02increased-incidence-of-sterile-endophthalmitis.pdf

Downloaded from bjo.bmj.com on June 6, 2013 - Published by group.bmj.com Increased incidence of sterile endophthalmitisfollowing intravitreal preserved triamcinoloneacetonide J Jonisch,1 J C Lai,1,2 V A Deramo,1,2 A J Flug,1 D M Fastenberg1,2 possible aetiologies have been proposed. It has been Aim: To report an increased incidence of sterile hypothesised that sterile endophthalmitis repre- endophthalmitis following intravitreal injection of pre- sents an inflammatory reaction to the triamcino- USA; 2 Long Island and QueensVitreo-Retinal Consultants, Great served triamcinolone acetonide (IVTA) from 1 May to 31 lone acetonide, the preservatives in which it is suspended, or a form of bacterial endophthalmitis Methods: Charts were reviewed for all patients who caused by contamination with bacterial toxins or underwent IVTA injections between 1 January 2005 and endotoxin not detected by standard culture meth- Dr J C Lai, 98-1079 MoanualuaRd, Suite 470, Aiea, HI 96701, 31 July 2006 at the offices of a referral vitreo-retinal practice. Patients were included if they presented post- endophthalmitis ranges between 0.1% and 1.6% IVTA with a clinical picture consistent with endophthal- when using the preserved formulation.14 16–18 In the months of May–July 2006, we observed Results: Between 1 January 2005 and 31 July 2006, 554 an increased number of patients presenting with eyes underwent IVTA. Eleven eyes (1.9%) developed an severe intraocular inflammation following injec- endophthalmitis. All eleven eyes underwent vitreous tap tion of preserved IVTA. The purpose of this study and intravitreal injection of antibiotics. All cultures and is to analyse the incidence of sterile endophthalmi- gram stains were negative for bacterial or fungal tis following intravitreal injection of preserved organisms. From 1 May to 31 July 2006, 97 eyes triamcinolone acetonide from 1 January 2005 to 31 underwent IVTA. Nine eyes (9.3%) developed sterile July 2006, to evaluate whether there was a endophthalmitis. This represented a statistically significant statistically significant increased incidence.
(p,0.0001) clustering of cases. Triamcinolone acetonidephials from affected lot numbers were analysed and were all found to be negative for bacterial endotoxin The North Shore-Long Island Jewish University Conclusion: Over the 19-month period analysed, 11 approved the study protocol. Charts were reviewed cases of sterile endophthalmitis occurred following IVTA, for all patients who underwent intravitreal injec- and nine of these cases were clustered over a 3-month tion with preserved triamcinolone acetonide period. No endotoxin was detected in the phials tested.
(Kenalog; Bristol-Myers Squibb, Princeton, NJ) The aetiology of this increased incidence of sterile between 1 January 2005 and 31 July 2006 at the offices of a referral vitreo-retinal practice. Chartswere obtained by searching the computer databasefor all intravitreal injections performed, and Intravitreal injection of triamcinolone acetonide included only those patients who underwent (IVTA) has been shown to be beneficial in the intravitreal injection with preserved triamcinolone treatment of macular oedema secondary to vein acetonide. Records were reviewed of all patients occlusion, diabetes and uveitis, as well as adjunc- tive treatment of exudative macular degenera- endophthalmitis following intravitreal injection tion.1–10 The most common side effects include of preserved triamcinolone acetonide. Patients ocular hypertension and cataract progression.11–14 were included if they presented with a clinical Infectious endophthalmitis, pseudoendophthalmi- picture consistent with endophthalmitis defined as tis and sterile endophthalmitis are also well-known postinjection vitritis, with fibrinoid anterior cham- ber reaction and/or hypopyon. Patients with Pseudoendophthalmitis has been defined as cases pseudoendophthalmitis, with suspended triamci- where the injected agent, triamcinolone acetonide, creates the appearance of intraocular inflammation Written informed consent was obtained from and/or hypopyon.14 19 Non-infectious or sterile each patient prior to steroid injection. Standard endophthalmitis is defined as true intraocular aseptic techniques were used, and the procedure inflammation following injection of IVTA not was performed in the office setting for all cases.
attributed to an infectious process.14 Historically, The operative eye was given a preoperative topical the commercially available form of triamcinolone antibiotic of the physician’s choice. After the eye acetonide used for intravitreal injection in the was anaesthetised with topical anaesthetic, a United States has been Kenalog (Bristol-Myers sterile lid speculum was placed in the eye. The Squibb, Princeton, NJ) which comes in a preserva- temporal conjunctiva was then anaesthetised with tive-containing formulation. The aetiology of a 4% lidocaine-hydrochloride soaked cotton tip. A sterile endophthalmitis is unknown, but several 5% povidone-iodine solution was applied to the eye Br J Ophthalmol 2008;92:1051–1054. doi:10.1136/bjo.2007.136069 Downloaded from bjo.bmj.com on June 6, 2013 - Published by group.bmj.com CF, count fingers; CME, cystoid macular oedema secondary to pseudophakia; DME, diabetic macular oedema; HM, hand motion; IVTA, intravitreal injection of triamcinoloneacetonide; NA, not applicable; RVO, retinal vein occlusion.
several minutes prior to intravitreal injection, as well as to the events occur at an average rate and independently of the time rubber stopper of the individual phials. The triamcinolone since the last event. A standard chi-square goodness of fit test acetonide was prepared by drawing out 0.1 ml from a 1 ml was used to test the Poisson hypothesis, where the Poisson single-use phial (Kenalog 40 mg/ml) after vigorously shaking parameter, l, was estimated as the total number of observed the suspension. The formulation was neither diluted nor events/number of months in the study.
changed, and the solvent was not removed. Intraocular pressurepostinjection was measured. The injection protocol and the physicians performing the procedure were similar throughout From 1 January 2005 through 31 July 2006, 554 eyes underwent the studied period. Patients were instructed to use a topical IVTA. Eleven eyes (1.9%) developed an endophthalmitis third- or fourth-generation flouroquinolone four times per day (table 1). Patient ages ranged from 62 to 85. Indications for injection for these eyes included macula oedema secondary to Patient age, phakic status, status of capsular bag, any history vein occlusion (n = 4), diabetes (n = 4) and pseudophakia of intraocular inflammation, indication for injection, month of (n = 3). All patients presented by day 4 post-IVTA (avera- injection and number of days to presentation with endophthal- ge = 1.33 days). Seven of 11 eyes were pseudophakic, and six of mitis were recorded for affected patients. Visual acuity was the seven pseudophakic eyes had intact posterior capsules. None recorded on the day of IVTA injection, on day of presentation of the 11 affected eyes had a prior history of intraocular and at 1 month post-IVTA. The data were analysed using the inflammation. Pre-IVTA visual acuity ranged from 20/50 to Fisher exact test. Triamcinolone acetonide phials from three of hand motion. All patients with endophthalmitis presented with the lot numbers affected were analysed for bacterial endotoxin worsened visual acuity. Visual acuity at presentation with endophthalmitis was either hand motion or counting fingers North Shore-Long Island Jewish Hospital’s Department of vision. Visual acuity at 1 month post-IVTA injection ranged Biostatistics was consulted to evaluate the significance of the from 20/50 to 20/400. In nine of the 11 eyes affected, visual cluster. The statistical question was whether the number of acuity at 1 month was equal to or better than the pre-IVTA events (ie, cases of sterile endophthalmitis) follows a Poisson injection visual acuity. All 11 eyes underwent vitreous tap and distribution. The Poisson distribution is frequently used in intravitreal injection of antibiotics with 1 mg of vancomycin situations where events are rare, and one wishes to evaluate the and 2.25 mg of ceftazidime. All cultures and Gram stains were significance of a cluster. The Poisson distribution assumes rare negative for bacterial or fungal organisms.
Between 1 May and 31 July 2006, 97 eyes underwent IVTA injections. Nine eyes (9.3%) following the 97 injectionsdeveloped a clinical picture of endophthalmitis.
Phials used from these cases were from varying lot numbers.
Three phials from separate lot numbers affected were sent forendotoxin analysis using the limulus amebocyte assay, and eachreturned negative (,0.05 EU/ml) for bacterial endotoxin.
From 1 May to 31 July 2005, 86 eyes underwent IVTA injections. One eye (1.1%) underwent a vitreous tap andintravitreal injection of antibiotics for endophthalmitis. In 2006,there were three cases in May, two cases in June and four casesin July. In 2005, there was one case in May and no cases in Juneor July. In the same 3-month time period the incidence rosefrom 1.1% to 9.7% (p = 0.02) from 2005 to 2006. No patient ineither group had culture-positive endophthalmitis. The numberof cases and the total number of IVTA injections for each 3-month period studied are shown in fig 1. Beginning in August2006, we began using a preservative-free formulation of Incidence of sterile endophthalmitis.
Br J Ophthalmol 2008;92:1051–1054. doi:10.1136/bjo.2007.136069 Downloaded from bjo.bmj.com on June 6, 2013 - Published by group.bmj.com To evaluate the statistical significance of this cluster of cases, injection of preservative free triamcinolone acetonide would a standard chi-square goodness-of-fit (GOF) test was used to suggest that there is a yet-to-be-identified aetiology for this test the whether the number of cases of a rare event occur in a Poisson distribution. The Poisson distribution assumes that rare There does not appear to be a good explanation for the events occur at an average rate and independently of the time statistically significant spike in the number of cases of sterile since the last event. The parameter, l, was estimated as the endophthalmitis that was witnessed in our practice during the total number of observed events/number of months in the spring of 2006. It is unknown how many other ophthalmolo- study. The estimated mean for the Poisson distribution was gists experienced a similar increased incidence in this time l = 11/19 = 0.58 events/month. The GOF test showed a period. There have been anecdotal reports of a similar rise in the significant lack of fit for the Poisson distribution (p,0.0001).
number of cases of sterile endophthalmitis throughout parts of The data were not consistent with the Poisson distribution the country during the same time period (Eaton AM, personal assumption and support the hypothesis of a true cluster.
communication). However, we are unaware of any publishedreports of this trend in a peer reviewed journal.
The development of complications following the off-label Preserved intravitreal triamcinolone acetonide has been reported usage of a drug is particularly worrisome, particularly in light of to be therapeutically useful in cases of macular oedema due to the letter issued by the manufacturer of Kenalog (November multiple aetiologies and adjunctively in exudative macular 2006 letter to healthcare providers from Bristol-Myers Squibb degeneration.1–10 Infectious and non-infectious endophthalmitis Company, Princeton, NJ) (Lewis-Hall F, written communica- remain important clinical entities. The reported incidence of tion, 22 November 2006). Reporting on the side-effect profile of sterile endophthalmitis following intravitreal injection of medications becomes increasingly important with off-label preserved triamcinolone acetonide ranges from 0.1% to usage, and the importance of the peer-review process cannot 1.6%.16–18 Our observed incidence of 9.7% from 1 May to 31 be overstated in these instances. As demonstrated by the recall July 2006 represents a statistically significant increased inci- of contact lens solution following the outbreak of Fusaruim dence when compared with the same time period 1 year earlier, keratitis, postmarketing vigilance is critical in detecting alarm- and was a dramatic increase from our prior experience with ing trends that could alter currently accepted practice patterns.24 Specifically in this case, the spike in sterile endophthalmitis was The reported incidence varies throughout the literature partly the impetus for our decision to switch to preservative-free due to the variability in terminology used. We reserve the term triamcinolone acetonide in an attempt to minimise the sterile endophthalmitis, in the post-IVTA setting, to include a incidence of sterile endophthalmitis.
severe intraocular inflammation, which includes vitritis with an The side-effect profile of triamcinolone acetonide with and anterior chamber fibrinoid reaction and/or hypopyon not without preservatives needs further study. Recently the United directly attributed to an infectious aetiology. The term States Food and Drug Administration (FDA) has approved a pseudoendophthalmitis, in the post-IVTA setting, is reserved preservative-free formulation for intraocular use (Triesence; for cases in which the triamcinolone crystals appear in the Alcon Laboratoy, Fort Worth, TX). Furthermore, a new anterior chamber with minimal associated inflammation.
formulation of triamcinolone acetonide designed for intraocular et al reported seven cases of noninfectious use is currently being examined in national clinical trials for endophthalmitis following 440 intravitreal Kenalog injections macular oedema secondary to diabetes and vein occlusions.25 (1.6%), although included in that number was at least one Until we gain a better understanding for the cause of sterile patient with only steroid particles within the anterior chamber endophthalmitis, caution should be advised for the use of 30 min postinjection.17 The actual incidence of non-infectious endophthalmitis was likely lower when eliminating the cases ofpseudoendophthalmitis. Sutter and Gillies reported four cases following approximately 600 injections (0.6%) that were Ethics approval: The North Shore-Long Island Jewish University Hospital System described by the authors as pseudo-endophthalmitis, though institutional review board approved the study protocol.
each case presented with a dense vitreous haze.20 In a study by Roth et al, the incidence of sterile endophthalmitis was noted tobe much higher (6.7%, seven cases out of 104 injections) during a 14-month period between 1 May 2001 and 30 June 2002.21 Greenberg PB, Martidis A, Rogers AH, et al. Intravitreal triamcinolone acetonide for The aetiology of sterile endophthalmitis is unclear. It has macular oedema due to central retinal vein occlusion. Br J Ophthalmol 2002;86:247– been postulated that sterile endophthalmitis may represent an Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory atypical form of bacterial endophthalmitis caused by bacterial diabetic macular edema. Ophthalmology 2002;109:920–7.
toxins or endotoxins not detected by standard culture meth- Jonas JB, Kreissig I, et al. Intravitreal injection of triamcinolone for diffuse diabetic ods.17 However, in our series, the triamcinolone acetonide was macular edema. Arch Ophthalmol 2003;121:57–61.
sent for analysis, and no endotoxin was detected. To our Jonas JB, Sofker A. Intraocular injection of crystalline cortisone as adjunctivetreatment of diabetic macular edema. Am J Ophthalmol 2001;132:425–7.
knowledge, this is the first reported formal analysis looking for Antcliff RJ, Spalton DJ, Stanford MR, et al. Intravitreal triamcinolone for uveitic endotoxin contamination of the triamcinolone.
cystoid macular edema: an optical coherence tomography study. Ophthalmology Another theory is that sterile endophthalmitis represents an inflammatory reaction to the preservatives and additives Jonas JB, Kreissig I, Degenring RF. Intravitreal triamcinolone acetonide forpseudophakic cystoid macular edema. Am J Ophthalmol 2003;136:384–6.
contained in the Kenalog phials which includes benyzl alcohol, Challa JK, Gillies MC, Penfold PL, et al. Exudative macular degeneration and carboxymethylcellulose sodium, and polysorbate 80 in suspen- intravitreal triamcinolone: 18-month follow-up. Aust N Z J Ophthalmol 1998; sion.17 21 This hypothesis is supported by the work of Jonas et al, who report an incidence of 0% in 454 eyes when the solvent was Danis RP, Ciulla TA, et al. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina 2000;20:244–50.
Jonas JB, Kreissig I, Hugger P, et al. Intravitreal triamcinolone acetonide for recent reports of sterile endophthalmitis following intravitreal exudative age related macular degeneration. Br J Ophthalmol 2003;87:462–8.
Br J Ophthalmol 2008;92:1051–1054. doi:10.1136/bjo.2007.136069 Downloaded from bjo.bmj.com on June 6, 2013 - Published by group.bmj.com Spaide RF, Sorenson J, Maranan L. Photodynamic therapy with verteporfin Westfall AC, Osborn A, Kuhl D, et al. Acute endophthalmitis incidence: intravitreal combined with intravitreal injection of triamcinolone acetonide for choroidal triamcinolone, Arch Ophthalmol 2005;123:1075–7.
neovascularization. Ophthalmology 2005;112:301–4.
Moshfeghi AA, Scott IU, et al. Pseudohypopyon after intravitreal triamcinolone Wingate RJ, Beaumont PE. Intravitreal triamcinolone and elevated intraocular acetonide injection for cystoid macular edema. Am J Ophthalmol 2004;138:489–92.
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Sutter FK, Gillies MC. Pseudo-endophthalmitis after intravitreal injection of Bakri SJ, Beer PM. The effect of intravitreal triamcinolone acetonide on intraocular triamcinolone. Br J Ophthalmol 2003;87:972–4.
pressure. Ophthalmic Surg Lasers Imaging 2003;34:386–90.
Roth DB, Chieh J, Spirn MJ, et al. Noninfectious endophthalmitis associated with Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of intravitreal triamcinolone injection. Arch Ophthalmol 2003;121:1279–82.
triamcinolone acetonide. Br J Ophthalmol 2003;87:24–7.
Pearson FC, Dubczak J, Weary M, et al. Detection of endotoxin in the plasma of Jager RD, Aiello LP, et al. Risks of intravitreous injection: a comprehensive review.
patients with Gram-negative bacterial sepsis by the Limulus amoebocyte lysate assay. J Clin Microbiol 1985;21:865–8.
Jonas JB, Kreissig I, Degenring RF. Endophthalmitis after intravitreal injection of Lorenzo CJ, Gonza´lez BM, Pe´rez FI. Sterile endophthalmitis after benzyl alcohol triamcinolone acetonide. Arch Ophthalmol 2003;121:1663–4.
filtered triamcinolone acetonide injection. Arch Ophthalmol 2008;126:142–3.
Moshfeghi DM, Kaiser PK, Scott IU, et al. Acute endophthalmitis following Chang DC, Grant GB, O’Donnell K, et al. Multistate outbreak of Fusarium keratitis intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2003;136:791–6.
associated with use of a contact lens solution. JAMA 2006;296:953–63.
Nelson ML, Tennant MT, Sivalingam A, et al. Infectious and presumed noninfectious Bhavsar AR, Ip MS, Glassman AR, DRCRnet and the SCORE Study Groups. The risk endophthalmitis after intravitreal triamcinolone acetonide injection. Retina of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol 2007;144:454–6.
Endocapsular phacoemulsification without hydrodissec-tion: an effective technique for cataract surgery followinganterior capsular tear ABSTRACTA radial tear of the anterior capsule can occur either as a primary tear-out during capsulorrhexisor as a secondary event during phaco. Endocapsular surgery in this situation is hazardous and therisk of posterior propagation of the tear is significantly increased by performing hydrodissection.
We describe an alternative technique of endocapsular phacoemulsification without primaryhydrodissection. The risk of tear propagation is reduced whilst at the same time auto-hydrodissection of the cortico-capsular connections occurs, enabling rotation and removal of thenucleus. This simple modification of conventional phacoemulsification reduces the risk ofposterior extension in cases of radial anterior capsular tear and allows the relatively safecompletion of endocapsular phacoemulsification.
http://bjo.bmj.com/cgi/content/full/92/8/1054/DC1 Department of Ophthalmology, Royal Free Hospital, London, UK report and accompanying video please go to: http://bjo.bmj.com/cgi/content/full/92/8/1054/DC1 Department of Ophthalmology, Royal Free Hospital, London, UK All videos from the BJO video report collection are available from: Correspondence to: Mr B Little, Consultant Ophthalmologist, Royal Free Hospital, London NW3 2QG, UK;

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