Preferred Practices for Managing Risk of Endophthalmitis With Intravitreal Injections

TAKESHI IDE, MD, PhD. TERRENCE P. O'BRIEN, MD

Advances in pharmacotherapies effective against a range of retinal diseases have led to a reexamination of the preferred routes of ocular drug delivery. Intravitreal injection has rapidly emerged as a preferred method to deliver pharmaceutical agents aimed against posterior segment disorders, including neovascular age-related macular degeneration (AMD),^1-5 proliferative diabetic retinopathy (PDR),⁶ and macular edema from a variety of disorders.^7-10

Retina specialists worldwide have now widely adopted intravitreal injections into their armamentarium for the management of many posterior segment diseases.^11-13 Historically, experience with intravitreal injections began with the treatment of endophthalmitis, in which a vitreous tap was performed followed by injection of intravitreal antibiotics.¹⁴ Further experience with intravitreal injections was gained through the use of pneumatic retinopexy, in which a long-acting gas bubble was injected into the vitreous to facilitate retinal detachment repair.¹⁵ In addition, pharmaceutical interventions in the form of triamcinolone acetonide (Kenalog, Bristol-Myers Squibb), pegaptanib sodium (Macugen, OSI/Pfizer), bevacizumab (Avastin, Genentech), and ranibizumab (Lucentis, Genentech), among others, are now becoming increasingly useful to ophthalmologists. This trend in pharmaceutical therapy for retinal disease is actually reflected in the steadily increasing number of intravitreal injections at our institute, Bascom Palmer Eye Institute, University of Miami (Figure 1).

Figure 1. Graph showing the increasing trend in intravitreal injections at Bascom Palmer Eye Institute.

In this article, we will focus on the risk of endophthalmitis with intravitreal injections, especially on prevention of infection.

EVOLVING GUIDELINES FOR MANAGING RISK

In 2004, experienced investigators gathered to create practical guidelines in an attempt to minimize complications and optimize outcomes following intravitreal injections of retinal pharmacotherapies.¹¹ While these guidelines may be widely followed, intravitreal injection experience has increased since their initial publication, and as such, the guidelines continue to evolve.

The following steps in the guidelines have been affirmed as effective for risk reduction with increased injection experience:

► Use povidone-iodine antiseptic for ocular surface, eyelids, and eyelashes (Figure 2).

► Use eyelid speculum.

Figure 2. Preparation of the lids and lashes and surrounding areas with povidone-iodine prior to intravitreal injection.

► Avoid contamination of the needle with eyelashes or eyelid margin.

► Avoid extensive massage of eyelids whether pre- or post-injection (to avoid expressing meibomian gland secretions).

► Avoid injection of patients who have active eyelid or ocular adnexal infection.

► Dilate pupil (to view posterior segment after injection).

► Use adequate anesthetic for a given patient (topical drops, gel, and/or subconjunctival injection).

► Avoid prophylactic or postinjection anterior chamber paracentesis.

The following are steps from the guidelines for which no clear consensus exists as to their impact on risk reduction:

► Use povidone-iodine flush (most doctors prefer drops, and no benefits have been attributed to allowing the povidone-iodine to dry).

► Use sterile drape (most doctors do not).

► Use gloves (most doctors advocate use of gloves).

► Use pre- or postinjection topical antibiotics (little published scientific data to support reduction in endophthalmitis rates).

► Check intraocular pressure (IOP) following injection (no agreement on IOP level at which physicians are comfortable to discharge patient).

► Follow up with clinical exam (no data showing advantage over telephone interchange with physician or nurse).

In a comprehensive review of published clinical studies comprising nearly 15000 intravitreal injections, the overall rate of endophthalmitis was 0.3% per injection. This rate decreased to 0.2% per injection when noninfectious cases of pseudoendophthalmitis associated with the off-label use of triamcinolone acetonide were excluded. Even this 0.2% per injection rate may be an overestimation for intravitreal injections as a whole, since infectious endophthalmitis appears to be more common following intravitreal triamcinolone acetonide injections, where an overall prevalence of 0.6% per injection has been reported. In the first year of the pegaptanib sodium clinical trials, the prevalence of endophthalmitis was reported as 0.16% per injection/1.3% per eye, for 12 total cases (although 8 of these 12 cases involved protocol violations).²

TOPICAL PROPHYLAXIS

Many risk factors exist for endophthalmitis in patients undergoing ophthalmic surgical procedures. Reports have linked the patient's own flora as the origin of many cases of pseudophakic endophthalmitis. In clinical practice, topical antibiotics are frequently administered before, during, or after invasive ophthalmic procedures, including intravitreal injections. However, such use of prophylactic antibiotics is seldom substantiated by rigorously conducted, controlled, comparative clinical trials providing level 1 evidence for sound clinical guidelines. Thus, use of pre- or postinjection topical antibiotics was not firmly recommended in the 2004 expert guidelines referenced above.

Some data support the administration of antibiotics preinjection. In addition, multiple studies indicate a significant reduction in conjunctival bacterial flora with the use of topical antibiotics. So, to minimize the risk, there is a rationale that reducing ocular surface bacterial colonization with use of antibiotics prior to the intravitreal injection can by extension reduce the likelihood of intraocular contamination.

The choice of antibiotic for use preinjection is important. Although no single antibiotic is universally effective against the broad spectrum of organisms known to cause endophthalmitis, clinicians are obliged to select the optimal antibiotic agent. The ideal antibiotic has broad-spectrum activity, is fast at killing organisms, has good tissue penetration, and is nontoxic and well tolerated by the eye. Clinicians must be aware of microbial epidemiology and also need to consider antimicrobial resistance when selecting an appropriate topical antibiotic.

In addition, a keen awareness of the current trends of pathogens contributing to endophthalmitis assists effective agent selection. Surveys on endophthalmitis postcataract surgery,¹⁶ postvitrectomy,¹⁷ and postintravitreal triamcinolone injection¹⁸ have shown that more than 80% of cultures were caused by gram-positive organisms.

Of the current commercially available choices, ophthalmic fluoroquinolone agents are used most widely and conveniently in ophthalmic practice. These agents became very popular in the early 1990s because of their broad spectrum of activity and other favorable properties. Unlike the aminoglycosides, when ciprofloxacin (Ciloxan, Alcon), ofloxacin (Ocuflox, Allergan), and later levofloxacin (Quixin, Santen) were first introduced, they had excellent coverage against both gram-positive and gram-negative ocular organisms. However, during the ensuing years, this activity against gram-positive organisms became compromised by the emergence of resistant strains.^19-21 There is increased resistance in ocular isolates, a situation that reflects the increased resistance of bacteria in the population due to the widespread use of these drugs for the treatment of systemic disease, as well as the prevalent use of quinolone agents in the animal-feed industry. Numerous studies of older anti-infectives have demonstrated a loss of efficacy against many microbial ocular pathogens and that earlier generation fluoroquinolones are ineffective against many pathogens, especially those that cause endophthalmitis.^19,22

Fighting Bacterial Resistance

Recently, new fourth-generation 8-methoxy fluoroquinolones have been introduced that are considered more potent with activity beyond that of ofloxacin and ciprofloxacin against gram-positive isolates. These 8-methoxy fluoroquinolone agents include gatifloxacin 0.3% (Zymar, Allergan) and moxifloxacin 0.5% (Vigamox, Alcon). Gatifloxacin is a 0.3% solution preserved with benzalkonium chloride (BAK) 0.005%, and moxifloxacin is a self-preserved 0.5% solution.

These new antibiotics offer greater advantages against resistant strains and discouraging development of pathogen resistance. Earlier generation fluoroquinolones target DNA gyrase in gram-negative bacteria and topoisomerase IV in gram-positive organisms, meaning that pathogens had to overcome only 1 step to acquire resistance against earlier fluoroquinolones. Fourth-generation fluoroquinolones, however, target both DNA gyrase and topoisomerase IV at the same time.²³ Therefore, the fourth-generation fluoroquinolones require 2 steps for resistance. As a result, 8-methoxy-fluoroquinolones show improved activity against important pathogens, including gram positive bacteria that are increasingly resistant to earlier-generation fluoroquinolones.^23-26 The differences observed between the in vitro spectrum of activity of the 2 drugs are not great and do not significantly favor one over another for clinical selection. Fluoroquinolones exhibit concentration-dependent killing. This killing is faster than that with aminoglycosides, penicillin, and vancomycin, all of which are time-dependent "killers." With the fluoroquinolones, it is not uncommon to see 3 logs of killing at 2 to 4 times the minimum inhibitory concentration (MIC) within 2 to 4 hours for gram-positive organisms. Fast-killing limits (1) the accumulation of harmful bacterial toxic products, (2) the time that therapeutic levels need to be maintained in the target tissue to ensure sterilization, and (3) the emergence of resistant strains.

Mather et al. investigated the comparison of median MICs determined for 18 bacterial endophthalmitis isolates resistant to ciprofloxacin and ofloxacin. Resistant isolates included Staphylococcus aureus (n = 8) and coagulase-negative Staphylococcus (n = 10); fourth-generation fluoroquinolones were found to be far more effective than third-generation fluoroquinolones.²⁷

Additional Factors in Prophylaxis

Clinically, sutures are not routinely placed following intravitreal injection, but a channel representing a potential conduit from conjunctiva into the posterior chamber exists for a while after intervention. Taban et al. studied clear corneal incision for cataract surgery. Histological examination in this study disclosed India ink particles in all incisions for up to three-fourths of the length of the wound with the potential for fluid flow across the cornea and into the anterior chamber, with the attendant risk of endophthalmitis.^28,29 Postoperative hypotony was shown as a risk factor for wound gape and migration of particles from the external to internal ocular milieu. Though this mechanism has not been directly demonstrated with intravitreal injection as with sutureless cataract surgery, the same mechanical forces might lead to direct inoculation of subconjunctival fluid through the sclerotomy site.

In addition, human and rabbit studies show that both gatifloxacin and moxifloxacin in the commercial preparations of Zymar and Vigamox penetrate well into ocular tissues. With respect to aqueous levels, both drugs can provide concentrations that are above the MIC in the aqueous humor. Moxifloxacin 0.5% has been shown in several human studies to achieve statistically higher concentrations in aqueous humor than gatifloxacin 0.3% — beyond that which can be explained by differences in formulation concentration alone. However, neither moxifloxacin nor gatifloxacin achieve therapeutic levels in the vitreous.³⁰

Because bacteria may migrate from the ocular surface and subconjunctival space through the injection site and into the vitreous combined with failure to achieve antibiotic concentrations above the MICs in vitreous, clinicians must strive to maximally reduce bacterial colonization from the ocular surface and adnexa in advance of intravitreal injection to reduce likelihood of inoculation.

In prescheduled surgeries, clinicians may prescribe topical antibiotics for patients to instill for several days in advance of the planned procedure. For intravitreal injections, however, often the clinical decision for a procedure is contemporaneously decided with examination. Therefore, the killing speed of the topical antibiotic selected matters. As previously mentioned, 8-methoxy fluoroquinolones can kill organisms very fast with less incidence of resistance compared with earlier generation fluoroquinolones. Eser et al. compared antimicrobial efficacy of gatifloxacin 0.3% (containing BAK) with that of moxifloxacin 0.5% against Staphylococcus species used in vitro model. Test samples were assayed at 15, 30, and 60 minutes. As seen in these killing curves, Zymar containing gatifloxacin 0.3% plus benzalkonium chloride 0.005% has more potential for killing bacteria faster than moxifloxacin 0.5% alone. Zymar was able to reduce the numbers of bacteria in Staphylococcus species cultures in vitro by 99.9% in 15 minutes, a rate that is more rapid compared to Vigamox. Gatifloxacin 0.3% containing BAK provides faster killing in vitro than moxifloxacin 0.5% without BAK.³¹ Moxifloxacin 0.5% penetrates to achieve higher concentrations after topical administration than gatifloxacin 0.3%. No comparative data of level 1 evidence quality from controlled clinical trials exist to document the precise role and optimal selection for topical antibiotic agents prior to intravitreal injection.

In addition to topical antibiotics, preoperative povidone-iodine antisepsis showed the strongest support in the literature for preventing bacterial endophthalmitis. Half-strength (5%) povidone-iodine or topical anti-infective produced similar and substantial decreases in bacteria cultured from conjunctiva with results even more striking with combined use. Combination of 3 days of ofloxacin, an earlier generation fluoroquinolone of lesser potency than 8-methoxy-fluoroquinolones, plus povidone iodine irrigation, resulted in a 95% reduction in the positive culture.^32-34 Based upon these and other prior studies, recent recommendations include the use of: aseptic technique, a broad-spectrum topical antibiotic for 3 days before the injection, 5% povidone iodine solution before procedure, and topical antibiotic for 2 days after the injection.^11,13

In the pegaptanib sodium clinical trials, investigators combined antibiotics, povidone iodine, sterile preparation, drape, and speculum. A lower incidence of endophthalmitis was observed after institution of the revised protocol.^2,35,36

These intravitreal drug study protocols analyzed at the meeting in 2004 varied greatly regarding use of topical antibiotics, drug injection technique, and follow-up requirements. An attempt was made to achieve consensus, but there was often disagreement among participants as to the value of a particular maneuver when there was little scientific data to support use or non-use. Perhaps the strongest area of agreement was for the use of povidone-iodine on the conjunctiva as well as on the lid margins and lashes. Povidone-iodine is well recognized as the most effective means of bacterial prophylaxis for intraocular surgery.^37,38 Though excessive care increases the patients' financial and physical burden, we cannot be too careful in treating patients undergoing intravitreal injections. The guidelines, while general and inconclusive, due to the lack of level 1 scientific evidence from well-controlled, randomized clinical trials, should probably be followed with more agreement. Prophylactic intracameral or intraocular antibiotics, as suggested with intracameral cefuroxime use for prevention of endophthalmitis from the recently reported European Society of Cataract and Refractive Surgery (ESCRS) multicenter European study,³⁹ are impractical with intravitreal injection. The ESCRS postoperative endophthalmitis study was limited in part to the unusually high level of infection among the control group compared to other published studies of endophthalmitis with cataract surgery. Moreover, the use of cephalosporins in prophylaxis may not adequately cover all organisms resulting in endophthalmitis due to methicillin-resistant staphylococci as observed in the ESCRS study and may be associated with severe allergy in patients with known allergy potential to penicillins. While the intraocular route may be a more effective delivery compared with topical antibiotics, the potential for toxicity (eg, toxic anterior segment syndrome) and contamination exists.

Beyond prophylactic antibiotic use, clinicians should carefully examine the "No Clear Consensus" list measures. Endophthalmitis, though rare after intravitreal injection, remains devastating with treatment requiring possible vitrectomy, intraocular antibiotics, and intraocular anti-inflammatory agents. Even with such aggressive treatment, it is still difficult to preserve useful vision after endophthalmitis.

In summary, there is a risk of endophthalmitis after intravitreal injections. Fourth-generation 8-methoxy-fluoroquinolones provide superior coverage (compared with older quinolone antibiotics) against gram-positive bacteria and atypical mycobacteria, yet are not universally protective. No single antibiotic agent is omnipotent in spectrum and action nor protected from bacterial evolution of resistance. Reduction of ocular surface bacterial colonization with combined use of povidone iodine antiseptic and perhaps an 8-methoxy-fluoroquinolone or other broad spectrum antibiotic may be appropriate for prophylaxis prior to and following intravitreal injections for AMD, PDR, cystoid macular edema, and other retinal disorders. Endophthalmitis has occurred despite recommended prophylaxis measures and clinicians should institute a postoperative plan to monitor for development of endophthalmitis after intravitreal injections in order to institute aggressive management. RP

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6. Jorge R, Costa RA, Calucci D, et al. Intravitreal bevacizumab (avastin) for persistent new vessels in diabetic retinopathy (IBEPE Study). Retina. 2006;26:1006-1013.

7. Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab (avastin) therapy for persistent diffuse diabetic macular edema. Retina. 2006;26:999-1005.

8. Greenberg PB, Martidis A, Rogers AH, et al. Intravitreal triamcinolone acetonide for macular oedema due to central retinal vein occlusion. Br J Ophthalmol. 2002;86:247-248.

9. Scott IU, Flynn HW Jr, Rosenfeld PJ. Intravitreal triamcinolone acetonide for idiopathic cystoid macular edema. Am J Ophthalmol. 2003;136:737-739.

10. Martidis A, Duker JS, Puliafito CA. Intravitreal triamcinolone for refractory cystoid macular edema secondary to birdshot retinochoroidopathy. Arch Ophthalmol. 2001;119:1380-1383.

11. Aiellon LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina. 2004;24:S3-S19.

12. Jager RD, Aiello LP, Patel SC, et al. Risks of intravitreous injection: a comprehensive review. Retina. 2004;24:676-698.

13. Ta CN. Minimizing the risk of endophthalmitis following intravitreous injections. Retina. 2004;24:699-705.

14. Forster RK, Zachary IG, Cottingham AJ Jr.,et al. Further observations on the diagnosis, cause and treatment of endophthalmitis. Am J Ophthalmol. 1976;81:52-56.

15. Tornambe, PE, Hilton GF; Retinal Detachment Study Group. Pneumatic retinopexy. A multicenter randomized controlled clinical trial comparing pneumatic retinopexy with scleral buckling. Ophthalmology. 1989;96:772-784.

16. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1996;122;1-17.

17. Cohen SM, Flynn HW Jr, Murray TG, et al. Endophthalmitis after pars plana vitrectomy. The Postvitrectomy Endophthalmitis Study Group. Ophthalmology. 1995;102:705-712.

18. Moshfeghi AM, Kaiser PK, Scott IU, et al. Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol. 2003;136:791-796.

19. Jensen HG, Felix C. In vitro antibiotic susceptibilities of ocular isolates in North and South America. In Vitro Antibiotic Testing Group. Cornea. 1998;17:79-87.

20. Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology. 1999;106:1313-1318.

21. Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology. 2000;107:1497-1502.

22. Kowalski RP, Karenchak LM, Romanowski EG. Infectious disease: changing antibiotic susceptibility. Ophthalmol Clin N Am. 2003;16:1-9.

23. Tungsiripat T, Sarayba MA, Kaufman MB, et al. Fluoroquinolone therapy in multiple-drug resistant staphylococcal keratitis after lamellar keratectomy in a rabbit model. Am J Ophthalmol. 2003;136:76-81.

24. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol. 2003;136:500-505.

25. Fukuda H, Kishii R, Takei M, et al. Contributions of the 8-methoxy group of gatifloxacin to resistance selectivity, target preference, and antibacterial activity against Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45:1649-1653.

26. Takei M, Fukuda H, Kiishii R, et al. Target preference of 15 quinolones against Staphylococcus aureus, based on antibacterial activities and target inhibition. Antimicrob Agents Chemother. 2001;45:3544-3547.

27. Karenchak MR, Romanowski LM, E. G. Kowalski EG, et al. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133:463-466.

28. Taban M, Rao B, Reznik J, et al. Dynamic morphology of sutureless cataract wounds-effect of incision angle and location. Surv Ophthalmol. 2004;49:S62-S72.

29. McDonnell PJ, Taban M, Sarayba M, et al. Dynamic morphology of clear corneal cataract incisions. Ophthalmology. 2003;110:2342-2348.

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35. Ho H-KV, Hu N, Sanislo SR, et al. Prevalence of Bacterial Contamination of needles Following Intravitreal Injection of Triamcinolone Acetonide. Poster presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; May 2005; Fort Lauderdale, FL.

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DISCUSSION

Harry W. Flynn Jr., MD, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine

In this article and in another recent issue of Retinal Physician,¹ endophthalmitis following intravitreal injections and practices to reduce the risk of this complication are discussed. In both articles, a major point of discussion was the use of topical fourth-generation fluoroquinolones. One article even describes the number of drops of 5% povidone-iodine solution and fourth-generation fluoroquinolones placed 5 and 10 minutes prior to the injection.¹ Clinical evidence showing benefit to this approach is not described. Some studies have reported an endophthalmitis "surrogate model" using bacterial colony counts from the conjunctiva of treated vs untreated patients. The validity of these models remains unproved because the rates of endophthalmitis after intravitreal injection are so low.

As practicing retinal specialists, we are inundated by infomercials, journal advertisements, and pharmaceutical representatives, leaving us with the false perception that use of the fourth-generation fluoroquinolones is "the standard of care" for prophylaxis.

Two publications report a significant and possibly increasing microbial resistance to the fourth-generation fluoroquinolones.^2,3 In addition, a recent review of 20013 patients who received pre- and postoperative topical fourth-generation fluoroquinolones for cataract surgery were reported.⁴ The rates in this study were within the range of previously reported rates of endophthalmitis in the literature and were not reduced by topical fourth-generation fluoroquinolones.

An important, rarely discussed, issue is the cost of prophylaxis with fourth-generation fluoroquinolones for every patient receiving an intravitreal injection. The number of intravitreal injections given per year will greatly exceed the 2.5 million cataract operations performed annually in the United States. The average wholesale price for fourth-generation fluoroquinolones across the United States is about $65. If one assumes a substantial markup by pharmacies and hospitals, the cost of this unproved treatment is enormous. This cost may not be justified given the lack of evidence-based data showing a benefit in rates of endophthalmitis.

What is the best approach to protect our patients from endophthalmitis? General guidelines from a committee of experienced specialists have been published regarding prophylaxis for intravitreal injections.⁵ Under the section of "Guidelines with no clear consensus," the publication stated that the use of pre- or postinjection topical antibiotics was not uniformly recommended by the panel because there were little scientific data to support reduction in endophthalmitis rates. Retina specialists should keep this in mind when asking their patients to purchase an expensive and unproved medication. There is no absolute "standard of care" requiring the use of topical fluoroquinolones before and after intravitreal injections. If one elects to use topical antibiotics, multiple options are available, but the mainstays of prophylaxis are careful sterile technique and topical povidone-iodine. RP

REFERENCES

1. Olson RJ. Endophthalmitis prophylaxis for intravitreal injections. Retinal Physician. 2007;4(3):42-43.

2. Deramo VA, Lai JC, Fastenberg DM, Udell IJ. Acute endophthalmitis in eyes treated prophylactically with gatifloxacin and moxifloxacin. Am J Ophthalmol. 2006;142:721-725.

3. Miller D, Flynn PM, Scott IU, Alfonso FC, Flynn HW Jr. In vitro fluoroquinolone resistance in Staphylococcal endophthalmitis isolates. Arch Ophthalmol. 2006;124:479-483.

4. Moshirfar M, Feiz V, Vitale AT, et al. Endophthalmitis after uncomplicated cataract surgery with the use of fourth-generation fluoroquinolones: a retrospective observational case series. Ophthalmology. 2007;114:686-691.

5. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina. 2004;24:S3-S19.