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诺卡菌性角膜炎

Nocardia Keratitis

作者信息

Gurnani Bharat, Moshirfar Majid

机构信息

Gomabai Netralaya and Research Centre

University of Utah/John Moran Eye Center; Hoopes Vision/HDR Research Center; Utah Lions Eye Bank

出版信息


DOI:
PMID:31751092
Abstract

is a gram-variable, aerobic, weakly acid-fast bacterium that infrequently causes ocular disease, most often as a corneal infection (see . Filamentous ). Misdiagnosis or delayed recognition of keratitis commonly stems from nonspecific clinical features that resemble those produced by more prevalent pathogens. The organism often responds poorly to standard empiric agents for bacterial keratitis, including fluoroquinolones, leading to treatment delays and avoidable visual morbidity. A rare but potentially vision-threatening corneal infection, keratitis typically follows direct inoculation of the epithelium by the pathogen, which is found in soil, decaying vegetation, and water (see .  Keratitis). While most frequently causes pulmonary or cutaneous disease, ocular involvement may arise from systemic spread or primary infection. Corneal entry usually occurs through epithelial defects associated with trauma, contact lens wear, ocular surface disease, or prior surgery, underscoring the relevance of both environmental and iatrogenic risk factors. keratitis accounts for fewer than 2% of bacterial keratitis cases in temperate climates but appears more frequently in tropical and subtropical regions where agricultural exposure and humid conditions favor organism growth. The risk increases among patients with impaired ocular surface defenses, including those with dry eye, neurotrophic keratitis, prior herpetic infection, and immunodeficiency. Although systemic immunocompromise is not required for corneal involvement, chronic topical steroid use and systemic diseases such as diabetes mellitus may contribute to more severe disease courses. Clinically, keratitis presents insidiously, with patients reporting photophobia, foreign-body sensation, tearing, and blurred vision developing over several days to weeks. On slit-lamp examination, the hallmark feature is a multifocal, superficial stromal infiltrate with a characteristic “wreath-like” or “serpiginous” pattern and satellite lesions radiating from a central nidus. Corneal epithelial defects often appear irregular and overlay thin, yellowish stromal infiltrates. A dense perineural infiltrate—radial, bead-like accumulations along corneal nerves—is another suggestive finding, though not pathognomonic. Hypopyon formation is uncommon but, when present, may indicate deeper anterior chamber involvement. Rapid, accurate diagnosis remains challenging. Standard smear techniques using gram, modified acid-fast (eg, Kinyoun), and Giemsa stains can reveal delicate, branching filamentous organisms. However, low organism load and atypical morphology may lead to misidentification as fungal filaments or other actinomycetes. Culture on selective media such as blood agar, Sabouraud dextrose agar (SDA), and Lowenstein-Jensen medium supports the growth of colonies, typically chalky, matte, and white to tan over 3 to 5 days. Species-level identification may require biochemical assays, high-performance liquid chromatography, or molecular methods such as polymerase chain reaction (PCR) and 16S rRNA gene sequencing—tools that enable faster turnaround times and precise speciation to guide antimicrobial therapy. Effective treatment depends on the timely initiation of targeted topical and, when needed, systemic antibiotics. Historically, sulfonamides, particularly topical trimethoprim-sulfamethoxazole (TMP-SMX), were used based on ’s susceptibility profile. Topical amikacin 2.5% is now widely considered first-line therapy for its potent and activity, superior corneal penetration, and favorable safety profile. A typical regimen includes hourly instillation during the acute phase, followed by tapering over 4 to 6 weeks, depending on clinical response. Systemic TMP-SMX (160/800 mg twice daily) may be added for deep stromal involvement or scleral extension due to its complementary ocular tissue penetration. Alternative agents, such as topical linezolid, clarithromycin, or minocycline, may be used in cases of amikacin resistance, intolerance, or disseminated disease, highlighting the need for species-specific susceptibility data. Despite targeted therapy, keratitis may remain refractory, with prolonged healing and risk of corneal thinning, perforation, and scarring. Surgical interventions, including epithelial debridement, lamellar keratectomy, and therapeutic penetrating keratoplasty (TPK), are often required for persistent infiltrates, progressive stromal melt, or impending perforation. Adjunctive strategies such as corneal cross-linking have been evaluated in small case series to slow collagen degradation and microbial proliferation, though controlled clinical trials are lacking. Outcomes vary widely and depend on diagnostic timing, species virulence, stromal depth of infection, host immune status, and the prompt initiation of effective antimicrobial therapy. Visual prognosis ranges from near-complete recovery with early treatment to severe impairment or globe loss in advanced or mismanaged cases. The high morbidity of keratitis underscores the need for clinical vigilance, especially in at-risk individuals such as contact lens users, agricultural workers, and those with ocular surface disease. From a systems perspective, keratitis exposes key deficiencies in current ophthalmic practice, including the following: Underrecognition due to clinical overlap with fungal keratitis. Limited access to rapid species-level diagnostics. Inconsistent empiric antibiotic regimens lacking coverage. Addressing these gaps requires interprofessional collaboration among ophthalmologists, microbiologists, pharmacists, and primary care providers. Optimizing outcomes depends on streamlining diagnostic workflows, standardizing laboratory protocols, and disseminating guideline-based treatment strategies. The expanding use of molecular diagnostics and the emergence of antimicrobial resistance demand continued surveillance and prospective studies. Comparative trials of topical agents, novel drug-delivery platforms (eg, antibiotic-loaded contact lenses or intracorneal implants), and evaluation of adjunctive therapies such as collagen cross-linking offer promising avenues for investigation. The potential utility of immunomodulators, biologics targeting inflammatory mediators, and photodynamic therapy remains largely unexplored, presenting opportunities to personalize treatment for this uncommon infection. keratitis presents significant diagnostic and therapeutic challenges with potentially severe visual consequences. A clear understanding of its epidemiology, clinical features, microbiology, and treatment is essential for managing corneal infections, especially in settings with high environmental exposure risk or ocular surface compromise. Improved outcomes depend on early recognition, targeted antimicrobial therapy, timely surgical intervention when warranted, and sustained interprofessional collaboration. Ongoing education, research, and quality-improvement efforts will be critical to advancing care and reducing the global burden of keratitis.

摘要

是一种革兰氏染色可变、需氧、弱抗酸的细菌,很少引起眼部疾病,最常见的是角膜感染(见丝状菌)。角膜溃疡的误诊或延迟诊断通常源于非特异性临床特征,这些特征与更常见病原体产生的特征相似。该病原体对细菌性角膜炎的标准经验性用药(包括氟喹诺酮类)反应通常较差,导致治疗延迟和可避免的视力损害。角膜溃疡是一种罕见但可能威胁视力的角膜感染,通常由病原体直接接种上皮引起,病原体存在于土壤、腐烂植被和水中(见角膜溃疡)。虽然最常引起肺部或皮肤疾病,但眼部受累可能源于全身播散或原发性感染。角膜感染通常通过与外伤、佩戴隐形眼镜、眼表疾病或先前手术相关的上皮缺损发生,强调了环境和医源性危险因素的相关性。在温带气候中,角膜溃疡占细菌性角膜炎病例的不到2%,但在热带和亚热带地区更为常见,在这些地区,农业接触和潮湿条件有利于病原体生长。眼表防御受损的患者风险增加,包括干眼症、神经营养性角膜炎、先前疱疹感染和免疫缺陷患者。虽然角膜受累不需要全身免疫功能低下,但长期局部使用类固醇和糖尿病等全身性疾病可能导致更严重的病程。临床上,角膜溃疡隐匿出现,患者报告在数天至数周内出现畏光、异物感、流泪和视力模糊。在裂隙灯检查中,标志性特征是多灶性、浅层基质浸润,具有特征性的“花环样”或“匐行性”模式,以及从中央病灶放射状分布的卫星病灶。角膜上皮缺损通常不规则,覆盖薄的、淡黄色的基质浸润。密集的神经周围浸润——沿角膜神经呈放射状、串珠状积聚——是另一个提示性发现,尽管不是特异性的。前房积脓形成不常见,但出现时可能表明前房更深层受累。快速、准确的诊断仍然具有挑战性。使用革兰氏、改良抗酸(如金扬氏)和吉姆萨染色的标准涂片技术可以显示纤细的、分支的丝状菌。然而,病原体载量低和形态不典型可能导致误诊为真菌丝或其他放线菌。在选择性培养基如血琼脂、沙保弱葡萄糖琼脂(SDA)和罗氏培养基上培养支持菌落生长,通常在3至5天内呈灰白色、无光泽、白色至棕褐色。种属水平的鉴定可能需要生化分析、高效液相色谱或分子方法,如聚合酶链反应(PCR)和16S rRNA基因测序——这些工具能够更快地周转并进行精确的种属鉴定,以指导抗菌治疗。有效的治疗取决于及时开始针对性的局部治疗,并在需要时进行全身抗生素治疗。历史上,根据病原体的药敏谱使用磺胺类药物,特别是局部用甲氧苄啶-磺胺甲恶唑(TMP-SMX)。目前,2.5%的局部用阿米卡星因其强大的抗菌活性、优越的角膜穿透力和良好的安全性而被广泛认为是一线治疗药物。典型的治疗方案包括在急性期每小时滴眼一次,然后根据临床反应在4至6周内逐渐减量。由于其对眼组织的互补穿透力,对于深层基质受累或巩膜扩展的情况,可添加全身用TMP-SMX(160/800 mg,每日两次)。在阿米卡星耐药、不耐受或播散性疾病的情况下,可使用替代药物,如局部用利奈唑胺、克拉霉素或米诺环素,这突出了需要种属特异性药敏数据。尽管进行了针对性治疗,角膜溃疡可能仍然难治,愈合时间延长,并有角膜变薄、穿孔和瘢痕形成的风险。对于持续浸润、进行性基质溶解或即将穿孔的情况,通常需要手术干预,包括上皮清创、板层角膜切除术和治疗性穿透性角膜移植术(TPK)。在小病例系列中对角膜交联等辅助策略进行了评估,以减缓胶原蛋白降解和微生物增殖,但缺乏对照临床试验。结果差异很大,取决于诊断时间、病原体毒力、感染的基质深度、宿主免疫状态以及有效抗菌治疗的及时启动。视力预后范围从早期治疗后的近乎完全恢复到晚期或管理不当病例中的严重损害或眼球丧失。角膜溃疡的高发病率强调了临床警惕的必要性,特别是对于高危个体,如隐形眼镜使用者、农业工人和眼表疾病患者。从系统角度来看,角膜溃疡暴露了当前眼科实践中的关键缺陷,包括以下几点:由于与真菌性角膜炎的临床重叠而未被充分认识。快速种属水平诊断的可及性有限。缺乏针对病原体覆盖的不一致经验性抗生素方案。解决这些差距需要眼科医生、微生物学家、药剂师和初级保健提供者之间的跨专业合作。优化结果取决于简化诊断工作流程、标准化实验室方案以及传播基于指南的治疗策略。分子诊断的广泛应用和抗菌药物耐药性的出现需要持续监测和前瞻性研究。局部药物、新型给药平台(如载抗生素隐形眼镜或角膜内植入物)的比较试验以及对胶原交联等辅助治疗的评估提供了有前景的研究途径。免疫调节剂、靶向炎症介质的生物制剂和光动力疗法的潜在效用在很大程度上仍未被探索,为这种罕见感染的个性化治疗提供了机会。角膜溃疡带来了重大的诊断和治疗挑战,可能产生严重的视觉后果。清楚了解其流行病学、临床特征、微生物学和治疗方法对于管理角膜感染至关重要,特别是在环境暴露风险高或眼表受损的情况下。改善结果取决于早期识别、针对性抗菌治疗、必要时及时进行手术干预以及持续的跨专业合作。持续的教育、研究和质量改进努力对于推进护理和减轻全球角膜溃疡负担至关重要。

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