0
Clinical Sciences |

Risk of Endophthalmitis After Intravitreal Drug Injection When Topical Antibiotics Are Not Required:  The Diabetic Retinopathy Clinical Research Network Laser-Ranibizumab-Triamcinolone Clinical Trials FREE

Abdhish R. Bhavsar, MD; Joseph M. Googe Jr, MD; Cynthia R. Stockdale, MSPH; Neil M. Bressler, MD; Alexander J. Brucker, MD; Michael J. Elman, MD; Adam R. Glassman, MS; Diabetic Retinopathy Clinical Research Network
[+] Author Affiliations

Author Affiliations: Retina Center of Minnesota (Dr Bhavsar), Minneapolis; Southeastern Retina Associates Professional Corporation (Dr Googe), Knoxville, Tennessee; Jaeb Center for Health Research (Ms Stockdale and Mr Glassman), Tampa, Florida; Wilmer Eye Institute (Dr Bressler) and Elman Retina Group (Dr Elman), Baltimore, Maryland; and Scheie Eye Institute (Dr Brucker), Philadelphia, Pennsylvania.


Arch Ophthalmol. 2009;127(12):1581-1583. doi:10.1001/archophthalmol.2009.304.
Text Size: A A A
Published online

Objective  To report the incidence of endophthalmitis after intravitreal drug injection by means of a standardized procedure that does not require topical antibiotics, sterile gloves, or a sterile drape.

Methods  Intravitreal injections of preservative-free triamcinolone acetonide or ranibizumab were administered in 2 prospective randomized clinical trials performed by the Diabetic Retinopathy Clinical Research Network. The standardized procedure for these trials requires the use of a topical combination product of povidone-iodine, a sterile lid speculum, and topical anesthetic, but does not require the use of topical antibiotics before, on the day of, or after injection.

Results  As of February 23, 2009, a total of 3226 intravitreal injections of ranibizumab and 612 injections of preservative-free triamcinolone had been administered. Topical antibiotics were given on the day of injection in 361 (9.4%) of the 3838 cases, for several days after injection in 813 cases (21.2%), on the day of injection and after injection in 1388 cases (36.2%), and neither on the day of injection nor after injection in 1276 cases (33.3%). Three cases of culture-positive endophthalmitis occurred after ranibizumab injections (0.09%), and no cases occurred after triamcinolone injections. In all 3 cases of endophthalmitis, topical antibiotics were given for several days after the injection but not before injection.

Conclusions  The results suggest that a low rate of endophthalmitis can be achieved by means of a protocol that includes use of topical povidone-iodine, a sterile lid speculum, and topical anesthetic, but does not require topical antibiotics, sterile gloves, or a sterile drape.

Trial Registration  clinicaltrials.gov Identifiers: NCT00444600 and NCT00445003

Intravitreal injections have become an increasingly common route of administration of medications in the treatment of posterior segment disease. Endophthalmitis is one of the most serious complications of intravitreal injection of medication, with a reported per-injection incidence that ranges from 0.02% to 1.9%.15 Optimum management of the ocular surface before, during, and after intravitreal injections remains controversial.3,6 A topical combination of povidone-iodine is the only preoperative substance proven in a randomized clinical trial to reduce the risk of endophthalmitis after intraocular surgery.7 To our knowledge, no adequate studies have evaluated the role of topical antibiotics; thus, uncertainty still exists with regard to the efficacy of topical antibiotics in the prevention of postinjection endophthalmitis. Although combined use of topical povidone-iodine and antibiotics may have a synergistic effect in reduction of the preoperative culture-positive rate of the conjunctival surface,8,9 we have identified little evidence that suggests topical antibiotics reduce the rate of endophthalmitis in humans. In addition, there is little evidence that the pharmacokinetics of the topical regimens provided would result in adequate antibiotic levels, which would be expected to have a protective effect.1013 Despite this, topical antibiotics before intravitreal drug injection have been required in several recent clinical trial protocols.1416 Furthermore, recent surveys have suggested that 40% of retina specialists use topical antibiotics before anti–vascular endothelial growth factor intravitreal injections, and 86% use topical antibiotics after anti–vascular endothelial growth factor intravitreal injections.17,18

Previous studies19,20 have indicated a low rate of endophthalmitis after preservative-free intravitreal triamcinolone acetonide injections in patients for whom prolonged topical antibiotic use for multiple days before the injection was not required, ie, for whom antibiotics were required only the day of and the day after the injection. We report the endophthalmitis rate in the Diabetic Retinopathy Clinical Research (DRCR) Network laser-ranibizumab-triamcinolone (LRT) trials in which topical antibiotics administered before or on the day of injection and used for several days afterward were not required but could be administered at the discretion of the investigator.

The ongoing DRCR Network LRT trials use a standardized protocol for ocular surface preparation and intravitreal injection of ranibizumab or preservative-free triamcinolone. Topical antibiotics may be administered before or on the day of injection at the discretion of the investigator, although neither these nor sterile gloves nor a sterile drape is required. A drop of topical anesthetic is applied to the eye. Two or 3 drops of 5% povidone-iodine may be placed in the lower fornix. The use of povidone-iodine lid scrubs is also optional. Although the use of additional topical anesthetic via cotton-tipped applicators is optional, subconjunctival anesthetic and lidocaine gel or other viscous anesthetic is not permitted, per the protocol. A cotton-tipped applicator soaked in 5% or 10% povidone-iodine is placed directly over the intended injection site or, alternatively, a 5% povidone-iodine–forced stream flush from an angiocatheter is used. In all cases, a sterile lid speculum is used to stabilize the lids. Preservative-free triamcinolone or ranibizumab is injected through the pars plana. Although it is not required, topical antibiotics may be provided and used for several days after injection, at the discretion of the investigator.

Diagnosis of endophthalmitis was given on the basis of the judgment of the investigator, and a culture was required before the initiation of antibiotic treatment for presumed endophthalmitis. The 95% confidence interval (CI) for the incidence of endophthalmitis per injection was computed on the basis of the binomial distribution under the assumption of independence.

As of February 23, 2009, a total of 3838 intravitreal injections in 733 eyes have been administered by 124 physicians as part of the DRCR Network LRT trials. This number includes 612 injections of preservative-free triamcinolone in 272 eyes and 3226 injections of ranibizumab in 461 eyes. Topical antibiotics were given on the day of but not after the injection in 361 (9.4%) of the 3838 cases, for several days after but not on the day of injection in 813 cases (21.2%), both on the day of and for several days after the injection in 1388 cases (36.2%), and neither on the day of nor the day after the injection in 1276 cases (33.3%). Topical antibiotics were also given for several days before the day of injection in 10 cases in which topical antibiotics were given both on the day of and for several days after the injection.

Among the 3226 ranibizumab injections in 461 eyes, there have been 3 cases of culture-positive endophthalmitis (0.09%; 95% CI, 0.02%-0.27%) in 3 eyes (0.65%; 95% CI, 0.13%-1.89%). In all 3 cases, antibiotics were not given before but were given for several days after injection. The 3 cases occurred at 2 of 60 clinical centers and were from 2 of 11 lots of ranibizumab. The 2 cases that occurred at the same clinical center were from different investigators who used different lots of ranibizumab. An additional 681 injections were given without incident using the same lot from which 2 of the 3 cases occurred. One case occurred after a first injection and 2 cases occurred after a second injection. The bacteria isolated by cultures included heavy growth of Streptococcus viridans and methicillin-resistant Staphylococcus aureus (scant growth) in case 1 and coagulase-negative staphylococcus in cases 2 and 3. Among the 612 triamcinolone injections, no cases of culture-positive endophthalmitis have been found. In addition, no cases of culture-negative endophthalmitis from either type of injection have been found.

The protocol for the injection procedure in the DRCR Network LRT trials offers an opportunity to evaluate the role of topical antibiotics for potential reduction of the risk of endophthalmitis after intravitreal injection. The standardized injection protocol required the application of topical povidone-iodine to the conjunctival surface and the use of a sterile lid speculum. The use of topical antibiotics was optional. Medication was administered from prefilled syringes (triamcinolone) and syringes that required filling by the investigator from a separate vial at the time of injection (ranibizumab). As in multiple previous studies, a low rate of postinjection endophthalmitis occurred.

Although several retrospective studies13 have reported relatively low rates of endophthalmitis after intravitreal injections, this report presents data from 2 large, multicenter, prospective randomized clinical trials that used a standardized injection protocol that did not require the use of topical antibiotics. In expansion of the findings from a previous DRCR Network intravitreal study19 that suggested the omission of several days of preinjection topical antibiotics did not increase the risk of endophthalmitis, these current studies suggest it is extremely unlikely that the omission of topical antibiotics on the day of or after injection would trigger a moderate or large increase of the risk of endophthalmitis on the days after the injection. However, because of the low incidence of endophthalmitis, no study can rule out the possibility that topical antibiotics might have a minor effect on the risk of endophthalmitis. Therefore, the results of this study do not prove that topical antibiotics have no effect on the risk of endophthalmitis after intravitreal injection.

The results herein indicate that a low rate of endophthalmitis can be achieved by means of an intravitreal injection protocol that includes the use of topical povidone-iodine, a lid speculum, and topical anesthetic. However, achievement of that rate does not require topical antibiotic prophylaxis before, the day of, or the day after the injection.

Correspondence: Cynthia R. Stockdale, MSPH, Jaeb Center for Health Research, 15310 Amberly Dr, Ste 350, Tampa, FL 33647 (drcrnetstat5@jaeb.org).

Submitted for Publication: April 23, 2009; final revision received June 24, 2009; accepted June 29, 2009.

Financial Disclosure: A complete list of all Diabetic Retinopathy Clinical Research (DRCR) Network investigator financial disclosures can be found at http://public.drcr.net

Funding/Support: This study was supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, United States Department of Health and Human Services, grants EY14231, EY14269, and EY14229. Genentech Inc provided the ranibizumab (Lucentis). Allergan Inc provided the triamcinolone acetonide (Trivaris). Both companies provided funds for part of the clinical care costs of the DRCR Network Laser-Ranibizumab-Triamcinolone trial protocols. Allergan Inc also has provided unrestricted funds to the DRCR Network for its discretionary use. Per the DRCR Network Industry Collaboration Guidelines (available at http://public.drcr.net), the DRCR Network had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol.

Role of the Sponsor: The funding organization participated in oversight of the conduct of the study and review of the manuscript but not directly in the design of the study, the conduct of the study, data collection, data management, data analysis, interpretation of the data, or preparation of the manuscript.

Fintak  DRShah  GKBlinder  KJ  et al.  Incidence of endophthalmitis related to intravitreal injection of bevacizumab and ranibizumab. Retina 2008;28 (10) 1395- 1399
PubMed
Mason  JO  IIIWhite  MFFeist  RM  et al.  Incidence of acute onset endophthalmitis following intravitreal bevacizumab (Avastin) injection. Retina 2008;28 (4) 564- 567
PubMed
Pilli  SKotsolis  ASpaide  RF  et al.  Endophthalmitis associated with intravitreal anti-vascular endothelial growth factor therapy injections in an office setting. Am J Ophthalmol 2008;145 (5) 879- 882
PubMed
Scott  IUFlynn  HW  Jr Reducing the risk of endophthalmitis following intravitreal injections. Retina 2007;27 (1) 10- 12
PubMed
Meyer  CHMennel  SEter  N Incidence of endophthalmitis after intravitreal Avastin injection with and without postoperative topical antibiotic application [in German]. Ophthalmologe 2007;104 (11) 952- 957
PubMed
Aiello  LPBrucker  AJChang  S  et al.  Evolving guidelines for intravitreous injections. Retina 2004;24 (5) ((suppl)) S3- S19
PubMed
Speaker  MGMenikoff  JA Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology 1991;98 (12) 1769- 1775
PubMed
Ta  CNEgbert  PRSingh  KShriver  EMBlumenkranz  MSMiño de Kaspar  H Prospective randomized comparison of 3-day versus 1-hour preoperative ofloxacin prophylaxis for cataract surgery. Ophthalmology 2002;109 (11) 2036- 2040
PubMed
Isenberg  SJApt  LYoshimori  RKhwarg  S Chemical preparation of the eye in ophthalmic surgery, IV: comparison of povidone-iodine on the conjunctiva with a prophylactic antibiotic. Arch Ophthalmol 1985;103 (9) 1340- 1342
PubMed
Hariprasad  SMBlinder  KJShah  GK  et al.  Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous. Arch Ophthalmol 2005;123 (1) 39- 44
PubMed
Puustjärvi  TTeräsvirta  MNurmenniemi  PLokkila  JUusitalo  H Penetration of topically applied levofloxacin 0.5% and ofloxacin 0.3% into the vitreous of the non-inflamed human eye. Graefes Arch Clin Exp Ophthalmol 2006;244 (12) 1633- 1637
PubMed
Sakamoto  HSakamoto  MHata  YKubota  TIshibashi  T Aqueous and vitreous penetration of levofloxacin after topical and/or oral administration. Eur J Ophthalmol 2007;17 (3) 372- 376
PubMed
Yalvac  ISBasci  NEBozkurt  ADuman  S Penetration of topically applied ciprofloxacin and ofloxacin into the aqueous humor and vitreous. J Cataract Refract Surg 2003;29 (3) 487- 491
PubMed
Gragoudas  ESAdamis  APCunningham  ET  JrFeinsod  MGuyer  DRVEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group, Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351 (27) 2805- 2816
PubMed
Kaiser  PKBrown  DMZhang  K  et al.  Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol 2007;144 (6) 850- 857
PubMed
Rosenfeld  PJBrown  DMHeier  JS  et al. MARINA Study Group, Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355 (14) 1419- 1431
PubMed
Bhavsar  ARIp  MSGlassman  ARDRCRnet and the SCORE Study Groups, The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol 2007;144 (3) 454- 456
PubMed
Martidis  ADuker  JSGreenberg  PB  et al.  Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmol 2002;109 (5) 920- 927

Figures

Tables

References

Fintak  DRShah  GKBlinder  KJ  et al.  Incidence of endophthalmitis related to intravitreal injection of bevacizumab and ranibizumab. Retina 2008;28 (10) 1395- 1399
PubMed
Mason  JO  IIIWhite  MFFeist  RM  et al.  Incidence of acute onset endophthalmitis following intravitreal bevacizumab (Avastin) injection. Retina 2008;28 (4) 564- 567
PubMed
Pilli  SKotsolis  ASpaide  RF  et al.  Endophthalmitis associated with intravitreal anti-vascular endothelial growth factor therapy injections in an office setting. Am J Ophthalmol 2008;145 (5) 879- 882
PubMed
Scott  IUFlynn  HW  Jr Reducing the risk of endophthalmitis following intravitreal injections. Retina 2007;27 (1) 10- 12
PubMed
Meyer  CHMennel  SEter  N Incidence of endophthalmitis after intravitreal Avastin injection with and without postoperative topical antibiotic application [in German]. Ophthalmologe 2007;104 (11) 952- 957
PubMed
Aiello  LPBrucker  AJChang  S  et al.  Evolving guidelines for intravitreous injections. Retina 2004;24 (5) ((suppl)) S3- S19
PubMed
Speaker  MGMenikoff  JA Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology 1991;98 (12) 1769- 1775
PubMed
Ta  CNEgbert  PRSingh  KShriver  EMBlumenkranz  MSMiño de Kaspar  H Prospective randomized comparison of 3-day versus 1-hour preoperative ofloxacin prophylaxis for cataract surgery. Ophthalmology 2002;109 (11) 2036- 2040
PubMed
Isenberg  SJApt  LYoshimori  RKhwarg  S Chemical preparation of the eye in ophthalmic surgery, IV: comparison of povidone-iodine on the conjunctiva with a prophylactic antibiotic. Arch Ophthalmol 1985;103 (9) 1340- 1342
PubMed
Hariprasad  SMBlinder  KJShah  GK  et al.  Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous. Arch Ophthalmol 2005;123 (1) 39- 44
PubMed
Puustjärvi  TTeräsvirta  MNurmenniemi  PLokkila  JUusitalo  H Penetration of topically applied levofloxacin 0.5% and ofloxacin 0.3% into the vitreous of the non-inflamed human eye. Graefes Arch Clin Exp Ophthalmol 2006;244 (12) 1633- 1637
PubMed
Sakamoto  HSakamoto  MHata  YKubota  TIshibashi  T Aqueous and vitreous penetration of levofloxacin after topical and/or oral administration. Eur J Ophthalmol 2007;17 (3) 372- 376
PubMed
Yalvac  ISBasci  NEBozkurt  ADuman  S Penetration of topically applied ciprofloxacin and ofloxacin into the aqueous humor and vitreous. J Cataract Refract Surg 2003;29 (3) 487- 491
PubMed
Gragoudas  ESAdamis  APCunningham  ET  JrFeinsod  MGuyer  DRVEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group, Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351 (27) 2805- 2816
PubMed
Kaiser  PKBrown  DMZhang  K  et al.  Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol 2007;144 (6) 850- 857
PubMed
Rosenfeld  PJBrown  DMHeier  JS  et al. MARINA Study Group, Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355 (14) 1419- 1431
PubMed
Bhavsar  ARIp  MSGlassman  ARDRCRnet and the SCORE Study Groups, The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol 2007;144 (3) 454- 456
PubMed
Martidis  ADuker  JSGreenberg  PB  et al.  Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmol 2002;109 (5) 920- 927

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics