三只犬的推测性抗生素相关光毒性（多西环素和磺胺甲恶唑） ...

王帆

Putative antimicrobial-associated phototoxicity in three dogs

三只犬的推测性抗生素相关光毒性

作者：Diane T. Lewis | William F. Craft | Michael A. Rossi | Jason B. Pieper

 

翻译：王帆

 

Abstract

摘要

This case series describes putative doxycycline phototoxicity in three dogs, with one also undergoing a possible sulfamethoxazole phototoxic reaction.

本病例分析描述了三只犬推测性多西环素光毒性，同时一只犬也可能是磺胺甲恶唑光毒性反应。

KEYWORDS

关键词

dogs, doxycycline, photosensitivity, phototoxicity, sulfamethoxazole

犬、多西环素、光敏感性、光毒性、磺胺甲恶唑

 

CASE 1

病例1

A two-year-old, male-neutered white American bulldog was treated empirically with doxycycline (5 mg/ kg orally twice daily) for bacterial folliculitis and ketoconazole (5mg/kg p.o. twice daily) for Malassezia spp. pododermatitis. Fifteen days later, erythema and crusts developed on the sparsely haired skin of the dorsal muzzle and bilaterally on the dorsal aspect of the pinnal folds (Figure 1). Adjacent areas of pigmented skin were unaffected. Doxycycline was discontinued, sun exposure was avoided, and crusts resolved 21days later. Histopathological findings of affected skin from a dorsal pinnal fold and the dorsal muzzle were indicative of a phototoxic reaction. Vacuolar and reticular keratinocyte degeneration leading to the formation of vesicles and vesicopustules, scattered apoptotic keratinocytes in all levels of the epidermis, dermal oedema and haemorrhage associated with vasculopathy of superficial dermal small-calibre blood vessels, mild superficial dermal inflammation, and epidermal erosion and ulceration with thick serocellular crusts were present (Figure 2). Staphylococcus pseudintermedius sensitive to marbofloxacin, trimethoprim sulfamethoxazole and rifampin subsequently was isolated. Twenty days after starting trimethoprim sulfamethoxazole (30mg/kg p.o. twice daily), marked erythema of the trunk, dorsal muzzle and dorsal ear pinnae occurred. A phototoxic reaction to sulfamethoxazole was suspected and antimicrobial therapy was changed to marbofloxacin (3.3 mg/kg p.o. once daily). No relapse was noted over a five year follow-up period with continued access to the outdoors and daily sun exposure.

一只两岁雄性已去势的白色美国拳师犬，使用多西环素经验性治疗细菌性毛囊炎(5mg/kg口服，每日两次)，使用酮康唑治疗马拉色菌足皮炎(5mg/kg口服，每日两次)。15天后，在口鼻背侧和双耳廓背侧稀疏的有毛皮肤上出现皮肤发红和结痂(图1)。相邻的有色素皮肤区域未受影响。停用多西环素，避免日光照射，21天后结痂消失。来耳廓背侧和口鼻背侧患病皮肤的组织病理学结果表明有光毒性反应。空泡性和网状角化细胞变性导致水疱水疱脓疱的形成，表皮各层散在的角质形成细胞凋亡，真皮浅层小倍血管病变相关的真皮水肿和出血，真皮浅层轻度炎症反应，表皮糜烂和溃疡伴厚浆液性结痂(图2)。随后分离出对马坡沙星、磺胺甲恶唑和利福平敏感的假中间型葡萄球菌。服用磺胺甲恶唑(30mg/kg口服，每日2次)20天后，出躯干、口鼻背侧、耳廓背侧出现明显的皮肤发红。怀疑磺胺甲恶唑有光毒性反应，抗生素治疗改为马波沙星(3.3 mg/kg口服，每日一次)。在5年随访期内，持续有户外活动和每日日光照射，但没有发现复发。

 

 

FIGURE 1 (a) Circular, coalescing crusts on dorsal muzzle of a 2-year-old American bulldog with a probable phototoxic reaction to doxycycline. Note that crusts do not affect adjacent pigmented areas of skin. (b) Erythema and crusts on dorsal pinnal folds of same dog shown in (a).

图1（a）一只2岁美国牛犬推测为多西环素光毒性反应，口鼻背侧环形融合的结痂。注意邻近有色素皮肤无结痂。（b）图（a）同一只犬耳廓背侧皱褶皮肤发红和结痂。

 

FIGURE 2 (a) Severe vacuolar and reticular keratinocyte degeneration forming small-to-large coalescing vesicopustules and large serocellular crusts. The epidermis is multifocally eroded and focally ulcerated. There are remnants of follicular infundibula in the crusts that have full-thickness coagulation necrosis of the infundibular walls. Haematoxylin & eosin, ×100. (b) Keratinocyte reticular degeneration forming small vesicles in the superficial epidermis. Small-calibre blood vessels in the superficial dermis have swollen vessel walls with perivascular haemorrhage and fragmentation of the erythrocytes (vasculopathy). There is superficial dermal oedema and scattered haemorrhage. H&E, ×400.

图2 (a)严重的空泡性和网状角质形成细胞变性形成小到大的合并性水疱脓疱和大的血清细胞结痂。表皮多灶性糜烂和局部溃烂。结痂处可见毛囊漏斗部残余，漏斗壁全层凝固性坏死。苏木精和伊红，×100。(b)角质形成细胞网状变性，在表皮浅层形成水疱。真皮浅层小口径血管血管壁肿胀，伴有血管周围出血和红细胞碎裂(血管病)。皮肤浅表水肿，散在出血。HE染色,×400。

 

CASE 2

病例2

A 9-year-old, female-spayed Dalmatian dog received immunomodulatory treatment with doxycycline (6.7 mg/kg p.o. twice daily), niacinamide (500mg p.o. three times a day), and omega-3 fatty acids [Derma-3 Twist Tips (Ceva Animal Health, LLC) p.o. once daily] for multiple erythematous plaques on the soft palate. Treatment started during the winter season in a cold climate. Four months later, with the onset of spring and increased sun exposure, mild crusts, erosions of the ventral nonpigmented eyelid, and an extensive crust of the nonpigmented skin of the dorsal muzzle developed (Figure 3a). The nasal planum and pigmented skin of the dorsal muzzle were spared. Histopathological findings of affected skin of the dorsal muzzle indicated multifocal superficial small dermal vessel fibrinoid necrosis, dermal oedema, ulceration and dermal elastosis compatible with a phototoxic reaction. Doxycycline was discontinued and lesions resolved within three weeks. As a result of the benefits of doxycycline treatment for the soft palate lesions, doxycycline was re-instituted one month later. Lesions compatible with phototoxicity were noted by the owner 20days later and resolved with sun avoidance despite continued doxycycline therapy.

一只9岁的已绝育雌性斑点犬使用了多西环素(6.7 mg/kg口服，每日两次)、烟酰胺(500mg p.o.，每日三次)和ω -3脂肪酸[Derma-3 Twist Tips(诗华) 口服，每日一次]进行免疫调节治疗，以治疗软腭上的多灶性发红斑块。寒冷冬季开始治疗。4个月后，随着春天的到来和日晒的增加，腹侧无色素眼睑出现了轻度结痂、糜烂，口鼻背侧无色素皮肤的大面积结痂(图3a)。鼻平面和鼻背有色素皮肤色素正常。口鼻背侧患病皮肤的组织病理学表现为多灶性浅表小真皮血管纤维样坏死、真皮水肿、溃疡和真皮弹性增生，并伴有光毒性反应。停用多西环素，病变在三周内消失。由于多西环素治疗软腭病变的优势，多西环素在一个月后重新开始使用。患犬在20天后发现了与光毒性相一致的病变，并在继续多西环素治疗的情况下通过避免日光照射得到缓解。

 

 

FIGURE 3 Crusts on nonpigmented skin of the dorsal muzzle of (a) a 9-year-old Dalmatian dog and (b) a 7-year-old pit bull dog, each with a putative phototoxic reaction to doxycycline.

图3：（a）一只9岁斑点犬和（b）一只7岁比特犬口鼻背侧无色素皮肤的结痂，两只患犬都推测是多西环素的光毒性反应。

 

CASE 3

病例3

A 7-year-old, female-spayed tan & white pit bull dog received doxycycline (9.2mg/kg p.o. twice daily) for a meticillin- and clindamycin-resistant Staphylococcus pseudintermedius pododermatitis. Within 17days, erythema occurred on the concave aspects of both pinnae and the dorsal muzzle which progressed to ulcerations and crusts over seven days (Figure 3b). It was noted that the dog had recently had more access to the outdoors with increased temperatures and sunlight. Doxycycline was continued for 14 more days while sun exposure was restricted. The ulcerations and crusts became static. Three weeks later, only a 2.5 cm erosion and mild erythema were noted on the dorsal muzzle. The dog's skin was normal three months after discontinuation of doxycycline. No new dermatological lesions developed with routine sun exposure, and the patient was euthanised for gastric dilatation-volvulus five months later.

一只7岁的已绝育雌性棕白色比特犬因甲氧西林和克林霉素耐药性假中间葡萄球菌足皮炎接受多西环素(9.2mg/kg p.o.，每日两次)治疗。17天内，鼻翼和口鼻和耳廓背侧出现皮肤发红，7天内发展为溃疡和结痂(图3b)。研究人员指出，随着温度和日光的升高，这只犬最近有了更多的户外活动。多西环素继续使用14天，同时限制日光照射。溃疡和结痂变得稳定没有加重。三周后，只在口鼻背侧发现2.5厘米的糜烂和轻度皮肤发红。停用多西环素3个月后，犬的皮肤恢复正常。常规的日光照射没有出现新的皮肤病变，5个月后患犬因胃扩张扭转被安乐死。

 

DISCUSSION

讨论

Doxycycline is frequently used in dogs, yet to the best of the authors' knowledge the case series described herein constitutes the first reported cases of probable phototoxic reactions associated with its use in dogs. Phototoxicity attributable to doxycycline was suspected in three dogs, and to sulfamethoxazole also in one of the dogs.

犬经常会使用多西环素，但据作者所知，本文所述的病例系列是首例描述可能与犬使用多西环素出现光毒性反应。3只犬怀疑多西环素的光毒性，1只犬怀疑磺胺甲恶唑的光毒性。

 

Phototoxicity is a well-known adverse effect of doxycycline use in humans and is mediated by excited-state singlet oxygen and free radical damage to mitochondria. Doxycycline has an aromatic ring that can absorb radiant energy within the UV-A (320–400nm) range resulting in the excitation of electrons from the stable singlet state to an excited triplet state. Reactive oxygen intermediates damage mitochondrial membranes. Signal transduction pathways that lead to the production of proinflammatory cytokines and arachidonic acid metabolites also are activated, resulting in an inflammatory response that has the clinical appearance of an exaggerated sunburn reaction. Numerous medications are known to cause photosensitivity (phototoxicity or photoallergy) in people.

光毒性是人类使用多西环素的一个众所周知的不良反应，由激发态单线态氧和自由基对线粒体的损伤介导。多西环素具有一个芳香环，可以吸收UV-A (320-400nm)范围内的辐射能，使电子从稳定的单线态激发到三线激发态。活性氧中间体破坏线粒体膜。导致产生促炎细胞因子和花生四烯酸代谢物的信号转导途径也被激活，导致临床表现为过度晒伤反应的炎症反应。已知有许多药物会引起人的光敏反应(光毒性或光敏性)。

 

Drug-induced photosensitisation has been reported only rarely in dogs and cats. Known forms of photosensitivity in veterinary medicine are limited to horses, cattle, sheep and goats, and include primary, porphyria, hepatogenous and undetermined pathogenesis. Owing to the delayed onset of lesions and overall uncommon incidence in dogs, we suspect that doxycycline phototoxicity may be idiosyncratic rather than dose-dependent. In two dogs of this case series, treatment started during winter in a cold climate and lesions became evident in the spring with increased sun exposure. The cutaneous absorption of UV light in the dogs of this report was facilitated by their lack of pigmented skin and sparse haircoat. Lesions resolved in Case 1 after both sun restriction and doxycycline withdrawal. In the two incidences of suspected doxycycline phototoxicity in Case 2, lesions initially resolved with doxycycline withdrawal alone then subsequently with sun avoidance but continued doxycycline administration. For Case 3, lesions became static with sun avoidance while doxycycline was continued for two additional weeks. Lesions completely resolved with doxycycline withdrawal and continued sun avoidance. The dog then was allowed daily access to sunlight without lesion recurrence, although it succumbed from an unrelated cause. Allowing access to sunlight while discontinuing doxycycline alone might strengthen the relationship between doxycycline as the cause of phototoxicity in these patients although this is not recommended.Animals with solar diseases should be removed from sunlight immediately. In people receiving doxycycline, skin reactions and proper sun protection with appropriate sunscreens, sun avoidance behaviours and protective clothing are emphasised. Sunscreens should be broad spectrum to cover the UVA1 (340–400nm) wavelength spectrum.

药物引起的光敏反应在犬和猫中很少报道。兽医学中已知的光敏反应形式仅限于马、牛、绵羊和山羊，包括原发性、卟啉症、肝源性和未确定的发病机制。由于病变的延迟发作和犬的总体发病率不高，我们怀疑多西环素的光毒性可能是特质性的，而不是剂量依赖性的。在该病例系列中的两只犬中，治疗始于寒冷气候的冬季，春季随着日光照射的增加，病变变得明显。在本报告的犬中，皮肤对紫外线的吸收是易感于无色素皮肤和被毛稀疏皮肤。病例1在限制日照和停用多西环素后，病变消退。在病例2中发生的两例疑似多西环素光毒性的病例中，病变最初通过单独停用多西环素得以缓解，随后避免光照，但仍继续使用多西环素。在病例3中，当多西环素继续使用两周后，避免光照的病变变得稳定。在停用多西环素和继续避免光照后，病变完全消失。然后，这只犬被允许每天接触日光，没有病变复发，但它死于一个不相关的病因。在这些患犬中，允许接触日光而单独停用多西环素可能会加强多西环素作为光毒性的原因之间的关系，但不建议这样做，患有日光性疾病的动物应立即远离日光。在接受多西环素治疗的人中，皮肤反应和适当的防晒、防晒行为和防护服被强调。防晒霜应该是广谱的，以覆盖UVA1 (340-400nm)波长光谱。

 

The histological lesions of phototoxicity do not show pathognomonic microscopic changes that can help to definitively distinguish them from acute to subacute solar damage alone. However, in general, the lesions in phototoxic dermatitis are more severe than the lesions from solar damage. When compared with solar damage alone, phototoxic reactions are more likely to have coagulation necrosis of the epidermis and follicular walls that extends into the superficial dermis, as seen in Figure 2a, along with the vascular changes seen in Figure 2b. The microscopic lesions in these cases also lacked the changes that are associated with chronic solar dermatosis, which would be expected with the duration of the lesions, if caused by solar damage alone. Changes associated with chronic solar dermatosis that were not observed in these cases include solar elastosis, superficial dermal pallor with loss of collagen fibrillar detail (smudging), and epidermal dysplasia. Other changes that are associated with chronic solar dermatosis that were present and expected in these cases include basilar epidermal hyperplasia, parakeratotic hyperkeratosis and scattered apoptotic epidermal keratinocytes (sunburn cells). The presumptive diagnosis of a phototoxic reaction requires the combination of clinical history and clinical signs, supporting compatible microscopic lesions, improvement and resolution of the lesions with withdrawal of the suspected phototoxic agent, and lack of reemergence of the lesions with subsequent sun exposure. The presumptive diagnosis requires communication and collaboration with the clinical and pathological evaluation personnel, to include submission of a complete clinical history.

光毒性的组织学损害不显示病理特异性的显微改变，这有助于明确区分它们是急性还是亚急性光损伤。然而，一般情况下，光毒性皮炎的病变比光损伤的病变更严重。与单独的光损伤相比，光毒性反应更有可能出现表皮和毛囊壁的凝固性坏死，并延伸到真皮浅层，如图2a所示，以及图2b所示的血管变化。这些病例中的显微病变也缺乏与慢性日光性皮肤病相关的变化，如果仅由光损伤引起，这将与病变的持续时间有关。在这些病例中未观察到的与慢性日光性皮肤病相关的变化包括日光弹性、皮肤浅表苍白伴胶原纤维细节丧失(模糊)和表皮发育不良。在这些病例中，与慢性日光性皮肤病相关的其他变化包括基底层表皮增生、角化不全性角化过度和散在的表皮角质形成细胞凋亡(晒伤细胞)。光毒性反应的推测诊断需要结合临床病史和临床症状，支持的显微病变，病变的改善和解决与可疑的光毒性药物的停用，以及随后的日光照射没有复发的病变。假定诊断需要与临床和病理评估人员沟通和合作，包括提交完整的临床病史。

 

While uncommon, cutaneous lesions may occur with sun exposure and concomitant doxycycline administration in some dogs. Lack of, or loss of, pigmentation in the skin and short haircoat or alopecia may contribute to the likelihood of this phenomenon. Veterinarians should be aware of the potential of phototoxicity with doxycycline therapy and owners of at-risk dogs should be informed to restrict access of their dogs to sunlight during treatment, including sunbathing indoors by windows. If possible, treatment with doxycycline and/or exposure to sunlight should be discontinued at the first evidence of erythema.

虽然不常见，皮肤病变可能发生在日光照射和伴随多西环素给药的一些犬。少色素或无色素皮肤，短毛或脱毛皮肤可能易患病。兽医应了解多西环素治疗的潜在光毒性，应告知有风险的犬的主人在治疗期间限制他们的犬日光暴露，包括在室内靠窗户晒太阳。如果可能，在出现皮肤发红的第一时间，应停止多西环素治疗和/或日光照射。

 

 

 

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