外耳炎和中耳炎的药物治疗（2004）--（1） - 宠医帮

The medical approach to therapy of otitis externa and media may currently be best described as an art rather than a science. Although the veterinary literature evaluating diagnostic techniques for otitis has grown considerably in the past few years, veterinary studies documenting medical therapies (beyond ototoxicity research) are quite scarce. Review articles and discussions of medical approaches within the published proceedings of continuing education meetings are not uncommon, because medical therapy of otitis is a popular topic among veterinary practitioners. Information based on prospective studies that adhere to the principles of evidence-based medicine is definitely rare, however. This is not the case in human medicine.

目前外耳炎和中耳炎的药物治疗可能最好被描述为是一门艺术而不是一门科学。虽然在过去几年评估耳炎诊断技术的兽医文献有很多，但记录药物治疗(除了耳毒性研究)的兽医研究相当少。在继续教育会议上发表的评论文章和医疗方法的讨论并不少见，因为耳炎的药物治疗在临床兽医中是热门话题。但是，基于循证医学原则的前瞻性研究的研究信息绝对是罕见的。这在人类医学中并非如此。

The potential predisposing factors and direct/indirect causes of otic inflammation or otic immunosuppression are discussed elsewhere in this issue. Bacterial and fungal (yeast) infections of the ear canals are thought to be secondary problems in most cases. Although veterinarians universally agree that it is of utmost importance to resolve the primary otic disease, this article focuses solely on medical therapy for the infectious component of otitis externa and media.

导致耳炎或耳部免疫抑制的潜在易感因素和直接/间接病因在本期刊其他文章进行讨论。在大多数病例中，耳道的细菌和真菌（酵母菌）感染被认为是继发性疾病。虽然兽医普遍认为解决原发性耳病最重要，但本文只关注感染性外耳炎和中耳炎的药物治疗。

Because dermatologists deal with otic infections on a daily basis, this group of specialists has contributed much to the anecdotal knowledge base on the subject. Multiple approaches are routinely discussed, which often vary in the empiric choices of topical drugs and cleansers employed, the frequency and technique of ear canal lavage (both in-office and as administered by the pet owner at home), and the types and frequencies of prophylactic therapies recommended after resolution of chronic infections. One point of agreement (and much concern) is the growing evidence for multidrug-resistant strains of Pseudomonas aeruginosa and methicillinresistant Staphylococcus spp.

因为皮肤科医生每天都要处理耳部感染，这组专家对这一主题的轶事知识基础做出了很大的贡献。通常讨论多种方法,根据经验选择不同的外用药物和洗耳液、耳道灌洗的频率和技术(包括在门诊操作和由宠主在家操作),以及当慢性感染治愈后的预防性治疗的类型和频率。有一观点比较一致（且备受关注），即越来越多的证据表明，铜绿假单胞菌和耐甲氧西林葡萄球菌是多重耐药菌株。

Active ingredients available for otic therapy in the acute and chronic/ recurrent case of bacterial or yeast otitis are discussed here, along with the potential topical cutaneous reactions and ototoxicities that may be associated with them. Special considerations for treatment of attendant otitis media/interna and resistant bacterial strains are also presented.

Most commercially produced topical products contain one or more active ingredients (antibacterial, antifungal, and anti-inflammatory) in various combinations as well as a vehicle and various solubilizers, stabilizers, and surfactants . The formulation of the topical product with regard to the vehicle may be as important as the active ingredient to the success of therapy.

Vehicles are chosen to maximize drug solubility, to maintain drug activity locally for the maximum period, and to minimize systemic absorption. The most commonly used vehicles are water (which may be buffered and pH-adjusted to maximize drug activity), demulcents, and emollients. Demulcents are compounds of high molecular weight capable of forming stable emulsions or suspensions of drugs that are not water soluble. They coat and protect underlying tissue. Polyhydroxy demulcents, which are the most hydrophilic yet potentially irritating compounds within this class, are also the most commonly used carriers used in otic products. They include polyethylene glycol, propylene glycol, and glycerin. The former two are commonly implicated in contact/irritant reactions in the author’s practice. Emollients are occlusive agents used as carriers for water-insoluble drugs and are protective and hydrating to the stratum corneum. Examples include vegetable oils, animal fats (eg, lanolin), and hydrocarbons (eg, petrolatum, mineral oil, paraffin). For a more complete discussion of vehicles and excipients than can be presented here, the reader is referred to the excellent article on otopharmacology by Wilcke.

载体的选择是为了最大限度地提高药物的溶解度，使药物在外部维持活性最大，并尽量减少全身吸收。最常用的载体是水(它可以被缓冲和调节pH值，使药物活性达最大化)、缓和剂和软化剂。缓和剂是一种高分子量的化合物，能够形成稳定的不溶于水的药物乳剂或悬浮液。它们覆盖并保护下面的组织。多羟基缓和剂是该类化合物中最亲水但有潜在刺激性的化合物，也是耳部产品中最常用的载体。它们包括聚乙二醇、丙二醇和甘油。在作者的临床诊疗中，前两者通常涉及接触/刺激反应。软化剂是一种封闭剂，用作不溶于水的药物的载体，并对角质层起到保护和保湿作用。例如植物油、动物脂肪(如羊毛脂)和碳氢化合物(如凡士林油、矿物油、石蜡)。关于载体和赋形剂的更全面的讨论，读者可以参考Wilcke关于耳药理学的精选文章。

A ‘‘first-line’’ topical antibacterial with low potency yet broad-spectrum activity, chloramphenicol is no longer available as a commercially produced topical product. Chloramphenicol is considered to be a bacteristatic agent (except at high concentrations) against susceptible bacterial strains. Known to be associated with aplastic anemia in human beings, concern over potential drug exposure to the pet owner limited its topical use by many veterinarians when a topical product was available.

氯霉素是一种“一线”外用抗菌药物，药效低，但具有广谱活性，氯霉素不再用于商品化的外用产品。氯霉素被认为是一种对敏感菌株的抑菌剂(高浓度除外)。已知氯霉素与人类再生障碍性贫血有关，由于担心宠物主人可能接触到药物，在有外用产品时许多兽医不选择其外用。

This is a narrow-spectrum bacteristatic antimicrobial that inhibits bacterial protein synthesis by a unique mechanism. Its spectrum is limited to gram-positive cocci; gram-negative bacilli are inherently resistant because of their impermeable cell membranes. The usual clinical indication is otitis caused by staphylococcal species. Fusidic acid preparations are unavailable in the United States, but otic preparations are used in Europe and Canada.

这是一种窄谱抑菌抗菌素，通过独特的机制抑制细菌蛋白质的合成。其抗菌谱仅限于革兰氏阳性球菌;革兰氏阴性杆菌具有先天耐药性，因为它们的细胞膜不可渗透。常见的临床指征是由葡萄球菌性耳炎。在美国没有夫西地酸制剂，但在欧洲和加拿大有可使用的耳药制剂。

The aminoglycoside antibiotics are the most commonly used class of topical otic products. They act on susceptible bacteria by binding to the 30s ribosomal subunit in the bacterial nucleus, thereby inhibiting protein synthesis, and are considered to be bactericidal. Their antibacterial spectra vary by individual drug potency but include some aerobic gram-positive bacteria and many aerobic gram-negative species. They are ineffective for anaerobes and fungi. Their antimicrobial activity is enhanced in an alkaline environment, which is germane to topical therapy of the ear canal. If acidifying cleansers are used in conjunction with aminoglycosides, the products should be applied at least 1 hour apart. Also of noted importance is the ototoxic potential of aminoglycosides, especially when administered parenterally. Auditory symptoms are more common with neomycin and amikacin, whereas vestibular symptoms are most typical of gentamicin, especially in the cat. The ototoxic potential of this class of drugs when topically applied may be overestimated.

氨基糖苷类抗生素是最常用的外用抗生素。它们通过与敏感菌细胞核内的30s核糖体亚基结合，从而抑制蛋白质合成，被认为是杀菌剂。它们的抗菌谱因单个药物效力而异，但包括一些需氧革兰氏阳性菌和许多需氧革兰氏阴性菌。它们对厌氧菌和真菌无效。它们的抗菌活性在碱性环境中增强，这与耳道外部治疗密切相关。如果酸化洗耳液与氨基糖苷类一起使用，则产品使用应至少间隔1小时。同样重要的是氨基糖苷类药物的耳毒性，特别是静脉给药时。新霉素和阿米卡星的听觉症状更常见，而庆大霉素的前庭症状最典型，特别是在猫。这类药物外部应用时的耳毒性可能会被高估。

Often considered to be a first-line topical antibacteria, neomycin has the lowest potency of the class, showing significantly less efficacy against several gram-negative organisms; most notably Escherichia coli and P aeruginosa. Its activity against gram-positive cocci remains quite good. Manufactured topical products containing neomycin are plentiful and are recommended for acute bacterial otitis in which cocci predominate cytologically. Neomycin is one of the most commonly implicated topical agents for contact/irritant reactions in dogs, however (Fig. 1).

新霉素通常被认为是一线外部抗菌素，但其效力是这类抗菌素中最低的，对几种革兰氏阴性菌的效力明显较低;最明显的是大肠杆菌和铜绿假单胞菌。其抗革兰氏阳性球菌的活性依旧很好。有许多含有新霉素的外用产品，推荐用于在细胞学检查中以球菌为主的急性细菌性耳炎。但是，新霉素是犬接触/刺激反应中最常见的外用药物之一(图1)。

Considered to be a ‘‘second-line’’ antibacterial, gentamicin has intermediate potency within the class. Its activity against gram-positive cocci is excellent; however, resistant strains of E coli and P aeruginosa are not uncommon. Manufactured topical products containing gentamicin are plentiful and are recommended for chronic/recurrent otitis when clinical evidence of neomycin-resistant rods is available. In general practice, these products are often used as first-line antibacterials. Despite continuing anecdotal concern over the ototoxic potential of topical gentamicin, a study in dogs designed to simulate clinical exposure via a ruptured tympanum failed to document any toxicity. In human medicine, however, the risk of topical gentamicin ototoxicity in clinical practice is now thought to have been underestimated in the past.

庆大霉素被认为是二线抗菌药物，在该类药物中具有中等效力。其对革兰氏阳性球菌的活性极好;然而，常见大肠杆菌和铜绿假单胞菌的耐药菌株。含庆大霉素的外用产品很多，临床证明慢性/复发性耳炎有新霉素耐药杆菌则推荐使用。在全科门诊中，这些产品常被用作一线抗菌药物。虽然坊间对外用庆大霉素的耳毒性持续关注，但一项旨在模拟临床暴露于鼓膜破裂的犬的研究未能证明任何毒性。然而，在人医临床中，目前认为外用庆大霉素耳毒性的风险在以前被低估了。

Considered by the author to be a third-line antibacterial, amikacin is most commonly indicated for chronic/recurrent otitis caused by gentamicin-resistant gram-negative bacilli (especially P aeruginosa). Amikacin is not available as a commercially produced topical product, but the injectable product (Amiglyde) is often diluted to a concentration of 30 to 50 mg/mL (in sterile saline or a tromethamine–ethylenediamine-tetraacetate [TrisEDTA] product) by veterinarians for topical use.

作者认为阿米卡星是一种三线抗菌药物，最常用于对庆大霉素耐药的革兰氏阴性杆菌(尤其是铜绿假单胞菌)引起的慢性/复发性中耳炎。没有商品化的阿米卡星外用产品，但兽医常将阿米卡星注射液(Amiglyde)稀释为30至50 mg/mL(混入无菌生理盐水或三乙醇胺-乙二酸四乙酸盐[TrisEDTA]产品中)用于外用。

Also a third-line antibacterial, indications for use of tobramycin are similar to those for amikacin. Although an otic topical product is not available, ophthalmic formulations are. Dilution of injectable tobramycin (Nebcin) with sterile saline to a concentration of 8 mg/mL has been used by the author, but the long-term stability (>1 week) of the solution is unknown and remains a concern.

This class of antibiotics acts by inhibiting bacterial DNA-gyrase, which prevents DNA supercoiling and synthesis and is thus bactericidal. Bactericidal activity is dependent on concentration, and bacterial resistance is known to occur by rapid mutation, especially in the presence of subtherapeutic concentrations. Fluoroquinolones have good activity against a wide range of gram-negative bacilli and gram-positive cocci (including staphylococci, although activity is variable for streptococci). Their use as second- or third-line antibiotics for chronic/recurrent bacterial otitis, especially cases associated with P aeruginosa, has become common. Studies comparing two human-labeled topical fluoroquinolone products (ciprofloxacin [Cipro HC otic solution] and ofloxacin [Floxin otic solution]) with polymyxin B (Cortisporin otic) have shown the fluoroquinolones to be safe, with less ototoxic potential.

这类抗生素通过抑制细菌的DNA旋旋转酶而起作用，该酶可阻止DNA的超螺旋和合成，因此是杀菌剂。杀菌活性依赖于浓度，已知细菌通过快速突变发生耐药，特别是在低于治疗浓度时。氟喹诺酮类药物对广泛的革兰氏阴性杆菌和革兰氏阳性球菌(包括葡萄球菌，但是对链球菌的活性多变)有良好的活性。它们作用慢性/复发性细菌性耳炎的二线或三线抗生素使用，特别是与铜绿假单胞菌相关的病例，应用变得很常见。比较两种人医使用的外用氟喹诺酮类药物(环丙沙星[盐酸环丙沙星滴耳液]和氧氟沙星[氧氟沙星滴耳液])与多粘菌素B(Cortisporin耳药)的研究表明，氟喹诺酮类药物是安全的，耳毒性较小。

This drug has long been used for resistant Pseudomonas otitis. Although a commercially produced veterinary-labeled topical product is now available (Baytril otic), veterinarians have used enrofloxacin topically for many years by diluting the injectable product for otic use. Reports of resistant strains of P aeruginosa have become common, with up to 87.5% of strains being nonsusceptible in vitro.

这种药长期以来被用于治疗耐药假单胞菌性耳炎。虽然现在已经有一种商品化兽医标记的外用产品(拜有利耳药)，但兽医们多年来一直使用稀释的恩诺沙星注射液作为外用耳药。铜绿假单胞菌耐药株的报道已经很常见，高达87.5%的菌株在体外试验中不敏感。

With a spectrum of activity similar to that of enrofloxacin (ciprofloxacin is an active metabolite of enrofloxacin), there may be little indication for choosing this drug over the former now that a veterinary-labeled topical formulation of enrofloxacin is available. Although resistance of P aeruginosa to ciprofloxacin has been reported to be less common than to enrofloxacin, there are also several laboratory-dependent explanations for the discrepancy that may prove it technical rather than clinical. Regardless, a human-labeled ciprofloxacin otic product (Cipro HC) is available and has been used successfully in dogs by many veterinary dermatologists.

与恩诺沙星的活性谱相似(环丙沙星是恩诺沙星的一种活性代谢产物)，目前可能很少有证据表明选择环丙沙星比选择兽用的恩诺沙星外用制剂更有优势。尽管有报道称铜绿假单胞菌对环丙沙星的耐药性比恩诺沙星的耐药性要少，但对于这种差异。也有一些依赖于实验室的解释，可能证明这种差异是技术上的，而不是临床上的。无论如何，一种可用的人医的环丙沙星耳药(盐酸环丙沙星)，已被许多兽医皮肤科医生用于犬的有效治疗。

This fluoroquinolone may exhibit a better MIC for Pseudomonas spp than enro/cipro. Although unavailable in the United States as a topical product, it is now available in Europe in an otic formulation (Aurizon). Because an injectable product is also unavailable in the United States, topical use has been limited; however, its systemic (oral) use in otitis media/ interna is increasing.

这种氟喹诺酮对假单胞菌的MIC可能比恩诺沙星/环丙沙星好。虽然在美国不能作为外用产品使用，但目前在欧洲有可用的耳药(Aurizon)。由于在美国也没有可注射的产品，外部使用受到限制;然而，它更多用于中耳炎/内耳炎的全身(口服)使用。

This class includes the expanded-spectrum penicillins, which exhibit activity against gram-negative organisms (including Pseudomonas spp) because of their ability to penetrate the gram-negative cell membrane. Ticarcillin is the carboxycillin for which topical use has been most commonly reported in the treatment of canine Pseudomonas otitis. One pair of authors recommends dilution of the 6-g bottle with 12 mL of sterile water and the addition of reconstituted ticarcillin, 2 mL, to 40 mL of an acidifying ear cleanser (with the remainder frozen for future use). The stability of this solution is unknown but may not exceed 3 days.

这一类包括广谱青霉素，它对革兰氏阴性菌(包括假单胞菌)也有活性，因为它们有穿透革兰氏阴性细胞膜的能力。替卡西林是一种羧西林，在治疗犬假单胞菌性耳炎中最常作为外用药使用。两位作者建议用12毫升无菌注射用水稀释一瓶6克的替卡西林，并将稀释后的2毫升替卡西林加入40毫升酸性洗耳液中(剩余的冷冻备用)。这种溶液的稳定性是未知的，但可能不超过3天。

Polymyxin B and colistin sulfate (polymyxin E) are polypeptide antibiotics that exert bactericidal effect by increasing permeability of the bacterial cell membrane via chelation of membrane phospholipid components, leading to osmotic damage. The ototoxic potential of polymyxin B has been well described experimentally in several species of animals, both in vivo and in vitro. There is speculation that the ototoxicity of these products could be more specifically attributable to the propylene glycol vehicle, however. One positive aspect of topical polymyxin B is its reduction of the inflammation induced by endotoxin components of gramnegative bacterial cell walls. The relevance of these findings to dogs and cats is unknown. Currently, there is no polymyxin B product marketed specifically for otic use. Ophthalmic products are available (Polytrim ophthalmic solution), but the author prefers to use a more cost-effective formulation intended for dilution and use as an irrigating solution (Neosporin GU). This product comes in 1-mL ampules containing 200,000 U of polymyxin B sulfate and 40 mg of neomycin base, and it may be diluted with sterile water to 10,000 U/mL for otic use. Colistin sulfate is still available under a proprietary human label (Cortisporin-TC otic suspension).

多粘菌素B和硫酸粘菌素(多粘菌素E)是多肽类抗生素，它们通过螯合细胞膜磷脂成分，增加细菌细胞膜的通透性，从而破坏通透性，发挥杀菌作用。多粘菌素B的耳毒性已经在几种动物的体内实验和体外实验中被详细描述。然而，有人猜测，这些产品的耳毒性可能更具体地归因于丙二醇载体。外用多粘菌素B的一个优势是它能减少由革兰氏阴性细菌细胞壁内毒素成分引起的炎症。这些发现与犬和猫的相关性尚不清楚。目前，还没有多粘菌素B耳药产品。有可使用的眼药(Polytrim滴眼液)，但作者更喜欢使用性价比更高的配方，稀释和作为灌洗液使用(一种多粘菌素软膏)。本品为1ml安瓿，含20万U硫酸多粘菌素B和40 mg新霉素，可用无菌注射用水稀释至1万U/mL作为耳药使用。硫酸粘菌素仍有可用的人医用药(Cortisporin-TC otic suspension)。

Used for more than three decades in human medicine as a burn wound protectant, silver sulfadiazine (SSD) has broad-spectrum antibacterial activity (most notably against P aeruginosa) and does not interfere with re-epithelialization and neovascularization of wounds. In fact, it may enhance wound healing. The spectrum of activity includes most pathogens associated with otitis (including methicillin-resistant staphylococci), with the exception of Malassezia pachydermatis, against which activity is low. Resistant strains of P aeruginosa have been reported but are extremely rare in the author’s practice. Silver exerts its antibacterial effect via impairment of DNA replication and bacterial cell wall damage, leading to osmotic changes. Supplied as a 1% cream (Silvadene) and as a micronized powder (Spectrum pharmacy products; available at: www.spectrumRx.com), concentrations as low as 0.02% have shown 100% efficacy against P aeruginosa and Staphylococcus spp. Although the cream is not readily miscible in water, a homogeneous emulsion can be achieved with gentle mixing. The author prefers to use the powder as a suspension in sterile water at 0.5% to 1.0%. A proprietary product that combines 1% SSD with 0.5% enrofloxacin (Baytril otic) is now available. SSD has become the favored topical therapy for Pseudomonas otitis in the author’s group practice, especially when the external ear canals are ulcerated. Our clinical impression is that re-epithelialization is hastened.

磺胺嘧啶银(SSD)在人医作为烧伤创面保护剂使用了30多年，具有广谱抗菌活性(特别是对铜绿假单胞菌)，且不干扰伤口的上皮形成和新生血管形成。事实上，它可以促进伤口愈合。活性谱包括大多数与耳炎相关的病原体(包括耐甲氧西林葡萄球菌)，但厚皮马拉色菌除外，对其活性较低。铜绿假单胞菌的耐药菌株已有报道，但在作者的诊疗中极为罕见。银通过破坏DNA复制和破坏细菌细胞壁，导致渗透改变来发挥抗菌作用。有1%乳霜(Silvadene)和微粉产品(Spectrum制药产品;可在www.spectrumRx.com网站上找到)，0.02%的低浓度就能对铜绿假单胞菌和葡萄球菌有100%的疗效。虽然这种乳膏不容易溶于水，但轻微混合可得到均匀的乳剂。作者更倾向于将该粉末作为悬浮液在无菌注射用水中稀释成0.5%-1.0%的浓度。一种混合1% SSD和0.5%恩诺沙星(baytrl otic)的专利产品现已上市。在作者的临床团队中，SSD已经成为最受欢迎的假单胞菌性耳炎外部治疗，特别是当外耳道有溃疡时。我们的临床印象是，加速了上皮形成。

The ototoxic potential of SSD is unknown, although the collective experience of a large group of veterinary dermatologists suggests that it is safe for use even in the context of a ruptured tympanum. Because it is known that significant amounts of silver can be absorbed from burn wounds of human beings and silver has the potential to produce systemic toxicity, caution may be warranted in veterinary patients with extensive ulceration. Evidence implicating SSD in systemic toxicity of dogs or cats has not been reported to the knowledge of the author, and a 1% suspension has been used in scores of dogs and several cats for more than 3 months without incident at the University of Pennsylvania.

尽管大量兽医皮肤科医生的集体经验表明，SSD即使在鼓室破裂的情况下使用也是安全的，但SSD的耳毒性潜力尚不清楚。因为众所周知，大量的银可以从人的烧伤伤口中吸收，而且银有可能产生全身毒性，所以对于广大面积溃疡的病例，应该谨慎使用。据作者所知，还没有证据表明SSD对犬或猫有全身毒性，宾夕法尼亚大学已经对几十只犬和几只猫安全的使用1%的悬液3个多月。

This is commonly used as either a presoak or a carrier vehicle (for aminoglycoside antibiotics) in the treatment of gram-negative infections. EDTA promotes increased permeability to extracellular solutes and increased sensitization to antibiotics, whereas Tris serves as a buffer. Two proprietary products are now available in the United States: TRIZEDTA and a similar chemical combination of Tris and tetrasodium edetate (T8 solution).

这通常作为预浸剂或载体(氨基糖苷类抗生素)用于治疗革兰氏阴性感染。EDTA可以增加细胞外溶质的渗透性，增加对抗生素的敏感性，而Tris则起到缓冲作用。目前在美国有两种专利产品:TRIZEDTA和Tris和依地酸四钠(T8溶液)的类似化学组合。