Nocardia and the Eye
Nocardia is a rare cause of ocular infections. Ocular infections caused by Nocardia include keratitis, scleritis, conjunctivitis, canaliculitis, dacrocystitis, orbital cellulitis, and endophthalmitis. Corneal infections being the most common. The diagnosis is often missed or delayed as the the clinical picture may resemble other causative organisms. Patients often suffer from significant ocular morbidity for a prolonged period before an accurate diagnosis is made. Nocardia infections do not respond to commonly used first-line medications for bacterial keratitis, such as fluoroquinolones. With the initiation of appropriate therapy, Nocardia infections respond promptly and carries a good prognosis.
Nocardia belong to the bacterial order Actinomycetales that comprises three families and more than 40 genera; 14 of which seem to be relevant to human and veterinary medicine. Originally classified as a fungus, Nocardia are now recognised as true bacteria. Nocardia are aerobic, gram-positive, non-motile, branching, filamentous bacteria (less than 1.5 micrometers in diameter). There are at least 12 accepted species within the genus Nocardia. These include N. asteroides, N. amarae, N. brasilinesis, N. brevicatea, N. carnea, N. farcinica, N. nova, N. otitidis-caviarum (N. caviae), N. pinensis, N. seriolae, N. transvalensis and N. vaccinni.
Nocardia represent indigenous microflora of soil, mud, dust and decaying vegetation. Pathogenic species of Nocardia have been detected in house dust, beach sand, garden soil, and swimming pools. Nocardia species do not present as normal flora either in the eye or in the respiratory tract. Actinomycetes are found around the word with no racial or occupational predilection noted. Nocardia asteroides is prominent in temperate regions and Nocardia brasiliensis is found in tropical and subtropical areas.
Predisposing factors are trauma, surgery, corticosteroid use, and contact lens wear. Traumatising agents reported include vegetative material, dirt, stone, gravel, flying insects; as well as injuries from nails and fish line sinkers. Nocardia has been isolated from eyes with contact lens associated keratitis. Inappropriate lens hygiene and extended wear can predispose to infectious keratitis.
N.asteroides keratitis has been found following surgical trauma. Nascimento et al reported a case following an uncomplicated myopic keratomileusis. Perez-San-tonja et al found Nocardia following uncomplicated LASIK treatment for myopia. One case has been reported following penetrating keratoplasty. The use of topical corticosteroids may also be a predisposing factor. A rabbit model of topical corticosteroid use in Nocardia keratitis observed the development of large granulomatous lesions with extension into the anterior chamber in those treated with topical steroids, whereas no extension was noted in those not treated with steroids.
The rate of growth and multiplication of Nocardia is slow and does not cause a fulminant infection immediately post invasion. It is presumed that parasite-related virulence is involved, as the organism can infect healthy individuals. The virulence is partly due to structural and biochemical cellular changes that occur in the growth cycle. A combination of mycolic acids within the cell wall are altered throughout nocardial growth, that contributes to its toxicity and virulence throughout the growth cycle.A toxic cell wall component known as trehalose 6,6’-dimycolate is associated with the virulence of Nocardia through the inhibition of phagosome-lysosome fusion in macrophages and the escape of lysosome fusion in macrophages. There is a probably role of nocardial surface membrane-bound catalase and superoxide dismutase (SOD) in its resistance to being killed by polymorphonuclear leukocytes. There is also a possible role of Nocardia exotoxins in causing host-tissue damage.
Primary prevention of Nocardia eye infections involves avoiding the above risk factors. This includes proper contact lens use, avoidance of potential insults by wearing protective eyewear, avoiding topical steroid use, and employing proper aseptic technique during surgical procedures.
A detailed history should be taken from patients presenting with suspected microbial ocular infections. This should begin with the characteristics and onset of the symptoms; including any pain, photophobia or vision changes. It is important to inquire about any predisposing factors, such as contact lens wear including the type of lens, wearing time and lens hygiene, recent trauma including surgical procedures, use of immunosuppressive agents and pre-existing eye conditions such as dry eye and neurotrophic keratopathy. Other relevant medical history such as decreased immunologic defences or systemic immunosuppression medications is useful in assessing the risk of microbial ocular infections.
A comprehensive ocular examination should be conducted. This includes vision, pupil assessment, extraocular motility and alignment, intraocular pressures, confrontation and external examination. This is followed by a slit-lamp examination. This involves the systematic assessment of the lids, lashes and lacrimal system, conjunctiva and sclera, cornea, anterior chamber, iris, lens and anterior vitreous. A dilated examination should be performed to assess the optic nerve, macula, vessels and periphery to rule out posterior pole involvement. Clinical features of Nocardia infections of the eye are found below.
The conjunctiva may show a fine papillary reaction. Keratitis can present as a nonspecific punctate epitheliopathy or an ulcer with margins studded with yellow white pin-head sized superficial infiltration (Figure. 1). Patchy infiltrations are predominantly anterior stromal with involvement of the epithelial and subepithelial tissues. These infiltrates often present in a classical wreath like pattern with satellite lesions (Figure. 2). Infiltrates are usually situated in the midperiphery of the cornea adjacent to the sites of minor corneal trauma or abrasion.
Usually, there is an overlying epithelial defect and the surrounding stroma is clear. Anterior chamber reaction and hypopyon are usually associated. Introocular pressure is usually normal.  Keratic precipitates and endothelial ring deposits on the endothelium have also been reported. Peripheral deep neovascularisation may be seen. The cornea may be hypesthetic. Superficial granular infiltrates can coalesce into white plaque, resulting in corneal ulceration.  A summary of the typical and atypical features of Nocardia keratitis is detailed in Table 1.
Intraocular nocardiosis is rare. Reported Nocardia endophthalmitis are commonly from haematogenous (endogenous) spread of the organism and occasionally exogenously. Hematogenous spread occurs to the eye, resulting in choroidal abscess or endophthalmitis. The clinical picture consists of a large, yellow choroidal lesion with haemorrhage in the overlying retina. Chorioretinal lesions are usually located in the central and paracentral regions. Retinal thickening and exudative retinal detachment can occur, as well as optic nerve head elevation. Nocardia endophthalmitis can present with a hypopyon and no posterior findings. Endogenous Nocardia endophthalmitis is most commonly unilateral. Bilateral nocardial infections have been reported in cases of pulmonary Nocardia asteroides infection and in those with hypogammaglobulaemia. Exogenous Nocardia can occur after cataract surgery, penetrating injury and trabeculectomy. There is anterior segment inflammation and hypopyon. Yellowish-white nodules can be seen over the iris (Figure 3) and puffball opacities may be visible in the anterior vitreous.
Isolated Nocardia scleritis is rare and results as an extension of corneal infection. Predisposing factors including cataract surgery, exposed scleral buckle following cataract surgery, explantation of scleral buckle and trauma. Signs include conjunctival and scleral inflammation and areas of necrosis, thinning, hemorrhage, and discharge. Scleral abscesses and engorged episcleral vessels may be seen. Anterior chamber reaction is associated.
Other ocular manifestations of Nocardia include conjunctivitis, infection of the lacrimal system, preseptal cellulitis, and dacryoadenitis.
Nocardia eye infections usually run a protracted course. Presenting symptoms consist of pain, photophobia, blepharospasm, and lid swelling. The amount of pain may be out of proportion to clinical findings.
A diagnosis of Nocardia eye infection is made based on the history, symptoms and clinical signs found during the systematic ocular examination.
The gold standard for the diagnosis of Nocardia keratitis is a scraping from the corneal lesion using a spatula or blade. Usually, multiple scrapings are collected for three smears and to inoculate several culture media allowing for the growth of all types of bacteria (aerobic, facultatively anaerobic, and anaerobic), fungi and Acanthameoba.
Smears are collected and stained by gram stain, Giemsa stain, and potassium hydroxide with calcoflour white stain. The presence of gram-positive, branching, beaded filaments that stain with 1% acid-fast stain (using 1% sulfuric acid, modified Kinyoun’s method) is suggestive of a Nocardia infection.
Nocardia organisms in culture are not fastidious and grow aerobically on media as tiny, white, dry colonies. They usually grow within 48-72 hours on blood agar, chocolate agar, and Sabouraud’s dextrose agar (without antiobiotics). Growth on one medium is considered significant with corresponding smear results and a clinical picture suggestive of Nocardia. Nocardia isolation is considered significant, given that it is not a common contaminant.
Differentials for Nocardia infections include Moraxella, nontuberculous Mycobacteria and filamentous fungi. Moraxella is a gram-positive diplobacillus that can produce corneal ulcers in select patient groups including diabetics, alcoholics and the malnourished. Moraxella ulcers are oval and located inferiorly on the cornea. Nontuberculous Mycobacteria are acid-fast bacilli that cause slowly progressive corneal infections. The infiltrate in Myobacterial infections have indistinct fluffy or feather-like appearances with radiating projections, described as a “snow-flake” or “cracked windshield” appearances. Filamentous fungi produce slow growing, corneal ulcers with dry, raised infiltrates with hyphate edges and satellite lesions.
General treatment consists of medical and surgical therapies. Medical therapies are inclusive of topical and systemic antibiotic treatment. In the case of advanced Nocardia infections, surgical treatment may be warranted. In addition, general measures such as the discontinuation of contact lens wear, avoidance of immunosuppressive agents and avoidance of further insults should be facilitated.
Nocardia organisms show good susceptibility to amikacin and sulphonamides. Present research indicates excellent in vitro activity of amikacin against all Nocardia species, including N. amamiensis, N. thailandica, N. levis, and N. puris. Aminoglycosides such as gentamicin and tobramycin are second line treatment of this infection. Antimicrobial susceptibility of Nocardia to fluoroquinolones such as ciprofloxacin and clarithromycin varies across species. Gulpczynski et al. reported that Nocardia species including Nocardia nova, N. cyriacigeorgica, N. abscessus and N.brasiliensis showed resistance to ciprofloxacin. Keratitis and scleritis cases respond well to amikacin therapy, the outcome of endophthalmitis management is not encouraging.
Medical follow up
Nocardia infections usually require admission or daily follow up to assess for progress and the suitability of the treatment regimen.
Nocardia keratitis is usually well treated with medical therapy. However, surgical treatment may be warranted in the case of progressive corneal thinning, extension beyond the limbus, or presentation at an advanced stage. Surgical options are therapeutic lamellar keratectomy, penetrating keratoplasty, and conjunctival flap. 
Surgical follow up
Close follow up is recommended with a review day one post-operatively.
Complications described in the literature include progressive thinning leading to perforation, endophthalmitis, and extension to adjoining sclera.
With medical treatment, the ulcer heals rapidly. The infiltrate resolves with minimal scarring, forming a fine superficial nebular opacity (Figure. 5). Nocardia keratitis tends to heal with peripheral vascularization or with vascularized scars. Patients usually continue to be asymptomatic with no recurrences. Visual prognosis is good and if the infection responds well to medical therapy, visual acuity improves.
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