Avoiding Endophthalmitis Following Intravitreal Injections

A review with a focus on data from the DRCR.net.

ABDHISH R. BHAVSAR, MD

Intravitreal injections have become the most common route of administering medications for the treatment of posterior-segment disease. Endophthalmitis is one of the most serious complications of intravitreal injections, with a reported incidence per injection ranging from 0.02% to 1.9%.^1-5

Optimal management of the ocular surface prior to, during, and after intravitreal injections remains controversial.^3,6 Areas of controversy include topical antibiotics, topical povidone-iodine, anesthetics, and instrumentation, including a sterile lid speculum, a sterile drape, sterile gloves, and masks.

INSTRUMENTATION

With respect to instrumentation, the use of a lid speculum did not appear to affect the rate of endophthalmitis in one retrospective series.⁷ However, the author and the Diabetic Retinopathy Clinical Research Network (DRCR. net) require a lid speculum to reduce potentially the risk of endophthalmitis, because clear visualization of the surgical site for injecting and removing the lashes and lids from the vector of injection seem prudent.

The use of a mask has been shown in experimental models to reduce the potential risk for transmission of bacteria from the surgeon to the injection site.⁸ However, the DRCR.net has not required a mask during intravitreal injections and has reported very low rates of endophthalmitis in multiple clinical trials.

Furthermore, the DRCR.net has not required the use of sterile gloves or sterile drapes during intravitreal injections and has reported very low rates of endophthalmitis in multiple large randomized clinical trials.⁹

CHEMOPROPHYLAXIS

The main area of controversy regarding intravitreal injections relates to the use of topical povidone-iodine and the use of topical antibiotics. Topical povidone-iodine is the only preoperative substance proven in a randomized clinical trial to reduce the risk of endophthalmitis after intraocular surgery.¹⁰

Adequate studies have not yet evaluated the role of topical antibiotics; thus, uncertainty still exists as to the efficacy of topical antibiotics in preventing postinjection endophthalmitis. Although the combined use of topical povidone-iodine and antibiotics may have a synergistic effect in reducing the preoperative culture-positive rate of the conjunctival surface,^11,12 little evidence suggests that topical antibiotics reduce the rate of endophthalmitis in humans.

On the contrary, several series have shown a possible association of endophthalmitis cases with topical antibiotic use.^9,13,14 In addition, little evidence has shown that the pharmacokinetics of topical regimens provided would result in adequate antibiotic levels expected to have a protective effect.^15-18

Despite this, topical antibiotics prior to intravitreal injections have been required in several recent clinical trial protocols.^19-21 Furthermore, recent surveys have suggested that 40% of retina specialists use topical antibiotics prior to intravitreal anti-VEGF injections, and 86% use topical antibiotics after intravitreal anti-VEGF injections.²²

Previous studies have indicated a low rate of endophthalmitis following preservative-free intravitreal triamcinolone injections, for which prolonged topical antibiotic use for multiple days prior to the injection was not required, and antibiotics were required only on the day of and after the injection.^23,24

We also reported a low rate of endophthalmitis in two DRCR.net trials in which topical povidone-iodine was required but in which topical antibiotics were not. Those results included 3,838 injections of ranibizumab or preservative-free triamcinolone.

Of 1,276 injections given without antibiotics before or after the injections, three cases of endophthalmitis occurred in eyes that received ranibizumab, injections and all of those eyes received topical antibiotics for several days postinjection.¹⁴

DRCR.NET DATA ON PROPHYLAXIS AND ANESTHESIA

Recently, we reported the endophthalmitis rates in DRCR.net’s laser-ranibizumab-triamcinolone (LRT) (Protocols I and J), bevacizumab for DME (Protocol H), and ranibizumab for vitreous hemorrhage (Protocol N) trials, in which topical antibiotics prior to, on the day of injection, and used for several days after injections, were not required but could be administered at the discretion of the investigator.⁹

Protocols H, I/J, and N utilize a standardized protocol for ocular surface preparation and intravitreal injection of ranibizumab or preservative-free triamcinolone. Topical antibiotics can be administered prior to the day of injection or preinjection on the same day at the discretion of the investigator, although they are not required.

A drop of topical anesthetic is applied to the eye. Topical povidone-iodine is required as part of the protocol and must be administered in one or more ways as described later. Two or three drops of 5% povidone-iodine may be placed in the lower fornix. The use of povidone-iodine lid scrubs is also optional.

Figure. Images from a patient with endophthalmitis. Anterior segment biomicroscopy showed severe conjunctival hyperemia, severe cellularity, and hypopyon (left). After surgery (right), anterior segment biomicroscopy showed an improvement in conjunctival hyperemia.

IMAGES ORIGINALLY APPEARED IN VELEZ-MONTOYA R, RASCÓN-VARGAS D, MIELER WF, FROMOW-GUERRA J, MORALESCANTÓN V. INTRAVITREAL AMPICILLIN SODIUM FOR ANTIBIOTIC-RESISTANT ENDOPHTHALMITIS: STREPTOCOCCUS UBERIS FIRST HUMAN INTRAOCULAR INFECTION REPORT. J OPHTHALMOL. 2010;169739, REUSED UNDER A CREATIVE COMMONS LICENSE.

While the use of additional topical anesthetic on cotton tip applicators is optional, subconjunctival anesthetic and lidocaine gel or another viscous anesthetic is not permitted as part of the protocol.

More recently, viscous lidocaine was permitted. A cotton-tipped applicator soaked in 5% povidone-iodine or a 10% povidone-iodine swab is placed directly over the intended injection site, or alternatively a 5% povidone-iodine forced stream flush from an angiocatheter is employed. DRCR. net determined that none of the investigators was using this flush technique, and it has been eliminated recently from the ongoing trials.

In all cases, a sterile eyelid speculum is used to stabilize the eyelids. Preservative-free triamcinolone acetonide or ranibizumab is injected through the pars plana. Although not required and not part of the protocol, at the discretion of the investigator, topical antibiotics may be provided and used for several days postinjection.

Diagnosis of endophthalmitis was based on the investigator’s judgment, and a culture was required prior to initiating antibiotic treatment for presumed endophthalmitis. We reported data as of November 21, 2011, including 8,027 intravitreal injections in 1,066 eyes, which were administered as part of the DRCR.net’s Protocol H, I/J, and N trials.⁹

Seven cases of endophthalmitis were reported, including six (0.13% [n=4,697]) that occurred with the use of topical antibiotics, compared with one (0.03% [n=3,333]) that occurred without the use of topical antibiotics (P = .25). In other words, in only one case of endophthalmitis, no antibiotics were given before, on the day of, or after injection.

In the majority of endophthalmitis cases, topical antibiotics were administered after the injection. The bacteria that were isolated by cultures included coagulase-negative Staphylococcus in cases 1, 2, 4, and 6, heavy growth of Streptococcus viridans, and scant growth of methicillin-resistant Staphylococcus aureus (MRSA) in case 5, while cases 3 and 7 were culture-negative.

DISCUSSION

The protocol for the injection procedure in the DRCR.net trials offers an opportunity to evaluate the role of topical antibiotics for potentially reducing the risk of endophthalmitis following intravitreal injection. The standardized injection protocol required the application of topical povidone-iodine to the conjunctival surface, as well as the use of a sterile eyelid speculum. The use of topical antibiotics was optional.

Medication was administered from both prefilled syringes (triamcinolone) and from syringes that required filling by the investigator from a separate vial at the time of injection (ranibizumab), as well as from syringes that required filling by the investigator from a separate masked vial at the time of injection (saline or ranibizumab). As in multiple previous studies, a low rate of postinjection endophthalmitis occurred.

The protocol for ocular surface preparation has undergone some evolution since the first DRCR.net trial involving intravitreal injections. In Protocol B, topical antibiotics were initially used on the day of injection as part of the required protocol. Topical antibiotics were not required as part of postinjection management. A low rate of endophthalmitis was previously reported.²³

DRCR.net has purposefully continued to move to a more minimalist approach for intravitreal injection technique. When the first DRCR.net trial involving injections (Protocol B) was designed, the standard trial design at the time mandated topical antibiotics for one week prior to the injection and on the day of the injection, as well as after.

DRCR.net began minimizing the ocular preparation protocol at that time and eliminated requiring topical antibiotics on the days prior to injections. Since that time, antibiotics at any time coincident with the intravitreal injection have been eliminated from DRCR.net protocols (Protocol H, I, J, and N).

The driving thought behind this minimalist approach revolves around the concept of minimal manipulation of the ocular surface and eyelids, with the exception of three items: topical anesthetic and topical povidone-iodine placed on the conjunctival surface and a sterile eyelid speculum.

These current studies suggest it is extremely unlikely that omitting topical antibiotics prior to, on the day of, or after injections incurs a moderate or large increase in the risk of endophthalmitis. Furthermore, other retrospective series involving intravitreal injections without topical antibiotics have also demonstrated a low risk of endophthalmitis.^23-28

However, because of the very 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 reducing the risk of endophthalmitis following intravitreal injection.

On the contrary, because six out of the seven cases of endophthalmitis across the DRCR.net studies were associated with topical antibiotic use, there may be a suggestion that topical antibiotic use and/or additional manipulation of the ocular surface is associated with endophthalmitis.

The results presented here indicate that a low rate of endophthalmitis can be achieved using an intravitreal injection protocol that includes topical povidone-iodine, the use of a lid speculum, and topical anesthetic but that does not require topical antibiotic prophylaxis prior to, on the day of, or after the injection.

CONCLUSION

Given his interpretation of extensive and ongoing DRCR. net experience in multiple randomized clinical trials, many of which involve intravitreal injections using the same standardized intravitreal injection protocol, the author recommends a minimal manipulation approach, including the use of topical povidone-iodine, a sterile speculum, and topical anesthetic without the use of antibiotic prophylaxis prior to, on the day of, or after the injection. RP

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