication.

总共有16只犬发生了22起不良事件。HCA组的10只犬（10.3%）经历了14例不良事件（两种消化疾病、3例贫血、1例蛋白质/肌酐比率升高、2只皮肤病和湿疹、2例D0未患病耳的耳炎、1例结膜炎、1例肿瘤、1次创伤、1例共济失调），CTRL组经历了8例不良事件（3例消化道疾病、1例皮肤病和湿疹、1例睑缘炎、1例乳腺疾病、1例跛行、1例共济失调）。所有不良事件均被评为与耳部治疗无关，除了HCA组有一只头倾斜的犬，其与治疗的关系既不能被证实也不能被排除。在这个病例中，治疗没有停止，患犬经历了快速、自发和完全的恢复，没有任何其他药物治疗。

 

At the end of the study, the subjective clap test did not lead to any suspicion of hearing loss.

在研究结束时，主观拍手测试没有导致任何听力损失。

 

No differences were observed between the two groups during the trial in terms of physical examination findings or blood parameters: All of which remained within the normal reference range.

在试验期间，两组患犬在体检结果和血液参数方面均无差异，均保持在正常参考范围内。

 

DISCUSSION

讨论

In this article, we report the results of a randomised, controlled, investigator-blinded trial in which dogs with ECOE were treated either with a commercial hydrocortisone aceponate spray (HCA) or a commercially available otic product (CTRL) containing a glucocorticoid (prednisolone), an antifungal (miconazole) and an antibiotic (polymyxin B).

在这篇文章中，我们报告了一个随机、对照、研究者盲法试验的结果犬ECOE治疗商业氢化可的松醋丙酯（HCA）或含有糖皮质激素（泼尼松龙）、一种抗真菌药物（咪康唑）和一种抗生素（多粘菌素B）的CTRL。

 

Even though micro-organisms (and most commonly Malassezia yeast) were found equally in most dogs before treatment, all clinical parameters evaluated (OTIS3, pain and pruritus VAS) improved without statistical difference between both treatment groups. The reduction in the clinical scores over time was associated with higher overall assessments of treatment response by both investigators and owners.

尽管大多数犬接受治疗前发现了微生物（最常见的是马拉色菌），但所有评估的临床参数（OTIS 3、疼痛和瘙痒VAS）均有所改善，两组治疗组之间没有统计学差异。随着时间的推移，临床评分的降低与研究人员和所有者对治疗反应的总体评估更高相关。

 

Observational cytological subgroup analyses, separating dogs on D0 with only yeast overgrowth, only bacterial overgrowth or both bacterial and yeast overgrowth, highlighted some interesting trends. Although a return to normal flora in individual dogs is difficult to define and was not attempted in this study, and while statistical significance was not attempted because of the numbers of cases, both products appeared to substantially reduce yeast overgrowth and bacterial overgrowth when associated with yeast overgrowth. There were even fewer dogs with bacterial overgrowth only (nine in each group) and the cytological reduction in bacterial overgrowth in this group was not as marked as the other groups. Evidence for microbial efficacy of treatment in those particular cases will require further study.

观察细胞学亚组分析，在D0犬只有酵母菌过度增殖，只有细菌过度增殖或细菌和酵母菌都过度增殖，突出了一些有趣的趋势。虽然在单只犬上恢复正常菌群很难定义，且在本研究中没有尝试定义这一内容，而且，由于病例数量没有统计学意义，但当与酵母菌过度增殖相关时，这两种产品似乎都显著降低了酵母菌过度增殖和细菌过度增殖。仅细菌过度增殖的犬甚至更少（每组9只），而且这一组的细菌过度增殖的细胞学减少没有其他组那么明显。这些特殊病例中微生物疗效的证据需要进一步研究。

 

Although the semiquantitative methodology of cytological assessment may have limited interpretation, bacteria and yeast seemed to reappear during treatment when they were not present at the start of treatment, suggesting a possible return to normal flora. To confirm these trends and findings, additional studies are needed to examine the changes in the ear canal microflora after treatment with various ear medications.

虽然细胞学评估的半定量方法可能解释有限，一开始没有的细菌和酵母菌似乎在治疗期间再次出现，这表明可能与恢复正常的菌群相关。为了证实这些趋势和发现，需要更多的研究来检查各种耳道药物治疗后耳道微生物菌群的变化。

 

An important observation of this trial is that, even though the ECOE was treated only for 7–14 days, the improvement of clinical parameters and the overall response to treatment was maintained up to at least D28 in both groups. Although larger studies are required, these results suggest that a glucocorticoid might not worsen existing ear dysbiosis or infection, a phenomenon that has been confirmed recently using high-throughput next-generation sequencing of the ear microbiota and mycobiota. Some of the recorded relapses may have been a consequence of rapid relapse of a new infection and others to an incomplete recovery. The identification of the microorganisms did not allow confirmation of the cause of these relapses.

该试验的一个重要观察结果是，尽管ECOE只治疗了7-14天，但在两组中，临床参数的改善和对治疗的总体反应均维持在至少D28。虽然还需要更大规模的研究，但这些结果表明糖皮质激素可能不会恶化现有的耳生态失调或感染，这一现象最近通过耳微生物群和真菌微生物群的高通量下一代测序得到证实。一些记录的复发可能是新感染快速复发的结果，其他可能是不完全恢复的结果。对这些微生物的鉴定并不能确认这些复发的原因。

 

It is noteworthy that such a positive outcome was reached with the sole use of the HCA diester glucocorticoid. It cannot be excluded that the vehicle of the HCA spray solution had some effects in this study; however, a major action is considered unlikely owing to its very high volatility. To further study this potential effect, a placebo-controlled clinical study of the tested product compared with the vehicle only in the treatment of canine OE should be performed.

值得注意的是，仅使用HCA氢化可的松醋丙酯就达到了这种积极的结果。不能排除HCA喷雾溶液的载体在本研究中有一定的影响；然而，由于其非常高的挥发性，人们认为不太可能产生重大作用。为了进一步研究这种潜在的影响，应该进行安慰剂对照的临床研究，并与该药物进行比较。

 

Our study on canine ECOE has raised similar questions to some of those in human AD, where treatment of lesions infected with staphylococci have been proposed to be treated without the use of antibiotics, although systematic reviews on the topic have failed to establish clear recommendations.

我们对犬类ECOE的研究提出了一些与人类ECOE类似的问题，治疗葡萄球菌感染的病变已经被建议不使用抗生素治疗，但对该主题的系统综述未能建立明确的建议。

 

The clinical benefit of HCA monotherapy is mirrored by its safety in dogs with intact tympanic membranes. In this trial, all adverse events seen were deemed not related to the treatment, except for a transient and selfresolving head tilt. Laboratory parameters likewise remained within the reference range.

HCA单药治疗的临床益处反映在其在鼓膜完整的犬中的安全性上。在这项试验中，所有看到的不良事件都被认为与治疗无关，除了一个短暂的和自限性的头倾斜。实验室参数同样保持在参考范围内。

 

CONCLUSIONS 

结论

The topical application of a commercial HCA diester glucocorticoid-containing ear spray solution for 7–14days to dogs with ECOE was safe and led to a comparable improvement to a commercially available antibiotic–antifungal–glucocorticoid formulation, controlling both the primary inflammation and associated microbial (bacterial and yeast) overgrowth.

局部应用商业HCA耳喷7-14天治疗犬ECOE是安全的，导致相当改进商用抗生素抗真菌糖皮质激素配方，控制主要炎症和相关微生物（细菌和酵母菌）过度增殖。

 

Even though further studies are required to confirm these findings, the results of this trial suggest that, in canine ECOE, even if microbial overgrowth is detected on cytological examination, the use of a commercial topical glucocorticoid spray without the addition of antimicrobials (antibiotic and antifungal) could be used as a first-line therapy. This is a positive and welcome observation in light of increasing frequencies of antimicrobial resistance in animal and human patients.

尽管需要进一步的研究来证实这些发现，这个试验的结果表明，在犬ECOE，即使微生物过度增殖，使用商业局部糖皮质激素喷雾没有添加抗微生物（抗生素和抗真菌）可以用作一线治疗。鉴于动物和人类患犬中抗生素耐药性频率的增加，这是一个积极和受欢迎的观察。

 

 

zrr2001

张蝶

喵喵可以用吗

王帆

张蝶 发表于 2024-7-14 12:10
喵喵可以用吗

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