耳部外部治疗-目前治疗选择、适应症和局限性（2016） ...

王帆

Topical ear treatment – options, indications and limitations of current therapy

耳部外部治疗-目前治疗选择、适应症和局限性

作者：S.Paterson

翻译：王帆

 

Topical otic products form an integral part of the overall management of otitis externa. With an ever increasing array of ear drops and cleaners to choose from, appropriate selection of therapy can be difficult. The investigation of all cases of otitis externa should consider primary and secondary causes and predisposing and perpetuating factors. This article considers topical therapy under these same broad headings and discusses, through literature review, the various properties of the components of the ear cleaning solutions and drops.

外用耳药产品是外耳炎整体治疗的一个必不可少的部分。随着越来越多的滴耳剂和洗耳液可供选择，选择合适的治疗方法可能会很困难。所有外耳炎病例的调查应考虑主原发和继发病因以及易感因素和持久因素。这篇文章在相同的大标题下考虑外部治疗，并通过文献回顾，讨论了洗耳液和滴耳剂的各种成分的特性。

 

INTRODUCTION

介绍

Whilst the management of otitis externa (OE) and otitis media (OM) involves more than just topical therapy, there is no doubt that unless appropriate topical ear cleaners and prescription ear drops are selected, ear disease will not resolve. Griffin has proposed a new classification of OE that divides the aetiology of the disease into primary and secondary causes (Tables 1 and 2 ) which are respectively diseases or infections that directly cause inflammation in the ear, and perpetuating or predisposing factors (Tables 3 and 4 ) which are agents or elements that contribute to ear disease . Based on this classification, the key steps in successful therapy of otitis are to diagnose and manage primary skin diseases affecting the ear, identify and treat secondary infections and then recognise any perpetuating or predisposing factors and manage them to prevent recurrence of disease. Rather than list and discuss all of the different available topical otic products this review will consider how topical therapy can best be used to manage each of these components of ear disease.

当管理外耳炎(OE)和中耳炎(OM)，外部治疗应用会更多，毫无疑问，除非选择适当的外用洗耳液和处方滴耳药，否则耳病将无法解决。Griffin提出了一种新的OE分类方法，将该病的病因分为原发病因和继发病因(表1和表2)，前者是直接导致耳部炎症的疾病，后者是导致耳部炎症的感染，以及易感因素或持久因素(表3和表4)，即使耳病加重的因素或事件。基于这种分类，成功治疗耳炎的关键步骤是诊断和管理耳病原发皮肤病，识别和治疗继发感染，然后识别所有持久或易感因素，并对其进行管理，以防止疾病复发。本文不涉及和讨论所有不同的外用耳部产品，而是考虑如何最好地使用外用治疗来管理耳部疾病的每个病因。

 

TOPICAL THERAPY TO MANAGE PRIMARY CAUSES OF OTITIS

外部治疗管理耳炎原发病因

The most important causes of OE are listed in Table 1 . Allergy is the most common of the primary triggers and can account for up to 75% of all cases. If otitis is part of more generalised allergic skin disease then management of the ear disease can often be achieved using systemic drugs or with allergen-specific immunotherapy. In some dogs, allergy only affects the ears, or affects the ears more severely than other areas. In other cases, systemic medication is inadequate in controlling allergic otitis and additional therapy is needed. In such situations topical drugs can be used as the sole source of therapy or can be used to supplement other modalities such as allergen-specific immunotherapy. Treatment of secondary infection is important and will be dealt with under the appropriate sections below but the allergic reaction itself is best treated with anti-inflammatory therapy.

表1列出了OE最重要的病因。过敏症是最常见的原发诱因，可占所有病例的75%。如果耳炎是全身性过敏性皮肤病的一部分，那么耳病的管理通常可以使用全身性药物或过敏原特异性免疫疗法来实现。在一些犬上，过敏症只导致耳部患病，或者耳部患病比其他部位更严重。在其他病例中，全身性药物治疗在控制过敏性耳炎是不够的，需要其他的治疗。在这种情况下，外用药物可作为单一治疗管理，或可用于其他方式的辅助治疗，如过敏原特异性免疫治疗。继发感染的治疗很重要，将在下文中讨论，但过敏反应本身最好的治疗是抗炎治疗。

 

Topical anti-inflammatory therapy

外用抗炎治疗

Topical products containing either glucocorticoids or tacrolimus have been described as useful forms of anti-inflammatory therapy in dogs and cats for both allergic and immune-mediated disease. Licensed veterinary ear products containing glucocorticoids range from potent anti-inflammatory agents such as mometasone, hydrocortisone aceponate, fluocinolone, dexamethasone and betamethasone to moderately potent drugs such as triamcinolone acetonide and prednisolone . Almost without exception these glucocorticoids are found as components of compound products that also contain an antibiotic and an antiyeast drug. Glucocorticoid-only drops tend to be human products used off-license for dogs and cats. An exception is fluocinolone acetonide combined with dimethyl sulfoxide (DMSO). DMSO has many potential effects, but in this preparation specifically acts as a drug delivery system to carry the corticosteroid into the skin and is particularly suited to treating hyperplastic ear conditions. In an attempt to use a veterinary corticosteroid-based product to treat allergic otitis, a recent study demonstrated that off-license use of a spray containing hydrocortisone aceponate, at a dose of three drops twice weekly, into atopic dogs’ ears, reduced the relapse rate of disease. Weak glucocorticoids such as 1% hydrocortisone are found in some countries as components of ear cleaning solutions where they are combined with other active ingredients such as Burow’s solution, acetic acid, boric acid, ketoconazole and ethylenediamine tetra-acetic acid tromethamine (EDTA-Tris). The choice of an appropriate corticosteroid preparation should be based on a variety of factors, including the potency of the glucocorticoid that is required for therapy, the potency and concentration of the glucocorticoid in the topical preparation, the base that the glucocorticoid is in and the potential for systemic absorption of the drug relative to the animal ’ s general health and the length of course that is needed. Two studies looking at the anti-inflammatory effects of glucocorticoids in otitis showed that topical prednisolone produced a significant reduction in ear thickness and erythema but that when compared to dexamethasone, prednisolone was less effective in reducing pain,production of exudate, and odour. Many different studies have shown that topical otic glucocorticoids can be absorbed systemically to affect both adrenal and hepatic function tests . The study design and clinical finding for each investigation are outlined in Table 5 . Findings in all studies in normal dogs showed that dexamethasone- and triamcinolone-based otic preparations cause suppression of the adrenocorticotropic hormone (ACTH) response, elevation in liver function tests and, for dexamethasone, suppression of thyroid function tests. Betamethasone appeared to produce fewer systemic affects than triamcinolone or dexamethasone . Only a single study has considered the systemic absorption of topical glucocorticoids in ears with OE. This study showed that no dogs showed signs of suppression of their ACTH response after 7 days of topical mometasone but that some dogs from the other treatment groups, betamethasone (9%), triamcinolone (17%) and dexamethasone (50%) did show suppression. The effect of the otic vehicle and glucocorticoid concentration on systemic absorption of glucocorticoid has also been assessed. This study describes a comparison of dexamethasone at two concentrations (0.1 and 0.01%) and in two different vehicles (propylene glycol and saline). After 2 weeks of twice-daily application of topical glucocorticoid all dogs receiving dexamethasone 0.01% in saline had normal ACTH stimulation tests and liver enzyme levels but 57% of dogs receiving the 0.1% solution in saline had signs of adrenal suppression and 66% of dogs receiving dexamethasone in propylene glycol showed signs of adrenal suppression, which, in some cases, was marked. The study elegantly demonstrated that adrenal suppression caused by otic dexamethasone is concentration- and possibly vehicle-dependent. Two studies investigating the effects of otic glucocorticoids on intradermal skin testing showed that 2 weeks of topical betamethasone or mometasone suppressed intradermal reactions in laboratory beagles and dogs with atopic otitis, respectively. However, a withdrawal period of only 7 days was found to be necessary for mometasone to allow recovery of intradermal reactivity. Tacrolimus is a macrolide lactone drug labelled for use in people with moderate to severe atopic dermatitis. Recently tacrolimus ointment has been found to be effective in treating refractory non-infectious otitis in people. There are limited reports of its use in dogs and cats. One report has shown when a sterile olive oil-based 0.1% tacrolimus suspension was used in the ears of atopic beagles without OE that it produced no signs of adverse local reactions, development of OE, change in otic cytology, vestibular dysfunction or hearing loss. Topical 0.1% tacrolimus has also been used successfully to treat proliferative necrotising otitis in three adult cats. 

含有糖皮质激素或他克莫司的外用产品，是犬和猫过敏症和免疫介导疾病抗炎治疗的有用形式。含有糖皮质激素的有许可的抗炎兽药耳部产品范围广泛，从莫莫米松、氢化可的松、氟轻松、地塞米松和倍他米松等强效抗炎药，到曲安奈德和泼尼松龙等中效药物。几乎毫无例外，这些糖皮质激素被作为复合产品的组成部分，也含有抗生素和抗酵母菌药物。只含糖皮质激素的滴剂往往是未经许可用于犬和猫的人医产品。一个例外是氟轻松联合二甲基亚砜(DMSO)。DMSO具有许多潜在的作用，但在这种制剂中，它特别充当药物载体，将皮质类固醇带入皮肤，特别适合治疗耳部增生性耳病。最近的一项研究表明，在尝试使用一种以兽医皮质类固醇为基础的产品来治疗过敏性耳炎时，标签外使用含有氢化可的松醋丙酯的喷雾，每周两次，每次三滴，滴入特应性皮炎患犬的耳部，可以降低疾病的复发率。弱效糖皮质激素，如1%氢化可的松，在一些国家被作为洗耳液的成份，与其他活性成分联合使用，如Burow溶液、乙酸、硼酸、酮康唑和乙二胺四乙酸三丁三胺(EDTA-Tris)。选择适当的皮质类固醇制剂基于多种因素，包括治疗所需的糖皮质激素的效力，外用制剂中糖皮质激素的效力和浓度，糖皮质激素所在的载体，以及药物的潜在性全身吸收，对于动物的整体健康状况的影响，和所需疗程。两项关于糖皮质激素在耳炎中的抗炎作用的研究表明，外用泼尼松龙产品能显著减少耳部皮肤厚度和发红，但与地塞米松相比，泼尼松龙在降低疼痛、减少分泌物和异味方面效果较差。许多不同的研究表明，外用糖皮质激素耳药可以全身吸收，影响肾上腺和肝功能测试。每项研究的研究设计和临床发现列于表5。对正常犬的所有研究结果表明，地塞米松和曲安奈德耳部制剂会抑制促肾上腺皮质激素(ACTH)反应，提高肝功能测试，对于地塞米松，会抑制甲状腺功能测试。倍他米松似乎比曲安奈德或地塞米松产生更少的全身影响。只有一项关于外用糖皮质激素在OE患耳中的全身性吸收研究。这项研究表明，外用莫米松7天后，没有犬表现出ACTH反应抑制的症状，但其他治疗组的一些犬，倍他米松(9%)，曲安奈德(17%)和地塞米松(50%)确实表现出抑制。也评估了耳药载体和糖皮质激素浓度对糖皮质激素全身吸收的影响。这项研究对比了地塞米松在两种浓度(0.1%和0.01%)和两种不同载体(丙二醇和生理盐水)。每天两次外用糖皮质激素2周后，所有外用0.01%地塞米松生理盐水的犬的ACTH刺激试验和肝酶水平正常，但57%外用0.1%地塞米松生理盐水的犬有肾上腺抑制的症状，66%外用地塞米松丙二醇的犬有肾上腺抑制的症状，在某些病例中症状明显。这项研究很好地证明了含地塞米松耳药引起的肾上腺抑制是浓度依赖性的，而且可能是载体依赖性的。两项关于糖皮质激素耳药对皮内测试的影响研究，结果表明，外用2周倍他米松或莫米松分别对实验比格犬和有特应性皮炎的耳炎患犬的皮内测试有抑制作用。但是，莫米松仅停药7天就能恢复皮内测试反应。他克莫司是一种大环内酯内酯类药物，人医中度至重度特应性皮炎患者的标签用药。最近发现他克莫司软膏可有效治疗人的难治性非感染性耳炎。关于它在犬和猫上使用的报道有限。一份报告显示，当无菌橄榄油为基质的0.1%他克莫司悬浮液用于没有OE的特应性皮炎比格犬的耳部时，它没有产生局部不良反应，OE没有进一步发展，耳分泌物细胞学没有变化，没有前庭功能障碍或听力损失的症状。外用0.1%他克莫司也已成功用于治疗三只成年猫的增生性坏死性耳炎。

 

Topical acaricidal drugs

外用杀螨药

A number of different liquid aural preparations are licensed for the topical treatment of Otodectes cynotis in dogs and cat. Most products contain a recognised acaracide but a number of non-acaricidal products have been shown to be effective. These three studies investigated the efficacy of two different oil-based ear drops to kill O. cynotis . One product contained miconazole, polymyxin and prednisolone and the other contained diethanolamine fusidate, framycetin, nystatin and prednisolone. Both products were found to be highly effective. The authors of the reports concluded that although some of the component of the ear drops may have unknown acaricidal activities it was more likely that it was the oil base that created an incompatible environment in the ear for mite survival. Acaricides in licensed veterinary ear drops include ivermectin, milbemycin, monosulfiram, permethrin, piperonyl butoxide, pyrethrins and rotenone. With the exception of the avermectins (ivermectin, milbemycin) these drugs have a limited residual action and require regular re-application for at least 10 days, to ensure that all ova have hatched and that the newly emerged larvae are exposed to the drug. Thiabendazole has been shown to be effective in eliminating O . cynotis in dogs when used at a dose of 50 mg per ear for 7 days and has been shown to be effective as therapy when combined with dexamethasone and neomycin . An auricular ointment containing 10 mg/g of permethrin was shown to be an effective treatment for O . cynotis in cats in two studies. In the second study, it was found to be superior, in its improvements of clinical signs of OE, to a selamectin spot-on preparation.Off-licence use of topical ivermectin , fipronil and pyriproxyfen have also been described. A 1% ivermectin solution diluted 1:9 with propylene glycol was administered daily for 21 days to 32 affected cats. A complete response to therapy without any adverse reactions was recorded. In another study involving 35 dogs and 14 cats a single otic application of two drops of 10% solution of fipronil was effective in controlling O . cynotis without any adverse effects. A third study used four drops of a 10% solution of pyriproxyfen to a single ear of eight affected cats. Although the product controlled the mites it failed to prevent re-infestation at day 60. Demodectic OE is an uncommon primary trigger for ear disease. There are few reports in the literature of topical treatment protocols. Some authors have suggested similar treatment regimens with ivermectin to those used for O. cynotis. Other authors have suggested a mixture of amitraz at a concentration of 0.13% or 0.5% in liquid paraffin or mineral oil, applied topically every 3 days.

许多不同的液体耳药产品被批准外用治疗犬猫的耳螨。大多数产品含有公认的杀螨剂，但一些非杀螨产品已被证明有效。有三项研究调查了两种不同的油基滴耳剂杀耳螨功效。一种产品含有咪康唑、多粘菌素和泼尼松龙，另一种产品含有二乙醇胺、新霉素、制霉菌素和泼尼松龙。两种产品都被发现非常有效。该报告的作者得出结论，虽然滴耳液的某些成分可能没有杀螨活性，但更有可能是油基在耳部中创造了一个不适合螨虫生存的环境。批准的兽医滴耳剂中的杀螨剂包括伊维菌素、米尔贝肟、单硫脲、氯菊酯、胡椒酰丁氧酯、除虫菊酯和鱼藤酮。除了阿维菌素(伊维菌素、米尔贝肟)外，这些药物的残留作用有限，需要至少10天定期再次使用，以确保所有卵都已孵化，新幼虫暴露在药物中。噻苯咪唑，当使用剂量为50毫克每耳，使用7天时，可有效清除犬耳螨，并且联合地塞米松和新霉素也已证明有效。两项研究已证明一种含10 mg/g氯菊酯的耳用软膏可有效治疗猫耳螨。在第二项研究中，发现在改善OE临床症状方面优于塞拉菌素滴剂。也描述了外用伊维菌素、非泼罗尼和吡丙醚的非标签使用。将1%伊维菌素溶液与丙二醇1:9稀释，每日一次连用21天治疗32只患猫。记录治疗完全有效，且无不良反应。在另一项研究35只犬和14只猫，单一耳部外用两滴10%非泼罗尼溶液，可以有效控制耳螨，且无任何不良反应。第三项研究，8只患猫单耳使用四滴10%的吡丙醚溶液。虽然该产品控制了螨虫，但未能防止第60天的再次复发。蠕形螨性OE是耳病的一个不常见的原发诱因。文献中很少有外部治疗方案的报道。一些作者建议用伊维菌素治疗，类似于耳螨治疗方案。其他作者建议将浓度为0.13%或0.5%的双甲脒混合在液体石蜡油或矿物油中，每3天外用一次。

 

TOPICAL THERAPY TO MANAGE SECONDARY CAUSES OF OTITIS

外部治疗管理耳炎继发病因

Infection is always secondary in cases of OE. Both bacterial and yeast infection can occur as a result of the inflammatory process created by the primary disease. Numerous papers have reported antibacterial and antiyeast activity of both ear cleaners and ear drops.

感染总是OE病例的继发病因。细菌感染和酵母菌感染都可能是原发疾病引起的炎症过程的结果。许多文章都报道了洗耳液和滴耳液的抗细菌和抗酵母菌活性。

 

Topical products with antiyeast activity

抗酵母菌外用产品

Licensed veterinary products with medicinal claims to treat Malassezia , the most important yeast found in cases of otitis, contain either polyenes, azoles or allylamines. Most of these antiyeast drugs are combined with a corticosteroid and an antibiotic to form compound ear drops. The exception is a few veterinary products that contain only clotrimazole (1%) or miconazole (1%). Nystatin is the principal polyene antifungal found in veterinary ear drops. It works by binding to sterols in the fungal cell membrane, leading to changes in permeability and fungal death due to osmotic destruction. Nystatin is available as a combination ear product in both Europe and America. In Europe it is combined with framycetin, prednisolone and fusidic acid, in America it is combined with triamcinolone acetonide, neomycin and thiostepton. Azole antifungal drugs disrupt the biosynthesis of the ergosterol in the fungal cell wall. Topical azoles are available in ear products as imidazoles (clotrimazole, miconazole, ketoconazole) or triazoles (itraconazole, posaconazole). All of the azoles have excellent in vitro activity against Malassezia species. Several studies which have used different methodologies have tried to establish the relative potency of the different azoles. One study suggested that itraconazole was the most potent followed by ketoconazole, miconazole and clotrimazole. However, another in vitro study suggested ketoconazole, itraconazole and terbinafine were equipotent. More recently a comparison of miconazole and clotrimazole suggested miconazole was the more potent. The triazole posaconazole was found to be more effective than three other antifungal drugs: miconazole, clotrimazole and nystatin when used to treat Malassezia infection in dogs. A study looking at a product combining marbofloxacin, clotrimazole and dexamethasone showed that although drops consisting of miconazole only treated the Malassezia as well as the combined drops, the dexamethasone-based product reduced signs of erythema, pruritus and wax production more effectively . Allylamines disrupt ergosterol biosynthesis and prevent fungal cell wall formation. Terbinafine is the most widely used product in this class and has recently become available as a long acting veterinary ear drop combined with betamethasone and florfenicol, licensed for once weekly aural application for two consecutive weeks per month. In America there is long-acting product containing florfenicol, terbinafine and mometasone which is licensed for once-monthly application. Many different antiseptic ear cleaners have been shown in vitro to have antiyeast activity. Several studies have looked at the in vitro activity of ear cleaning solutions against Malassezia pachydermatis. Whilst it is difficult to conclude the exact reason for the extent of in vitro activity of the ear cleaners tested because they varied widely in their ingredients, there are components of many of them with proven antiyeast activity. Ketoconazole as an azole has good activity against Malassezia reinforced by two ear cleaner studies. Parachlorometaxylenol (PCMX), a component of many ear cleaners, is also suggested to confer antiyeast activity. All of the cleaners in Mason ’ s study that contained PCMX had excellent or good anti- Malassezia activity. Isopropyl alcohol and propylene glycol may also provide antimicrobial benefits. Organic acids such as lactic acid, salicylic acid, acetic acid, boric acid, oleic acid and citric acid are ingredients in many of the cleaners showing good antiyeast activity. Of these acids, salicylic and boric acid have been shown to have good antiyeast activity. Chlorhexidine at a concentration of 2 to 4% is an antiseptic with good activity against Malassezia as demonstrated by several shampoo studies. However, the low concentration of chlorhexidine in ear cleaners (0.15%) may reduce its antiMalassezia action.

批准的兽用耳药产品都标明治疗马拉色菌，一种耳炎病例最常见的酵母菌，产品含有多烯、唑类或烯丙胺。这些抗酵母菌药物大多与皮质类固醇和抗生素联合，形成复方滴耳剂。此外，有少数兽医产品仅含有克霉唑(1%)或咪康唑(1%)。制霉菌素是兽医滴耳液中主要的多烯类抗真菌成分。它通过与真菌细胞膜上的甾醇结合，导致渗透性的变化，真菌因渗透破坏而死亡。制霉菌素在欧洲和美国都可作为一种复方耳药产品。在欧洲，它与新霉素b、泼尼松龙和夫西地酸联合使用，在美国，它与曲安奈德、新霉素和硫链丝菌素联合使用。唑类抗真菌药物破坏真菌细胞壁中麦角甾醇的生物合成。可用于耳部外用唑类产品，如咪唑类(克霉唑、咪康唑、酮康唑)或三唑类(伊曲康唑、泊沙康唑)。所有唑类化合物对马拉色菌均有较好的体外抑菌活性。使用不同方法的几项研究试图确定不同唑类的相对效力。一项研究表明伊曲康唑是最有效的，其次是酮康唑、咪康唑和克霉唑。然而，另一项体外研究表明酮康唑、伊曲康唑和特比萘芬是等效的。最近，一项咪康唑和克霉唑对比研究，表明咪康唑更有效。发现三唑类泊沙康唑在治疗犬马拉色菌感染时比其他三种抗真菌药物:咪康唑、克霉唑和制霉菌素更有效。一项研究观察了一种联合马波沙星、克霉唑和地塞米松的产品，结果表明，虽然耳药含有咪康唑只为治疗马拉色菌，但以地塞米松为基础的产品更有效地减少了皮肤发红、瘙痒和耳垢的产生。烯丙胺破坏麦角甾醇的生物合成，阻止真菌细胞壁的形成。特比萘芬是该类别中使用最广泛的产品，最近已成为一种与倍他米松和氟苯尼考联合使用的长效兽医滴耳剂，标签为每月连续两周，每周耳道外用一次。在美国，有一种含有氟苯尼考、特比萘芬和莫米松的长效产品，许标签每月使用一次。许多不同的抗菌洗耳液在体外已被证明具有抗酵母菌活性。几项关于洗耳液对厚皮马拉色耳炎的体外活性研究。虽然很难得出所测试的洗耳液体外活性程度的确切原因，因为它们的成分差异很大，但其中许多成分具有可证实的抗酵母菌活性。酮康唑作为一种抗马拉色菌的唑类药物，在两种洗耳液研究中得到证实。对氯间二甲苯酚(PCMX)，一种许多洗耳液都有的成分，也提示有抗酵母菌活性。梅森研究中所有含有PCMX的洗耳液都具有极好的抗马拉色菌活性。异丙醇和丙二醇也可提供抗菌作用。有机酸，如乳酸、水杨酸、乙酸、硼酸、油酸和柠檬酸，是许多洗耳液中显示出良好抑菌活性的成分。在这些酸中，水杨酸和硼酸已被证明具有良好的抗酵母菌活性。几项香波研究表明，浓度为2%至4%的氯己定是一种对马拉色菌具有良好活性的防腐剂。但氯己定在洗耳液中的低浓度(0.15%)可能会降低其抗马拉色菌的作用。

 

Topical antibiotic products

外用抗生素产品

There are numerous ear products containing antibiotics or disinfectants with antibacterial activity. The most common topical antibiotics are aminoglycosides (framycetin, gentamicin, neomycin); fluoroquinolones (ciprofloxacin, enrofloxacin, marbofloxacin, orbifloxacin); polymyxins (colistin sulphate, polymyxin B) fusidic acid, florfenicol and silver sulphadiazine.

有许多含抗生素或有抗细菌活性的消毒剂的耳用产品。最常见的外用抗生素是氨基糖苷类(新霉素b、庆大霉素、新霉素);氟喹诺酮类(环丙沙星、恩诺沙星、马波沙星、奥比沙星);多粘菌素(硫酸粘菌素，多粘菌素B)、夫西地酸、氟苯尼考和磺胺嘧啶银。

 

Fusidic acid

夫西地酸 

Fusidic acid is a narrow spectrum bacteriostatic antimicrobial. Its principal mode of action is as an anti-staphylococcal antibiotic and has been shown to be useful against methicillin-resistant strains of staphylococcus. It also has good activity against Corynebacterium species, which is now recognised as a significant aural pathogen and anaerobes. It is an excellent empirical first choice for staphylococcal infections and is found in a combination product with framycetin, prednisolone and nystatin in Europe.

夫西地酸是一种窄谱抑细菌抗菌剂。它的主要作用模式是作为一种抗葡萄球菌抗生素，已被证明对耐甲氧西林葡萄球菌菌株有用。它对棒状杆菌也有很好的活性，棒状杆菌现在被认为是一种重要的耳部病原体和厌氧菌。它是葡萄球菌感染的最佳经验首选，在欧洲被发现与新霉素b、泼尼松龙和制霉菌素的联合产品。

 

Aminoglycosides

氨基糖苷类

Aminoglycoside antibiotics are bactericidal and act on susceptible bacteria by binding to the 30s ribosomal subunit in the bacterial nucleus thereby inhibiting protein synthesis. Framycetin, neomycin and gentamicin are all found in licensed veterinary ear drops. Framycetin is a broad spectrum bactericidal drug with good activity against Staphylococcus species. It has been shown to be synergistic when used in vitro with fusidic acid. It also has good activity against many Gram-negative pathogens including Proteus species and some strains of Pseudomonas species. Framycetin is available in Europe as a combination product with fusidic acid, prednisolone and nystatin. Neomycin is the least potent of the veterinary aminoglycosides. It has good activity against Grampositive cocci but only very limited activity against Gram-negative bacteria. It is often recommended as a good first-line drug when cocci are found on otic cytology. Synergistic activity has been observed when EDTA-Tris plus neomycin were tested against Staphylococcus pseudintermedius , Proteus mirabilis , Pseudomonas aeruginosa and Escherichia coli. Neomycin is reported to be a common aural contact sensitizer in dogs, it is also recognised in humans as the most common topical antibiotic to cause contact allergy. The most recent of these publications showed that all neomycin-allergic patients are also allergic to framycetin and gentamicin. If the same is true in dogs, switching to another aminoglycoside is probably unwise if a reaction is seen to neomycin. Neomycin is found in four different topical products these are in combination with (1) hydrocortisone and polymyxin B; (2) triamcinolone acetonide, nystatin and thiostrepton; (3) isoflupredone, tetracaine hydrochloride and (4) dexamethasone with thiabendazole. Gentamicin has a good range of activity against both Grampositive and Gram-negative bacteria. Numerous clinical studies have shown activity against Staphylococcus species; as well as Corynebacterium species; Proteus species, E . coli and Pseudomonas species. A wide range of veterinary commercial products are available containing gentamicin combined with a corticosteroid and, usually, an antifungal drug. Combinations include with betamethasone; mometasone furoate and clotrimazole; betamethasone and clotrimazole and hydrocortisone aceponate and miconazole. Other aminoglycosides that have been used as extra-label products include amikacin and tobramycin. Amikacin and tobramycin should, in the opinion of the author, only be used when dictated by culture and sensitivity and only when other drugs are unsuitable. Amikacin has excellent activity against Gram-positive otic pathogens Staphylococcus species and Corynebacterium species. It also has excellent activity against Gram-negative organisms Pseudomonas species. Injectable formulations of amikacin can be used as an off licence product diluted to a concentration of 30 to 50 mg/ mL in sterile saline or EDTA-Tris. Synergistic activity has been observed when EDTA-Tris plus amikacin were tested against S. pseudintermedius , P. mirabilis , P. aeruginosa and E . coli. Tobramycin is available as ophthalmic drops for human therapy which can be used extra-label in the ears of dogs and cats. Injectable solutions may be mixed with sterile saline or EDTA-Tris to concentrations of 8 mg/mL for otic use. The longterm stability of tobramycin and amikacin solution made up for off-licence usage is unknown. Both antibiotics are potentially ototoxic.

氨基糖苷类抗生素具有杀细菌作用，通过与细菌核中的30s核糖体亚基结合，从而抑制蛋白质合成，对易感细菌起作用。在批准兽医滴耳液中都可以找到新霉素b、新霉素和庆大霉素。新霉素b是一种广谱杀细菌药物，对葡萄球菌具有良好的抗菌活性。在体外与夫西地酸使用时，已显示出增效作用。它对许多革兰氏阴性病原体，包括变形杆菌种和一些假单胞菌种也有良好的活性。在欧洲可与夫西地酸、泼尼松龙和制霉菌素联合使用。新霉素是药效最低的兽药氨基糖苷类药物。它对革兰氏阳性球菌有良好的活性，但对革兰氏阴性细菌的活性非常有限。当在细胞学上发现球菌时，它通常被推荐作为一个良好的一线药物。EDTA-Tris加新霉素对假中间型葡萄球菌、奇异变形杆菌、铜绿假单胞菌和大肠杆菌均有增效作用。据报道，新霉素是一种常见的犬耳道接触性刺激药，在人医上也是最常见引起接触性过敏的外用抗生素。这些最新的出版物表明，所有新霉素过敏的患者也对新霉素b和庆大霉素过敏。如果在犬上也是如此，如果对新霉素有反应，那么改用另一种氨基糖苷类可能是不明智的。有四种不同的外用产品中含有新霉素，(1)与氢化可的松和多粘菌素B联用;(2)与曲安奈德、制霉菌素、硫代链球菌素联用;(3)异氟哌酮、盐酸丁卡因联用，(4)与地塞米松、噻苯咪唑联用。庆大霉素对革兰氏阳性和革兰氏阴性细菌都有良好的活性范围。大量的临床研究显示对葡萄球菌的活性;以及棒状杆菌属、变形杆菌属、大肠杆菌和假单胞菌属有效。大量兽医商业化产品含有庆大霉素与皮质类固醇联用，通常也有抗真菌药物。联合用药包括倍他米松、糠酸莫米松、克霉唑;倍他米松和克霉唑，以及氢化可的松和咪康唑。其他被用作标签外产品的氨基糖苷类药物包括阿米卡星和妥布霉素。笔者认为，阿米卡星和妥布霉素应根据细菌培养和药敏试验，在其他药物不宜使用的情况下使用。阿米卡星对革兰氏阳性病原菌葡萄球菌和棒状杆菌有良好的抑制作用。对革兰氏阴性菌假单胞菌也有良好的活性。阿米卡星注射液可作为非批准产品在无菌生理盐水或EDTA-Tris中稀释至30-50mg/mL。EDTA-Tris加阿米卡星对假中间葡萄球菌、奇异假单胞菌、铜绿假单胞菌和大肠杆菌均有增效作用。妥布霉素是人医治疗用眼药水，可标签外用于犬猫耳道。其注射液可与无菌生理盐水或EDTA-Tris混合，浓度为8 mg/mL，用于耳部使用。妥布霉素和阿米卡星溶液的长期稳定性是未知的。这两种抗生素都有潜在的耳毒性。

 

Fluoroquinolones

氟喹诺酮

Fluoroquinolones are bactericidal antibiotics that act by inhibiting bacterial DNA gyrase which prevents DNA supercoiling and synthesis. They have good activity against a wide range of bacteria, especially Gram-negative bacilli and Gram-positive rods (including Staphylococcus species but with variable activity against Streptococcus species. Ciprofloxacin, enrofloxacin, marbofloxacin and orbifloxacin have all been shown to have good activity against Pseudomonas species in cases of OE which has led to the widespread use of these drugs as second or third line antibiotics in chronic, recurrent otitis especially in cases associated with P . aeruginosa . Unfortunately as a result of this increased usage, resistance of Pseudomonas species to fluoroquinolones is being reported more commonly and some studies have shown very high rates of resistance, in one case up to 87.5% of Pseudomonas species strains were not susceptible to enrofloxacin. Enrofloxacin is available as a veterinary ear drop combined with silver sulphadiazine in the USA. Marbofloxacin and orbifloxacin are widely available as otic drops. In some countries they are only obtainable under limited licence to restrict their usage. Veterinary products are available containing marbofloxacin combined with dexamethasone and clotrimazole and orbifloxacin combined with posaconazole and mometasone. Off-licence use of injectable fluoroquinolones mixed with sterile saline or EDTA-Tris have been employed where licensed veterinary products are not available or where they are deemed unsafe due to damage to the tympanic membrane (see section on otitis media). Injectable 2% enrofloxacin diluted 1:6 in water has been recommended. Other dilutions include a 1:3 dilution of 2% enrofloxacin or 1% marbofloxacin mixed with EDTA-Tris. A study investigating the stability of 0.9% enrofloxacin made up in different solutions, showed it had good chemical stability and antibacterial activity for 28 days made up in (1) sterile water; (2) EDTA-Tris ear cleaner (with and without 0.15% chlorhexidine); (3) 0.1% salicylic acid and 0.1% parachlorometaxlenol (with either 2.5% lactic acid or 0.5% EDTA).When ciprofloxacin is prescribed it is generally as extra-label usage of a human ophthalmic solution.

氟喹诺酮类抗生素是通过抑制细菌DNA旋回酶来抑制DNA超盘绕和合成的杀菌抗生素。它们对许多细菌具有良好的活性，特别是革兰氏阴性菌和革兰氏阳性杆状菌(包括葡萄球菌，但对链球菌具有不同的活性)。环丙沙星、恩诺沙星、马波沙星和奥比沙星都被证明对OE病例中的假单胞菌具有良好的活性，这导致这些药物被广泛用作慢性复发性耳炎的二线或三线抗生素，特别是与铜绿假单胞菌相关的病例。不幸的是，由于这种使用的增加，假单胞菌对氟喹诺酮类药物的耐药性越来越普遍，一些研究显示了非常高的耐药率，在一个案例中，高达87.5%的假单胞菌菌株对恩诺沙星不敏感。在美国，恩诺沙星可作为兽医滴耳剂与磺胺嘧啶银联合使用。马波沙星和奥比沙星作为耳滴药剂被广泛使用。在一些国家，只有在有限的许可下才能获得它们，以限制它们的使用。兽药中含有马波沙星联合地塞米松和克霉唑,奥比沙星联合泊沙康唑和莫米松。氟喹诺酮注射液与无菌生理盐水或EDTA-Tris混合标签外使用，适用于没有可用的批准的兽医产品或由于鼓膜损伤而被认为不安全的情况下(见中耳炎部分)。推荐2%恩诺沙星注射液与水1:6稀释。其他稀释剂包括2%恩诺沙星或1%马波沙星与EDTA-Tris1:3稀释混合。研究了0.9%恩诺沙星在不同溶液中的稳定性，表明其在(1)无菌水中(2) EDTA-Tris洗耳液(含或不含0.15%氯己定);(3) 0.1%水杨酸和0.1%对氯间二甲苯酚(或与2.5%乳酸或与0.5% EDTA)，具有持续28天的良好的化学稳定性和抗细菌活性。当使用环丙沙星时，通常是人医眼药的标签外使用。;

 

Polymyxins

多粘菌素

Polymyxin B and colistin sulphate are polypeptide antibiotics that exert bactericidal effects by increasing permeability of the bacterial cell membrane via chelation of membrane phospholipid components leading to osmotic damage. Polymyxins have excellent activity against most Gram-negative bacilli. They appear to be less effective against Gram-positive bacteria unless combined with miconazole . Polymyxin B is widely available as a veterinary preparation combined with prednisolone and miconazole. Several veterinary publications have considered this product: an early Australian study demonstrated that it was superior to two different neomycin-corticosteroid preparations when relapse rates were considered for cases of otitis. More recent reports have shown that there is marked synergy of the two products for Gram-negative infection with E . coli and Pseudomonas species and although there was no demonstrable synergy the combination product also had good activity against methicillin-resistant Staphylococcus species. A marbofloxacin, dexamethasone, clotrimazole veterinary preparation has been shown to be equivalent in its antibacterial and antiyeast activity to a polymyxin, miconazole, prednisolone product but superior in regard to pain relief and decrease in pus quantity and smell. These benefits may be attributed to the dexamethasone, a more potent corticosteroid in the comparative product. Colistin sulphate is not available as a veterinary preparation but extra-label use of human otic products is advocated by some clinicians .

多粘菌素B和硫酸粘菌素是多肽抗生素，通过螯合膜磷脂成分增加细菌细胞膜的渗透性，导致渗透损伤，从而发挥杀细菌作用。多粘菌素对大多数革兰氏阴性杆菌具有良好的活性。除非与咪康唑联合使用，否则它们对革兰氏阳性细菌的效果较差。多粘菌素B被广泛用于与泼尼松龙和咪康唑联合的兽药制剂。一些兽医出版物已经考虑了这种产品:一项早期的澳大利亚研究表明，当考虑到耳炎病例的复发率时，它优于两种不同的新霉素皮质类固醇制剂。最近的报告显示，这两种产品对革兰氏阴性菌感染有显著的协同作用。虽然没有明显的协同作用，但组合产品对耐甲氧西林葡萄球菌也有良好的活性。马波沙星、地塞米松、克霉唑兽医制剂在抗细菌和抗酵母菌活性方面与多粘菌素、咪康唑、泼尼松龙产品相当，但在镇痛和减少脓汁量和气味方面优于后者。这些好处可能归因于地塞米松，在对比产品中是更有效的皮质类固醇。硫酸粘菌素不能作为兽医制剂，但一些临床医生提倡在标签外使用人医耳药产品。

 

Silver sulphadiazine

磺胺嘧啶银

Silver exerts its antibacterial effects via impairment of DNA replication and bacterial cell wall damage, leading to osmotic change. The spectrum of activity of silver sulphadiazine includes many of the pathogens associated with otitis including methicillin-resistant strains of Staphylococci and Pseudomonas species. A veterinary product containing 1% silver sulphadiazine with 0.5% enrofloxacin is available in the USA. Where silver sulphadiazine is not available as proprietary veterinary products 1% silver sulphadiazine cream can be diluted in EDTA-Tris. A recent study has shown that EDTA-Tris potentiates the activity of silver sulphadiazine against resistant strains of P. aeruginosa. A further study has shown that even if the cream is diluted 1 in 100 it will still exceed the MIC for P . aeruginosa when applied to the ear canal.

银通过破坏DNA复制和细菌细胞壁而发挥抗细菌作用，从而导致渗透变化。磺胺嘧啶银的活性谱包括许多与耳炎相关的病原体，包括耐甲氧西林葡萄球菌和假单胞菌种。在美国可以买到含有1%磺胺嘧啶银和0.5%恩诺沙星的兽药。如果没有兽药专用产品磺胺二嗪银，1%磺胺二嗪银乳膏可用EDTA-Tris稀释。最近的一项研究表明，EDTA-Tris增强了磺胺嘧啶银对铜绿假单胞菌耐药菌株的活性。一项进一步的研究表明，即使乳霜被稀释为1/100，它仍然会超过铜绿假单胞菌的MIC值。应用于耳道的铜绿假单胞菌。

 

Florfenicol

氟苯尼考

Florfenicol is a bacteriostatic antibiotic that works by inhibiting protein synthesis. Its spectrum of activity is similar to chloramphenicol. It has been shown to have good activity against Gram-positive bacteria Staphylococcus species and Gram-negative bacteria Proteus species and Enterococcus species. It has very limited activity against Pseudomonas species. A retrospective study looking at the susceptibility of Corynebacterium species to a range of different antibiotics showed chloramphenicol had excellent activity against Corynebacterium species. It can be assumed that florfenicol will have similar efficacy. Florfenicol is available in two different long acting topical otic products. In one it is combined with betamethasone and terbinafine to be applied once a week for two consecutive weeks each month; in the other it is combined with terbinafine and mometasone for once monthly application.

氟苯尼考是一种抑细菌抗生素，通过抑制蛋白质合成起作用。它的活性谱与氯霉素相似。已证明对革兰氏阳性细菌葡萄球菌和革兰氏阴性细菌变形杆菌和肠球菌有良好的活性。它对假单胞菌的活性非常有限。一项关于棒状杆菌物种对一系列不同抗生素敏感性的回顾性研究显示氯霉素对棒状杆菌物种具有极好的活性。可以认为氟苯尼考具有类似的疗效。氟苯尼考有两种不同的长效外用耳科产品。一种是与倍他米松和特比萘芬联合使用，每周一次，每月连续两周;另一种是联合特比萘芬和莫米松，每月一次。

 

Other antibiotics

其他抗生素

Ticarcillin has been described as a useful therapy for OE complicated by P. aeruginosa. The protocol described by Nuttall in his paper suggests that a 6-g vial of ticarcillin is mixed with 12 mL of sterile diluent. This may be divided into 2 mL aliquots and frozen. The vials can be thawed and mixed with 40 mL of sterile saline which can be then frozen in 10 mL amounts to be thawed and used as needed. The stability and efficacy of the ticarcillin used in this way was investigated in a further study. This work indicated that storage of the ticarcillin stock solution at −20°C does not compromise efficacy for at least 12 months. In addition, the ticarcillin diluted in carrier vehicle Methopt remained stable for 28 days when stored at 4 or 24°C. Although ticarcillin is a useful drug for the therapy of multiply-resistant bacterial isolates its use should be reserved for cases where sensitivity has been undertaken and no other drug is deemed suitable. It should also be used with care if the ear drum is ruptured. Ticarcillin is unavailable in commercial products in America.

替卡西林被认为是治疗OE合并铜绿假单胞菌的有效方法。纳托尔在他的论文中描述的方案表明，6克小瓶替卡西林与12毫升无菌稀释剂混合。这可以分成2毫升等份并冷冻。小瓶可以解冻，并与40毫升无菌生理盐水混合，然后可以冷冻10毫升，以便解冻和根据需要使用。进一步研究了这种方法所使用的替卡西林的稳定性和有效性。这项工作表明，在−20°C储存替卡西林原液至少12个月不会影响疗效。此外，用Methopt载体稀释的替卡西林在4°C或24°C下保存可稳定28天。虽然替卡西林是治疗多重耐药细菌分离株的有用药物，但应保留用于已发生敏感性且认为没有其他药物适合的病例。如果鼓膜破裂，也应小心使用。替卡西林在美国没有商业产品。

 

Topical ear cleaners with antibacterial activity

有抗细菌活性的外用洗耳液

Many different ear cleaning solutions have been shown to have antibacterial activity. Antimicrobial activity of topical products may be due to the active ingredients or in some cases it is thought it may be due to the pH of the solution. One study suggested that ear cleaning solutions with a low pH were likely to have good antimicrobial properties. However, a more recent study identified an ear cleaning solution with a pH of 2.8 which had no antibacterial activity against Pseudomonas species suggesting that the acidity of a solution is not as important as once thought. Isopropyl alcohol (IPA) is known to have excellent antibacterial properties, is a common component of many ear cleaning solutions and is thought to contribute to the antibacterial properties of some products. Monosaccharides in ear cleaning solutions act as microbial adhesion-blocking carbohydrates and have been shown to have antibacterial effects. PCMX is a broad spectrum phenolic germicide that has antibacterial properties. Although it may have activity against Gram-positive organisms , it has an inconsistent activity in vitro against Pseudomonas species. Organic acids such as acetic acid, citric acid, lactic acid and salicylic acid are ingredients in many of the cleaners showing good antibacterial activity. Acetic acid is known to have good activity against a wide range of bacteria. One study showed that 2 and 3% acetic acid used to treat otitis in humans had good in vitro activity against P. aeruginosa , Staphylococcus aureus and P. mirabilis . The anti-pseudomonas effect of acetic acid has been demonstrated in several subsequent veterinary studies. Citric acid has also been shown to have anti-pseudomonas activity . Lactic acid is known to disrupt the outer cell membrane of Gram-negative bacteria. Several studies have shown that lactic acid, which is typically used at a concentration of 2.5% in veterinary ear cleaners, has excellent in vitro activity against not only Pseudomonas species but also Gram-positive bacteria such as Staphylococcus species . Burow ’ s solution, an aqueous solution of aluminium acetate, is topical product used commonly in the USA. It is found as a component of ear cleaning solutions. Although it has not been the subject of any veterinary trials it has been recognised for some time as an effective antibacterial therapy against Pseudomonas species, Staphylococcus species and Proteus species for otitis in people. Chlorhexidine at a concentration of 0.15% is found in several European and American ear cleaning products and has good activity against both Gram-positive and Gram-negative organisms. Hypochlorous acid is a broad spectrum antimicrobial with a rapid action against Gram-positive and Gram-negative bacteria. Its bactericidal action relies on disruption of the bacterial cell membrane. EDTA-Tris is an antimicrobial product that works by blocking the Pseudomonas efflux pump; disrupting the cell walls of Gramnegative bacteria by chelating metalions and rendering the bacterial cell more porous and by inhibiting the effects of ulcerating bacterial enzymes. Despite its mode of action, recent in vitro studies have shown that EDTA-Tris has, at best, weak antibacterial properties but has excellent antibioticand antiseptic-potentiating activity. Used as an otic flush 15 to 20 minutes prior to the addition of other antimicrobials it has strong potentiating effects with chlorhexidine, silver sulphadiazine , aminoglycosides , fluoroquinolones and chloramphenicol . One study investigating an ear-rinse containing EDTA-Tris and benzoyl alcohol showed that this product had good in vitro antibacterial activity, although the authors suggested that it may be the alcohol rather than the EDTA-Tris that produced the antibacterial effects.

许多不同的洗耳液已被证明具有抗细菌活性。外用产品的抗菌活性可能是由于有效成分，在某些病例中，人们认为这可能是由于溶液的pH值。一项研究表明，低pH值的洗耳液可能具有良好的抗菌性能。然而，最近的一项研究发现，一种pH值为2.8的洗耳液对假单胞菌没有抗菌活性，这表明溶液的酸度并不像以前认为的那么重要。众所周知，异丙醇(IPA)具有出色的抗菌性能，是许多洗耳液的常见成分，被认为有助于某些产品的抗菌性能。洗耳液中的单糖作为阻止微生物粘附的碳水化合物，已被证明具有抗菌作用。PCMX是一种广谱酚类杀菌剂，具有抗菌性能。虽然它可能对革兰氏阳性菌有活性，但在体外对假单胞菌的活性不一致。乙酸、柠檬酸、乳酸和水杨酸等有机酸是许多清洁剂中显示出良好抗菌活性的成分。已知醋酸对各种细菌都有良好的活性。一项研究表明，用于治疗人耳炎的2%和3%醋酸对铜绿假单胞菌、金黄色葡萄球菌和奇异假单胞菌具有良好的体外活性。醋酸的抗假单胞菌作用已在随后的几项兽医研究中得到证实。柠檬酸也被证明具有抗假单胞菌活性。已知乳酸会破坏革兰氏阴性菌的外细胞膜。一些研究表明，通常用于兽医洗耳液的浓度为2.5%的乳酸，不仅对假单胞菌有活性，而且对葡萄球菌等革兰氏阳性细菌具有优异的体外活性。布洛溶液是一种醋酸铝水溶液，是美国常用的外用产品。它被发现是洗耳液的组成部分。虽然它还没有成为任何兽医试验的对象，但一段时间以来，它已经被认为是一种有效的抗菌疗法，可以对抗假单胞菌、葡萄球菌和变形杆菌，用于治疗人们的耳炎。在几种欧美洗耳液产品中发现了浓度为0.15%的氯己定，对革兰氏阳性和革兰氏阴性微生物都有良好的活性。次氯酸是一种广谱抗菌剂，对革兰氏阳性和革兰氏阴性细菌有快速作用。它的杀菌作用依赖于破坏细菌细胞膜。EDTA-Tris是一种抗菌产品，通过阻断假单胞菌外排泵起作用;通过螯合金属离子破坏革兰氏阴性菌的细胞壁，使细菌细胞更多孔，并抑制溃疡细菌酶的作用。尽管它的作用模式，最近的体外研究表明，EDTA-Tris充其量具有较弱的抗菌性能，但具有极好的抗生素和增强抗菌活性。在添加其他抗菌剂前15至20分钟用于冲洗，它与氯己定、磺胺嘧啶银、氨基糖苷类、氟喹诺酮类和氯霉素有很强的增强作用。一项调查含EDTA-Tris和苯甲酰醇的洗耳液的研究表明，该产品具有良好的体外抗菌活性，尽管作者认为可能是酒精而不是EDTA-Tris产生了抗菌作用。

 

Other topical products with antibacterial activity

其他抗细菌活性的外用产品

Natural topical products have been investigated as potential alternatives to antibiotics. Most of the studies are in vitro and are not blinded or placebo-controlled, so all data should be interpreted with this knowledge. Propolis or bee glue is a resinous substance that honey bees collect from tree buds and sap flowers. One study found it had antimicrobial properties against both coagulase positive Staphylococcus species and M. pachydermatis from cases of OE. Beta-thujaplicin is an organic compound found in the essential oil of the Pacific red cedar tree. An in vitro investigation showed that it had activity against M. pachydermatis. An ethyl acetate leaf extract of Harungana madagascariensis Lam. Ex Poir (Hypericaceae) was assessed for activity against otic pathogens M. pachydermatis , S. pseudintermedius and Pseudomonas species. Results from the study suggest that the extract could be used as an antimicrobial preparation for OE. A recent open pilot study considered the efficacy of medical grade honey (MGH) in the management of canine OE. In vitro assays of the biocidal activity of MGH showed activity against all bacterial isolates including methicillin-resistant S. pseudintermedius . Dogs with otitis were prescribed MGH (1.0 mL daily per ear) until cure was achieved for a maximum of 21 days. Dogs were scored on the basis of swelling, erosion/ulceration and exudate to a maximum of 12. Dogs were deemed to be clinically cured if the score was reduced to 3 or below. On this basis 90% of dogs achieved a clinical cure at 21 days, although not all of them were cytologically normal at this time.

天然外用产品已被研究为抗生素的潜在替代品。大多数研究都是在体外进行的，不是盲法或安慰剂对照，所以所有的数据都应该在此基础上进行解释。蜂胶或蜂胶是一种树脂物质是蜜蜂从树芽和花液中采集的。一项研究发现，它对凝固酶阳性葡萄球菌和厚皮马拉色酵母菌导致的OE都有抗菌性能。β-欧侧柏酚是在太平洋红雪松树的精油中发现的一种有机化合物。体外实验表明，其对厚皮马拉色菌皮肤病有一定的抑制作用。评估了一种马达加斯加海参叶乙酸乙酯提取物Ex Poir(金丝桃科)对耳部病原菌厚皮马拉色酵母菌、假中间型葡萄球菌和假单胞菌的活性。研究结果表明，该提取物可作为OE的抗菌制剂。最近一项开放的试点研究考虑了医用级蜂蜜(MGH)在犬OE管理中的功效。体外生物杀灭活性测定显示MGH对包括耐甲氧西林假中间型葡萄球菌在内的所有细菌菌株都有活性。耳炎患犬使用MGH(每只耳部每天1.0 mL)，直到治愈，时间最多21天。根据肿胀、糜烂/溃疡和分泌物对犬进行评分，评分最高为12分。如果得分降至3分或以下，则认为犬已被临床治愈。在此基础上，90%的犬在21天内实现了临床治愈，但此时并非所有犬的细胞学检查都正常。

 

TOPICAL THERAPY TO MANAGE PREDISPOSING FACTORS

外部治疗管理易感因素

Although predisposing factors do not cause otitis they need to be managed to promote resolution of disease and prevent recurrence of the problem. Conformation and environmental factors are some of the most important predisposing factors, together with inappropriate treatment choices. Although many of the veterinary ear cleaners have excellent antibacterial and antiyeast activity, their ability to effective clean and dry the ear is often overlooked. Hairy ear canals, stenotic ear canals and dogs with pendulous ears need to have their ears cleaned effectively. Where animals with predisposing conformational problems such as these have primary triggers such as allergy causing inflammation within the ear canal, the prudent use of antibacterial ear flushes can help reduce the risk of secondary infection. Effective ear cleaning is also important in to remove wax to allow penetration of other drugs and to be able to assess the integrity of the tympanic membrane.

虽然易感因素不会引起耳炎，但需要管理以促进疾病的解决和防止问题的复发。结构和环境因素是一些最重要的易感因素，还有不适当的治疗选择。虽然许多兽医用的洗耳液具有出色的抗菌和抗酵母菌活性，但它们有效清洁和干燥耳部的能力往往被忽视。耳道有毛、耳道狭窄、耳道下垂的犬需要有效清洁耳道。对于有结构易感问题的动物，其原发诱因是过敏症导致耳道炎症反应，谨慎使用抗菌耳冲洗液有助于降低继发感染的风险。有效的洗耳液对于清除耳垢以允许其他药物渗透以及能够评估鼓膜的完整性也很重要。

 

Ceruminolytic ear cleaners

洗耳液耵聍溶解剂

The ability to effective clean ears to remove wax is an important part of the treatment and then ongoing maintenance therapy for otitis. True ceruminolytics ear cleaners disrupt the integrity of cerumen by inducing lysis of the squames. They emulsify debris breaking it up and keep it in solution. Diocytl sodium sulphosuccinate (DOSS), calcium sulphosuccinate, urea or carbamide peroxide are potent ceruminolytics. Urea and carbamide peroxide are foaming agents that release oxygen in situ to help break up debris. There are numerous American and European ear cleaners that contain these ingredients. Ceruminosolvent ear cleaners are organic oils and solvents that soften and loosen cerumen. Examples of these are butylated hydroxytoluene, cocamidopropyl betaine, glycerine, lanolin, propylene glycol and squalene. Squalene is the most potent of these wax-removing agents and is found in several veterinary ear cleaners. Some cleaners have it present at low concentrations of 2% whilst other more potent ceruminosolvent cleaners have squalene at concentrations of 22 to 25%. A synthetic canine cerumen has been designed and used, in slightly varying formulations, in several studies to look at the ceruminolytic properties of different ear cleaners. In all cases, antiseptic ear cleaning solutions that contained components such as chlorhexidine, without a recognised ceruminolytic, showed a poor ability to remove wax. However, propylene glycol, glycerine and squalene-based products consistently performed well. In one study, a propylene glycol and glycerine ear cleaner appeared to be able to remove 90% of the synthetic cerumen from a test tube. No urea or carbamide peroxide cleaners were tested but cleaners containing DOSS appeared to be less successful at wax removal in these three in vitro studies. The author would generally recommend the use of a suitable ceruminolytic/ceruminosolvent cleaner for dogs with hirsute ears rather than plucking out the hair, which can cause microtrauma in the ear canal and predispose to infection.

洗耳液清除耳垢的效力是耳炎治疗和持续维持治疗的重要组成部分。真正的耵聍溶解剂洗耳液通过诱导角质溶解来破坏耵聍的完整性。它们乳化碎片，将其分解并保持在溶液中。二胞特磺丁二酸钠(DOSS)、磺丁二酸钙、尿素或过氧化脲是强效耵聍溶解剂。尿素和过氧化脲是发泡剂，在原地释放氧气，帮助分解碎片。有许多美国和欧洲的洗耳液含有这些成分。耵聍溶剂洗耳液是一种有机油和可以软化和松动耳垢的溶剂。例如丁基羟基甲苯、椰油酰胺丙基甜菜碱、甘油、羊毛脂、丙二醇和角鲨烷。角鲨烷是这些耵聍溶解剂中最有效的，在几种兽医洗耳液中都有发现。一些洗耳液含有2%的低浓度角鲨烷，而其他更强效的耵聍溶解剂洗耳液含有22-25%的角鲨烷。在几项研究中，设计并使用了一种合成的犬耵聍，配方略有不同，以观察不同洗耳液的耵聍溶解性能。在所有病例中，含有氯己定等成分的杀菌洗耳液，不含公认的耵聍溶解能力，除耳垢能力较差。然而，以丙二醇、甘油和角鲨烷为主产品始终表现良好。在一项研究中，丙二醇和甘油的洗耳液似乎可以从试管中去除90%的人造耵聍。没有对尿素或过氧化脲洗耳液进行测试，但在这三项体外研究中，含有DOSS的洗耳液在去除耳垢方面似乎不太成功。对于多毛的犬，作者一般会建议使用合适的耵聍溶解剂/耵聍溶剂洗耳液，而不是拔毛，拔毛会造成耳道微创伤，容易感染。

 

Drying ear cleaners

洗耳液干燥剂

Astringents dry the ear canal surface to prevent maceration. Drying agents are typically used after the ear has been cleaned with a ceruminolytic/ceruminosolvent product or are used prophylactically after water is introduced into the ear canal either by aqueous-based treatments, bathing or swimming. Astringents are usually isopropyl alcohol or an acid. Acids found in ear cleaners for this purpose include acetic acid, boric acid, benzoic acid and salicylic acid as well as aluminium acetate and silicon dioxide. In the USA, there are many different ear cleaning solutions designed specifically for their antiseptic astringent effects. In Europe drying agents are often incorporated into more general ear cleaning products.

收敛剂干燥耳道表面，防止浸渍。干燥剂通常在用过耵聍溶解剂/耵聍溶剂洗耳液后使用，或在以水为基础的治疗、或洗澡或游泳等将水引入耳道后的操作后，预防性地使用。收敛剂通常是异丙醇或酸类。洗耳液中的酸包括乙酸、硼酸、苯甲酸、水杨酸以及醋酸铝和二氧化硅。在美国，有许多不同的洗耳液溶液专门有抗菌收敛效果。在欧洲，干燥剂通常被加入到更常规的洗耳液中。

 

TOPICAL THERAPY TO MANAGE PERPETUATING FACTORS

外部治疗管理持久因素

Management of perpetuating factors is important to facilitate resolution of otitis. Chronic change is often inadequately addressed in cases of otitis and is a common reason for disease relapse. Where there is marked hyperplastic change of the walls of the canal and/or the glandular tissue within the wall, potent steroid treatment is needed to reverse these changes. A full discussion on the management of chronic changes in otitis is beyond the scope of this article. Some of the liquid bandages, ear packs and other “stay in place” otics, together with topical corticosteroids in ear drops, in aqueous solution in ear wicks or systemic corticosteroids are useful. OM is a common sequel to chronic OE and is another perpetuating factor that needs to be treated. Selection of topical therapy for cases of OM can be challenging because of the risk of ototoxicity. No topical products are licensed for the therapy of OM, so it is important that the attending clinician should select the safest possible product available (which may sometimes be a systemic drug) based on current knowledge. For a detailed description of the clinical signs and diagnosis of OM the reader is advised to consult more detailed texts. Propylene glycol is a solvent and penetration enhancer and is a common component of many different ear drops and cleaners. It has been shown in experimental studies to be ototoxic when instilled into the middle ear. Ear drops and cleaners containing propylene glycol should therefore be used with care if the ear drum cannot be seen. A study looking at four commercial ear cleaning solutions containing squalene, DOSS, carbamide peroxide and triethanolamine instilled into canine ears showed only the ear cleaner containing squalene produced no morphological or neurological changes. Antiseptic solutions show differing degrees of ototoxicity. Alcohol-based preparation of iodine and povidone iodine applied to the middle ear of guinea pigs produced cochlear and vestibular damage whereas aqueous solution of iodine produced no damage. Chlorhexidine at concentrations up to 0.2% appears to be safe as an irrigating solution in dogs. However, when combined with cetrimide in a commercial human antiseptic, it is otototoxic. In cats’ ears, solutions of chlorhexidine as dilute as 0.05% appear to cause cochlear, vestibular and mucosal damage. Ear cleaners containing chlorhexidine should therefore be avoided in cats. Anecdotal reports suggest that a 2 to 2.5% solution of acetic acid solution is safe in the face of a ruptured tympanic membrane. EDTA-Tris is a common component of many different otic cleaners, including several products where it is available as crystals to be reconstituted with sterile water. It has been widely promoted by many different sources as a safe and efficacious therapy, especially when combined with aqueous antibiotics, for Gram-negative OM. Many of the studies assessing the ototoxicity of antibiotics have been performed in guinea pigs and chinchillas and extrapolation of data between species can be misleading. Canine studies to assess the use of gentamicin in OM have shown no noticeable degree of cochlear or vestibular ototoxicity. Other topical aminoglycosides such as tobramycin, as well as the semi-synthetic penicillin ticarcillin, have been associated with severe hearing loss when used to treat OM. Aqueous solutions of fluoroquinolones including enrofloxacin and marbofloxacin appear to be safe when used in the canine middle ear. Conflicting information appears to be available regarding the use of topical azoles in cases of OM. Although some veterinarians consider antifungal drugs such as clotrimazole, miconazole, nystatin and tolnaftate safe in cases of OM based on studies in guinea pigs, the author has seen numerous cases of temporary deafness associated with ear drops containing clotrimazole and miconazole. Although this may be associated with other components of the drops she would caution against such products in cases of OM. Aqueous forms of dexamethasone and fluocinolone appear to be safe in the middle ear.

持久因素管理是促进耳炎恢复的重点。未彻底解决的耳炎会出现慢性改变，是疾病复发的一个常见的原因。当耳道壁和/或壁内的腺组织有明显的增生时，需要强效类固醇治疗来逆转这些变化。关于耳炎慢性变化的管理的充分讨论超出了本文的范围。一些液体绷带、耳包扎和其他“原地不动”的耳药，以及外用糖皮质激素滴耳液、耳芯水溶液或全身性糖皮质激素是有用的。OM是慢性OE的常见结果，是另一个需要治疗的持久因素。由于耳毒性的风险，对中耳炎病例选择外部治疗可能具有挑战性。没有批准治疗OM 的外用药，因此重要的是主治医生应该根据现有的知识选择最安全的可用产品(有时可能是全身性药物)。对于OM的临床症状和诊断的详细描述，建议读者查阅更详细的文本。丙二醇是一种溶剂和透皮剂，是许多不同滴耳剂和洗耳液的常见成分。实验研究表明，当注入中耳时，它具有耳毒性。因此，如果无法看到鼓膜，应小心使用含有丙二醇的滴耳剂和洗耳液。一项研究观察了四种含有角鲨烷、DOSS、过氧化脲和三乙醇胺的市售洗耳液注入犬耳，结果显示，只有含有角鲨烷的洗耳液没有产生形态学或神经学上的变化。抗菌溶液表现出不同程度的耳毒性。碘的醇基制剂和聚维酮碘对豚鼠中耳造成耳蜗和前庭损伤，而碘的水溶液对耳蜗和前庭无损伤。氯己定在浓度达到0.2%时作为犬的洗耳液似乎是安全的。然而，当与商用人医防腐剂西曲溴铵联用时，它具有耳毒性。在猫耳中，稀释至0.05%的氯己定溶液似乎会引起耳蜗、前庭和粘膜损伤。因此，猫应避免使用含有氯己定的洗耳液。坊间报道表明，在鼓膜破裂的情况下，2-2.5%的醋酸溶液是安全的。EDTA-Tris是许多不同的洗耳液的常见成分，包括几种产品，其中它可以以晶体形式与无菌水重新组合。是许多来源广泛应用的一种安全有效的治疗方法，特别是与水溶性抗生素联合使用时，用于治疗革兰氏阴性菌的OM。许多评估抗生素耳毒性的研究都是在豚鼠和龙猫上进行，在物种之间推断数据可能会产生误导。评估庆大霉素在犬中耳炎中使用研究显示，没有明显程度的耳蜗或前庭耳毒性。其他外用氨基糖苷类药物，如妥布霉素，以及半合成青霉素替卡西林，在用于治疗中耳炎时与严重的听力损失有关。氟喹诺酮类药物包括恩诺沙星和马波沙星的水溶液在犬中耳使用时似乎是安全的。相互矛盾的信息似乎是OM的病例外用唑类。虽然一些兽医认为根据对豚鼠的研究，抗真菌药物如克霉唑、咪康唑、制霉菌素和托萘酯对OM病例是安全的，但作者已经看到许多与含有克霉唑和咪康唑的滴耳剂有关的暂时性耳聋病例。虽然这可能与滴眼液的其他成分有关，但她要警告在OM病例中不要使用此类产品。地塞米松和氟喹诺酮的水剂型在中耳似乎是安全的。

 

Table 1 . Primary causes of otitis externa

表1：外耳炎原发病因

原发诱因		外部治疗重点
过敏症	特应性皮炎、食物、接触	洗耳液必须对敏感患耳温和。酸性、醇基、收敛性溶液和强效耵聍溶解剂应谨慎使用。 含糖皮质激素的滴耳液是有用的。糖皮质激素的效力取决于炎症程度和使用频率。 可导致接触性过敏的外用产品包括丙二醇和新霉素。
内分泌	甲减	在甲退中当有耵聍性分泌物时，洗耳液需要有良好的耵聍溶解活性。在疾病的早期阶段，可以使用角鲨烷或多库酯钠等耵聍溶解剂，但随着耳病的改善，应使用效力较弱的耵聍溶解剂，例如油和丙二醇类洗耳液。 治疗继发性酵母菌感染时通常需要洗耳液。含有唑类、多烯类或丙酰胺类（见文章）的滴耳液有效。
自体免疫/免疫介导	落叶型天疱疮、大疱性类天疱疮、盘状红斑狼疮、多形红斑	洗耳液必须温和（如上所述）因为耳部敏感，经常溃疡。 滴耳剂需要含有强效外用糖皮质激素，如莫米松、氢化可的松醋丙酯。
角化异常	皮脂腺炎（SA）、原发性特发性皮脂溢（PIS）	角化异常疾病的洗耳液取决于耳内耵聍的含量。 在SA中，耵聍急剧减少，因此耳道干燥。应使用温和的油基洗耳液。在PIS中需要强效清除耳垢制剂，如过氧化脲、多库酯钠和角鲨烷。 滴耳液通常不如洗耳液重要。外用糖皮质激素可能有助于管理PIS。如发现继发酵母菌感染，参考上文内分泌疾病用药物。
外寄生虫	耳螨、蠕形螨	耳螨病例中洗耳液必须能够打破厚的干燥分泌物。耵聍溶解剂如多库酯钠和角鲨烷可能有用。蠕形螨性耳炎需要更温和的洗耳液，例如丙二醇洗耳液。 滴耳液通常具有杀螨作用，即使不含特定的杀螨药物。含有杀螨剂的滴耳液:阿维菌素、氯菊酯、噻苯咪唑、鱼藤酮是有用的。

 

Table 2 . Secondary causes of otitis

表2：耳炎继发病因

感染		外部治疗
细菌	革兰氏阳性菌 葡萄球菌属、链球菌属、肠球菌属、棒状杆菌属 革兰氏阴性菌 假单胞菌属、变形杆菌属、大肠杆菌 厌氧菌	详见本文外用抗生素和抗细菌洗耳液部分
酵母菌	马拉色菌属	详见本文外用抗酵母菌药和洗耳液

 

Table 3 . Important predisposing factors in otitis

表3：耳炎重要易感因素

易感因素
结构	多毛耳道、狭窄耳道、垂耳	定期使用耵聍溶解剂/耵聍溶剂产品（见文章）
耳道过度潮湿	环境因素（热和湿度）；水（游泳耳）	定期使用外用干燥剂能有助于管理游泳耳
阻塞性耳病	肿瘤、息肉	定期洗耳清除分泌物，以及控制继发感染有作用，但是不能长期解决
治疗作用	洗耳液不合适、洗耳和拔耳毛的损伤	谨慎选择洗耳液，敏感耳重点应避免使用酸性、强效耵聍溶解剂和收敛性洗耳液。更推荐常规洗耳而不是常规拔耳毛。

 

Table 4 . Important perpetuating factors in otitis

表4：耳炎重要持久因素

持久因素
外耳道病理性改变	耳道壁炎症反应导致上皮迁移丧失   腺体组织炎症反应导致耳道狭窄和耵聍增多	定期使用合适的溶耵聍溶解剂/耵聍溶剂洗耳液清洗耳道以去除分泌物。适当使用强效外用皮质类固醇来减少肿胀、增生性改变和耵聍的产生。在某些病例中氟喹诺酮联合DMSO是有用的。
中耳炎	鼓膜破溃         鼓泡内粘膜性骨膜的炎症反应导致粘液脓性分泌物     中耳内产生生物膜	适当使用外用抗生素和洗耳液治疗感染，但尽量减少耳毒性的风险，注意，所有中耳炎的药物都是未经许可使用的。 适当使用外用皮质类固醇以减少炎症反应和分泌物(见上文关于耳毒性和非许可使用药物的说明) 外用药可能有助于打破耳道和中耳内形成的生物膜
DMSO：二甲基亚砜

 

 

Table 5 . A review of veterinary studies assessing systemic absorption of otic glucocorticoids

表5：兽医研究综述，评估糖皮质激素耳药的全身性吸收

研究	犬健康情况	研究设计（糖皮质激素耳药和应用）	结果
Moriello等人(1988)	健康	地塞米松或曲安奈德，按使用说明每日两次连用7天	所有犬7天后ACTH反应下降。所有犬恢复期>21天。
Meyer等人(1990)	健康	曲安奈德或地塞米松都每日一次连用3周	7天后肝酶结果升高，21天达峰值。恢复期35天。地塞米松组升高最大。
Ghubash等人(2004)	健康、小型	地塞米松或倍他米松，按使用说明每日两次连用2周	2周后进行ACTH测试。倍他米松组NAD；地塞米松组>70%ACTH降低，2周后恢复
Abraham等人（2005）	健康	地塞米松每日两次连用21天	所有犬治疗第7和14天，ACTH都有抑制。第14天抑制>第7天。所有犬治疗后7天ACTH持续抑制。第7和14天肝酶升高，治疗后7天没有恢复。
Reeder等人(2008）	外耳炎	地塞米松（每日两次）或莫米松（每日一次）或倍他米松（每日两次）或曲安奈德（每日两次）（按说明使用）连用7天	第7天进行ACTH。莫米松组NAD。其他组患犬ACTH降低比例：地塞米松组50%、曲安奈德组17%、倍他米松组9%。
Gottschalk等人(2011)	健康	地塞米松每日一次连用3周	第21天T4、T3、可的松都降低，胰岛素升高。T4、T3恢复期>7天。

 

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