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ORIGINAL ARTICLE
Year : 2000  |  Volume : 48  |  Issue : 3  |  Page : 217-21

Nocardia Asteroides Keratitis: Report of seven patients and literature review


Medical Research Foundation, 18 College Road, Chennai-600 006, India

Correspondence Address:
S K Rao
Medical Research Foundation, 18 College Road, Chennai-600 006
India
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Source of Support: None, Conflict of Interest: None


PMID: 11217254

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  Abstract 

Purpose: To describe clinical features and treatment outcomes in patients with advanced Nocardia asteroides keratitis.
Methods: Retrospective review of case records of 7 patients with culture-proven Nocardia keratitis.
Results: Corneal infection occurred after corneal trauma in two patients, cataract surgery in three patients, penetrating keratoplasty in one patient and was associated with a silicone buckle element infection in one patient. Mean duration of infection at presentation was 33.4 days (7-75 days), and five patients had received prior treatment with corticosteroids. Six of seven patients had deep corneal suppuration at the time of: presentation, clinically suggestive of mycotic keratitis. In two patients who had received prolonged corticosteroid therapy (≥ 45 days), the eyes could not be salvaged. Complete resolution of infection was achieved in all 4 eyes treated with topical fortified cefazolin eye drops (50mg / ml).

Keywords: Adolescent, Adult, Aged, Cefazolin, administration & dosage, Cephalosporins, administration & dosage, Child, Child, Preschool, Comparative Study,


How to cite this article:
Rao S K, Madhavan H N, Sitalakshmi G, Padmanabhan P. Nocardia Asteroides Keratitis: Report of seven patients and literature review. Indian J Ophthalmol 2000;48:217

How to cite this URL:
Rao S K, Madhavan H N, Sitalakshmi G, Padmanabhan P. Nocardia Asteroides Keratitis: Report of seven patients and literature review. Indian J Ophthalmol [serial online] 2000 [cited 2020 Apr 8];48:217. Available from: http://www.ijo.in/text.asp?2000/48/3/217/14871



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Nocardial infection of the ocular surface was first reported by Bruce and Locatcher-Khorazo in 1942, as a punctate keratoconjunctivitis that resolved following treatment with topical and oral Potassium iodide.[1] Since then there have been sporadic case reports of nocardial infection of the eye and ocular adnexa manifesting as dacryocystitis, conjunctivitis, episcleral granuloma, persistent epithelial defect, keratitis, scleritis and endophthalmitis.[2-8] The most frequent, however, is keratitis and traditional treatment consists of the "triple drug regimen" using ampicillin, trimethoprim-sulphamethoxazole (TMP-SMZ), and sulphacetamide.[7]

Results of treatment of Nocardia asteroides with sulfonamides have, however, been controversial,[6] and susceptibility tests suggest a 92.5% resistance to TMP-SMZ.[9] A recent report described the successful treatment of Nocardia scleritis with cefazolin after antibiotic sensitivity testing found resistance to TMP-SMZ.[7] Sridhar et al[10] described 16 patients with Nocardia keratitis: all isolates were sensitive to gentamicin, though 30% sulphacetamide was the preferred drug for treatment. In this report, we describe 7 patients with culture-proven Nocardia asteroides keratitis, one of whom also had scleritis. The predisposing factors, clinical features, response to antibiotic therapy, eventual outcomes, and results of in-vitro antibiotic susceptibility testing are described.


  Materials and Methods Top


The case records of 7 patients with culture-proven Nocardia keratitis, seen at our institute between November 1990 and February 1995, were retrospectively reviewed. The clinical findings of the 7 patients are summarized in [Table:1a]. Treatment details and final outcomes are listed in [Table:lb].


  Microbiology Top


Corneal scrapings were collected and processed as described by Agarwal et al.[11] Multiple scrapings of the ulcer bed and margins were obtained using topical 4% lignocaine. The material obtained was used to inoculate culture media and prepare smears. The specimens were inoculated on to 10% sheep blood agar (incubated aerobically at 35C), Brucella blood agar (incubated anaerobically at 36C in anaerobic work station - Don Whitley, India), chocolate agar (incubated at 36C in 10% carbon-dioxide incubator, Forma Scientific, USA), Sabouraud's dextrose agar without cycloheximide (incubated aerobically at 25C - Remi cooling incubator, India) and brain-heart infusion broth. All media were obtained from a commercial source - HiMedia, India. The isolated Nocardia species were identified by standard bacteriological methods.[12]

Two strains of Nocardia asteroides (isolated from Patients # 5 and # 6) were tested for susceptibility to cefazolin, using the macrodiiution (tube) broth method.[12] Two-fold dilutions of cefazolin, from 100 mg / ml onwards, in 1 ml amounts, were prepared in Mueller-Hinton broth (MHB), obtained from HiMedia, India. A reference strain of Staphylococcus aureus (ATCC 25923) was also included in the test Since the isolated Nocardia asteroides strains did not form a uniform suspension, 4-5 colonies were suspended in 2 ml of MHB, vortexed for 2 minutes and left undisturbed for 15 minutes. After large particles settled down, 100 ml of fine suspension of the organism from the supernatant was inoculated into each dilution tube of cefazolin. The results were read at 24 hours. The lowest concentration of cefazolin that resulted in complete inhibition of visible growth represented the minimum inhibitory concentration (MIC). The tests were repeated twice to confirm the results.


  Results Top



  Clinical Features Top


The median age of the patients (5 males, 2 females) was 44 years (range: 2-72 years). Four of the patients, all diabetic, were above 40 years of age. Two patients presented within 10 days of symptoms, while four others presented a month or more after onset of symptoms. Mean duration of infection at the time of presentation was 33.4 days (range: 7-75 days).

Treatment prior to presentation included topical antibiotics (not cefazolin) in all patients, and corticosteroids in five patients (topical, four patients; oral, one patient). Predisposing corneal trauma was present in two patients (injury by an insect, patient # 6; stone concrete, patient # 2). The sites of infection were corneoscleral wound of extracapuslar cataract surgery (n=3; Patients # 3, 5, 7), at site of loose suture in an eight month-old corneal graft (Patient # 4), and concurrent keratitis and scleral buckle infection (Patient # 1); one patient (# 7) also had scleral involvement.

All patients presented with intense conjunctival congestion and minimal or no mucopurulent discharge. One patient (# 6) had an ulcer with feathery margins and midstromal infiltrates [Figure - 1]. The other six patients had deep corneal suppuration with overlying epithelial breakdown [Figure - 2]. A moderate-to-severe anterior chamber reaction was noted in all patients and four patients (# 3, 5, 6, 7) had a hypopyon on presentation. In one patient (# 2), a transient hypopyon occurred after cessation of topical corticosteroids.


  Microbiology Top


Gram-positive, thin filamentous bacilli were seen in smears in four patients (# 1, 2, 3, 4). These filamentous bacilli were acid fast, demonstrated by staining the smears with the Kinyoun staining method. Cultures were positive for Nocardia asteroides in all patients by the fourth day. The isolated strains were identified as Nocardia asteroides by their characteristic chalky white colonies with tiny aerial hyphae, which fragmented into bacillary and coccoid forms in smears. Inability of the isolates to hydrolyze casein, hypoxanthine and tyrosine, and ability to produce urease confirmed their identity as Nocardia asteroides. In-vitro antibiotic susceptibility testing of two isolates of Nocardia asteroides with cefazolin showed a mean inhibitory concentration (MIC) of 50 mg / ml, for each of the isolates.


  Treatment Top


Nocardia keratitis resolved with treatment in five eyes. Topical antibiotics (Table 2) were applied at hourly intervals in all eyes, for the first 3 days. Thereafter, the dosage was reduced according to the clinical response. The corneal infection in patient # 1 resolved with removal of the infected buckle and use of 20% sulphacetamide drops. In two patients, complete resolution of keratitis was achieved using fortified cefazolin eye drops (50 mg / ml), either alone (patient # 6), or in combination with 0.3% ciprofloxacin eye drops (patient # 4). These two patients did not receive any other antibiotics described in literature as specific for nocardiosis. In two other patients (patients # 2,7) keratitis resolved using fortified cefazolin eye drops (50 mg / ml) in combination with 20% sulphacetamide eye drops and / or oral TMP-SMZ [Figure - 3].

In patients # 3 and 5, multi-drug therapy including 20% sulphacetamide, TMP-SMZ, ampicillin, penicillin, tetracycline and ciprofloxacin (cefazolin was not used) did not control the keratitis. Despite therapeutic penetrating keratoplasty, nocardial keratitis recurred and progressed to endophthalmitis, in both the patients. Hence, the eyes were eviscerated.

Functional vision was retained in 4 of 5 eyes that responded to medical treatment; visual acuity was 6 / 12 or better in two of these patients (patients # 1 and 6). The average duration of treatment in these 5 eyes was 31.2 days (range: 15 - 60 days). One patient (patient # 2) later sustained injury and developed inoperable retinal detachment with poor vision.


  Discussion Top


Nocardia are ubiquitous aerobic bacteria belonging to the order actinomycetes. Nocardia asteroides is a gram-positive branching filamentous organism, which is part of the normal soil microflora. It has been described as causing opportunistic infections, usually occurring in immunosuppressed patients or after trauma.[12]

Except for the presence of well-controlled diabetes mellitus in four patients, none of the patients were on any immunosuppressive therapy and all were in good general health. All patients had an altered ocular surface environment caused by trauma and recent / prior ocular surgery [Table:1a]. Although occurrence of Nocardia keratitis following ocular trauma has been documented in literature, [5, 10, 13, 14] the association with diabetes mellitus noted in this study, has not been previously reported. The male preponderance in this series has been described in earlier reports. [10, 13, 14]

Two patients (Patients # 3, and 5) with the longest duration of infection in this series (45 and 75 days respectively) underwent evisceration. The other five patients (Patients # 1, 2, 4, 6, 7) who presented earlier in the course of their disease (mean 22.8 days), healed with medical therapy after an average treatment period of 31.2 days. This data is similar to that reported by Sridhar et al.[10] The mean interval from onset of symptoms to diagnosis was 26.7 days and average duration of treatment was 27.1 days. Perry et al[5] have inferred that the corneal nocardiosis is longer lasting and slowly progressive, though Srinivasan et al[13] have described four patients of Nocardia keratitis healing in 7-10 days with topical 10% sodium sulphacetamide and ampicillin trihydrate. This highlights the importance of prompt diagnosis and early treatment in obtaining good results in nocardial keratitis.

Both patients (Patients # 3 and 5) treated initially with corticosteroids for extended periods of time (30 and 60 days respectively) did poorly; the eyes were eviscerated despite therapeutic penetrating keratoplasty. Three of the five patients (Patients # 2, 4, 7) in our series in whom the infection was controlled had received topical corticosteroids in the initial treatment period for a shorter duration (10, 7 and 20 days respectively). Probably these eyes were salvaged because of the limited use of corticosteroids for a short duration. Incidentally, patient # 1 was not treated with corticosteroids at all and he required the shortest duration of therapy (15 days), for complete healing. It thus appears that the use of topical and / or systemic corticosteroids in Nocardia keratitis can prolong the duration of treatment and worsen prognosis. This is confirmed in an animal model (rabbit)[15] and emphasized in clinical situations.[16] None of the patients in this study were treated by us with corticosteroids [Table:1b].

The typical clinical picture described by various authors in Nocardia keratitis is a well-defined epithelial defect with scalloped margins and a white granular appearance. The margins of the ulcer have discrete, yellowish-white, pinhead-sized infiltrates. [4,13] The stromal infiltrate has feathery margins and a wreath pattern with satellite lesions. [10,14]

Most reports also describe the occurrence of a moderate anterior chamber reaction and hypopyon. [10, 12, 14, 15] However, the above typical appearance of Nocardia keratitis was seen in only one of the seven patients in this series (Patient # 6). Other patients presented with deep corneal suppuration and the peripheral lesions developed corneal stromal vascularization with prolonged disease. Patient # 7 had scleral involvement with necrosis adjacent to the cataract wound, in addition to the peripheral corneal abscess. A hypopyon was present in four patients (patients # 3, 5, 6, 7) who had the longest duration of infection.

The deep corneal lesions in our series reflect the prolonged duration of infection, and may also be a result of the modified growth pattern of Nocardia organisms due to use of corticosteroids. It is noteworthy that Patient # 6 in this series, the only one whose keratitis resembled earlier descriptions of Nocardia corneal infection, did not receive any corticosteroid therapy.

The antibiotics used in our patients are listed in [Table:1b] and corresponded with other reports. [7, 12, 13] Commercially available preparations of norfloxacin, 20% sulphacetamide, natamycin, trimethoprim-sulphamethoxazole, and ciprofloxacin were used topically. Fortified cefazolin (50 mg / ml), penicillin (1,00,000 units / ml) and ampicillin trihydrate (100 mg / ml) were also used topically in some patients [Table:1b]. Two patients (Patients # 3, # 5) in this series did not respond to "specific" antibiotics such as ampicillin, sulphacetamide, and TMP-SMZ. In four others (Patients # 2, 4, 6, 7), keratitis resolved with fortified cefazolin eye drops (50mg / ml) in conjunction with "specific" antibiotics (Patients # 2, 7) or without (Patients # 4, # 6). In Patient # 6 resolution occurred with topical fortified cefazolin after topical 30% sulphacetamide and ampicillin proved ineffective. Successful treatment of Nocardia scleritis with cefazolin has been reported earlier.[7]

In-vitro antibiotic susceptibility testing performed in two of the Nocardia isolates from patients in this study revealed sensitivity to cefazolin, and MIC was 50 mg / ml. Both In-vitro sensitivity[7] and resistance[17] to cefazolin has been reported, so also varied clinical response to treatment.[18]

In conclusion, this study indicates that long-term corticosteroid therapy may alter the clinical appearance, prolong the duration of infection and worsen the outcome in patients with Nocardia keratitis. Cefazolin, either alone or in combination with sulphacetamide, appears to be effective in the management of these recalcitrant infections. Early diagnosis can help to effectively manage Nocardia keratitis, but requires a high index of clinical suspicion and microbiology laboratory support.



 
  References Top

1.
Bruce GM, Locatcher-Khorazo D. Actinomyces: Recovery of the Streptothrix in a case of superficial punctate keratitis. Arch Ophthalmol 1942;27:294-98.  Back to cited text no. 1
    
2.
Peniket EJK, Rees DL. Nocardia asteroides infection of the nasolacrimal system. Am J Ophthalmol 1962;53:1006-8.  Back to cited text no. 2
    
3.
Benedict WL, Iverson HA. Chronic keratoconjunctivitis associated with Nocardia. Arch Ophthalmol 1944;32:84-92.  Back to cited text no. 3
    
4.
Henderson JW, Wellman WE, Weed LA. Nocardiosis of the eye - Report of a case. Mayo Clin Proc 1960;35:614-18.  Back to cited text no. 4
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5.
Perry HD, Nauheim JS, Donnenfeld ED. Nocardia keratitis presenting as a persistent epithelial defect. Cornea 1989;8:41-43.  Back to cited text no. 5
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6.
Douglas RM, Grove Dl, Elliot J, Looke DFM, Jordan AS. Corneal ulceration due to Nocardia asteroides. Aust NZ J Ophthalmol 1991;19;317-20.  Back to cited text no. 6
    
7.
Basti S, Gopinathan U, Gupta S. Nocardia necrotizing scleritis after trauma - Successful outcome using Cefazolin. Cornea 1994;13:274-76.  Back to cited text no. 7
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8.
Zimmerman PL, Mamalis N, Alder JB, Teske MP, Tamura M, Jones GR. Chronic Nocardia asteroides endophthalmitis after extracapsular cataract extraction. Arch Ophthalmol 1993;111:837-40.  Back to cited text no. 8
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9.
Chen CJ. Nocardia asteroides endophthalmitis. Ophthalmic Surg 1983;14:502-5.  Back to cited text no. 9
    
10.
Sridhar MS, Sharma S, Reddy MK, Mruthyunjay P, Rao GN. Clinicomicrobiological review of Nocardia keratitis. Cornea 1998;17:17-22.  Back to cited text no. 10
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11.
Agarwal V, Biswas J, Madhavan HN, Mangat G, Reddy MK, Saini JS, et al. Current perspectives in infectious keratitis. Indian J Ophthalmol 1994;42:171-91.  Back to cited text no. 11
    
12.
Gordon MA. Aerobic pathogenic Actinomycetaceae. In: Lennette EH, Balows A, Hausler WJ, Shadomy HJ, editors. Manual of Clinical Microbiology, 4th ed. Washington DC: American Society for Microbiology 1985. pp 249-62.  Back to cited text no. 12
    
13.
Srinivasan M, Sharma S. Nocardia asteroides as a cause of corneal ulcer. Arch Ophthalmol 1987;105:464.  Back to cited text no. 13
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14.
Hirst LW, Harrison GK, Merz WG, Stark WJ. Nocardia asteroides keratitis. Br J Ophthalmol 1979;63:449-54.  Back to cited text no. 14
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15.
Newmark E, Polack FM, Ellison AC. Report of a case of Nocardia asteroides keratitis. Am J Ophthalmol 1971;72:813-15.  Back to cited text no. 15
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16.
Parsons MR, Holland EJ, Agapitos PJ. Nocardia asteroides keratitis associated with extended-wear soft contact lenses. Can J Ophthalmol 1989;24:120-22.  Back to cited text no. 16
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17.
Husain N, Matoba AY, Wilhelmus KR, Jones DB. Isolation and therapy of Nocardia asteroides keratitis. Invest Ophthalmol Vis Sci 1995;36:sl55.  Back to cited text no. 17
    
18.
Helm CJ, Holland GN, Lin R, Berlin OGW, Bruckner DA. Comparison of topical antibiotics for treating Mycobacterium fortuitum keratitis in an animal model. Am J Ophthalmol 1993;116:700-7.  Back to cited text no. 18
    


    Figures

  [Figure - 1], [Figure - 2], [Figure - 3]
 
 
    Tables

  [Table - 1], [Table - 2]


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