Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Current Infectious Endophthalmitis Rates After Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Agents and Outcomes of Treatment

Ninel Z. Gregori, MD; Harry W. Flynn, MD; Stephen G. Schwartz, MD, MBA; Philip J. Rosenfeld, MD, PhD; Kamyar Vaziri, MD; Andrew A. Moshfeghi, MD, MBA; Jorge A. Fortun, MD; Jaclyn L. Kovach, MD; Sander R. Dubovy, MD; Thomas A. Albini, MD; Janet L. Davis, MD; Audina M. Berrocal, MD; William E. Smiddy, MD

Abstract

BACKGROUND AND OBJECTIVE:

To assess the incidence and outcomes of infectious endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents.

PATIENTS AND METHODS:

Patient records at the Bascom Palmer Eye Institute (BPEI) from January 1, 2005, through December 31, 2014, were reviewed. The largest commercial claims and encounters database in the U.S. (MarketScan) was utilized to calculate the population-based endophthalmitis rate for 2011 to 2013.

RESULTS:

The population-based rate of endophthalmitis after anti-VEGF injections for 2011 to 2013 was 391/740,757 (0.053%). BPEI’s rate was 20/121,285 (0.016%) during the study period: eight after bevacizumab (0.012%), six after ranibizumab (0.018%), and six after aflibercept (0.031%) injection. Nine BPEI cases (45%) were culture-positive: Streptococcus species (5), coagulase-negative Staphylococcus (3), and non-anthracis Bacillus (1). Final visual acuity varied from 20/25 to no light perception.

CONCLUSION:

Endophthalmitis after anti-VEGF injection was uncommon in our institution and in the population-based database. Treatment outcomes were variable but generally fared better in the culture-negative cases.

[Ophthalmic Surg Lasers Imaging Retina. 2015;46:643–648.]

From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (NZG, HWF, SGS, PJR, AAM, JAF, JLD, KV, SRD, TAA, JLD, AMB, WES); and the University of Southern California Eye Institute, Keck School of Medicine, Los Angeles, California (AAM).

Supported by NIH Center Core Grant P30EY014801 and an unrestricted grant from Research to Prevent Blindness. Funding for purchase of the MarketScan database was provided by a research donation from the Celia Lipton Farris and Victor W. Farris Foundation, Inc.

The authors report no relevant financial disclosures.

Address correspondence to Ninel Z. Gregori, MD, Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33136; email: ngregori@med.miami.edu.

Received: September 20, 2014
Accepted: May 05, 2015

Abstract

BACKGROUND AND OBJECTIVE:

To assess the incidence and outcomes of infectious endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents.

PATIENTS AND METHODS:

Patient records at the Bascom Palmer Eye Institute (BPEI) from January 1, 2005, through December 31, 2014, were reviewed. The largest commercial claims and encounters database in the U.S. (MarketScan) was utilized to calculate the population-based endophthalmitis rate for 2011 to 2013.

RESULTS:

The population-based rate of endophthalmitis after anti-VEGF injections for 2011 to 2013 was 391/740,757 (0.053%). BPEI’s rate was 20/121,285 (0.016%) during the study period: eight after bevacizumab (0.012%), six after ranibizumab (0.018%), and six after aflibercept (0.031%) injection. Nine BPEI cases (45%) were culture-positive: Streptococcus species (5), coagulase-negative Staphylococcus (3), and non-anthracis Bacillus (1). Final visual acuity varied from 20/25 to no light perception.

CONCLUSION:

Endophthalmitis after anti-VEGF injection was uncommon in our institution and in the population-based database. Treatment outcomes were variable but generally fared better in the culture-negative cases.

[Ophthalmic Surg Lasers Imaging Retina. 2015;46:643–648.]

From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (NZG, HWF, SGS, PJR, AAM, JAF, JLD, KV, SRD, TAA, JLD, AMB, WES); and the University of Southern California Eye Institute, Keck School of Medicine, Los Angeles, California (AAM).

Supported by NIH Center Core Grant P30EY014801 and an unrestricted grant from Research to Prevent Blindness. Funding for purchase of the MarketScan database was provided by a research donation from the Celia Lipton Farris and Victor W. Farris Foundation, Inc.

The authors report no relevant financial disclosures.

Address correspondence to Ninel Z. Gregori, MD, Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33136; email: ngregori@med.miami.edu.

Received: September 20, 2014
Accepted: May 05, 2015

Introduction

The use of intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents has increased as clinical trials have shown visual and anatomic treatment benefits in various macular diseases.1 The most feared complication of this therapy is infectious endophthalmitis, which can result in severe visual loss. The rate of endophthalmitis was reported to range from 0.038% to 0.065% per injection in large meta-analysis studies.2,3 In a previous report from the Bascom Palmer Eye Institute, the infectious endophthalmitis rate was 12 of 60,322 injections (0.02%) administered between 2005 and 2010.1 Streptococcal species, which are common upper respiratory tract organisms, were the most common bacteria isolated in that time period and resulted in the worst visual outcomes.1

The aim of the current study is to report the updated endophthalmitis rate at our university medical center and in a large U.S. population database, and to assess the causative organisms and visual outcomes at our academic center in the recent years.

Patients and Methods

This noncomparative consecutive case series was approved by the University of Miami Institutional Review Board and was compliant with the Health Insurance Portability and Accountability Act. All previously injected patients with clinically suspected endophthalmitis who had intraocular cultures and intravitreal antibiotics after anti-VEGF injections administered at the Bascom Palmer Eye Institute (BPEI) and its satellites were included, based on the BPEI Infection Control Committee’s records. This committee prospectively collects records of patients with clinically suspected endophthalmitis after all ocular procedures. The time period included in the study was January 1, 2005, to December 31, 2014. This series represents an extension of our previously published data set, which included cases through December 31, 2010.1

All intravitreal anti-VEGF injections were performed with nursing staff or equivalently trained personnel administering topical antisepsis and anesthesia according to a standard protocol that has been previously published.1 The protocol includes the use of topical povidone-iodine 5%, lidocaine 4% drops, 10% povidone-iodine to the lids and lashes, sterile speculum, and sterile calipers. It does not include the use of a sterile drape, sterile gloves, or mandatory facial mask (which is used at the discretion of each individual physician). In the first half of the study period, many patients were prescribed post-injection topical antibiotics, mainly fluoroquinolones. Starting in 2008, there was a transition toward not prescribing peri- or post-injection antibiotics for home use. Toward the later years of the study, the majority of patients were not treated with antibiotics.

In addition, a retrospective analysis of the 2011 to 2013 data (more than 155 million unique patients) from the largest proprietary commercial claims and encounters database in the U.S. (MarketScan; Truven Health Analytics, Ann Arbor, MI) was performed, consisting of de-identified inpatient and outpatient health records provided by employer-sponsored or supplemental insurance plans, including Medicare.4 The funding for purchase of the MarketScan databases was provided by a research donation from the Celia Lipton Farris and Victor W. Farris Foundation. Patients were identified based on a Current Procedural Terminology (CPT) code of 67028 (intravitreal injection of a pharmacological agent) coded in the same session as one of the following CPT codes: J9035 or C9257 for bevacizumab, J2778 for ranibizumab, J2503 for pegaptanib, J0178 for aflibercept, and J3490 or J3590 for unclassified injection or unclassified biologics, respectively. These were then narrowed down to include those cases with ICD-9 codes for purulent endophthalmitis (360.00 to 360.04) within 14 days of recorded intravitreal injections.

Results

Over the 10-year study period at BPEI, a total of 121,285 anti-VEGF injections were performed: 67,043 off-label bevacizumab (55%), 33,134 ranibizumab (27%), 19,103 aflibercept (16%), and 2,005 pegaptanib (2%) (Figure). There were 20 eyes of 19 patients (0.016% or one per 6,064 injections) with clinically diagnosed endophthalmitis: eight after bevacizumab (0.012%), six after ranibizumab (0.018%), and six after aflibercept (0.031%) injection (Tables 1 and 2). There was no significant difference between endophthalmitis rates with different medications (P = .24, chi-square). The endophthalmitis rates per year (cases per total number of injections) varied from zero to 0.038%, as displayed in Table 1. One patient (cases 9 and 10) developed culture-negative endophthalmitis in the same eye after two injections of off-label bevacizumab given 8 months apart. The incidence of culture-positive cases at BPEI was nine in 121,285 (0.007% or 1:13,476) and of culture-negative cases was 11 of 121,285 (0.009% or 1:11,026). Culture-negative cases tended to follow a less severe clinical course, with nine of 11 cases recovering to within one Snellen line (better or worse) of pre-injection visual acuity (Table 2).

Graph shows the number of injections per year of each anti-vascular endothelial growth factor agent administered at the Bascom Palmer Eye Institute between 2005 and 2014.

Figure.

Graph shows the number of injections per year of each anti-vascular endothelial growth factor agent administered at the Bascom Palmer Eye Institute between 2005 and 2014.

Clinically Suspected Endophthalmitis Rates for Each Anti-VEGF Medication Administered at the Bascom Palmer Eye Institute, 2005 to 2014

Table 1:

Clinically Suspected Endophthalmitis Rates for Each Anti-VEGF Medication Administered at the Bascom Palmer Eye Institute, 2005 to 2014

Summary of Patients with Clinically Suspected Endophthalmitis treated at the Bascom Palmer Eye Institute, 2005 to 2014

Table 2:

Summary of Patients with Clinically Suspected Endophthalmitis treated at the Bascom Palmer Eye Institute, 2005 to 2014

All cases were initially managed by vitreous tap with or without aqueous tap and injection of intravitreal antibiotics (vancomycin and ceftazidime or amikacin, and/or dexamethasone). Nine cases (45%) yielded positive culture results: five (56%) Streptococcus species, three (33%) coagulase-negative Staphylococcus, and one (11%) Bacillus non-anthracis (Table 2). Four of five Streptococcus cases had poor final visual acuity of light perception of worse. All Streptococcus cases occurred in the first part of the study, 2007 to 2009, when Streptococcus species were the most commonly isolated organisms (71%). Six of the eight new cases added to the original data set (2005 to 2010)5 previously published were culture-negative, and all six occurred after aflibercept injections. Coagulase-negative Staphylococci were isolated in two other cases, following bevacizumab and ranibizumab injections (cases 14 and 16, Table 2).

Nineteen patients presented within 3 days of injection, and one culture-negative case within 15 days after the injection. Presenting symptoms and signs included decreased vision (20), mild to moderate or transient pain (19), red eye (18), anterior chamber cells (20), and vitritis (20). Fibrin and hypopyon were associated with culture-positive and Gram-positive cases. The study eyes had received two to 39 previous anti-VEGF injections. Thirteen eyes (cases 1–12 and 16) received topical fluoroquinolone drops for 3 days after the injection. Five other eyes (13 and 17–20) had received only a drop of fluoroquinolone at the end of the injection.

From the MarketScan 2011–2013 database, which encompasses more than 155 million unique insured individuals, the recorded purulent endophthalmitis cases per total number of injections per year were as follows: 22/79,998 (2011), 172/319,269 (2012), and 197/341,490 (2013). This yielded an endophthalmitis rate of 0.028% or 1 per 3,636 injections in 2011, 0.054% or 1 per 1,856 injections in 2012, and 0.058% or 1 per 1,733 injections in 2013. The overall endophthalmitis rate for 2011 to 2013 was 391/740,757 (0.053%) or 1 per 1,895 injections.

Discussion

The results of this study indicate that the incidence of clinically suspected endophthalmitis after anti-VEGF injections is low: approximately one in 6,000 (0.016%) in our institution and one in 1,900 (0.053%) injections in a large population-based database. These rates compare favorably to many other studies reporting the incidence of infectious endophthalmitis after intravitreal injections of anti-VEGF agents.2,3

All clinically suspected endophthalmitis cases treated with intraocular culture and intravitreal injection of antibiotics were included in our university-based cohort of patients. Cases with suspected non-infectious inflammation treated with topical steroids and close observation, without intraocular cultures, were excluded. Intraocular cultures were positive in 45% of our cases, which is similar to the rate of approximately 50% vitreous culture positivity reported in a recent meta-analysis of prospective and retrospective studies of infectious endophthalmitis after anti-VEGF injections.3 The causative organisms isolated in our cohort were Streptococcus (55%), coagulase-negative Staphylococcus (33%), and Bacillus species (11%). The most commonly isolated bacteria in the meta-analysis were coagulase-negative Staphylococcus (38.24%) and Streptococcus species (29.41%).3

Because it is challenging to distinguish infectious from noninfectious cases based on clinical presentation alone, the current study cohort may have included noninfectious inflammatory cases, particularly among the eyes with culture-negative aflibercept-associated inflammation.6 Overall, culture-negative cases tended to follow a less severe clinical course, with nine of 11 cases returning to baseline vision. Lack of growth may correspond to either a small bacterial load, which is difficult to isolate in culture, or a truly noninfectious inflammation. While fibrin and hypopyon tend to be associated with infectious cases,7 noninfectious inflammation cases may also rarely present with a hypopyon.6,8 Moreover, the timing of presentation (most commonly within 3 days of injection in both infectious5 and noninfectious6 cases) and the presence of decreased vision (several lines of vision may be lost in noninfectious cases6,9) and pain (tends to be mild in noninfectious cases, but has been reported in both infectious5 and noninfectious6,9 cases) are not entirely reliable in differentiating true infections from sterile inflammation.

Interestingly, all six aflibercept-associated cases in the current study were culture-negative. Four aflibercept patients presented with no or mild transient pain, four with conjunctival injection, all with blurred vision, and only one with a hypopyon. The eye with hypopyon yielded a dry vitreous tap but showed polymorphonuclear leukocytes on Gram stain of the aqueous humor without any growth in culture. All aflibercept cases presented within 1 day of injection, and at the last follow-up all but one returned to within one line of pre-injection visual acuity. It is possible that at least some of these culture-negative cases represent sterile aflibercept-related inflammation.6,8 The American Society of Retina Specialists Therapeutic Surveillance Committee reported 15 cases of sterile inflammation after intravitreal aflibercept from five separate drug lots. All but one patient presented within 3 days of injection with pain (prevalence of 60%) and redness (40%), noted only in eyes presenting with pain.8 Goldberg et al reported 20 cases of noninfectious inflammation after aflibercept (incidence of 0.37%), which presented 1 to 13 days after injection (median: 3 days) with decreased vision (100%), pain (15%), conjunctival injection in two eyes with pain (10%), hypopyon in only one eye (5%), and vitritis (100%).6 All patients regained pre-injection visual acuity after a variable number of days (7 to 73 days).

Based on these case series, noninfectious inflammation after aflibercept injection seems to present more commonly without pain, conjunctival injection, or hypopyon. Differentiating infectious from noninfectious endophthalmitis may be difficult, therefore patients in whom noninfectious endophthalmitis is initially diagnosed should be monitored closely for signs of improvement if managed with topical steroids for presumed sterile inflammation.

In order to reduce the risk of endophthalmitis, patients in the current study had preparation with a standard protocol, using 5% povidone-iodine and sterile lid speculum to avoid contact of the needle with lids and lashes. Beginning in 2008, there was a transition to not using topical antibiotics after injections, with only one patient during 2011 to 2014 receiving post-injection antibiotics for home use. The endophthalmitis rate remained the same during 2005 to 2010 (0.02%) and 2011 to 2014 (0.013%), P = .38 (Fisher’s exact test). The one patient treated with a topical antibiotic (ciprofloxacin) specifically requested that antibiotic based on the usual policy of his referring ophthalmologist in the Northeast. This use of post-injection antibiotics was not the usual policy of the treating BPEI ophthalmologist at that time. It is possible that there were other isolated patients treated with topical antibiotics during this time frame but these patients not developing endophthalmitis could not be identified.

Many studies have reported that topical antibiotics have no apparent beneficial effect on endophthalmitis rates after intravitreal injections,10–12 which might be due to the fact that repeated exposure to topical antibiotics may alter ocular flora and increase rates of more virulent and possibly more antimicrobial-resistant organisms on the ocular surface.13

In the current study, no difference in endophthalmitis rates was identified between compounded bevacizumab (0.012%) and non-compounded ranibizumab (0.018%) and aflibercept (0.031%). The Bascom Palmer Eye Institute obtains bevacizumab-containing syringes from pharmacies that adhere to United States Pharmacopoeia Chapter 797 requirements for compounding medications. It has been documented that adherence to these standards and aseptic technique are the key factors in preventing microbial contamination when using compounded medication.14 In addition, stability of compounded bevacizumab has been extensively studied. A recent study reported no significant difference over a 6-month period in the quality of bevacizumab repackaged into pre-filled polycarbonate and polypropylene syringes when compared with bevacizumab that is supplied directly from the vial.15 These data must be taken into consideration by the federal agencies regulating the use of repackaged bevacizumab. At our pharmacy bevacizumab syringes are released to clinical use only after the microbiology laboratory reports negative cultures from 10% of aliquots held for 14 days. The prepared syringes are kept in the refrigerator and used in the clinics within 3 months of the repackaging date.

The rate of endophthalmitis after anti-VEGF injections is low, but the risk has not been eliminated.14 The entity of noninfectious inflammation presents diagnostic and management challenges to the clinician. Regardless, patients should be counseled about the possibility of post-injection inflammation, which may result in visual loss. Moreover, the importance of immediate medical attention should be stressed if visual loss or redness and pain occur.

References

  1. Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr, et al. Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six-year experience at a university referral center. Retina. 2011;31(4):662–668. doi:10.1097/IAE.0b013e31821067c4 [CrossRef]
  2. McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina. 2011;31(4):654–661.
  3. Fileta JB, Scott IU, Flynn HW Jr, . Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surg Lasers Imaging Retina. 2014;45(2):143–149. doi:10.3928/23258160-20140306-08 [CrossRef]
  4. Connell PP, O’Neill EC, Fabinyi D, et al. Endogenous endophthalmitis: 10-year experience at a tertiary referral centre. Eye (Lond). 2011;25(1):66–72. doi:10.1038/eye.2010.145 [CrossRef]
  5. Moshfeghi AA. Endophthalmitis following intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration. Semin Ophthalmol. 2011;26(3):139–148. doi:10.3109/08820538.2011.570847 [CrossRef]
  6. Goldberg RA, Shah CP, Wiegand TW, Heier JS. Noninfectious inflammation after intravitreal injection of aflibercept: clinical characteristics and visual outcomes. Am J Ophthalmol. 2014;158(4):733–737. doi:10.1016/j.ajo.2014.06.019 [CrossRef]
  7. Agrawal S, Joshi M, Christoforidis JB. Vitreous inflammation associated with intravitreal anti-VEGF pharmacotherapy. Mediators Inflamm. 2013;2013:943409. doi:10.1155/2013/943409 [CrossRef]
  8. Hahn P, Kim JE, Stinnett SAmerican Society of Retina Specialists Therapeutic Surveillance C. Aflibercept-related sterile inflammation. Ophthalmology. 2013;120(5):1100–1101. doi:10.1016/j.ophtha.2012.11.018 [CrossRef]
  9. Kay CN, Tarantola RM, Gehrs KM, et al. Uveitis following intravitreal bevacizumab: a non-infectious cluster. Ophthalmic Surg Lasers Imaging. 2011;42(4):292–296. doi:10.3928/15428877-20110603-04 [CrossRef]
  10. Bhavsar AR, Stockdale CR, Ferris FL 3rd, Brucker AJ, Bressler NM, Glassman AR. Update on risk of endophthalmitis after intravitreal drug injections and potential impact of elimination of topical antibiotics. Arch Ophthalmol. 2012;130(6):809–810. doi:10.1001/archophthalmol.2012.227 [CrossRef]
  11. Bhavsar AR, Googe JM Jr, Stockdale CR, et al. Risk of endophthalmitis after intravitreal drug injection when topical antibiotics are not required: the diabetic retinopathy clinical research network laser-ranibizumab-triamcinoloneclinical trials. Arch Ophthalmol. 2009;127(12):1581–1583. doi:10.1001/archophthalmol.2009.304 [CrossRef]
  12. Cheung CS, Wong AW, Lui A, Kertes PJ, Devenyi RG, Lam WC. Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections. Ophthalmology. 2012;119(8):1609–1614. doi:10.1016/j.ophtha.2012.02.014 [CrossRef]
  13. Yin VT, Weisbrod DJ, Eng KT, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol. 2013;131(4):456–461. doi:10.1001/jamaophthalmol.2013.2379 [CrossRef]
  14. Gonzalez S, Rosenfeld PJ, Stewart MW, Brown J, Murphy SP. Avastin doesn’t blind people, people blind people. Am J Ophthalmol. 2012;153(2):196–203e191. doi:10.1016/j.ajo.2011.11.023 [CrossRef]
  15. Khalili H, Sharma G, Froome A, Khaw PT, Brocchini S. Storage stability of bevacizumab in polycarbonate and polypropylene syringes. Eye (Lond). 2015;29(6):820–827. doi:10.1038/eye.2015.28 [CrossRef]
  16. Schachat AP, Rosenfeld PJ, Liesegang TJ, Stewart MW. Endophthalmitis is not a “never event”. Ophthalmology. 2012;119(8):1507–1508. doi:10.1016/j.ophtha.2012.03.048 [CrossRef]

Clinically Suspected Endophthalmitis Rates for Each Anti-VEGF Medication Administered at the Bascom Palmer Eye Institute, 2005 to 2014

YearBevacizumab*Ranibizumab*Aflibercept*Pegaptanib*Totals*
20050/998000/13130/2311 (0.0%)
20060/31391/252300/6721/6334 (0.016%)
20072/61982/431700/84/10523 (0.038%)
20082/93452/3399004/12744 (0.031%)
20093/106800/3630003/14310 (0.021%)
20100/93400/4738000/14078 (0.0%)
20111/96410/54340/1920/121/15279 (0.007%)
20120/68850/34442/43680/02/14697 (0.014%)
20130/50361/28824/66480/05/14566 (0.034%)
20140/57810/27670/78950/00/16443 (0.0%)
2005–2014 endophthalmitis cases/total number of injections8/67043 (0.012%)6/33134 (0.018%)6/19103 (0.031%)0/2005 (0%)20/121285 (0.016%)
Intraocular culture positive/negative5/34/20/6NA9/11

Summary of Patients with Clinically Suspected Endophthalmitis treated at the Bascom Palmer Eye Institute, 2005 to 2014

Case No.YearBaseline DiagnosisMedicationPre-injection Visual AcuityVisual Acuity at Time of EndophthalmitisIntraocular Culture ResultsFinal Visual AcuityFollow-up (mos)
12007CRVOBevacizumab20/40HMStreptococcus sanguinis/S. gordoniiNLP36
22007AMDRanibizumab20/50HMStreptococcus intermediusLP25
32008AMDRanibizumab20/200LPStreptococcus salivarius/S. intermediusNLP3
42007BRVOBevacizumab20/504/200Streptococcus intermedius/S. mitis20/4024
52007AMDRanibizumab20/100HMStaphylococcus epidermidis20/7039
62009AMDBevacizumab20/30LPStreptococcus mitisLP8
72009AMDBevacizumab20/601/200Bacillus non-anthracis20/608
82006AMDRanibizumab20/100HMCulture negative20/8036
9*2008AMDBevacizumab20/40HMCulture negative20/3029
10*2008AMDRanibizumab20/60HMCulture negative20/3021
112008AMDBevacizumab20/4020/250Culture negative20/4010
122009AMDBevacizumab20/2002/200Culture negativeCF1
132013AMDAflibercept20/5020/70Culture negative20/406
142011BRVOBevacizumab20/40HMCoagulase-negative Staphylococcus warneri20/4006
152013AMDAflibercept20/400HMCulture negative4/200E2
162013AMDRanibizumab20/3020/50Coagulase-negative Staphylococcus20/801
172013AMDAflibercept20/5020/200Culture negative20/601
182012AMDAflibercept20/8020/300Culture negative20/10012
192013AMDAflibercept20/5020/200Culture negative20/601
202012AMDAflibercept20/3020/50Culture negative20/252

10.3928/23258160-20150610-08

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