Outbreak of Nocardia keratitisafter photorefractive keratectomy

Clinical, microbiological, histopathological,and confocal scan study

Mohammad-Ali Javadi, MD, Mozhgan Rezaei Kanavi, MD, Siamak Zarei, MD, Firooz Mirbabaei, MD,Hosein Jamali, MD, Mohamadreza Shoja, MD, Manijeh Mahdavi, MD, Nima Naghshgar, MD,

Shahin Yazdani, MD, Amir Faramarzi, MD

Nocardia keratitis occurred in 4 eyes of 3 patients (2 women and 1 man) who had photorefractivekeratectomy (PRK) by the same surgeon at the same center. Two eyes of the first 2 patients re-quired lamellar keratectomy to debulk the involved stroma and obtain specimens for microbiolog-ical and histopathological evaluation. Light microscopic examination disclosed gram-positive andacid-fast filaments of Nocardia that were confirmed by the microbiological results. Diagnosis ofNocardia keratitis in the third case was not as challenging as in the first 2 cases because ofa high index of suspicion. Confocal scans of all cases disclosed hyperreflective and slender, fi-bril-like structures in the corneal stroma. All eyes responded favorably to topical amikacin andthe infection resolved without recurrence. The most probable cause of the outbreak was inade-quate attention to sterility during surgery.

J Cataract Refract Surg 2009; 35:393–398 Q 2009 ASCRS and ESCRS

CASE REPORT

Use of the excimer laser in refractive surgery has in-creased exponentially since the laser was approvedby the United States Food and Drug Administrationin 1995.1 Infectious keratitis after keratorefractive sur-gery is a rare but potentially devastating complication2

that may be refractory to standard medical therapy.3–7

There are several reports of bacterial,3,5,8–11 viral,12

Submitted: July 14, 2008.Final revision submitted: August 11, 2008.Accepted: August 12, 2008.

From the Labbafinejad Ophthalmic Research Center (M.A. Javadi,Kanavi, Naghshgar, Yazdani) and Department of Ophthalmology(M.A. Javadi, Yazdani, Faramarzi), Shaheed Beheshti Medical Uni-versity, Tehran and Labbafinejad Medical Center (Zarei, Mirbabaei,H. Jamali, Mahdavi) Shaheed Beheshti Medical University, ShaheedSadooghi Medical Center (Shoja), Shaheed Sadooghi Medical Uni-versity, Yazd, Iran.

No author has a financial or proprietary interest in any material ormethod mentioned.

Corresponding author: Mohammad-Ali Javadi, MD, Ophthalmic Re-search Center, Labbafinejad Medical Center, Boostan 9 Street, Pas-daran Avenue, Tehran 16666, Iran. E-mail: ma_javadi@yahoo.com.

Q 2009 ASCRS and ESCRS

Published by Elsevier Inc.

fungal,13 and Acanthamoeba keratitis14 following pho-torefractive keratectomy (PRK). In a study by Donnen-feld et al.,2 gram-positive bacteria were the mostcommon cause of post-PRK infectious keratitis andStaphylococcus aureus, Staphylococcus epidermidis, Strep-tococcus pneumoniae, and Streptococcus viridans themost commonly cultured organisms. Microorganismssuch as S aureus induce acute-onset fulminant keratitisafter PRK, but nontuberculous mycobacteria and No-cardia species may lead to late-onset infection.2,4 Riskfactors for post-PRK infections are corneal epithelialdefects, use of extended-wear bandage soft contactlenses, and topical steroids.2,15

Nocardia species are aerobic, gram-positive, andacid-fast filaments that may rarely induce keratitiswith a characteristicwreath-like pattern of patchy ante-rior stromal infiltrates.16 Predisposing factors to infec-tion include trauma or surgery, contact lens wear,and use of topical corticosteroids.17,18 Several sporadiccases and an outbreak ofNocardia keratitis after laser insitu keratomileusis (LASIK) have been reported,19–22

but to our knowledge, this is the first report of an out-breakofNocardiakeratitis followingPRK that describesthe clinical, microbiological, histopathological, andconfocal scan features of this rare infection.

0886-3350/09/$dsee front matter 393doi:10.1016/j.jcrs.2008.08.045

394 CASE REPORT: NOCARDIA KERATITIS AFTER PRK

CASE REPORT

Over a period of less than onemonth, 3 patients with late-on-set keratitis following bilateral myopic PRK performed bythe same surgeon at the same center were referred to our cen-ter. Based on the surgeon’s report, the patients did not havelocal or systemic predisposing factors and the procedure wasuneventful in all eyes. Ethyl alcohol (20%) had been appliedfor epithelial removal andmitomycin-C (MMC) (0.02%) usedfor 40 seconds. The entire procedure had been performed un-der less than optimal sterility; the eyes were not prepared ordraped and surgical gloves were not used. After surgery,a bandage soft contact lens had been used for 3 days. Postop-erative medications included topical chloramphenicol 0.5%

Figure 1. Corneal ulcer in a wreath-like pattern with featheryborders (Case 1, left eye).

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and betamethasone 0.1% eyedrops 4 times a day. No casehad developed persistent epithelial defects.

Case 1

A 28-year-old woman presented to her surgeon with pho-tophobia, red eye, and reduced vision in the left eye 28 daysafter PRK. The ocular examination revealed a moderate cor-neal haze andmild infiltration. The surgeon suspected a ster-ile infiltration and increased the frequency of topical steroidsto every hour. The condition progressively deteriorated, andsystemic acyclovir was initiated to treat a presumed herpeticinfection. After 2 weeks, dense central corneal infiltrationalongwith satellite lesions appeared. Corneal smear and cul-ture were performed at this stage; the culture was negative.Because of the suspicion of fungal keratitis, topical natamy-cin 5% was administered but no improvement was noted af-ter 2 weeks. The patient was referred to our center 2 monthsafter the PRK procedure.

The visual acuity in the left eye was 20/400, and slitlampbiomicroscopy revealed a central corneal epithelial defect to-gether with diffuse stromal edema and multiple discretegranular infiltrates with feathery borders in the deep stromain awreath-like pattern (Figure 1). Amoderate inflammatoryreaction was also present in the anterior chamber. A confocalscan (Confoscan 3.4, Nidek Technologies) did not reveal hy-phae- or cyst-like structures. After the cornea was scrapedfor microbiological studies, cefazolin 50 mg/dL and genta-micin 14 mg/dL were started every hour.

Because there was no significant response to the medicalregimen, lamellar keratectomy was performed after 3 daysto debulk the involved stroma and obtain a specimen forbacteriological and histopathological evaluations. Histo-pathological examination demonstrated foci of intrastromal

Figure 2. A: Intrastromal necrosiswith acute and chronic inflamma-tory cell infiltrates (hematoxylinand eosin stain; original magnifica-tion �200) B: A few gram-positivefilaments in the necrotic areas(Gram-Twort stain; original magni-fication �1000), which were acid-fast (C) on modified Ziehl-Neelsonstaining (original magnification�1000). D: Acid-fast filaments ofNocardia species taken from theNocardia colonies (modified Ziehl-Neelson staining; original magnifi-cation �1000).

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Figure 3. Hyperreflective and thinfibril-like structures (arrows) onconfocal scan (image size 340 mm� 455 mm).

necrosis with scattered acute and chronic inflammatory cellinfiltrates (Figure 2, A). On Gram-Twort staining, small clus-ters of gram-positive filaments were found in the necroticareas (Figure 2, B); they were acid-fast on modified Ziehl-Neelson staining (Figures 2, C). Histopathological featureswere strongly suggestive of Nocardia keratitis, which wasconfirmed by the results of culture 1 week after incubation(Figure 2, D). The confocal scan was repeated after the newdiagnosis and disclosed a few hyperreflective and slender fi-bril-like intrastromal structures about 9.0 mm in length and1.5 mm inwidth (Figure 3). The structures were similar in ap-pearance to the filament-like elements found on the histo-pathological examination.

Fortified cefazolin and gentamicin were discontinued andamikacin 40 mg/dL eyedrops started based on disk diffu-sion sensitivity. After 2 days, significant improvement wasnoted and by day 14, the corneal infiltrates resolved andthe epithelial defect healed completely. After 1 month, thebest corrected visual acuity (BCVA) was 20/160. At thelast follow-up examination, scar formation and corneal thin-ning were noted (Figure 4).

Case 2

Ten days after the first case was referred to our center,a 24-year-old woman was seen for post-PRK keratitis inthe left eye that had developed 3 weeks after surgery andwas unresponsive to frequent application of ciprofloxacin0.3%. The visual acuity was 20/500, and slitlamp biomicro-scopy revealed multiple patches of deep stromal infiltrateswith a 2.0 mm � 2.0 mm epithelial defect in the left centralcornea (Figure 5, A).

The diagnostic and therapeutic approach to this case wassimilar to the approach in the first case with the exception ofa clinical suspicion of fungal keratitis that prompted the ini-tiation of topical natamycin 5%. As in the first case, lamellarkeratectomy was performed because of the lack of response;the results were similar to those in the first case. Review ofrecorded confocal scan images showed one image of hyper-reflective and slender, fibril-like elements. The infection re-sponded favorably to amikacin, and at the last follow-upexamination, the BCVA was 20/500 and there was no signof recurrent infection (Figure 5, B).

Case 3

While Cases 1 and 2were being treated, a 23-year-oldmanwas referred with pain, decreased vision, and redness in the

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left eye 40 days after bilateral PRK. The visual acuitywas 20/40 in the left eye and 20/25 in the right eye. Slitlamp exam-ination disclosed multiple patchy anterior stromal infiltratesin a wreath-like pattern with feathery borders in the left cor-nea (Figure 6, A). Although the patient had no complaint inthe right eye, mild corneal haze was noted in this apparentlyuninvolved eye.

With a high index of suspicion ofNocardia keratitis, a con-focal scan was performed, followed by corneal smear andculture. Amikacin 40 mg/dL was promptly initiated await-ing the microbiological results. The confocal scan and micro-biological features of this case were similar to those in theprevious cases. The infection responded favorably to ther-apy, and the stromal infiltrates gradually decreased. Duringthe treatment course in the left eye, the right corneal hazeprogressed to a focus of anterior stromal infiltration (Figure 6,B), reducing visual acuity. Slitlamp examination was consis-tent with early Nocardia keratitis, and amikacin 40 mg/dLeyedrops were started. Despite a favorable response to ther-apy, flare-up of the lesion occurred in the left cornea. Thiswas adequately controlled by increasing the frequency ofamikacin eyedrops. At the last follow-up examination, theuncorrected visual acuity was 20/20 in the right eyeand 20/25 in the left eye and there was no sign of recurrence(Figure 6, C).

Figure 4. Resolved keratitis with scar formation after treatment(Case 1, left eye).

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Figure 5. Corneal ulcer with a 2.0mm � 2.0 mm epithelial defect (A)and residual scarring 2 months af-ter treatment (B) (Case 2, left eye).

DISCUSSION

Nocardia are worldwide inhabitants of soil and wa-ter.23 They are gram-positive and acid-fast to 1% sul-phuric acid and stain with the Kinyoun technique,a modification of the Ziehl-Neelson method.24 Theygrow slowly on most culture media; therefore, cultureplates should be kept for at least 5 to 7 days.22

Nocardia keratitis has been reported in immunocom-promised patients; following trauma; and after ocularsurgery such as LASIK, implantation of intracornealring segments, keratoplasty, and cataract sur-gery.22,25–28 It follows a slowly progressive, indolent,and recalcitrant course. To our knowledge, this reportis the first describing an outbreak of Nocardia keratitisfollowing PRK, posing a challenging diagnosis in thefirst 2 cases.Nocardiakeratitis appears as awell-defined

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corneal ulcer with a grey sloughing bed and incom-plete necrotic boundaries. The superficial stromal infil-trates are pinhead-sized, granular or nodular in shape,and occur in a wreath-like configuration together with‘‘brush-fire’’ or feathery borders; multifocal or satellitelesions may be seen.22,24,29 The clinical presentation ofthis rare infection may resemble a fungal or atypicalmycobacterial keratitis, possibly delaying the correctdiagnosis and management and leading to significantocular morbidity.24,30 The diagnostic confusion wasdemonstrated in our 2 patients; the infection was con-sidered a mycotic keratitis before the microbiologicalresults were obtained. Although the wreath-like con-figuration of the stromal infiltrates was noted in all 4eyes, early treatment was started in only the third pa-tient in whom there was a high index of suspicion.

Figure 6. Keratitis in a wreath-likepattern (A), early keratitis (B), andimproved infection with scar for-mation after therapy (C) (Case 3,left eye).

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Possible sources of contamination in post-PRK kera-titis are the patient’s skin or conjunctival surfaces, sur-gical instruments, topical anesthetic agents, andairborne particles.2,31 Garg and Sharma32 reportNocar-dia keratitis after LASIK surgery in 4 eyes of 3 patientsoperated on the same day at the same center. Use of thesame blade and microkeratome during surgery wasconsidered the most probable route of contaminationin these cases. In the current report, although the pa-tients were not operated on the same day, they wereoperated on by the same surgeon. The most probablesource of infection seemed to be inadequate attentionto strict sterility rules during surgery; povidone–io-dine preparation, draping of the surgical field, andwearing sterile gloveswere important issues neglectedby the surgeon. Although glove-free surgery may bean acceptable alternative in certain settings, adherenceto completely sterile conditions may be more appro-priate in communities in which the rate of infectiouscorneal ulcers is high. Contact lens wear and use ofcorticosteroids after PRK may also be considered con-tributing factors but do not seem to induce an out-break. Application of MMC during PRK is anotherpotential factor because of the predisposition to devel-opment of persistent corneal epithelial defects. How-ever, none of our 3 patients developed persistentepithelial defects after surgery; the development oflate-onset infection also points to possible inoculationof the microorganisms during surgery. The occurrenceof infection in the left eye in all 3 cases may suggestcontamination of the instruments during the courseof surgery in the right eye.

Nocardia species are highly sensitive to amikacin,sulphamethazole, and imipenem. Monotherapy withamikacin appears to be the treatment of choice inNocardia keratitis, with favorable prognosis if startedearly.17,33 Based on disk diffusion test results, all theisolates from our cases were sensitive to amikacinand monotherapy with amikacin was successful inall eyes.

A confocal scan is a noninvasive diagnostic toolwith high sensitivity and specificity for rapid diagno-sis of Acanthamoeba and fungal keratitis.34 It is particu-larly valuable when the infective organisms arerelatively large (R15 mm).35 Vaddavalli et al.36 reportthe distinct confocal microscopic features for Nocardiakeratitis as highly reflective, short, and thin branchingfilaments at the edge of the inflammatory infiltrates. Inour cases, Nocardia organisms were hyperreflectiveand slender, fibril-like structures about 9.0 mm inlength and 1.5 mm in width, slightly distant from thestromal infiltrates. These features are consistent withthe histopathological appearance of Nocardia keratitisin the first 2 cases. Since there was no suspicion of No-cardia infection before the microbiological results were

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obtained, the confocal scan features were noncontribu-tory to the diagnosis in the first 2 cases.

In conclusion, to our knowledge, this is the first re-port of an outbreak of Nocardia keratitis followingPRK. Diagnosis may be challenging because of thelack of clinical suspicion of this rare infection. Thecharacteristic clinical appearance and use of confocalscan imaging together with appropriate microbiologi-cal staining techniques can facilitate early diagnosis,leading to proper management and a favorableresponse to therapy in Nocardia keratitis.

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First author:Mohammad-Ali Javadi, MD

Ophthalmic Research Center,Labbafinejad Medical Center,Tehran, Iran

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