nocardia asteroides keratitis - british journal of …nocardia asteroides keratitis in pure culture....

British Journal of Ophthalmology, 1979, 63, 449-454

Nocardia asteroides keratitisLAWRENCE W. HIRST,' G. KENNETH HARRISON,2 WILLIAM G. MERZ,2AND WALTER J. STARK'From the 'Wilmer Ophthalmological Institute of Johns Hopkins Hospital, Baltimore, Maryland,and the 2Department of Laboratory Medicine, Johns Hopkins Hospital

SUMMARY Nocardia asteroides has been reported as the cause of keratitis in only 7 cases and ofother ocular disease in another 12 cases. We report a case of N. asteroides keratitis that presented3 weeks after rural trauma and progressed despite trials of appropriate antibiotics. Seven weeksafter the original injury a successful conjunctival flap was placed over the cornea. The morphologyand the sensitivity testing of N. asteroides with agar dilution methods are described. Furtherstandardisation of susceptibility testing of N. asteroides to antibiotics appears necessary beforereliable information can be obtained for clinical use. Moreover, our case did not show the relativelybenign course of other reported cases of nocardia keratitis.

Although fungal keratitis has been reported moreoften since the introduction of topical ocularsteroid preparations (Haggerty and Zimmerman,1958) there have been only 7 reports of Nocardiaasteroides as the causative organism. A further 13cases (3 bilateral) of ocular or periocular infectionwith this organism have also been reported.We report a case of a progressive N. asteroides

corneal ulcer that was unresponsive to intensive oraland topical antibiotics. One year after a Gundersenconjunctival-flap operation the eye is quiet, and apotentially useful eye has been retained.

Case report

CLINICAL SUMMARYA 17-year-old Caucasian boy sustained injury fromforeign bodies in both corneas when dirt and debrisfrom an exploding tractor tyre peppered his eyes.He had numerous foreign bodies removed fromboth eyes on the day of the accident and on thefollowing day, and received topical sulphadiazinedrops. His vision and comfort gradually improvedover the ensuing 3 weeks, after which his left eyebecame painful and visual acuity progressivelydiminished. He was admitted to a local hospital andgiven sodium sulphacetamide eyedrops for 1 weekwithout improvement. When seen at the JohnsHopkins Hospital about 1 month after the initialinjury his right eye had 20/20 vision. There was a

Address for reprints: Lawrence W. Hirst, MD, WilmerInstitute, Johns Hopkins Hospital, 600 North Wolfe Street,Baltimore, Maryland 21205, USA

Fig. 1 Nocardia asteroides ulcer on initial presentationat the Johns Hopkins Hospital, 4 weeks after trauma

half-thickness healed corneal laceration inferona-sally, with a few foreign bodies trapped within thescar. His left eye was rather photophobic and hadgross conjunctival chemosis and ciliary injection.There was a 5 x 5 mm one-third-thickness stromalulcer inferonasally with irregular opaque edges(Fig. 1). Feathery projections from these edgesextended for a further 1 to 2 mm at mid-stromaldepth and there was a mid-stromal 'satellite' infil-trate 2 mm above the ulcer. The base of the ulcerwas irregular and filled with mucus and cornealdebris. The pupil was mid-dilated, and there wasan intense fibrinous exudate in the anterior chamber.The lens, vitreous, and retina were normal. Vision

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Lawrence W. Hirst, G. Kenneth Harrison, William G. Merz, and Walter J. Stark

was reduced to counting fingers at 3 ft (I m).Before the accident the patient had been in good

health and had 20/20 vision, with surgery at the ageof 3 for correction of strabismus. He had been onlong-term tetracycline therapy for acne before thiseye infection, but he ceased this medication on hisfirst hospital admission after the infection. He gavea reliable history of penicillin allergy.

Smears and cultures taken on his initial admissionto the community hospital were reported a weeklater as positive for Nocardia asteroides and Alcali-genes species. At the Johns Hopkins Hospital, 28days later, the corneal ulcer was again scraped forsmears and cultures and the patient was begun onsulphadiazine orally, 2 g every 6 hours, 30%sulphacetamide drops every 2 hours, 3% atropinedrops 3 times a day, achromycin drops every 2hours, and gentamicin drops every 2 hours. Smearstaken from corneal scrapings confirmed the presenceof partially acid-fast Gram-positive organisms withbranching hyphae, and after 2 days cultures con-firmed the presence of N. asteroides. Other cyto-logical examinations were normal except forneutrophilia.One week later the lesion and the surrounding

infiltrate and anterior-chamber reaction had in-creased slightly. The ulcer was again scraped. Noorganisms were noted on smear, but cultures againgrew N. asteroides.

Six weeks after the initial injury, despite dailyirrigation of the ulcer and continuation of theintensive antibiotics, an endothelial line of keraticprecipitates developed around the ulcer. This lineand the ulcer size and depth showed progressionover the next 2 days. A hypopyon formed, and theendothelial line extended towards the limbus(Fig. 2). Topical antibiotics were discontinued and

Fig. 2 Progressive Nocardia asteroides ulcer, 6 weeksafter trauma and 2 weeks after chemotherapy

Fig. 3 Nocardia asteroides ulcer, I year after successfultreatment with conjunctival flap

subconjunctival gentamicin was begun, with con-tinuation of the oral sulphadiazine.Over the next 5 days the ulcerated cornea thinned

to less than one-quarter thickness, and the anterior-chamber reaction increased. A further scraping wasperformed, but no organisms were seen on smear.A conjunctival flap was placed over the entire cornea,and the eye soon became quiet. The oral sulpha-diazine was continued for 2 months. One year later,the conjunctival flap had thinned and the anteriorchamber, lens, and retina (posterior pole only) werevisualised as normal. The intraocular pressure asmeasured by pneumotonometry was 15 mmHg.The nasal half of the cornea was thinned to half-thickness over an area of 5 x 4 mm (Fig. 3). Thecornea in this area was opaque, but the eye wasquiet, and the uncorrected vision was 20/200.Later a 7-mm penetrating keratoplasty was success-fully performed, and no organisms were found onhistological examination of the corneal specimen.

MICROBIOLOGICAL EXAMINATION

Corneal scrapings submitted soon after the patientwas admitted to the Johns Hopkins Hospitalrevealed an aerobic growth of a pure culture ofsmall, white, raised, dry colonies. Gram stainingshowed Gram-positive branching pleomorphic rods.Acid-fast staining by the Ziehl-Neelsen techniquewith a 3 % HC1-ENH decolorisation for 10 secondsshowed partially acid-fast organisms. Biochemicaltesting revealed no acid production from lactoseand xylose, urea was decomposed but tyrosine andxanthine were not, and there was no casein hydro-lysis. The organism was identified as Nocardiaasteroides. Subsequent specimens from the cornealulcer submitted 7 days later grew the same organisms

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Nocardia asteroides keratitis

in pure culture. Susceptibility testing of the organ-isms cultured at the Johns Hopkins Hospital wasdone by an agar dilution technique as follows. Theinoculum was prepared by incubating the organismin Mueller Hinton broth for 24 hours at 35°C.After vigorous vortexing, the larger particles wereallowed to settle, and the suspension was removedand standardised against a 0-5 MacFarland BaSO4standard. This suspension was diluted 1:10 and0-01 ml was applied to the surface of the antibiotic-containing Mueller Hinton agar by means of areplicating device. All plates were incubated at35°C for 48 hours before being examined. Inhibitionwas defined as no growth, 3 or fewer colonies, orthe presence of a slight haze.The minimal inhibitory concentration (MIC)

results of the antibiotics tested were as follows:methicillin, greater than 16 jig/ml; penicillin, 16,ug/ml; erythromycin, greater than 2 jig/ml; clinda-mycin, 2 jig/ml; tetracycline, 16 [±g/ml; chloram-phenicol, greater than 8 ,ug/ml; cephalothin, greaterthan 32 ,ug/ml; ampicillin, 2 ,ug/ml; gentamicin,greater than 1 ,ug/ml.

Discussion

Nocardia are usually soil organisms, and, althoughthey are worldwide in distribution, nocardialinfections are rare, especially in the eye. The 2most usual modes of infection are inhalation oforganisms, leading to pulmonary nocardiosis; andcontamination of skin wounds with soil, leading tochronic destructive mycetomas. Nocardia asteroidesis usually an opportunistic pathogen, and pulmonaryor generalised nocardiasis has become increasinglyprevalent in patients with severe systemic diseaseswho are receiving corticosteroids or antineoplasticdrugs. In addition, nocardia may rarely cause infec-tions in other sites.The Nocardia genus and the genus Actinomyces

are members of the family Actinomycetaceae. Bothgenera grow as fragile branching filaments thatreadily fragment into bacillary rod and twig-likeelements. Nocardia are aerobic and somewhat acid-fast, whereas Actinomyces are anaerobic and notacid-fast. With their filamentous growth andmycelia-like colonies, the actinomycetes have astriking resemblance to fungi. However, a numberof basic biological properties establish them asbacteria (Davis et al., 1969; Bach, 1975). Occasion-ally confusion arises in differentiating Nocardiafrom rapidly growing mycobacteria. Similaritybetween the genus Mycobacterium and the genusNocardia has also been reported with respect toantigenic structure, cell-wall composition, andbacteriophage susceptibility. Nocardia, however,

may be differentiated from mycobacteria becauseNocardia is only partially acid-fast, it forms frag-menting mycelia and has true branching (Tsuka-mura, 1970). In addition, the 2 groups differ in thelipid composition of their cell walls (Davis et al.,1969; Lechevalier et al., 1971).Nocardia is commonly involved in pulmonary

infections, but its role in ocular infections is limited,as is evident from a search of the available literature(Table 1) (Bruce and Locatcher-Khorazo, 1942;Benedict and Iverson, 1944; Smith, 1952; Schardtet al., 1956; Sigtenhorst and Gingrich, 1957; Hen-derson et al., 1960; Gingrich, 1962; Rees, 1962;Davidson and Foerster, 1967; Meyer et al., 1970;Burpee and Starke, 1971; Newmark et al., 1971;Panijayanond et al., 1972; Jampol et al., 1973;Rogers and Johnson, 1977; Sher et al., 1977). Mostof the intraocular cases of nocardia infection can betraced to metastatic spread of proved primaryinfections elsewhere, (Davidson and Foerster,1967; Meyer et al., 1970; Burpee and Starke, 1971;Panijayanond et al., 1972; Jampol et al., 1973;Rogers and Johnson, 1977; Sher et al., 1977) orfollowing exogenous trauma such as cataractextraction (Meyer et al., 1970). Five of the 7 pre-viously reported nocardia infections of the corneawere preceded by trauma; 4 of these occurred in arural setting (Schardt et al., 1956; Sigtenhorst andGingrich, 1957; Gingrich, 1962; Newmark et al.,1971), and 1 was from a fishing accident (Ralphet al., 1976). The trauma in all cases was consideredtrivial. The cases ran variable courses, but allresolved with retention of the eye and with reason-ably good vision. The remaining 2 cases wereassociated with a keratoconjunctivitis of obscureorigin (Bruce and Locatcher-Khorazo, 1942; Bene-dict and Iverson, 1944). One of the cases respondedto therapy, but the other was deteriorating whenlost to follow-up.

In only 3 of the 7 cases was the topical adminis-tration of corticosteroids (Sigtenhorst and Gingrich,1957; Newmark et al., 1971; Ralph et al., 1976) apossible predisposing factor, and in these cases thedrugs had been administered only briefly beforethe diagnosis of nocardial infection. These patientsretained excellent vision. Often, however, the iso-lation of the causative organism may be delayed,and steroids may have been given for several months.Our case emphasises the rural trauma, the slow

initial course of the disease, the characteristicmorphology of a 'fungal-type' ulcer, and the pro-gressive nature of a nocardial infection when it isunresponsive to treatment. In this case intensivesulphonamide therapy, topically and systemically,was given in conjunction with tetracycline andgentamicin. Daily toilet of the ulcer, and 3 of the

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Table 1 Review of literature on ocular nocardiosis

(A) NOCARDIA KERATITIS

Case report Age Sex Predisposing cause Site of infection Treatment Outcome Diagnostic criteria

Bruce and Locatcher- 50 M Punctate kerato- Potassium Quiet eyeKhorazo (1942) conjunctivitis iodide (a, b)*

Benedict and 23 F ? Scarlet fever Chronic kerato- Sulphanilamide (a) 4 years gradual Positive smearIverson (1944) conjunctivitis Potassium iodide (a) deterioration and culture

Copper sulphate (a)Zinc sulphate (a)Metaphen (a)Penicillin (a)

Schardt et al. (1956) 33 M Stone trauma on Corneal ulcer Argyrol (a) 20/80 quiet Positive culturefarm Cautery oxytetra-

cline (a)Atropine (a)Achromycin (a, b)

Sigtenhorst and ? Cotton branch Corneal ulcer Sulphacetamide (a) ExcellentGingrich (1957) injury Atropine (a)

Cortisone (a)

Gingrich (1962) 53 M Cotton plant Corneal ucler Sulphacetamide (a) 20/50 Positive culturescratch Penicillin (c)

Sulphadiazine (b)

Newmark et al. (1971) 6 M Dirt injury Corneal ulcer Oxytetracycline (a) 20/25 Positive cultureCorticosteroid (a)Chloramphenicol (a)Sulphacetamide (a)Tetracycline (a)Idoxuridine (a)Sulphadiazine (b)

Ralph et al. (1976) 11 F Fishline sinker Corneal ulcer Neomycin (a) Positive cultureabrasion Prednisone (a)

Homatropine (a)Polymixin (a)Gentamicin (a)Erythromycin (a)Ampicillin (d)Sulphacetamide (a)Penicillin (a)Bacitracin (a)

*Route of administration: a, topical; b, systemic oral; c, systemic parenteral; d, periocular; e, intraocular

scrapings during the early course of the infection,always revealed only the presence of nocardia. Theinitial growth of alcaligenes was not observed onsubsequent scrapings. Although it is not at allcertain that long-term use of a broad-spectrumantibiotic contributed to a predisposing state, it isinteresting to note that the patient was on continuousoral tetracycline therapy for acne at the time of hisinjury and subsequent infection, until he discon-tinued the tetracycline when he first entered thehospital. In-vitro testing revealed resistance of thenocardia to tetracycline.

In the face of progressive corneal thinning andincreased anterior-chamber reaction despite a 3-week period of intensive chemotherapy, an operationfor conjunctival flap was performed, and the oralsulphadiazine was continued for 2 months post-operatively. Therefore the dramatic response aftersurgery is more difficult to evaluate; it could have

been due to the prolonged chemotherapy, but thelack of favourable response to sulphadiazine pre-operatively makes this unlikely.

Sulphonamides, both systemic and topical, haveremained the drugs of choice for ocular nocardiainfections (Lerner and Baum, 1973; Ripon, 1974).Sulphadiazine and sulphamethoxazole still appearto be superior to newer antimicrobial agents fortreatment of nocardiosis (Black and McNellis,1971; Ripon, 1974). Cephaloridine and also atrimethoprim-sulphamethoxazole combination haveboth been used successfully in systemic nocardiosis(Baikie et al., 1970; Lerner and Baum, 1973;Maderazo and Quintiliani, 1974; Ripon, 1974).With the nocardia recovered in the present case,however, susceptibility testing against other anti-microbials was done by agar dilution, and theresults were as reported above.

There are many reports of antibiotic susceptibility

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Nocardia asteroides keratitis

Table 1-continued

(B) OTHER OCULAR NOCARDIOSES

Case report Age Sex Predisposing cause Site of intection Treatment Outcome Diagnostic criteria

Smith (1952) Cutler's implant Chronic orbital Nocardia isolateddischarge

Corn grain trauma Dacryocystitis

49 F Cow's tail injury Nodular scleritis Excision lump Normal eye Positive histologyatropine (a)

Chloramphenicol (b)Staphylococcus toxoid (c)Typhoid vaccine (c)Sulphadiazine (b)Sulphacetamide (a)

Penikett and Rees(1962)

Davidson andFoerster (1967)

Meyer et al. (1970)

Meyer et al. (1970)

Meyer et al. (1970)

80 F

46 M ? Pulmonary,primary

76 F Cataractextraction

Dacryocystitis Curetted; chlortetra-cycline (d)

Endophthalmitis Corticosteroids (a, b)

Endophthalmitis Corticosteroids (a, b)Amphotericin (e)Tetracycline (b)

67 M Gunshot to chest, Chorioretinitispneumonia

56 M

Penicillin (c)Sulphadiazine (b)Cycloserine (b)

Chorioretinitis OD Iodides (a)Endophthalmitis OS Eviscerated

Burpee and Starke(1971)

Panijayanond et al.(1972)

20 M Bomb injury; soft- Endophthalmitis ODtissue sepsis

30 M Renal transplanta- Endophthalmitistion

ImmunosuppressionNephric abscess

Penicillin (c)Limb surgery

tetracycline (b)Chloramphenicol

cephalothin (c)Gentamicin

sulphadiazine (b)Kanamycin (c)

Cycloserine (b)Sulphisoxazole (b)

Enucleation Positive bloodand eye culture

20/20 OS

Enucleation Positive cultureSubmandibular

gland, nephricabscess

40 M Arm abscess Episcleritis

Renal transplant ChorioretinitisPulmonary abscess

Sher et a. (1977 )

Rogers and Johnson(1977)

Streptomycin (c) Died

Sulphisoxazole (b)Sulphadiazine (b)Ampicillin

38 M Hypogammaglobu- Endophthalmitis OS Vitrectomylinaemia

Pulmonary Chorioretinitis OD Ampicillin (e)nocardiosis Atropine (a)

Dexamethasone (a)Neomycin (a)Minocycline (b)Erythromycin (c)

77 F Malignant Endophthalmitislymphoma

Immunosuppres- Necropsy diagnosission

20/200

Died

of nocardia (Black and McNellis, 1971; Bach et al.,1973; Lerner and Baum, 1973). It is difficult tocompare the results of our single strain of nocardiawith those in the literature, since different strainsvary in susceptibility. There are numerous problems

and variations inherent in the testing (Lerner andBaum, 1973; Bach, 1975). However, our method ofsusceptibility testing, which closely follows themethod of Wallace et al. (1977), produced resultssimilar to theirs.

Smith (1952)

Henderson et al.(1960)

Clear Positive culture

Enucleated

Enucleated

Died

20/300

Positive histology

Positive histology

Positive histology

Positive histology

Jampol et al. (1973) Positive culture,arm

Positive culture,eye

Blood andpulmonary

Positive, vitreoushistology

Positive necropsy

Histology

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Because nocardia tends to grow in clumps it isdifficult to prepare uniform and reproducible sus-pensions containing equivalent numbers of organ-isms. In addition,.in-vitro susceptibility is influencedby pH and type of agar used in the assay. Variationin these parameters may well explain conflicts inresults of susceptibility testing reported in the past.Further, in-vitro susceptibility may not correlatewell with clinical response (Black and McNellis,1971; Bach et al., 1973; Lerner and Baum, 1973;Lennette et al., 1974). For example, cycloserine oreven the sulphonamides may appear ineffective byin-vitro testing despite a good clinical response.

After the present case 2 further isolates of Nocar-dia asteroides were obtained from 2 other patientswith non-ocular nocardiosis. Antimicrobial sus-

ceptibility testing was performed as before. Markeddifferences from the present results were obtainedwith some of the antibiotics. We can conclude thatsusceptibility testing will continue to be difficult toevaluate until standardised methods of testing forthis species are established.The favourable long-term result in this case

appears to have been achieved by covering thecornea with a conjunctival flap, followed by pene-trating keratoplasty 24 months later.

References

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Bach, M. C., Sabath, L. D., and Finaldn, M. (1973).Susceptibility of Nocardia asteroides to 45 antimicrobialagents in vitro. Antimicrobial Agents and Chemotherapy, 3,1-8.

Baikie, A. G., MacDonald, C. B., Mundy, G. R. (1970).Systemic nocardiosis treated with trimethoprim andsulphamethoxazole. Lancet, 2, 261.

Benedict, W. L., and Iverson, H. A. (1944). Chronic kerato-conjunctivitis associated with Nocardia. Archives ofOphthalmology, 32, 89-92.

Black, W. A., and McNellis, D. A. (1971). Susceptibility ofNocardia species to modern antimicrobial agents. InAntimicrobial Agents and Chemotherapy-1970, Proceed-ings of the Tenth Interscience Conference on Anti-microbial Agents and Chemotherapy, Chicago, Ill., 18-21October 1970, pp. 346-349. Edited by Gladys L. Hobby.American Society for Microbiology: Bethesda, Md.

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Henderson, J. W., Wellman, W. E., and Weed, L. A. (1960).Nocardiosis of the eye. Report of case. Proceedings ofStaff Meetings of the Mayo Clinic, 35, 614-618.

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Newmark, E., Polack, F. M., and Ellison, A. C. (1971).Report of a case of Nocardia asteroides keratitis. AmericanJournal of Ophthalmology, 72, 813-815.

Panijayanond, P., Olsson, C. A., Spivack, M. L., Schmitt,G. W., Idelson, B. A., Sachs, B. J., and Nasbeth, D. C.(1972). Intraocular nocardiosis in a renal transplantpatient. Archives of Surgery, 104, 845-847.

Penikett, E. J. K., and Rees, D. L. (1962). Nocardia asteroidesinfection. American Journal of Ophthalmology, 53, 1006-1008.

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Rogers, S. J., and Johnson, B. L. (1977). EndogenousNocardia endophthalmitis: Report of a case in a patienttreated for lymphocytic lymphoma. Annals of Ophthal-mology, 9, 1123-1131.

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