Purpose
To report a series of patients with Streptococcus endophthalmitis after injection with intravitreal bevacizumab prepared by the same compounding pharmacy.
Design
Noncomparative consecutive case series.
Methods
Medical records and microbiology results of patients who presented with endophthalmitis after injection with intravitreal bevacizumab between July 5 and July 8, 2011, were reviewed.
Results
Twelve patients were identified with endophthalmitis, presenting 1 to 6 days after receiving an intravitreal injection of bevacizumab. The injections occurred at 4 different locations in south Florida. All patients received bevacizumab prepared by the same compounding pharmacy. None of the infections originated at the Bascom Palmer Eye Institute, Miami, Florida, although 9 patients presented to its tertiary-care ophthalmic emergency room for treatment, and 3 additional patients were seen in consultation. All patients were treated initially with a vitreous tap and injection; 8 patients subsequently received a vitrectomy. Microbiology cultures for 10 patients were positive for Streptococcus mitis/oralis . Seven unused syringes of bevacizumab prepared by the compounding pharmacy at the same time as those prepared for the affected patients also were positive for S. mitis/oralis . After 4 months of follow-up, all but 1 patient had count fingers or worse visual acuity, and 3 required evisceration or enucleation. Local, state, and federal health department officials have been investigating the source of the contamination.
Conclusions
In this outbreak of endophthalmitis after intravitreal bevacizumab injection, Streptococcus mitis/oralis was cultured from the majority of patients and from all unused syringes. Visual outcomes were generally poor. The most likely cause of this outbreak was contamination during syringe preparation by the compounding pharmacy.
Over the past 6 years, the use of vascular endothelial growth factor (VEGF) inhibitors has become commonplace in the treatment of age-related macular degeneration (AMD), as well as other inflammatory and neovascular retinal diseases, including retinal vein occlusion (RVO) and diabetic macular edema (DME). These agents are injected directly into the vitreous cavity and are generally well tolerated, with a low overall complication rate. Endophthalmitis, one of the most feared complications, has previously been reported to have an incidence after intravitreal injection of 0.02% to 0.05%. In the recently published data from the Comparison of AMD Treatments Trials (CATT) study, 6 cases of endophthalmitis developed after 10 957 intravitreal anti-VEGF injections (0.05%).
In the current study, an endophthalmitis outbreak is reported after intravitreal injection of bevacizumab (Avastin, Genentech/Roche, South San Francisco, California, USA), a full-length humanized VEGF inhibitor commonly used off-label in the treatment of AMD, RVO, and DME. All patients received intravitreal injections of bevacizumab prepared by the same compounding pharmacy in south Florida. This is the largest reported outbreak of infectious endophthalmitis after intravitreal injection of a contaminated group of prefilled bevacizumab syringes.
Methods
After approval of the Institutional Review Board of the University of Miami, and in cooperation with local and state Departments of Health, the charts of all patients in this outbreak of endophthalmitis after intravitreal injection were retrospectively reviewed.
The data collected include the age and sex of each patient, the affected eye and its lens status, the date of the most recent bevacizumab injection, the underlying diagnosis and clinical indication for intravitreal injection, and the preinjection visual acuity. Presentation and diagnostic data were recorded as well, including the date of presentation, the visual acuity and intraocular pressure, the pain score, the presenting symptoms and signs, and the initial management as well as the microbiology results. The patients’ clinical courses were recorded, including the visual acuity, the number of antibiotic and steroid injections, and the use of pars plana vitrectomy and other surgical interventions, as well as the last recorded visual acuity outcome at 4 months follow-up.
Results
A total of 12 patients were included in this study, 9 actively managed at the Bascom Palmer Eye Institute and 3 seen in consultation, although initially managed by outside vitreoretinal specialists. The average age of patients at the time of presentation was 78.0 years (median 77.3 years, range 68.1–88.2 years). There were 7 women (58%) and 5 men (42%). The indications for treatment with an anti-VEGF agent included neovascular AMD (9 patients; 75%), macular edema (2 patients; 17%), and RVO with neovascular glaucoma (1 patient; 8%). Preinjection visual acuities ranged from 20/25 to count fingers.
In this outbreak, the affected patients were injected by 4 physicians in 4 separate office locations over a 4-day span. All patients received bevacizumab prepared by the same compounding pharmacy. All treating physicians report similar injection preparation techniques, including the use of povidone-iodine and sterile lid speculums. All patients were given a fourth-generation fluoroquinolone topical antibiotic drop (gatifloxacin or moxifloxacin) for postinjection endophthalmitis prophylaxis.
Eleven of the affected patients were members of the same managed care organization (MCO), which contracted with the compounding pharmacy to supply the treating ophthalmologists with prefilled bevacizumab syringes for each patient. The MCO of the twelfth patient contracted with the same compounding pharmacy for bevacizumab syringe preparation. One patient (Case 12) received a bilateral injection of bevacizumab, though the fellow eye was treated with bevacizumab prepared by a different pharmacy.
Patients presented complaining of redness, pain, and decreased visual acuity. Two patients (17%) presented within 1 day of their injection, 6 patients (50%) presented on postinjection day 2, 2 patients (17%) presented 3 days after their injection, and 2 patients (17%) presented 6 days after their intravitreal injection. Presenting visual acuities were light perception (8 patients; 67%), hand motions (2 patients; 17%), count fingers (1 patient; 8%), and 20/200 (1 patient; 8%). Nine patients (75%) presented with an intraocular pressure greater than 33 by Tonopen tonometry, with self-reported pain scores of 8 to 10 out of 10.
All 12 patients were treated with initial vitreous tap and injection of antibiotics, including intravitreal vancomycin 1.0 mg/0.1 mL. Culture results for 10 vitreous specimens were positive for Streptococcus mitis/oralis ; susceptibility testing demonstrated that the bacteria were sensitive to vancomycin . Four patients received repeat intravitreal injections of vancomycin and steroids; 1 of these patients received a second diagnostic vitreous tap as well, which was positive for S. mitis/oralis. Eight patients underwent pars plana vitrectomy, and in 6 of these cases the vitreous cassettes were sent for microbiological evaluation; 2 were culture-positive for S. mitis/oralis . Additionally, 2 patients underwent evisceration 6 and 8 weeks (Cases 5 and 9, respectively) after presentation, and the intraocular contents in 1 of these cases was culture-positive for S. mitis/oralis . One patient (Case 8) had persistent inflammation after vitrectomy surgery and was subsequently enucleated.
All patients showed marked improvement in their clinical appearance during the days after their initial treatment. Signs and symptoms of improvement included consolidation and contraction of the anterior chamber fibrin, decreased conjunctival injection and chemosis, and increased patient comfort ( Figures 1 through 3 show representative examples). For all but 1 patient (Case 7), the visual acuity remained poor: at 4 months follow-up, 5 patients (42%) were no light perception, 4 patients (33%) were hand motions, 2 patients (17%) were count fingers, and 1 patient (8%) had a visual acuity of 20/25. Table 1 provides a summary of the clinical course.
| Case | Baseline Diagnosis | Preinjection Visual Acuity | Visual Acuity at the Time of Endophthalmitis | Days to Presentation | Initial Treatment | Surgical Intervention | Visual Acuity at 4 Months |
|---|---|---|---|---|---|---|---|
| 1 | AMD | 20/400 | LP | 2 | V,C,D | PPV | NLP |
| 2 | CME | 20/100 | HM | 2 | V,C,D | PPV | HM |
| 3 | AMD | 20/30 | LP | 2 | V,C,D | PPV | CF |
| 4 | AMD | 20/400 | LP | 2 | V,C,D | PPV | NLP |
| 5 | AMD | 20/400 | LP | 1 | V,C,D | Ev | NLP |
| 6 | AMD | 20/50 | LP | 1 | V,C,D | PPV | HM |
| 7 | AMD | 20/40 | 20/200 | 3 | V,C,D | 20/25 | |
| 8 | CME | CF | LP | 6 | V,C,D | PPV, Enuc | NLP |
| 9 | VO/NVG | CF | LP | 6 | V,C,D | Ev | NLP |
| 10 | AMD | 20/40 | LP | 3 | V,C | HM | |
| 11 | AMD | 20/25 | CF | 2 | V,A | PPV | HM |
| 12 | AMD | 20/25 | HM | 2 | V,A | PPV | CF |
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