Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-014-2644-0
REVIEW ARTICLE
Prevention and treatment of injection-related endophthalmitis Charles Q. Yu & Christopher N. Ta
Received: 4 February 2014 / Revised: 4 April 2014 / Accepted: 9 April 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Intravitreal injections are the fastest growing cause of endophthalmitis and can result in severe vision loss. The prevention, diagnosis and management of such infections remain unclear and at times controversial. Methods We searched Pubmed for keywords "prophylaxis," "endophthalmitis," "intravitreal injection." We focused on studies published in the last 2 years as well as other recent studies with particular attention to data on the incidence, microbiology, prevention, and treatment of injection-related endophthalmitis. Results Over 20 relevant studies were found. With povidone– iodine preparation, the per–injection endophthalmitis rate is low at about 0.03%. Antibiotics do not appear to be beneficial for prevention of post–injection endophthalmitis. The best timing of vitrectomy is unclear. Conclusions Antibiotic prophylaxis is probably not needed when giving intravitreal injections. More data is needed to help determine the proper treatment for post-injection endophthalmitis. Keywords Endophthalmitis . Intravitreal injection . Antibiotic . Prophylaxis . Bevacizumab
million injections covered by Medicare were given in the United States [2]. Taking into account increased usage, nonMedicare use, and global usage, perhaps as many as 2 million injections are currently given in a year worldwide. The number of cases of injection-related endophthalmitis, the most feared complication of intravitreal injection, has no doubt also grown. It is now the second most common cause of endophthalmitis after cataract surgery [3]. This is especially important given that a patient may undergo many more intravitreal injections in a lifetime than cataract surgeries. We here review the latest developments in the literature regarding the incidence, prophylaxis, and treatment of injection–related endophthalmitis.
Methods A literature search on PubMed was conducted for the keywords "prophylaxis," "endophthalmitis," and "intravitreal injection." Original studies dating from 2011 onward are the focus of this review. In addition a few studies of particular interest dating from prior to that time are also included. Only articles written in English are reviewed.
Incidence Introduction The use of intravitreally injected anti-VEGF agents for exudative age-related macular degeneration, diabetic macular edema, and retinal vasocclusive disease has grown dramatically in the past half decade [1]. In 2008, approximately 1 C. Q. Yu : C. N. Ta (*) Byers Eye Institute at Stanford, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303, USA e-mail: [email protected]
The incidence of endophthalmitis after injection has varied from study to study. Given the rarity of infection and the effect that a single case can have on a data set, the range has been wide. However recent studies with large sample sizes have narrowed down the estimated rate to be between 0.02-0.03%. (Table 1, estimated rates). A Boston study reviewed 10,208 injections that resulted in three infections, all of which were culture proven. This yields a rate of 0.029% per injection [4]. A review of the British Ophthalmological Surveillance unit
Graefes Arch Clin Exp Ophthalmol Table 1 Estimated rates of endophthalmitis from three large retrospective studies
Prophylaxis
Rate
Setting
Study
Sample size
0.025% 0.029% 0.02%
BOSUa University University
Lyall et al. [5] Englander et al. [4] Moshfeghi et al. [6]
∼187,000 10,208 60,322
The exact technique used to deliver intravitreal injections is variable. The use of povidone–iodine on the lids and ocular surface is standard procedure. However, treatment regimens used to prevent infection are controversial. With regard to antibiotics, numerous studies have been conducted, though most have been retrospective. Some studies have favored the use of prophylactic antibiotic for intravitreal injections. The aforementioned study of the British Ophthalmological Surveillance Unit found that no antibiotics immediately before or after injection to be a risk factor for developing endophthalmitis [5]. Their study, however, did not examine the use of povidone–iodine, which should theoretically provide sterility in the immediate injection environment. An animal model showed that moxifloxacin administered shortly before contaminated intravitreal injection and for 3 days afterwards dramatically reduced cases of endophthalmitis. However this study did not use povidone– iodine, and better represents a proof of concept animal model rather than clinically applicable data [9]. A study of 15,144 injections in Japan found zero cases of endophthalmitis with the use of povidone–iodine, mask, and three-day course of preoperative and post–injection antibiotics.[10] Other studies, however, suggest that antibiotic prophylaxis may not be needed. We conducted a prospective trial with approximately 130 patients in each group that showed no additional benefit of a course of pre-injection antibiotics when used in addition to povidone–iodine with regard to bacterial cultures [11]. Data from the Diabetic Retinopathy Clinical Research Network found three cases of endophthalmitis in a group of approximately 4,000 injections receiving variable methods of prophylaxis. All three cases occurred in the group which received post-injection antibiotic. There were no cases in the group that received no antibiotics at all [12]. An update to this study reported six cases among 4,695 injections that used antibiotics and one case that occurred in 3,333 injections without antibiotics [13]. A retrospective review comparing cohorts of approximately 2,000 patients each did not find a statistical difference in groups with or without antibiotic use [14]. Examination of 15,000 injections in Canada found a rate of endophthalmitis of 0.061% in those patients receiving antibiotic for 5 days post-injection, 0.084% in those receiving antibiotics immediately after injection, and 0.034% in those not given antibiotics [15] (Fig. 2). The authors proposed that repeated use of antibiotics perhaps promoted more resistant and virulent bacteria which could increase the overall rate of infection. Another retrospective study found a suspected endophthalmitis rate of 0.049% in 57,654 injections given with antibiotic prophylaxis, and 0.032% in 34,900 injections given without antibiotic prophylaxis [16]. A prospective study of antibiotic resistance examined two groups of patients with approximately 100 patients either not
a
British Ophthalmologic Surveillance Unit
found 47 cases in an estimated 186,972 injections, giving a per-injection rate of 0.025%.[5] The number of total injections in this study was extrapolated. These two studies note that the first infection occurred after the 7th and 5th injections respectively, suggesting that the rate of infection is not affected by whether it is early or later on during a treatment course. A study from Miami found 11 cases in 60,322 injections, a rate of 0.02% [6]. Though there remains a wide range, a perinjection rate of 0.03% is likely near to the actual risk. With this data we can calculate a rate of approximately 0.7% chance of getting at least one case of endophthalmitis for a patient undergoing a 24-injection course of treatment.
Microbiology The organisms that cause injection-related endophthalmitis are suspected to be from the normal ocular flora, the injection environment, and the clinical staff providing the injection. A meta-analysis examined the bacterial isolates from 26 cases, finding that coagulase negative Staphylococcus was the cause in 65.4% of cases and Streptococcus species in 30.8%. The culture-positive rate was 50% [7]. A study comparing the microbiologic profile of cases of injection-related infection and post-cataract infection found the percentage of coagulase negative Staphylococcus to be 42.4%, Streptococcus to be 39.4%, and Staphylococcus aureus 9.1% in the postinjection group for culture-positive cases. Comparing this to their post-cataract group, they found a significantly higher rate of Streptococcus infection in the injection-related group (24.53% vs 6.24%, p=0.022) [8]. McCannel has proposed that contamination from oral flora may be the cause of the higher rates of streptococcus in intravitreal injections as compared to cataract surgery [7]. Both these studies suggested the higher rate of Streptococcus infections results in a worse outcome for injection-related infections. The study resulting from the British Ophthalmological Surveillance Unit identified 28 cases. The overall culture positivity rate was 59%. Coagulase-negative Staphylococcus was identified in 60.7%, Staphylococcus aureus in 17.9%, and Streptococcus species in 10.7% [5]. This agrees with most studies, in which Staphylococcus species is the most common organism with Streptococcus species being the second. (Fig. 1)
Graefes Arch Clin Exp Ophthalmol Fig. 1 The most common bacteria implicated in injectionrelated endophthalmitis. Coagulase negative staphylococcus remains the most common cause, with streptococcus species being second most common
receiving or receiving antibiotic prophylaxis with injections. The authors found increased bacterial minimal inhibitory concentrations in the group receiving antibiotics [17]. A prospective study followed eyes of 24 patients undergoing intravitreal injections with antibiotic prophylaxis demonstrated selection for resistant strains of bacteria [18]. The same research group in another study demonstrated selection for Staphylococcus epidermidis in eyes with antibiotic prophylaxis [19]. With regard to relatively minor technique differences, a recent study found that applying povidone–iodine for 15 seconds did not significantly reduce bacterial concentration, but applying it for 30 seconds did [20]. Lid speculum use also was not found to increase bacterial counts [20]. Masks and silence have been promoted given their low/no cost, especially in light of studies showing higher rates of oral flora being the causative agent. A recent study demonstrated bacterial Fig. 2 Cheung et al. [15] demonstrated a lower incidence of injection-related endophthalmitis when antibiotic prophylaxis was not given. Antibiotics given immediately after injection had the highest rate, followed by patients given a 5-day course of post-injection antibiotics
inoculation of culture plates in an experimental setting replicating a typical injection [21]. We do not feel there is adequate evidence to support or argue against any particular technique variations of speculum type, conjunctival displacement, and location of injection. Compounding of bevacizumab has been a problem. Oneyear outcomes reported recently for 12 patients that developed streptococcal endophthalmitis after intravitreal injection revealed poor outcomes, with only one patient regaining preinjection visual acuity [22]. Compounding pharmacies have also been the source of rare infectious organisms such as fungus [23]. Reports suggest problems with the quality and stability of compounded bevacizumab [24, 25]. It is imperative that compounding pharmacies follow best laboratory practice techniques when preparing intravitreal injections. Physicians should keep careful track of lot numbers and be
Graefes Arch Clin Exp Ophthalmol
clinically suspicious of clustering of cases. With proper precautions, the use of compounded bevacizumab can be safe and cost effective. A conclusive randomized clinical trial to establish the efficacy or lack thereof for antibiotics on the rates of endophthalmitis remains to be done. However, the weight of the current evidence suggests that careful pre-injection antisepsis with povidone iodine, applied for at least 30 seconds, should provide adequate microbiologic control. Silence or a mask should be used, given the low cost and potential benefit. We feel preoperative and postoperative course of antibiotics could cause resistance, given the typical monthly frequency of injections. Immediate preoperative antibiotic would not greatly reduce bacterial concentration in addition to povidone–iodine, and immediate postoperative topical antibiotic would not adequately penetrate the vitreous.
Treatment There is little data on the treatment of cases of injection-related endophthalmitis. It is suggested that outcomes from injectionrelated infections are worse than those in cataract surgery [8]. Because coagulase-negative Staphylococcus was found to be the most common etiologic agent similar to post-cataract endophthalmitis, some clinicians have used the recommendations of the Endophthalmitis Vitrectomy Study (EVS) to guide their treatment with regard to vitrectomy. Whether early or late vitrectomy is most helpful in injection-related endophthalmitis remains unclear. A retrospective examination of 23 cases found that 90% of those treated with vitreous tap and injection of antibiotics regained prior vision, as compared to 46% of those who later also underwent vitrectomy [26]. It is difficult to draw conclusions given that those with more severe diseases were those that required vitrectomy, but the authors suggest that initial treatment with tap and inject is reasonable. Another retrospective study examined 19 cases, and suggested that due to the different clinical aspects the results of the EVS cannot be applied to post-injection endophthalmitis [27]. Yet another retrospective study examining nine cases recommended tap and inject for cases in which the retina could be visualized, and vitrectomy for those where the retina could not be visualized. Post-injection endophthalmitis is complicated by the possible presence of a cataract, which is not an issue in post-cataract cases. Given this and the apparently differing microbiologic profiles, much more clinical information is needed before the appropriate timing of vitrectomy can be determined. Though it is unclear whether the timing of vitrectomy is comparable to post-cataract cases of endophthalmitis, clinicians generally use the same initial antibiotic treatment for both conditions: vancomycin 1.0 mg/0.1 ml with either ceftazidime 2.25 mg/0.1 ml or amikacin 0.4 mg/0.1 ml.
Subsequent injections should be tailored to culture results. Repeat injections of amikacin should be avoided [3]. An inflammatory response can occur in the vitreous and anterior chamber that is difficult to distinguish from infectious endophthalmitis, especially with injections of triamcinolone [28]. These have been less common with the anti-VEGF medicines [29]. Although studies have attempted to establish clinical criteria which are suggestive of inflammatory noninfectious endophthalmitis, such as lack of conjunctiva injection, these methods are not reliable enough to be used safely. Every case of suspected endophthalmitis should be treated as infectious.
Outcomes Visual outcomes after injection-related endophthalmitis vary from study to study, given the small cohorts usually reported. The results from the British Ophthalmological Surveillance Unit showed that in 47 cases of post-injection endophthalmitis, visual acuity dropped from on average 0.6±0.3 LogMAR (Snellen 20/80) to 1.23±0.91 logMAR (Snellen 20/340) at 6 months, four developed retinal detachment, one narrow-angle glaucoma and one phthsis bulbi [5].
Conclusion Injection-related endophthalmitis is a growing concern, given the number of injections being given. Fortunately, with proper povidone–iodine preparation, the per-injection rate is low at about 0.03%, and per 24-injection course at 0.7%. Antibiotic prophylaxis does not appear to be beneficial, and has been shown to increase resistance [15, 17]. More studies need to be conducted to establish the best management of injectionrelated endophthalmitis especially with regard to timing of vitrectomy.
Conflicts of interest None
References 1. Lanzetta P, Mitchell P, Wolf S, Veritti D (2013) Different antivascular endothelial growth factor treatments and regimens and their outcomes in neovascular age-related macular degeneration: a literature review. Br J Ophthalmol 97:1497–1507 2. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S (2011) Pharmacotherapy for neovascular age-related macular degeneration:
Graefes Arch Clin Exp Ophthalmol an analysis of the 100% 2008 medicare fee-for-service part B claims file. Am J Ophthalmol 151:887–895 3. Durand ML (2013) Endophthalmitis. Clin Microbiol Infect 19:227– 234 4. Englander M, Chen TC, Paschalis EI, Miller JW, Kim IK (2013) Intravitreal injections at the Massachusetts Eye and Ear Infirmary: analysis of treatment indications and postinjection endophthalmitis rates. Br J Ophthalmol 97:460–465 5. Lyall DA, Tey A, Foot B et al (2012) Post-intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye (Lond) 26:1517–1526 6. Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr et al (2011) Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six-year experience at a university referral center. Retina 31:662–668 7. McCannel CA (2011) Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina 31: 654–661 8. Simunovic MP, Rush RB, Hunyor AP, Chang AA (2012) Endophthalmitis following intravitreal injection versus endophthalmitis following cataract surgery: clinical features, causative organisms and post-treatment outcomes. Br J Ophthalmol 96:862–866 9. Kowalski RP, Romanowski EG, Mah FS, Yates KA, Gordon YJ (2008) Topical 0.5% moxifloxacin prevents endophthalmitis in an intravitreal injection rabbit model. J Ocul Pharmacol Ther 24:1–7 10. Shimada H, Hattori T, Mori R, Nakashizuka H, Fujita K, Yuzawa M (2013) Minimizing the endophthalmitis rate following intravitreal injections using 0.25 % povidone–iodine irrigation and surgical mask. Graefes Arch Clin Exp Ophthalmol 251:1885–1890 11. Moss JM, Sanislo SR, Ta CN (2009) A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections. Ophthalmology 116:1498–1501 12. Bhavsar AR, Googe JM Jr, Stockdale CR et al (2009) Risk of endophthalmitis after intravitreal drug injection when topical antibiotics are not required: the diabetic retinopathy clinical research network laser–ranibizumab–triamcinolone clinical trials. Arch Ophthalmol 127:1581–1583 13. Bhavsar AR, Stockdale CR, Ferris FL 3rd, Brucker AJ, Bressler NM, Glassman AR (2012) Update on risk of endophthalmitis after intravitreal drug injections and potential impact of elimination of topical antibiotics. Arch Ophthalmol 130:809–810 14. Bhatt SS, Stepien KE, Joshi K (2011) Prophylactic antibiotic use after intravitreal injection: effect on endophthalmitis rate. Retina 31:2032– 2036 15. Cheung CS, Wong AW, Lui A, Kertes PJ, Devenyi RG, Lam WC (2012) Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections. Ophthalmology 119:1609–1614
16. Storey P, Dollin M, Pitcher J et al (2014) The role of topical antibiotic prophylaxis to prevent endophthalmitis after intravitreal injection. Ophthalmology 121:283–289 17. Yin VT, Weisbrod DJ, Eng KT et al (2013) Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol 131:456–461 18. Kim SJ, Toma HS (2011) Antimicrobial resistance and ophthalmic antibiotics: 1-year results of a longitudinal controlled study of patients undergoing intravitreal injections. Arch Ophthalmol 129:1180– 1188 19. Dave SB, Toma HS, Kim SJ (2013) Changes in ocular flora in eyes exposed to ophthalmic antibiotics. Ophthalmology 120:937–941 20. Friedman DA, Mason JO 3rd, Emond T, McGwin G Jr (2013) Povidone–iodine contact time and lid speculum use during intravitreal injection. Retina 33:975–981 21. Doshi RR, Leng T, Fung AE (2012) Reducing oral flora contamination of intravitreal injections with face mask or silence. Retina 32: 473–476 22. Goldberg RA, Flynn HW Jr, Miller D, Gonzalez S, Isom RF (2013) Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology 120:1448–1453 23. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM (2013) An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. JAMA Ophthalmol 131:864–869 24. Palmer JM, Amoaku WM, Kamali F (2013) Quality of bevacizumab compounded for intravitreal administration. Eye (Lond) 27:1090– 1097 25. Liu L, Ammar DA, Ross LA, Mandava N, Kahook MY, Carpenter JF (2011) Silicone oil microdroplets and protein aggregates in repackaged bevacizumab and ranibizumab: effects of long-term storage and product mishandling. Invest Ophthalmol Vis Sci 52:1023– 1034 26. Chaudhary KM, Romero JM, Ezon I, Fastenberg DM, Deramo VA (2013) Pars plana vitrectomy in the management of patients diagnosed with endophthalmitis following intravitreal anti-vascular endothelial growth factor injection. Retina 33:1407–1416 27. Irigoyen C, Ziahosseini K, Morphis G, Stappler T, Heimann H (2012) Endophthalmitis following intravitreal injections. Graefes Arch Clin Exp Ophthalmol 250:499–505 28. Nelson ML, Tennant MT, Sivalingam A, Regillo CD, Belmont JB, Martidis A (2003) Infectious and presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide injection. Retina 23:686–691 29. Fagan XJ, Al-Qureshi S (2013) Intravitreal injections: a review of the evidence for best practice. Clin Experiment Ophthalmol 41(5):500–507
REVIEW ARTICLE
Prevention and treatment of injection-related endophthalmitis Charles Q. Yu & Christopher N. Ta
Received: 4 February 2014 / Revised: 4 April 2014 / Accepted: 9 April 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Intravitreal injections are the fastest growing cause of endophthalmitis and can result in severe vision loss. The prevention, diagnosis and management of such infections remain unclear and at times controversial. Methods We searched Pubmed for keywords "prophylaxis," "endophthalmitis," "intravitreal injection." We focused on studies published in the last 2 years as well as other recent studies with particular attention to data on the incidence, microbiology, prevention, and treatment of injection-related endophthalmitis. Results Over 20 relevant studies were found. With povidone– iodine preparation, the per–injection endophthalmitis rate is low at about 0.03%. Antibiotics do not appear to be beneficial for prevention of post–injection endophthalmitis. The best timing of vitrectomy is unclear. Conclusions Antibiotic prophylaxis is probably not needed when giving intravitreal injections. More data is needed to help determine the proper treatment for post-injection endophthalmitis. Keywords Endophthalmitis . Intravitreal injection . Antibiotic . Prophylaxis . Bevacizumab
million injections covered by Medicare were given in the United States [2]. Taking into account increased usage, nonMedicare use, and global usage, perhaps as many as 2 million injections are currently given in a year worldwide. The number of cases of injection-related endophthalmitis, the most feared complication of intravitreal injection, has no doubt also grown. It is now the second most common cause of endophthalmitis after cataract surgery [3]. This is especially important given that a patient may undergo many more intravitreal injections in a lifetime than cataract surgeries. We here review the latest developments in the literature regarding the incidence, prophylaxis, and treatment of injection–related endophthalmitis.
Methods A literature search on PubMed was conducted for the keywords "prophylaxis," "endophthalmitis," and "intravitreal injection." Original studies dating from 2011 onward are the focus of this review. In addition a few studies of particular interest dating from prior to that time are also included. Only articles written in English are reviewed.
Incidence Introduction The use of intravitreally injected anti-VEGF agents for exudative age-related macular degeneration, diabetic macular edema, and retinal vasocclusive disease has grown dramatically in the past half decade [1]. In 2008, approximately 1 C. Q. Yu : C. N. Ta (*) Byers Eye Institute at Stanford, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303, USA e-mail: [email protected]
The incidence of endophthalmitis after injection has varied from study to study. Given the rarity of infection and the effect that a single case can have on a data set, the range has been wide. However recent studies with large sample sizes have narrowed down the estimated rate to be between 0.02-0.03%. (Table 1, estimated rates). A Boston study reviewed 10,208 injections that resulted in three infections, all of which were culture proven. This yields a rate of 0.029% per injection [4]. A review of the British Ophthalmological Surveillance unit
Graefes Arch Clin Exp Ophthalmol Table 1 Estimated rates of endophthalmitis from three large retrospective studies
Prophylaxis
Rate
Setting
Study
Sample size
0.025% 0.029% 0.02%
BOSUa University University
Lyall et al. [5] Englander et al. [4] Moshfeghi et al. [6]
∼187,000 10,208 60,322
The exact technique used to deliver intravitreal injections is variable. The use of povidone–iodine on the lids and ocular surface is standard procedure. However, treatment regimens used to prevent infection are controversial. With regard to antibiotics, numerous studies have been conducted, though most have been retrospective. Some studies have favored the use of prophylactic antibiotic for intravitreal injections. The aforementioned study of the British Ophthalmological Surveillance Unit found that no antibiotics immediately before or after injection to be a risk factor for developing endophthalmitis [5]. Their study, however, did not examine the use of povidone–iodine, which should theoretically provide sterility in the immediate injection environment. An animal model showed that moxifloxacin administered shortly before contaminated intravitreal injection and for 3 days afterwards dramatically reduced cases of endophthalmitis. However this study did not use povidone– iodine, and better represents a proof of concept animal model rather than clinically applicable data [9]. A study of 15,144 injections in Japan found zero cases of endophthalmitis with the use of povidone–iodine, mask, and three-day course of preoperative and post–injection antibiotics.[10] Other studies, however, suggest that antibiotic prophylaxis may not be needed. We conducted a prospective trial with approximately 130 patients in each group that showed no additional benefit of a course of pre-injection antibiotics when used in addition to povidone–iodine with regard to bacterial cultures [11]. Data from the Diabetic Retinopathy Clinical Research Network found three cases of endophthalmitis in a group of approximately 4,000 injections receiving variable methods of prophylaxis. All three cases occurred in the group which received post-injection antibiotic. There were no cases in the group that received no antibiotics at all [12]. An update to this study reported six cases among 4,695 injections that used antibiotics and one case that occurred in 3,333 injections without antibiotics [13]. A retrospective review comparing cohorts of approximately 2,000 patients each did not find a statistical difference in groups with or without antibiotic use [14]. Examination of 15,000 injections in Canada found a rate of endophthalmitis of 0.061% in those patients receiving antibiotic for 5 days post-injection, 0.084% in those receiving antibiotics immediately after injection, and 0.034% in those not given antibiotics [15] (Fig. 2). The authors proposed that repeated use of antibiotics perhaps promoted more resistant and virulent bacteria which could increase the overall rate of infection. Another retrospective study found a suspected endophthalmitis rate of 0.049% in 57,654 injections given with antibiotic prophylaxis, and 0.032% in 34,900 injections given without antibiotic prophylaxis [16]. A prospective study of antibiotic resistance examined two groups of patients with approximately 100 patients either not
a
British Ophthalmologic Surveillance Unit
found 47 cases in an estimated 186,972 injections, giving a per-injection rate of 0.025%.[5] The number of total injections in this study was extrapolated. These two studies note that the first infection occurred after the 7th and 5th injections respectively, suggesting that the rate of infection is not affected by whether it is early or later on during a treatment course. A study from Miami found 11 cases in 60,322 injections, a rate of 0.02% [6]. Though there remains a wide range, a perinjection rate of 0.03% is likely near to the actual risk. With this data we can calculate a rate of approximately 0.7% chance of getting at least one case of endophthalmitis for a patient undergoing a 24-injection course of treatment.
Microbiology The organisms that cause injection-related endophthalmitis are suspected to be from the normal ocular flora, the injection environment, and the clinical staff providing the injection. A meta-analysis examined the bacterial isolates from 26 cases, finding that coagulase negative Staphylococcus was the cause in 65.4% of cases and Streptococcus species in 30.8%. The culture-positive rate was 50% [7]. A study comparing the microbiologic profile of cases of injection-related infection and post-cataract infection found the percentage of coagulase negative Staphylococcus to be 42.4%, Streptococcus to be 39.4%, and Staphylococcus aureus 9.1% in the postinjection group for culture-positive cases. Comparing this to their post-cataract group, they found a significantly higher rate of Streptococcus infection in the injection-related group (24.53% vs 6.24%, p=0.022) [8]. McCannel has proposed that contamination from oral flora may be the cause of the higher rates of streptococcus in intravitreal injections as compared to cataract surgery [7]. Both these studies suggested the higher rate of Streptococcus infections results in a worse outcome for injection-related infections. The study resulting from the British Ophthalmological Surveillance Unit identified 28 cases. The overall culture positivity rate was 59%. Coagulase-negative Staphylococcus was identified in 60.7%, Staphylococcus aureus in 17.9%, and Streptococcus species in 10.7% [5]. This agrees with most studies, in which Staphylococcus species is the most common organism with Streptococcus species being the second. (Fig. 1)
Graefes Arch Clin Exp Ophthalmol Fig. 1 The most common bacteria implicated in injectionrelated endophthalmitis. Coagulase negative staphylococcus remains the most common cause, with streptococcus species being second most common
receiving or receiving antibiotic prophylaxis with injections. The authors found increased bacterial minimal inhibitory concentrations in the group receiving antibiotics [17]. A prospective study followed eyes of 24 patients undergoing intravitreal injections with antibiotic prophylaxis demonstrated selection for resistant strains of bacteria [18]. The same research group in another study demonstrated selection for Staphylococcus epidermidis in eyes with antibiotic prophylaxis [19]. With regard to relatively minor technique differences, a recent study found that applying povidone–iodine for 15 seconds did not significantly reduce bacterial concentration, but applying it for 30 seconds did [20]. Lid speculum use also was not found to increase bacterial counts [20]. Masks and silence have been promoted given their low/no cost, especially in light of studies showing higher rates of oral flora being the causative agent. A recent study demonstrated bacterial Fig. 2 Cheung et al. [15] demonstrated a lower incidence of injection-related endophthalmitis when antibiotic prophylaxis was not given. Antibiotics given immediately after injection had the highest rate, followed by patients given a 5-day course of post-injection antibiotics
inoculation of culture plates in an experimental setting replicating a typical injection [21]. We do not feel there is adequate evidence to support or argue against any particular technique variations of speculum type, conjunctival displacement, and location of injection. Compounding of bevacizumab has been a problem. Oneyear outcomes reported recently for 12 patients that developed streptococcal endophthalmitis after intravitreal injection revealed poor outcomes, with only one patient regaining preinjection visual acuity [22]. Compounding pharmacies have also been the source of rare infectious organisms such as fungus [23]. Reports suggest problems with the quality and stability of compounded bevacizumab [24, 25]. It is imperative that compounding pharmacies follow best laboratory practice techniques when preparing intravitreal injections. Physicians should keep careful track of lot numbers and be
Graefes Arch Clin Exp Ophthalmol
clinically suspicious of clustering of cases. With proper precautions, the use of compounded bevacizumab can be safe and cost effective. A conclusive randomized clinical trial to establish the efficacy or lack thereof for antibiotics on the rates of endophthalmitis remains to be done. However, the weight of the current evidence suggests that careful pre-injection antisepsis with povidone iodine, applied for at least 30 seconds, should provide adequate microbiologic control. Silence or a mask should be used, given the low cost and potential benefit. We feel preoperative and postoperative course of antibiotics could cause resistance, given the typical monthly frequency of injections. Immediate preoperative antibiotic would not greatly reduce bacterial concentration in addition to povidone–iodine, and immediate postoperative topical antibiotic would not adequately penetrate the vitreous.
Treatment There is little data on the treatment of cases of injection-related endophthalmitis. It is suggested that outcomes from injectionrelated infections are worse than those in cataract surgery [8]. Because coagulase-negative Staphylococcus was found to be the most common etiologic agent similar to post-cataract endophthalmitis, some clinicians have used the recommendations of the Endophthalmitis Vitrectomy Study (EVS) to guide their treatment with regard to vitrectomy. Whether early or late vitrectomy is most helpful in injection-related endophthalmitis remains unclear. A retrospective examination of 23 cases found that 90% of those treated with vitreous tap and injection of antibiotics regained prior vision, as compared to 46% of those who later also underwent vitrectomy [26]. It is difficult to draw conclusions given that those with more severe diseases were those that required vitrectomy, but the authors suggest that initial treatment with tap and inject is reasonable. Another retrospective study examined 19 cases, and suggested that due to the different clinical aspects the results of the EVS cannot be applied to post-injection endophthalmitis [27]. Yet another retrospective study examining nine cases recommended tap and inject for cases in which the retina could be visualized, and vitrectomy for those where the retina could not be visualized. Post-injection endophthalmitis is complicated by the possible presence of a cataract, which is not an issue in post-cataract cases. Given this and the apparently differing microbiologic profiles, much more clinical information is needed before the appropriate timing of vitrectomy can be determined. Though it is unclear whether the timing of vitrectomy is comparable to post-cataract cases of endophthalmitis, clinicians generally use the same initial antibiotic treatment for both conditions: vancomycin 1.0 mg/0.1 ml with either ceftazidime 2.25 mg/0.1 ml or amikacin 0.4 mg/0.1 ml.
Subsequent injections should be tailored to culture results. Repeat injections of amikacin should be avoided [3]. An inflammatory response can occur in the vitreous and anterior chamber that is difficult to distinguish from infectious endophthalmitis, especially with injections of triamcinolone [28]. These have been less common with the anti-VEGF medicines [29]. Although studies have attempted to establish clinical criteria which are suggestive of inflammatory noninfectious endophthalmitis, such as lack of conjunctiva injection, these methods are not reliable enough to be used safely. Every case of suspected endophthalmitis should be treated as infectious.
Outcomes Visual outcomes after injection-related endophthalmitis vary from study to study, given the small cohorts usually reported. The results from the British Ophthalmological Surveillance Unit showed that in 47 cases of post-injection endophthalmitis, visual acuity dropped from on average 0.6±0.3 LogMAR (Snellen 20/80) to 1.23±0.91 logMAR (Snellen 20/340) at 6 months, four developed retinal detachment, one narrow-angle glaucoma and one phthsis bulbi [5].
Conclusion Injection-related endophthalmitis is a growing concern, given the number of injections being given. Fortunately, with proper povidone–iodine preparation, the per-injection rate is low at about 0.03%, and per 24-injection course at 0.7%. Antibiotic prophylaxis does not appear to be beneficial, and has been shown to increase resistance [15, 17]. More studies need to be conducted to establish the best management of injectionrelated endophthalmitis especially with regard to timing of vitrectomy.
Conflicts of interest None
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