Daniel O. Morris, DVM
Antifungals
抗真菌药
Nystatin
制霉菌素
A polyene antifungal, nystatin binds to sterols in the fungal cell membrane, thereby altering permeability and mediating cell death by osmotic destruction. Nystatin is primarily used to treat infections by Candida spp, but it also exhibits activity against M pachydermatis clinically. Nystatin is considered a first-line anti-Malassezia drug by at least one author. In an in vitro study, neomycin exhibited only partial inhibition of M pachydermatis growth on Sabouraud’s agar. Because most preparations containing nystatin are occlusive ointments, this author typically avoids using them in cases of exudative or ceruminous otitis externa.
一种多烯类抗真菌药，制霉菌素与真菌细胞膜上的固醇结合，从而改变渗透性并通过渗透破坏介导细胞死亡。制霉菌素主要用于治疗念珠菌感染，但在临床上也表现出对厚皮马拉色菌的活性。至少有一位作者认为制霉菌素是抗马拉色菌的一线药物。在体外实验中，新霉素对沙波罗氏琼脂上的厚皮马拉色菌仅表现出部分抑制作用。由于大多数含有制霉菌素的制剂是封闭式软膏，本文作者通常避免在渗出性或耵聍性外耳炎的病例中使用它们。
Azole antifungals
唑类抗真菌药
Benzimidazoles (eg, thiabendazole), imidazoles (eg, clotrimazole, miconazole, ketoconazole), and triazoles (eg, itraconazole, fluconazole) all share a common mode of action against fungi: disruption of cell wall ergosterol biosynthesis via P450 enzyme inhibition. An in vitro study comparing the efficacy of the azoles against Malassezia spp yeast indicated that thiabendazole is the least effective, followed by clotrimazole (with efficacy comparable to nystatin), miconazole (with 10 times the potency of nystatin), ketoconazole, and itraconazole, respectively. A more recent in vitro study showed equal efficacy of ketoconazole, itraconazole, and terbinafine against M pachydermatis, whereas a Hungarian study suggested that ketoconazole is the most effective, followed by clotrimazole, miconazole, and nystatin, respectively. Regional variation in strain susceptibility may therefore exist.
苯并咪唑类(如噻苯达唑)、咪唑类(如克霉唑、咪康唑、酮康唑)和三唑类(如伊曲康唑、氟康唑)都有一个共同的作用模式:通过抑制P450酶破坏细胞壁麦角甾醇生物合成。一项体外研究比较了唑类药物对马拉色菌的药效，结果表明噻苯达唑的药效最低，其次是克霉唑(药效与制霉菌素相当)、咪康唑(药效是制霉菌素的10倍)、酮康唑和伊曲康唑。最近的一项体外研究显示酮康唑、伊曲康唑和特比萘芬对厚皮马拉色菌的疗效相同，而匈牙利的一项研究表明酮康唑是最有效的，其次是克霉唑、咪康唑和制霉菌素。因此，菌株易感性可能存在区域差异。
Veterinary topical preparations of thiabendazole, clotrimazole, and miconazole are commonly employed for the treatment of Malassezia otitis in dogs and cats. Ketoconazole (Nizoral) is available only under human labels as oral tablets and a topical cream. Both may be used to formulate 1% to 2% solutions for otic treatment of veterinary patients when other more available azoles are failing clinically. A human-labeled 1% oral itraconazole elixir (Sporanox Oral Solution) has also been used topically by the author. Although sticky (in a syrup base), the product has been effective. Miconazole is the topical agent most commonly employed against Malassezia otitis in the author’s group practice, whereas clinical resistance to clotrimazole has been noted on numerous occasions. Topical azole antifungals are said to be uniformly nontoxic to the inner ear. Although antifungal ototoxicity does not seem to be clinically problematic in dogs and cats, contact/irritant reactions may be noted with any of the azoles. It is difficult to exclude the role of vehicle versus the azole drug in many cases, however. Oral ketoconazole or itraconazole may be used for canine otitis media associated with Malassezia spp, whereas itraconazole is generally preferred for this purpose in cats.
噻苯达唑、克霉唑和咪康唑的兽用外用制剂通常用于治疗犬和猫马拉色菌性耳炎。酮康唑(Nizoral)仅有人医用药作为口服片剂和外用乳膏提供。当其他可用的唑类在临床上失效时，这两种药物都可用来配制1%到2%的溶液，用于患病动物的耳部治疗。作者还外用过人医的1%伊曲康唑口服药(斯皮仁诺口服溶液)。虽然(在糖浆的基础上)药物粘性，但是该产品是有效的。在作者的临床团队中，咪康唑是最常用于治疗马拉色菌性耳炎的外用药物，然而临床已多次观察到对克霉唑的耐药性。外用唑类抗真菌药据说对内耳均无毒。虽然抗真菌耳毒性在犬和猫的临床上似乎没有问题，但任何一种唑类可能都观察到有接触/刺激反应。然而，在许多病例中，很难排除载体作用还是唑类药物的作用。口服酮康唑或伊曲康唑可用于与马拉色菌相关的犬中耳炎，而伊曲康唑通常用于猫中耳炎。
Allylamines
丙烯胺类
This class of antimycotic agents exerts a cell-wall effect by disruption of ergosterol biosynthesis via inhibition of squalene epoxidase. Because the effect does not involve P450 enzymes, this class of antifungal drugs is generally considered to be safer for mammalian use than the azole antifungals. Terbinafine has been shown to have excellent in vitro efficacy for many species of Malassezia, including M pachydermatis. Although not marketed as a topical product under a veterinary label, a 1% human-labeled solution (Lamisil) is available over the counter in various preparations for the treatment of tinea. Its use for Malassezia otitis in animals has not been reported, although the author has used it successfully in a single canine patient. Oral use of terbinafine for feline dermatophytosis has been reported, and adverse effects were not noted, suggesting its potential utility for Malassezia otitis media in cats.
这类抗真菌药物通过抑制角鲨烯环氧化酶破坏麦角甾醇生物合成，作用于细胞壁。由于其作用不涉及P450酶，这类抗真菌药物通常被认为比唑类抗真菌药物更安全。特比萘芬已被证明对多种马拉色菌具有良好的体外疗效，包括厚皮马拉色菌。虽然没有兽用的外用产品，但用于治疗皮肤癣菌病的1%的人用溶液(兰美抒)各种非处方制剂可购买到。虽然该药在动物马拉色菌耳炎的应用还没有报道过，但作者已经成功用于一只患犬病例。口服特比萘芬治疗猫皮肤癣菌病已有报道，未观察到副作用，这表明它对猫马拉色菌中耳炎有潜在的疗效。
Anti-inflammatory agents
抗炎药
Almost every case of otitis deserves the benefits of topical corticosteroids because of their anti-inflammatory, antiproliferative, antipruritic, and antiexudative (glandular secretory) effects. Systemic steroids [preferably predniso(lo)ne or methylprednisolone orally] are also highly efficacious in reducing acute stenosis caused by edema as well as more chronic stenosis caused by proliferative hyperplasia and fibrosis.
由于皮质类固醇具有抗炎、抗增殖、止痒和抗渗出(腺体分泌)的作用，几乎所有耳炎病例都值得外用皮质类固醇。全身性类固醇[最好是口服泼尼松（龙）或甲泼尼松龙]对减少水肿引起的急性狭窄以及增殖性增生和纤维化引起的慢性狭窄也非常有效。
Topical steroids are present in a large proportion of commercially prepared otic products, and their potency may depend not only on the drug’s inherent anti-inflammatory quotient but on the drug concentration and vehicle used in the product. In general, the potency of topical steroids is assumed to concur with their biologic activities. Relative potencies compared with hydrocortisone are: hydrocortisone (1), prednisolone (5), triamcinolone (5), isoflupredone (14), dexamethasone (25), betamethasone (25), and fluocinolone (100). Some authors believe that nothing more potent than hydrocortisone should be used in cases of ulcerative Pseudomonas otitis. The reader is referred to the excellent article by Logas for more complete information regarding the indications and uses of topical steroids. Side effects related to topical steroids include systemic absorption with suppression of the hypothalamic-pituitary-adrenal axis (which likely increases with the higher potency steroids) and topical contact reactions. Although well described in human beings, contact allergy to topical corticosteroids has not received attention in veterinary medicine.
大多数商用耳部制剂中都存在外用类固醇，它们的效力可能不仅取决于药物固有的抗炎作用，而且取决于药物浓度和产品中使用的载体。一般来说，外用类固醇的效力被认为与其生物活性一致。与氢化可的松相比，其相对效力为:氢化可的松(1)、泼尼松龙(5)、曲安奈德(5)、异氟泼尼松(14)、地塞米松(25)、倍他米松(25)和氟轻松(100)。一些作者认为，在溃疡性假单胞菌性耳炎病例中，最好使用氢化可的松。读者可以参考Logas的精选文章，获得关于外用类固醇的适应症和使用的更详细的信息。与外用类固醇相关的副作用包括全身吸收和下丘脑-垂体-肾上腺轴的抑制(可能随着药效更强的类固醇而增加)和外用接触反应。虽然在人医中有详细描述，但是外用皮质类固醇的接触性过敏反应在兽医中还没观察到。
The only nonsteroidal agent available in a topical otic preparation is dimethyl sulfoxide (DMSO). In addition to its significant anti-inflammatory activity, DMSO may reduce fibroplasia. A 60% DMSO solution with 0.01% fluocinolone (Synotic) is quite useful for severe inflammatory and hyperplastic otitis but should be used with caution in the face of infection.
外用耳部制剂中唯一可用的非甾体药物是二甲基亚砜(DMSO)。DMSO除了具有显著的抗炎活性外，还可减少纤维增生。60% DMSO溶液与0.01%氟轻松(Synotic)对严重炎症反应和增生性耳炎非常有效，但当出现感染时应谨慎使用。
Therapy of acute otitis externa
急性外耳炎治疗
In general a first-line antimicrobial should be chosen based on cytologic and otoscopic findings. Twice-daily therapy for a minimum of 7 to 14 days depending on the degree of inflammatory changes (edema, hyperplasia, and erosion/ulceration) combined with at-home cleansing is the author’s prescribed regimen. Of utmost importance is delivering a sufficient volume of topical agent to the canal. For example, large-breed dogs (eg, retrievers, shepherds) should receive a minimum of 10 to 12 drops (or 1 mL) per application. Re-evaluation at the end of the regimen to evaluate the cytologic and otoscopic status of the ears is recommended but not mandatory for success in most cases.
一般来说，应根据细胞学和检耳镜检查结果选择一线抗菌药物。根据炎症变化(水肿、增生、糜烂/溃疡)的程度，每天两次治疗，最少7-14天，并结合家庭洗耳操作，以上是作者的治疗方案。最重要的是耳道内外耳药剂量要足够。例如，大型犬(如寻回犬、牧羊犬)每次至少应注入10至12滴(或1毫升)。建议在治疗结束时重新评估耳道的细胞学检查和检耳镜检查情况，但在大多数病例中，这并不是成功治疗的必要条件。
Therapy of chronic/recurrent otitis externa
慢性/复发性外耳炎的治疗
A complete history, physical examination, and otoscopic examinations to search for predisposing, primary, and perpetuating factors are indicated. The status of the tympanic membranes should be confirmed. If edema or proliferative changes preclude visualization of the entire canal to the level of the tympanum, topical therapy should be initiated based on cytologic findings, and the patient should be discharged on an anti-inflammatory regimen or oral predniso(lo)ne (0.5 mg/kg every 12 hours tapered weekly to every 24 hours and then every 48 hours) and scheduled for a follow-up visit in 2 to 4 weeks for recheck. Treatment with second-line or third-line antimicrobials may be indicated depending on the history of prior therapies. The client should be prepared for longer term topical therapy (at least 4 weeks in duration). In extremely chronic cases, several months of rigorous topical therapy may be necessary to return the external canals to their normal state. Systemic antibiotics may be indicated if there is extensive tissue swelling (potentially indicating deeper infection), ulceration, or significant periaural dermatitis. Rechecks should be scheduled every 2 to 4 weeks for cytologic and otoscopic examination until complete resolution is achieved.
需要完整的病史、体格检查和检耳镜检查，以明确易感因素、原发因素和持久因素。应确定鼓膜的状况。如果水肿或增生性改变使整个耳道无法观察到鼓膜，应根据细胞学检查结果开始外部治疗，患病动物应使用抗炎治疗或口服泼尼松（龙）(0.5 mg/kg，每12小时逐渐减少到每24小时，然后每48小时)，并计划在2 - 4周后复诊。根据以往的病史和治疗史，可能提示要使用二线或三线抗菌素治疗。应告知客户需要接受较长期的外部治疗(至少4周)。在极其慢性的病例中，可能需要严格使用数月的外部治疗，以使外耳道恢复到正常状态。如果有大面积的组织肿胀(可能表明感染更深)、溃疡，或严重的耳周皮炎，可能需要使用全身性抗生素。应每2至4周安排复诊，进行细胞学检查和耳镜检查，直到完全康复。
Therapy of otitis media
中耳炎治疗
Because otitis media is typically the result of extension of chronic otitis externa through a ruptured tympanic membrane, all the principles discussed for chronic/recurrent otitis externa apply here. In addition, a thorough lavage of the bulla to remove infective and inflammatory exudates gives medical therapy a good head start. In the case of bulla impaction with inflammatory exudates and debris, medical failure is virtually guaranteed without a thorough lavage.
由于中耳炎是慢性外耳炎通过鼓膜破裂蔓延的结果，所以所有关于慢性/复发性外耳炎的原则在这里都适用。此外，彻底灌洗大疱以清除感染性和炎性分泌物为药物治疗提供了良好的条件。在大疱内有炎性分泌物和碎片的病例中，如果不彻底灌洗，药物治疗肯定会失败。
The choice of antimicrobial agents becomes more complicated when otitis media is involved. This author prefers to avoid the topical use of fluoroquinolones completely unless a systemic form of the same drug is used concurrently because of the potential for subtherapeutic concentrations of the topical drug to reach the middle ear via the ruptured tympanum. Development of fluoroquinolone resistance is documented to occur in vitro with a single exposure to the drug.
当涉及中耳炎时，抗菌剂的选择就变得更加复杂。本文作者倾向于完全避免外用氟喹诺酮类药物，除非全身性应用同种药物，因为外部药物的低治疗浓度可能通过鼓膜破裂到达中耳。在体外使用单一成份药物被证明会发生氟喹诺酮类药物耐药。
Many veterinary dermatologists recommend starting an oral fluoroquinolone pending culture/susceptibility results. Systemic antimicrobial therapy based on culture/susceptibility testing of samples retrieved from the middle ear is indicated whenever possible. In fact, it has been stated that otitis media cannot be resolved with topical therapy alone. Many chronic cases of otitis media involve P aeruginosa, however, and an oral drug is not always available because of broad-spectrum resistance.
许多兽医皮肤科医生建议在细菌培养/药敏试验结果出来之前开始口服氟喹诺酮类药物。可能的话，应根据中耳采样进行的细菌培养/药敏试验的结果进行全身性抗生素治疗。事实上，中耳炎不能仅通过外用治疗得以解决。但是，许多慢性中耳炎病例涉及铜绿假单胞菌，由于广谱耐药性，口服药物并不总是可用。
Several systemic antipseudomonal drugs intended for intravenous use can also be used subcutaneously, allowing therapy by the client at home.
一些全身静脉使用的抗铜绿假单胞菌药也可以皮下使用，允许客户在家治疗。
Examples include meropenem (Merrem; 8 mg/kg every 12 hours), ticarcillin (Ticar; 40–80 mg/kg every 6 hours), and ceftazidime (Fortaz; 30 mg/kg every 4 hours). The downfall of these systemic injectable drugs is their extremely high cost. In cases of Pseudomonas otitis media in which an oral antibiotic is unavailable and the cost of subcutaneous therapy is prohibitive to the client, the clinicians in the author’s group practice have shown success with thorough bulla lavage followed by high-throughput topical therapy. The later entails application of large volumes (1–2 mL) of topical drug (most often, an SSD solution) twice daily and regular (daily or every other day) at-home flushing of the canals using an acidifying cleanser. It is our contention that high-volume application of low-viscosity antimicrobial preparations and cleansers promotes a continued ‘‘flushing’’ of the bullae as long as the tympani remain open.
例如包括美罗培南(Merrem;8 mg/kg每12小时)、替卡西林(Ticar;40 - 80 mg/kg每6小时)和头孢他啶(Fortaz;30mg/kg，每4小时)。这些全身注射药物的失败原因，在于其极高的成本。在假单胞菌中耳炎的病例中，没有可用的口服抗生素，而皮下治疗的费用对客户来说难以接受，在作者的临床团队中，临床医生已经证明彻底大疱灌洗后高剂量外用治疗有效。后者需要大量(1-2毫升)外用药(通常是SSD溶液)，每天两次，并定期(每天或隔日一次)使用酸化清洗耳液在家中灌洗耳道。我们认为，在鼓室保持开放的情况下，大量使用低粘度抗菌制剂和洗耳液可促进大疱的持续冲洗。
Methicillin-resistant Staphylococcus spp also present a dilemma in selecting a systemic antibiotic. Methicillin resistance (indicated by resistance to oxacillin in most susceptibility profiles) confers resistance to all β-lactam antibiotics, and many of these strains also show broad fluoroquinolone resistance patterns. Fortunately, most strains isolated from patients presenting to the dermatology service at the University of Pennsylvania have been susceptible to chloramphenicol or macrolide antibiotics (erythromycin, azithromycin [Zithromax], and clarithromycin [Biaxin]).
耐甲氧西林葡萄球菌在选择全身性抗生素方面也面临困境。甲氧西林耐药(在大多数药敏谱中表现为对苯唑西林的耐药)导致对所有β-内酰胺类抗生素的耐药，其中许多菌株还表现出广泛的氟喹诺酮类耐药模式。幸运的是，从宾夕法尼亚大学皮肤科诊所的病例中分离出来的大多数菌株对氯霉素或大环内酯类抗生素(红霉素、阿奇霉素[Zithromax]和克拉霉素[Biaxin])敏感。
Regardless, the successful therapy of bacterial or fungal otitis media relies on an initial thorough cleansing of the bulla, aggressive targeted antimicrobial therapy for an absolute minimum of 6 to 8 weeks, and consistent cleansing/flushing of the external canal by the client at home. Therapy can only be discontinued when the ear canals are negative for microorganisms on cytologic examination, the external canals have no residual edema, and the epithelium has normalized. In some cases, the tympanic membrane may not regenerate, although most do. In cases in which these criteria cannot be achieved, a prophylaxis program that incorporates regular use of cleansers and drying agents must be instituted. The level of commitment on the part of the client cannot be overly stressed. In the author’s group practice, the mean time to resolution of chronic otitis media in 44 dogs was 117±86.7 days (range: 30–360 days).
无论如何，成功治疗细菌性或真菌性中耳炎，依赖于最初彻底灌洗大疱，至少6至8周的积极靶向抗生素治疗，以及客户在家持续清洗/灌洗外耳道。只有当细胞学检查发现耳道微生物阴性，外耳道无水肿，上皮细胞正常时，方可停止治疗。虽然在某些病例，鼓膜可能不能再生，但是大多数可以再生。在无法达到这些标准的病例中，必须制定一个预防治疗计划，包括定期使用洗耳液和干燥剂。不要让客户的护理工作量太大。在作者的临床团队中，44只慢性中耳炎患犬的平均恢复时间为117±86.7天(范围:30-360天)。
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发表于 2021-10-11 11:36:03
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